Type 2 Diabetes Mellitus: Update on Diagnosis, Pathophysiology, and Treatment

SIXTEEN million individuals in the United States with type 2 diabetes mellitus and an additional 30–40 million with impaired glucose tolerance result in health care costs exceeding 100 billion dollars annually (1). Treatment is predominantly directed at microvascular and macrovascular complications (2). In type 1 diabetes mellitus the relationship between glycemic control and microvascular complications has been well established (3). The relationship between tight glycemic control and microvascular disease in type 2 diabetes mellitus appears to be established in the recently completed United Kingdom prospective diabetes study (4, 5). Despite the morbidity and mortality associated with retinopathy, nephropathy, and neuropathy, cardiovascular disease remains the leading cause of death in type 2 diabetes mellitus (6, 7). Consequently, the treatment of confounding risk factors of obesity, hypertension, and hyperlipidemia assumes major importance and must be coordinated with good glycemic control for reduction in total mortality in type 2 diabetes mellitus (6–11). Based on the emerging relationship between the degree of glycemic control and microvascular complications as well as the contribution of hyperglycemia in the development of macrovascular disease, it is the purpose of this review to summarize the current state of knowledge to provide a rational basis for the treatment of type 2 diabetes mellitus. The definition of type 2 diabetes mellitus, previously termed noninsulin-dependent diabetes mellitus, was recently modified by the American Diabetes Association. Several criteria may be used independently to establish the diagnosis: 1) a 75-g oral glucose tolerance test with a 2-h value of 200 mg/dL or more, 2) a random plasma glucose of 200 mg/dL or more with typical symptoms of diabetes, or 3) a fasting plasma glucose of 126 mg/dL or more on more than one occasion (7). Fasting glucose values are preferred for their convenience, reproducibility, and correlation with increased risk of microvascular complications. The term impaired fasting glucose has been defined as fasting plasma glucose of 110 or more and 125 mg/dL or less (7). Impaired glucose tolerance (IGT) is defined as a 2-h plasma glucose value of 140 or more and of less than 200 mg/dL during an oral glucose tolerance (12). Individuals with impaired fasting glucose and IGT are considered to be at high risk for the development of diabetes and macrovascular disease (13, 14). Although one third of these patients will eventually develop diabetes, dietary modification and exercise can lower the risk of progression from impaired glucose tolerance to type 2 diabetes; and may also prevent the development of IGT in nondiabetic individuals at high risk (14). Pharmacological agents may also be of benefit in limiting the progression from IGT to diabetes (13, 15). Type 2 diabetes mellitus is a heterogeneous disorder with varying prevalence among different ethnic groups. In the United States the populations most affected are native Americans, particularly in the desert Southwest, Hispanic-Americans, and Asian-Americans (1). The pathophysiology of type 2 diabetes mellitus is characterized by peripheral insulin resistance, impaired regulation of hepatic glucose production, and declining β-cell function, eventually leading toβ -cell failure. The primary events are believed to be an initial deficit in insulin secretion and, in many patients, relative insulin deficiency in association with peripheral insulin resistance (16, 17). β-Cell dysfunction is initially characterized by an impairment in the first phase of insulin secretion during glucose stimulation and may antedate the onset of glucose intolerance in type 2 diabetes (18). Initiation of the insulin response depends upon the transmembranous transport of glucose and coupling of glucose to the glucose sensor. The glucose/glucose sensor complex then induces an increase in glucokinase by stabilizing the protein and impairing its degradation. The induction of glucokinase serves as the first step in linking intermediary metabolism with the insulin secretory apparatus. Glucose transport inβ -cells of type 2 diabetes patients appears to be greatly reduced, thus shifting the control point for insulin secretion from glucokinase to the glucose transport system (19, 20). This defect is improved by the sulfonylureas (21, 22). Later in the course of the disease, the second phase release of newly synthesized insulin is impaired, an effect that can be reversed, in part at least in some patients, by restoring strict control of glycemia. This secondary phenomenon, termed desensitization or β-cell glucotoxicity, is the result of a paradoxical inhibitory effect of glucose upon insulin release and may be attributable to the accumulation of glycogen within the β-cell as a result of sustained hyperglycemia (23). Other candidates that have been proposed are sorbital accumulation in the β-cell or the nonenzymatic glycation ofβ -cell proteins. Other defects in β-cell function in type 2 diabetes mellitus include defective glucose potentiation in response to nonglucose insulin secretagogues, asynchronous insulin release, and a decreased conversion of proinsulin to insulin (24, 25). An impairment in first phase insulin secretion may serve as a marker of risk for type 2 diabetes mellitus in family members of individuals with type 2 diabetes mellitus (26–30) and may be seen in patients with prior gestational diabetes (31). However, impaired first