Catecholamines released from the sympathochromaffin system produce metabolic changes similar to those of diabetes mellitus. However, increased sympathochromaffin activity does not appear to be a feature of insulin-dependent diabetes mellitus (IDDM), although physiologic catecholamine increments may contribute to short-term metabolic derangements under some conditions. Increased glycemic sensitivity to epinephrine is a feature of IDDM but is the result of the inability to secrete insulin rather than of increased cellular sensitivity to catecholamines. Absolute insulin deficiency results in increased metabolic (glycemic, lipolytic, and ketogenic) sensitivity to catecholamines. More generalized hypersensitivity occurs in diabetic autonomic neuropathy. However, the clinical relevance of these alterations in sensitivity remains to be established. On the other hand, decreased sympathochromaffin activity is common and causes considerable morbidity and some mortality in people with diabetes. In addition to increased sensitivity to catecholamines, decreased sympathochromaffin activity results in the clinical syndromes of postural hypotension, hypoglycemia unawareness, defective glucose counterregulation, or a combination of these. The latter two syndromes cause an increased frequency of severe iatrogenic hypoglycemia, at least during intensive therapy of IDDM. Thus, decreased rather than increased sympathochromaffin activity often complicates IDDM. Clearly, ways to prevent, correct, or compensate for this component of diabetic autonomic neuropathy must be learned before diabetes can be managed effectively and safely in all patients who suffer from the disease until diabetes mellitus is eradicated.

Numerous studies have demonstrated that poor glycemic control is associated with elevated plasma cholesterol levels in diabetic patients. Experiments have shown that cholesterol synthesis is increased in the small intestine of various diabetic animals. This increase is a generalized phenomenon occurring in all segments of the small intestine. Insulin therapy that normalizes blood glucose levels markedly decreases intestinal cholesterol synthesis in diabetic animals to a level similar to that observed in control animals. Studies have suggested that the hyperphagia that accompanies poorly controlled diabetes is the chief stimulus for the increase in intestinal cholesterol synthesis. However, the direct contact of the intestinal mucosa with nutrients is not the sole trigger for increasing cholesterol synthesis in the small intestine, suggesting that circulating and/or neurological factors play a role. The transport of newly synthesized cholesterol, most of which is in the chylomicron lipoprotein fraction, from the intestines to the circulation is increased in diabetic rats. The sterols associated with these chylomicrons are rapidly cleared from the circulation and delivered to the liver. The increased transport of chylomicrons from the intestine to the circulation in diabetic patients could potentially result in several alterations in lipid metabolism that may increase the risk of atherosclerotic vascular disease.

From December 1966 to March 1988, 1394 pancreas transplants were reported to the International Pancreas Transplant Registry. For the 1129 cases since 1982, the overall 1-yr graft and recipient survival rates were 46 and 82%, respectively. When analyzed according to the three most common duct-management techniques, polymer injection (n = 324), intestinal drainage (n = 282), and bladder drainage (n = 462), the 1-yr function rates were 47, 45, and 54%, respectively. The graft survival rates were also similar, whether whole (n = 492) or segmental (n = 634) grafts were transplanted (47 vs. 46% at 1 yr). Graft survival rates according to preservation times were 49, 42, and 43% at 1 yr for those stored less than 6 h (n = 694), 6-12 h (n = 237), and greater than 12 h (n = 89), respectively. Immunosuppressive regimens that included both cyclosporin and azathioprine were associated with significantly (P less than .03) higher graft survival rates than those that included only one of the drugs, with 1-yr graft survival rates for technically successful grafts of 67, 54, and 39% for patients treated with azathioprine plus cyclosporin (n = 602), cyclosporin without azathioprine (n = 201), and azathioprine without cyclosporin (n = 44). Pancreas-graft survival rates differed according to whether a kidney was or was not transplanted and according to the timing of the transplant: 53, 40, and 32%, respectively, at 1 yr for cases in which a simultaneous kidney was transplanted (n = 685), a kidney had previously been transplanted (n = 201), or a kidney had never been transplanted (n = 202).(ABSTRACT TRUNCATED AT 250 WORDS)

