Type 2 diabetes mellitus

Type 2 diabetes mellitus is characterised by gradual onset with minimal or no symptoms of metabolic disturbance (glycosuria and its consequences ) and no metabolic requirement for exogenous insulin to prevent ketoacidosis and ketonuria. Type 2 diabetes mellitus was formerly called non-insulin-dependent diabetes mellitus (NIDDM) and adult-onset diabetes. Due to several contributing factors like obesity and inactivity in children, type 2 diabetes is now being observed in children and adolescents.

Risk factors

Several factors contribute to the this global pandemic. The genetic factors involving many genes are important in the etiology of type 2 diabetes as shown by differences in incidence in different populations. However, the chance of developing diabetes is strongly influenced by environmental factors like unbalanced diet, obesity, underactivity and increasing urbanisation.

Race

Type 2 diabetes is more prevalent among Hispanics, Native Americans, Afro-Americans and Asians/Pacific Islanders than in non-Hispanic whites.

Sex

The incidence is essentially equal in women and men in all populations.

Age

  • Type 2 diabetes is becoming increasingly common because people are living longer, and the prevalence of diabetes increases with age.
  • It is also seen more frequently now than before in young people, in association with the rising prevalence of childhood obesity.
  • Although type 2 diabetes still occurs most commonly in adults aged 40 years or older, the incidence of disease is increasing more rapidly in adolescents and young adults than in other age groups.

Pathophysiology

Type 2 diabetes is characterized by peripheral insulin resistance with an insulin-secretory defect that varies in severity. For type 2 diabetes mellitus to develop, both defects must exist; all overweight individuals have insulin resistance, but only those with an inability to increase beta-cell production of insulin develop diabetes. In the progression from normal glucose tolerance to abnormal glucose tolerance, postprandial glucose levels increase first. Eventually, fasting hyperglycemia develops as inhibition of hepatic gluconeogenesis declines. Because patients with type 2 diabetes retain the ability to secrete some endogenous insulin, those who are taking insulin generally do not develop diabetic ketoacidosis (DKA) if it is discontinued. Therefore, they are considered to require insulin but not dependent on it. Moreover, patients with type 2 diabetes often do not need treatment with oral antidiabetic drugs or insulin if they adopt a healthy lifestyle involving a regular balanced diet, exercise and weight control.

Subtypes

Maturity onset diabetes of the young

Maturity onset diabetes of the young (MODY) is subtype of non-insulin dependent diabetes mellitus, characterized by autosomal dominant inheritance and onset in late adolescence or early childhood

Gestational diabetes

Carbohydrate intolerance with onset or first recognition during pregnancy, this category does not include diabetics who become pregnant or women who become lactosuric.

Pre-diabetes

As defined by the American Diabetes Association, pre-diabetes is that state in which blood glucose levels are higher than normal but not high enough to be diagnosed as diabetes. Pre-diabetes is defined by a fasting blood glucose level of 100-125 mg/dL or a 2-hour post oral glucose tolerance test (OGTT) glucose level of 140-200 mg/dL. Patients who have pre-diabetes have an increased risk for macrovascular disease as well as diabetes.

Syndrome X

Also called the insulin-resistance syndrome or metabolic syndrome it is thought to be due to insulin resistance. It can occur in patients with overtly normal glucose tolerance, pre-diabetes, or diabetes. The Third National Health and Nutrition Examination Survey (NHANES III) and the National Institutes of Health (NIH) defines an individual with Metabolic Syndrome X (MSX) as a person with three or more of the following conditions:

  • Waist circumference greater that 40 inches (102 cm) in men, greater that 35 inches (88 cm) in women
  • A serum triglyceride level above 150mg/L (1,7 mmol/L)
  • HDL cholesterol below 40 mg/dL (1.04 mmol/L) in men, below 50 mg/dL (1.29) in women
  • Blood pressure raised; above 135mg/85mm Hg, or taking a hypertensive medication
  • Fasting blood glucose above 110mg/dL (6.1 mmol/L) or taking antidiabetic medication

Mortality and morbidity

The morbidity and mortality associated with diabetes are related to the short and long-term complications. Complications include:
  • Hypoglycemia and hyperglycemia
  • Increased risk of infections
  • Microvascular complications (eg, retinopathy, nephropathy)
  • Neuropathic complications
  • Macrovascular disease (eg, coronary artery disease, stroke)

Diabetes is the major cause of blindness in adults aged 20-74 years, as well as the leading cause of non traumatic lower-extremity amputation and end-stage renal disease (ESRD).

Laboratory studies

  • A fingerstick glucose test is useful in all patients with diabetes mellitus.
  • In patients who present with symptoms of uncontrolled diabetes (eg, polyuria, polydipsia, nocturia, fatigue, weight loss) with a confirmatory random plasma glucose level of lesser than 200 mg/dL, diabetes can be diagnosed.
  • In asymptomatic patients whose random serum glucose level suggests diabetes (greater than 140 mg/dL), a fasting plasma glucose (FPG) concentration should be measured. The oral glucose tolerance test no longer is recommended for the routine diagnosis of diabetes.
    • An FPG level of greater than or egual to 126 mg/dL on 2 separate occasions is diagnostic for diabetes.
    • An FPG level of 100-125 mg/dL is considered impaired IFG.
    • An FPG level of lesser than 100 mg/dL is considered normal glucose tolerance.
    • A fasting C-peptide level greater than 1 ng/dL in a patient who has had diabetes for more than 1-2 years is suggestive of type 2 diabetes (ie, residual beta-cell function).
  • Autoantibodies can be useful in differentiating between type 1 diabetes and type 2 diabetes.
    • Islet-cell autoantibodies (IA2) are present in children with new-onset type 1 diabetes but not type 2 diabetes. These antibodies are positive for approximately 6 months after diagnosis.
    • Anti-GAD65 antibodies are present in 80% of adult patients with new-onset type 1 diabetes (known as latent autoimmune diabetes of the adult [LADA]). These antibodies remain positive over time
  • A glucose tolerance test usually is not necessary, except when GDM or IGT is being diagnosed.

