Pathogenesis of Insulin Resistance and Hyperglycemia in Non-Insulin-Dependent Diabetes Mellitus

Transcription

1 Introduction Pathogenesis of Insulin Resistance and Hyperglycemia in Non-Insulin-Dependent Diabetes Mellitus JERROLD M. OLEFSKY, M.D. H uman diabetes is currently classified into two general categories [1]: type I, or insulin-dependent diabetes mellitus and type II, or non-insulin-dependent diabetes mellitus. Insulin-dependent diabetes mellitus is due to an absolute deficiency of insulin secondary to profound beta cell destruction. In non-insulin-dependent diabetes mellitus, the cause of the abnormal metabolic state is less well understood. A major factor that has clouded the etiologic picture is the heterogeneous constellation of disease syndromes represented by non-insulin-dependent diabetes mellitus [2,3], all leading to a final common pathway-- hyperglycemia. Thus, non-insulin-dependen t diabetes mellitus may be considered a rather nonspecific diagnosis featuring hyperglycemia as the cardinal clinical finding, and diverse etiologic factors, either alone or in combination, are capable of causing hyperglycemia. Shortly after the discovery of insulin, most diabetoloo gists thought that insuli n deficiency was the single abnormality in all diabetic states. With this line of reasoning, it, was thought that insulin-dependent diabetes mellitus was due to absolute insulin deficiency, whereas non-insulindependent diabetes mellitus was due to partial insulin deficiency with a variable degree of residual insulin secretory capacity depending on the severity of the diabetic state. However, it is now recognized that the situation is not so simple and that three major metabolic abnormalities coexist and contribute to the hyperglycemic state in non-insulin-dependent diabetes mellitus [4-9] (Figure 1). These include (1) peripheral insulin resistance, (2) increased basal hepatic glucose production, and (3) impaired insulin secretion. Although the causal mechanisms may be het- erogeneous in different groups of patients with non-insulin-dependent diabetes mellitus, the ultimate expression of the hyperglycemic disease state involves some combination of these three metabolic defects. In understanding this disease state, the pathogenesis of the underlying metabolic defects, the pathogenesis of the hyperglycemia, and, finally, the pathogenesis of non-insulin-dependent diabetes mellitus itself must be considered. Each of these topics will be considered throughout this symposium, and specific papers are presented dealing with each of these individual issues. By way of introduction to the material presented in the symposium, this paper will provide a brief overview of the Pathogenesis of insulin resistance, increased hepatic glucose production, and impaired insulin secretion, followed by a more detailed consideration of the causes of the hyperglycemia. Finally, a few Comments about the pathogenesis of the non-insulin-dependent diabetic state will be offered. PATHOGENESlS OF METABOLIC DEFECTS IN NON- INSULIN-DEPENDENT DIABETES MELLITUS Peripheral Insulin Resistance. Skeletal muscle comprises the major glucose-consuming tissue in the insulinstimulated state [10]; therefore, skeletal muscle insulin resistance i s the functionally important abnormality in considering total body resistance to insulin's effects to stimulate glucose disposal. In non-insulin-dependent diabetes mellitus, this tissue resistance is due to a combination of receptor and post-receptor defects [5-7,11]. The receptor defect is due to a decreased number of cell surface insulin receptors on insulin target tissues, and the post-receptor J From the Department of Medicine, University of Califomia at San Diego, La Jolla, California, and the Medical Research Service, Veterans Administration Medical Center, San Diego, California. This work was supported by Grants AM and AM from the National Institutes of Health and by the Medical Research Service Of the Veterans Administration Medical Center. Requests for reprints should be addressed to Dr. Jerrold M. Olefsky, Department of Medicine, M-O23E, Ut~iversity of California at San Diego, La Jol/a, California September 20, 1985 The American Journal of Medicine Volume 79 (euppl 3B) 1

