Intensive Insulin Therapy Symposium Insulin-Dependent Diabetes Mellitus: Pathophysiology
JOHN E. GERICH, M.D., Endocrine Research Unit Diabetes mellitus is a heterogeneous disorder. About 80% of the patients with this disease are categorized as having non-insulin-dependent diabetes mellitus, a disorder resulting from varied degrees of insulin resistance and impaired insulin secretion; the causes for these abnormalities are unknown. The remaining 15 to 20% of patients have insulindependent diabetes mellitus, a disorder caused by the destruction of insulin-producing endocrine cells within the pancreas and currently considered to be the result of an autoimmune process. During the course of both types of diabetes mellitus, the so-called long-term complications of diabetes invariably occur to some extent in all patients. These complications include retinopathy, nephropathy, neuropathy, and premature atherosclerosis. The molecular basis for these complications is not completely understood, but recent evidence obtained from both experiments in animals and prospective clinical studies indicates that metabolic derangements associated with poor glycemic control are a major determinant of the frequency and severity of these complications. Such evidence is the rationale for current attempts to maintain near-normal glycemia in patients with diabetes mellitus.
Diabetes mellitus is a heterogeneous disorder. 1 Currently, it is classified into five major categories: (1) insulin-dependent or type I diabetes mellitus (formerly, juvenile-onset diabetes); (2) noninsulin-dependent or type II diabetes mellitus (formerly, maturity- or adult-onset diabetes); (3) maturity-onset diabetes in the young; (4) secondary diabetes mellitus (for example, postpancreatectomy diabetes); and (5) diabetes mellitus associated with genetic syndromes (such as muscular dystrophy). 2 Insulin-dependent diabetes mellitus and non-insulin-dependent diabetes mellitus constitute about 15% and 80%, respectively, of all cases of the disease. DIFFERENTIAL DIAGNOSIS Insulin-dependent diabetes mellitus is distinguishable from non-insulin-dependent diabetes mellitus both clinically and biochemically. 3,4 PaAddress reprint requests to Dr. J. E. Gerich, Endocrine Research Unit, Mayo Clinic, Rochester, MN 55905. Mayo Clin Proc 61:787-791, 1986
tients with insulin-dependent diabetes mellitus almost always have the onset of their diabetes before age 30 years; they are usually not overweight, they are prone to ketosis, and without exogenous insulin they would die. Biochemically, the diagnosis of insulin-dependent diabetes mellitus can be confirmed by measurement of plasma C-peptide responses after an intravenous injection of glucagon. 4 Many patients with non-insulindependent diabetes mellitus may require insulin therapy for optimal glycemic control; such patients should be considered insulin-requiring rather than insulin-dependent. Although the goals of therapy for these two types of diabetes are similar, non-insulin-dependent diabetes has a different pathogenesis from insulin-dependent diabetes mellitus. 5 Occasionally, elderly patients with non-insulin-dependent diabetes mellitus may become ketosis-prone and require insulin therapy. 4 Such patients may have a deficient plasma C-peptide response to glucagon comparable to that of patients with insulin-dependent diabetes mellitus. Although they may resemble patients
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with insulin-dependent diabetes mellitus clinically, it is probably best not to classify them as insulin-dependent inasmuch as the underlying pathologic process (depletion of pancreatic insulin) differs from that in insulin-dependent diabetes mellitus. ETIOLOGY There is considerable evidence that insulindependent diabetes mellitus is an autoimmune disease caused by destruction of the insulinproducing cells within the pancreatic islets. 6,7 At the clinical onset of the disease, patients with insulin-dependent diabetes mellitus have evidence of ongoing cell-mediated and humoral Immunologie processes.6"10 Initially, patients have circulating antibodies to islet B cells and pancreatic insulitis. 