Diabetes mellitus type 2

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Seyedmahdi Pahlavani, M.D. [2],Tarek Nafee, M.D. [3],Basir Gill, M.B.B.S, M.D.[4]

Diabetes mellitus type 2 (T2DM) (formerly called non insulin-dependent diabetes (NIDDM), obesity related diabetes, or adult-onset diabetes) is a metabolic disorder that is primarily characterized by insulin resistance, relative insulin deficiency, and hyperglycemia. The defective responsiveness of body tissues to insulin almost certainly involves the insulin receptor in cell membranes. In the early stage the predominant abnormality is reduced insulin sensitivity, characterized by elevated levels of insulin in the blood. At this stage hyperglycemia can be managed by engaging in exercise, modifying one’s diet and medications that improve insulin sensitivity or reduce glucose production by the liver. As the disease progresses the impairment of insulin secretion worsens, and therapeutic replacement of insulin often becomes necessary. It is rapidly increasing in the developed world, and there is some evidence that this pattern will be followed in much of the rest of the world in coming years. The CDC has characterized the increase as an epidemic.

Historical Perspective

Diabetes mellitus is a well-recognized disease from ancient times. In 1812 diabetes mellitus became a recognized clinical entity in The New England Journal of Medicine and Surgery. In 1889, the pancreas was identified as playing a major role in the pathogenesis of the disease. The discovery of insulin in 1921 was a major turning point in the history of diabetes when Frederick Banting and Charles Best were able to reverse the diabetic state in dogs by injecting the pancreatic isolate from healthy dogs.

Type 2 diabetes doesn’t have any specific classification. Although diabetes mellitus is classified in to 3 main categories:

• Diabetes mellitus type 1(T1DM)
• Diabetes mellitus type 2(T2DM)
• Gestational diabetes

T2DM develops from a combination of insulin resistance and progressive β‑cell dysfunction. Contrary to T1DM, patients with T2DM sufficiently produce insulin; however, cellular response to the circulating insulin is diminished. The mechanism by which the insulin resistance develops is postulated to be influenced by both genetic and environmental factors. Contributing mechanisms include increased hepatic glucose production, impaired incretin response, elevated renal glucose reabsorption, reduced insulin-mediated glucose uptake in muscle/adipose tissue, and dysregulated glucagon secretion. Over 600 genetic variants are associated with T2DM risk, although lifestyle factors remain dominant. Environmental influences on the pathogenesis of T2DM include high glycemic diets, central obesity, older age, male gender, low-fiber diet, and high saturated fat diet.

The underlying cause of T2DM is insulin resistance. The exact cause of insulin resistance is not known, however several theories exist. Central obesity, aging, and high glycemic diets are most commonly implicated in the development of T2DM.

T2DM must be differentiated from other disorders that can present with polyuria, polydipsia, weight change, or hyperglycemia. These include other forms of diabetes mellitus such as type 1 diabetes, latent autoimmune diabetes in adults (LADA), and monogenic diabetes (MODY)—as well as secondary causes like pancreatic disease and endocrine disorders including hypothyroidism, Cushing syndrome, Wolfram syndrome, and Alström syndrome. Several medications, particularly glucocorticoids and immunotherapies, may also induce hyperglycemia. Distinguishing these conditions relies on careful clinical evaluation alongside targeted testing: autoantibodies (GAD, IA-2, ZnT8) help identify autoimmune forms, while C-peptide levels assess endogenous insulin production. MODY should be considered in lean young adults with a strong autosomal dominant family history.

T2DM must be differentiated from other disorders that may present with polyuria, polydipsia, weight loss or weight gain. Such disorders may include other forms of diabetes mellitus (e.g.T1DM, MODY) or other endocrine disorders (e.g. hypothyroidism, cushing’s syndrome, wolfram syndrome, alstrom syndrome) or drug that can cause hyperglycemia (e.g. glucocorticoids)

Type 2 diabetes mellitus T2DM (DM) is a chronic metabolic disease, accounting for 90–95% of all diabetes cases. Although its prevalence is well studied in the United States and other developed nations, global estimates from 2022–2024 indicate that between 589 and 828 million adults are living with diabetes worldwide, with an overall prevalence of 11–14% of adults. Despite this burden, substantial variation exists across developing countries, particularly in rural regions with limited access to healthcare, where an estimated 50% of adults with diabetes remain undiagnosed. In the United States, T2DM affects roughly 1 in 6 adults and disproportionately affects individuals with overweight/obesity, physical inactivity, older age, family history of diabetes, history of gestational diabetes, and certain ethnic groups, including Hispanic/Latino, Asian, Black, and American Indian populations. Prevalence increases sharply after age 65, though childhood-onset T2DM is rising. Interestingly, the prevalence of type 2 diabetes is 39.2%among patients with kidney failure. Globally, men are more commonly affected than women, and low- to middle-income countries carry the highest burden. The continued rise in T2DM parallels rapid urbanization and lifestyle transitions, underscoring its designation as a global epidemic.

Common risk factors associated with development of T2DM include: positive family history, certain ethnicity, obesity, smoking, physical inactivity, poor dietary habits, certain drugs (.eg. glucocorticoids) and certain medical conditions that may result in weight gain and inactivity.

Diabetes screening is recommended for many people at various stages of life, and for those with any of several risk factors. Screening tests are the same tests used for diagnosis. Early diagnosis and treatment can control the complications and result in better clinical outcomes.

Criteria for testing for diabetes or prediabetes in asymptomatic adults
Testing should be considered in overweight or obese (BMI ≥25 kg/m2 or ≥23 kg/m2 in Asian Americans) adults who have one or more of the following risk factors: A1C  ≥5.7% (39 mmol/mol), IGT (Impaired Glucose Tolerance), or IFG (Impaired Fasting Glucose) on previous testing First-degree relative with diabetes (every 1-3 years) High-risk race/ethnicity (e.g., African American, Latino, Native American, Asian American, Pacific Islander) Women who were diagnosed with GDM (Gestational DM) History of CVD Hypertension ( ≥140/90 mmHg or on therapy for hypertension) HDL cholesterol level <35 mg/dL (0.90 mmol/L) and/or a triglyceride level >250 mg/dL (2.82 mmol/L) Women with polycystic ovary syndrome Physical inactivity Other clinical conditions associated with insulin resistance (e.g., severe obesity, acanthosis nigricans).
For all patients, testing should begin at age 35 years.
If results are normal, testing should be repeated at a minimum of 3-year intervals, with consideration of more frequent testing depending on initial results (e.g., those with prediabetes should be tested yearly) and risk status.

If T2DM left untreated, it may result in hyperosmolar hyperglycemic state (HHS) and in rare circumstances diabetic ketoacidosis (DKA). These are classified as acute complications of diabetes. Chronic complications of diabetes mellitus include microvascular (retinopathy, nephropathy, neuropathy) and macrovascular (myocardial infarction, stroke, cardiovascular death) complications. Updated estimates show that 32% of individuals with T2DM have existing cardiovascular disease. Diabetes is a leading cause of kidney failure, blindness, nontraumatic amputations, and increased mortality. Additional associations include metabolic dysfunction–associated steatotic liver disease (MASLD), colorectal and breast cancers, and dementia. Early diagnosis and prompt treatment of these complications may result in improved prognosis and less long term morbidity and mortalities.

A detailed history must be taken from every person presenting with diabetes symptoms. Classic symptoms of diabetes include: weight loss, polyphagia, polydipsia and polyuria. Less common symptoms include vision changes, tingling or numbness in exterimities, fatigue and skin changes.

Usually patients with T2DM have normal physical examination findings unless complications develop in these patients. Common physical examination findings include, pigmented skin patches and acanthosis nigricans.

Laboratory findings of T2DM are diagnostic for this disease. Diabetes may be diagnosed based on plasma glucose criteria, either the fasting plasma glucose (FPG) or the 2-hours plasma glucose (2-h PG) value after a 75-g oral glucose tolerance test (OGTT) or A1C criteria. A1c remains the preferred test for most adults, but clinicians should recognize its limitations in conditions such as anemia, hemoglobinopathies, pregnancy, transfusion, dialysis, or altered red cell turnover.

Criteria for the diagnosis of diabetes
FPG ≥126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at least 8 hours.
OR
2-hours Plasma Glucose (PG) ≥200 mg/dL (11.1 mmol/L) during an OGTT. The test should be performed as described by the WHO, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water.
OR
A1C ≥6.5% (48 mmol/mol).
OR
In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose ≥200 mg/dL (11.1 mmol/L).

Lifestyle modification is fundamental for diabetes management and it’s a part of therapy. It includes, diabetes self-management education (DSME), diabetes self-management support (DSMS), nutrition therapy, physical activity, smoking cessation counseling, and psychosocial care. Randomized clinical trials have reported absolute reductions in microvascular disease (3.5%), such as retinopathy and nephropathy, myocardial infarction (3.3%-6.2%), and mortality (2.7%-4.9%), with intensive glucose-lowering strategies (hemoglobin A1C <7%) vs conventional treatment 2 decades after trial completion. The overall objectives of DSME and DSMS are to support informed decision making, self-care behaviors, problem solving, and active collaboration with the health care team to improve clinical outcomes, health status, and quality of life in a cost-effective manner.

