presentation diabetes

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Slideshow: A Visual Guide to Type 2 Diabetes

What Is It?

When you have this disease, your body does a poor job turning the carbohydrates in food into energy. This causes sugar to build up in your blood. Over time it raises your risk for heart disease, blindness, nerve and organ damage, and other serious conditions. It strikes people of all ages, and early symptoms are mild. About 1 out of 3 people with type 2 diabetes don't know they have it. 

What Will You Notice First?

People with type 2 diabetes often have no symptoms. When they do appear, one of the first may be being thirsty a lot. Others include dry mouth, bigger appetite, peeing a lot -- sometimes as often as every hour -- and unusual weight loss or gain.

Later Symptoms

As your blood sugar levels get higher, you may have other problems like headaches, blurred vision, and fatigue.

Signs of Serious Problems

In many cases, type 2 diabetes isn't discovered until it takes a serious toll on your health. Some red flags include:

• Cuts or sores that are slow to heal
• Frequent yeast infections or urinary tract infections
• Itchy skin, especially in the groin area

It Can Affect Your Sex Life

Diabetes can damage blood vessels and nerves in your genitals. This could lead to a loss of feeling and make it hard to have an orgasm. Women are also prone to vaginal dryness. About 1 in 3 who have diabetes will have some form of sexual trouble. Between 35% and 70% of men who have the disease will have at least some degree of impotence in their lifetime.

Risk Factors You Can Control

Some health habits and medical conditions related to your lifestyle can raise your odds of having type 2 diabetes, including:

• Being overweight, especially at the waist
• A couch potato lifestyle
• Eating a lot of red meat, processed meat, high-fat dairy products, and sweets
• Unhealthy cholesterol and triglyceride levels     

Risk Factors You Can't Control

Other risk factors are out of your control, including:

• Race or ethnicity: Hispanics, African-Americans, Native Americans, and Asians are more likely to get it
• Family history of diabetes: Having a parent or sibling with diabetes boosts your odds.
• Age: Being 45 and older raises your risk of type 2 diabetes.

The more risk factors you have, the more likely you'll get type 2 diabetes.

Risk Factors for Women

You're more likely to get type 2 diabetes later on if you:

• Had gestational diabetes when you were pregnant
• Delivered a baby that weighed over 9 pounds
• Had polycystic ovary syndrome

How Does Insulin Work?

In a healthy person, insulin helps turn food into energy. Your stomach breaks down carbohydrates into sugars. They enter the bloodstream, prompting your pancreas to release the hormone insulin in just the right amount. It helps your cells use the sugar for fuel.

Metabolism Mishaps

In type 2 diabetes, your cells can’t use sugar properly. That means there's a lot of it in your blood. If you have a condition called insulin resistance, your body makes the hormone, but your cells don’t use it or respond to it like they should. If you’ve had type 2 diabetes for a while but haven’t treated it, your pancreas will make less insulin.

How Is It Diagnosed?

Your doctor will take some blood and do an A1c test. It shows your average blood sugar level over the past 2-3 months. If you already have symptoms, they might give you a random blood glucose test, which shows what your current level is.

Your Diet Makes a Difference

You can control blood sugar levels by changing your diet and losing extra weight. That will also cut your risk of complications. Carefully track the carbs in your diet. Keep amounts the same at every meal, watch how much fat and protein you eat, and cut calories. Ask your doctor to refer you to a dietitian to help you make healthy choices and an eating plan.

Exercise Is Important

Regular exercise, like strength training or walking, improves your body's use of insulin and can lower blood sugar levels. Being active also helps get rid of body fat, lower blood pressure, and protect you from heart disease. Try to get 30 minutes of moderate activity on most days of the week.

Relaxation Is Key

Stress can boost your blood pressure and blood sugar. Some people don't do anything for it. Others turn to food to cope with it. Instead, practice relaxation techniques like deep breathing, meditation, or visualization. Talking to a friend, family member, counselor, or a religious leader could help. If you can’t beat it, reach out to your doctor.

Oral Medications Can Help

If diet and exercise can’t get your blood sugar under control, your doctor may add medication. There are many types of diabetes pills available. They’re often combined. Some work by telling your pancreas to make more insulin. Others help your body use it better or block the digestion of starches. Some slow insulin breakdown. Newer oral drugs help your body pee out more sugar. 

Insulin: It's Not Just for Type 1

Your doctor may prescribe insulin early in your treatment and combine it with pills. It can also help people with type 2 diabetes who develop "beta-cell failure." This means the cells in your pancreas no longer make insulin when blood sugar is high. If this happens, insulin will become part of your daily routine.

Non-Insulin Injectables

Drugs called non-insulin injectables are available for people with type 2 diabetes. These injectables cause your body to make insulin to control blood sugar levels.

Why Blood Sugar Testing Matters

Your doctor can show you how to use a glucose meter to check your blood sugar. This lets you know how your treatment plan is working. How often and when you test will be based on how well controlled your diabetes is, the type of treatment you use, and how stable your blood sugar is. Common testing times are when you wake up, before and after meals and exercise, and at bedtime.

Heart and Artery Troubles

If you don't treat diabetes with a healthy diet and exercise, you're more likely to get plaque in your arteries than people who don't have it. This sticky substance slows blood flow and increases your risk of clots. It leads to hardening of the arteries (called atherosclerosis), which makes you more likely to have a heart attack or stroke. About 2 of 3 people with diabetes die of heart disease.

Kidney Complications

The longer you have diabetes, the greater the chance you’ll get chronic kidney disease. Diabetes is the leading cause of kidney failure. It's to blame for about half of new cases. Controlling your blood sugar, blood pressure, and cholesterol can lower your risk for this complication. Yearly tests and medications can slow the disease and keep your kidneys healthy.

Eye Problems

High blood sugar can damage the tiny blood vessels that bring oxygen and nutrients to the retina, a critical part of your eye. This is known as diabetic retinopathy, and it can lead to vision loss. It’s the leading cause of new cases of blindness in people between the ages of 20 and 74. Pools of blood, or hemorrhages, on the retina of an eye are visible in this image.

Diabetic Nerve Pain

Over time, uncontrolled diabetes and high blood sugar can cause nerve damage. Symptoms include tingling, numbness, pain, and a pins and needles sensation -- often in your fingers, hands, toes, or feet. The damage can’t be reversed, but there are treatments. Controlling your diabetes can help prevent further harm.

Foot Injuries Can Take a Toll

Diabetic nerve damage can make it hard to feel your feet. You might not notice wounds. At the same time, hardening of the arteries reduces blood flow to the area. Even a small injury can cause foot sores and gangrene. In severe cases, infections can result in an amputation.

Teeth and Gums Are Targets

High blood sugar levels can feed the bacteria that make plaque. Plaque buildup leads to cavities, tooth decay, and gum disease. Severe gum disease can cause tooth loss. It weakens gums and the tissues and bones that hold teeth in place. That makes it easier to get an infection, too.

Can It Be Prevented?

One of the most surprising things about type 2 diabetes is that you can avoid it. To lower your risk, follow the same guidelines for warding off heart disease:

• Eat a healthy diet.
• Exercise for 30 minutes, 5 days a week.
• Stay at a healthy weight.
• Talk to your doctor about being tested for prediabetes.

People with prediabetes can avoid getting diabetes with lifestyle changes and medication.

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American College of Endocrinology. American Diabetes Association. American Heart Association. Diabetes Care. FDA. Fenton, J. Annals of Family Medicine , 2006. Fox, C. Circulation , 2006. Joslin Diabetes Center. MedlinePlus, National Institutes of Health: "Type 2 Diabetes." National Diabetes Education Program. National Diabetes Information Clearinghouse. National Heart, Lung, and Blood Institute. National Institute of Diabetes and Digestive and Kidney Diseases. PDR.net. Stumvoll, M. Lancet, 2005. Sullivan, P. Diabetes Care , 2005. Thorens, B. New England Journal of Medicine, 2006. UptoDate.

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Understanding Type 2 Diabetes

• What is type 2 diabetes?
• Symptoms of type 2 diabetes
• Risk factors for type 2 diabetes
• Complications of type 2 diabetes
• Prevention of type 2 diabetes
• Outcomes for type 2 diabetes
• Diagnosis of Type 2 Diabetes
• How is type 2 diabetes diagnosed?
• How is type 2 diabetes monitored?
• What problems can occur with type 2 diabetes?
• Importance of diabetes education in managing the disease
• Management and Treatment of Type 2 Diabetes
• Treatment goals for type 2 diabetes
• Medications for type 2 diabetes
• Diet and exercise for type 2 diabetes treatment
• Alternative treatment of type 2 diabetes
• Hypoglycemia
• Tips for type 2 diabetes self-management
• Expert Videos
• Patient Videos
• Slide Shows
• About this Educational Activity
• Module Content
• Animation - Understanding Type 2 Diabetes
• Slide Show - Understanding Type 2 Diabetes
• Expert Video - What is type 2 diabetes?
• Expert Video - Difference between type 1 and type 2 diabetes
• Expert Video - Symptoms of type 2 diabetes
• Expert Video - Risk factors for diabetes
• Expert Video - What is prediabetes?
• Expert Video - What problems can occur with type 2 diabetes?
• Expert Video - Can type 2 diabetes be prevented?
• Expert Video - Can diabetes be cured?

*Please note: This slide show represents a visual interpretation and is not intended to provide, nor substitute as, medical and/or clinical advice.

Type 2 diabetes is a metabolic disorder that causes sugar, in the form of glucose, to accumulate in the blood rather than being used as fuel by the cells in our body.

When we eat, food is broken down by our digestive system into nutrient molecules that are then absorbed through our digestive tract for use by the body.

Foods containing carbohydrates or various sugars are broken down into glucose.

Glucose is an important source of fuel for many organs in our body.

However, to be able to use the glucose for fuel, the glucose molecule must first enter into the cell.

The pancreas produces a hormone called insulin, a chemical messenger essential for the entry of glucose into cells.

As the blood glucose levels rise after a meal, insulin is released into the bloodstream and sets processes in motion to trigger the removal of glucose from the blood to enter into the cells.

In type 2 diabetes, the cells become resistant to insulin and ignore its message to absorb glucose. This is known as insulin resistance.

In addition, in type 2 diabetes, the pancreas is unable to produce the greater amounts of insulin needed to trigger these resistant cells to take in glucose from the bloodstream.

The most noticeable symptom of diabetes is frequent urination and excessive thirst.

Other symptoms include weakness, drowsiness, and blurred vision. These are caused by chemical imbalances in the blood related to high levels of blood glucose.

About one in four people with type 2 diabetes are unaware that they have the disease.

It is important to catch diabetes early.

Over time, high blood glucose damages the blood vessels This can damage the organs that these vessels supply leading to a variety of health complications.

Damage to the small, or micro blood vessels can cause vision problems, including loss of sight, nerve damage, and kidney disease.

Damage to larger, or macro blood vessels can lead to cardiovascular complications such as heart disease, stroke, and poor blood circulation.

Overweight and inactivity are major causes of diabetes.

A family history of diabetes significantly increases your risk of developing the disease.

Certain ethnic populations are also at increased risk of developing type 2 diabetes

Finally, some medications may increase your diabetes risk, specifically corticosteroids, thiazide diuretics, drugs used to treat certain mental illnesses, and some antiretrovirals used to treat HIV infection.

In summary, type 2 diabetes is a metabolic disorder. It causes sugar, in the form of glucose, to accumulate in the blood rather than being used as fuel for the cells in our body.

If not diagnosed and treated in a timely manner type 2 diabetes can lead to many health complications.