6,7 Moreover, the disease is associated with certain HLA types linked to immune response genes. 11 Finally, insulin-dependent diabetes mellitus is also occasionally associated with an autoimmune phenomenon in other tissues— that is, thyroid, adrenal, and gastric parietal antibodies. 12 There is now evidence that the immune destruction of the pancreas begins many years before the clinical onset of the disease, because patients have been found to have circulating antibodies to islet B cells long before the development of insulin-dependent diabetes mellitus; 13,14 however, whether circulating islet antibodies are a good marker for ultimate development of the disease and what initiates the autoimmune destructive process are currently unknown. 15 Examination of the pancreas in patients with insulin-dependent diabetes mellitus reveals a near-total absence of insulin-secreting B cells and normal amounts of other islet cells, glucagonsecreting A cells, somatostatin-secreting D cells, and pancreatic polypeptide-secreting (PP) cells.16 In contrast, examination of the pancreas in patients with non-insulin-dependent diabetes mellitus may show normal or only moderately decreased concentrations of insulin. 16 Therefore, non-insulin-dependent diabetes mellitus is thought to result from a combination of insulin resistance and a functional impairment in the ability to secrete compensatory amounts of insulin. 5 All the metabolic derangements in insulindependent diabetes mellitus can be attributed to insulin deficiency.17 In severe insulin deficiency, oversecretion of anti-insulin hormones results in
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excessive production of glucose and ketone bodies, mobilization of stored free fatty acids, impaired utilization of glucose and ketone bodies, and, ultimately, diabetic ketoacidosis. 18 All these abnormalities can be reversed by the administration of exogenous insulin. In patients with poorly controlled insulin-dependent diabetes mellitus, the ability of tissues to respond to insulin is impaired; in other words, there is resistance to insulin. 17 The same phenomenon has been shown to occur in animals made diabetic experimentally by destruction of the insulin-producing B cells of the pancreas. This insulin resistance is thought to be due to lack of activation or to low levels of key enzymes. Intensive treatment of patients with insulin-dependent diabetes mellitus to the point of achieving near-normal glycemia has been shown to cause complete reversal ofthe insulin resistance associated with this condition. 7 COMPLICATIONS A highly controversial issue has been the relationship between insulin deficiency (or its consequences) and the pathogenesis of the so-called longterm complications of diabetes mellitus (retinopathy, nephropathy, neuropathy, and premature atherosclerosis). 1921 Currently, the specific metabolic event that leads to each of these complications is unknown. Several possibilities under active investigation are the glycosylation of tissue proteins, which alters their structure, turnover, or function; 22 the accumulation of intracellular polyols due to the metabolism of glucose by noninsulin-dependent pathways 2 3 (this factor has been established as the cause of diabetic cataracts and, in association with depletion of neural myoinositol, is believed to be involved in diabetic neuropathy); 24 excessive secretion of growth hormone and overproduction of insulin-like growth factors thought by some investigators to be involved in the pathogenesis of diabetic retinopathy; 25 and alterations in metabolism of prostaglandin, thromboxane, and leukotriene, in platelet responsiveness, and in metabolism of insulin-like growth factors that may contribute to both microvascular and macrovascular disease in patients with diabetes. 22 It has not been possible to distinguish between the lack of insulin per se and the secondary metabolic consequences of the lack of insulin (for example, hyperglycemia) in the involvement of the long-term complications of diabetes mellitus.
