Chapter: Modern Pharmacology with Clinical Applications: Insulin and Oral Drugs for Diabetes Mellitus

Diabetes Mellitus

Diabetes mellitus affects approximately 5 to 8% of the population.



Diabetes mellitus affects approximately 5 to 8% of the population. A large number of individuals are asympto-matic and do not know they have the disease. The re-cent rise in obesity in the United States accounts for much of the observed and anticipated rise in cases of di-abetes mellitus in this country. Although insulin treat-ment has greatly increased the life expectancy of the di-abetic patient, diabetes remains the third leading cause of death by disease, the second leading cause of blind-ness, and the second leading cause of renal failure.


Diabetes mellitus is a heterogeneous group of disor-ders characterized by abnormalities in carbohydrate, protein, and lipid metabolism. The central disturbance in diabetes mellitus is an abnormality in insulin produc-tion or action or both, although other factors can be in-volved. Hyperglycemia is a common end point for all types of diabetes mellitus and is the parameter that is measured to evaluate and manage the efficacy of dia-betes therapy.


Diabetes mellitus has been traditionally classified into insulin-dependent diabetes mellitus (IDDM), also known as type I- (formerly called juvenile-onset dia-betes mellitus), and non–insulin-dependent diabetes mellitus (NIDDM), also known as type II (formerly re-ferred to as adult-onset diabetes mellitus). There are clearly varying degrees of overlap, and though it is often important to know whether a particular individual pos-sesses relative insulin deficiency or relative insulin re-sistance or both, some of the more salient differences between IDDM and NIDDM are summarized in Table 67.1.


The pathogenesis of type I- diabetes is autoimmune destruction of the cells of the pancreas. The factor or fac-tors that trigger this autoimmune response are un-known. Predisposing factors appear to include certain major histocompatibility complex haplotypes and au-toantibodies to various islet cell antigens. The progres-sion of the autoimmune response is characterized by lymphocytic infiltration and destruction of the pancre-atic cells resulting in insulin deficiency. Type I- diabetes mellitus constitutes about 10% of cases of diabetes mellitus.


The other type of diabetes mellitus, type II, is far more common. In contrast, type II is not an autoimmune process and may or may not be insulin dependent; that is, a diabetic state that is most effectively managed by in-sulin therapy. Frequently, NIDDM is used interchangeably with type II diabetes mellitus, and efforts are being made to avoid the term adult onset, since many adoles-cents (and occasionally children) are developing NIDDM. Because the incidence of diabetes is high in families of persons with NIDDM, a strong genetic pre-disposition is suspected. However, NIDDM is most likely a polygenic disease, involving multiple genetic predispositions to the development of the diabetic state.


The three major metabolic abnormalities that con-tribute to hyperglycemia in NIDDM are defective glucose-induced insulin secretion, increased hepatic glu-cose output, and inability of insulin to stimulate glucose uptake in peripheral target tissues. These abnormalities also involve the cellular glucose transport in cells, liver, adipose tissue, and skeletal muscle, and they may be the result of alterations in GLUTs. Another essential prob-lem in NIDDM may be reduced sensitivity of fat and muscle cells to the effects of insulin (i.e., insulin resist-ance). Consequently, in early stages of NIDDM, the pan-creas may produce normal or even excessive amounts of insulin and only become impaired at insulin production at a later stage of the disease. Recently, a hormone pro-duced in adipose tissue, resistin, has been identified and is postulated to cause many of the derangements that ul-timately result in insulin resistance.


Several putative sites of insulin resistance have been identified in humans, including a defective binding of in-sulin to a receptor and a blunting of insulin signal trans-duction. Conditions associated with elevated insulin lev-els (hyperinsulinism), such as obesity, may be the result of down-regulation in the number of insulin receptors, effectively resulting in a state of insulin resistance. Conversely, decreases in insulin levels (e.g., diabetes) may lead to an up-regulation of the receptors, which may shift the insulin dose–response curve to the left; that is, less insulin would be required to produce a given bio-logical effect. The extent to which receptor regulation actually participates in adjustments to changing physio-logical conditions has not been definitively established.

Insulin resistance also has been associated with a number of hormonal and metabolic states, including Cushing’s syndrome (excessive corticosteroids), acro-megaly (excessive growth hormone), and gestational di-abetes. Physiological or psychological stress also can contribute to insulin resistance. Gestational diabetes mellitus is a condition that develops during the second trimester of pregnancy; the cause may be rises in human placental lactogen and other hormones that contribute to insulin resistance. This condition usually resolves dur-ing the postpartum period. Another relatively common form of insulin resistance is often seen in women with polycystic ovarian syndrome, a disorder that is associ-ated with hyperandrogenism, hirsutism, menstrual ir-regularities, obesity, and infertility.


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