Self‑monitoring of blood glucose (SMBG) provides modest benefit in non‑insulin‑treated T2DM but remains essential for individuals on insulin. Continuous glucose monitoring (CGM) improves HbA1c, reduces hypoglycemia, and increases time‑in‑range. Adults with T2DM on basal‑bolus insulin should be offered CGM. Time‑in‑range goal: >70% between 70–180 mg/dL.

Lifestyle modification remains foundational. Clinically meaningful HbA1c reductions occur with Mediterranean, DASH, and low‑carbohydrate dietary patterns. Structured medical nutrition therapy and diabetes self‑management education improve glycemic control. Physical activity targets include ≥150 minutes/week of moderate intensity activity, with evidence showing 0.4–1.0% HbA1c reduction and improves cardiovascular risk factors (i.e., hypertension and dyslipidemia). Weight loss of ≥5–10% improves glycemia, and intensive weight‑loss interventions can induce diabetes remission in select patients.

The main goals of treatment are, eliminate hyperglycemic symptoms, control the long term complications and improve the patient’s quality of life. T2DM is initially treated by lifestyle modification and weight loss, especially in obese patients. Metformin is the first line pharmacologic therapy prescribed once the diagnosis is confirmed unless contraindications exist. If glycemic goals are not achieved, a second agent must be added to metformin. A wide range of options are available to add as combination therapy based on the patient’s condition and comorbidities. DPP‑4 inhibitors, sulfonylureas, and thiazolidinediones remain options but lack cardiorenal benefits and carry class‑specific risks.

Metformin monotherapy is recommended unless there is a contraindication to it. In the following conditions, dual therapy is initiated:

• HbA1C greater than 9 commence dual oral blood glucose lowering agent.
• HbA1C greater than 10 OR blood glucose level greater than 300 mg/dl OR a markedly symptomatic patient; consider combination therapy with insulin.
• . For individuals with T2DM and established ASCVD, heart failure, or chronic kidney disease, guidelines recommend early initiation of SGLT2 inhibitors and/or GLP‑1 receptor agonists—independent of Hb_A1c.

High‑potency GLP‑1RA and dual GIP/GLP‑1 agonists (e.g., semaglutide, tirzepatide) achieve A1c reductions up to ~2.5% and weight loss >5–10%. Large, randomized trials show SGLT2 inhibitors reduce major adverse cardiovascular events (MACE) by ~10%, heart failure hospitalization by 18–25%, and kidney disease progression by 24–39%. GLP‑1 receptor agonists reduce MACE by 12–26% and promote significant weight loss. These benefits support a comorbidity driven instead of purely HbA1c‑driven therapeutic approach.

Pancreas and islet cell transplantation is considered in patients with chronic diabetes who have frequent metabolic complications and are intolerant to exogenous insulin or have failed insulin therapy.

Life style modification is the mainstay for diabetes mellitus prevention. Metformin is another adjunctive measure to prevent diabetes in high risk persons. Studies have shown that 7% weight loss within a duration of 6 months in obese individuals is effective for diabetes prevention.

The most important secondary prevention strategy in T2DM is to decrease the macrovascular complications. Lipid control, smoking cessation and treatment of hypertension are the most important secondary preventive measures.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dima Nimri, M.D. [2]; Tarek Nafee, M.D. [3],Seyedmahdi Pahlavani, M.D. [4]

Diabetes mellitus is a well-recognized disease from ancient times. In 1812 diabetes mellitus became a recognized clinical entity in The New England Journal of Medicine and Surgery. In 1889, the pancreas was identified as playing a major role in the pathogenesis of the disease. The discovery of insulin in 1921 was a major turning point in the history of diabetes when Frederick Banting and Charles Best were able to reverse the diabetic state in dogs by injecting the pancreatic isolate from healthy dogs.

Diabetes mellitus is a well-recognized disease from ancient times, but the major advancement in the disease was the isolation of insulin and its use in treatment. The historical perspective of diabetes mellitus can be summarized in the following points:^[1]

• Around 1500 B.C., diabetes mellitus was a condition first recognized by the Egyptians. They noted that the affected person had urinary frequency, as well as weight loss.

• The Greek physician Areatus was the first to come up with the term diabetes mellitus, which refers to the fact that urine has a sweet taste. However, it was not until 1776 that the concentration of glucose in urine was measured in such patients and levels were found to be elevated.
• In 1812, diabetes mellitus became recognized as a clinical entity in The New England Journal of Medicine and Surgery.
• In 1889, scientists suggested that the pancreas plays a major role in the pathogenesis of diabetes mellitus, as removing the pancreas from dogs resulted in fatal diabetes.
• The discovery of insulin in 1921 was a major turning point in the history of diabetes mellitus. Two scientists, Frederick Banting and Charles Best, were able to reverse the diabetic condition in dogs by injecting some of the pancreatic isolate from healthy dogs.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Priyamvada Singh, M.B.B.S. [2]; Cafer Zorkun, M.D., Ph.D. [3],Seyedmahdi Pahlavani, M.D. [4]Anahita Deylamsalehi, M.D.[5]

The exact pathophysiology of type 2 diabetes mellitus is not fully understood. The underlying pathology is the development of insulin resistance. Contrary to type 1 diabetes, patients with type 2 diabetes sufficiently produce insulin. However, the cellular response to the circulating insulin is diminished in type 2 DM. The mechanism by which the insulin resistance develops is postulated to be influenced by both genetic and environmental factors. Environmental influences on the pathogenesis of type 2 DM include high glycemic diets, central obesity, older age, male gender, low-fiber diet, and highly saturated fat diet.There are some genetic variants and HLA related to type 2 diabetes mellitus. Diabetes type 2 is associated with metabolic disorders, sarcopenia and liver cancer. It also has some associated features with insulin resistance. Gross pathology of pancreas shows serrated borders and reduced volume, which is due to pancreatic cells necrosis. Amyloid deposition, inflammation and fibrosis are some of the microscopic changes in diabetic pancreas.

• The development of Insulin resistance is the underlying pathology; the cells in the body do not respond appropriately when insulin is present.

• Other important contributing factors:
  • Increased hepatic glucose production (e.g., from glycogen degradation), especially at inappropriate times.
  • Decreased insulin-mediated glucose transport in (primarily) muscle and adipose tissues (receptor and post-receptor defects).
  • Impaired beta-cell function, loss of early phase of insulin release in response to hyperglycemic stimuli.
  • Cancer survivors who received allogenic Hematopoeitic Cell Transplantation (HCT) are 3.65 times more likely to report type 2 diabetes than their siblings. Total body irradiation (TBI) is also associated with a higher risk of developing diabetes.

• This is a more complex problem than type 1 diabetes, but is sometimes easier to treat, especially in the initial years when insulin is often still being produced internally.
• Type 2 DM may go unnoticed for years in a patient before diagnosis, since the symptoms are typically milder (no ketoacidosis) and can be sporadic. However, severe complications can result from unnoticed type 2 diabetes, including renal failure, blindness, wounds that fail to heal, and coronary artery disease. The onset of the disease is most common in middle age and later life.

• Although primary Diabetes mellitus type 2 is presently of unknown etiology, there are some known etiologies responsible for the secondary diabetes mellitus. These known etiologies are known gene defects, trauma, surgery, hemochromatosis, pancreatic insufficiency, or certain types of medications (e.g. long-term steroid use).
• 23 years follow up in a study showed that enough level of tocopherol has been linked to lower risk of type 2 diabetes development.^[1] Furthermore low level of vitamin E is related to increased risk of diabetes mellitus.^[2] These data are suggestive of the role of dietary antioxidant and decreased risk of diabetes mellitus. Moreover animal models suggested the role of dietary antioxidants in suppressing the beta cell apoptosis due to oxidative stress.^[3]

• Insulin production is more or less constant within the beta cells.

• It is stored within vacuoles pending release, via exocytosis, which is triggered by increased blood glucose levels.

• Insulin is the principal hormone that regulates uptake of glucose from the blood into most cells (primarily muscle and fat cells, but not central nervous system cells). Therefore deficiency of insulin or the insensitivity of its receptors plays a central role in all forms of diabetes mellitus.

• Much of the carbohydrate in food is converted within a few hours to the monosaccharide glucose, the principal carbohydrate found in blood and used by the body as fuel.

• Some carbohydrates are not converted e.g fruit sugar (fructose) is usable as cellular fuel but it is not converted to glucose, and it therefore does not participate in the insulin/glucose metabolic regulatory mechanism.

• Additionally, the carbohydrate cellulose (though it is actually many glucose molecules in long chains) is not converted to glucose, as humans and many animals have no digestive pathway capable of breaking up cellulose.

• Insulin is released into the blood by beta cells (β-cells), found in the Islets of Langerhans in the pancreas, in response to rising levels of blood glucose after eating.

