INSULIN RESISTANCE AND HYPERINSULINEMIA
What are insulin resistance (IR) and hyperinsulinemia?
Beta cells in the pancreas produce insulin. Insulin stimulates uptake of glucose (sugar) from the blood to the cells in the body. When the body's cells are resistant to the action of the insulin, it is called insulin resistance (IR). As a result of the insulin resistance, the pancreas produces much more insulin than normal. This is called hyperinsulinemia (Figures 1,2). As an example, in a normal person, 1 unit of insulin might be needed to help 10 mg of glucose go into the cell, but in a hyperinsulinemic person, 10 units of insulin might be needed to get the same 10 mg of glucose into the cell (Figure 2). With hyperinsulinemia and IR come a myriad of problems including the following:
High insulin can also stimulate the kidney to produce angiotension, a substance which increases blood pressure (Figure 1).
Leptin, a hormone secreted by fat cells, is an important part of weight regulation. Leptin acts to control food intake and energy expenditure. Leptin concentrations increase with obesity and tend to decrease with weight loss. This is important because leptin levels correlate with insulin levels (both are high in hyperinsulinemia2).
IR causes abnormal ovarian and adrenal androgen secretion which results in PCOS.3 This insulin resistance, along with one or all of these problems is referred to as the insulin resistance syndrome or the metabolic syndrome 8
Insulin resistance syndrome promotes:
Hyperinsulinemia is a significant independent risk factor for coronary heart disease;8 IR has a direct impact on how the lining of the blood vessels respond to changes in blood pressure.2 These effects are separate from the other dangerous effects on fat composition and blood pressure. Treating insulin resistance syndrome can significantly reduce the health risks as summarized above.
Early in the decades-long process which leads to type 2 diabetes (Figures 2, 3), the great majority of type 2 patients have hyperinsulinemia. However, long before development of diabetes, under certain metabolic stress conditions such as pregnancy, the beta cells of the pancreas are forced to produce much more insulin to overcome IR of pregnancy but fail to do this. As a result blood glucose levels rise. This is called gestational diabetes and is a marker for developing diabetes later. After a few years, a new equilibrium is reached with normal blood glucose and high insulin, and this may continue for years (Figure 2). Then, usually by ages 50-60 years, in many patients, the beta cells "burn out". The insulin levels may be "normal" but they can no longer overcome the insulin resistance, and diabetes appears (Figure 2). At this point, the patient can benefit both by reducing insulin resistance with insulin sensitizer drugs like Avandia, Actos, and Glucophage, or by adding a drug which stimulates insulin production such as Starlix, Glucovance (Glucophage + glyburide), or a longer acting insulin secretogogue, Glucotrol XL.
A simple, inexpensive, shorthand way to diagnose insulin resistance and hyperinsulinemia is a fasting serum insulin and a c-peptide level. In the pancreas, when insulin is made, it starts out as two fragments attached to each other by a connecting peptide called c-peptide. When this molecule comes out of the pancreas, two pieces split off the c-peptide, to form regular insulin, and the insulin and c-peptide exist separately. For each molecule of insulin made, a molecule of c-peptide is made, so that high insulin secretion by the pancreas is associated with high c peptide levels. If fasting serum insulin is high (greater than 20), or if c-peptide is high (greater than 4.6), then it is very likely that insulin resistance syndrome is present. This can occur with normal blood glucose or commonly in type 2 diabetes, with high blood glucose, can lead to the insulin resistance syndrome.
Early on, lifestyle modification is often effective in controlling insulin resistance syndrome. This involves achieving ideal body weight and doing aerobic exercise 5 or more times per week (Figure 2). Later, well before the onset of hyperglycemia, treatment with Glucophage, Avandia, or Actos) is very effective. Later, as functional hyperglycemia appears, addition of a sulfonlyurea or Repaglinide may be useful. The early treatment of choice is Metformin, an oral drug used in the treatment of type 2 diabetes. The dose is 500 or 850mg, three times per day with meals. By lowering insulin resistance and insulin, this will help:
Another advantage of Metformin is that it does not lower glucose in non-diabetics.
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