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. 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. It has only recently been adopted for diagnosis following an effort to nationally standardize the test. This test measures the percentage of glycosylated 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 conatining 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 individual (patient #1; blue), blood glucose rises and then falls, usually within an hour.

The response measured reflects two things:

the ability of the beta cells to secrete insulin
the responsiveness of cells in the body to insulin

Diabetes is indicated by either of the following:

fasting plasma glucose above 126 mg/dL
a 2-hour reading greater than 200 mg/dL

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. 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 fatty acids, changes in the secretion of adipocyte regulatory molecules, and increased inflammation.

Increased fatty acids

In an obese individual, there is more visceral adipose tissue, which 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.

Reduced insulin signal transduction. The insulin receptor is a tyrosine kinase, phosphorylating several identified substrates on tyrosine residues. These phosphorylated insulin receptor substrates then activate the rest of the insulin signaling cascade. Fatty acids activate serine-threonine kinases that phosphorylate insulin receptor substrates on different amino acids, inhibiting tyrosine phosphorylation by the insulin receptor.
Altered metabolism. Fatty acids stimulate gluconeogenesis in the liver. Thus hepatic glucose production, which should be inhibited by insulin, persists.
Increased inflammation. Saturated fatty acids cause intracellular inflammatory changes through stimulation of the innate immune system.

Changes in adipocyte regulatory molecules

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

Inflammatory paracrines. Some adipokines whose secretion is increased in obesity are inflammatory paracrines such as TNF-alpha and IL-6. These regulatory molecules increase insulin resistance by interfering with insulin signal transduction. They also probably contribute to the increased risk for cardiovascular disease by promoting inflammation in blood vessels.
Decreased adiponectin. Adiponectin is a peptide whose secretion is decreased in obesity. Adiponectin increases insulin sensitivity and improves metabolism by stimulating fatty acid oxidation. Adiponectin is being investigated for a possible therapeutic role in the treatment of insulin resistance.
Increased cortisol. Another effect of adipocytes is on local levels of cortisol. Remember that cortisol is one of the post-absorptive state hormones that decrease responsiveness to insulin. Adipocytes have an enzyme that converts an inactive cortisol metabolite back into active cortisol.

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. Thus inflammatory paracrines that cause insulin resistance may come from macrophages as well as adipocytes.

Therapies to Improve Insulin Sensitivity

Diet
Weight loss improves insulin sensitivity. Unfortunately, weight loss may be difficult to achieve and maintain. There is a negative feedback loop involving the hormone leptin which works to maintain body weight at a set point. In obese individuals, this negative feedback loop works to maintain body weight at a higher than normal set point. Weight loss leads to decreased leptin secretion, which causes increased hunger along with a decrease in metabolic rate. Thus, the body responds to weight loss with mechanisms that promote weight gain, making it difficult to sustain weight loss.

Bariatric surgery
Surgical procedures such as Roux-en-Y gastric bypass create a much smaller stomach (restriction) and limit nutrient absorption through bypass of the initial part of the small intestine (malabsorption). This type of surgery can cause profound weight loss and in many cases (up to 70%) a resolution of insulin resistance and diabetes mellitus. Weight loss plays a role, 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
Exercise is beneficial because it promotes glucose uptake in skeletal muscle. Independently of insulin action, exercise promotes the translocation of glucose transporters to the muscle cell plasma membrane. Furthermore, as a means of energy expenditure, exercise may lead to weight loss.

Metformin
Metformin is one of two types of antidiabetic drugs that work to improve insulin sensitivity. Although metformin has been used as an antidiabetic drug for years, its mechanism of action has only recently been understood. Metformin indirectly activates a cellular kinase called AMP-activated protein kinase (AMPK) that is a master regulator of diverse metabolic processes. AMPK generally activates enzymes involved in catabolism and inhibits enzymes involved in anabolism. In the liver, for instance, metformin promotes fatty acid oxidation while inhibiting gluconeogenesis.

Thiazolidinediones (TZD's; Glitazones)
TZD's act as agonists for the intracellular receptor known as PPAR-gamma. This receptor is primarily expressed in adipocytes and pre-adipocytes. When a ligand is bound to PPAR-gamma, it works as a transcription factor, stimulating 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 toxic effects of fatty acid accumulation in other tissues. They 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. The insulin receptor is a _______________.[serine-threonine kinase, tyrosine kinase, G-protein coupled receptor]
5. Visceral adipocytes express an enzyme that produces this active hormone from an inactive metabolite.
6. In an obese individual, what happens to adiponectin secretion? (increases or decreases)
7. Which of the following is an *adipokine* that promotes inflammation? [cortisol, IL-6, adiponectin, leptin]
8. Which of the following is stimulated by fatty acids?[lipolysis, glucose uptake, gluconeogenesis, tyrosine kinase, glycogen synthesis]
9. Name the insulin-sensitizing drug that indirectly activates AMP kinase.
10. This can cause translocation of glucose transporters to the plasma membrane, independently of insulin action.
	(Spelling must be correct)

Back to Home Page