The Biochemical Pathology of Insulin Resistance and the Metabolic Syndrome

Over the past decade the metabolic syndrome has become prominent in the literature in addition to emerging as a major public health concern. The metabolic syndrome presents many diagnostic problems for clinicians and laboratorians alike. The metabolic syndrome is a constellation of symptoms and signs that include central obesity, insulin resistance, dysglycemia, dyslipidemia, and hypertension. The definition has many subtleties and clinically, there are a multitude of presentations. Included in the current understanding of the metabolic syndrome is a subtext of a pro-inflammatory and a pro-thrombotic state.

There is certainly no agreement on any single causative agent; however, it is clear that the modern calorie-rich Western diet in the setting of little or no regular exercise plays a central role. A recent concise review on metabolic syndrome was published in this journal. The current review addresses the biology of insulin resistance, viz., what is it and how does it present? The insulin resistance of the metabolic syndrome remains somewhat of an enigma, but a number of plausible models have come to light in recent years.

Here we review: (a) the many metabolic actions of insulin, (b) the pathogenesis of type 2 diabetes mellitus, (c) insulin resistance (in general), (d) the ectopic fat hypothesis of insulin resistance, (e) the possible role of the hormones leptin, resistin, and adiponectin, and (f) the connection between insulin resistance and islet amyloid.

Insulin and insulin resistance

Insulin is an essential polypeptide hormone produced under conditions of feeding by the beta cells of the pancreatic islets of Langerhans. Insulin is critical for entry of glucose into multiple tissues, including skeletal muscle and adipose tissue (via activation of the glucose transporter molecule [GLUT4]), but is not necessary for glucose entry into erythrocytes, liver, or brain. Insulin promotes the oxidation of glucose to carbon dioxide and water by tissues and also blocks "new" glucose biosynthesis (i.e., gluconeogenesis) by hepatic tissue. I

nsulin is also very important in promoting the storage of glucose in the form of glycogen by liver and muscle. The drive of glucose into the cells with its subsequent oxidation is the basis for the glucose-lowering effect of insulin. Insulin also has major effects on lipid metabolism. It blocks the breakdown of triacylglycerols (triglycerides) by adipose tissue and promotes the biosynthesis of fatty acids and triacylglycerols by liver and adipose tissue. In short, insulin promotes fat storage.

This summary of insulin's many actions helps to clarify the effects of insulin deficiency. In the absence of sufficient insulin, glucose (now unable to enter cells) accumulates in excess within the extracellular fluid. This has two major effects: (a) the cells undergo a functional starvation and (b) the high plasma glucose has many untoward physiologic effects, including osmotic problems and tissue damage from protein glycation.

Cell starvation manifests as increased synthesis of ketone bodies. Furthermore, there is adipose tissue breakdown with production and release of fatty acids. The latter are delivered to the liver in such high quantities that hepatic lipoprotein synthesis is increased and the liver puts out abundant very low-density lipoproteins (VLDLs). Insulin is required for VLDL breakdown in the capillary beds via lipoprotein lipase and so, in cases of insulin deficiency, these large triglyceride-rich lipoproteins persist.

Diabetes is a disease that results from decreased insulin action. Insulin action is a product of insulin concentration and tissue insulin sensitivity. For many decades, researchers have been aware of the essential differences between type 1 and type 2 diabetes. In type 1 diabetes, there is a true deficiency of insulin due to pancreatic beta-cell damage by an autoimmune, cell-mediated response. Insulin concentrations are very low. In type 2 diabetes, insulin concentrations may be normal or even high. In type 2 diabetes, there is an insensitivity of the tissues to the effects of insulin--an effect termed insulin resistance. Insulin is present, but it cannot get its message through to the cells. What has happened? Before addressing this, let us review what normally happens when insulin interacts with a cell.

In order to initiate its many metabolic effects, insulin must interact with a specific cell-surface receptor that belongs to a family of receptor-enzymes known as tyrosine kinases. The binding of insulin to the insulin receptor initiates a complex chain of events that ultimately generates a multitude of intracellular second messengers. The latter eventually produce the characteristic effects of insulin, for example, by promoting the movement of GLUT4 molecules to the cell surface.

Although cases of insulin resistance have been described due to specific mutations in the insulin cell-surface receptor tyrosine kinase, these are rather rare and constitute only a minority of cases. They have, however been extensively studied and have shed much light on the biology of insulin action. The insulin resistance of the common type 2 diabetes is not related to receptor mutations, but is somehow related to the amount of fat in the body.

The standard model of type 2 diabetes is that the body tissues progressively become more insulin resistant, so that ever-higher blood concentrations of the hormone are needed to produce the identical effect. In the early stages of the disease, plasma insulin concentrations tend, therefore, to be higher than normal. The insulin resistance eventually achieves a level where the person is relatively insulinopenic. He has above-normal concentrations of insulin, but the circulating insulin nevertheless is still not sufficient to fully activate the insulin-resistant tissues, such as skeletal muscle and adipose tissue. There is a price to pay for this profligate expenditure of insulin. The beta cells cannot keep up with the demand and begin to fail--an event that may also be promoted by body-fat content. Such individuals enter a stage where they are truly insulinopenic. Indeed, even when the beta cells are still able to secrete large amounts of insulin, the temporal pattern of insulin secretion is no longer normal.

Initially, the insulin resistance is most likely sub-clinical, since insulin is not routinely measured in the clinical laboratory as part of a standard clinical chemistry analysis. As the condition progresses, there will be evidence of pre-diabetes, either impaired fasting glucose and/or impaired glucose tolerance, the latter based upon a standard oral two-hour glucose-tolerance test. Eventually, frank hyperglycemia sets in and the physician can make the diagnosis of diabetes. Interestingly, insulin resistance, besides producing diabetes, may produce other physical signs. One of these is a skin condition termed acanthosis nigricans--a velvety, brown-black skin discoloration, often in skin folds or at the back of the neck.

Insulin resistance has important effects on the vascular bed. It leads to decreased nitric oxide synthesis by endothelial cells with subsequent endothelial dysfunction. Nitric oxide is an important vasodilator that reduces resistance in blood vessels. This may be one of the mechanisms underlying the hypertension of the metabolic syndrome. Hyperinsulinism is also responsible for other phenomena not typically associated with carbohydrate metabolism. It produces hyperandogenism in females; hyperinsulinism is a key feature of the polycystic ovarian syndrome, a close relative of the metabolic syndrome. The polycystic ovarian syndrome is a constellation of signs that include insulin resistance, hyperandrogenism, hirsutism, obesity, infertility, and menstrual irregularities.