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Several lines of evidence suggest that the longterm complications of diabetes are linked to metabolic control and are not a separate, parallel, genetically determined abnormality. For example, studies in identical twins who are discordant for diabetes mellitus have shown that the patients with diabetes have increased widths of glomerular, tubular, and muscle capillary basement membranes, whereas their twins without diabetes mellitus have normal widths. 26 If one accepts that thickening of basement membranes is a marker for diabetic microangiopathy that is determined by genetic factors rather than environmental factors such as glycemic control, then identical widths of basement membranes would be expected in the identical twins, despite the fact that they were discordant for diabetes. The fact that this does not occur is strongly suggestive of environmental factors being involved in the pathogenesis of diabetic microangiopathy. Furthermore, a recent review by Barbosa and Saner 27 indicated that "there is no direct and conclusive evidence that genetic factors play a role in the pathogenesis of microangiopathy in diabetes." Another line of evidence against genetic factors being involved in diabetic microangiopathy is the observation that microangiopathy can develop in kidneys from normal rats that are transplanted to rats that have been made diabetic. 28 Recently, the same phenomenon has been shown to occur when kidneys from nondiabetic donors are transplanted to patients with diabetes. 29,30 In contrast, transplantation of pancreatic islets to animals made experimentally diabetic, which normalizes the previously diabetic milieu, either prevents the development of diabetic microangiopathy or ameliorates the condition. 28,31 Improvement in human diabetic nephropathy has recently been reported to occur when kidneys from diabetic donors were transplanted to nondiabetic recipients: in two patients from the Near East who had terminal polycystic kidney disease, no donor kidneys were available except for those from patients who had mild diabetic nephropathy; after transplantation of these kidneys to the nondiabetic recipients, thickening of the glomerular capillary basement membrane and mesangium decreased, as did proteinuria. 32 Further evidence suggesting that the metabolic milieu may be important in the pathogenesis of the long-term complications of diabetes has come from studies in animals made experimentally
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diabetic and then maintained in either poor or good glycemic control. Bloodworth and Engerman 3 3 showed that more severe retinopathy and nephropathy developed in dogs that were maintained in poor glycemic control than in those that had been maintained in good control. Greene and colleagues 24 reported that optimal glycemic control can reverse the impairment in the conduction velocity of muscle and nerve that develops after the experimental induction of diabetes in rats. The same degree of improvement was shown after supplementation with myo-inositol, a finding that suggests involvement of the polyol pathway in the pathogenesis of diabetic neuropathy. 23 Retrospective studies examining the relationship of glycemic control to the long-term complications of diabetes in humans have generally yielded inconclusive results. 34 During the past 6 or 7 years, several prospective studies have demonstrated the beneficial effect of good glycemic control. Eschwege and colleagues 35 reported that improved glycemic control using multiple injections of insulin, as opposed to poor glycemic control using one injection of insulin, decreased the rate of the appearance of microaneurysms in patients with insulin-dependent diabetes mellitus; in the poorly controlled group, the yearly increase in the number of aneurysms was 3 times that in the well-controlled group. Raskin and colleagues 36 reported that improved glycemic control using intensive insulin therapy reduced previously increased widths in the basement membranes of quadriceps capillaries in patients with insulindependent diabetes mellitus during a 2-year period; in contrast, the control group of patients who were maintained in their usual degree of poor control had a progressive increase in the width of the capillary basement membranes during this period. One of the most impressive prospective studies of this question is that of Pirart, 37 which consisted of observations in more than 4,000 patients treated by one physician between 1947 and 1973. During this time, the degree of glycemic control, recorded at each office visit, was given a score based on fasting and postprandial levels of plasma glucose, glycosuria, and the presence or absence of ketosis. Each year, the patients' retinopathy, nephropathy, and neuropathy were evaluated (Table 1). At the end of 25 years, the prevalence of retinopathy was 60%, that of neuropathy 50%, and that of nephropathy 20%. Patients
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Table 1.—Relationship of Metabolic Control to Long-Term Complications of Diabetes Mellitus* Prevalence after 25 yr of diabetes (%) Patients with Poor control Overall Good control Neuropathy 65 50 10 Nephropathy 20 20 <1 Retinopathy 80 60 10 (proliferative) (20) «D *Data from Pirart. 37
considered to have been in good metabolic control after 25 years had a prevalence of neuropathy of only 10 to 15%, whereas patients in poor metabolic control had a prevalence of between 60 and 70%. Patients in good metabolic control had virtually no nephropathy, whereas the prevalence of nephropathy in patients with poor control was between 20 and 30%; similar observations were recorded for retinopathy. The most impressive finding was the difference in proliferative retinopathy, which was virtually absent after 25 years of diabetes in patients with good glycemic control but was present in approximately 20% of the patients who had poor glycemic control. Against this background, two recent prospective studies (the Kroc Collaborative Study Group conducted in the United States, England, and Canada 3 8 and the Steno Study Group conducted in Denmark 39 ) have indicated greater progression of diabetic retinopathy during an approximately 1-year period in patients given intensive insulin therapy in comparison with patients maintained with conventional insulin therapy. Follow-up of these patients in as-yet unpublished studies, however, indicates that this deterioration is transient. The initial progression is believed to be due to marginally perfused areas of the retina becoming infarcted because of reduced retinal blood flow that occurs in association with decreased levels of plasma glucose.39 A similar, but much larger, multicenter trial (the Diabetes Control and Complications Trial) sponsored by the National Institutes of Health) concerning the relationship between glycemic control and diabetic retinopathy is currently under way. It will probably be several years before the results of this study are known. For the present, however, the predominance of evidence seems to indicate that good glycemic control can prevent, attenuate, and, in some instances, reverse some of the longterm complications of diabetes mellitus. On the
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basis of this evidence, there has been a general trend toward trying to achieve near-normal glycemic control in patients with diabetes mellitus.