• Insulin is used by about two-thirds of the body’s cells to absorb glucose from the blood for use as fuel, for conversion to other needed molecules, or for storage.

• Insulin is also the principal control signal for conversion of glucose to glycogen for internal storage in liver and muscle cells.

• Lowered glucose levels result both in the reduced release of insulin from the beta cells and in the reverse conversion of glycogen to glucose when glucose levels fall. This is mainly controlled byglucagon which acts in an opposite manner to insulin. Glucose thus recovered by the liver and re-enters the bloodstream; muscle cells lack the necessary export mechanism.

• Higher insulin levels increase some anabolic processes such as cell growth and duplication, protein synthesis, and fat storage. Insulin (or its lack) is the principal signal in converting many of the bidirectional processes of metabolism from a catabolic to an anabolic direction, and vice versa. In particular, a low insulin level is the trigger for entering or leaving ketosis (the fat burning metabolic phase).

• If the amount of insulin available is insufficient, if cells respond poorly to the effects of insulin (insulin insensitivity or resistance), or if the insulin itself is defective, then glucose will not be absorbed properly by those body cells that require it nor will it be stored appropriately in the liver and muscles. The net effect is persistent high levels of blood glucose, poor protein synthesis, and other metabolic derangement, such as acidosis.

• In 1923, when Banting and Bests were awarded the Nobel Prize for insulin discovery, most researchers believed that this had led to a cure for diabetes. However, despite the advances in the blood glucose management, there is no cure for diabetes or for the prevention of its major complications.
• Scientists have observed that people with type 2 diabetes have overly active, and sometimes dysfunctional immune systems, which are linked to some complications. In current times, diabetes is seen as the disease of high blood glucose, or lack of insulin, however chronic inflammatory states and the overabundance of reactive oxygen species (ROS) also play a part in the disease process.^[4].
• Inflammation is part of a healthy immune response, an orchestrated onslaught of cells and chemicals that heal injury and fight infection. Chronic inflammation is a process which occurs throughout the body when a trigger activates the immune system. This inflammation results in the cascade of reactive oxygen species and further damage to tissue. ^{[4] [5]}.
• In 1993, scientists showed that the tumor necrosis factor α (TNF-α) expression was up-regulated in the adipose tissue of obese mice with type 2 diabetes ^[6]. When mice deficient in TNF-α were bred, diabetes did not develop. It appeared that inflammation preceded diabetes, long before diagnosis.

• Leukocytes and innate immunity is the main source of inflammation in humans. In animal species, adipose tissue is the mediator of innate immunity. In insects, adipocytes have a receptor for the cell wall of bacteria and fungi, called toll like receptor. It is responsible for nuclear factor 1 β (NF1β) activation which induces the secretion of antibacterial peptides and other defense mechanisms. This induces the inflammatory cascades. Fat tissue also manages the storage of lipids in the liver ^[7].However some aspects of innate immunity are still preserved in the adipocytes. Moreover adipose tissue is populated with tissue resident macrophages, which is significantly increased by diet induced weight gain ^[8].

• The first theory in regards to fat tissue being the source of inflammation and diabetes, is that there is an overabundance of energy in the form of glucose and lipid in obesity. This leads to mitochondrial dysfunction and reactive oxygen species (ROS) production from the adipocytes. ROS can activate the immunity by inducing the NF1β and hence secretion of the inflammatory cytokines ^[8]. The second theory is the hypoxia theory reported by Trayhurn and Wood ^[9]. The fat cells expand when a person gains weight. These fat cells sometimes do not get enough oxygen. In response to hypoxia; they induce cytokines, which activate the angiogenesis, metabolism and cellular stress. These cytokines induce insulin resistance and hence lead to diabetes.
• The adipose tissue is not usually considered as an immune or inflammatory organ, however these observations provide evidence for the link between obesity and inflammation.

• A growing body of evidence demonstrates that adipose tissue inflammation eventually results in systemic inflammation^[5]. C reactive protein (CRP) is an inflammatory marker produced by the liver in response to TNFα and Interleukin-6.
• CRP has been shown to precede diabetes years before diagnosis. Elevated CRP levels are unquestionably associated with obesity and increased risk of cardiovascular disorders. Patients with a high CRP levels are at a higher mortality risk from heart disease.
• Other inflammatory markers are also disproportionately elevated in diabetes which results into systemic inflammation. The systemic inflammation result into insulin resistance and insulin resistance results into obesity. Hence both diabetes and inflammation reinforce each other via a positive feedback ^[5].

• Variants in 11 genes have been related to type 2 diabetes mellitus development. these genes include:^[10]
  • TCF7L2
  • PPARG,
  • FTO,
  • KCNJ11,
  • NOTCH2,
  • WFS1,
  • CDKAL1,
  • IGF2BP2,
  • SLC30A8,
  • JAZF1,
  • HHEX
• 8 variants of these genes are related to beta cell dysfunction.^[11]
• Carriers of the PPARG P12/P12 and CAPN10 SNP43/44 GG/TT genotypes, who also had obesity and elevated fasting plasma glucose (FPG), showed 21.2 –fold increased risk for type 2 diabetes development.^[12]
• HLA-DR4 or HLA-DR3/DR4 frequency has been increased in diabetes type 2, compared to normal population. Even though these findings were limited to patients with insulin deficiency or islet cell antibodies (ICAs) and/or Glutamic Acid Decarboxylase Antibodies (GADAs).^[13]
• Variable number tandem repeat (VNTR) polymorphism in the promoter region of insulin gene on chromosome 11p15 has been detected in both type 1 and type 2 diabetes mellitus. A follow-up study in a population from the U.K. showed that class III homozygosity was related to higher risk for type 2 diabetes in women, but not in men.^[14][15]

• Diabetes mellitus type 2 is often associated with obesity and hypertension and elevated cholesterol (combined hyperlipidemia), and with the condition Metabolic syndrome. It is also associated with acromegaly, Cushing’s syndrome, Nonalcoholic steatohepatitis(NASH) and a number of other endocrinological disorders.^[16]

• Additional factors found to increase risk of type 2 diabetes include aging^[17], high-fat diets^[18] and a less active lifestyle^[19].
• There is a bidirectional relationship between Diabetes mellitus and sarcopenia. Numerous factors like accumulation of advanced glycation end-product, inflammation, insulin resistance, vascular complications and oxidative injury can interfere with muscle health. This impaired muscle health can eventually lead to type 2 diabetes.^[20]
• Based on a review study using data from years 1990 to 2017, diabetes is linked to higher mortality from primary liver cancers. This study suggests diabetes as a significant risk factor for primary liver cancers.^[21]
• Diabetic patients have higher concentration of bile acid in feeding state, compared to normal population. This change in bile acid level also showed some correlations with higher triglyceride level, insulin resistance index, blood pressure, and BMI.^[22]

• Based on a study, the following pancreatic changes have been reported in patients with type 2 diabetes, compared to the control group: ^[23]
  • 33% reduction in The mean pancreatic volume
  • 23% elevation in triglyceride content
  • Serrated borders
  • Involution of pancreas

• The following pancreatic microscopic changes have been found in diabetes type 2 patients, compared to the normal population: ^[24][25][26]
  • Amyloid deposition
    • Can be detected as a positive congo red deposition of pink, amorphous material in the extracellular matrix.
  • Fibrosis
  • Lipomatosis
  • Apoptotic or necrotic cells
  • Increased numbers of macrophages
  • Increased numbers and activity of mononuclear cells
  • Increased IL-1β mRNA expression

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Seyedmahdi Pahlavani, M.D. [2]

The underlying cause of type 2 diabetes is insulin resistance. The exact cause of insulin resistance is not known, however several theories exist. There is often an interplay of multiple risk factors coupled with the effect of environmental factors in a genetically susceptible person, which results in hyperglycemia and insulin resistance. Central obesity, aging, sedentary life style, high glycemic diets and some medications are most commonly implicated in the development of type 2 diabetes.

• The etiology of type 2 diabetes is multifactorial.^[1] There is often an interplay of multiple risk factors coupled with the effect of environmental factors in a genetically susceptible person, which results in hyperglycemia and insulin resistance. Numerous theories exist as to the exact cause and mechanism in type 2 diabetes.

Common causes of diabetes mellitus type 2 may include:^[2][3]

• Insulin resistance
• Central obesity
  • Predispose individuals to insulin resistance
  • Abdominal fat is especially active hormonally, secreting a group of hormones called adipokines that may possibly impair glucose tolerance
  • Obesity is found in approximately 55% of patients diagnosed with type 2 diabetes
  • In the last decade, type 2 diabetes has increasingly begun to affect children and adolescents, likely in connection with the increased prevalence of childhood obesity
• Positive family history
  • Diabetes mellitus type 2 is much more common in those with close relatives who have type 2 DM

• Aging^[4]
  • About 20% of elderly patients in North America have diabetes
• Hemochromatosis
• Chronic pancreatitis
• Medications
  • Desogestrel and Ethinyl Estradiol
  • Dexamethasone
  • Estropipate
  • goserelin
  • Indinavir
  • interferon alfacon-1
  • Pasireotide
  • Pegylated interferon alfa-2b
  • Pergolide
  • Ritonavir
  • Saquinavir mesylate
  • Tipranavir

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Seyedmahdi Pahlavani, M.D. [2]Basir Gill, M.B.B.S, M.D.[3]

Type 2 diabetes mellitus must be differentiated from other disorders that may present with polyuria, polydipsia, weight loss or weight gain. Such disorders may include other forms of diabetes mellitus (e.g. type 1 DM, MODY), other endocrine disorders (e.g. hypothyroidism, cushing’s syndrome, wolfram syndrome, alstrom syndrome) or drug-related disorders.