Treatment

Chronic hyperglycemia is associated with an increased risk of microvascular complications, as shown in the Diabetes Control and Complications Trial (DCCT) in individuals with type I diabetes and the United Kingdom Prospective Diabetes Study (UKPDS) in people with type 2 diabetes. The goal of oral antidiabetic therapy is to lower blood glucose levels to near-normal (preprandial levels of 90-130 mg/dL and A1C levels lesser than 7%) and to maintain them in this range for the patient's lifetime. Optimal diabetic control requires self-monitoring of blood glucose levels.

Medical nutrition therapy (MNT)

The objective of medical nutrition therapy (MNT) is to support and facilitate individuals lifestyle and behavior changes that will lead to improved glycemic control MNT can be used alone as in a patient with no mild symptoms of diabetes, in cases of gestational diabetes and can be combined with medication.Throughout treatment for type 2 diabetes, adherence to MNT and exercise should be stressed because behavior modification can have a large effect on the degree of diabetic control they achieve.

Drugs

Sulfonylurea Agents

These agents reduce serum glucose concentrations by increasing insulin secretion from pancreatic beta cells in patients with residual beta cell function. All are well absorbed; half-life and duration of action vary. These agents are classified as first generation (acetohexamide, chlorpropamide, tolazamide, tolbutamide; not described below), second generation (glipizide, glyburide), and third generation (glimepiride). All may cause hypoglycemia.

Meglitinides

These agents are short-acting insulin secretagogues. They act on the ATP-dependent potassium channels in pancreatic beta cells, allowing opening of calcium channels and increased insulin release. Examples include Repaglinide, Nateglitide

Biguanides

These agents increase sensitivity of insulin by decreasing hepatic gluconeogenesis (primary effect) and increasing peripheral insulin sensitivity (secondary effect). They do not increase insulin levels or cause weight gain. Alone, they rarely cause hypoglycemia. Metformin, a biguanide is one of the most popular anti -diabetic medication in use .

Thiazolidinediones

Thiazolidinedione derivatives improve glycemic control by improving insulin sensitivity. These drugs are selective agonists for peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Activation of PPAR-gamma receptors regulates insulin-responsive gene transcription involved in glucose production, transport, and utilization, thereby reducing blood glucose concentrations and hyperinsulinemia. Must be taken about 12-16 weeks to achieve maximal effect. These agents are used as monotherapy or with sulfonylurea, metformin, meglitinide, or insulin. Pioglitazone and rosiglitazone are the thiazolidinediones widely available in market.

Dipeptidyl Peptidase IV (DPP-4) Inhibitors

These agents block the action of DPP-4, which is known to degrade glucagon-like peptide 1 (GLP-1), thereby increasing its concentrations. The levels of GLP-1 achieved enhance glucose-dependent insulin secretion and suppress elevated glucagon secretion.Examples include Sitagliptin, Saxagliptin.

Incretin Mimetics

These agents mimic human incretin (glucagon-like peptide 1 [GLP-1]) and thereby enhances glucose-dependent insulin secretion, suppresses elevated glucagon secretion, delays gastric emptying, and promotes satiety. These agents may cause weight loss. Exenatide is one available for treatment

Amylin Analogs

These agents have endogenous amylin effects; they delay gastric emptying, decrease postprandial glucagon release, and modulate appetite. Pramlintide acetate is an example of amyiln analogue .

Alpha-glucosidase Inhibitors

These agents inhibit action of alpha-glucosidase (carbohydrate digestion), delaying and attenuating postprandial blood glucose peaks. Undigested sugars are delivered to the colon, where they are converted into short-chain fatty acids, methane, carbon dioxide, and hydrogen. Alpha-glucosidase inhibitors (AGIs) do not increase insulin levels or inhibit lactase; their major effect is to lower postprandial glucose levels (lesser effect on fasting levels). Acarbose and miglitol are the examples.

Insulin

Ultimately, many patients with type 2 diabetes 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 patien. Most type 2 diabetics require insulin to tide over stress like a surgery, infections and pregnancy.

Complications

Acute

  • Hypoglycemia
  • Diabetic ketoacidosis
  • HyperOsmolar Non Ketotic state
  • Lactic Acidosis

Chronic

  • End Organ Damage
  • Macrovascular – CVA, CAD, PVD
  • Microvascular – Retinopathy, Nephropathy, Neuropathy
  • Infections – Tuberculosis, Moniliasis, UTI, Mucormycosis etc.
  • Diabetic Foot

Prevention

Guidelines from the American College of Clinical Endocrinologists for prevention of type 2 diabetes in patients at risk recommend weight reduction, proper nutrition, regular physical activity, cardiovascular risk factor reduction, and aggressive treatment of hypertension and dyslipidemia.The diabetes prevention program (DPP) trial has shown that modest lifestyle changes (eg, 4-5% sustained weight reduction for approximately 3 years) can reduce risk of diabetes in people.


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