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.

Recent studies indicate that insulin directly regulates the acinar pancreas. Morphologic and hemodynamic studies indicate the presence of a portal system that conveys islet blood to acinar cells. Studies both in humans with diabetes mellitus and in animals given beta cell toxins indicate that insulin is necessary for normal acinar cell function. Studies in the perfused rat pancreas indicate that endogenous insulin potentiates zymogen release. Isolated rat and mouse acini have insulin receptors, and in these cells, after binding to its receptors, insulin regulates a number of functions including: sugar transport, protein synthesis, and the number of cholecystokinin receptors. These in vivo and in vitro studies suggest, therefore, that there is an insulin-pancreatic acinar axis that plays a major role in pancreatic function.

Most studies of gestational diabetes mellitus (GDM) have reported a marked reduction in perinatal mortality with appropriate dietary regimens and good medical and obstetrical surveillance. Nevertheless, fetal morbidity, including macrosomia, has remained high and appears to be linked to factors other than plasma glucose control. In a review of six investigations in which insulin therapy was combined with an appropriate diet, the incidence of fetal macrosomia was reduced in five studies as compared with diet-only treatments. Again, the improvement did not always correlate with altered plasma glucose profiles. Other studies suggest that maternal plasma substrate disturbances other than glucose may contribute to the development of fetal macrosomia. To what extent insulin administration reduces morbidity by containing circulating maternal fuels, such as lipids and amino acids, in a more normal range remains to be determined. Moreover, the role of diet, maternal obesity, and weight gain during pregnancy adds to the complexity of factors influencing obstetrical outcome in gestational diabetes. Until the relative importance of all of these variables is adequately assessed, criteria for selection of women with pregnancy-onset diabetes for insulin therapy are most likely to be based on fasting and postprandial plasma glucose concentrations.

Treatment with conventional insulin preparations results in appreciable insulin antibody formation in nearly all subjects. High titers of insulin antibodies are undesirable. They might induce insulin allergy and insulin resistance, and they influence metabolic regulation. Also, lipoatrophy is related to the immunogenicity of insulin preparations. Insulin antibodies are transferred from insulin-treated diabetic mothers to the fetus and contribute to the increase of free plasma insulin in the fetus, thus influencing the development of macrosomia and neonatal hypoglycemia. Therefore, the risk of insulin antibody formation should be reduced. This is possible by using purified, nonbeef insulin preparations. The risk of insulin allergy, insulin resistance, lipoatrophy, and prolonged hypoglycemia in mother and child is reduced by treating pregnant diabetic subjects with purified pork or human insulin preparations. The reduction of insulin requirement that accompanies the change from conventional insulin to purified nonbeef insulin treatment will compensate to some extent for the higher costs of new insulins.

The prevalence of diabetes and of gestational diabetes varies considerably between countries and within countries. There are also major national and international differences in the important end points of fetal or neonatal death and congenital fetal abnormality. These differences relate to multiple factors, of which diabetes or gestational diabetes represents only a part of the total pathologic effect. There is also international disagreement on the most appropriate diagnostic criteria for gestational diabetes. The main uncertainty is whether to adopt the World Health Organization figures, e.g., venous plasma glucose 2 h after 75 g glucose greater than or equal to 140 mg/dl (8.0 mmol/L) as gestational impaired glucose tolerance, and greater than or equal to 200 mg/dl (11.0 mmol/L) as gestational diabetes, or to use the Boston figures, e.g., venous plasma glucose 2 h after 100 g glucose greater than or equal to 165 mg/dl (9.5 mmol/L) as gestational diabetes. It is hoped that standards for pathologic hyperglycemia in pregnancy can be agreed on for use in all countries for all populations.

In pregnancy, several physiologic changes take place, the sum of which tends to reset the glucose homeostasis in the direction of diabetes. About 1-2% of all pregnant women develop an abnormal glucose tolerance in pregnancy, but most often glucose tolerance returns to normal postpartum. This condition is called gestational diabetes mellitus (GDM). The possibility that glucose tolerance deteriorates in pregnancy because of diabetes-like changes in the secretory function of the endocrine pancreas has been investigated in healthy controls and in normal-weight gestational diabetic subjects. The insulin responses to oral glucose and mixed meals are equally large in these two groups, but the insulin response per unit of glycemic stimulus is significantly lower in the gestational diabetic subjects than in the controls. Diabetes-like changes in glucagon secretion are not observed in either group. Insulin degradation is unaffected by human pregnancy and the proinsulin share of the total plasma insulin immunoreactivity does not increase in pregnancy. Insulin receptor binding to monocytes from normal pregnant women is increased in midpregnancy but is significantly decreased in late pregnancy. No difference in insulin binding (at tracer insulin concentration) to monocytes from healthy pregnant controls and gestational diabetic subjects is found. The insulin concentration necessary to reduce tracer insulin binding by 50% (ID50) is lower in the gestational diabetic subjects diagnosed in late pregnancy than in the pregnant controls. Together, these findings indicate that the number of insulin receptors on monocytes is decreased in GDM at this stage of pregnancy.(ABSTRACT TRUNCATED AT 250 WORDS)

This article reviews the effects of pregnancy on carbohydrate metabolism and insulin production in the normal rat and discusses some animal models of potential value for the study of gestational diabetes mellitus (GDM). Against the background of current clinical and laboratory experiences it is suggested that GDM reflects a deficiency in islet B-cell proliferation in response to the increased insulin requirement during pregnancy. Although this hypothesis lends itself for testing in animal experiments, a suitable animal model for GDM needs to be described.