Insulin resistance (IR) 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 reduces the effects of insulin and results in elevated hydrolysis of stored triglycerides in the absence of measures which either increase insulin sensitivity or which provide additional insulin. Increased mobilization of stored lipids in these cells elevates free fatty acids in the blood plasma. Insulin resistance in muscle cells reduces glucose uptake (and so local storage of glucose as glycogen), whereas insulin resistance in liver cells results in impaired glycogen synthesis and a failure to suppress glucose production.Elevated blood fatty-acid concentrations (associated with insulin resistance and diabetes mellitus Type 2), reduced muscle glucose uptake, and increased liver glucose production all contribute to elevated blood glucose concentration. High plasma levels of insulin and glucose due to insulin resistance are believed to be the origin of metabolic syndrome and type 2 diabetes, including its complications. 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 Gastroparesis Tobacco Smoking Coffee (A Canadian study has found that consumption of caffeine makes insulin more resistant to alterations in blood sugar in patients with and without diabetes.) Polycystic ovarian syndrome (PCOS) Hypercortisolism (e.g., steroid use or Cushing's disease) Drugs (e.g., rifampicin, isoniazid, olanzapine, risperidone, progestogens, corticosteroids, glucocorticoids, 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 having undergone a defect of insulin receptors in hepatocytes . Insulin resistance means that body cells do not respond appropriately when insulin is present. Unlike type 1 diabetes mellitus, insulin resistance is generally "post-receptor", meaning it is a problem with the cells that respond to insulin rather than a problem with the production of insulin. Other important contributing factors: increased hepatic glucose production (e.g., from glycogen -> glucose conversion), especially at inappropriate times (typical cause is deranged insulin levels, as those levels control this function in liver cells) decreased insulin-mediated glucose transport in (primarily) muscle and adipose tissues (receptor and post-receptor defects) impaired beta-cell functionloss of early phase of insulin release in response to hyperglycemic stimuli Pathophysiology Type 2 diabetes is due to insufficient insulin production from beta cells in the setting of insulin resistance.[3] Insulin resistance, which is the inability of cells to respond adequately to normal levels of insulin, occurs primarily within the muscles, liver, and fat tissue.[24] In the liver, insulin normally suppresses glucose release. However, in the setting of insulin resistance, the liver inappropriately releases glucose into the blood.[4] The proportion of insulin resistance versus beta cell dysfunction differs among individuals, with some having primarily insulin resistance and only a minor defect in insulin secretion and others with slight insulin resistance and primarily a lack of insulin secretion.[3] Other potentially important mechanisms associated with type 2 diabetes and insulin resistance include: increased breakdown of lipids within fat cells, resistance to and lack of incretin, high glucagon levels in the blood, increased retention of salt and water by the kidneys, and inappropriate regulation of metabolism by the central nervous system.[4] However, not all people with insulin resistance develop diabetes, since an impairment of insulin secretion by pancreatic beta cells is also required.[3] Pathophysiology Insulin is secreted by beta cells, which is one of four types of cells in the islets of Langerhans in the pancreas. Insulin is an anabolic, or storage hormone. When a person eats meal, insulin secretion increases and moves glucose from the blood into muscle, liver and fat cells. In those cells, insulin transports and metabolizes glucose for energy, stimulates storage of glucose in the liver and muscle, signals the liver to stop release of glucose, enhances storage of dietary fat in adipose tissues, and accelerates transport of amino acids into cells. Insulin also inhibits the breakdown of stored glucose, protein and fat. During fasting periods, the pancreas continuously releases a small amount of insulin; another pancreatic hormone called glucagon is released when blood glucose levels decrease and stimulates the liver to release stored glucose. The insulin and the glucagon in the blood by stimulating the release of glucose from the liver. Initially, the liver produces glucose through the breakdown of glycogen. After 8-12 hours without food, the liver forms glucose from the breakdown of non-carbohydrate substances, including amino acids. In type II diabetes, the two main problems are insulin resistance and impaired insulin secretion. Insulin resistance refers to a decreased tissue sensitivity to insulin. Normally, insulin binds to special receptors on cell surfaces and initiates a series of reactions involved in glucose metabolism. In type II diabetes, these intracellular reactions are diminished, making insulin less effective at stimulating glucose uptake by the liver. The exact mechanisms that lead to insulin resistance and impaired insulin secretion in type II diabetes are unknown, although genetic factors are ought to play a role. To overcome insulin resistance and prevent the buildup of glucose in the blood, increased amounts of insulin must be secreted to maintain the glucose level at a normal or slightly elevated level. However, if the beta cells cannot keep up with the increased demand for insulin, the glucose level rises and type II diabetes develops.

Despite the impaired secretion of insulin that is a characteristic of type II diabetes, there is enough insulin present to prevent the breakdown of fat the accompanying production of ketone bodies. Therefore, DKA does not typically occur in type II diabetes. However, uncontrolled type II diabetes may lead to another acute problem. Because type II diabetes is associated with a slow, progressive glucose intolerance, its onset may go undetected for many years. If the patient experiences symptoms, they are frequently mild and may include fatigue, irritability, polyuria, polydipsia, poor healing skin wounds, vaginal infections or blurred vision if glucose levels are very high.