TYPE 2 DIABETES MELLITUS (T2DM)

EPIDEMIOLOGY

According to WHO, the number of people with diabetes has risen from 108 million in 1980 to 422 million in 2014. The global prevalence of diabetes among adults over 18 years of age has risen from 4.7% in 1980 to 8.5% in 2014. In 2012, an estimated 1.5 million deaths were directly caused by diabetes and another 2.2 million deaths were attributable to high blood glucose.⁽¹⁾ WHO projects that diabetes will be the 7th leading cause of death in 2030.⁽²⁾

In 2015, the International Diabetes Federation’s (IDF) Diabetes Atlas estimates that:⁽³⁾

• One in 11 adults has diabetes (415 million)
• One in two (46.5%) adults with diabetes is undiagnosed
• One in seven births is affected by gestational diabetes
• Three-quarters (75%) of people with diabetes live in low- and middle-income countries
• Every six seconds a person dies from diabetes (5.0 million deaths)

Pakistan ranks at number six in terms of number of people with diabetes worldwide. It was estimated that in 2000 there were 5.2 million diabetic patients and this will rise to 13.9 million by 2020, leading Pakistan to 4th most populous country for patients with diabetes mellitus.⁽⁴⁾ According to WHO prevalence of diabetes in Pakistan is 9.8%.⁽⁵⁾ According to diabetes international federation, there were over 7 million cases of diabetes in Pakistan in 2015.⁽⁶⁾

Type II diabetes is a worldwide health problem and affecting more than 415 million individual and expected to reach 642 million individuals by end of 2040.⁽⁷⁾

It is reported that 120,000 people die in Pakistan every year as a result of type II diabetes and its related complications.⁽⁸⁾

Prevalence of Type 2 diabetes in Pakistan is high ranging from 7.6 % (5.2 million populations) to 11 %^(9-11) and for 2030 it will increase to around 15% (14 million populations).

PATHOPHYSIOLOGY:

Type 2 diabetes is characterized by a combination of peripheral insulin resistance and inadequate insulin secretion by pancreatic beta cells. Insulin resistance, which has been attributed to elevated levels of free fatty acids and proinflammatory cytokines in plasma, leads to decreased glucose transport into muscle cells, elevated hepatic glucose production, and increased breakdown of fat.

A role for excess glucagon cannot be underestimated; indeed, type 2 diabetes is an islet paracrinopathy in which the reciprocal relationship between the glucagon-secreting alpha cell and the insulin-secreting beta cell is lost, leading to hyperglucagonemia and hence the consequent hyperglycemia.⁽¹²⁾

For type 2 diabetes mellitus to occur, both insulin resistance and inadequate insulin secretion must exist. For example, all overweight individuals have insulin resistance, but diabetes develops only in those who cannot increase insulin secretion sufficiently to compensate for their insulin resistance. Their insulin concentrations may be high, yet inappropriately low for the level of glycemia.

With prolonged diabetes, atrophy of the pancreas may occur. This may also explain the associated exocrine deficiency seen in prolonged diabetes.
BETA-CELL DYSFUNCTION: Beta-cell dysfunction is a major factor across the spectrum of prediabetes to diabetes. Beta-cell dysfunction develops early in the pathologic process and does not necessarily follow the stage of insulin resistance.⁽¹³⁾ Singular focus on insulin resistance as the "be all and end all" is gradually shifting, and hopefully better treatment options that address the beta-cell pathology will emerge for early therapy.

INSULIN RESISTANCE: In the progression from normal to abnormal glucose tolerance, postprandial blood glucose levels increase first. Eventually, fasting hyperglycemia develops as suppression of hepatic gluconeogenesis fails.
During the induction of insulin resistance (such as occurs with a high-calorie diet, steroid administration, or physical inactivity), increased glucagon levels and increased glucose-dependent insulinotropic polypeptide (GIP) levels accompany glucose intolerance. However, the postprandial glucagon like peptide-1 (GLP-1) response is unaltered.⁽¹⁴⁾

GENOMIC FACTORS: Genome-wide association studies of single-nucleotide polymorphisms (SNPs) have identified a number of genetic variants that are associated with beta-cell function and insulin resistance. Some of these SNPs appear to increase the risk for type 2 diabetes. Over 40 independent loci demonstrating an association with an increased risk for type 2 diabetes have been shown.⁽¹⁵⁾ A subset of the most potent are shared below:⁽¹⁶⁾

• Decreased beta-cell responsiveness, leading to impaired insulin processing and decreased insulin secretion (TCF7L2)
• Lowered early glucose-stimulated insulin release (MTNR1B, FADS1, DGKB,GCK)
• Altered metabolism of unsaturated fatty acids (FSADS1)
• Dysregulation of fat metabolism (PPARG)
• Inhibition of serum glucose release (KCNJ11)⁽¹⁷⁾
• Increased adiposity and insulin resistance (FTO and IGF2BP2)^(18,19)
• Control of the development of pancreatic structures, including beta-islet cells (HHEX)⁽²⁰⁾
• Transport of zinc into the beta-islet cells, which influences the production and secretion of insulin (SLC30A8)⁽²⁰⁾
• Survival and function of beta-islet cells (WFS1)⁽²¹⁾

Susceptibility to type 2 diabetes may also be affected by genetic variants involving incretin hormones.For example, reduced beta-cell function has been associated with a variant in the gene that codes for the receptor of gastric inhibitory polypeptide (GIPR).⁽²²⁾

AMINO ACID METABOLISM: Amino acid metabolism may play a key role early in the development of type 2 diabetes. Wang et al reported that the risk of future diabetes was at least 4-fold higher in normoglycemic individuals with high fasting plasma concentrations of 3 amino acids (isoleucine, phenylalanine, and tyrosine). Concentrations of these amino acids were elevated up to 12 years prior to the onset of diabetes.⁽²³⁾ 

DIABETES COMPLICATIONS: Although the pathophysiology of the disease differs between the types of diabetes, most of the complications, including microvascular, macrovascular, and neuropathic, are similar regardless of the type of diabetes. Hyperglycemia appears to be the determinant of microvascular and metabolic complications. Macrovascular disease may be less related to glycemia.

CARDIOVASCULAR RISK: Cardiovascular risk in people with diabetes is related in part to insulin resistance, with the following concomitant lipid abnormalities:

• Elevated levels of small, dense low-density lipoprotein (LDL) cholesterol particles
• Low levels of high-density lipoprotein (HDL) cholesterol
• Elevated levels of triglyceride-rich remnant lipoproteins

Thrombotic abnormalities (i.e. elevated type-1 plasminogen activator inhibitor [PAI-1], elevated fibrinogen) and hypertension is also involved. Other conventional atherosclerotic risk factors (e.g. family history, smoking, elevated LDL cholesterol) also affect cardiovascular risk.

Insulin resistance is associated with increased lipid accumulation in liver and smooth muscle, but not with increased myocardial lipid accumulation.⁽²⁴⁾ Persistent lipid abnormalities remain in patients with diabetes despite the use of lipid-modifying drugs, although evidence supports the benefits of these drugs. Statin dose up-titration and the addition of other lipid-modifying agents are needed.⁽²⁵⁾

Increased cardiovascular risk appears to begin prior to the development of frank hyperglycemia, presumably because of the effects of insulin resistance.

COGNITIVE DECLINE: Diabetic individuals aged 55 years and more are more likely to have brain atrophy than cerebrovascular lesions, with patterns resembling those of preclinical Alzheimer disease. Type 2 diabetes was associated with hippocampal atrophy; temporal, frontal, and limbic gray-matter atrophy; and, to a lesser extent, frontal and temporal white-matter atrophy.

