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 triglycerides (increased risk of heart and stroke)
high plasminogen activator inhibitor activity (PAI-Fx), causing increased risk of clotting
low HDL cholesterol (increased risk of heart attack and stroke)
high uric acid (gout)
polycystic ovary syndrome (endocrine disorder with oligo-amenorrhea, infertility, hirsutism, obesity, high Leptin levels
type 2 diabetes
obesity (Figures 1,3)

High insulin can also stimulate the kidney to produce angiotension, a substance which increases blood pressure (Figure 1).

How is hyperinsulinemia related to Leptin?

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).

Why is insulin resistance medically important?

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:

heart attack
stroke
type 2 diabetes
morbid obesity
hypertension
endocrine disorders in women
clotting problems.

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.

How is insulin resistance syndrome related to type 2 diabetes (adult onset diabetes)?

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.

How can you diagnose insulin resistance?

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.

How can you treat 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:

lower triglycerides
elevate HDL cholesterol
treat type 2 diabetes
lower blood pressure
lower PAI-Fx
lower uric acid
reduce body weight

Another advantage of Metformin is that it does not lower glucose in non-diabetics.

INSULIN RESISTANCE SYNDROME (figure 1)

BACKGROUND: Many patients with high levels of plasma triglycerides, low HDL cholesterol, high uric acid, Type 2 (mature onset) diabetes Mellitus, obesity, increased risk of clotting by virtue of high Plasminogen Activator Inhibitor Activity (PAI-Fx), and essential hypertension have an inherited resistance to the action of insulin. This causes the pancreas to overproduce insulin. To get the same amount of glucose (sugar) from the blood into cells, a normal person might require 1 unit of insulin for 10 mg of glucose (arbitrary numbers), while you might require 10 units of insulin for the same 10 mg of glucose. Thus, your cells are resistant to the action of your own insulin, which is INSULIN RESISTANCE.

DIAGNOSIS: A simple, inexpensive, shorthand way to diagnose insulin resistance and hyperinsulinemia is a fasting serum insulin. If serum insulin is high (L>20 uU/mL), or c-peptide is high (>4.6 ng/mL), insulin resistance may be present.

TREATMENT: The treatment of choice is Metformin, the oral drug of choice in Type 2 diabetes, at a dose of 500 or 850 mg, three times/day with meals. By lowering insulin resistance and insulin, this will help to do the following: Lower triglycerides, Elevate HDL cholesterol; Treat Type 2 diabetes (if present); Prevent the eventual appearance of Type 2 diabetes Lower blood pressure; Lower PAI-Fx; Lower uric acid; Lower body weight.

Because Metformin does not lower blood glucose in normal subjects (non-diabetics), it can be given safely to people who are not diabetic.

InsRes 98-12

Figure Legends:

Figure 1: Clinical Ramifications of Insulin Resistance Syndrome
Figure 2: Fasting blood glucose and serum insulin-Natural History of Type 2 diabetes
Figure 3: Natural history of type 2 diabetes

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