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Type 2 Diabetes Mellitus Clinical Presentation

• Author: Romesh Khardori, MD, PhD, FACP; Chief Editor: George T Griffing, MD  more...
• Sections Type 2 Diabetes Mellitus
• Practice Essentials
• Pathophysiology
• Epidemiology
• Patient Education
• Physical Examination
• Approach Considerations
• Glucose Studies
• Glycated Hemoglobin Studies
• Urinary Albumin Studies
• Diabetes Testing in Asymptomatic Patients
• Tests to Differentiate Type 2 and Type 1 Diabetes
• Pharmacologic Therapy
• Management of Glycemia
• Dietary Modifications
• Activity Modifications
• Bariatric Surgery
• Laboratory Monitoring
• Monitoring for Diabetic Complications
• Management of Hypertension
• Management of Dyslipidemia
• Management of Coronary Heart Disease
• Management of Ophthalmologic Complications
• Management of Diabetic Neuropathy
• Management of Infections
• Management of Intercurrent Medical Illness
• Management of Critical Illness
• Pharmacologic Considerations in Surgery
• Prevention of Type 2 Diabetes Mellitus
• Stroke Prevention in Diabetes
• Consultations
• Medication Summary
• Antidiabetics, Biguanides
• Antidiabetics, Sulfonylureas
• Antidiabetics, Meglitinide Derivatives
• Antidiabetics, Alpha-Glucosidase Inhibitors
• Antidiabetics, Thiazolidinediones
• Antidiabetics, Glucagonlike Peptide-1 Agonists
• Dual GIP/GLP-1 Agonists
• Antidiabetics, Dipeptidyl Peptidase IV Inhibitors
• Antidiabetics, Amylinomimetics
• Selective Sodium-Glucose Transporter-2 Inhibitors
• Bile Acid Sequestrants
• Antidiabetics, Rapid-Acting Insulins
• Antidiabetics, Short-Acting Insulins
• Antidiabetics, Intermediate-Acting Insulins
• Antidiabetics, Long-Acting Insulins
• Dopamine Agonists
• Questions & Answers
• Media Gallery

The diagnosis of diabetes mellitus is readily entertained when a patient presents with classic symptoms (ie, polyuria, polydipsia, polyphagia, weight loss). Other symptoms that may suggest hyperglycemia include blurred vision, lower extremity paresthesias, or yeast infections, particularly balanitis in men. However, many patients with type 2 diabetes are asymptomatic, and their disease remains undiagnosed for many years.

In older studies, the typical patient with type 2 diabetes had diabetes for at least 4-7 years at the time of diagnosis. [ 152 ] Among patients with type 2 diabetes in the United Kingdom Prospective Diabetes Study, 25% had retinopathy; 9%, neuropathy; and 8%, nephropathy at the time of diagnosis. (For more information, see Diabetic Neuropathy .)

Patients with established diabetes

In patients with known type 2 diabetes, inquire about the duration of the patient's diabetes and about the care the patient is currently receiving for the disease. The duration of diabetes is significant because the chronic complications of diabetes are related to the length of time the patient has had the disease.

A focused diabetes history should also include the following questions:

Is the patient's diabetes generally well controlled (with near-normal blood glucose levels) - Patients with poorly controlled blood glucose levels heal more slowly and are at increased risk for infection and other complications

Does the patient have severe hypoglycemic reactions - If the patient has episodes of severe hypoglycemia and therefore is at risk of losing consciousness, this possibility must be addressed, especially if the patient drives or has significant underlying neuropathy or cardiovascular disease

Does the patient have diabetic nephropathy that might alter the use of medications or intravenous (IV) radiographic contrast material

Does the patient have macrovascular disease, such as coronary artery disease (CAD) that should be considered as a source of acute symptoms

Does the patient self-monitor his or her blood glucose levels - If so, note the frequency and range of values at each time of day

When was the patient's hemoglobin A1c (HbA1c; an indicator of long-term glucose control) last measured, and what was it

What is the patient’s immunization history - Eg, influenza, pneumococcal, hepatitis B, tetanus, herpes zoster

As circumstances dictate, additional questions may be warranted, as follows:

Does the patient give a history of recent polyuria, polydipsia, nocturia, or weight loss - These are symptoms of hyperglycemia

Has the patient had episodes of unexplained hypoglycemia - If so, when, how often, and how does the patient treat these episodes

Does the patient have hypoglycemia unawareness (ie, does the patient lack the adrenergic warning signs of hypoglycemia) - Hypoglycemia unawareness indicates an increased risk of subsequent episodes of hypoglycemia

Regarding retinopathy, when was the patient's last dilated eye examination, and what were the results

Regarding nephropathy, does the patient have known kidney disease; what were the dates and results of the last measurements of urine protein and serum creatinine levels

Does the patient have hypertension (defined as a blood pressure of 130/80 mm Hg or higher); what medications are taken

Does the patient have CAD

Regarding peripheral vascular disease, does the patient have claudication or a history of vascular bypass

Has the patient had a stroke or transient ischemic attack

What are the patient's most recent lipid levels; is the patient taking lipid-lowering medication

Does the patient have a history of neuropathy or are symptoms of peripheral neuropathy or autonomic neuropathy present (including impotence if the patient is male)

Does the patient have a history of foot ulcers or amputations; are any foot ulcers present

Are frequent infections a problem; at what site

Dawn phenomenon

The Dawn phenomenon, defined as a blood glucose increase of over 20 mg/dL occurring at the end of the night, appears to be common in type 2 diabetes. In a study of 248 noninsulin-treated patients with type 2 diabetes who underwent continuous glucose monitoring for 2 consecutive days, approximately half were found to have the dawn phenomenon. [ 153 , 154 ] Patients with the dawn phenomenon had HbA1c levels and 24-hour mean glucose values that were significantly higher than in other patients, the mean differences being 4.3 mmol/mol for HbA1c (0.39%) and 12.4 mg/dL for average 24-hour glucose concentrations. Mean 24-hour glucose did not significantly differ between patients treated with diet alone and those treated with oral antihyperglycemic agents (ie, oral antidiabetic drugs did not eliminate the dawn phenomenon). [ 153 , 154 ]

Early in the course of diabetes mellitus, the physical examination findings are likely to be unrevealing. Ultimately, however, end-organ damage may be observed. Potential findings are listed in the image below.

A diabetes-focused examination includes vital signs, funduscopic examination, limited vascular and neurologic examinations, and a foot assessment. Other organ systems should be examined as indicated by the patient's clinical situation.

Assessment of vital signs

Baseline and continuing measurement of vital signs is an important part of diabetes management. In addition to vital signs, measure height, weight, and waist and hip circumferences.

In many cases, blood pressure measurement will disclose hypertension, which is particularly common in patients with diabetes. Patients with established diabetes and autonomic neuropathy may have orthostatic hypotension. Orthostatic vital signs may be useful in assessing volume status and in suggesting the presence of an autonomic neuropathy.

If the respiratory rate and pattern suggest Kussmaul respiration, diabetic ketoacidosis (DKA) must be considered immediately, and appropriate tests ordered. DKA is more typical of type 1 diabetes, but it can occur in type 2.

Funduscopic examination

The funduscopic examination should include a careful view of the retina. The optic disc and the macula should be visualized. If hemorrhages or exudates are seen, the patient should be referred to an ophthalmologist as soon as possible. Examiners who are not ophthalmologists tend to underestimate the severity of retinopathy, especially if the patients' pupils are not dilated.

Whether patients develop diabetic retinopathy depends on the duration of their diabetes and on the level of glycemic control maintained. [ 155 , 156 ] Because the diagnosis of type 2 diabetes often is delayed, 20% of these patients have some degree of retinopathy at diagnosis. The following are the 5 stages in the progression of diabetic retinopathy:

Dilation of the retinal venules and formation of retinal capillary microaneurysms

Increased vascular permeability

Vascular occlusion and retinal ischemia

Proliferation of new blood vessels on the surface of the retina

Hemorrhage and contraction of the fibrovascular proliferation and the vitreous

The first 2 stages of diabetic retinopathy are known as background or nonproliferative retinopathy. Initially, the retinal venules dilate; then microaneurysms (tiny red dots on the retina that cause no visual impairment) appear. As the microaneurysms or retinal capillaries become more permeable, hard exudates appear, reflecting the leakage of plasma.

Larger retinal arteriolar and venular calibres have been associated with lower scores on memory tests but not with lower scores on other cognitive tests. [ 157 ] This association was strong in men. Impaired arteriolar autoregulation may be an underlying mechanism of memory decrements.

Rupture of intraretinal capillaries results in hemorrhage. If a superficial capillary ruptures, a flame-shaped hemorrhage appears. Hard exudates are often found in partial or complete rings (circinate pattern), which usually include multiple microaneurysms. These rings usually mark an area of edematous retina. The patient may not notice a change in visual acuity unless the center of the macula is involved.

Macular edema can cause visual loss; therefore, all patients with suspected macular edema must be referred to an ophthalmologist for evaluation and possible laser therapy. Laser therapy is effective in decreasing macular edema and preserving vision but is less effective in restoring lost vision. (For more information, see Macular Edema in Diabetes .)

Preproliferative and proliferative diabetic retinopathy are the next stages in the progression of the disease. Cotton-wool spots can be seen in preproliferative retinopathy. These represent retinal microinfarcts caused by capillary occlusion; they appear as patches that range from off-white to gray, and they have poorly defined margins.

Proliferative retinopathy is characterized by neovascularization, or the development of networks of fragile new vessels that often are seen on the optic disc or along the main vascular arcades. The vessels undergo cycles of proliferation and regression. During proliferation, fibrous adhesions develop between the vessels and the vitreous. Subsequent contraction of the adhesions can result in traction on the retina and retinal detachment. Contraction also tears the new vessels, which hemorrhage into the vitreous.

Patients with preproliferative or proliferative retinopathy must immediately be referred for ophthalmologic evaluation because laser therapy is effective in this condition, especially before actual hemorrhage occurs.

Often, the first hemorrhage is small and is noted by the patient as a fleeting, dark area, or "floater," in the field of vision. Because subsequent hemorrhages can be larger and more serious, the patient should be referred immediately to an ophthalmologist for possible laser therapy. Patients with retinal hemorrhage should be advised to limit their activity and keep their head upright (even while sleeping), so that the blood settles to the inferior portion of the retina, thus obscuring less central vision.

Patients with active proliferative diabetic retinopathy are at increased risk of retinal hemorrhage if they receive thrombolytic therapy; therefore, this condition is a relative contraindication to the use of thrombolytic agents.

One study has shown that individuals with gingival hemorrhaging have a high prevalence of retinal hemorrhage. [ 158 ] Much of this association is driven by hyperglycemia, making it possible to use gingival tissue to study the natural course of microvascular disease in patients with diabetes.

Foot examination

The dorsalis pedis and posterior tibialis pulses should be palpated and their presence or absence noted. This is particularly important in patients who have foot infections, because poor lower-extremity blood flow can slow healing and increase the risk of amputation.

Documenting lower-extremity sensory neuropathy is useful in patients who present with foot ulcers because decreased sensation limits the patient's ability to protect the feet and ankles. This can be assessed with the Semmes Weinstein monofilament or by assessment of reflexes, position, and/or vibration sensation.

If peripheral neuropathy is found, the patient should be made aware that foot care (including daily foot examination) is very important for preventing foot ulcers and avoiding lower-extremity amputation. (For more information, see Diabetic Foot and Diabetic Foot Infections .)

Differentiation of type 2 from type 1 diabetes

Type 2 diabetes mellitus can usually be differentiated from type 1 diabetes mellitus on the basis of history and physical examination findings and simple laboratory tests (see Workup for more information). Patients with type 2 diabetes are generally obese, and may have acanthosis nigricans and/or hirsutism in conjunction with thick necks and chubby cheeks.

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• Simplified scheme for the pathophysiology of type 2 diabetes mellitus.
• Prevalence of type 2 diabetes mellitus in various racial and ethnic groups in the United States (2007-2009 data).
• Prevalence of diabetes mellitus type 2 by age in the United States (2007 estimates).
• Possible physical examination findings in patients with type 2 diabetes mellitus.
• Diagnostic criteria (American Diabetes Association) for diabetes mellitus type 2.
• Major findings from the primary glucose study in the United Kingdom Prospective Diabetes Study (UKPDS).
• Results from metformin substudy in the United Kingdom Prospective Diabetes Study (UKPDS).
• Findings from the blood pressure substudy in the United Kingdom Prospective Diabetes Study (UKPDS).
• Laboratory monitoring guidelines for patients with type 2 diabetes mellitus.
• American Diabetes Association guidelines for low-density lipoprotein cholesterol in diabetes mellitus type 2.
• Treatment of type 2 diabetes mellitus.
• Types of insulin. Premixed insulins can be assumed to have a combination of the onset, peak, and duration of the individual components.
• Simplified scheme for using insulin in treating patients with type 2 diabetes mellitus.
• Simplified scheme of idealized blood glucose values and multiple dose insulin therapy in type 2 diabetes mellitus.

