Insulin Resistance

The key feature of type 2 diabetes mellitus is insulin resistance. What this means is that the response to insulin is deficient. This is neatly illustrated by the test depicted in the graph. Two subjects are given a dose of insulin, and then the concentration of glucose in the blood (plasma glucose) is measured at different times following the insulin injection. The various actions of insulin promote a decrease in blood glucose. In a subject who is insulin resistant (red line), this decrease is less.

In practice, such a test is not used to evaluate patients suspected of having type 2 diabetes mellitus. Instead, diabetes mellitus is diagnosed by tests that reveal evidence of hyperglycemia.

One such test is the HbA1c test.  Traditionally, this test has been used to monitor the effectiveness of diabetes treatments in controlling hyperglycemia (glycemic control).  It has only recently been adopted for diagnosis following an effort to nationally standardize the test.  This test measures the percentage of glycated hemoglobin in the blood, which will be higher if there have been more periods of hyperglycemia in the recent past.  An HbA1c of 6.5% or greater is diagnostic for diabetes mellitus.  The advantage of this test is that it doesn't require fasting, and can be done at any time of the day.

Another way to reveal hyperglycemia is to look at the fasting plasma glucose. This test needs to be performed in the morning when the subject hasn't eaten for the previous 8 hours.

A more sensitive test is the oral glucose tolerance test, as shown in the figure below. This test measures how the body responds to a glucose challenge, usually a drink containing 75 grams of glucose.  At various times following consumption of the glucose drink, the blood glucose is measured. Blood glucose increases as the glucose is absorbed, stimulating insulin secretion. In a normal test (patient #1; blue), blood glucose rises and then falls, usually within an hour.

The response measured reflects two things:

Diabetes is indicated by either of the following:

Individuals taking the test may not be considered diabetic, but may still show higher than normal readings indicative of insulin resistance. These individuals are considered to have impaired glucose homeostasis, and are at increased risk for the development of type 2 diabetes. Someone with a fasting glucose that is greater than 100 mg/dL is categorized as having impaired fasting glucose. In the data shown, patient #2 (green) has a normal fasting plasma glucose, but has impaired glucose tolerance, which involves a 2-hour reading of greater than 140 mg/dL. Patient #3 (red) is clearly diabetic since fasting plasma glucose exceeds 126 mg/dL, and this patient is glucose intolerant.

In someone in which type 2 diabetes mellitus is diagnosed, insulin resistance is usually accompanied by a defect in insulin secretion. Initially, someone who is insulin resistant can compensate for decreased insulin responsiveness by secreting more insulin. In fact, another way to reveal insulin resistance is to look at the amount of circulating insulin. Hyperinsulinemia is the term that describes a higher than normal concentration of insulin in the blood. When beta cells can no longer secrete enough insulin to compensate for reduced insulin function, then a relative insulin deficiency will ensue, and the person will begin to have episodes of hyperglycemia.

Causes of Insulin Resistance

What causes insulin resistance is complicated, and may vary for different individuals. The factor that is most commonly associated with insulin resistance and type 2 diabetes mellitus is excess adiposity (excess adipose tissue). Roughly 85% of type 2 diabetics are overweight or obese. Several major changes associated with overweight/obesity are thought to be the causes of insulin resistance: increased levels of circulating fatty acids, changes in the secretion of adipocyte regulatory molecules, and increased inflammation.

Increased fatty acids and ectopic lipid

In an obese individual, there is more visceral adipose tissue.  Visceral adipose tissue is located in the mesenteries attached to the digestive organs. There are higher rates of lipolysis in visceral adipocytes, resulting in higher levels of circulating fatty acids. Lipid deposits form in non-adipose tissues such as muscle and liver.  This ectopic lipid interferes with insulin sensitivity in several ways.

Changes in adipocyte regulatory molecules

Adipocytes are not just storage lockers for triacylglycerol; they also synthesize and secrete a host of regulatory molecules that are collectively known as adipokines.