• Type 2 DM must be differentiated from other forms of diabetes mellitus as well as other endocrine disorders based on the symptoms and laboratory findings.^[1][2][3] The following table shows the appropriate history and symptoms, and laboratory findings that may distinguish type 2 DM from other diseases:

Disease	History and symptoms					Laboratory findings								Additional findings
	Polyuria	Polydipsia	Polyphagia	Weight loss	Weight gain	Serum glucose	Urinary Glucose	Urine PH	Serum Sodium	Urinary Glucose	24 hrs cortisol level	C-peptide level	Serum glucagon
Type 1 Diabetes mellitus	+	+	+	+	–	↑	↑	Normal	Normal	N/↑	Normal	↓	Normal	Auto-antibodies present (Anti GAD-65 and anti insulin antibodies)
Type 2 Diabetes mellitus	+	+	+	+	–	↑	↑	Normal	Normal	↑	Normal	Normal	↑	Acanthosis nigricans
MODY	+	+	+	–	+	↑	↑	Normal	Normal	↑	Normal	Normal	N	–
Psychogenic polydipsia	+	+	–	–	–	Normal	Normal	Normal	↓	Normal	Normal	Normal	Normal	–
Diabetes insipidus	+	+	–	–	–	Normal	Normal	Normal	↑	Normal	Normal	Normal	Normal	–
Transient hyperglycemia	–	–	–	–	–	↑	↑	Normal	Normal	↑	Normal	Normal	N/↑	In hospitalized patients especially in ICU and CCU
Steroid therapy	+	–	–	–	+	↑	↑	Normal	Normal	↑	↑	N/↑	N/↑	Acanthosis nigricans,
RTA 1	–	–	–	+	–	Normal	Normal	↑	Normal	↑	Normal	Normal	Normal	Hypokalemia, nephrolithiasis
Glucagonoma	–	–	–	–	–	↑	Normal	Normal	Normal	–	Normal	Normal	↑	Necrolytic migratory erythema
Cushing syndrome	–	–	–	–	+	↑	–	Normal	↓	N/↑	↑	Normal	Normal	Moon face, obesity, buffalo hump, easy bruisibility

Category	Type 2 diabetes	Type 1 diabetes	Monogenic diabetes syndromes (ie, MODY)	Types of diabetes secondary to other medical conditions
Epidemiologya	90%-95%	5%-10%	<5%	<5%
Pathophysiology	Nonautoimmune progressive loss of insulin secretion from β cells, usually in the setting of insulin resistance	Autoimmune β-cell destruction, usually leading to absolute or near-absolute insulin deficiency	Rare form of diabetes caused by a variant in a single gene disrupting β-cell glucose sensing or insulin production, inherited in an autosomal dominant manner; the most common forms are GCK-MODY (MODY2; glucose-sensing defect), HNF1A-MODY (MODY3), and HNF4A-MODY (MODY1)	Many different secondary forms of diabetes exist; examples include diseases of the exocrine pancreas (such as cystic fibrosis and pancreatitis), diabetes due to endocrinopathies such as Cushing syndrome or acromegaly, or diabetes secondary to SARS-CoV-2 infection
Age at diagnosis	Usually ≥35 y but increasingly seen in youth and younger adults, especially in the setting of obesity and/or family history	Can occur in adults at any age, often with more indolent onset compared with children (termed latent autoimmune diabetes in adults)	Usually <25 y	Any age
Degree of hyperglycemia on presentation	Usually mild (blood glucose <250 mg/dL) if detected early; however, can be moderate or severe in long-standing undiagnosed diabetes	Usually moderate (blood glucose of 250-600 mg/dL); can be severe (blood glucose >600 mg/dL) in some cases	Mild; usually HbA1c <7.5% at diagnosis	Mild, moderate, or severe
Symptoms	Can be asymptomatic or with symptoms	Usually with catabolic symptoms (polyuria, polydipsia, weight loss); can be asymptomatic in adults	Usually asymptomatic	Can be asymptomatic or with symptoms
BMI	Usually BMI ≥25	Usually BMI <25, but can be diagnosed in those with overweight or obesity	Variable, but obesity usually not present	Any
Family history	Often a first-degree relative with type 2 diabetes, but not always	Sometimes a first-degree relative with type 1 diabetes or other autoimmune disease; 85% have no family history	Autosomal dominant family history, confirmed to be MODY diabetes	Not usually
Diabetic ketoacidosis	Can be seen on presentation in those with severe insulin deficiency or glucotoxicity (termed ketosis-prone type 2 diabetes); euglycemic diabetic ketoacidosis has been described in individuals taking SGLT2i	Ketoacidosis common on presentation in children; variable on presentation in adults	Unlikely	Rare; has been reported with SARS-CoV-2 infection and can occur with severe pancreatitis
Autoantibodies present	Not usually seen, but can be present in up to 10% of individuals, depending on the population	Common, but 5%-10% will not have antibodies present on diagnosis, and levels can wane over time; the following antibodies are often tested: glutamic acid decarboxylase (GAD), islet tyrosine phosphatase–related islet antigen 2 (IA-2), zinc transporter 8 (ZnT8) and/or insulin autoantibodies (IAA)	Unlikely	Unlikely
Race and ethnicity	Any; more common in Asian American and Pacific Islander, Black, Latino, and Native American individuals than White individuals	Any; more common with European ancestry	Any; most described in populations of European ancestry	Any
Genetic testing	Not commercially available	Not commercially available; currently only in research studies	Yes; required for definitive diagnosis	Not commercially available
Duration prior to diagnosis	Long (years)	Short (months)	Long (years; potentially lifelong undiagnosed in mild cases)	Variable
Stimulated C-peptideb	Detectable	Low or undetectable (<200 pmol/L); may be detectable soon after diagnosis or for prolonged duration in adult-onset	Detectable	Variable
Drugs that may exacerbate or contribute to development of diabetes	Long-term glucocorticoids, use of immunosuppressant drugs after organ transplantation (e.g., new-onset diabetes after transplant),c and second-generation antipsychotics such as olanzapine and clozapined	Immune checkpoint inhibitors such as nivolumab and pembrolizumab (for cancer)	None	Antiretroviral therapies (ie, certain protease inhibitors and nucleoside reverse transcriptase inhibitors) in people with HIV; glucocorticoid treatment with active COVID-19
Related comorbidities	See Figure 1 in the Supplement	Other autoimmune conditions	Associated features of a specific MODY type (eg, renal cysts, partial lipodystrophy, maternally inherited deafness, severe insulin resistance in the absence of obesity)	Depends on secondary medical condition
Treatment	Lifestyle change, oral agents, noninsulin injectables, insulin	Insulin	Depends on type; no treatment (GCK-MODY), sulfonylureas (HNF1A-MODY or HNF4A-MODY), sometimes insulin is needed	Variable; depends on secondary medical condition; DPP4i or GLP-1 less preferred in patients with pancreatitis

Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); DPP4i, DPP-4 inhibitor; GLP-1RA, glucagon-like peptide-1 receptor agonist; MODY, maturity-onset diabetes of the young; SGLT2i, sodium-glucose cotransporter 2 inhibitor.

a The exact prevalence of different types of diabetes may depend on the population; thus, ranges are provided for each type.

b Refer to endocrinologist for testing; usually performed after stimulation with glucagon injection or mixed meal test. A C-peptide measurement (with simultaneous glucose) obtained within 5 hours of eating can replace a formal C-peptide stimulation test for classification.

c Screen with oral glucose tolerance test after immunosuppressive regimen is stable.

d Screen for prediabetes or diabetes at baseline when prescribed these drugs; repeat at 3 months, if clinically indicated, and annually.^[4]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dima Nimri, M.D. [2];Tarek Nafee, M.D. [3],Seyedmahdi Pahlavani, M.D. [4]

The prevalence of type 2 diabetes mellitus (DM) is well studied in the United States and other developed countries. However, worldwide there is a large variation in the results of the population studies in developing countries and particularly in rural areas with poor access to healthcare. For this reason, diabetes is estimated to be undiagnosed in approximately 50% of adults worldwide. In the United States, African Americans, Mexican Americans, American Indians and non-Hispanic blacks are at a higher risk of developing type 2 diabetes compared to non-Hispanic whites. It is more prevalent among those older than 65 years, although there is a growing trend of childhood-onset of the disease. In 2011, 335 million people were estimated to have type 2 diabetes and that number is on a trajectory to reach over 500 million people by 2050. These figures correlate with a prevalence of approximately 5000 and 7500 per 100,000 in 2011 and 2050, respectively. Type 2 diabetes is more prevalent among men than women and in countries with low to mid income levels compared to high income level countries. It is classified as a global epidemic that is growing in parallel to massive urbanization.