Type 2 diabetes was also linked with poorer performance on certain cognitive tests. Patients with type 2 diabetes were more likely to have gray-matter atrophy in several bilateral regions of the cortices, especially in the left hemisphere, similar to the distribution of cortical atrophy described in early Alzheimer disease.⁽²⁶⁾

SECONDARY DIABETES: Various other types of diabetes, previously called secondary diabetes, are caused by other illnesses or medications. Depending on the primary process involved (e.g. destruction of pancreatic beta cells or development of peripheral insulin resistance), these types of diabetes behave similarly to type 1 or type 2 diabetes.
The most common causes of secondary diabetes are as follows:

• Diseases of the pancreas that destroy the pancreatic beta cells (e.g. hemochromatosis, pancreatitis, cystic fibrosis, pancreatic cancer)
• Hormonal syndromes that interfere with insulin secretion (e.g. pheochromocytoma)
• Hormonal syndromes that cause peripheral insulin resistance (e.g. acromegaly, Cushing syndrome, pheochromocytoma)
• Drugs (e.g. phenytoin, glucocorticoids, estrogens)

GESTATIONAL DIABETES: Gestational diabetes mellitus is defined as any degree of glucose intolerance with onset or first recognition during pregnancy. A steady decline in insulin sensitivity as gestation progresses is a normal feature of pregnancy; gestational diabetes mellitus results when maternal insulin secretion cannot increase sufficiently to counteract the decrease in insulin sensitivity.

NATURAL HISTORY:

Type 2 diabetes, previously referred to as adult-onset or non-insulin-dependent diabetes, progresses from an early asymptomatic stage with insulin resistance to mild postprandial hyperglycemia to frank diabetes requiring pharmacological intervention. Understanding this natural history of type 2 diabetes will guide primary care providers in formulating effective treatment regimens that reflect the pathological differences between these stages of the disease. The optimal medication regimen, when used in conjunction with dietary changes and exercise, will require modifications for each patient as the disease progresses.

This stage of mild postprandial hyperglycemia is an extremely useful marker of patients at risk for the eventual development of type 2 diabetes. Patients with Impaired Glucose Tolerance (IGT) may benefit from timely patient education and perhaps even more aggressive forms of intervention, such as diet, exercise, or medication.

SIGN AND SYMPTOMS:

Type 2 DM may present to the clinician in one of 4 ways:

• Classical symptoms
• Incidental diagnosis
• Hyperosmolar nonketotic coma.
• Complications of diabetes mellitus

CLASSICAL SYMPTOMS:

Symptoms of type 2 DM that may be seen at diagnosis are increased thirst, polyuria, increased hunger, weight loss, fatigue, blurred vision, slow healing sores or frequent infections and acanthosis nigricans.

• Increased thirst and polyuria: Excess sugar building up in blood stream causes fluid to be pulled from the tissues. Due to which patient may feel thirsty. As a result, patient may drink and urinate more than usual.
• Increased hunger: Without enough insulin to move sugar into cells, patient’s muscles and organs become depleted of energy. This triggers intense hunger.
• Weight loss: Despite eating more than usual to relieve hunger, patient may lose weight. Without the ability to metabolize glucose, the body uses alternative fuels stored in muscle and fat. Calories are lost as excess glucose is released in the urine.
• Fatigue: If cells are deprived of sugar, patient may become tired and irritable.
• Blurred vision: If blood sugar is too high, fluid may be pulled from the lenses of eyes. This may affect patient’s ability to focus.
• Slow-healing sores or frequent infections: Type 2 diabetes affects ability to heal and resist infections. Elevated glucose levels may make it harder for body to heal. Therefore, injuries like cuts and sores stay open longer. This makes them more susceptible to infection.
• Acanthosis nigricans: Some people with type 2 diabetes have patches of dark, velvety skin in the folds and creases of their bodies, usually in the armpits and neck. This condition, called acanthosis nigricans, may be a sign of insulin resistance.

INCIDENTAL DIAGNOSIS:

Type 2 DM may be an incidental finding. Opportunistic urine and blood testing for glucose is often done in older individuals at the time of intercurrent illness, either at the primary or secondary care level, or as part of an annual health check. In population surveys, up to 50% of type 2 DM patients are relatively asymptomatic at diagnosis.

HYPEROSMOLAR NONKETOTIC COMA (HONK):

Hyperglycemic hyperosmolar nonketonic syndrome (HHNS) is a serious complication of diabetes that involves a cycle of increasing blood sugar levels and dehydration, without ketones. It is often triggered by a serious infection or another severe illness, or by medications that lower glucose tolerance or increase fluid loss (especially in people who are not drinking enough fluids).

Symptoms of HHNS include high blood sugar levels, dry mouth, extreme thirst, dry skin, and high fever. HHNS can lead to loss of consciousness, seizures, coma, and death.

COMPLICATIONS OF DIABETES⁽²⁷⁾:

It is important to recognise that all diabetic patients are at risk of complications and type 2 DM may present with complications. Diabetic complications have two major subdivisions:

1. Microvascular complication: which are specific to diabetes mellitus and do not occur in non-diabetic subjects. The principal sites that are damaged are the eye (retinopathy), the kidney (nephropathy) and the nervous system (neuropathy) and the clinical consequences can be blindness, renal failure and foot problems with risk of amputation.
2. Macrovascular complications: which are not unique to diabetes but occur much more commonly in diabetic subjects. They are often termed nonspecific complications. The main large vessels that are involved are those supplying the heart, the brain and the legs. Thus, macrovascular disease gives rise to heart attack, stroke and gangrene.

MICROVASCULAR DISEASE AND TYPE 2 DM:

DIABETIC RETINOPATHY: Diabetes mellitus is the most common cause of blindness in people between the ages of 20 and 60 years. About five to 10 percent of type 2 DM patients may have retinopathy at the time of diagnosis because of the insidious onset of the disease. In type 2 DM patients the threat to vision is from diabetic maculopathy which affects central vision. Laser photocoagulation therapy is successful in prevention of blindness in about 60–70% of patients treated provided the retinopathy is detected early. Therefore, regular screening for retinopathy at annual intervals is essential.

DIABETIC NEPHROPATHY: Diabetic renal disease affects 15–20% of type 2 DM subjects, in 50% of whom it will progress to renal failure. With this condition, the tiny filters in the kidney (called glomeruli) become damaged and leak protein into the urine. Over time this can lead to kidney failure. Urine tests showing microalbuminuria (small amounts of protein in the urine) are important markers for kidney damage.

Symptoms of kidney failure may include swelling in the feet and ankles, itching, fatigue, and pale skin color.

DIABETIC NEUROPATHY: Diabetes reduces or distorts nerve function, causing a condition called neuropathy. Neuropathy refers to a group of disorders that affect nerves. The two main types of neuropathy are:

• Peripheral (affects nerves in the toes, feet, legs, hand, and arms)
• Autonomic (affects nerves that help regulate digestive, bowel, bladder, heart, and sexual function)

Peripheral neuropathy particularly affects sensation. It is a common complication for nearly half of people who have lived with type 1 or type 2 diabetes for more than 25 years. The most serious consequences of neuropathy occur in the legs and feet and pose a risk for ulcers and, in unusually severe cases, amputation. Peripheral neuropathy usually starts in the fingers and toes and moves up to the arms and legs (called a stocking-glove distribution). Symptoms include:

• Tingling
• Weakness
• Burning sensations
• Loss of the sense of warm or cold
• Numbness (if the nerves are severely damaged, the patient may be unaware that a blister or minor wound has become infected)
• Deep pain

Autonomic neuropathy can cause:

• Digestive problems (such as constipation, diarrhea, nausea, and vomiting)
• Bladder infections and incontinence
• Erectile dysfunction
• Heart problems
• Rapid heart rates
• Lightheadedness when standing up (orthostatic hypotension)

DIABETIC FOOT PROBLEMS: About 15% of patients with diabetes have serious foot problems. People with diabetes who are overweight, smokers, and have a long history of diabetes tend to be at most risk. People who have the disease for more than 20 years and are insulin-dependent are at the highest risk. Related conditions that put people at risk include peripheral neuropathy, peripheral artery disease, foot deformities, and a history of ulcers.