We report on 92 pancreas transplantations with exocrine diversion by pancreaticoenterostomy. All recipients suffered from long-term type I (insulin-dependent) diabetes. In most transplantations, cadaveric segmental grafts were used (n = 89). In a few patients, segmental grafts from related donors were used (n = 3), and in a few other patients, whole-organ cadaveric grafts were used (n = 4). There were 9 retransplantations. Most pancreas transplantations were performed in uremic diabetic patients in combination with a kidney transplantation (n = 58). In a few patients the pancreas transplantation was performed after a kidney transplantation (n = 6). The remaining transplantations were in nonuremic diabetic patients who received only a pancreas (n = 25). Over the years, the results have improved considerably; in the 1986-1987 series the overall 1-yr patient survival (ps) and graft survival (gs) rates were 97 and 56%, respectively. The best results were achieved with the combined procedure (ps 100%, gs 77%); with pancreas only, the figures were inferior (ps 92%, gs 34%). Several factors explain the improved results. The incidence of graft thrombosis has been reduced by the use of anticoagulation, and posttransplantation pancreatitis has been reduced by avoiding ischemic injury to the graft. Cyclosporin has helped reduce the incidence of graft rejection, and monitoring of the exteriorized pancreatic juice has helped in the diagnosis of rejection.

Between November 1977 and January 1987, 55 transplantations of pancreas segments from living donors related to their recipients were performed at the University of Minnesota. A preliminary analysis of metabolic test results in donors tested 1 yr after hemipancreatectomy showed an increase in mean glucose and a decrease in mean insulin values during oral glucose tolerance tests (OGTTs) in 18 donors, a 14% increase in the mean of the mean glucose levels during 24-h metabolic profiles in 12 donors, and a decrease of 45% in the mean 24-h urinary C-peptide excretion in 21 donors. Including the studies performed postdonation, 11 of 31 (35%) donors developed an abnormal OGTT result. In a retrospective analysis, preoperative results of intravenous glucose tolerance tests (IVGTTs) and cortisone-stimulated OGTTs were found to be statistically significant predictors of an abnormal OGTT after hemipancreatectomy. The mean of the 5- to 50-min IVGTT insulin values was the best predictive test. With the cutoff value set at 62 microU/ml, this test result had a sensitivity of 100%, a specificity of 83%, and a positive predictive value of 75% for identifying donors who developed an abnormal OGTT. The sum of the 5- and 10-min IVGTT insulin (cutoff 140 microU/ml) had a sensitivity of 100%, a specificity of 67%, and a predictive value of only 60%, whereas the delta-insulin had values of 86, 71, and 60%, respectively. Both the IVGTT mean insulin and the sum of the 5-min and 10-min insulin test results were 100% predictive of an abnormal test (0% risk), but the IVGTT mean insulin excluded the lowest proportion of otherwise suitable donors (a low "false-alarm" rate). The IVGTT mean insulin can be used to identify or exclude potential donors who would develop an abnormal OGTT result should hemipancreatectomy be performed.

Glucose counterregulation is the sum of processes that protect against development of hypoglycemia and that restore euglycemia if hypoglycemia should occur. In order of importance, the key counterregulatory factors are glucagon, epinephrine, growth hormone, cortisol, and hepatic autoregulation. These act primarily by increasing hepatic glucose output, initially via breakdown of glycogen and later by gluconeogenesis. In people without diabetes and in people with type II (non-insulin-dependent) diabetes, suppression of endogenous insulin secretion during hypoglycemia is also important in permitting full expression of the effects of counterregulation. People with diabetes are more prone to develop hypoglycemia for various reasons (e.g., insulin overdose, skipped meals, and intensive exercise); one that has recently been identified is impaired glucose counterregulation: patients with type I (insulin-dependent) diabetes (and to a lesser extent, patients with type II diabetes) lose the glucagon response to hypoglycemia; subsequent development of autonomic neuropathy with concomitant loss of the epinephrine response leads to almost complete paralysis of counterregulation and loss of recognition of hypoglycemia. To make matters worse, an episode of hypoglycemia that causes activation of counterregulation can lead to rebound hyperglycemia (Somogyi phenomenon); if this is improperly treated, brittle diabetes may follow. Thus, abnormalities in glucose counterregulation may predispose to severe hypoglycemia and prevent achievement of optimal glycemic control in patients with diabetes.