phase insulin secretion alone will not cause impaired glucose tolerance. Autoimmune destruction of pancreatic β-cells may be a factor in a small subset of type 2 diabetic patients and has been termed the syndrome of latent autoimmune diabetes in adults. This group may represent as many as 10% of Scandinavian patients with type 2 diabetes and has been identified in the recent United Kingdom study, but has not been well characterized in other populations (4–6, 30). Glucokinase is absent within the β-cell in some families with maturity-onset diabetes of young (31). However, deficiencies of glucokinase have not been found in other forms of type 2 diabetes (32, 33). In summary, the delay in the first phase of insulin secretion, although of some diagnostic import, does not appear to act independently in the pathogenesis of type 2 diabetes. In some early-onset patients with type 2 diabetes (perhaps as many as 20%) (4, 5), there may be a deficiency in insulin secretion that may or may not be due to autoimmune destruction of the β-cell and is not due to a deficiency in the glucokinase gene. In the great majority of patients with type 2 diabetes (±80%), the delay in immediate insulin response is accompanied by a secondary hypersecretory phase of insulin release as a result of either an inherited or acquired defect within the β-cell or a compensatory response to peripheral insulin resistance. Over a prolonged period of time, perhaps years, insulin secretion gradually declines, possibly as a result of intraislet accumulation of glucose intermediary metabolites (34). In view of the decline in β-cell mass, sulfonylureas appear to serve a diminishing role in the long term management of type 2 diabetes (35). Unanswered is whether amelioration of insulin resistance with earlier detection or newer insulin-sensitizing drugs will retard the progression of β-cell failure, obviating or delaying the need for insulin therapy. Emanating from the prismatic demonstration by Yalow and Berson of the presence of hyperinsulinism in type 2 diabetes, insulin resistance has been considered to play an integral role in the pathogenesis of the disease (36). Recent critical reviews, however, have questioned the primacy, specificity, and contribution of insulin resistance to the disease state (37, 38). As chronic hyperinsulinemia inhibits both insulin secretion (39) and action (40), and hyperglycemia can impair both the insulin secretory response to glucose (41) as well as cellular insulin sensitivity (42, 43), the precise relation between glucose and insulin level as a surrogate measure of insulin resistance has been questioned. Lean type 2 diabetic patients over 65 yr of age have been found to be as insulin sensitive as their age-matched nondiabetic controls (44). Moreover, in the majority of type 2 diabetic patients who are insulin resistant, obesity is almost invariably present (45, 46). As obesity or an increase in intraabdominal adipose tissue is associated with insulin resistance in the absence of diabetes, it is believed by some that insulin resistance in type 2 diabetes is entirely due to the coexistence of increased adiposity (47). Additionally, insulin resistance is found in hypertension, hyperlipidemia, and ischemic heart disease, entities commonly found in association with diabetes (16, 48, 49), again raising the question as to whether insulin resistance results from different pathogenetic disease processes or is unique to the presence of type 2 diabetes (16, 50, 51). Prospective studies have demonstrated the presence of either insulin deficiency or insulin resistance before the onset of type 2 diabetes (48). Two studies have reported the presence of insulin resistance in nondiabetic relatives of diabetic patients at a time when their glucose tolerance was still normal (52, 53). In addition, first degree relatives of patients with type 2 diabetes have been found to have impaired insulin action upon skeletal muscle glycogen synthesis due to both decreased stimulation of tyrosine kinase activity of the insulin receptor and reduced glycogen synthase activity (54, 55). Other studies in this high risk group have failed to demonstrate insulin resistance, and in the same group, impaired early phase insulin release and loss of normal oscillatory pattern of insulin release have been described (56, 57). Based upon these divergent studies, it is still impossible to dissociate insulin resistance from insulin deficiency in the pathogenesis of type 2 diabetes. However, both entities unequivocally contribute to the fully established disease. The ability of insulin to suppress hepatic glucose production both in the fasting state and postprandially is normal in first degree relatives of type 2 diabetic patients (26). It is the increase in the rate of postprandial glucose production that heralds the evolution of IGT (52). Eventually, both fasting and postprandial glucose production increase as type 2 diabetes progresses. Hepatic insulin resistance is characterized by a marked decrease in glucokinase activity and a catalytic increased conversion of substrates to glucose despite the presence of insulin (53). Thus, the liver in type 2 diabetes is programmed to both overproduce and underuse glucose. The elevated free fatty acid levels found in type 2 diabetes may also play a role in increased hepatic glucose production (50). In addition, recent evidence suggests an important role for the kidney in glucose production via gluconeogenesis, which is unrestrained in the presence of type 2 diabetes (58). Diet. Diet therapy, although important