Contributor Information and Disclosures

Romesh Khardori, MD, PhD, FACP (Retired) Professor, Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Eastern Virginia Medical School Romesh Khardori, MD, PhD, FACP is a member of the following medical societies: American Association of Clinical Endocrinology , American College of Physicians , American Diabetes Association , Endocrine Society Disclosure: Nothing to disclose.

George T Griffing, MD Professor Emeritus of Medicine, St Louis University School of Medicine George T Griffing, MD is a member of the following medical societies: American Association for Physician Leadership , American Association for the Advancement of Science , American College of Medical Practice Executives , American College of Physicians , American Diabetes Association , American Federation for Medical Research , American Heart Association , Central Society for Clinical and Translational Research , Endocrine Society , International Society for Clinical Densitometry , Southern Society for Clinical Investigation Disclosure: Nothing to disclose.

Howard A Bessen, MD Professor of Medicine, Department of Emergency Medicine, University of California, Los Angeles, David Geffen School of Medicine; Program Director, Harbor-UCLA Medical Center

Howard A Bessen, MD is a member of the following medical societies: American College of Emergency Physicians

Disclosure: Nothing to disclose.

Barry E Brenner, MD, PhD, FACEP Professor of Emergency Medicine, Professor of Internal Medicine, Program Director, Emergency Medicine, Case Medical Center, University Hospitals, Case Western Reserve University School of Medicine

Barry E Brenner, MD, PhD, FACEP is a member of the following medical societies: Alpha Omega Alpha , American Academy of Emergency Medicine , American College of Chest Physicians , American College of Emergency Physicians , American College of Physicians , American Heart Association , American Thoracic Society , Arkansas Medical Society , New York Academy of Medicine , New York Academy ofSciences ,and Society for Academic Emergency Medicine

William L Isley, MD Senior Associate Consultant, Associate Professor of Medicine, Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic of Rochester

William L Isley, MD is a member of the following medical societies: Alpha Omega Alpha , American College of Physicians , American Diabetes Association , American Federation for Medical Research , Endocrine Society , and Phi Beta Kappa

Kenneth Patrick L Ligaray, MD Fellow, Department of Endocrinology, Diabetes and Metabolism, St Louis University School of Medicine

Kenneth Patrick Ligaray, MD is a member of the following medical societies: American Association of Clinical Endocrinologists and Endocrine Society

Anne L Peters, MD, CDE Director of Clinical Diabetes Programs, Professor, Department of Medicine, University of Southern California, Keck School of Medicine, Los Angeles, California, Los Angeles County/University of Southern California Medical Center

Anne L Peters, MD, CDE is a member of the following medical societies: American College of Physicians and American Diabetes Association

Disclosure: Amylin Honoraria Speaking and teaching; AstraZeneca Consulting fee Consulting; Lilly Consulting fee Consulting; Takeda Consulting fee Consulting; Bristol Myers Squibb Honoraria Speaking and teaching; NovoNordisk Consulting fee Consulting; Medtronic Minimed Consulting fee Consulting; Dexcom Honoraria Speaking and teaching; Roche Honoraria Speaking and teaching

David S Schade, MD Chief, Division of Endocrinology and Metabolism, Professor, Department of Internal Medicine, University of New Mexico School of Medicine and Health Sciences Center

David S Schade, MD is a member of the following medical societies: American College of Physicians , American Diabetes Association , American Federation for Medical Research , Endocrine Society , New Mexico Medical Society , New York Academy of Sciences , and Society for Experimental Biology and Medicine

Don S Schalch, MD Professor Emeritus, Department of Internal Medicine, Division of Endocrinology, University of Wisconsin Hospitals and Clinics

Don S Schalch, MD is a member of the following medical societies: American Diabetes Association , American Federation for Medical Research , Central Society for Clinical Research , and Endocrine Society

Erik D Schraga, MD Staff Physician, Department of Emergency Medicine, Mills-Peninsula Emergency Medical Associates

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Scott R Votey, MD Director of Emergency Medicine Residency, Ronald Reagan UCLA Medical Center; Professor of Medicine/Emergency Medicine, University of California, Los Angeles, David Geffen School of Medicine

Scott R Votey, MD is a member of the following medical societies: Society for Academic Emergency Medicine

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Pathophysiology of diabetes: An overview

Mujeeb z. banday.

Department of Biochemistry, Government Medical College and Associated Shri Maharaja Hari Singh Hospital, Srinagar, Kashmir, India

Aga S. Sameer

1 Department of Basic Medical Sciences, College of Medicine, King Saud Bin Abdul Aziz University for Health Sciences, King Abdullah International Medical Research Centre, National Guard Health Affairs, Jeddah, Saudi Arabia

Saniya Nissar

Diabetes mellitus is a chronic heterogeneous metabolic disorder with complex pathogenesis. It is characterized by elevated blood glucose levels or hyperglycemia, which results from abnormalities in either insulin secretion or insulin action or both. Hyperglycemia manifests in various forms with a varied presentation and results in carbohydrate, fat, and protein metabolic dysfunctions. Long-term hyperglycemia often leads to various microvascular and macrovascular diabetic complications, which are mainly responsible for diabetes-associated morbidity and mortality. Hyperglycemia serves as the primary biomarker for the diagnosis of diabetes as well. In this review, we would be focusing on the classification of diabetes and its pathophysiology including that of its various types.

INTRODUCTION

Diabetes mellitus (DM), also known simply as diabetes is a complex metabolic disorder characterized by hyperglycemia, a physiologically abnormal condition represented by continued elevated blood glucose levels. Hyperglycemia results from anomalies in either insulin secretion or insulin action or both and manifests in a chronic and heterogeneous manner as carbohydrate, fat, and protein metabolic dysfunctions. Diabetes follows a progressive pattern with complex pathogenesis and varied presentation.[ 1 , 2 ]

Hyperglycemia and its associated carbohydrate, fat, and protein metabolic dysfunctions affect multiple organs of the body and disrupt their normal functioning. These disruptions progress gradually and arise mostly due to the adverse effects of hyperglycemia and its associated metabolic anomalies on the normal structure and functioning of micro- and macrovasculature, which lie at the core of organ structure, and function throughout the body. The structural and functional disruptions in organ system vasculature lead to micro- and macrovascular complications. Organ damage, dysfunction, and, ultimately, organ failure characterize these complications and affect body organs, which include, in particular, eyes, kidneys, heart, and nerves. Eye-related complications result in retinopathy with progression to blindness. Kidney-associated complications lead to nephropathy and potential renal failure. Heart-related complications include hypertension and coronary heart disease. Nerve-associated complications lead to neuropathy, which can be autonomic and/or peripheral. Cardiovascular, gastrointestinal, and genitourinary (including sexual) dysfunctions are characteristic manifestations of autonomic neuropathy, whereas foot infections including ulcers requiring amputations and Charcot joint (osteoarthropathy) are often associated with long-term peripheral neuropathy.[ 3 , 4 , 5 ] The cerebrovascular disease, peripheral arterial disease, and coronary heart disease, together termed as atherosclerotic cardiovascular disease, are of common occurrence in diabetes and constitute one of the major causes of diabetes-associated morbidity and mortality.[ 1 , 4 , 5 ]

Diabetes with its ever-increasing global prevalence has emerged as one of the most important and challenging health issues confronting the human population of the present world. The increase in the prevalence of diabetes in most regions across the globe has been parallel to the rapid economic development, leading to urbanization and adoption of modern lifestyle habits.[ 6 ] In the year 2019, the number of adult people aged 20–79 years with diabetes has been estimated to be about 463 million, which represents 9.3% of the total world adult population. By the year 2030, this number has been estimated to increase to 578 million, representing 10.2% of the total world adult population and further increase to 700 million by the year 2045, which represents 10.9% of the total world adult population. In the year 2019, the prevalence of diabetes among men and women has been estimated to be 9.6% and 9.0%, respectively, of the total respective gender world population.[ 7 ] Furthermore, in the year 2019, approximately 4.2 million adult people aged 20–99 years died due to diabetes, and its associated complications and health expenditure on diabetes estimated to at least 760 billion USD, which represents 10% of the total spending on adults. Diabetes during pregnancy has been estimated to have affected more than 20 million live births (1 in 6 live births) in the year 2019.[ 8 ]

CLASSIFICATION AND PATHOPHYSIOLOGY

DM is characterized by complex pathogenesis and varied presentation and any classification of this disorder, therefore, is arbitrary, but nevertheless useful, and is often influenced by the physiological conditions present at the time of assessment and diagnosis. The classification currently used is based on both the etiology and the pathogenesis of disease and is useful in the clinical assessment of disease and for deciding the required therapy. According to this classification, diabetes can be divided into four main types or categories: type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), gestational diabetes mellitus (GDM), and diabetes caused or associated with certain specific conditions, pathologies, and/or disorders [ Figure 1 ].[ 1 , 9 ]

Four types of diabetes mellitus

Type 1 diabetes mellitus

T1DM, also known as type 1A DM or as per the previous nomenclature as insulin-dependent diabetes mellitus (IDDM) or juvenile-onset diabetes, constitutes about 5–10% of all the cases of diabetes. It is an autoimmune disorder characterized by T-cell-mediated destruction of pancreatic β-cells, which results in insulin deficiency and ultimately hyperglycemia.[ 10 , 11 ] The pathogenesis of this autoimmunity, though not yet fully understood, has been found to be influenced by both genetic and environmental factors. The rate of development of this pancreatic β-cell-specific autoimmunity and the disorder itself is rapid in most of the cases as in infants and children (juvenile onset) or may be gradual as in adults (late onset).

The variability in the rate at which the immune-mediated destruction of the pancreatic β-cells occurs often defines the eventual progression of this disease. In some cases, children and adolescents, the β-cell destruction and subsequent failure occur suddenly, which can lead to diabetic ketoacidosis (DKA), often described as the first manifestation of the disease. In others, the disease progression is very slow with a mild increase in fasting blood glucose levels, which assumes a severe hyperglycemic form with or without ketoacidosis, only in the presence of physiological stress conditions such as severe infections or onset of other disorders. In some other cases, which include adults, β-cells may retain some degree of function to secrete only that quantity of insulin, which is only sufficient to prevent ketoacidosis for many years. However, due to progressive insulin deficiency, these individuals become insulin-dependent with the emergence of severe hyperglycemia and subsequent ketoacidosis. Despite the variable progression of this type of diabetes, the affected individuals in the beginning or in the middle or even in the later stages of their life become severely or absolutely insulin-deficient and become dependent on insulin treatment for their survival. This severe or absolute insulin deficiency irrespective of its occurrence at any age manifests itself as low or undetectable levels of plasma C-peptide.[ 1 , 10 , 11 ]

T1DM is an autoimmune disorder characterized by several immune markers, in particular autoantibodies. These autoantibodies are associated with the immune-mediated β-cell destruction, characteristic of this disease. The autoantibodies include glutamic acid decarboxylase autoantibodies (GADAs) such as GAD65, islet cell autoantibodies (ICAs) to β-cell cytoplasmic proteins such as autoantibodies to islet cell antigen 512 (ICA512), autoantibodies to the tyrosine phosphatases, IA-2 and IA-2α, insulin autoantibodies (IAAs), and autoantibodies to islet-specific zinc transporter isoform 8 (ZnT8). At least one of these autoantibodies can be used for the clinical diagnosis of this disease but usually more of these immune markers have been observed in approximately 85–90% of patients with new-onset T1DM.[ 1 , 12 ] Of these autoantibodies, GAD65 is the most important and is present in about 80% of all T1DM individuals at the time of diagnosis, followed by ICAs present in 69–90% and IA-2α found in 54–75% of all T1DM individuals at clinical presentation.