2 INCRrr.ASED GLUCOSE PRODUCTION IMPAIRED INSULIN SECRETION PERIPHERAL TISSUES \ \(MUSCLE),,0,:,o, Figure 1. Summary of the metabolic abnormalities in noninsulin-dependent diabetes mellitus that contribute to the hyperglycemia. Increased hepatic glucose production, impaired insulin secretion, and insulin resistance due to receptor and post-receptor defects all combine to generate the hyperglycemic state. (Reproduced with permission from [.9].) defect involves a decrease in glucose transport activity [12-i5] plus possible additional intracellular defects in glucose metabolism [16]. Overall, the receptor defect leads to mild insulin resistance, whereas the addition of a post-receptor defect results in the more severe insulin resistance commonly seen in non-insulin-dependent diabetes mellitus. The magnitude of the post-receptor defect increases with the severity of the fasting hyperglycemia [11], and in subjects with non-insulin-dependent diabetes mellitus and fasting glucose levels in excess of 180 mg/dl, " the post-receptor abnormality is the predominant cause of the peripheral insulin resistance. This insulin resistance is at least partially reversible and can be returned towards normal with either sulfonylurea therapy [17-19], weight reduction [20-23], or intensive insulin therapy [24-27]. Importantly, however, the insulin resistance is not completely normalized by anti-diabetic therapy and can only be reversed by 50 to 70 percent [26,27]. Increased Hepatic Glucose Production. Increased basal hepatic glucose production rates are a characteristic feature of patients with non-insulin-dependent diabetes mellitus and fasting hyperglycemia [11,27,26]. The greater the degree of fasting hyperglyce~nia, the greater the elevation in hepatic glucose preducti~bn, and an excellent correlation exists between these variables [29], indicating that the rate of glucose entry into the circulation from the liver closely regulates the level of glycemia in the basal or fasting state. The cause of this increase in hepatic glucose production is not entirely clear; however, hyperglucagonemia is commonly noted in non-insulin,- dependent diabetes mellitus [30], and glucagon's stimula- tion of hepatic glucose production is well known [31]. Furthermore, it has recently been shown that approximately two thirds of the hepatic glucose production rate is glucagon-dep'endent in non-insulin-dependent diabetes meltitus [32,33]. In addition, hepatic insulin resistance may also play a role by diminishing insulin's normal effects to suppress hepatic glucose production and by allowing relatively unopposed glucagon action. This increased hepatic glucose production is largely due to enhanced gluconeogenesis, and this is sustained by an increased delivery of gluconeogenic precursors from peripheral tissues. Finally, elevated free fatty acid levels could provide the necessary source of intracelluiar energy, via fatty acid oxidation, to drive the gluconeogenic process. In responsive patients, sulfonylurea therapy [17-19], weight reduction [20-23], and intensive insulin therapy [26,27] are all capable of completely normalizing this hepatic abnormality in glucose metabolism. Impaired Insulin Secretion. Various functional abnormalities of beta cell insulin secretion have been described in non-insulin-dependent diabetic subjects [4,6]. Most prominently, this involves a specific defect in glucose recognition by beta cells. Thus, glucose-mediated insulin secretion is markedly decreased or absent in non-insulindependent diabetic subjects with fasting hyperglycemia [34,35], and the effect of hyperglycemia to potentiate insulin secretion to n0n-glucose stimuli is also strikingly impaired [36,37]. Finally, the maximal capacity for insulin secretion appears to be markedly restricted in these patients [37]. In general, the more severe the diabetic state, the greater the defect in insulin secretion. Again, all forms of anti-diabetic therapy, i.e., sulfonylureas, weight reduction, and iniensive insulin treatment, are capable of partially reversing these insulin secretory defects. However, although insulin secretion can be returned towards normal, it is unusual for the insulin secretory defects to be completely reversed. PATHOGENESlS OF HYPERGLYCEMIA Overall glucose uptake is divided into non-insulin-medi. ated glucose uptake and insulin-mediated glucose uptake, and because of the differences in the relative proportions of insulin-mediated and non-insulin-mediated glucose uptake with fasting and feeding, the cause of fasting hyperglycemia is different from the cause of postprandial hyperglycemia. By definition, insulin-mediated glucose uptake occurs only in insulin target tissues under the influence of insulin. Non-insulin-mediated glucose uptake comprises glucose uptake not under the influence of insulin and has two components. Non-insulin-mediated glucose uptake occurs in tissues (primarily the central nervous system ) that are not targets for insulin action; non-insulin-mediated glucose uptake also involves insulin target cells consisting of the basal rate (non-insulin-mediated) of glucose disposal by these tissues. Total glucose 2 September 20, 1985 The American Journal of Medicine Volume 79 (suppl 3B)