for the prevention as well as the treatment of all stages of type 2 diabetes, continues to remain poorly understood and high controversial (59, 60). When obesity coexists with hyperglycemia, as seen in the majority of individuals with type 2 diabetes, weight reduction is the major goal of dietary therapy (61–64). Traditional recommendations emphasize reduction of both the total and saturated fat content and replacement with complex carbohydrates to 50–55% of the dietary calories. In type 2 diabetic patients, such diets may cause marked postprandial hyperglycemia. As there is considerable patient variability in the rate of glucose absorption, arduous attention to postprandial glucose monitoring and the addition of high fiber contents to the diet become critically important. Moreover, as the glycemic response of the diet is also dependent upon the texture and content of other food stuffs in the diet as well as the rate of intestinal motility, the diet as well as the stage and duration of type 2 diabetes have to be considered on an individual basis (59, 65, 66). Exercise. Exercise has been shown to be beneficial in the prevention of the onset of type 2 diabetes mellitus as well as in the improvement of glucose control as a result of enhanced insulin sensitivity (67–70). Decreased intraabdominal fat, an increase in insulin-sensitive glucose transporters (GLUT-4) in muscle, enhanced blood flow to insulin-sensitive tissues, and reduced free fatty acid levels appear to be the mechanisms by which exercise restores insulin sensitivity (71). In addition, exercise provides the added benefits of lowering blood pressure, improving myocardial performance, and lowering serum triglycerides while raising high density lipoprotein cholesterol levels. Current therapeutic agents available for type 2 diabetes mellitus include sulfonylureas and related compounds, biguanides, thiazolidenediones, α-glucosidase inhibitors and insulin (Table 1). In addition, several other classes of therapeutic agents will soon become available. A rational approach would be to begin with the agents particularly suited to the stage and nature of the disease, progressing, if necessary, to combination therapy. Pharmacological agents acting through different mechanisms of action should be chosen to improve glucose values while minimizing adverse effects. Oral agents used in the management of type 2 diabetes mellitus Oral agents used in the management of type 2 diabetes mellitus Sulfonylureas and related agents. Sulfonylureas have been used to treat type 2 diabetes since 1942 and require functional pancreatic β-cells for their hypoglycemic effect (22, 73). All currently available sulfonylureas bind to specific receptors on β-cells, resulting in closure of potassium ATP channels. As a result, calcium channels open, leading to an increase in cytoplastic calcium that stimulates insulin release (74). A newer sulfonylurea, glimiperide, given in doses of 1, 4, or 8 mg preprandially, appears to have a more rapid onset than previous sulfonylureas (both glyburide and glipizide) and consequently less risk of hypoglycemia (75). To a lesser degree than insulin administration, sulfonylureas, through endogenous hyperinsulinemia, cause a propensity for hypoglycemia and weight gain (76). Still controversial is the influence of sulfonylureas on cardiovascular mortality, an observation first described by the University Group Diabetes Program (77). Because of the variability of baseline data and subsequent studies that failed to substantiate the observation, sulfonylureas have not been considered to potentiate cardiovascular risk in diabetic patients (78). However, newer data has shown that sulfonylureas, with the exception of glimiperide, block the vasodilator response to ischemia in animals, thereby potentially increasing cardiovascular risk. At present, the question regarding sulfonylurea use in cardiac mortality in humans remains unanswered (79, 80). Placed in the context of our increasing understanding of the pathogenesis of type 2 diabetes, sulfonylureas would be most appropriate in those patients in whom hypoinsulinemia is the predominant cause of hyperglycemia. These patients would typically be lean, with lower basal and postprandial insulin levels. In addition, based upon the recent United Kingdom study, these patients tend to be younger (<46 yr of age) and are more likely to require insulin therapy (81). Repaglinide is a new agent that binds to pancreaticβ -cells and stimulates insulin release. It is structurally different from sulfonylureas and binds to a nonsulfonylurea receptor (82). The drug is taken preprandially and has a rapid onset and limited duration of action, which may decrease the incidence of weight gain and hypoglycemic episodes. Limited published clinical data demonstrate an efficacy similar to that of sulfonylureas; as with sulfonylureas, repaglinide shows an added benefit when given with metformin (82, 83). Biguanides. After withdrawal of the biguanide, phenformin, from the U.S. market in 1975, a second generation biguanide, metformin, was introduced and widely distributed throughout Western Europe, Canada, and Mexico. With a frequency of lactic acidosis 1/10th that of the parent compound and a strong record of safety and efficacy, the drug was carefully introduced into the American market in 1995. Glucose lowering by the drug occurs primarily by decreasing hepatic glucose production and, to lesser extent, by decreasing peripheral insulin resistance. The drug acts by causing the translocation of glucose transporters from the