The IAAs are important immune markers present in infants and young children who are prone to diabetes and its prevalence decreases as the age of onset of diabetes increases. The presence of IAAs in these individuals who have not been previously treated with insulin is an important indication of developing T1DM. IAAs are present in about 70% of all infants and young children at the time of diagnosis. The IAAs also play an important inhibitory role toward insulin function in patients on insulin therapy. Although not often clinically significant but nevertheless, this immune response has been observed with varying degrees of severity in at least 40% of patients on insulin treatment and therefore shows differential clinical manifestations.[ 13 ] These autoantibodies mostly consist of polyclonal immunoglobulin G (IgG) antibodies and differ in their affinities and binding capacities toward insulin. IAAs can either be high insulin affinity/low insulin-binding capacity or low insulin affinity/high insulin-binding capacity. The low insulin affinity/high insulin-binding capacity IAAs are responsible for clinical manifestations. At high titers, the binding of these antibodies to insulin prevents or delays its action and is responsible for characteristic hyperglycemia in the immediate postprandial period, which leads to significantly increased insulin requirements followed by unpredictable hypoglycemic episodes (postprandial hypoglycemia) observed later.[ 14 ]

These autoantibodies assume more clinical and diagnostic importance in some cases, particularly adults, with late-onset of this disease where the destruction of the pancreatic β-cells occurs at a very slow rate and often the disease masquerades as in T2DM. In such cases, these autoantibodies enable the correct diagnosis of this disorder as the T1DM, rather than the most common T2DM. This type of diabetes is often described as “Latent Autoimmune Diabetes in Adults (LADA),” also known as “slowly progressing insulin-dependent diabetes.”[ 15 ]

LADA is the most common form of adult-onset autoimmune diabetes and accounts for 2–12% of all diabetic cases in the adult population.[ 16 ] Of the autoantibodies, GADAs are the most important and sensitive markers for LADA followed by ICAs. However, the IAAs, autoantibodies to the tyrosine phosphatases—IA-2 and IA-2α, and autoantibodies to islet-specific zinc transporter isoform 8 (ZnT8) which are observed in patients with juvenile- or young-onset T1DM are detectable in only a small number of cases in LADA.[ 17 ] In a study on LADA (Action LADA study), GADAs were the only diabetes-specific autoantibodies detected in 68.6% of total screened subjects whereas IA-2α and ZnT8A represented the single-type autoantibody detections in 5% and 2.3% of all the screened study subjects. In the same study, more than one type of autoantibody was detected in 24.1% of study subjects.[ 18 ] LADA is also sometimes referred to as T2DM with ICAs.

Besides the characteristic immune-mediated pancreatic β-cell destruction, several other autoimmune disorders including myasthenia gravis, Addison’s disease (primary adrenal insufficiency), celiac sprue (celiac disease), pernicious anemia, vitiligo, Hashimoto’s thyroiditis, Graves’ disease, dermatomyositis, autoimmune gastritis, and autoimmune hepatitis have been observed with an increased incidence in patients with T1DM.[ 1 , 10 , 19 , 20 ] The autoimmune nature of this disease and its association with other autoimmune conditions mainly stem from the strong association of this disorder with human leukocyte antigen (HLA), its linkage to the DQA and DQB genes, and its direct influence by DRB genes. All of these are hotspot gene regions associated with immune response including autoimmunity. The genome-wide association studies have shown a strong association of this disease with HLA-DR3 and HLA-DR4 haplotypes and the exclusive association of DR4-DQB1I0302 haplotype with the autoimmune destruction of the β-cells. As with other diseases, these various HLA haplotypes can increase or decrease the susceptibility toward the T1DM.[ 21 , 22 , 23 ] However, several non-HLA genes or gene regions also influence the susceptibility to this disease. The most prominent among them is the insulin gene (INS) region, designated as IDDM2 located on chromosome 11p5.5. The variable number of tandem repeats in the promoter region of this gene region has been observed to influence the susceptibility toward this disease.[ 24 ] Besides IDDM2, CTLA-4, PTPN-22, and CD25 are other non-HLA genes associated with the disease.[ 25 ] The patients with this type of diabetes can be but are rarely obese at the time of assessment and diagnosis.[ 1 , 10 ]

Idiopathic diabetes

Idiopathic diabetes, also referred to as ICA-negative or type 1B diabetes, includes the forms of diabetes which are similar to T1DM in presentation but characterized by variable nonimmune β-cell dysfunction without any observed HLA association unlike T1DM and hence, sometimes it is also described as a separate type of DM. This type of diabetes exhibits a strong pattern of inheritance and has been observed in only a minority of patients, of Asian or African-Caribbean origin. The etiology of idiopathic diabetes remains largely unknown.

The disease is characterized by severe but varying degrees of insulin deficiency (insulinopenia) which can exhibit episodic patterns concomitant with varying degrees of severity and episodic DKA. These patients, therefore, may require insulin replacement therapy initially but the need for the therapy may not be absolute and may vary in accordance with the episodic patterns of insulinopenia and ketoacidosis characteristic of these forms of T1DM.[ 26 ]

Type 2 diabetes mellitus

T2DM, also known as non-insulin-dependent diabetes mellitus (NIDDM) or adult-onset diabetes, as per the previous nomenclature, constitutes about 90–95% of all the cases of diabetes. This type of diabetes is characterized by two main insulin-related anomalies: insulin resistance and β-cell dysfunction.[ 27 , 28 , 29 ] Insulin resistance results from disruption of various cellular pathways, which lead to a decreased response, or sensitivity of cells in the peripheral tissues, in particular the muscle, liver, and adipose tissue toward insulin. In the early stages of the disease, decreased insulin sensitivity triggers β-cells hyperfunction to achieve a compensatory increase in insulin secretion to maintain normoglycemia. The higher levels of circulating insulin (hyperinsulinemia), thus, prevent hyperglycemia. However, gradually, the increased insulin secretion by β-cells is not able to compensate sufficiently for the decrease in insulin sensitivity. Moreover, β-cell function begins to decline and β-cell dysfunction eventually leads to insulin deficiency. As a result, normoglycemia can no longer be maintained and hyperglycemia develops. Although insulin levels are decreased, the secretion of insulin in most cases is sufficient to prevent the occurrence of DKA.[ 29 ] But DKA may occur during severe stress conditions such as those associated with infections or other pathophysiological scenarios. DKA may also be precipitated by the use of certain drugs including sodium-glucose co-transporter-2 (SGLT2) inhibitors, corticosteroids, and atypical antipsychotics (second-generation antipsychotic drugs).[ 30 , 31 ] In absence of any severe physiological stress conditions, patients with T2DM often do not require any insulin therapy both at the time of disease onset and even after, throughout their lifetime.[ 27 , 28 , 29 ]

T2DM progresses very slowly and asymptomatically with even mild hyperglycemia developing over years and as such remains largely undiagnosed until the appearance of classic symptoms associated with severe hyperglycemia such as weight loss, growth impairment, blurred vision, polyuria, and polydipsia in the advanced stages of the disease. The pathogenesis/etiology of this form of diabetes is complex and involves multiple known and unknown factors, which in a conclusive manner can be described as a combination of genetic (polygenic) predispositions and strong environmental influences. T2DM has been more frequently associated with increasing age, obesity, family history of diabetes, physical inactivity, and adoption of modern lifestyles: with prior GDM in women and with pathophysiological conditions such as hypertension and dyslipidemia. It occurs more frequently in individuals belonging to certain racial or ethnic groups including Native Americans (American Indians), Asian Americans, African Americans, Hispanic, and Latino. The frequent occurrence of T2DM in the mentioned racial or ethnic groups and its observed strong association with first-degree blood relations point strongly toward the role of genetic factors in the etiology of this disease, but these factors are complex and remain largely unspecified. However, unlike T1DM, no association of this disease has been found with genes involved in the immune response including autoimmunity and consequently there is no immune-mediated pancreatic β-cell destruction.[ 32 , 33 ]

Obesity plays an important role in the homeostatic regulation of systemic glucose due to its influence on the development of insulin resistance through its effect on the sensitivity of tissues to insulin and as such most but not all patients with T2DM are overweight or obese.[ 34 ] The increased body fat content, a characteristic of obesity, is such an important risk factor for T2DM that not only the total amount but also the distribution of body fat itself defines the development of insulin resistance and subsequently hyperglycemia. The increased abdominal fat or visceral obesity has been frequently associated with this type of diabetes in comparison to increased gluteal/subcutaneous fat or peripheral obesity.[ 35 ] Due to its strong association with increased body fat content or obesity, the patients with T2DM often present with various cardiovascular risk factors such as hypertension and lipoprotein metabolic abnormalities characterized by elevated triglycerides and low levels of high-density lipoproteins (HDLs). Due to its lifelong duration and associated diverse metabolic derangements characteristic of hyperglycemia, T2DM, particularly in the middle and later decades, is frequently associated with the development of various microvascular and macrovascular complications. Figure 2 enlists some of the main risk factors of T2DM.

Some of the main risk factors of type 2 diabetes mellitus

Gestational diabetes mellitus

GDM is defined as any degree of glucose intolerance or diabetes diagnosed at the outset or during pregnancy, usually the second or third trimester. This definition earlier also included any undetected T2DM which may begin prior to or occur at the time of pregnancy onset. However, the latest recommendations of the International Association of the Diabetes and Pregnancy Study Groups exclude from this definition diabetes diagnosed at the pregnancy onset or afterward in high-risk women such as with obesity where any degree of glucose intolerance is described as previously undiagnosed overt diabetes rather than GDM. GDM is different from any preexisting diabetes in women undergoing pregnancies and usually resolves soon after childbirth or termination of pregnancy.[ 1 , 36 ]

During early pregnancy, both the fasting and post-prandial blood glucose levels are usually lower than normal but the blood glucose levels increase during the third trimester of pregnancy, and in cases where this blood glucose level reaches the diabetic levels, the condition is described as GDM. More than 90% of all the cases of diabetes and its complications that occur during pregnancy can be attributed to GDM. The incidence of GDM varies from 1% to 14% of all pregnancies and its prevalence is greatly influenced by the populations under study. GDM occurs more frequently in certain racial or ethnic groups than others and this influence of ethnicity on risk of GDM is very important and has long been established. The prevalence of GDM is highest among Asian Indians, higher in aboriginal Australians, Middle Eastern (Lebanese, Syrian, Iranian, Iraqi, or Afghanistan), Filipina, Pacific Islanders, and Chinese, Japanese, Korean, and Mexican women. The prevalence is lower in blacks and lowest among non-Hispanic white women.[ 37 , 38 ] The risk of GDM increases with age, obesity, previous pregnancy with large babies, and any previous history of impaired glucose tolerance or GDM.[ 39 , 40 ] Furthermore, GDM has been associated with an increased lifetime risk of developing T2DM. The regular and lifetime screening for any kind of glucose impairment is, therefore, highly recommended in order to ensure early diagnosis of T2DM in such individuals.[ 41 , 42 , 43 ]

Other types of diabetes

Besides T1DM, T2DM, and GDM, diabetes in various other forms, though in smaller percentages with respect to overall diabetic incidence scenario, has been found to be associated with some specific conditions including various pathologies and/or several disorders. The prominent among these types of diabetes include diabetes resulting from the monogenic defects in β-cell function and those due to genetic abnormalities in insulin action, endocrinopathies, exocrine pancreatic pathologies, and several other specific conditions.

Diabetes caused due to the monogenic defects in β-cell function

Diabetes resulting from monogenic defects in β-cell function constitutes only 0.6–2% of all the cases of diabetes and mainly includes maturity-onset diabetes of the young (MODY) and neonatal diabetes, besides other but rare types.