3 disposal equals the sum of non-insulin-mediated glucose uptake plus insu!in-mediated glucose uptake. Non-insulinmediated glucose uptake can be assessed in vivo by measuring glucose disposal under conditions of severe insulinopenia induced by an infusion of somatostatin [38,39]. Thus, following measurement of basal glucose disposal (at basal or fasting insulin and glucose levels), somatostatin is administered to inhibit insulin secretion to negligable levels. Glucose disposal gradually falls to a new steady state that equals non-!nsulin-mediated glucose uptake, since insulin action is absent under these conditions. The proportion of basal glucose disposal that is non-insulin-mediated is about 70 percent in normal euglycemic subjects and in non-insulin-dependent diabetic subjects studied at their basal level of hyperglycemia [38] (Table I). This means that, in the basal state, at all levels of glycerol.a, most of the glucose is disposed of by non-insulin-mediated mechanisms and that the elevated rates of basal glucose disposal (due to increased hepatic glucose production) that prevail in non-insulin-dependent diabetes mellitus are associated with increased rates of non-insulin-mediated glucose uptake. How does this consideration of non-insulin-mediated and insulin-mediated glucose uptake relate to the cause of fasting hyperglycemia. This is summarized in Table I1. The major point is that, in the basal state, non-insulinmediated glucose uptake predominates and accounts for about 70 percent of overall glucose disposal. Thus, an impairment in insulin-mediated glucose uptake due to insulin resistance and/or decreased insulin secretion would have a relatively minor effect on overall glucose disposal, since insulin-mediated glucose uptake comprises only 30 percent of glucose disposal. For example, if basal glucose disposal consists of 70 percent non-insulin-mediated glucose uptake and 30 percent insulin-mediated glucose uptake, then a 50 percent reduction in insulin-mediated glucose uptake will lead to only a 15 percent decrease in overall glucose disposal. To be specific (Table II), if a normal basal rate of glucose disposal is 2 mg/kg per minute, then non-insulin-mediated glucose uptake equals 1.4 mg/ kg per minute and insulin-mediated glucose uptake is equal to 0.6 mg/kg per minute. A 50 percent decrease in insulin-mediated glucose uptake will lower glucose disposal by 0.3 mg/kg per minute to 1.7 mg/kg per minute, which is a 15 percent reduction. A slight (about 15 percent) rise in plasma glucose level is all that is necessary to provide a sufficient mass action effect~f glucose to restore glucose disposal back to the origidal level. Thus, the restriction of insulin-mediated glucose uptake in non-insulin-dependent diabetes mellitus is not the proximate cause of fasting hyperglycemia. Since the fasting glucose level reflects the balance between glucose output and glucose disposal, then if reduced glucose disposal does not lead to significant fasting hyperglycemia,!t follows that increased glucose output TABLE I Non-Insulin-Mediated Glucose Uptake and Insulin-Mediated Glucose Uptake in Normal Subjects and Non-Insulin- Dependent Diabetic Subjects in the Basal State Normal Non-Insulin-Dependent Diabetes Mellitus Basal glucose disposal (mg/kg/minute)" Percent non-insulin-mediated glucose uptake Absolute non-insulin-mediated glucose uptake "Basal glucos e disposal equals glucose output (or hepat!c glucose p=;ocluction) and hepatic glucose production is elevated in non-insulindependent diabetes mellitus accounting for the increased basal glucose disposal. Non-insulin-mediated glucose uptake is the same percentage of basal glucose disposa! in normal subjects and non-insulindependent diabetic subjects, but since basal glucose disposal is ele ~ vated in non-insulin-dependent diabetes mellitus, absolute rates of non-insulin-mediated glucose uptake are also elevated in non-insulindependent diabetes mellitus [38]. TABLE II Etiology of Fasting versus Postprandial Hyperglycemia Basal State 9 Non-insulin-mediated glucose uptake predominates (70 percent of basal glucose disposal) 9 Glucose output (hepatic glucose production) equals glucose disposal (insulin-mediated glucose uptake plus