1. Fajans SS, Cloutier MC, Crowther RL: Clinical and etiologic heterogeneity of idiopathic diabetes mellitus. Diabetes 27:1112-1125, 1978 2. National Diabetes Data Group: Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes 28:1039-1057, 1979 3. Cudworth AG, Woodrow JC: Genetic susceptibility in diabetes mellitus: analysis of the HLA association. Br Med J 2:846-848, 1976 4. Faber OK, Binder C: C-peptide response to glucagon: a test for the residual /3-cell function in diabetes mellitus. Diabetes 26:605-610, 1977 5. Gerich JE: Assessment of insulin resistance and its role in non-insulin-dependent diabetes mellitus. J Lab Clin Med 103:497-505, 1984 6. Cahill GF Jr, McDevitt HO: Insulin-dependent diabetes mellitus: the initial lesion. N Engl J Med 304:1454-1465, 1981 7. Bottazzo GF, Dean BM, McNally JM, MacKay EH, Swift PG, Gamble DR: In situ characterization of autoimmune phenomena and expresion of HLA molecules in the pancreas in diabetic insulitis. N Engl J Med 313:353-360, 1985 8. Buschard K, Ropke C, Madsbad S, Mehlsen J, Rygaard J: T lymphocyte subsets in patients with newly diagnosed type I (insulin-dependent) diabetes: a prospective study. Diabetologia 25:247-251, 1983 9. Lernmark A, Baekkeskov S: Islet cell antibodies: theoretical and practical implications. Diabetologia 21:431-435, 1981 10. Lernmark A: Molecular biology of type I (insulindependent) diabetes mellitus. Diabetologia 28:195-203, 1985 11. Rotter JI, Rimoin DL: Heterogeneity in diabetes mellitus—update, 1978: evidence for further genetic heterogeneity within juvenile-onset insulin-dependent diabetes mellitus. Diabetes 27:599-608,1978 12. Irvine WJ: Autoimmunity in endocrine disease. Recent Progr Horm Res 36:509-556, 1980 13. Irvine WJ, Gray RS, McCallum CJ: Pancreatic islet-cell antibody as a marker for asymptomatic and latent diabetes and prediabetes. Lancet 2:1097-1102, 1976 14. Srikanta S, Ganda OP, Rabizadeh A, Soeldner JS, Eisenbarth GS: First-degree relatives of patients with type I diabetes mellitus: islet-cell antibodies and abnormal insulin secretion. N Engl J Med 313:461-464, 1985 15. Craighead JE: Current views on the etiology of insulindependent diabetes mellitus. N Engl J Med 299:1439-1445, 1978 16. Rahier J, Goebbels RM, Henquin JC: Cellular composition of the human diabetic pancreas. Diabetologia 24:366371, 1983 17. Lager I, Lonnroth P, Von Schenck H, Smith U: Reversal of insulin resistance in type I diabetes after treatment with continuous subcutaneous insulin infusion. Br Med J 287:1661-1664, 1983 18. McGarry JD, Foster DW: Regulation of ketogenesis and clinical aspects of the ketotic state. Metabolism 21:471489, 1972
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19. Raskin P: Diabetic regulation and its relationship to microangiopathy. Metabolism 27:235-252, 1978 20. Tchobroutsky G: Relation of diabetic control to development of microvascular complications. Diabetologia 15:143-152, 1978 21. Siperstein MD: Diabetic microangiopathy and the control of blood glucose (editorial). N Engl J Med 309:1577-1579, 1983 22. Brownlee M, Cerami A: The biochemistry of the complications of diabetes mellitus. Annu Rev Biochem 