microsomal fraction to the plasma membrane of hepatic and muscle It does not insulin release and does when given cause hypoglycemia Moreover, it does not cause weight and it the by causing a decline in total and density lipoprotein total and density cholesterol levels and an increase in high density lipoprotein cholesterol levels It is suited for patients with type 2 diabetes who are to diet alone and are to be insulin When introduced gradually in or to a of mg a reduction in to mg/dL in glucose can be It is as or in combination with other such as insulin secretagogues, other insulin-sensitizing or inhibitors of glucose The major risk continues to be that of lactic which occurs with a frequency of patient As the major of of the drug is through the it should not be given to those with disease in in in the presence of hepatic disease, or in patients with tissue In addition, the drug should be for This new of agents has been since To the drug to market is although and are from other in that it an as part of its which may also provide some appears to act by to the This receptor the of into and free fatty acid levels its major effect is to decrease peripheral insulin resistance, although at doses it may also decrease hepatic glucose production Although acting at a different than metformin, both and metformin appear to function as insulin and require the presence of insulin for their In to metformin, the of may be over time, and its hypoglycemic may not be of therapy When given in doses of mg a in of may be when the drug is given metformin glycemic control in than of patients, a response to is seen in of patients An elevated level may to a beneficial response of either and as metformin and act at different to insulin improvement is seen when the drugs are used in combination Moreover, as insulin resistance is invariably accompanied by a relative insulin either metformin or will be when either or both drugs are given with an insulin may cause peripheral or limiting its use in disease. However, the major of the drug is that of in of patients, it has been reported as early as and as as 8 the onset of therapy. of and for the first 8 of therapy and 2 for the first of therapy is detection has invariably to of of this act by the of carbohydrates from the and thereby the postprandial in blood glucose require over to therapy is adverse are and weight gain may be with this therapy. the agent of this in clinical may be added to most other available therapy is in the treatment of type 2 diabetes for initial therapy of hyperglycemia, of oral or during or other has been used in in type 2 diabetes, and new insulin are in clinical The first available insulin is a acid modification of insulin does not when it to have a more rapid onset and a duration of action than insulin Although these may the postprandial in glucose and decrease the risk of hypoglycemia the use of insulin in type 2 diabetes is not as well as therapy can cause weight gain in type 2 and increase the risk of hypoglycemia less commonly than in type 1 In addition, the peripheral hyperinsulinemia by insulin therapy may be a risk factor for cardiovascular disease available agents have been used in combination to treat type 2 diabetes. Although many are not for a rational for combination therapy would include an agent that insulin levels and one that sensitivity to insulin and glucose This combination of agents would appear to most of the defects found in type 2 diabetic It is well established that an oral glucose a insulin response than glucose given by the of the for this observation is or through the glucose and role as an treatment of type 2 diabetes is currently in its will be in those patients with is a β-cell with to be absent or reduced in type 1 diabetes its presence in type 2 diabetes with the state of β-cell When given it appears to decrease the level and delay thereby insulin action will require in its use in patients with factor levels decline with in with the decline in insulin sensitivity Although a cause and effect relationship has not been the of can cause a improvement in insulin sensitivity benefit must be with the for administration, and to particularly Because of these have been approach to treatment of type 2 diabetes must and management of risk of and is of less than and a density lipoprotein cholesterol level mg/dL density lipoprotein cholesterol mg/dL if disease is are a of care The degree of glycemic control will upon and risk In of the level is and in all a level therapeutic In those patients in whom is the likely cause of hyperglycemia by younger and enhanced insulin a sulfonylurea or other β-cell would be those patients who are likely to be insulin with of hypertension, hyperlipidemia, and obesity would more likely to an insulin-sensitizing either metformin or values to a second agent may be either a or insulin-sensitizing agent upon patient and if postprandial hyperglycemia may be insulin therapy may become either early in the course of the disease to establish control or in the disease course as β-cell (2). The addition of insulin to sulfonylureas may some and studies with insulin and the insulin-sensitizing drugs have shown results in -cell such will provide long term benefit remains to be In a in the United for hyperglycemia has greatly many patients diabetes was by insulin alone to be with oral agents. However, remains to be will to as into mechanisms our therapeutic However, must to all type 2 diabetic individuals at an earlier stage and begin treatment in an to the of complications. and will play an part in this