Maturity-onset diabetes of the young

MODY is a genetically, metabolically, and clinically heterogeneous group of mostly non-insulin-dependent diabetes, resulting from mutations in several specific genes involved in pancreatic β-cell function, which affects glucose sensing and subsequent insulin secretion with no or minimal defects, if any, in insulin action. MODY, as the name suggests, has an early onset with glucose tolerance impairment and hyperglycemia occurring usually before the age of 25 years and is often misdiagnosed as T1DM or T2DM.[ 44 , 45 ] MODY accounts for less than 2% of all the cases of diabetes[ 46 ] and 1–6% of all the pediatric cases of diabetes.[ 47 ] MODY follows an autosomal dominant inheritance pattern and typically involves the vertical transmission of the disorder through at least three generations and exhibits a phenotype shared by all family members with diabetes.[ 48 ] To date, MODY has been associated with mutations in one of the 14 genes identified so far and these genes are mostly located on different chromosomes.[ 1 , 9 , 46 , 49 ] Figure 3 provides a graphical representation of various MODY subtypes along with their alternative names based on genes involved. The most common forms of this group of diabetes are designated as MODY2 and MODY3 which together account for more than 80% of all the cases of this type of diabetes.[ 50 , 51 ]

Types of maturity-onset diabetes of the young and their alternative names based on genes involved

MODY2 (GCK MODY ). MODY2 results from one or several of more than 200 loss-of-function mutations in the glucokinase (GCK) gene located on chromosome 7p13 and accounts for 15–25% of all MODY cases.[ 50 , 52 ] GCK gene codes for GCK enzyme, which catalyzes the first and rate-limiting step of glycolytic phosphorylation of glucose to glucose-6-phosphate at a rate proportional to the glucose concentration. This unique catalytic property allows the GCK enzyme to function as a sort of a glucose sensor and enables the β-cells to elicit an insulin secretion response appropriate to the existing concentrations of glucose.[ 53 ] The loss-of-function mutations characteristic of MODY2 disrupt this glucose-sensing function of the GCK enzyme such that only hyperglycemic but not normoglycemic levels can elicit a normal insulin secretion response from the β-cells. In MODY2, the fasting hyperglycemia remains mild but persistent and stable and the disorder is non-insulin-dependent. MODY2 is clinically nonprogressive with mild or no symptoms and is usually not associated with the development of microvascular and macrovascular complications. GCK gene is a mutational hotspot region and more than 600 mutations have been identified in the 10 exons of this gene, which have been associated with both hyperglycemia and hypoglycemia.[ 54 ]

MODY3 (HNF-1α MODY) and MODY1 (HNF-4α MODY ). MODY3 results from the loss-of-function mutations in hepatocyte nuclear factor (HNF)-1α gene located on chromosome 12q24, which codes for the transcription factor, HNF-1α (transcription factor MODY) and accounts for 30–50% of all MODY cases.[ 51 ] HNF-1α is expressed in the kidney, liver, intestine, and pancreatic β-cells and is involved in regulating the expression of several hepatic genes many of which are involved in glucose metabolism including glucose transporter 1 and 2 (GLUT1 and GLUT2). More than 400 mutations have been identified in HNF-1α gene.[ 55 ] MODY3 presents with a symptomatic rapid progression to overt diabetes reflected through a progressive impairment from glucose intolerance to severe hyperglycemia, often leading to T1DM and T2DM like microvascular and macrovascular complications. MODY3 has been associated with a decreased pancreatic β-cell mass due to an increased rate of β-cell apoptosis, particularly from the third decade of life onward, and therefore, MODY3 is characterized by a progressive decrease in insulin secretion.[ 56 ] Depending on the hyperglycemic severity and duration since onset, MODY3 may be or may not be insulin-dependent.

MODY1 accounts for around 5% of all MODY cases. MODY1 is caused due to the loss-of-function mutations in the transcription factor, HNF-4α gene located on chromosome 20q13. HNF-4α is mainly expressed in the liver and also in kidney and pancreatic β-cells and regulates the expression of genes involved in glucose transport, metabolism, and nutrient-induced insulin secretion and also triglyceride metabolism and lipoprotein biosynthesis.[ 57 ] HNF-4α mutation is characterized by a progressive defect and a decline in insulin secretion from infancy onward and resembles clinically with MODY3. It is associated with hyperinsulinemic hypoglycemia in the neonatal period, which begins to remit during infancy, and as such, the decline in insulin production starts in infancy but the emergence of hyperglycemia and subsequent full-blown diabetes occurs during adolescence.[ 47 , 58 ] HNF-4α mutation and hence MODY1 have been associated with decreased levels of apolipoprotein—apoAII, apoCIII, and apoB and HDLs and increased levels of low-density lipoproteins (LDLs).

Hyperglycemia associated with HNF-1α and HNF-4α mutations in MODY3 and MODY1, respectively, can be efficiently controlled through the treatment with low-dose sulfonylureas. These agents maintain efficacy or remain effective for many years and are preferred first-line of treatment in these patients compared to insulin and other therapies used in T1DM and T2DM. However, to ensure proper treatment, an early and accurate diagnosis is very important to avoid mislabeling these MODY types as T1DM or T2DM and prevent administration of inappropriate avoidable therapies in these patients.[ 59 , 60 ]

MODY5 (HNF-1β MODY ). MODY5 results from mutations in the transcription factor, HNF-1β gene located on chromosome 17q12 and accounts for around 5% of all cases of MODY.[ 61 , 62 ] HNF-1β is involved in the regulation of genes that are associated with various embryonic developmental processes, in particular, the genesis of various organs including the liver, pancreas, lungs, gut, kidney, and genitourinary tract.[ 63 ] MODY5 develops in early adolescence or adulthood. HNF-1β mutations that result in MODY5 often present as renal cysts, renal cysts and diabetes syndrome, renal dysplasia, hypoplastic glomerulonephritic kidney disease, urinary tract malformation,[ 64 , 65 ] and reduced birth weight.[ 66 ] Some of these conditions are evident from the 17th week of gestation[ 65 ] or are seen in infants or young children, independent of the hyperglycemic status.[ 47 ] Renal dysfunction,[ 65 ] liver dysfunction, and pancreatic abnormalities[ 67 ] are common as the disorder develops and end-stage renal disease develops in half of the patients with MODY5 by 45 years of age independent of diabetic kidney disease status.[ 65 ] Genitourinary tract malformations especially uterine abnormalities such as rudimentary uterus in addition to vaginal aplasia have also been reported in MODY5.[ 67 ] Insulin dependence develops relatively earlier due to liver and pancreatic abnormalities, in particular, hepatic insulin resistance and pancreatic hypoplasia.[ 47 , 68 ] Hyperuricemia, gout, low HDL levels, and elevated triglyceride levels are commonly observed in patients with MODY5.[ 61 , 69 ]

Other types of MODY . Relatively rare and less common types of MODY, which account for less than 1% of all MODY cases, include as follows:

• MODY4 (PDX-1/IPF-1 MODY ): MODY4 results from mutations in the transcription factor, pancreatic and duodenal homeobox-1(PDX-1), also known as insulin promoter factor (IPF)-1 gene located on chromosome 13q12.2.[ 70 ] PDX-1/IPF-1 is involved in the development of exocrine and endocrine pancreas and plays an important role in regulating the expression of insulin, glucagon, GLUT2, and GCK encoding genes.[ 71 , 72 ] Homozygous mutations in PDX-1/IPF-1 gene result in pancreas agenesis, hypoplasia, and pancreatic exocrine insufficiency and in permanent neonatal diabetes (PND) whereas heterozygous PDX-1/IPF-1 gene mutations cause β-cell impairment, which leads to defective insulin secretion and hyperglycemia.[ 73 , 74 ]
• MODY6 (NEUROD1 MODY ): MODY6 results from mutations in the transcription factor, neurogenic differentiation factor-1(NEUROD1) gene located on chromosome 2q31.[ 75 ] NEUROD1 belongs to the basic helix-loop-helix family of transcription factors and is involved in the regulation of several cell differentiation pathways associated with neuronal and pancreatic development, in particular, those involved in endocrine islet cells (islets of Langerhans) differentiation including the pancreatic β-cells. NEUROD1 gene mutations interfere with the maturation of β-cells and impair their glucose-sensing ability and as a result, their insulin secretion response. Homozygous NEUROD1 gene mutations lead to neonatal diabetes and are associated with neurological abnormalities whereas heterozygous mutations result in childhood- or adult-onset diabetes.[ 76 , 77 ]

The other types of MODY in this category include MODY7 (KLF11 MODY), which results from the mutations in Kruppel-like factor 11 (KLF11) gene located on chromosome 2p25[ 78 ] and MODY8 (CEL MODY), which arises from the mutations in carboxyl ester lipase (CEL) gene located on chromosome 9q34.[ 79 ] This category also includes MODY9 (PAX4 MODY), caused due to the mutations in PAX family transcription factor, Paired box gene 4 (PAX4) gene located on chromosome 7q32[ 80 ] and MODY10 (INS MODY), which results from the mutations in the INS located on chromosome 11p15[ 81 , 82 ]; also, MODY11 (BLK MODY), which arises due to the mutations in the human homolog of a B-lymphocyte-specific protein tyrosine kinase (BLK) gene located on chromosome 8p23.1.[ 83 ]

Furthermore, there is MODY12 (ABCC8-MODY), which results from the mutations in ATP-binding cassette transporter subfamily C member 8 (ABCC8) gene located on chromosome 11p15 and ABCC8 which encodes sulfonylurea receptor-1 (SUR1) protein, a subunit of ATP-sensitive potassium (KATP) channel. MODY12 is responsive to sulfonylureas.[ 84 ]

The remaining types include MODY13 (KCNJ11-MODY) and MODY14 (APPL1-MODY). MODY13 (KCNJ11-MODY) is caused due to the mutations in potassium inwardly rectifying channel subfamily J member 11 (KCNJ11) gene located on chromosome 11p15.1 which encodes β-cell inward rectifier, BIR (inwardly rectifying potassium channel Kir6.2), a subunit of ATP-sensitive potassium (KATP) channel.[ 85 , 86 ] MODY14 (APPL1-MODY) results from the mutations in Adaptor Protein, Phosphotyrosine Interacting With PH Domain and Leucine Zipper 1 (APPL1) or DCC-interacting protein 13-α (DIP13-α) gene located on chromosome 3p14.3.[ 87 ]

Neonatal diabetes mellitus

Neonatal diabetes mellitus (NDM), also known as early-onset or congenital diabetes, is the diabetes diagnosed during the first 6 months of life. It is a rare disorder with a global incidence rate of 1 per 500,000–300,000 (1:500,000–1:300,000)[ 88 , 89 ] live births; though a study in Italy has reported a higher incidence of 1 per 90,000 (1:90,000).[ 88 ] NDM is predominantly of genetic origin with 80–85% cases occurring due to monogenic defects and is characterized by severe uncontrolled hyperglycemia along with hypoinsulinemia and requires insulin replacement therapy.[ 89 ] The genetic abnormalities lead to β-cell dysfunction and decreased β-cell mass due to increased apoptotic or non-apoptotic β-cell death. These defects also result in developmental abnormalities of pancreas and/or its islets or in very rare cases their complete absence leading to decreased production and secretion of insulin or hypoinsulinemia and in the latter case an absolute insulin deficiency.[ 90 ] Neonatal diabetes is highly distinct from early-onset T1DM and differs from it both in the origin and pattern of inborn pancreatic disorder and mostly occurs during the first 6 months of life whereas T1DM mostly develops after 6 months of life. Based largely on the clinical features, NDM can assume either of these two forms: transient neonatal diabetes mellitus (TNDM) and permanent neonatal diabetes mellitus (PNDM).

TNDM is the more common form representing approximately 55–60% of all cases of neonatal diabetes. It usually resolves within 12–18 months after birth but in a majority of cases, NDM relapses during the later years of life from late childhood to early or late adulthood and presents itself as T2DM, indicating the presence of varying degrees of severity, but persistent β-cell dysfunction, which leads to possible inadequate insulin secretion and/or insulin resistance. Furthermore, the diabetes may also precipitate under stress conditions such as hormonal changes as observed in puberty or in certain diseases.[ 89 , 91 ] TNDM results most often from the abnormalities in chromosome 6 specifically involving the overexpression of imprinted and paternally expressed genes in the 6q24 region. This includes the HYMAI (hydatiform mole associated and imprinted) gene, zinc finger protein, ZAC gene, and pituitary adenylate cyclase activating polypeptide-1 (PACAP1) gene. A small percentage of TNDM cases arises from the mutations in the ATP binding cassette subfamily C member 8 (ABCC8) gene also known as sulfonylurea receptor-1 (SUR1) gene and rarely from the mutations in the potassium voltage-gated channel subfamily J member 11 (KCNJ11 or Kir6.2).[ 89 ] Both ABCC8 and KCNJ11genes are functionally linked together as these genes encode for the proteins that constitute the individual subunits of the β-cell K ATP channel. The K ATP channel is an eight-subunit ATP-sensitive potassium channel with two types of subunits: four regulatory subunits encoded by ABCC8 (SUR1) gene and four pore-forming subunits encoded by KCNJ11 (Kir6.2) gene. This channel regulates the secretion of insulin from the pancreatic β-cells, thus providing a direct link with normal glucose homeostasis and its dysregulation in diabetes.