50:385-432, 1981 23. Gabbay KH: The sorbitol pathway and the complications of diabetes. N Engl J Med 288:831-836, 1973 24. Greene DA, De Jesus PV Jr, Winegrad AI: Effects of insulin and dietary myoinositol on impaired peripheral motor nerve conduction velocity in acute streptozotocin diabetes. J Clin Invest 55:1326-1336, 1975 25. Gerich JE: Role of growth hormone in diabetes mellitus (editorial). N Engl J Med 310:848-850, 1984 26. Steffes MW, Sutherland DER, Goetz FC, Rich SS, Mauer SM: Studies of kidney and muscle biopsy specimens from identical twins discordant for type I diabetes mellitus. N Engl J Med 312:1282-1287, 1985 27. Barbosa J, Saner B: Do genetic factors play a role in the pathogenesis of diabetic microangiopathy? Diabetologia 27:487-492, 1984 28. Mauer SM, Steffes MW, Michael AF, Brown DM: Studies of diabetic nephropathy in animals and man. Diabetes 25 Suppl 2:850-857, 1976 29. Mauer SM, Barbosa J, Vernier RL, Kjellstrand CM, Buselmeier TJ, Simmons RL, Najarian JS, Goetz FC: Development of diabetic vascular lesions in normal kidneys transplanted into patients with diabetes mellitus. N Engl J Med 295:916-920, 1976 30. Mauer SM, Steffes MW, Connett J, Najarian JS, Sutherland DER, Barbosa J: The development of lesions in the glomerular basement membrane and mesangium after transplantation of normal kidneys to diabetic patients. Diabetes 32:948-952, 1983
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31. Mauer SM, Steffes MW, Sutherland DER, Najarian JS, Michael AF, Brown DM: Studies on the rate of regression of the glomerular lesions in diabetic rats treated with pancreatic islet transplantation. Diabetes 24:280-285, 1975 32. Abouna GM, Kremer GD, Daddah SK, Al-Adnani MS, Kumar SA, Kusma G: Reversal of diabetic nephropathy in human cadaveric kidneys after transplantation into non-diabetic recipients. Lancet 2:1274-1276, 1983 33. Bloodworth JMB Jr, Engerman RL: Diabetic microangiopathy in the experimentally-diabetic dog and its prevention by careful control with insulin (abstract). Diabetes 22:290, 1973 34. Knowles HC Jr: The problem of the relation of the control of diabetes to the development of vascular disease. Trans Am Clin Climatol Assoc 76:142-146, 1965 35. Eschwege E, Guyot-Argenton C, Aubry JP, Tchobroutsky G: Delayed progression of diabetic retinopathy by divided insulin administration: a further follow-up. Diabetologia 16:13-15, 1979 36. Raskin P, Pietri AO, Unger R, Shannon W A Jr: The effect of diabetic control on the width of skeletal-muscle capillary basement membrane in patients with type I diabetes mellitus. N Engl J Med 309:1546-1550, 1983 37. Pirart J: Diabetes mellitus and its degenerative complications: a prospective study of 4,400 patients observed between 1947 and 1973. Diabetes Care 1:168-188; 252-263, 1978 38. The Kroc Collaborative Study Group: Blood glucose control and the evolution of diabetic retinopathy and albuminuria: a preliminary multicenter trial. N Engl J Med 311:365-372, 1984 39. Steno Study Group: Effect of 6 months of strict metabolic control on eye and kidney function in insulin-dependent diabetics with background retinopathy. Lancet 1:121-124, 1982