Insulin resistance

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

Insulin resistance is the condition in which normal amounts of insulin are inadequate to produce a normal insulin response from fat, muscle and liver cells. Insulin resistance in fat cells results in hydrolysis of stored triglycerides, which elevates free fatty acids in the blood plasma. Insulin resistance in muscle reduces glucose uptake whereas insulin resistance in liver reduces glucose storage, with both effects serving to elevate blood glucose. High plasma levels of insulin and glucose due to insulin resistance often lead to metabolic syndrome and type 2 diabetes.

Insulin resistance could be the earliest predictor of Diabetes Mellitus type 2. Obesity, especially fat accumulation on the abdominal and intra-abdominal visceral area, and insulin resistance are linked to series of complications such as cardiovascular disease or CVD and type 2 diabetes.

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

The concept that insulin resistance may be the underlying cause of diabetes mellitus type 2 was first advanced by Sir Harold Percival Himsworth of the University College Hospital Medical Center in London in 1936.^[1]

In the 1950’s, research scientists Solomon Berson and Rosalyn Yalow developed a technique to measure circulating levels of hormones and other substances in the blood, called radioimmunoassay. Using this technique lead Berson and Yalow to discover that individuals with type 2 diabetes exhibited higher than average levels of circulating insulin than individuals with normal glucose tolerance.

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

In a person with normal metabolism, insulin is released from the beta (β) cells of the Islets of Langerhans located in the pancreas after eating (“postprandial”), and it signals insulin-sensitive tissues in the body (e.g., muscle, adipose) to absorb glucose to lower blood glucose to a normal level (approximately 5 mmol/L (mM), or 90 mg/dL). In an insulin resistant person, normal levels of insulin do not trigger the signal for glucose absorption by muscle and adipose cells. To compensate for this, the pancreas in an insulin resistant individual releases much more insulin such that the cells are adequately triggered to absorb glucose. Occasionally, this can lead to a steep drop in blood sugar and a hypoglycemic reaction several hours after the meal.

The most common type of insulin resistance is associated with a disease state known as metabolic syndrome. Insulin resistance can progress to full type 2 diabetes. This is often seen when hyperglycemia develops after a meal, when pancreatic β-cells are unable to produce adequate insulin to maintain normal blood sugar levels (euglycemia). The inability of the β-cells to produce more insulin in a condition of hyperglycemia is what characterizes the transition from insulin resistance to type 2 diabetes.^[1]

Various disease states make the body tissues more resistant to the actions of insulin. Examples include infection (mediated by the cytokine TNFα) and acidosis. Recent research is investigating the roles of adipokines (the cytokines produced by adipose tissue) in insulin resistance. Certain drugs may also be associated with insulin resistance (e.g., glucocorticoids).

Elevated blood levels of glucose regardless of cause leads to increased glycation of proteins.

Insulin resistance is often found in people with visceral adiposity (i.e., a high degree of fatty tissue underneath the abdominal muscle wall – as distinct from subcutaneous adiposity or fat between the skin and the muscle wall), hypertension, hyperglycemia and dyslipidemia involving elevated triglycerides, small dense low-density lipoprotein (sdLDL) particles, and decreased HDL cholesterol levels.

Insulin resistance is also often associated with a hypercoagulable state (impaired fibrinolysis) and increased inflammatory cytokine levels.

Insulin resistance is also occasionally found in patients who use insulin. In this case, the production of antibodies against insulin leads to lower-than-expected falls of glucose levels (glycemia) after a given dose of insulin. With the development of human insulin and analogues in the 1980s and the decline in the use of animal insulins (e.g., pork, beef), this type of insulin resistance has become very uncommon.

Several associated conditions include

• Abnormally Sedentary Lifestyle, whether the result of the effects of aging on the body or lack of physical exercise (both of which can also produce obesity)
• Haemochromatosis
• Polycystic ovarian syndrome (PCOS)
• Hypercortisolism (e.g. steroid use or Cushing’s disease)
• Drugs (e.g. rifampicin, isoniazid, olanzapine, risperidone, progestogens, many antiretrovirals, possibly alcohol, methadone)
• Genetic causes
  • Insulin receptor mutations (Donohue Syndrome)
  • LMNA mutations (Familial Partial Lipodystrophy)

Insulin resistance may also be caused by the damage of liver cells which result in defect of insulin receptors in hepatocytes.

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

The exact cause of insulin resistance is not yet understood. The relationship between obesity, inactivity, a diet high in carbohydrates, and insulin resistance is not clear. It is not yet known if insulin resistance causes excess weight or if insulin resistance is a result of excess weight and obesity. However, They do reinforce each other and tend to coexist.

The cause of the vast majority of cases of insulin resistance remains unknown. However, scientists believe insulin resistance might be caused by excess weight, physical inactivity and a high carbohydrate diet. Some physicians also believe that glucosamine (often prescribed for joint problems), certain steroids and lack of sleep may cause insulin resistance.

Excess fat, especially around the belly area is believed to be the primary cause of insulin resistance. Studies have shown that belly fat produces hormones and other substances that can cause health problems such as insulin resistance, high blood pressure and cardiovascular disease or CVD. The inflammation caused by chronic belly fat can be a contributor to insulin resistance, type 2 diabetes and cardiovascular disease.

Weight loss and physical activity can help treat insulin resistance and high blood glucose. Muscles use glucose more than other tissues, leading active muscles to burn their stored glucose and to utilise glucose from bloodstream to replace lost glucose, which in turn would lead to lower blood glucose, provided a balanced low glycemic index diet is followed.

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