Resistance to insulin-stimulated glucose uptake is present in the majority of patients with impaired glucose tolerance (IGT) or non-insulin-dependent diabetes mellitus (NIDDM) and in approximately 25% of nonobese individuals with normal oral glucose tolerance. In these conditions, deterioration of glucose tolerance can only be prevented if the beta-cell is able to increase its insulin secretory response and maintain a state of chronic hyperinsulinemia. When this goal cannot be achieved, gross decompensation of glucose homeostasis occurs. The relationship between insulin resistance, plasma insulin level, and glucose intolerance is mediated to a significant degree by changes in ambient plasma free-fatty acid (FFA) concentration. Patients with NIDDM are also resistant to insulin suppression of plasma FFA concentration, but plasma FFA concentrations can be reduced by relatively small increments in insulin concentration. Consequently, elevations of circulating plasma FFA concentration can be prevented if large amounts of insulin can be secreted. If hyperinsulinemia cannot be maintained, plasma FFA concentration will not be suppressed normally, and the resulting increase in plasma FFA concentration will lead to increased hepatic glucose production. Because these events take place in individuals who are quite resistant to insulin-stimulated glucose uptake, it is apparent that even small increases in hepatic glucose production are likely to lead to significant fasting hyperglycemia under these conditions. Although hyperinsulinemia may prevent frank decompensation of glucose homeostasis in insulin-resistant individuals, this compensatory response of the endocrine pancreas is not without its price. Patients with hypertension, treated or untreated, are insulin resistant, hyperglycemic, and hyperinsulinemic. In addition, a direct relationship between plasma insulin concentration and blood pressure has been noted. Hypertension can also be produced in normal rats when they are fed a fructose-enriched diet, an intervention that also leads to the development of insulin resistance and hyperinsulinemia. The development of hypertension in normal rats by an experimental manipulation known to induce insulin resistance and hyperinsulinemia provides further support for the view that the relationship between the three variables may be a causal one.(ABSTRACT TRUNCATED AT 400 WORDS)

The effects of sympathetic neural activation on basal pancreatic hormone secretion cannot be explained solely by the actions of the classic sympathetic neurotransmitter norepinephrine. The nonadrenergic component may be mediated by the 29-amino acid peptide galanin in that this neuropeptide meets several of the criteria necessary to be considered a sympathetic neurotransmitter in the endocrine pancreas. 1) Galanin administration inhibits basal insulin and somatostatin secretion and stimulates basal glucagon secretion from the pancreas, qualitatively reproducing the effects of sympathetic nerve stimulation. These sympathomimetic effects appear to be mediated by direct actions of galanin on the islet. 2) Galanin-like immunoreactivity exists in fibers that innervate pancreatic islets. 3) Galanin is released during electrical stimulation of pancreatic nerves. The quantity released is sufficient to reproduce sympathetic nerve stimulation-induced effects on insulin secretion and to contribute to the neural effects on somatostatin and glucagon release. 4) Whether interference with galanin action or release reduces the islet response to sympathetic nerve stimulation remains to be determined. We hypothesize that galanin and norepinephrine act together to mediate the islet response to sympathetic neural activation. If galanin is a sympathetic neurotransmitter in the endocrine pancreas, it may contribute to the inhibition of insulin secretion that occurs during stress and thereby to the hyperglycemic response. Moreover, the local presence of this potent beta-cell inhibitor in the islet leads to speculation on galanin's contribution to the impairment of insulin secretion that occurs in non-insulin-dependent diabetes mellitus and therefore on the potential utility of a galanin antagonist in the treatment of this disease.

Analysis of HLA-associated susceptibility to insulin-dependent diabetes mellitus (IDDM) has largely focused on identifying the susceptibility gene. Adherents of a countertrend have long suggested the importance of analysis of HLA haplotypes (combinations of alleles on 1 chromosome) rather than individual genes. Accumulating data suggest that the relationship between IDDM susceptibility and HLA is much more complex than a single susceptibility gene. Consideration of this question should include the possibilities that 1) more than one HLA gene is involved in determining susceptibility or resistance; 2) different alleles of the same gene may be associated with different pathogenetic mechanisms; and 3) different susceptibility-associated haplotypes, even if they share an allele at an IDDM-relevant locus, may behave differently in IDDM. A better understanding of the genetics, and perhaps the pathogenesis, of IDDM may be obtained by following up the clues offered by analysis of the association of HLA haplotypes (rather than individual alleles) with one another, with clinical features of IDDM, and with possible non-HLA-linked susceptibility factors.

Recent studies have identified a high-affinity receptor on the plasma membrane of the beta-cell that is specific for all of the sulfonylureas. The most potent second-generation drugs, glyburide and glipizide, bind to the receptor and trigger insulin release at nanomolar concentrations. The affinity to the receptor-ligand interaction of all sulfonylureas correlates with their potency as insulin secretagogues, further implicating receptor occupancy with signal transduction. These drugs also inhibit the electrical activity of ATP-sensitive K+ channels and K+ efflux through these channels. The channels are also closed by the metabolism of the major insulin secretagogues, glucose and the amino acids, which signal insulin release by increasing the ATP level or the [ATP]-to-[ADP] ratio on the cytoplasmic side of the channel. Based on the channel number and the amount of K+ current they pass, it is possible to calculate that these channels control the resting membrane potential of the beta-cell. Inactivation of the ATP-inhibitable K+ channel results in a fall in the resting membrane potential, cell depolarization, and influx of extracellular Ca2+ through the voltage-dependent Ca2+ channel. The rise in intracellular free Ca2+ level triggers exocytosis. Thus, it is now possible to link either a stimulus from the metabolism of insulin secretagogues or the sulfonylureas to ionic and electrical events that elicit insulin release. These data also suggest that the sulfonylurea receptor or a closely associated protein is an ATP-sensitive K+ channel.