Foot ulcers usually develop from infections, such as those resulting from blood vessel injury. Numbness from nerve damage, which is common in diabetes, compounds the danger since the patient may not be aware of injuries. About one-third of foot ulcers occur on the big toe.

MACROVASCULAR DISEASE AND TYPE 2 DM⁽²⁷⁾:

CARDIOVASCULAR DISEASE: This is the major cause of death and hospitalization in type 2 DM subjects. Acute myocardial infarction (heart attack) is about two to four times more common in type 2 DM patients than in the general population and mortality from cardiac failure and heart attacks is also higher. Diabetes affects the heart in many ways:

• Both type 1 and 2 diabetes accelerate the progression of atherosclerosis (hardening of the arteries). Diabetes is often associated with low HDL ("good" cholesterol) and high triglycerides. This can lead to coronary artery disease, heart attack, or stroke.
• High blood pressure (hypertension) usually develops if the kidneys become damaged. High blood pressure is another major cause of heart attack, stroke, and heart failure.
• Impaired nerve function (neuropathy) associated with diabetes also causes heart abnormalities.

CEREBROVASCULAR DISEASE: Acute ischemic stroke and transient cerebral ischemic attacks are three to four times more common in type 2 DM.

PERIPHERAL VASCULAR DISEASE: The incidence of peripheral vascular disease is increased by up to six-fold in type 2 DM. It may present as intermittent claudication, ulceration or gangrene. Lower limb amputation is up to 20 times more common in type 2 DM subjects.

HYPOGLYCEMIA: Hypoglycemic symptoms may be adrenergic, due to sympathetic neural activation and epinephrine release, and neuroglycopenic, resulting from direct effects of hypoglycemia on the central nervous system. Behavioral changes also occur and are probably a consequence of adrenergic and neuroglycopenic responses.

• Adrenergic symptoms: Tremor, pallor, rapid heart rate, palpitations, and diaphoresis.
• Neuroglycopenic symptoms: Fatigue, lethargy, headaches, behavior changes, drowsiness, unconsciousness, seizures, or coma. The severity of the neuroglycopenic symptoms increases with the severity of hypoglycemia and resultant central nervous system energy deprivation.
• Behavioral symptoms: Behavioral symptoms include irritability, agitation, erratic behavior, quietness or tantrums.

DIAGNOSTIC TEST:

The American Diabetes Association (ADA) criteria for the diagnosis of diabetes are any of the following:⁽²⁸⁾

• An HbA1c level of 6.5% or higher; the test should be performed in a laboratory using a method that is certified by the National Glycohemoglobin Standardization Program (NGSP) and standardized or traceable to the Diabetes Control and Complications Trial (DCCT) reference assay, or
• A fasting plasma glucose (FPG) level of 126 mg / dL (7.0 mmol/L) or higher; fasting is defined as no caloric intake for at least 8 hours, or
• A 2-hour plasma glucose level of 200 mg / dL (11.1 mmol / L) or higher during a 75-g oral glucose tolerance test (OGTT), or
• A random plasma glucose of 200 mg / dL (11.1 mmol / L) or higher in a patient with classic symptoms of hyperglycemia (i.e. polyuria, polydipsia, polyphagia, weight loss) or hyperglycemic crisis

The American Association of Clinical Endocrinologists, however, recommends that HbA1c be considered an additional optional diagnostic criterion, rather than a primary criterion for diagnosis of diabetes.⁽²⁹⁾

If unequivocal hyperglycemia is absent, then HbA1c, FPG, and OGTT results should be confirmed by repeat testing. The ADA recommends repeating the same test for confirmation, since there will be a greater likelihood of concurrence. However, the diagnosis of diabetes is also confirmed if the results of 2 different tests are above the diagnostic thresholds.⁽³⁰⁾

In asymptomatic patients whose random serum glucose level suggests diabetes (>140 mg / dL), an FPG or HbA1c level should be measured. An FPG level of 100-125 mg / dL is considered an impaired fasting glucose (IFG), and an FPG level of less than 100 mg / dL is considered a normal fasting glucose. However, an FPG of 91-99 mg / dL is a strong independent predictor of future type 2 diabetes.⁽³¹⁾

An HbA1c below 6%is considered normal glucose tolerance. An HbA1C of 6-6.4% is neither normal glucose tolerance nor diabetes. With current assays, an HbA1c of less than 5.7% is considered normal and an HbA1c of greater than 6.4% is considered diagnostic for diabetes mellitus (DM). A value between 5.7% and 6.4% is considered diagnostic of prediabetes.

In the emergency department, a fingerstick glucose test is appropriate for virtually all patients with diabetes. All other laboratory studies should be individualized to the clinical situation.⁽³²⁾

GLUCOSE STUDIES:

Plasma glucose is determined using blood drawn into a gray-top (sodium fluoride) tube, which inhibits red blood cell glycolysis immediately. A serum glucose measurement (commonly obtained on chemistry panels, using a red- or speckled-top tube) may be significantly lower than a plasma glucose measurement. Capillary whole blood measurements are not recommended for the diagnosis of diabetes mellitus, but they are valuable for assessment of patients in acute care situations.

IMPAIRED GLUCOSE TOLERANCE: The World Health Organization (WHO) criteria for impaired glucose tolerance (IGT) are an FPG of less than 126 mg / dL (7 mmol/L), if measured, and a venous plasma glucose of 140 mg / dL to just below 200 mg/dL (≥7.8 to <11.1mmol / L) 2 hours after a 75-g glucose load with one intervening plasma glucose value at or above 200 mg / dL.⁽³³⁾  The WHO notes that IGT is not a clinical entity but a risk factor for future diabetes and / or adverse outcomes and that the risk of future diabetes, premature death, and cardiovascular disease begins to increase at 2-hour plasma glucose levels below the IGT range.

GLYCATED HEMOGLOBIN STUDIES: HbA1c measurements are the criterion standard for monitoring long-term glycemic control.
The American Association of Clinical Endocrinologists recommends that HbA1C be considered an additional, optional diagnostic criterion, rather than the primary criterion for diagnosis of diabetes.⁽³⁴⁾ Using HbA1c alone in initial diabetes screening identifies approximately 20% fewer cases of diabetes than diagnosis based on fasting and 2-hour post load plasma glucose levels.⁽³⁵⁾

Glucose measurement should remain the choice for diagnosing pregnant women or if HbA1c assay is unavailable. In addition, the use of HbA1c by itself represents a poor diagnostic tool for detection of prediabetes and diabetes in obese children and adolescents.⁽³⁶⁾

HbA1c cannot be used as an indicator of glycemic control in patients with neonatal diabetes mellitus because of the high levels of fetal hemoglobin (HbF) remaining in the blood.

URINARY ALBUMIN STUDIES:
Annual screening for microalbuminuria is recommended in all patients with diabetes. Measuring the albumin-to-creatinine ratio in a spot urine sample is probably the easiest method; the ratio, expressed in mg / g, is equivalent to albumin excretion in milligrams daily. A result greater than 30 mg / g indicates albuminuria, in which case a quantitation on a timed urine specimen (i.e. overnight, 10 h, or 24 h) should be performed.

Normal urine albumin excretion is defined as less than 30 mg daily. Microalbuminuria is defined as 30-300 mg daily (20-200 mcg / min). Because of wide variability among patients, microalbuminuria should be found on at least 2 of 3 samples over 3-6 months. Higher values can be detected by standard protein dipstick screening and are considered macroproteinuria.