non-insulinmediated glucose uptake) equals 2 mg/kg/minute 9 Non-insulin-mediated glucose uptake equal s 1.4, and insulinmediated glucose uptake equals 0.6 mg/kg/minute 9 A 50 percent decrease in insulin-mediated glucose uptake equals a 15 per~tent decrease in glucose disposal to 1.7 rng/kg! minute 9 Fasting blood glucose (85 mg/dl)!ncreases to about 100 mg/dl, and glucose disposal increases 15 percent back to 2.0 mg/kg/ minute 9 If glucose output increases from 2.0 to 2.6 mg/kg/minute then insulin-mediated glucose uptake must increase from 0.6 to 1.2 mg/kg/minute to prevent hyperglycemia 9 This requires a five- to Six-fold increase in insulin level, which cannot be readily achieved in non-insulin-dependent diabetes mellitus 9 Fasting hyperglycemia is largely secondary to increased glucose output (hepatic glucose production) Postprandial State Insulin-mediated glucose uptake predominates (80 to 90 percent of glucose disposal) Postprandial glucose disposal equals 7 mg/kg/minute Non-insulin-mediated glucose uptake equals 1.4, and insulinmediated glucose uptake equal s 5.6 A 50 percent decrease in insulin-mediated glucose uptake leads to a 40 percent decrease in glucose disposal Postprandial hyperglycemia is largely secondary to restricted rise in insulin-mediated glucose uptake.o September 20, 1985 The American Journal of Medicine Volume 79 (suppl 3B) 3

4 OOlj'---- 4O0 GLYBURIDE SYMPOSIUM--OLEFSKY 3OO 2OO I I I I ,000 10, Insulin Concentration (/JU/ml) i 1,000 10,000 Insulin Concentration (/JU/rnl) Figure 2. Dose-response curves for insulin-stimulated glucose disposal in normal versus non-insulin-dependent diabetic subjects. Insulin-mediated glucose disposal rates are plotted as a function of steady-state plasma insulin Concentration. Data were obtained by performing serial euglycemic glucose clamp studies at increasing steady-state plasma insulin levels in the normal subjects and serial glucose = clamp studies at the basal level of glycemia In the non-insulin-dependent diabetic subjects. Insulin-mediated glucose disposal was calculated by subtracting the rate of noninsulin-mediated glucose uptake (70 percent of basal glucose "disposal) from the total glucose disposal rates at each insulin concentration. (hepatic glucose production) is the most'direct factor responsible for fasting hyperglycemia. This is because, in the setting of peripheral insulin resistance and impaired insulin secretion, the ability of insulin-mediated glucose uptake to rise and accommodate an increase in glucose output is severely curtailed. For example (Table II), if basal glucose output and glucose disposal are 2 mg/kg per minute in euglycemia, and basal non:insulin-mediated glucose uptake is 1.4 mg/kg per minute (70 percent) with a basal insulin-mediated glucose uptake of 0.6 mg/kg per minute (30 percent), then a modest increase in hepatic glucose production to 2.6 mg/kg per minute would require a doubling of insulin-mediated glucose uptake (to 1.2 mg/ kg per minute) to maintain glucose disposal equal to glu-, cose output (hepatic glucose production) with no change in basal glucose level. With this in mind, the ability of normal subjects and noninsulin-dependent diabetic subjects to achieve a two-fold increase in insulin-mediated glucose uptake can be compared by examining the dose-response curve for insulinmediated glucose disposal (Figure 2). As can be seen, a normal subject can increase basal insulin-mediated glucose uptake two-fold with less than a two-fold increase in plasma insulin above the basal concentration. Thus, with a normal ability to secrete insulin and a normal capacity of peripheral tissues to respond to insulin, a control subject can easily accommodate a rise in glucose output from 2.0 to 2.6 mg/kg/per minute with little, if any, change in fasting glucose level. In non-insulin-dependent diabetes mellitus, the situation is quite different. As Figure 2 illustrates, a five- to six-fold increase in plasma insulin is necessary to increase insulin-mediated glucose uptake two-fold over the basal value. Thus, because of insulin resistance, noninsulin-dependent diabetic subjects need much larger increases in plasma insulin to increase insulin-mediated glucose uptake, and in view of their impaired insulin secretion, this is unlikely to be achieved. Therefore, to raise glucose disposal to the level of the increased glucose output and bring the system back into balance, the fasting glucose level must rise until the mass action effect of hyperglycemia raises glucose disposal to the level of glucose output. At this