• In the United States, approximately 4100 people are diagnosed with diabetes. 90-95% of these are type 2 diabetes diagnoses.^[1]

• In 2011, about 336 million people had type 2 diabetes mellitus worldwide. This is approximately 5,000 per 100,000.
• The prevalence of diabetes mellitus in the U.S is estimated at 7000 to 9,300 per 100,000^[2]. Approximately 20% of the population over age 65 have type 2 DM.^[3]

• In 2015, diabetes mellitus was the seventh leading cause of death in the United States.
• Based on a cohort study done on 40,286 deaths in patients with type 2 diabetes, middle age white men lost 5 years and middle age white women lost 6 years of life, compared with non-diabetics. Furthermore, this study revealed that South Asians and blacks with diabetes lost 1-2 years of life.^[4]

• The prevalence of type 2 diabetes mellitus is approximately 20% among people older than 65 years old, compared to a prevalence of approximately 5% in the general population.^[3][5]

• In the United States, the prevalence of diabetes mellitus is highest among American Indians and Alaska Natives, followed by non-Hispanic blacks and Mexican Americans. The lowest incidence of diabetes in the United States is among the non-Hispanic whites^[6][2].
• Compared to white diabetics, diabetic South Asians have lower mortality rate due to cardiovascular disorders, cancer and respiratory diseases.^[7]

• Type 2 diabetes mellitus is more prevalent in males than females with a ratio of 1.1:1.^[5]

• The prevalence of type 2 DM is higher among those with low socioeconomic status. Approximately 75% of patients with diabetes live in low to middle income countries.^[3][5]

• The global distribution of diabetes mellitus is reported by the international diabetes foundation (IDF). While prevalence of type 2 diabetes is not specifically reported, they do report that the vast majority of diabetes cases are type 2. Additionally, the IDF reports the prevalence of impaired glucose tolerance which alludes to the prevalence of diagnosed and undiagnosed diabetes.^[3][5]

Region	Prevalence of Diabetes (per 100,000)	Prevalence of Impaired Glucose Tolerance (per 100,000)	Maps
Africa	3200	7900
Europe	9100	4800
Middle East and North Africa	9100	7800
North America and Caribbean	12900	15000
South and Central America	9400	7900
Southeast Asia	8500	4600
Western Pacific	9300	6200

• Images are courtsey of The International Diabetes Federation. IDF Diabetes, 7 ed. Brussels, Belgium: International Diabetes Federation, 2015. http://www.diabetesatlas.org

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Seyedmahdi Pahlavani, M.D. [2]Anahita Deylamsalehi, M.D.[3]Template:Dima Nimri

Common risk factors in the development of diabetes mellitus type 2 include family history, obesity, aging, smoking and sedentary life style.

• Common risk factors in the development of diabetes type 2 include:^{[1][2][3][4][5][6][7][8][9][10][11][12][13][14][11][15][16][17][18][19][20][21]}
  • Family history
    • People with a first degree relative with diabetes mellitus type 2 have a 2-3 fold increased risk of developing diabetes mellitus type 2
    • Positive family history of diabetes mellitus type 2 in parents increases the risk by 5-6 folds.
  • Aging
  • Older age at menarche
  • Ethnicity
    • Prevalence of diabetes mellitus type 2 is high among American Indians, Alaska natives, non-Hispanic blacks and Mexican Americans.
  • Obesity
    • High incidence of impaired glucose tolerance and diabetes mellitus type 2 have been reported mores in patients with increased body weight and a higher BMI.
    • Increased waist circumference or an increased waist-to-hip ratio, increase the risk of diabetes mellitus type 2.
    • Decreased hip circumference is related to higher chance of diabetes type 2 development.
  • Smoking
    • Lower insulin sensitivity and higher blood glucose level has been found in smokers.
    • Result of a cross-sectional study using data from National Health and Nutrition Examination Survey, from 2005 to 2014, showed opposing data, demonstrated lower oral glucose tolerance test (OGTT) in smokers. Furthermore this study showed higher level of triglyceride and LDL-cholesterol and lower level of HDL in smokers.
  • Sedentary life style
    • Sedentary life style and low physical activity even without weight gain, is associated with an increased risk of diabetes mellitus type 2.
    • Habits such as long hours of television watching have been reported as risk factors of diabetes mellitus type 2.
  • Dietary habits
    • Western diet consists of processed red meat, high fat dairy products, sugar and sweets (as in sugar-sweetened beverages)
    • Mediterranean diet rich in fruits, vegetables and whole grains are associated with lower risk of diabetes mellitus type 2.
    • Higher coffee consumption is associated with a lower risk of diabetes mellitus type 2 (lowest among people who consume more than 6 cups per day).
    • Low intake if heme iron also increases the risk of diabetes mellitus type 2.
    • Moderate alcohol consumption is associated with lower risk of diabetes mellitus type 2.
  • Meditations:
    • Desogestrel and Ethinyl Estradiol
    • Dexamethasone
    • Estropipate
    • goserelin
    • Indinavir
    • interferon alfacon-1
    • Pasireotide
    • Pegylated interferon alfa-2b
    • Pergolide
    • Ritonavir
    • Saquinavir mesylate
    • Tipranavir
  • Medical conditions:
    • Gestational diabetes
    • High systolic blood pressure,
    • Metabolic syndrome
    • Preterm birth

• Less common risk factors in the development of diabetes mellitus type 2 include:^[22][23][24]
  • Air pollution and Particulate Matter (PM10)
  • A follow-up study in a population from the U.K. showed that class III homozygosity of insulin gene was related to higher risk for type 2 diabetes in women, but not in men.
  • Biomarkers:
    • Elevation in the following biomarkers are related to higher chance of diabetes type 2:
      • Alanine transaminase (ALT)
      • Gamma-glutamyl transferase (GGT)
      • Uric acid
      • C-reactive protein (CRP)
    • Reduction in the following biomarkers are related to higher chance of diabetes type 2:
      • Adiponectin
      • Vitamin D
  • SARS-CoV-2 (a subtype of coronavirus that causes coronavirus disease 2019)

• Overweight
  • Defined as BMI>85th percentile or weight for height >85th percentile, or weight >120% of ideal for height.
• Obesity
• Family history of type 2 diabetes in first or second degree relative
• Ethnicity
  • Prevalence of diabetes mellitus type 2 is high among American Indians, Alaska natives, non-Hispanic blacks and Mexican Americans.
• Signs of insulin resistance (or associated conditions) such as acanthosis nigricans, hypertension, dyslipidemia, polycystic ovary syndrome or small-for-gestational age birth weight.
• Maternal history of diabetes or GDM during the child’s gestation^[25]

• A systematic review of HbA1c levels with future risk of developing diabetes by Zhang et al.^[26] showed that the risk of diabetes increased steeply in patients with HbA1c levels across the range between 5 and 6.5%. It seems to be a better predictor of diabetes and cardiovascular outcomes than the fasting blood glucose test.
• The results of this study is tabulated below:

HbA1c	5 year DM incidence rate
≤ 5%	Around 0.1%
5.5 to 6%	Between 9 to 25%
6 to 6.5%	25 to 50%

• Also patients with HbA1c‘s more than 6% had a relative risk 20 times higher compared to those in lower HbA1c group (≤5%). Hence, the patients with HbA1c levels in the prediabetic range should be counselled about lifestyle modifications and weight reduction strategies in order to lower their risk. This should be followed with vigilant follow up visits and close scrutiny, particularly in high risk patients.

• Various hereditary conditions may feature diabetes, for example myotonic dystrophy and Friedreich’s ataxia and Wolfram’s syndrome.
• Wolfram’s syndrome is an autosomal recessive neurodegenerative disorder that first becomes evident in childhood. It consists of diabetes insipidus, diabetes mellitus, optic atrophy, and deafness, hence the acronym DIDMOAD.^[27]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Seyedmahdi Pahlavani, M.D. [2]

Diabetes screening is recommended for many people at various stages of life, and for those with risk factors. Screening tests are the same tests used for diagnosis. American Diabetes Association recommends screening starting at the age of 45 years in patients with risk factors. Moreover, there are screening strategies for women with history of gestational diabetes, in order to address higher chance of type 2 diabetes development in this specific population. Early diagnosis and treatment can control the complications and result in better clinical outcomes.

• Screening is recommended for persons at risk of developing diabetes, starting at the age 45 years.

The ADA updated their screening recommendations in 2022^[1].