Unlike type 1 diabetes mellitus, in which microalbuminuria is a good indicator of early kidney damage, microalbuminuria is a common finding (even at diagnosis) in type 2 diabetes mellitus and is a risk factor for macrovascular (especially coronary heart) disease. It is a weaker predictor of future kidney disease in type 2 diabetes mellitus.

DIABETES TESTING IN ASYMPTOMATIC PATIENTS:
The U.S. Preventive Services Task Force recommends screening for type 2 diabetes in asymptomatic adults with sustained blood pressure (either treated or untreated) greater than 135 / 80 mm Hg (grade B recommendation).⁽³⁷⁾

The ADA recommends considering testing for prediabetes and diabetes in asymptomatic adults who are overweight (body mass index [BMI] ≥25 kg / m²; may be lower in at-risk ethnic groups) and have 1 or more of the following additional risk factors:⁽³⁰⁾

• Physical inactivity
• First-degree relative with diabetes
• Member of a high-risk ethnic population (e.g. African American, Latino, Native American, Asian American, Pacific Islander)
• Delivered a baby weighing over 9 lb or diagnosed with gestational diabetes mellitus
• Hypertension (≥140 / 90 mm Hg or on therapy for hypertension)
• HDL cholesterol level under 35 mg / dL (0.90 mmol / L) and / or a triglyceride level above 250 mg / dL (2.82 mmol / L)
• Polycystic ovary disease
• IGT or IFG on previous testing
• Other clinical conditions associated with insulin resistance (e.g. severe obesity, acanthosis nigricans)
• History of cardiovascular disease

In the absence of the above criteria, the ADA recommends testing for prediabetes and diabetes beginning at age 45 years. If results are normal, testing should be repeated at least every 3 years. More frequent testing may be considered, depending on initial results and risk status.

TESTS TO DIFFERENTIATE TYPE 2 AND TYPE 1 DIABETES⁽³⁸⁾:
Measuring concentrations of insulin or C-peptide (a fragment of proinsulin that serves as a marker for insulin secretion) rarely is necessary to diagnose type 2 diabetes mellitus or differentiate type 2 diabetes from type 1 diabetes mellitus. Insulin levels generally are high early in the course of type 2 diabetes mellitus and gradually wane over time.

A fasting C-peptide level of more than 1 ng / dL in a patient who has had diabetes for more than 1-2 years is suggestive of type 2 diabetes (i.e. residual beta-cell function). Stimulated C-peptide concentrations (after a standard meal challenge such as Sustacal or after glucagon) are somewhat preserved until late in the course of type 2 diabetes mellitus. Absence of a C-peptide response to carbohydrate ingestion may indicate total beta-cell failure.

Latent autoimmune diabetes of adults (LADA) is a form of slow-onset type 1 diabetes that occurs in middle-aged (usually white) adults. It can be differentiated from type 2 diabetes by confirming the presence of antibodies against the 65-kd isoform of glutamic acid decarboxylase (GAD65), an enzyme found in pancreatic beta cells. Such patients may respond to insulin secretagogues for a brief period (months).

Autoantibodies can be useful in differentiating between type 1 and type 2 diabetes. Islet-cell (IA2), anti-GAD65, and anti-insulin autoantibodies can be present in early type 1 diabetes, but not in type 2 disease. IA2 autoantibodies titers typically decrease after 6 months. Anti-GAD65 antibodies can be present at diagnosis of type 1 diabetes and are more likely to be persistently positive over time.

THERAPY CONSIDERATION:

Treatment of patients with type 2 diabetes mellitus includes education, evaluation for microvascular and macrovascular complications, attempts to achieve near-normal glycemia, minimization of cardiovascular and other long-term risk factors, and avoidance of drugs that can aggravate abnormalities of insulin or lipid metabolism. All of these treatments need to be tempered based on individual factors, such as age, life expectancy, and comorbidities. Although several studies have noted remissions of type 2 diabetes mellitus that may last several years, most patients require continuous treatment in order to maintain normal or near-normal glycemia. Treatments to achieve normoglycemia focus on increasing insulin availability (either through direct insulin administration or through agents that promote insulin secretion), improving sensitivity to insulin, delaying the delivery and absorption of carbohydrate from the gastrointestinal tract, or increasing urinary glucose excretion.

TREATMENT OPTIONS:

Early initiation of pharmacologic therapy is associated with improved glycemic control and reduced long-term complications in type 2 diabetes. Drug classes used for the treatment of type 2 diabetes include the following:

• Biguanides
• Sulfonylureas
• Meglitinide derivatives
• Alpha-glucosidase inhibitors
• Thiazolidinediones (TZDs)
• Glucagonlike peptide–1 (GLP-1) agonists
• Dipeptidyl peptidase IV (DPP-4) inhibitors
• Selective sodium-glucose transporter-2 (SGLT-2) inhibitors
• Insulins
• Amylinomimetics
• Bile acid sequestrants
• Dopamine agonists

BIGUANIDES:
Metformin is the only biguanide in clinical use. Another biguanide, phenformin, was taken off the market in the United States in the 1970s because of its risk of causing lactic acidosis and associated mortality (rate of approximately 50%). Metformin has proved effective and safe.⁽³⁹⁾ Metformin lowers basal and postprandial plasma glucose levels. Its mechanisms of action differ from those of other classes of oral antidiabetic agents; metformin works by decreasing hepatic gluconeogenesis production. It also decreases intestinal absorption of glucose and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike oral sulfonylureas, metformin rarely causes hypoglycemia.

Patients on metformin have shown significant improvements in hemoglobin A1c and their lipid profile, especially when baseline values are abnormally elevated. In addition, metformin is the only oral diabetes drug that reliably facilitates modest weight loss.

SULFONYLUREAS:
Sulfonylureas (e.g. glyburide, glipizide, glimepiride) are insulin secretagogues that stimulate insulin release from pancreatic beta cells and probably have the greatest efficacy for glycemic lowering of any of the oral agents. However, that effect is only short-term and quickly dissipates. Sulfonylureas may also enhance peripheral sensitivity to insulin secondary to an increase in insulin receptors or to changes in the events following insulin-receptor binding.

Sulfonylureas are indicated for use as adjuncts to diet and exercise in adult patients with type 2 diabetes mellitus. They are generally well-tolerated, with hypoglycemia the most common side effect. The first-generation sulfonylureas are acetohexamide, chlorpropamide, tolazamide, and tolbutamide; the second-generation agents are glipizide, glyburide, and glimepiride. The structural characteristics of the second-generation sulfonylureas allow them to be given at lower doses and as once-daily regimens.

MEGLITINIDE DERIVATIVES:
Meglitinides (e.g. repaglinide, nateglinide) are much shorter-acting insulin secretagogues than the sulfonylureas are, with preprandial dosing potentially achieving more physiologic insulin release and less risk for hypoglycemia.⁽⁴⁰⁾ Although meglitinides are considerably more expensive than sulfonylureas, they are similar in their glycemic clinical efficacy.

Meglitinides can be used as monotherapy; however, if adequate glycemic control is not achieved, then metformin or a thiazolidinedione may be added. Meglitinides may be used in patients who have allergy to sulfonylurea medications. They have a similar risk for inducing weight gain as sulfonylureas do but possibly carry less risk for hypoglycemia.

ALPHA-GLUCOSIDASE INHIBITORS:
These agents delay sugar absorption and help to prevent postprandial glucose surges. Alpha-glucosidase inhibitors prolong the absorption of carbohydrates, but their induction of flatulence greatly limits their use. They should be titrated slowly to reduce gastrointestinal (GI) intolerance.

THIAZOLIDINEDIONES(TZDS):
TZDs (e.g. pioglitazone, rosiglitazone) act as insulin sensitizers; thus, they require the presence of insulin to work. They must be taken for 12-16 weeks to achieve maximal effect.

These agents are used as monotherapy or in combination with sulfonylurea, metformin, meglitinide, DPP-4 inhibitors, GLP-1 receptor agonists, or insulin. They are the only antidiabetic agents that have been shown to slow the progression of diabetes (particularly in early disease).