PNDM is the less common form of NDM, which unlike TNDM does not go into remission and persists permanently. PNDM most commonly results from the heterozygous autosomal dominant mutations in the ABCC8 and the KCNJ11 genes encoding, respectively, the SUR1 and Kir6.2 subunits of the β-cell K ATP channel.[ 9 , 89 ] Several mutations identified in the INS also cause PNDM.[ 9 ] Besides, this type of neonatal diabetes is associated with several syndromes including the immune-dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, and Wolcott–Rallison syndrome. IPEX syndrome is an autoimmune disorder that results from the mutations in the FOXP3 gene. The autoimmune disorders that characterize IPEX syndrome include autoimmune enteropathy (an autoimmune disorder of the intestines), dermatitis or eczema (an autoimmune disorder of the skin), and polyendocrinopathy (multiple autoimmune disorders of the endocrine glands, including pancreas and thyroid).[ 9 , 89 , 92 ] WRS is an autosomal recessive disorder, which results from the mutations in the EIF2AK3 gene.[ 9 , 89 , 93 ] The main characteristics of this disorder include multiple epiphyseo-metaphyseal dysplasia and hepatic dysfunction. Diabetes is a permanent feature associated with this syndrome and in consanguineous families; WRS has emerged as the most frequent cause of PNDM.[ 94 , 95 ] Clinically, it is not possible to predict whether a particular neonatal dysfunction of glucose homeostasis will eventually develop into TNDM or PNDM, which makes the correct diagnosis, and the assessment of the underlying cause of the disorder including the genetic factors involved, an important aspect in the management of this disorder.

Besides MODY and NDM, there are several other monogenic defects in β-cell function which result in DM. These include the point mutations in mitochondrial DNA such as 3243A-G mutation in the mitochondrial transfer RNA leucine-1 (MTTL1) gene, which leads to deafness and diabetes[ 96 ] and the autosomal dominant mutations, which result in a total inability or abnormal conversion of proinsulin to insulin.[ 97 ] Furthermore, it also includes the mutations that lead to the production of structurally abnormal insulin molecules with impaired receptor binding.

Diabetes caused due to genetic abnormalities in insulin action

Several genetic abnormalities in insulin action resulting either from insulin receptor functional impairment or decrease in the number of insulin receptors, caused mainly due to the mutations in insulin receptor (INSR) gene located on chromosome 19, have been identified. These abnormalities in insulin action lead to hyperinsulinemia or insulin resistance and subsequent mild to modest hyperglycemia or may even cause severe hyperglycemia characteristic of overt diabetes.[ 1 ] The various forms of diabetes resulting from the abnormalities in insulin action, often described as inherited severe insulin resistance syndromes, include type A insulin resistance syndrome, lipoatrophic diabetes, Donohue syndrome (leprechaunism), and Rabson–Mendenhall syndrome (RMS).

Type A insulin resistance syndrome results from mutations in INSR gene. This syndrome is associated with menstruation disorders (primary amenorrhea or oligomenorrhea) and specific forms of polycystic ovarian syndrome characterized by hirsutism due to hyperandrogenism and multiple enlarged cysts on the ovaries, in females[ 98 ]; also, acanthosis nigricans, a skin pigmentation disorder, most often in females than in males[ 99 ] and obesity,[ 100 ] most often in males than in females and severe insulin resistance.

Lipoatrophic diabetes is a monogenic but heterogeneous insulin resistance syndrome associated with lipoatrophy and lipodystrophy and characterized by paucity (insufficiency) of fat, insulin resistance, and dyslipidemia, more specifically, hypertriglyceridemia.[ 101 ] Lipoatrophic diabetes arises due to the mutations in several different genes, which manifests as different genetic syndromes. It may result from the mutations in Laminin A/C (LMNA) gene located on chromosome 1q21–22 and manifest as an autosomal dominant disorder known as familial partial lipoatrophy, also known as Dunnigan or Koberling-Dunnigan syndrome.[ 102 ] Lipoatrophic diabetes may also result from the mutations, either in the AGPAT2 gene or in the BSCL2 gene. AGPAT2 gene located on chromosome 9q34 encodes the enzyme 1-acyl-sn-glycerol-3-phosphate- d -acetyltransferase-2, which is involved in triglyceride synthesis. Berardinelli-Seip congenital lipodystrophy type-2 (BSCL2) gene, also known as γ3-linked gene (GNG3) or seipin gene, located on chromosome 11q13 encodes seipin, an endoplasmic reticulum-associated protein involved in lipid droplet biogenesis. Both these mutations manifest as an autosomal recessive disorder known as Congenital generalized lipoatrophy or Berardinelli-Seip syndrome.[ 103 , 104 ]

Furthermore, the mutations in insulin receptor gene may also lead to the Donohue syndrome (leprechaunism) and the RMS, both of which manifest in infancy, and diabetes in these syndromes is characterized by strong insulin resistance and severe hyperglycemia.[ 105 ]

Endocrinopathies

Several endocrinopathies resulting in or from abnormal functioning of various hormones can lead to diabetes. These include the endocrinopathies that involve the hyperactivity of those hormones which partly or fully antagonize the function of insulin such as Cushing syndrome, acromegaly, pheochromocytoma, glucagonoma, and hyperthyroidism, which result from hyperactivity of cortisol, growth hormone, norepinephrine (and epinephrine), glucagon, and thyroid hormones, respectively. Diabetes associated with these endocrine disorders usually occurs when a defect in insulin secretion and/or action is already present.[ 106 , 107 ] Some endocrinopathies induce diabetes through inhibition of insulin secretion and these include somatostatinoma, which leads to the excessive secretion of somatostatin and primary hyperaldosteronism[ 108 ] or Conn’s syndrome induced hypokalemia, which involves the hypersecretion and hyperactivity of the hormone, aldosterone.[ 109 ] Diabetes caused due to various endocrinopathies usually resolves when endocrinopathies are treated or managed.

Exocrine pancreatic pathologies

Several diseases of the exocrine pancreas have been found to cause diabetes but the contribution of these diseases to the overall incidence of diabetes is minimal with less than 0.5% of all the cases of diabetes resulting from the diseases of the exocrine pancreas. These include chronic pancreatitis (fibrocalculous pancreatopathy), trauma (pancreatectomy), infection, hereditary hemochromatosis, secondary hemochromatosis, cystic fibrosis, and pancreatic neoplasia (adenocarcinoma and glucagonoma).[ 110 , 111 , 112 ] All these pancreatic pathologies, with the exception of pancreatic neoplasia, lead to diabetes only when they are severe enough to cause extensive pancreatic damage, involving the endocrine pancreas, including the islets of Langerhans, which leads to a considerable reduction in the β-cell mass and impairment of β-cell function.[ 113 ] The pancreatic neoplasia-associated diabetes occurs even without any reduction in β-cell mass.[ 1 ]

Several infections caused by viruses are known to cause β-cell dysfunction, mainly through β-cell destruction, and lead to hyperglycemia, which gradually presents as overt diabetes. These include infections caused by cytomegalovirus, adenovirus, Coxsackie virus B, and mumps. Besides, congenital rubella syndrome, caused by rubella virus, has also been closely linked with diabetes, but this diabetes in most of the cases is associated with the presence of HLA and other immune markers, which are characteristic of T1DM.[ 1 , 114 , 115 ] Furthermore, insulin resistance has been associated with chronic hepatitis C virus infection and progression of fibrosis and a very high prevalence of T2DM has been reported among the individuals infected with the hepatitis C virus.[ 116 , 117 ]

Drug- or chemical-induced

Several drugs and chemicals are known to induce diabetes. These agents induce diabetes either through the impairment of insulin production or secretion, which mainly results from the destruction of β-cells or through a decrease in the sensitivity of tissues to insulin, which causes insulin resistance. Diabetes resulting from the drug- or chemical-induced increase in insulin resistance occurs only in susceptible individuals. Furthermore, these agents may worsen or increase the severity of hyperglycemia in individuals with already existing overt diabetes. The drugs and chemicals known to induce diabetes include glucocorticoids, diazoxide, thiazides, β 2 -receptor agonists (salbutamol and ritodrine), nonselective β-adrenergic antagonists, dilantin, hormones including growth hormone (in very high doses), thyroid hormone (thyroxine/triiodothyronine), somatostatin, estradiol, levonorgestrel, and glucagon. These also include γ-interferon, protease inhibitors (indinavir, nelfinavir, ritonavir, and saquinavir), nicotinic acid, and β-cell toxins including streptozocin (streptozotocin), cyclosporine, rodenticide vacor and pentamidine, and several antipsychotics.[ 118 , 119 ] Furthermore, immune checkpoint inhibitors, such as ipilimumab, nivolumab, and pembrolizumab, used in cancer immunotherapy for treatment of advanced-stage cancers, including head and neck cancer, renal cancer, urothelial cancers, non-small-cell lung carcinoma, and melanoma besides other cancers[ 120 , 121 , 122 , 123 , 124 , 125 ] have been reported to induce new-onset T1DM, through immune-mediated β-islet cell dysfunction.[ 125 , 126 ]

Other genetic syndromes associated with diabetes

There are many others, besides the already mentioned genetic syndromes, that are usually associated with an increased incidence of diabetes. These include Down’s syndrome, Turner’s syndrome, Wolfram’s syndrome, Klinefelter’s syndrome, Huntington’s chorea, Friedreich’s ataxia, myotonic dystrophy, Laurence-Moon-Biedl syndrome, Porphyria, and Prader-Willi syndrome among others.[ 127 ]

Uncommon forms of immune-mediated diabetes

The uncommon forms of immune-mediated diabetes are very rare in occurrence and mainly include diabetes associated with Moersch-Woltman syndrome (stiff-person syndrome [SPS]), anti-insulin receptor antibodies (AIRAs), and insulin autoimmune syndrome (IAS; Hirata’s disease).

Moersch-Woltman syndrome or the SPS is a very rare autoimmune disorder that affects the central nervous system and is characterized by progressive fluctuating rigidity of the axial muscles (muscles of the trunk and head), accompanied by painful muscle spasms. Patients with SPS generally present with high titers of GADAs and are frequently associated with various diseases including pernicious anemia, thyroiditis, vitiligo, and type 1-like diabetes. Although GADAs are detected in most of the individuals with T1DM alone; but the individuals with SPS with or without diabetes have 50–100 times more titers of GADAs.[ 128 ]

The AIRAs are often associated with various autoimmune diseases, including primary biliary cholangitis, systemic lupus erythematosus, and Hashimoto thyroiditis. AIRAs generally bind to insulin receptors on various insulin target tissues, which block the binding of insulin to these receptors and hence the subsequent signaling pathways. This leads to diabetes characterized by a rapidly progressive and extreme form of insulin resistance, earlier termed as type B insulin resistance. Alternatively, AIRAs once bound to target receptors may sometimes cause spontaneous hyperinsulinemic hypoglycemia by acting as insulin agonists. Diabetes associated with AIRAs is often characterized by acanthosis nigricans and impaired insulin degradation.[ 129 , 130 ]

IAS or Hirata’s disease is described as a condition, which is characterized by the presence of autoantibodies to the endogenous insulin (IAA) in the absence of any previous exposure to the exogenous insulin, absence of any pathological abnormalities of the pancreatic islets and presents as endogenous hyperinsulinemia hypoglycemia. Although, the predisposition to this condition is present from birth, but the overt disease most often presents itself during adulthood and can be triggered by exposure to certain drugs and viruses. IAS can be controlled through simple dietary management.[ 131 ]

Ketosis-prone diabetes mellitus

Ketosis-prone diabetes mellitus (KPD) describes another heterogeneous group of diabetes, which like T2DM, characteristically does not involve the immune-mediated destruction of pancreatic β-cells but unlike T2DM, this type presents with frequent episodes of DKA or unprovoked ketosis.[ 132 ] KPD occurs most frequently in African Americans and Africans in sub-Saharan Africa but has now been observed increasingly in Hispanic, Chinese, and Japanese populations.[ 132 , 133 , 134 , 135 ] One of the best described subtypes of this diabetes is Flatbush diabetes which along with characteristic episodic DKA is frequently associated with HLA-DR3 and/or HLA-DR4 haplotypes.[ 136 ] The patients with KPD show periodic but absolute requirement of insulin replacement therapy, concomitant with the episodes of DKA and outside of the frequent episodes of DKA, the diabetes can be controlled through simple diet management without insulin replacement therapy.