ADA criteria for testing for diabetes or prediabetes in asymptomatic adults[1]

2.7 Screening for prediabetes and type 2 diabetes with an informal assessment of risk factors or validated risk calculator should be done in asymptomatic adults. B 2.8 Testing for prediabetes and/or type 2 diabetes in asymptomatic people should be considered in adults of any age with overweight or obesity (BMI ≥25 kg/m2 or ≥23 kg/m2 in Asian Americans) who have one or more risk factors (Table 2.3). B 2.9 For all people, screening should begin at age 35 years. B 2.10 If tests are normal, repeat screening recommended at a minimum of 3-year intervals is reasonable, sooner with symptoms or change in risk (i.e., weight gain). C 2.11 To screen for prediabetes and type 2 diabetes, fasting plasma glucose, 2-h plasma glucose during 75-g oral glucose tolerance test, and A1C are each appropriate

It has been estimated that 15-50% of gestational diabetes mellitus-diagnosed mothers will go on to develop T2DM postpartum.^{[2][3][4][5][6]} Consequently, ACOG guidelines currently recommend the following screening methods for T2DM detection:

• 75g 2-hr oral glucose tolerance test (OGTT)

OR

• Fasting plasma glucose at 6-12 weeks postpartum

Data has been presented that estimates only 34% of women with IGT or type 2 diabetes had impaired fasting glucose and that 44% of those with type 2 diabetes had fasting levels 100 mg/day (5.5 mmol/l) during their postpartum visit. Given this risk, it has been suggested by this symposium in conjunction with the ADA that regardless of the 6-12 week screening result, GDM-diagnosed mothers ought to undergo the following screening strategy^[7][8]:

• Post-delivery (1–3 days): Fasting or random plasma glucose
• Early postpartum (6-12 weeks postpartum): 75-g 2-h OGTT
• 1 year postpartum: 75-g 2-h OGTT
• Annually: Fasting plasma glucose
• Tri-annually: 75-g 2-h OGTT
• Prepregnancy: 75-g 2-h OGTT

• Following the publication of the USPSTF statement, a randomized controlled trial was done and acarbose was prescribed to patients in the “high-risk population” between the ages of 40 and 70 years, whose body mass index (calculated as weight in kilograms divided by the square of height in meters) fell between 25 and 40 kg/m². They were eligible for the study if they had IGT according to the World Health Organization criteria, plus impaired fasting glucose (a fasting plasma glucose concentration of between 100 and 140 mg/dL or 5.5 and 7.8 mmol/L). The trial revealed a number needed to treat of 44 (over 3.3 years) to prevent a major cardiovascular event^[9].

• Other studies have shown that life-style changes^[10] and metformin^[11] can delay the onset of diabetes.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Seyedmahdi Pahlavani, M.D. [2]Anahita Deylamsalehi, M.D.[3] Fatemeh Dehghani Firouzabadi, MD [4] Javaria Anwer M.D.[5]

If diabetes mellitus type 2 is left untreated, it may result in hyperosmolar hyperglycemic state (HHS) and in rare circumstances, diabetic ketoacidosis (DKA). These are classified as acute complications of diabetes. Chronic complications of diabetes mellitus include microvascular and macrovascular complications. Early diagnosis and prompt treatment of these complications may result in improved prognosis and less long term morbidity and mortality.

• Type 2 diabetes may go unnoticed for years because symptoms are typically mild, non-existent or sporadic, and usually there are no ketoacidotic episodes. However, severe long-term complications can result from unnoticed type 2 diabetes, including renal failure due to diabetic nephropathy, vascular disease (including coronary artery disease), visual changes due to diabetic retinopathy, loss of sensation or pain due to diabetic neuropathy, and liver damage from non-alcoholic steatohepatitis secondary to metabolic syndrome.
• Untreated DM type 2 may also result in acute complications such as hyperosmolar hyperglycemic state (HHS) and in rare circumstances, diabetic ketoacidosis (DKA).

• Complications of diabetes mellitus type 2 are divided in to 2 major groups:^{[1] [2][3][4][5]}

• Acute complications include diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS).
• These complications are seen in type 2 diabetes but HHS is more common and usually is seen in old age with limited therapeutic resources.

• The following table summarizes the chronic complications of diabetes.^[6][7][8][9]

Chronic complications of Diabetes Type Organ system Compliaction Microvascular complications Eye Retinopathy (nonproliferative/proliferative) Macular edema Nervous system Sensory and motor neuropathy (mono and polyneuropathy) Autonomic neuropathy Kidneys Nephropathy (albuminuria and declining renal function) Macrovascular complications Coronary and vascular Coronary heart disease Peripheral arterial disease CNS Cerebrovascular disease Others Gastrointestinal (GI) Gastroparesis Diarrhea Fatty liver disease Genitourinary Uropathy Sexual dysfunction HEENT Hearing loss Periodontal disease Skin Pigmented pretibial patches Eye Cataracts Glaucoma CNS Depression Cognitive impairment Dementia[10]

• Unlike Type 1 diabetes, there is little tendency toward ketoacidosis in Type 2 diabetes, though it is not unknown. One effect that can occur is non ketotic hyperglycemia. Complex and multi-factorial metabolic changes lead to damage and function impairment of many organs, most importantly the cardiovascular system in both types. This leads to substantially increased morbidity and mortality in both Type 1 and Type 2 patients, but the two have quite different origins and treatments despite the similarity in complications.
• Type 2 diabetes has been related to reduction in verbal fluency and memory in a period of ~ 5 years. Furthermore, type 2 diabetes is related to earlier onset of dementia. Ten years follow up of diabetic patients in their midlife demonstrated rapid decline in global cognitive function, executive function and processing speed compared to normal population. Diabetic patients have higher chance of earlier onset of brain atrophy, included hippocampal and medial temporal atrophy.^[11]

• People with diabetes are more prone to heart and blood vessel disease. Diabetes carries an increased risk for heart attack, stroke, and complications related to poor circulation.^[12]
• Diabetic patients are more vulnerable to atherosclerosis, compared to normal population. They also have higher chance of severe heart failure development due to diabetic cardiomyopathy.^[13][14]
• 2 out of 3 people with diabetes die from heart disease or stroke.
• Diabetes management is more than control of blood glucose. People with diabetes must also manage blood pressure and cholesterol and talk to their healthcare provider to learn about other ways to reduce their chances for heart attacks and stroke. Lifestyle changes, such as healthy diet and being physically active, as well as taking medication can help. Many people find that changing what they eat can make a big difference in their blood glucose, blood pressure, and cholesterol levels.
• There is no need to perform screening exercise stress testing in asymptomatic diabetic patients and annual assessment for blood pressure, fasting lipid profile and smoking history is recommended for all patients.
• Diabetic patients have higher carotid intima-media thickness (CIMT), heart rate and QTc interval compared to normal population. Furthermore, investigations demonstrated lower flow-mediated dilatation (FMD) at the brachial artery and higher prevalence of left ventricle hypertrophy and diastolic dysfunction in diabetic patients.^[15]
• There are some data suggesting how diabetes mellitus can lead to cardiac complications. One of them suggests that high blood glucose can increase circulating fatty acids and subsequently activates cardiomyocyte’s PPARα. The augmented PPARα activity will increase fatty acid oxidation, which ultimately decreases cardiac fatty acid oxidation capacity. Reduction in cardiac fatty acid oxidation capacity causes intramyocardial lipid accumulation and ensuing cardiomyocyte lipotoxicity. Another explanation is pyruvate dehydrogenase inhibition due to PDK4 induction, fatty acid and ketone bodies, which result in glycolytic intermediates accumulation in a diabetic heart.^[16]

• South Asian population are more prone to develop diabetic nephropathy, compared to the Caucasian population.^[17]
• In a study done in China, 21.3% of diabetic patients developed chronic kidney disease.^[18]
• There are some data suggesting that there is a faster rate of renal function deterioration in diabetic kidney disease (DKD) or diabetic kidney disease (DKD) superimposed on nondiabetic renal disease (NDRD), compared to nondiabetic renal disease.^[19]
• There is a possible relationship between polymorphisms within the Carnosine Dipeptidase 1 (CNDP1) gene and diabetic nephropathy development.^[20]

• Diabetes can damage the filtering ability of kidneys. High levels of blood sugar make the kidneys filter too much blood. All this extra work is hard on the filters. After many years, they start to leak. Useful protein is lost in the urine. Having small amounts of protein in the urine is called microalbuminuria. When kidney disease is diagnosed early, (during microalbuminuria), several treatments may keep kidney disease from getting worse. Having larger amounts is called macroalbuminuria. When kidney disease is caught later (during macroalbuminuria), end-stage renal disease (ESRD) usually follows. In time, the stress of overwork causes the kidneys to lose their filtering ability. Waste products then start to build up in the blood. Finally, the kidneys fail. This failure, ESRD, is very serious. A person with ESRD needs to have a kidney transplant or to have the blood filtered by machine (dialysis). Diabetic kidney disease can be prevented by keeping blood sugar in the target range.
• A study done on Chinese population found an association between elevated tyrosine level and increased likelihood of diabetic nephropathy.^[21]
• There are some data that support uNCR (urinary neutrophil gelatinase-associated lipocalin (uNGAL)/Cr ratio) as a possible diagnostic tool for suspected diabetic kidney disease or in patients that required confirmatory kidney biopsy. Based on these data, diabetic patients with uNCR ratio more than 60.685 ng/mg has 7.595 times higher probability of nephrotic-range proteinuria compared to the group with uNCR≤60.685 ng/mg.^[22]