TZDs generally decrease triglyceride levels and increase HDL cholesterol levels. They increase LDL cholesterol, but this increase may involve large, buoyant LDL, which may be less atherogenic.

PIOGLITAZONE IN PATIENTS UNRESPONSIVE TO COMBINATION THERAPY: Charpentier et al concluded that the early addition of pioglitazone in patients who are not responding to dual therapy is beneficial, decreasing HbA1c, as well as improving FPG levels and other surrogate markers.⁽⁴¹⁾ 

ROSIGLITAZONE RESTRICTIONS: In response to data suggesting an elevated risk of myocardial infarction in patients treated with rosiglitazone, the FDA has restricted access to this drug.⁽⁴²⁾ The use of rosiglitazone is limited to patients already being successfully treated with this agent and to patients whose blood sugar cannot be controlled with other antidiabetic medicines and who do not wish to use pioglitazone, the only other TZD currently available.

GLUCAGONLIKE PEPTIDE–1 AGONISTS:
GLP-1 agonists (i.e. exenatide, liraglutide, albiglutide, dulaglutide) mimic the endogenous incretin GLP-1; they stimulate glucose-dependent insulin release, reduce glucagon, and slow gastric emptying. The use of a GLP-1 in addition to metformin and / or a sulfonylurea may result in modest weight loss. Animal data suggest that these drugs prevent beta-cell apoptosis and may in time restore beta-cell mass. The latter property, if proven in humans, would have tremendous therapeutic potential.

EXENATIDE: A comparison by Bunck et al of 1 year's therapy with either exenatide or insulin glargine in metformin-treated patients with type 2 diabetes found that exenatide provided significantly greater improvement in beta-cell function. Reduction in HbA1c was similar with the 2 drugs. Beta-cell function and glycemic control returned to pretreatment values following discontinuation of exenatide or insulin glargine, suggesting that long-term treatment is required to maintain the beneficial effects of these drugs.⁽⁴³⁾

The addition of exenatide in patients receiving insulin glargine as basal insulin helps to improve glycemic control without the risk of increased hypoglycemia or weight gain. This benefit, however, is accompanied by a significant increase in adverse events such as nausea, diarrhea, vomiting, and headache.⁽⁴⁴⁾

ALBIGLUTIDE AND LIRAGLUTIDE: The glucagonlike peptide-1 (GLP-1) receptor agonist albiglutide was approved by the FDA in April 2014 as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.^(45,46) GLP-1 agonists augment glucose-dependent insulin secretion.

DULAGLUTIDE: Dulaglutide was approved by the FDA in September 2014 as adjunctive therapy to diet and exercise to improve glycemic control in type 2 diabetes mellitus.⁽⁴⁷⁾ It is administered as a once-weekly subcutaneous injection.^(47,48) 

LIXISENATIDE: Lixisenatide was approved by the FDA in July 2016 as adjunctive therapy to diet and exercise to improve glycemic control in type 2 diabetes mellitus. It is administered by subcutaneous injection once daily within 1 hour before the first meal of the day. The starting dose is 10 mcg / day SC for 14 days and is then increased on day 15 to 20 mcg once daily.

DIPEPTIDYL PEPTIDASE IV INHIBITORS:
DPP-4 inhibitors (e.g. sitagliptin, saxagliptin, linagliptin) are a class of drugs that prolong the action of incretin hormones. DPP-4 degrades numerous biologically active peptides, including the endogenous incretins GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). DPP-4 inhibitors can be used as a monotherapy or in combination with metformin or a TZD. They are given once daily and are weight neutral.

A study comparing the efficacy and safety of monotherapy with sitagliptin or metformin in treatment-naive patients with type 2 diabetes found no statistical differences between the 2 drugs in terms of decreases in HbA1c and fasting glucose levels. The 1050 participants in the study had baseline HbA1c levels of 6.5-9% and received sitagliptin (100 mg qd) or metformin (1000 mg bid) for 24 weeks.⁽⁴⁹⁾

In this study, the incidence of adverse GI effects was lower with sitagliptin than with metformin (11.6% vs 20.7%). Specifically, diarrhea (3.6% vs 10.9%) and nausea (1.1% vs 3.1%) were significantly less common with sitagliptin.⁽⁴⁹⁾

Adding linagliptin to treatment in patients with type 2 diabetes mellitus that has been inadequately controlled with a metformin and sulfonylurea combination improves glycemic control. Because it has predominantly nonrenal excretion and is a clinically nonrelevant substrate for cytochrome-450 isoenzymes, this drug possesses the benefits of having a low risk of drug-drug interaction and of being safe to use in patients with renal insufficiency.⁽⁵⁰⁾

Upper respiratory tract infections have been increasingly reported among users of DPP-4 inhibitors compared with users of other antidiabetic drugs.⁽⁵¹⁾ However, further research is needed to evaluate the scope and underlying mechanisms of this phenomenon.

SELECTIVE SODIUM-GLUCOSE TRANSPORTER-2 INHIBITORS (SGLT-2):
Canagliflozin is the first SGLT-2 inhibitor approvedby the FDA .^(52,53) SGLT-2 inhibition lowers the renal glucose threshold (i.e. the plasma glucose concentration that exceeds the maximum glucose reabsorption capacity of the kidney). Lowering the renal glucose threshold results in increased urinary glucose excretion. A second SGLT-2 inhibitor, dapagliflozin, was approved by the FDA in January 2014,^(54,55) and another, empagliflozin, approved in August, 2014.^(56,57)

Dosage adjustments are required for canagliflozin in patients who have renal impairment (i.e. estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73 m²). Dapagliflozin should not be used if eGFR is < 60 mL/min/1.73 m². Also consider lowering the dose of insulin or insulin secretagogues to reduce the risk of hypoglycemia when coadministered with SGLT-2 inhibitors.

Canagliflozin add-on combination therapy to metformin and / or sulfonylureas showed a reduction in fasting glucose and a greater proportion of patients achieving an HbA1C level less than 7%.⁽⁵⁸⁾ Add-on therapy to insulin and comparative data to thiazolidinediones and to dipeptidyl peptidase-IV inhibitors have also shown improved postprandial glucose levels and HbA1C levels.⁽⁵⁸⁾

Dapagliflozin is FDA approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.^(54,55) Dapagliflozin is indicated as monotherapy, as initial therapy with metformin, or as an add-on to other oral glucose-lowering agents, including metformin, pioglitazone, glimepiride, sitagliptin, and insulin. 

Like dapagliflozin, empagliflozin is also approved as an adjunct to diet and exercise to improve glycemic control.

INSULINS:
Ultimately, many patients with type 2 diabetes mellitus become markedly insulinopenic. The only therapy that corrects this defect is insulin. Because most patients are insulin resistant, small changes in insulin dosage may make no difference in glycemia in some patients. Furthermore, because insulin resistance is variable from patient to patient, therapy must be individualized in each patient.

A range of insulin preparations, individual and premixed, is currently available.

LONG-ACTING INSULINS: include insulin glargine and insulin detemir Insulin glargine has no peak and produces a relatively stable level lasting more than 24 hours. In some cases, it can produce a stable basal serum insulin concentration with a single daily injection, though patients requiring lower doses typically are given twice-daily injections. Insulin detemir has duration of action that may be substantially shorter than that of insulin glargine but longer than those of intermediate-acting insulins.

A new ultralong-acting basal insulin, insulin degludec, which has a duration of action of up to beyond 42 hours, has been approved by the US Food and Drug Administration (FDA). This new basal insulin forms a soluble multihexamer after subcutaneous injection to provide a depot effect that is long lasting. It is indicated for diabetes mellitus types 1 and 2.