point, the system re-equilibrates so that the increased glucose output is now matched by increased glucose disposal in the presence of fasting hyperglycemia. Thus, in non-insulin-dependent diabetes mellitus, the inability to augment insulin-mediated glucose uptake, due to the presence of insulin resistance and restricted insulin secretion, provides the metabolic foundation that allows relatively small increases in glucose output (hepatic glucose production) to cause direct and proportionate increases in the fasting glucose level. The cause of postprandial hyperglycemia is quite different (Table II). Recent data show that the majority of ingested glucose (70 to 90 percent) bypasses the liver and enters the peripheral circulation [40]. This is accompanied by rapid suppression (70 to 90 percent) of hepatic glucose production for two to three hours after carbohydrate ingestion, even in non-insulin-dependent diabetic subjects [41,42]. Thus, in the postprandial state, glucose output predominantly comes from ingested carbohydrate, and this ingested carbohydrate largely enters the peripheral circulation where it is disposed of mostly by skeletal muscle through a several-fold increase in insulin-mediated glucose uptake. Thus, control of the postprandial glucose excursion depends on the ability to augment insulin-mediated glucose uptake. In the postprandial state, an average glucose disposal is in the range of 7 mg/kg per minute. Since insulin-mediated glucose uptake can make up 80 to 4 September 20, 1985 The American Journal of Medicine Volume 79 (suppl 3B)

5 GLYBURtDE SYMPOSIUM--OLEFSKY 90 percent of overall glucose disposal, decreases in insulin-mediated glucose uptake due to insulin resistance and insulin deficiency will markedly reduce glucose disposal at any given glucose level (Table II). Since non-insulin-dependent diabetic subjects have a very limited capacity for an acute increase in insulin-mediated glucose uptake, postprandial glucose levels must rise markedly until the mass action effect of glucose raises glucose disposal to match glucose output and allow disposal of the incoming glucose load. In summary, in the basal state, non-insulin-mediated glucose uptake predominates, and decreased insulinmediated glucose uptake will raise fasting blood glucose levels only modestly. Therefore, increased hepatic glucose production leads to fasting hyperglycemia. In the postprandial state, insulin-mediated glucose uptake normally predominates, and the limited ability of non-insulindependent diabetic subjects to increase insulin-mediated glucose uptake allows the marked postprandial glucose excursions. With these formulations, fasting hyperglycemia is primarily due to glucose overproduction by the liver, whereas postprandial hyperglycemia is primarily due to glucose unde~utilization by peripheral tissues (primarily muscle). PATHOGENESIS OF NON-INSULIN-DEPENDENT DIABETES MELLITUS Let us now turn to the cause of the disease state of noninsulin-dependent diabetes mellitus itself, which is a different kind of consideration from the pathogenesis of the hyperglycemia. Since elevated hepatic glucose production is essentially completely reversible by various forms of anti-diabetic therapy, this is likely to be a secondary abnormality. Thus, in terms of etiology, it seems quite likely that insulin resistance or impaired insulin secretion or both are the primary defects. Which of these two abnormalities comes first is currently unknown, and clearly it is possible that both develop simultaneously. One sequence would be that patients destined to have type II diabetes are unable to compensate for advancing insulin resistance by increasing beta cell insulin secretion and that the inability of the beta cell to match insulin secretion to target cell needs allows hyperglycemia to develop. This formulation, of course, does not indicate the defect that comes first, if in fact either defect develops before the other. Regardless of the sequence, it is clear that neither insulin resistance or deficiency alone can adequately explain the hyperglycemic state in most patients wffh non-insulin-dependent diabetes mellitus. Because of the substantial reserve in the insulin-mediated glucose uptake system, an 80 to 90 percent decrease in either insulin action or secretion would be needed before either defect alone would result in non-insulin-dependent diabetes mellitus. Thus, a combination of insulin resistance and impaired insulin secretion is necessary, and in almost all type II diabetic subjects, both exist together and additively combine