• People with diabetes are 40% more likely to suffer from glaucoma than people without diabetes.^[23]
• The duration of diabetes is directly related to higher risk of glaucoma development. Thus risk also increases with age. Glaucoma occurs when pressure builds up in the eye, and vision is gradually lost because the retina and nerve are damaged.
• Many people without diabetes get cataracts, but people with diabetes are 60% more likely to develop this eye condition. People with diabetes also tend to get cataracts at a younger age and have them progress faster.^[8] With cataracts, there is clouding of the clear lens of the eye, which blocks light.
• Diabetic retinopathy is a general term for all disorders of the retina caused by diabetes. In nonproliferative retinopathy, capillaries in the back of the eye balloon and form pouches. Nonproliferative retinopathy can move through three stages (mild, moderate, and severe), as more and more blood vessels become blocked. In some people, retinopathy progresses after several years to a more serious form, called proliferative retinopathy which can lead to blindness caused by retinal detachment. People who keep their blood sugar levels closer to normal are less likely to have retinopathy or have milder forms.^[24]
• A study done on hospitalized diabetic patients showed that rapid HbA1c reduction is related to higher chance of proliferative retinopathy, while gradual decrease is safe.^[25]
• A cross-sectional study demonstrated a positive association between retinopathy development and myostatin level in diabetic patients.^[26]
• Prevention of severe hypoglycemia, smoking cessation and maintaining renal function have been introduced as factors that prevent visual loss in diabetic patients.^[27]
• Apoptosis of retinal pigmented epithelial cells (RPEs) is one of the possible mechanisms of diabetic retinopathy development. A molecule named miR-203a-3p has been recognized as an important regulator of CoCl2-induced RPEs apoptosis. Deregulation of this molecule may serve as a path for limiting diabetic retinopathy.^[28]
• Recommendations for ophthalmologic screening is at the time of diagnosis and then yearly in the presence of retinopathy. Otherwise, ophthalmologic examinations can be done every 2 years if there is no sign of retinopathy.^[1]

• One of the most common complications of diabetes is diabetic neuropathy. Neuropathy means damage to the nerves that run throughout the body, connecting the spinal cord to muscles, skin, blood vessels, and other organs.^[29][9]
• There are two common types of nerve damage. The first is sensorimotor neuropathy, also known as peripheral neuropathy. This can cause tingling, pain, numbness, or weakness in feet and hands. The second is called autonomic neuropathy. The latter type can lead to:
  • Digestive problems such as feeling full, nausea,
  • Vomiting, diarrhea, or constipation
  • Uropathy
  • Sexual dysfunction
  • Dizziness or faint
  • Loss of the typical warning signs of a heart attack
  • Loss of the warning signs of low blood glucose
  • Increased or decreased sweating
  • Cranial neuropathies

• People with diabetes can also have what is called focal neuropathy. In this kind of nerve damage, a nerve or a group of nerves is affected, causing sudden weakness or pain. It can lead to double vision, a paralysis on one side of the face called Bell’s palsy, or pain in the front of the thigh or other parts of the body.
• People with diabetes also are at risk for compressed nerves. Carpal tunnel syndrome is a common cause of numbness and tingling in the fingers and can lead to muscle pain and weakness as well. Keeping blood glucose levels in the target range can prevent or delay further damage.
• Diabetic patients may experience impairment in the muscle endurance, regardless of neuropathy presence. On the contrary, explosive and maximal muscle strength is related to presence and severity of neuropathic complications in diabetic patients.^[30]

• Although it can hurt, diabetic nerve damage can also lessen the ability to feel pain, heat, and cold. A foot injury may go unnoticed until the skin breaks down and becomes infected.^[31][32]
• Nerve damage can also lead to changes in the shape of feet and toes. Ulcers occur most often on the ball of the foot or on the bottom of the big toe.^[32]
• Neglecting foot ulcers can result in infections, which can eventually lead to limb loss.
• Screening for peripheral vascular disease should be performed by checking the distal pulses.
  Test for sensation should be performed by using:
  • A Semmes-Weinstein 5.07 (10 g) monofilament at specific sites to detect loss of sensation in the foot

• • Vibration using a 128-Hz tuning fork

• • Pinprick sensation
  • Ankle reflexes
• A study done on diabetic patients with foot ulcer showed that piRNA, a factor related to better wound healing, have been elevated in wounds of diabetic who received negative pressure wound treatment(NPWT).^[33]
• A meta-analysis done on 2020 suggested that autologous platelet-rich plasma treatment for diabetic foot ulcer enhances complete wound healing and speeds up the healing process. This study reported that this method doesn’t increase the rate of side effects.^[34]

• Gastroparesis is a disorder affecting patient with both type 1 and type 2 diabetes, defined as delayed gastric emptying in the absence of any obstruction.^[35][36]
• It occurs when gastric nerves are damaged. The vagus nerve controls the movement of food through the digestive tract. If the vagus nerve is damaged, the muscles of the stomach and intestines do not function normally, which leads to stasis of food.^[36]
• Gastroparesis can make diabetes worse by making it more difficult to manage blood glucose level. When gastric emptying has been delayed, intestinal absorption of nutrition will be postponed too, which consequently will cause delay in blood glucose elevation. This can cause a mismatch between insulin or other postprandial anti-diabetic drugs which may present as uncontroled postprandial blood glucose level.^[35]
• The following is a list of some complications related to gastroparesis:^[37]
  • Mallory–Weiss tear from chronic nausea and vomiting
  • Malnutrition
  • Formation of bezoar
    • Food particles can harden into solid masses called bezoars that may cause nausea, vomiting, and GI obstruction in the stomach. Bezoars can be dangerous if they block food passage within the Gastrointestinal tract.
  • Esophagitis
  • Hypovolemia and consequent acute kidney injury
  • Electrolyte disturbances
  • Hyperglycemia emergencies such as diabetic ketoacidosis and hyperosmolar hyperglycemic state
  • If food stays too long in the stomach, it can cause problems like bacterial overgrowth due to food fermentation

• Although intensive therapy improves numerous diabetic complications, it can lead to coma and hypoglycemic related seizure with a relative risk of 3.02.^[38]
• Hypoglycemia could be asymptomatic in some patients, however if symptomatic the symptoms include:^[39]
  • Shakiness and tremor
  • Paresthesia
  • Palpitation
  • Dizziness
  • Sweating
  • Hunger
  • Headache
  • Pale skin
  • Sudden moodiness or behavior changes, such as crying for no apparent reason
  • Anxiety
  • Clumsy or jerky movements
  • Difficulty paying attention, or confusion
  • Tingling sensations around the mouth
  • Cognitive dysfunction, seizure and coma

• Diabetes mellitus, specifically type 2 diabetes has been recognized as one of the most common comorbidities of COVID-19, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). It has been estimated that 20-25% of patients with COVID-19 had diabetes.^[40]
• SARS-CoV-2 infection has been linked with higher rate of hospitalization and mortality in diabetic patients compared to non-diabetics.
• Records from the Centers for Disease Control and Prevention (CDC) and other national health centers and hospitals state that diabetic patients with COVID-19 have up to 50% higher chance of death compared to non diabetics with this infection.^[41]
• Another study done in the US reports more than fourfold mortality rate elevation in COVID-19 in diabetic patients.^[42]
• Study on COVID-19 patients in intensive care unit showed a twofold increase in incidence of diabetes, compared to non-intensive care patients.
• Older age and high C-reactive protein (CPR) level are two risk factors that increase mortality rate in diabetic patients who become infected with SARS-CoV-2. Therefore, A study suggests usage of C-reactive protein (CRP) as a tool to identify patients with higher chance of dying during hospitalization.^[43]
• Sever COVID-19 in diabetic patients were related to higher levels of serum amyloid A (SAA) and low CD4+ T lymphocyte counts.^[44]
• Diabetic patients with SARS-CoV-2 infection have lower levels of the following, compared to non-diabetics:^[45][46]
  • Lymphocytes
  • Red blood cells (RBC)
  • Albumin
  • Hemoglobin

• Diabetic patients with SARS-CoV-2 infection have higher levels of the following, compared to non-diabetics:^[46][45]
  • Neutrophils
  • Erythrocyte sedimentation rate (ESR)
  • D-dimer
  • A-hydroxybutyrate dehydrogenase
  • Lactic dehydrogenase
  • Alanine aminotransferase (ALT)
  • Fibrinogen
  • C reactive protein
  • Ferritin
  • Interleukin-6 (IL-6)

• Some possible factors that lead to more severe COVID-19 in diabetic patient have been summarized in the table below:^[47]

Confirmed factors	hypothesized factors
1- Glycemic instability 2- Immune deficiency (specially T-cell response) 3- Related comorbidities, like obesity and cardiac and renal disease	1- Chronic inflammation (elevated interleukin-6) 2- Elevated plasmin 3- Reduced ACE2 4- Increased furin (involved in virus entry into cell)

• Abnormal production of adipokines and cytokines like Tumor necrosis factor-alpha and interferon in diabetic patients have been associated with impairment in immune system and increased susceptibility to infections.