Alterations in myo-inositol and phosphoinositide metabolism, induced by hyperglycemia and prevented by aldose reductase inhibitors, are implicated in impaired Na+-K+-ATPase regulation in peripheral nerve and other tissues prone to diabetic complications by an increasing range of scientific observations. However, the precise role of these related metabolic derangements in various stages of clinical complications is complex. For instance, it appears that these biochemical defects may play a role not only in the initiation of diabetic neuropathy but also in its later progression. Therefore, full appreciation of the potential pathogenetic role of altered phosphoinositide metabolism in diabetic complications requires detailed studies of both the earliest and the more mature stages of these disease processes.

Eicosanoids both negatively and positively modulate glucose-induced insulin secretion. Although the identity of the positive modulator is uncertain, the negative modulator appears to be prostaglandin E2 (PGE2), because 1) glucose stimulates PGE2 synthesis from islet cells; 2) exogenous PGE2 inhibits glucose-induced insulin secretion; 3) inhibition of beta-cell PGE2 synthesis increases glucose-induced insulin secretion, and this increase is reversed by exogenous PGE2; and 4) PGE2 binds to specific beta-cell receptors that are coupled to inhibitory regulatory components of adenylate cyclase whose activation decreases cAMP levels. Other possible regulatory effects of eicosanoids on islet function include modulation of islet blood flow and its immune responsiveness. From these considerations, the perspective is offered that eicosanoids are pluripotential modulators of islet function.

In isolated islets, the hydrolysis of membrane phosphoinositides (PI) participates in the transduction of both extracellular and intracellular signals into an effective insulin secretory response. A wide variety of potential second-messenger molecules are generated during the phospholipase C-mediated cleavage of these strategically situated membrane phospholipids. Several distinct but interrelated issues are addressed in this perspective. These include 1) methodological approaches utilized to assess PI turnover, 2) the synergistic relationship between PI-derived second messengers and cAMP, 3) the contribution of changing PI turnover rates to the biphasic pattern of insulin output induced by 20 mM glucose, and 4) the role played by PI turnover in the phenomenon of "memory" displayed by islets after prior stimulation with various agonists. The concept that events unique to PI turnover contribute to beta-cell activation is well founded. Because of uncertainty regarding the exact nature of all PI-derived messengers, however, it is not yet possible to mold the available information into a comprehensive theory of beta-cell activation. Future studies will have to address various important unresolved issues.

Extant data suggest that a Ca2+- and phospholipid-dependent protein kinase C (PKC) exists (as a single enzyme or possibly a family of related enzymes) in rodent beta-cells. PKC activators probably induce secretion primarily through phosphorylation of key proteins, thereby sensitizing the exocytotic apparatus to Ca2+. PKC can be activated by several pharmacologic probes and by endogenous diacylglycerol (and possibly arachidonic acid) released by nutrient-activated phospholipases. Several nonspecific pharmacologic agents inhibit both PKC and physiologic insulin release. However, when a more specific inhibitor of PKC, H7 [1-(5-isoquinolinylsulfonyl)-2-methylpiperazine], was studied, it did not reduce glucose-induced insulin secretion. Moreover, prolonged preexposure of islets to a phorbol ester (believed to induce selective depletion of PKC) also failed to substantially reduce the subsequent secretory response to glucose. Thus, indisputable evidence for an obligatory physiological role of PKC in the islet is still missing, and the enzyme's status as a critical coupling signal should be viewed as putative only.

Evidence for an abnormal myocardial cell function in diabetes mellitus, influenced by acute metabolic changes, has appeared within recent years. Few but interesting clinical studies focus on this aspect of diabetic cardiopathy, and experimental studies have delivered possible explanations at the cellular level. These are concerned with the intracellular calcium homeostasis and transsarcolemmal receptor signaling. Because these changes are reversible by short-term insulin treatment, a new aspect for the study of diabetic heart disease has appeared.