CONCLUSIONS

DM is a heterogeneous metabolic disease, represented by diverse forms, each with a distinct pathophysiological origin but often manifest as a disorder with overlapping and difficult-to-differentiate characteristics. The treatment and management of each of these diabetic types are distinct in some characteristics but share a great deal of similarity as well as is the case with the disorder itself. All this emphasizes the importance of correct and timely diagnosis of each of these diabetic types and the critical role of their pathophysiological understanding. This is vital to safeguard diabetic individuals from exposures to potential adverse effects of improper, ineffective, or avoidable pharmaceutical interventions, which often delays the desired prognosis and increases the duration of hyperglycemic exposures. The long-term hyperglycemia, in turn, has often been associated with increased risk of microvascular and macrovascular diabetic complications, which affect the quality of life and mainly contribute to the diabetes-associated morbidity and mortality. For diabetes in general, and in particular, the diabetes types resulting from genetic mutations or associated genetic anomalies, the correct and timely molecular diagnosis can help in disease risk analysis and help in disease prediction and timely identification of individuals at an increased risk to the disorder, in particular, the family members. The predictive molecular/genetic testing and preventive management can play a vital role in such cases. Furthermore, irrespective of the diabetes type, various lifestyle modifications and interventions such as extensive diet control, physical exercises, change of daily sedentary routine, and control of obesity are important in the prevention and the management of diabetes. The educational campaigns, which make the general population aware of the pathogenesis of this disease and the various controllable risk factors associated with it, are also a vital tool in the management and control of diabetes mellitus.

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Diabetes infographics.

Information on health issues requires pedagogical resources to make it understandable to others. At Slidesgo we have created this diabetes infographic template so that you can easily and entertainingly report on this disease. It contains numerous icons and illustrations to make the data more visual and easier to remember. With...

World Diabetes Day

Diabetes is a serious illness that affects millions of people all around the world, and making proper treatment, care and information accessible to everyone who needs it is an unresolved issue that needs more awareness. For reasons like these, the United Nations decided to establish November 14th as the World...

Type 2 Diabetes Breakthrough

Type 2 diabetes is a metabolic disorder with a high prevalence in the world. Hundreds of millions of people suffer from it every year. Basically, a person cannot produce enough insulin, which can cause very severe consequences. Are there news on the treatment of type 2 diabetes? Waste no time...

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Gestational Diabetes

Gestational diabetes is diabetes that first appears during pregnancy. It usually occurs in the middle of the gestation period and it is necessary to take care of it so that it does not cause problems. For this, information is key, so we have created this beautiful pink template, with creative...

Diabetes Breakthrough: Insulin Increase

This is a modern template full of illustrations and resources that gives medical presentations a visual and creative touch. This design focuses on diabetes: a medical issue that affects the lives of millions of people. If you have investigated on this and have come up with a new treatment, these...

Diabetes Mellitus Breakthrough

Diabetes mellitus refers to a group of diseases that affects the way the body uses blood glucose. Many people in the world suffer from this disease, and we are sure that your breakthrough will give a new perspective to its diagnosis and treatment. Present it with this complete and impressive...

World Diabetes Day Infographics

Slidesgo is aware of how healthcare professionals love to have extra help when sharing information about diseases, treatments or breakthroughs. Today, we're releasing a series of infographic designs for presentations about diabetes, a serious illness that affects millions of people. Check them out! The main color used is blue, a...

Diabetes Devices and Technology Breakthrough

This modern and cool template is the perfect way to showcase the amazing breakthroughs in diabetes technologies and devices. With this template, you can easily present the latest developments to help treat and control diabetes. It features modern visuals and graphics that provide insight into the technology, as well as...

Treatment of Hypoglycemia Breakthrough

When the glucose levels in our blood drop below normal, our body can experience symptoms such as shakiness, confusion, sweating, and fatigue. A more correct name for this condition is hypoglycemia, but there's treatment (usually, ingesting sugar and carbohydrates), but perhaps there's more to it. Any new breakthrough in this...

Download the "Gestational Diabetes" presentation for PowerPoint or Google Slides. Taking care of yourself and of those around you is key! By learning about various illnesses and how they are spread, people can get a better understanding of them and make informed decisions about eating, exercise, and seeking medical attention....

Kidney Diseases: Diabetic Nephropathy

Download the Kidney Diseases: Diabetic Nephropathy presentation for PowerPoint or Google Slides. Taking care of yourself and of those around you is key! By learning about various illnesses and how they are spread, people can get a better understanding of them and make informed decisions about eating, exercise, and seeking...

Wolfram Syndrome Breakthrough

Download the Wolfram Syndrome Breakthrough presentation for PowerPoint or Google Slides.Treating diseases involves a lot of prior research and clinical trials. But whenever there’s a new discovery, a revolutionary finding that opens the door to new treatments, vaccines or ways to prevent illnesses, it’s great news. Should there be a...

Type 2 Diabetes Disease

Type 2 diabetes is a chronic condition that affects the way the body processes glucose. With this disease, the patient's body does not produce enough insulin or is resistant to it. Share your research on this important disease using this modern and minimalist template designed in pastel colors, with which...

Happy World Diabetes Day!

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Atypical Diabetic Ketoacidosis Case Report

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Diabetes Education Center

Running a medical center specialized on diabetes involves lots of organization and management. What is the admission procedure? How are patients going to be allocated? What fun/free time activities do you offer? That’s an important question to think about, because offering your patients activities to disconnect can improve their mental...

Diabetes Mellitus Disease

Diabetes mellitus refers to a group of diseases that affects the way the body uses blood glucose. Glucose is vital for health, as it is an important source of energy for the cells that make up muscles and tissues. Understanding a disease thoroughly is the first step to being able...

Diabetic Ketoacidosis Disease

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What Is Diabetes?

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Diabetes is a disease that occurs when your blood glucose, also called blood sugar, is too high. Glucose is your body’s main source of energy. Your body can make glucose, but glucose also comes from the food you eat.

Insulin is a hormone  made by the pancreas  that helps glucose get into your cells to be used for energy. If you have diabetes, your body doesn’t make enough—or any—insulin, or doesn’t use insulin properly. Glucose then stays in your blood and doesn’t reach your cells.

Diabetes raises the risk for damage to the eyes, kidneys, nerves, and heart. Diabetes is also linked to some types of cancer. Taking steps to prevent or manage diabetes may lower your risk of developing diabetes health problems.

What are the different types of diabetes?

The most common types of diabetes are type 1, type 2, and gestational diabetes.

Type 1 diabetes

If you have type 1 diabetes , your body makes little or no insulin. Your immune system  attacks and destroys the cells in your pancreas that make insulin. Type 1 diabetes is usually diagnosed in children and young adults, although it can appear at any age. People with type 1 diabetes need to take insulin every day to stay alive.

Type 2 diabetes

If you have type 2 diabetes , the cells in your body don’t use insulin properly. The pancreas may be making insulin but is not making enough insulin to keep your blood glucose level in the normal range. Type 2 diabetes is the most common type of diabetes. You are more likely to develop type 2 diabetes if you have risk factors , such as overweight or obesity , and a family history of the disease. You can develop type 2 diabetes at any age, even during childhood.

You can help delay or prevent type 2 diabetes  by knowing the risk factors and taking steps toward a healthier lifestyle, such as losing weight or preventing weight gain.

Gestational diabetes

Gestational diabetes is a type of diabetes that develops during pregnancy. Most of the time, this type of diabetes goes away after the baby is born. However, if you’ve had gestational diabetes, you have a higher chance of developing type 2 diabetes later in life. Sometimes diabetes diagnosed during pregnancy is type 2 diabetes.

Prediabetes

People with prediabetes  have blood glucose levels that are higher than normal but not high enough to be diagnosed with type 2 diabetes. If you have prediabetes, you have a higher risk of developing type 2 diabetes in the future. You also have a higher risk for heart disease than people with normal glucose levels.

Other types of diabetes

A less common type of diabetes, called monogenic diabetes , is caused by a change in a single gene . Diabetes can also come from having surgery to remove the pancreas, or from damage to the pancreas due to conditions such as cystic fibrosis or pancreatitis .

How common are diabetes and prediabetes?

More than 133 million Americans have diabetes or prediabetes. 1

As of 2019, 37.3 million people—or 11.3% of the U.S. population—had diabetes. 1 More than 1 in 4 people over the age of 65 had diabetes. Nearly 1 in 4 adults with diabetes didn’t know they had the disease. 2

About 90% to 95% of diabetes cases are type 2 diabetes. 3

In 2019, 96 million adults—38% of U.S. adults—had prediabetes. 4

What other health problems can people with diabetes develop?

Over time, high blood glucose can damage your heart , kidneys , feet , and eyes . If you have diabetes, you can take steps to lower your chances of developing diabetes health problems  by taking steps to improve your health  and learning how to manage the disease . Managing your blood glucose, blood pressure, and cholesterol levels can help prevent future health problems.

This content is provided as a service of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), part of the National Institutes of Health. NIDDK translates and disseminates research findings to increase knowledge and understanding about health and disease among patients, health professionals, and the public. Content produced by NIDDK is carefully reviewed by NIDDK scientists and other experts.

NIDDK would like to thank: Daniel Bessesen, M.D., University of Colorado; Domenico Accili, M.D., Columbia University

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The following presentations provide a multifaceted review of topics relating to diabetes. Overviews of Type 1 and Type 2 diabetes, metabolic syndrome, and gestational diabetes (diabetes developing during pregnancy) are discussed. In addition, complications associated with both forms of diabetes are discussed along with measures to lower the risk for these complications. The importance of monitoring maternal glucose in relation to infant growth and development is also discussed.

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Diabetes Presentation Template

Customize the Diabetes presentation template for PowerPoint & Google Slides to present your diabetes awareness presentations comprehensively. Diabetes is a chronic disease that alters the normal glucose level of the body and can lead to various complications. The major cause of diabetes is the decreased production of insulin. The prevalence of this disease is more than ever, and it’s crucial to understand the causes and risk factors associated with diabetes. We have specifically designed this interactive PowerPoint template for social workers, healthcare experts, and doctors. So that they can create useful presentations for the audience while accomplishing diabetes awareness campaigns. November is National Diabetes Month, and it is important to educate the public about diabetes.

Our Diabetes presentation template can also be used in executive sessions to present support for diabetes funding, research, and awareness. The title slide contains the diagram of a glucometer connected with a blue diabetes support ribbon. The further slides contain human illustrations with a diagram of the glucometer, pricker, and test strips, which can help the audience understand safe sugar levels and risky conditions. Moreover, in the following slide, a weighing balance shows that the significance of fruits is higher than fast food. Some other slides are:

• Symptoms slide to describe the signs of the poor health condition
• Horizontal timeline slide with editable textboxes to demonstrate the history of diabetes and its futuristic details.
• Data-driven charts slide and column chart slides to mention the relevant data about the prevalence and occurrence of diabetes patients and the increasing number of patients.

This creative diabetes template is compatible with all versions of Microsoft PowerPoint, Google Slides, and Keynote. The users can change the slides’ colors, relevant graphical elements, icons, and theme according to their preferences. So, download this useful PPT template and make amazing presentations in the diabetes month of November. Alternatively, you can download the Diabetes PPT template design with other useful slides that you can use in your presentation on diabetes topics.

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Diabetes prevention: 5 tips for taking control.

Changing your lifestyle could be a big step toward diabetes prevention — and it's never too late to start. Consider these tips.

Lifestyle changes can help prevent the onset of type 2 diabetes, the most common form of the disease. Prevention is especially important if you're currently at an increased risk of type 2 diabetes because of excess weight or obesity, high cholesterol, or a family history of diabetes.