AMYLINOMIMETICS:
Pramlintide acetate is an amylin analog that mimics the effects of endogenous amylin, which is secreted by pancreatic beta cells. This agent delays gastric emptying, decreases postprandial glucagon release, and modulates appetite.⁽⁵⁹⁾

BILE ACID SEQUESTRANTS:
Bile acid sequestrants were developed as lipid-lowering agents for the treatment of hypercholesterolemia but were subsequently found to have a glucose-lowering effect. The bile acid sequestrant colesevelam is FDA-approved as an adjunctive therapy to improve glycemic control. It has a favorable, but insignificant, impact on FPG and HbA1c levels.⁽⁶⁰⁾

DOPAMINE AGONISTS:
In 2009, the FDA approved a quick-release formulation of bromocriptine mesylate as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Bromocriptine is a centrally acting dopamine D2 receptor agonist. When given in a single timed morning dose, it is thought to act on circadian neuronal activities within the hypothalamus to reset the abnormally elevated drive for increased plasma glucose, triglyceride, and free fatty acid levels in fasting and postprandial states in insulin-resistant patients.⁽⁶¹⁾

Quick-release bromocriptine may be considered for obese patients who do not tolerate other diabetes medications or who need only a minimal reduction in HbA1c to reach their glycemic goal. This agent has the benefits of not causing hypoglycemia and weight gain.

Bromocriptine can cause orthostatic hypotension and syncope, particularly on initiation of therapy and dose escalation. Caution is advised when treating patients who are receiving antihypertensive therapy; orthostatic vital signs should be evaluated at baseline and periodically thereafter.

GOALS OF THERAPY:

The goals in caring for patients with diabetes mellitus are to eliminate symptoms and to prevent, or at least slow, the development of complications. Microvascular (i.e. eye and kidney disease) risk reduction is accomplished through control of glycemia and blood pressure; macrovascular (i.e. coronary, cerebrovascular, peripheral vascular) risk reduction, through control of lipids and hypertension, smoking cessation, and aspirin therapy; and metabolic and neurologic risk reduction, through control of glycemia.

GUIDELINES:

To review “Consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes guidelines - Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy” please click on below link:
http://care.diabetesjournals.org/content/32/1/193.long
To review “Management of Hyperglycemia in Type 2 Diabetes, 2015: A Patient-Centered Approach: Update to a Position Statement of the American Diabetes Association and the European Association for the Study of Diabetes” please click on below link:
http://care.diabetesjournals.org/content/38/1/140.long

CONSULTATION AND COUSELLING:

At the time diabetes mellitus is diagnosed, the patient should be given extensive information about the disease and its management, including the importance of self-management.

Self-management education is most effective when presented in collaboration with a provider who can reinforce this information. Therefore, an important part of the primary care provider’s role is to review and update the information the patient needs to manage the disease, ascertain the extent to which the patient is managing the disease appropriately, reinforce self-management behaviors, and refer to diabetes education programs or nutritionists.

The dietary counseling begins by determining the patient's and family's dietary preferences, patterns of physical activity, as well as sedentary behaviors, family time and financial constraints, cultural background, and educational level. Scheduling counseling visits at least every four weeks allows the family to implement changes, maintain motivation, and provide reinforcement.

Following instructions should be given to patient:

• Patients should be advised that frequent medication adjustments represent good care, and are not a sign of failed care or a reason for self-blame or guilt.
• The use of self-monitoring of blood glucose data to promptly identify loss of glucose control and proactively adjust therapy is an essential self-management skill when using multi-dose insulin regimens, and requires patient education and easy access to health team members between scheduled surgery visits. Insulin-treated patients generally monitor blood sugars before meals and at bedtime.
• All women of childbearing age with diabetes should be counseled about the importance of strict glycaemic control prior to conception.
• Patients should receive counseling on how to prevent and promptly identify eye, foot, kidney, and heart complications.
• Patients should be advised that hypoglycaemia (glucose <3.9 mmol / L [<70 mg / dL]) is often accompanied by symptoms such as tachycardia, sweating, shakiness, intense hunger, or confusion, and must be dealt with promptly by ingesting at least 20 g of carbohydrate (4 glucose tablets or equivalent). After self-treatment, blood sugar should be checked if possible.
• Instruct patients to promptly report nocturnal hypoglycaemia or recurrent episodes of hypoglycaemia so that therapy may be adjusted.
• Patients should have a carbohydrate snack prior to exercise if self-monitored blood glucose is <5.6 mmol / L (<100 mg / dL) and the patient is taking insulin or an insulin secretagogue (sulfonylurea or meglitinide).

LONG TERM MONITORING:

Optimal diabetes care requires a long-term relationship with the patient, appropriate use of consultants when needed, and regular monitoring and control of BP, HbA1c, tobacco use, and statin / aspirin use. Most patients require diabetes assessments every 3 to 4 months, and some patients may benefit from more frequent (monthly) visits, especially when motivated to improve their care.

It is suggested to obtain glycated hemoglobin (A1C) at least twice yearly in patients meeting glycemic goals and more frequently (quarterly) in patients whose therapy has changed or who are not meeting goals. Self-monitoring of blood glucose (SMBG) is not necessary for most patients with type 2 diabetes who are on a stable regimen of diet or oral agents and who are not experiencing hypoglycemia. SMBG may be useful for some type 2 diabetic patients who would take action to modify eating patterns or exercise, as well as be willing to intensify pharmacotherapy, based on SMBG results.

In addition to care required to achieve recommended levels of BP, statin use, aspirin use, tobacco use, and glucose control, the following periodic monitoring for complications is advised:⁽⁶²⁾

• Dilated eye examination every 1 to 2 years
• Annual assessment of renal function including a urinary albumin excretion test, and serum creatinine test with estimated GFR
• Annually or more frequent foot examinations including assessment of ankle reflexes, dorsalis pedis pulse, vibratory sensation, and monofilament touch sensation. All patients with insensate feet, foot deformities, or a history of foot ulcers have their feet examined at every visit.

Due to disease progression, comorbidities, and non-adherence to lifestyle or medication, about 30% to 40% of patients who achieve recommended levels of HbA1c, BP, and previously suggested LDL-cholesterol levels relapse to uncontrolled states of 1 or more of these within 1 year. Relapse is usually asymptomatic; frequent monitoring of clinical parameters is necessary to detect relapse early and adjust therapy.⁽⁶²⁾

Among all those with HbA1c <53 mmol / mol (<7%), about 20% to 30% will experience relapse to HbA1c >53 mmol / mol (>7%) within 1 year. Causes of poor glycaemic control include medication non-adherence, depression, musculoskeletal injury or worsening arthritis, competing illnesses perceived by the patient as more serious than diabetes, social stress at home or at work, substance abuse, occult infections, use of medications (such as corticosteroids) that elevate glucose, or other endocrinopathy such as Cushing's disease.⁽⁶²⁾

Loss of control of BP and lipids is also a common phenomenon. Close monitoring of patients with diabetes through frequent visits and lab work is necessary to help maintain treatment goals and prevent upward trends in BP or HbA1c, as well as to encourage statin use and non-smoking.⁽⁶²⁾

PRECAUTIONS:

Making a few lifestyle changes can dramatically lower the chances of developing type 2 diabetes. The same changes can also lower the chances of developing heart disease and some cancers. Offer following preventions to patient:

CONTROL YOUR WEIGHT: Excess weight is the single most important cause of type 2 diabetes. Being overweight increases the chances of developing type 2 diabetes seven fold. Being obese makes 20 to 40 times more likely to develop diabetes than someone with a healthy weight.⁽⁶³⁾

Losing weight can help if your weight is above the healthy-weight range. Losing 7 to 10 percent of your current weight can cut your chances of developing type 2 diabetes in half.