These effects on regulatory molecules may explain why the "apple shape" is worse than the "pear shape". The apple shape is due to increased visceral adipose tissue, while there is more subcutaneous adipose tissue in the pear shape. As you will learn next quarter, venous blood that drains visceral adipose tissue in the mesenteries flows first to the liver via the hepatic portal vein, before returning to the heart. Therefore, changes in regulatory molecules caused by visceral adipocytes are in a position to directly affect the liver, a key target of insulin.

Increased inflammation

There is growing evidence that obesity is associated with a state of chronic low-level inflammation. For various reasons, obese adipose tissue accumulates higher numbers of macrophages.  Macrophages (along with adipocytes; see above) release inflammatory paracrines that cause insulin resistance.

Therapies to Improve Insulin Sensitivity

Weight loss improves insulin sensitivity. Unfortunately, weight loss is often difficult to achieve and maintain.

Bariatric surgery
Bariatric surgery is the term for weight loss surgery.  Surgical procedures such as Roux-en-Y gastric bypass create a much smaller stomach to restrict what a person eats, while limiting nutrient absorption through bypass of the initial part of the small intestine. Bariatric surgery can cause profound weight loss and in many cases (up to 70%), resolution of insulin resistance and diabetes mellitus. Improvement of insulin sensitivity probably occurs due to major weight loss. However, insulin sensitivity begins to increase well before weight loss begins, suggesting that the reorganization of the digestive tract somehow alters the secretion of regulatory molecules that influence insulin sensitivity.

Exercise is beneficial because it promotes glucose uptake in skeletal muscle. Exercise promotes the movement of glucose transporters to the muscle cell plasma membrane, and it does so independently of insulin. Furthermore, as a means of energy expenditure, exercise may lead to weight loss.

Metformin is one of two types of antidiabetic drugs that are classified as "insulin sensitizers". Although metformin has been used as an antidiabetic drug for years, its mechanism of action is still not completely understood. The most recent work suggests that metformin affects mitochondrial function in hepatocytes.  The important outcome of these effects in liver cells is the inhibition of gluconeogenesis.

Thiazolidinediones (TZD's; Glitazones)
TZD's are the other type of insulin sensitizing drug.  TZDs are agonists for the nuclear receptor known as PPAR-gamma (review web page on Nuclear Receptors). PPAR-gamma is primarily expressed in adipocytes and pre-adipocytes. When a ligand is bound to PPAR-gamma, it alters gene expression to stimulate adipocyte differentiation and lipogenesis (triacylglycerol formation) in adipocytes. This may seem counter-productive because the above discussion has emphasized that too much adipose tissue is a bad thing. However, the damaging effects of increased adiposity depend in part on the type of adipocytes (large, hypertrophic adipocytes are the most problematic), and in part on the increased fatty acids in the circulation. TZD's stimulate the formation of greater numbers of small adipocytes, and stimulate apoptosis in hypertrophic adipocytes. They promote fat storage in adipocytes, thus decreasing the level of circulating fatty acids and preventing the pathological effects of ectopic lipid. TZD's also cause adipocytes to increase expression of adiponectin, which promotes insulin sensitivity.

Quick Quiz

Fill-in Answer Correct False Correct Answer
1. The HbA1c test measures the percentage of ________.
2. Diabetes mellitus is indicated by a fasting glucose measurement greater than ___________ mg/dL.
3. This term means a higher than normal level of insulin in the blood.
4. Which of the following is an effect of obesity that is thought to cause insulin resistance? [decreased cortisol; increased adiponectin; ectopic lipid; decreased inflammation; lower circulating fatty acids]
5. Name the steroid hormone that has an anti-insulin effect (decreases responsiveness to insulin).
6. In an obese individual, what happens to adiponectin secretion? (increases or decreases)
7. Do inflammatory paracrines increase or decrease insulin sensitivity?
8. Name the technical term for weight loss surgery.
9. Name the insulin-sensitizing drug that inhibits gluconeogenesis in the liver.
10. This can cause the movement of glucose transporters to the plasma membrane, independently of insulin action.

(Spelling must be correct)

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