If you have been diagnosed with prediabetes — high blood sugar that doesn't reach the threshold of a diabetes diagnosis — lifestyle changes can prevent or delay the onset of disease.

Making a few changes in your lifestyle now may help you avoid the serious health complications of diabetes in the future, such as nerve, kidney and heart damage. It's never too late to start.

1. Lose extra weight

Losing weight reduces the risk of diabetes. People in one large study reduced their risk of developing diabetes by almost 60% after losing approximately 7% of their body weight with changes in exercise and diet.

The American Diabetes Association recommends that people with prediabetes lose at least 7% to 10% of their body weight to prevent disease progression. More weight loss will translate into even greater benefits.

Set a weight-loss goal based on your current body weight. Talk to your doctor about reasonable short-term goals and expectations, such as a losing 1 to 2 pounds a week.

2. Be more physically active

There are many benefits to regular physical activity. Exercise can help you:

• Lose weight
• Lower your blood sugar
• Boost your sensitivity to insulin — which helps keep your blood sugar within a normal range

Goals for most adults to promote weight loss and maintain a healthy weight include:

• Aerobic exercise. Aim for 30 minutes or more of moderate to vigorous aerobic exercise — such as brisk walking, swimming, biking or running — on most days for a total of at least 150 minutes a week.
• Resistance exercise. Resistance exercise — at least 2 to 3 times a week — increases your strength, balance and ability to maintain an active life. Resistance training includes weightlifting, yoga and calisthenics.
• Limited inactivity. Breaking up long bouts of inactivity, such as sitting at the computer, can help control blood sugar levels. Take a few minutes to stand, walk around or do some light activity every 30 minutes.

3. Eat healthy plant foods

Plants provide vitamins, minerals and carbohydrates in your diet. Carbohydrates include sugars and starches — the energy sources for your body — and fiber. Dietary fiber, also known as roughage or bulk, is the part of plant foods your body can't digest or absorb.

Fiber-rich foods promote weight loss and lower the risk of diabetes. Eat a variety of healthy, fiber-rich foods, which include:

• Fruits, such as tomatoes, peppers and fruit from trees
• Nonstarchy vegetables, such as leafy greens, broccoli and cauliflower
• Legumes, such as beans, chickpeas and lentils
• Whole grains, such as whole-wheat pasta and bread, whole-grain rice, whole oats, and quinoa

The benefits of fiber include:

• Slowing the absorption of sugars and lowering blood sugar levels
• Interfering with the absorption of dietary fat and cholesterol
• Managing other risk factors that affect heart health, such as blood pressure and inflammation
• Helping you eat less because fiber-rich foods are more filling and energy rich

Avoid foods that are "bad carbohydrates" — high in sugar with little fiber or nutrients: white bread and pastries, pasta from white flour, fruit juices, and processed foods with sugar or high-fructose corn syrup.

4. Eat healthy fats

Fatty foods are high in calories and should be eaten in moderation. To help lose and manage weight, your diet should include a variety of foods with unsaturated fats, sometimes called "good fats."

Unsaturated fats — both monounsaturated and polyunsaturated fats — promote healthy blood cholesterol levels and good heart and vascular health. Sources of good fats include:

• Olive, sunflower, safflower, cottonseed and canola oils
• Nuts and seeds, such as almonds, peanuts, flaxseed and pumpkin seeds
• Fatty fish, such as salmon, mackerel, sardines, tuna and cod

Saturated fats, the "bad fats," are found in dairy products and meats. These should be a small part of your diet. You can limit saturated fats by eating low-fat dairy products and lean chicken and pork.

5. Skip fad diets and make healthier choices

Many fad diets — such as the glycemic index, paleo or keto diets — may help you lose weight. There is little research, however, about the long-term benefits of these diets or their benefit in preventing diabetes.

Your dietary goal should be to lose weight and then maintain a healthier weight moving forward. Healthy dietary decisions, therefore, need to include a strategy that you can maintain as a lifelong habit. Making healthy decisions that reflect some of your own preferences for food and traditions may be beneficial for you over time.

One simple strategy to help you make good food choices and eat appropriate portions sizes is to divide up your plate. These three divisions on your plate promote healthy eating:

• One-half: fruit and nonstarchy vegetables
• One-quarter: whole grains
• One-quarter: protein-rich foods, such as legumes, fish or lean meats

When to see your doctor

The American Diabetes Association recommends routine screening with diagnostic tests for type 2 diabetes for all adults age 45 or older and for the following groups:

• People younger than 45 who are overweight or obese and have one or more risk factors associated with diabetes
• Women who have had gestational diabetes
• People who have been diagnosed with prediabetes
• Children who are overweight or obese and who have a family history of type 2 diabetes or other risk factors

Share your concerns about diabetes prevention with your doctor. He or she will appreciate your efforts to prevent diabetes and may offer additional suggestions based on your medical history or other factors.

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• Robertson RP. Prevention of type 2 diabetes mellitus. https://www.uptodate.com/contents/search. Accessed April 12, 2021.
• American Diabetes Association. Prevention or delay of type 2 diabetes: Standards of Medical Care in Diabetes — 2021. Diabetes Care. 2021; doi:10.2337/dc21-S003.
• Diabetes mellitus. Merck Manual Professional Version. https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/diabetes-mellitus-and-disorders-of-carbohydrate-metabolism/diabetes-mellitus-dm. Accessed April 14, 2021.
• American Diabetes Association. Facilitating behavior change and well-being to improve health outcomes: Standards of Medical Care in Diabetes — 2021. Diabetes Care. 2021; doi:10.2337/dc21-S005.
• Your game plan to prevent type 2 diabetes. National Institute of Diabetes and Digestive and Kidney Diseases. https://www.niddk.nih.gov/health-information/diabetes/overview/all-content. Accessed April 8, 2021.
• Melmed S, et al. Therapeutics of type 2 diabetes mellitus. Williams Textbook of Endocrinology. 14th ed. Elsevier; 2020. https://www.clinicalkey.com. Accessed April 8, 2021.
• Interactive Nutrition Facts label: Dietary fiber. U.S. Food and Drug Administration. https://www.accessdata.fda.gov/scripts/interactivenutritionfactslabel/dietary-fiber.cfm. Accessed April 16, 2021.
• 2020-2025 Dietary Guidelines for Americans. U.S. Department of Health and Human Services and U.S. Department of Agriculture. https://www.dietaryguidelines.gov. Accessed April 16, 2021.
• Interactive Nutrition Facts label: Monounsaturated and polyunsaturated fats. U.S. Food and Drug Administration. https://www.accessdata.fda.gov/scripts/interactivenutritionfactslabel/fat.cfm. Accessed April 16, 2021.
• American Diabetes Association. Classification and diagnosis of diabetes: Standards of Medical Care in Diabetes — 2021. Diabetes Care. 2021; doi:10.2337/dc21-S002.

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Basal serum cortisol levels; significant predictors to DKA duration

• Original Article
• Published: 10 September 2024

Cite this article

• Mai Ali Sayed Abd El Ghaney   ORCID: orcid.org/0000-0002-7097-8456 1 &
• Yomna Ahmed Hosni   ORCID: orcid.org/0000-0003-2174-3535   nAff2  

Diabetes mellitus is the most common pediatric endocrinal disorder. Diabetic ketoacidosis is one of the most serious life-threatening complications and might be the initial presentation. Poor management, non-compliance and infection are the main triggers for DKA. Infection leads to activation of the hypothalamic-pituitary-adrenal axis leading to the production of cortisol, sometimes excessively which might affect the illness course.

The study aimed to measure basal serum cortisol levels during DKA as a significant predictor of DKA duration and to assess the time to recovery between children with newly diagnosed diabetes compared with known diabetics presenting with and without infection.

This cross-sectional study included 207 pediatric patients presenting with DKA where serum cortisol level was measured on admission.

The mean cortisol level was 41.54 µg/dl ± 21.36 µg/dL. Cortisol levels were inversely associated with serum pH and bicarbonate level with (r = -0.544; p  = <0.001) and ( r = -0.520; p = <0.001) respectively. There was a positive association of cortisol levels with the duration of DKA (r = 0.443; p  = <0.001). Thirty-four children (16.40%) with cortisol levels < 18 µg/dL showed higher serum pH, and bicarbonate levels and shorter duration of DKA with a statistically significant p value <0.001.  One-hundred and fourteen (55.1%) patients with cortisol levels >34 µg/dL had lower pH, bicarbonate level, and longer duration of DKA with a statistically significant p value <0.001.

Cortisol levels on admission higher than 34 µg/dL are associated with a longer duration of DKA while levels lower than 18 ug/dl were associated with a significantly shorter duration. Therefore, it’s recommended to measure basal serum cortisol levels on admission during DKA as significant predictor to DKA duration.

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Abbreviations

Diabetic Ketoacidosis

Diabetes, Endocrine and Metabolism Pediatric Unit

Standard Deviation

Adrenocorticotrophic

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Yomna Ahmed Hosni

Present address: The Diabetes Endocrine and Metabolism Pediatric Unit, Abo ELReesh Children’s Hospital, Faculty of Medicine Organization, Cairo University, Cairo, Egypt

Authors and Affiliations

Department of Clinical and Chemical Pathology, Faculty of Medicine, Cairo University Cairo, Hosny Othman Sefrat District, Nasr City, Cairo, Egypt

Mai Ali Sayed Abd El Ghaney

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Mai Ali Sayed Abd El Ghaney: shared in study design, revising the article, and statistical analysis of data, writing the manuscript, and final revision of the version to be published.

All authors have made a significant contribution to this manuscript, have seen and approved the final manuscript, and have agreed to its submission.

Yomna Ahmed Hosni: shared in study design, critical revision of the article, interpretation of data, statistical analysis, drafting and writing a manuscript, and final revision of the version to be published.

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Correspondence to Mai Ali Sayed Abd El Ghaney .

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Ethical approval and Consent of patient

The study protocol was approved by the Ethical committee and complied with the Declaration of Helsinki. Patients were screened for their eligibility to participate in the study and informed consent was obtained.

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Importance and reason of publication

Diabetes mellitus is a chronic complex metabolic disease in children requiring continuous medical care to decrease the possibility of lifelong complications. The initial presentation of diabetes is usually in the form of polyuria, polydipsia, enuresis, weight loss, or polyphagia. In addition, diabetes may present in its most critical form, ketosis or non-ketotic hyperosmolar syndrome. Unfortunately, this may lead to stupor, coma, and death if not promptly treated.

Diabetic ketoacidosis (DKA) is the presentation of more than half of the patients with type 1 diabetes mellitus (T1DM). DKA results in a rise of the proinflammatory markers, and oxidative stress and subsequently increases morbidity and mortality risk. Patients with type 1 diabetes are 25% more prone to develop autoimmune diseases. The most common are autoimmune thyroid disease, celiac disease, and primary adrenal insufficiency.

Many risk factors behind DKA in newly diagnosed individuals with T1DM as the absence of a family history of T1DM, low socioeconomic class younger age, and delayed diagnosis. On the contrary, DKA can occur in known diabetic patients due to several causes such as poor compliance to insulin intake, infection, dysfunction of the insulin pump, and dehydration.

Acute physical insult to the body, for example, febrile illness, poses a threat to survival and well-being. That initiates a physiological response to maintain homeostasis together with complex interactions between the immune and autonomic nervous systems. This activates the hypothalamic–pituitary–adrenal axis leading to the production of cortisol. An increase in the cortisol level occurs as a result of illness and stress to adjust the tone of the blood vessels, cardiac function, and the immune response.

Several studies have shown a positive correlation between serum total cortisol and the severity of critical illness as well as the risk of death. So, this study aimed to measure serum cortisol levels during DKA as significant predictors of DKA duration & to assess the time to recovery from (DKA) between children newly diagnosed with diabetes compared with known diabetics.

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Abd El Ghaney, M.A.S., Hosni, Y.A. Basal serum cortisol levels; significant predictors to DKA duration. Int J Diabetes Dev Ctries (2024). https://doi.org/10.1007/s13410-024-01392-8

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Received : 23 February 2024

Accepted : 21 August 2024

Published : 10 September 2024

DOI : https://doi.org/10.1007/s13410-024-01392-8

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