INCREASE YOUR ACTIVITY: Inactivity promotes type 2 diabetes.⁽⁶⁴⁾ Working your muscles more often and making them work harder improves their ability to use insulin and absorb glucose. This puts less stress on your insulin-making cells.

Long bouts of hot, sweaty exercise aren’t necessary to reap this benefit. Findings from the Nurses’ Health Study and Health Professionals Follow-up Study suggest that walking briskly for a half hour every day reduces the risk of developing type 2 diabetes by 30 percent.^(65,66) This amount of exercise has a variety of other benefits as well. And even greater cardiovascular and other advantages can be attained by more, and more intense, exercise.

TUNE UP YOUR DIET: Four dietary changes can have a big impact on the risk of type 2 diabetes.

• Choose whole grains and whole grain products over highly processed carbohydrates.
• Skip the sugary drinks, and choose water, coffee, or tea instead.
• Choose good fats instead of bad fats, such as the polyunsaturated fats found in liquid vegetable oils, nuts, and seeds can help ward off type 2 diabetes. Trans fats do just the opposite. These bad fats are found in many margarines, packaged baked goods, fried foods in most fast-food restaurants, and any product that lists “partially hydrogenated vegetable oil” on the label.
• Limit red meat and avoid processed meat; choose nuts, whole grains, poultry, or fish instead.

QUIT SMOKING: Add type 2 diabetes to the long list of health problems linked with smoking. Smokers are roughly 50 percent more likely to develop diabetes than nonsmokers, and heavy smokers have an even higher risk.⁽⁶⁷⁾

LIMIT YOUR ALCOHOL INTAKE: Evidence suggests that moderate alcohol consumption with reduced risk of heart disease. The same may be true for type 2 diabetes. Moderate amounts of alcohol, up to a drink a day for women, up to two drinks a day for men—increases the efficiency of insulin at getting glucose inside cells. And some studies indicate that moderate alcohol consumption decreases the risk of type 2 diabetes.

REFERENCES:

1. Global report on diabetes. World Health Organization, Geneva, 2016. (http://www.who.int/diabetes/global-report/en/)
2. Projections of global mortality and burden of disease from 2002 to 2030. Mathers CD, Loncar D. PLoS Med, 2006, 3(11):e442.
3. https://www.diabetesaustralia.com.au/diabetes-globally
4. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of Diabetes: estimates for year 2000 and projections for 2030. Diabetes Care 2004; 27: 1047-53
5. http://www.who.int/diabetes/country-profiles/pak_en.pdf?ua=1
6. http://www.idf.org/membership/mena/pakistan
7. Atlas ID. Brussels: International Diabetes Federation; 2015.
8. Reporter S. ‘120,000 die of diabetes in Pakistan every year’ [Accessed on 2 Nov 2015];The Dawn.2013
9. Jafar TH, Levey AS, White FM et al. Ethnic differences and determinants of diabetes and central obesity among South Asians of Pakistan. Diabet Med 2004; 21: 716-23.
10. Shera AS, Jawad F, Maqsood A. Prevalence of diabetes in Pakistan. Diabetes Res Clin Pract 2007; 76: 219-22.
11. Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract. Jan 2010; 87(1): 4- 14. available online from http://www.idf.org/home/index.cfm.
12. Unger RH, Orci L. Paracrinology of islets and the paracrinopathy of diabetes.Proc Natl Acad Sci U S A. 2010 Sep 14. 107(37):16009-12.
13. Bacha F, Lee S, Gungor N, Arslanian SA. From pre-diabetes to type 2 diabetes in obese youth: pathophysiological characteristics along the spectrum of glucose dysregulation.Diabetes Care. 2010 Oct. 33(10):2225-31.
14. Hansen KB, Vilsboll T, Bagger JI, Holst JJ, Knop FK. Increased postprandial GIP and glucagon responses, but unaltered GLP-1 response after intervention with steroid hormone, relative physical inactivity, and high-calorie diet in healthy subjects.J Clin Endocrinol Metab. 2011 Feb. 96(2):447-53.
15. Wheeler E, Barroso I. Genome-wide association studies and type 2 diabetes.Brief Funct Genomics. 2011 Mar. 10(2):52-60.
16. Billings LK, Florez JC. The genetics of type 2 diabetes: what have we learned from GWAS? Ann N Y Acad Sci. 2010 Nov;1212:59-77.
17. Nielsen EM, Hansen L, Carstensen B, Echwald SM, Drivsholm T, Glumer C, et al. The E23K variant of Kir6.2 associates with impaired post-OGTT serum insulin response and increased risk of type 2 diabetes.Diabetes. 2003 Feb. 52(2):573-7.
18. Ukkola O, Sun G, Bouchard C. Insulin-like growth factor 2 (IGF2 ) and IGF-binding protein 1 (IGFBP1) gene variants are associated with overfeeding-induced metabolic changes. Diabetologia. 2001 Dec. 44(12):2231-6.
19. Lindgren CM, McCarthy MI. Mechanisms of disease: genetic insights into the etiology of type 2 diabetes and obesity. Nat Clin Pract Endocrinol Metab. 2008 Mar. 4(3):156-63.
20. Sladek R, Rocheleau G, Rung J, Dina C, Shen L, Serre D, et al. A genome-wide association study identifies novel risk loci for type 2 diabetes.Nature. 2007 Feb 22. 445(7130):881-5.
21. Sandhu MS, Weedon MN, Fawcett KA, Wasson J, Debenham SL, Daly A, et al. Common variants in WFS1 confer risk of type 2 diabetes.Nat Genet. 2007 Aug. 39(8):951-3.
22. Saxena R, Hivert MF, Langenberg C, Tanaka T, Pankow JS, Vollenweider P, et al. Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge.Nat Genet. 2010 Feb. 42(2):142-8.
23. Wang TJ, Larson MG, Vasan RS, Cheng S, Rhee EP, McCabe E, et al. Metabolite profiles and the risk of developing diabetes.Nat Med. 2011 Apr. 17(4):448-53.
24. Krssak M, Winhofer Y, Gobl C, Bischof M, Reiter G, Kautzky-Willer A, et al. Insulin resistance is not associated with myocardial steatosis in women.Diabetologia. 2011 Jul. 54(7):1871-8.
25. Leiter LA, Lundman P, da Silva PM, Drexel H, Junger C, Gitt AK. Persistent lipid abnormalities in statin-treated patients with diabetes mellitus in Europe and Canada: results of the Dyslipidaemia International Study.Diabet Med. 2011 Nov. 28(11):1343-51.
26. Busko M. Gray-matter atrophy may drive cognitive decline in diabetes. Medscape Medical News. August 22, 2013.
27. Campbell IW. Epidemiology and clinical presentation of type 2 diabetes. Value Health. 2000 Nov-Dec;3 Suppl 1:3-6.
28. [Guideline] Diagnosis and classification of diabetes mellitus.Diabetes Care. 2010 Jan. 33 Suppl 1:S62-9.
29. Hujoel PP, Stott-Miller M. Retinal and gingival hemorrhaging and chronic hyperglycemia.Diabetes Care. 2011 Jan. 34(1):181-3.
30. [Guideline] American Diabetes Association. Standards of medical care in diabetes--2012.Diabetes Care. 2012 Jan. 35 Suppl 1:S11-63.
31. Brambilla P, La Valle E, Falbo R, Limonta G, Signorini S, Cappellini F, et al. Normal fasting plasma glucose and risk of type 2 diabetes.Diabetes Care. 2011 Jun. 34(6):1372-4.
32. Sacks DB, Arnold M, Bakris GL, Bruns DE, Horvath AR, Kirkman MS, et al. Executive summary: guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus.Clin Chem. 2011 Jun. 57(6):793-8.
33. World Health Organization. Definition and diagnosis of diabetes mellitus and intermediate hyperglycemia: report of a WHO/IDF consultation. World Health Organization, Geneva, 2006. Available at http://whqlibdoc.who.int/publications/2006/9241594934_eng.pdf.
34. American Association of Clinical Endocrinologists Statement on the Use of A1C for the Diagnosis of Diabetes. Available at https://www.aace.com/files/AACEpositionA1cfeb2010.pdf. Accessed: May 14 2012.
35. Wang W, Lee ET, Howard BV, Fabsitz RR, Devereux RB, Welty TK. Fasting plasma glucose and hemoglobin A1c in identifying and predicting diabetes: the strong heart study.Diabetes Care. 2011 Feb. 34(2):363-8
36. Nowicka P, Santoro N, Liu H, Lartaud D, Shaw MM, Goldberg R, et al. Utility of hemoglobin A(1c) for diagnosing prediabetes and diabetes in obese children and adolescents.Diabetes Care. 2011 Jun. 34(6):1306-11
37. S. Preventive Services Task Force. Screening for Type 2 Diabetes Mellitus in Adults. Available at http://www.ahrq.gov/clinic/uspstf/uspsdiab.htm.
38. Romesh, Khardori. "Type 2 Diabetes Mellitus Workup: Approach Considerations, Glucose Studies, Glycated Hemoglobin Studies". Emedicine.medscape.com. N.p., 2017. Web. 15 Feb. 2017.
39. Scarpello JH, Howlett HC. Metformin therapy and clinical uses.Diab Vasc Dis Res. 2008 Sep. 5(3):157-67
40. Bellomo Damato A, Stefanelli G, Laviola L, Giorgino R, Giorgino F. Nateglinide provides tighter glycaemic control than glyburide in patients with Type 2 diabetes with prevalent postprandial hyperglycaemia.Diabet Med. 2011 May. 28(5):560-6
41. Charpentier G, Halimi S. Earlier triple therapy with pioglitazone in patients with type 2 diabetes.Diabetes Obes Metab. 2009 Sep. 11(9):844-54.
42. US Food and Drug Administration. FDA Drug Safety Communication: Updated Risk Evaluation and Mitigation Strategy (REMS) to Restrict Access to Rosiglitazone-containing Medicines including Avandia, Avandamet, and Avandaryl. Available at http://www.fda.gov/Drugs/DrugSafety/ucm255005.htm. Accessed: January 20, 2012
43. Bunck MC, Diamant M, Corner A, Eliasson B, Malloy JL, Shaginian RM, et al. One-year treatment with exenatide improves beta-cell function, compared with insulin glargine, in metformin-treated type 2 diabetic patients: a randomized, controlled trial.Diabetes Care. 2009 May. 32(5):762-8.
44. Buse JB, Bergenstal RM, Glass LC, Heilmann CR, Lewis MS, Kwan AY, et al. Use of twice-daily exenatide in Basal insulin-treated patients with type 2 diabetes: a randomized, controlled trial.Ann Intern Med. 2011 Jan 18. 154(2):103-12
45. US Food and Drug Administration. FDA approves Tanzeum to treat type 2 diabetes [press release]. April 15, 2014. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm393289.htm. Accessed: April 21, 2014.
46. Busko M. FDA approves weekly injectable diabetes drug: albiglutide.Medscape Medical News. April 15, 2014.
47. Tucker M. FDA Approves Once-Weekly Dulaglutide for Type 2 Diabetes. Medscape Medical News. Available at http://www.medscape.com/viewarticle/831969. Accessed: September 26, 2014.
48. Wysham C, Blevins T, Arakaki R, Colon G, Garcia P, Atisso C, et al. Efficacy and safety of dulaglutide added onto pioglitazone and metformin versus exenatide in type 2 diabetes in a randomized controlled trial (AWARD-1).Diabetes Care. 2014 Aug. 37(8):2159-67.
49. Aschner P, Katzeff HL, Guo H, Sunga S, Williams-Herman D, Kaufman KD, et al. Efficacy and safety of monotherapy of sitagliptin compared with metformin in patients with type 2 diabetes.Diabetes Obes Metab. 2010 Mar. 12(3):252-61.
50. Owens DR, Swallow R, Dugi KA, Woerle HJ. Efficacy and safety of linagliptin in persons with type 2 diabetes inadequately controlled by a combination of metformin and sulphonylurea: a 24-week randomized study.Diabet Med. 2011 Nov. 28(11):1352-61
51. Willemen MJ, Mantel-Teeuwisse AK, Straus SM, Meyboom RH, Egberts TC, Leufkens HG. Use of dipeptidyl peptidase-4 inhibitors and the reporting of infections: a disproportionality analysis in the World Health Organization VigiBase.Diabetes Care. 2011 Feb. 34(2):369-74.
52. Nainggolan L. FDA approves canagliflozin, a first-in-class diabetes drug. March 29, 2013. Medscape Medical News. Available at http://www.medscape.com/viewarticle/781709. Accessed: April 2, 2013.
53. US Food and Drug Administration. FDA approves Invokana to treat type 2 diabetes [press release]. March 29, 2013. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm345848.htm. Accessed: April 2, 2013.
54. Tucker M. FDA Approves Dapagliflozin (Farxiga) for Type 2 Diabetes Treatment. Medscape Medical News. Available at http://www.medscape.com/viewarticle/818858. Accessed: January 13, 2014.
55. FDA News Release. FDA approves Farxiga to treat type 2 diabetes. U.S. Food and Drug Administration. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm380829.htm. Accessed: January 13, 2014.
56. Roden M, Weng J, Eilbracht J, et al. Empagliflozin monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes: a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet Diabetes Endocrinol. 2013 Nov. 1(3):208-19. [
57. Ridderstrale M, Andersen KR, Zeller C, Kim G, Woerle HJ, Broedl UC. Comparison of empagliflozin and glimepiride as add-on to metformin in patients with type 2 diabetes: a 104-week randomised, active-controlled, double-blind, phase 3 trial.Lancet Diabetes Endocrinol. 2014 Jun 16.
58. Clar C, Gill JA, Court R, Waugh N. Systematic review of SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes.BMJ Open. 2012. 2(5)
59. Shyangdan DS, Royle P, Clar C, Sharma P, Waugh N, Snaith A. Glucagon-like peptide analogues for type 2 diabetes mellitus.Cochrane Database Syst Rev. 2011 Oct 5. CD006423.
60. Handelsman Y, Goldberg RB, Garvey WT, Fonseca VA, Rosenstock J, Jones MR, et al. Colesevelam hydrochloride to treat hypercholesterolemia and improve glycemia in prediabetes: a randomized, prospective study.Endocr Pract. 2010 Jul-Aug. 16(4):617-28.
61. Sando KR, Taylor J. Bromocriptine: its place in type 2 diabetes Tx.J Fam Pract. 2011 Nov. 60(11):E1-5.
62. http://bestpractice.bmj.com/best-practice/monograph/24/follow-up/recommendations.html
63. Hu FB, Manson JE, Stampfer MJ, et al. Diet, lifestyle, and the risk of type 2 diabetes mellitus in women. N Engl J Med. 2001; 345:790-7.
64. Rana JS, Li TY, Manson JE, Hu FB. Adiposity Compared With Physical Inactivity and Risk of Type 2 Diabetes in Women. Diabetes Care. 2007; 30:53-58.
65. Tanasescu M, Leitzmann MF, Rimm EB, Hu FB. Physical activity in relation to cardiovascular disease and total mortality among men with type 2 diabetes. Circulation. 2003.
66. Hu FB, Sigal RJ, Rich-Edwards JW, et al. Walking compared with vigorous physical activity and risk of type 2 diabetes in women: a prospective study. JAMA. 1999; 282:1433-9.
67. Willi C, Bodenmann P, Ghali WA, Faris PD, Cornuz J. Active Smoking and the Risk of Type 2 Diabetes: A Systematic Review and Meta-analysis. JAMA. 2007; 298:2654-2664.