• Diabetic patients with SARS-CoV-2 infection had higher rate of complications like acute respiratory distress syndrome (ARDS), septic shock, acute kidney injury, acute heart injury, requirement of oxygen inhalation, multi-organ failure and both non-invasive and invasive ventilation (eg, extracorporeal membrane oxygenation (ECMO)). ^[48][49]

• Optimal metabolic control reduce the chance of complications in concurrent diabetes mellitus and COVID-19 in outpatients.

• Evaluation of electrolytes, blood glucose, blood PH, blood ketones or beta-hydroxybutyrate should be considered in patients in intensive care unit (ICU).^[50][51]
• Since hypokalemia is a feature of COVID-19 (possibly as a result of high angiotensin 2 concentration and consequent hyperaldosteronism), potassium level should be checked (especially in concurrent insulin treatment).^[50][51][52]
  • Severe hypokalaemia, which is defined as measures lower than 2∙5 mEq/L, has been related to elevated mortality rate in hospitalized patients.^[53]
• Plasma glucose concentration goal for diabetic outpatients infected with SARS-CoV-2 is 72-144 mg/dl, while plasma glucose concentration of patients in intensive care unit is recommended to be maintained between 72 and 180 mg/dl.^[54][55]
• Treatment with insulin was associated with poor prognosis in diabetic patients with COVID-19.^[56] Although, Insulin is the choice agent to control blood glucose in hospitalized diabetic patients with COVID-19.
• Possible β cell damage caused by SARS-CoV-2 can cause to insulin deficiency, which explain increased insulin requirement in these patients. Due to elevated insulin consumption, intravenous infusion must be considered.^[57]
• Although angiotensin-converting enzyme II (ACE) expression has been reduced in COVID-19, treatment with ACE inhibitors (ACEI) or angiotensin II type-I receptor blockers (ARB) in diabetic patient with hypertension had no significant difference compared to other anti-hypertensive treatments based on one study.^[58] On the other hand, another study done on diabetic patients showed higher risk of SARS-CoV-2 infection with ACE2-increasing drugs. Elevated ACE2 level can ease the entry of virus. Therefore It is hypothesized that medications like, Angiotensin-converting-enzyme inhibitors (ACEI), angiotensin II type-I receptor blockers (ARB), thiazolidinediones and ibuprofen augment the risk of a severe and lethal SARS-CoV-2 infection.^[59]
• Due to increased risk of chronic kidney disease and acute kidney injury, renal function should be monitored in patients who take metformin.^[60] There is also a recommendation to stop Metformin use in a patient with poor oral intake and vomiting.^[61] There are other data that suggest metformin as a possibly helpful anti-diabetic agent in concurrent SARS-CoV-2 infection. Since metformin leads to less elevation in interleukin-6 level, compared to other anti-diabetic agents. These data also assert an association between metformin use and albumin level elevation and a lower COVID-19 related death in patients who took metformin.^[62]
• A hypothesis state that since Sodium glucose cotransporter 2 (SGLT-2) inhibitors decrease lactate production and subsequently increase the cytosolic pH, they interfere with virus entry into the cells.^[63] Conversely, based on another study Sodium glucose cotransporter 2 (SGLT-2) inhibitors are also indirectly responsible for high ACE2 level, which is attributed as a risk factor for SARS-CoV-2 infection. High ACE2 level can be further elevated by concurrent Angiotensin-converting-enzyme inhibitors (ACEI) use.^[64] Current database suggests benefit from discontinuation of Sodium glucose cotransporter 2 (SGLT-2) inhibitors in diabetic patient with COVID-19.^[65]
• Initiation of Sodium-glucose-co-transporter 2 inhibitors should be avoided in respiratory illnesses.^[66]
• Although lactic acidosis due to metformin use and euglycaemic or moderate hyperglycaemic diabetic ketoacidosis associated with Sodium-glucose-co-transporter 2 inhibitors are rare, their usage has not been recommended. Nevertheless, there is no need to stop these medications prophylactically in diabetic patients with no sign of COVID-19.^[67]
• Dipeptidyl peptidase-4 inhibitors has been well tolerated in some diabetic patients with concurrent SARS-CoV-2 infection.^[68] It can be continue in mild to moderate COVID-19, nevertheless it is better to be discontinued in sever cases.^[69]
• Use of thiazolidinediones has been linked with increased fluid retention and congestive heart failure in diabetic patients with SARS-CoV-2 infection.^[70] Pioglitazone use can be continued in mild or moderate COVID-19.^[71]
• Dehydration in diabetic patients with COVID-19 should be avoided. Based on a practical recommendation, medications with possible dehydration side effect like Metformin, Sodium-glucose-co-transporter 2 inhibitors and Glucagon-like peptide-1 receptor agonists should be avoided to prevent further complications.^[72]
• A summary of anti-diabetic medications in diabetic patients with SARS-CoV-2 infection: ^[62][72][64]

Anti-diabetic medication	Relation to ACE2 expression	Advantage	Disadvantage
Metformin	None	Lower level of IL-6 Higher albumin level Lower COVID-19 related death Potential cardiovascular benefits	Higher chance of lactic acidosis and renal dysfunction higher chance of dehydration
Pioglitazone	Increased ACE2 production in animal models	Reduction in proinflammatory cytokines Lower chance of lung injury	Increased chance of SARS-CoV-2 infection due to ACE2 overexpression
Sulfonylurea	None	No specific advantage has been found in patients with COVID-19	Higher chance of hypoglycemia
Dipeptidyl peptidase-4 inhibitors	None	Some anti-inflammatory properties are reported	No specific disadvantage has been found in patients with COVID-19
Sodium-glucose-co-transporter 2 inhibitors	Increased ACE2 production by kidney in human studies	Decreased oxidative stress Anti-inflammatory effects	Higher chance of hypovolemia
Glucagon-like peptide-1 receptor agonists	Liraglutide has been linked with elevated ACE2 production in lung and heart in animal models	Potential cardiovascular benefits	Higher chance of dehydration higher chance of gastrointestinal side effects
Insulin	Increased Renal ACE2 production in animal models	Anti-inflammatory effects	No specific disadvantage has been found in patients with COVID-19

• Diabetes mellitus has been the seventh leading cause of death in the united states in 2015. Based on data reported by CDC, mortality rate has 2 fold increase in diabetic patients compared to non-diabetics at the same age.
• Depending on the extent of the disease, the time of diagnosis and glycemic control, the prognosis may varies.
• Timely diagnosis and prompt treatment with preventive measures will result in good prognosis, conversely delayed diagnosis or inadequate treatment may lead to multiple and severe complications such as limb amputation, blindness, coronary artery disease or renal failure.
• It seems that targeting multiple risk factors is more successful in prognosis improvement, compared to concentrating on one single factor.^[73]
• Based on a Cohort study, cardiac disease and cancer related deaths are the most common etiologies of death in diabetic patients.
• Premature death have been reported due to heart attack, stroke and kidney disease.
• Due to kidney failure, some patients may become dependent on dialysis or need a kidney transplant.
• Hypoglycemia is another worrisome complication in diabetic patients which can be a consequence of over treatment and both the healthcare provider and the patient must be aware of it.
• There are some strong results that state treatment with lipid-lowering agents like statins are able to significantly improve prognosis of diabetic patients with coronary heart disease (CHD).^[74]
• United Kingdom Prospective Diabetes Study (UKPDS), which followed 5000 patients with type 2 diabetes, demonstrated fewer microvascular complications when intense treatment were used. Nevertheless rates of macrovascular disease didn’t change except in obese patients on metformin monotherapy, possibly due to myocardial infarction risk reduction.
• Steno-2 study in Denmark also reported lower rate of cardiovascular disease and related death, end-stage renal disease progression, and need for retinal photo-coagulation in patients who received intensive treatment.^[75]
• It has been estimated that for every 1% of HbA1C elevation, there is a 66% increase in mortality rate. On the other hand, HbA1C lower than 6% has been related to better outcome in diabetic patients.
• One study suggests that HbA1C measured 3 months after diabetes mellitus type 2 diagnosis, can predict the subsequent mortality of these patients.^[76]
• A study proposed single-photon CT myocardial perfusion (SPECT) imaging as a possible predictive tool for cardiovascular events and subsequent cardiac death in asymptomatic patients with diabetes mellitus.^[77]
• In old diabetic patients with concurrent myocardial infarction a significant increase have been reported in their 5-year mortality rate. Conversely, in young diabetic patients with concurrent myocardial infarction, the mortality rate is strongly related to duration of diabetes mellitus.^[78] Furthermore, a cohort study suggests diabetes mellitus as an independent predictor of cardiac related complications and mortality in the first year after myocardial infarction.^[79]
• *Based on a meta-analysis by Palmer et al., SGLT-2 inhibitors and GLP-1 receptor agonists, together for the treatment of DM type 2, reduce mortality, non-fatal myocardial infarction, and serious hyperglycemia, and renal failure.^[80]

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