to cause the non-insulin-dependent diabetic state. Once hyperglycemia begins, it may lead to further impairment of insulin secretion and insulin resistance, and this is the so called glucotoxicity theory that has been discussed recently by Unger and Grundy [43]. Clearly, substantial evidence exists demonstrating that hyperglycemia can cause or certainly accentuate functional abnormalities of insulin secretion and can also cause or accentuate cellular insulin resistance. With this line of reasoning, hyperglycemia begets more hyperglycemia in a kind of self-perpetuating manner, and it would seem that this concept deserves further exploration. Finally, another way of linking abnormalities of insulin action and secretion together would be to propose a common cellular abnormality. It might be that there is a common defect in the glucose recognition system in peripheral target cells and islet cells involving the same or related proteins. In peripheral target cells, this defect is expressed as impaired glucose transport activity, whereas in islet cells, this defect might be expressed as impaired glucose recognition leading to decreased glucose-mediated insulin secretion. While either one of these unifying hypotheses is clearly oversimplistic, they nevertheless do offer some basis for future experimentation. CLINICAL IMPLICATIONS An understanding of the pathogenesis of fasting versus postprandial hyperglycemia in non-insulin-dependent diabetes mellitus has significant ramifications for the treatment of this condition. For example, a therapeutic regimen consistently able to restrain hepatic glucose production and bring it into the normal range would reproducibly lower fasting blood glucose levels to normal. However, if such a therapy had no effect on insulin secretion or insulin action, insulin-mediated glucose uptake would remain unchanged, and control of postprandial hyperglycemia would be unaffected. Likewise, if a form of anti-diabetic therapy improved only insulin-mediated glucose uptake, then there would be little lowering of fasting plasma glucose levels but only a reduction in postprandial increments. Thus, the ideal form of antidiabetic therapy will lower both fasting and postprandial glucose levels, and this will require normalization of hepatic glucose production in the basal state as well as a marked improvement in "insulin-mediated glucose uptake. Unfortunately, there is no current ideal therapy for non-insulin-dependent diabetes mellitus, but, as we will see throughout this symposium, sulfonylureas--specifically the second-generation agent glyburide--offer several advantages for type II diabetic patients. Although the degree of glyburide-induced improvement in hyperglycemia varies from patient to patient and is September 20, 1985 The American Journal of Medicine Volume 79 (suppl 3B) 5

6 clearly suboptimal in some, in those patients who achieve adequate clinical responses, the drug appears to work by improving all three of the major metabotic defects in noninsulin-dependent diabetes mellitus. Thus, glyburide treatment can result in improved peripheral insulin action, a reduction in hepatic glucose production, and enhanced pancreatic beta cell function. The articles in this symposium will discuss the overall clinical efficacy of glyburide in various dosage regimens and in combination with insulin treatment. Furthermore, the in vivo mechanisms underlying the clinical effects of this drug will be discussed in detail, and we will see that, in addition to its well-known effects to enhance insulin secretion and improve periph- eral insulin action, glyburide also leads to reduced rates of hepatic glucose production, and this may be the most important way in which this drug corrects fasting hyperglycemia. Finally, the cellular mechanisms underlying these therapeutically important drug effects will be discussed, showing that, in vitro, glyburide appears to exert direct effects on peripheral cells by improving insulin action at both the receptor and post-receptor level. ACKNOWLEDGMENT I would like to thank Elizabeth J. Martinez for her expert assistance in the preparation of this paper. 1. National Diabetes Data Group: Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes 1979; 28: Fajans SS, Cloutier MC, Crowther RL: Clinical and etiologic beterogeneity of idiopathic diabetes mellitus. Diabetes 1978; 27: Rotter JI, Anderson CT, Rimoin Dh Genetics of diabetes mellitus. In, Ellenberg M, Rifkin H, eds. Diabetes mellitus: theory and practice, 3rd ed. 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