Pancreas transplantation, when successful, is a reproducibly effective method to normalize glycemia without the use of exogenous insulin treatment in patients with diabetes mellitus. Success rates for combined pancreas and kidney transplantation are approximately 70%, and patient survival rates are approximately 90% 1 yr postoperatively. Metabolic benefits of this procedure include normalization of levels of fasting plasma glucose and HbA1C. Glucose-induced insulin secretion and intravenous glucose tolerance are normalized. Improvements are also observed in glucose recovery after insulin-induced hypoglycemia and in glucagon secretion during hypoglycemia. Pancreas transplantation is also associated with normalization of kidney structure and both motor and sensory nerve function. However, no benefits have been observed with regard to pancreatic polypeptide secretion, kidney function, and the retinal pathology of diabetes mellitus. Pancreas transplantation has reached a point in its history where the operative technique and its ancillary medical therapy have been optimized. Improvement in the rates of success, morbidity, and mortality will probably depend on improvement in immunosuppressive drugs and the physical condition of the recipients themselves. The time is at hand when we need to carefully consider whether it is ethical and advisable to make pancreas transplantation available to individuals who have fewer chronic complications of diabetes mellitus. Future studies of pancreas transplantation must incorporate more rigid experimental controls than have been used in the past to better assess the relative merits of this procedure.

Although we can now identify some nondiabetic individuals who will subsequently develop clinical insulin-dependent diabetes mellitus (IDDM), our ability to predict subsequent clinical IDDM is far from perfect. In this article, we discuss the status of knowledge regarding the natural history of preclinical IDDM and discuss, especially in relation to predicting IDDM, the genetic, immunologic, and metabolic components of the IDDM disease process.

Because the pathogenetic understanding of diabetic vascular complications remains fragmentary, and even the best available interventions may prove insufficient to arrest the progression of certain lesions, new avenuses of investigation should be pursued. One of these should be the early in vivo investigation of the cells that endure the pathological process (pericytes and endothelial and mesangial cells), preferably in humans. The abnormal vascular architecture (i.e., capillary acellularity, microaneurysms, thickened basement membranes, and mesangial expansion) and the hemostatic and hemodynamic alterations observed in diabetes point to an adaptive/maladaptive replicative and biosynthetic program triggered by the metabolic perturbation, but positive documentation of cellular changes in vivo remains grossly insufficient. Critical review of current knowledge of microangiopathy permits elaboration of specific questions that, with the tools provided by the new molecular technology, may be posed about vascular cells in situ. Knowing whether and how the cell types involved in the vascular complications of diabetes modify their differentiated functions may offer novel targets for intervention and, most important, should provide a much needed "sounding board" against which to test the viability and refine the focus of pathogenetic hypotheses.

Proposed mechanisms by which insulin exerts its effects are discussed. Evidence for a role for the tyrosine kinase activity of the insulin receptor and of a phosphorylation/dephosphorylation cascade is presented. The possible roles of phospholipid breakdown, diacylglycerol, and protein kinase C are discussed. The hypothesis that insulin elicits the hydrolysis of a glycosyl phosphatidylinositol to form a mediator of certain of its actions is considered in detail. The evidence that a G protein is involved in insulin action is analyzed.

The application of molecular biology to problems in diabetes mellitus has begun to reveal the underlying molecular defects contributing to the development of hyperglycemia. Islet amyloid represents the most common pathological lesion occurring in the islets of NIDDM subjects. The use of both biochemistry and molecular biology has lead to the identification of the major protein component of human islet amyloid and elucidation of the structure of its precursor. This protein, termed islet amyloid polypeptide, is related to two neuropeptides, calcitonin gene-related peptides 1 and 2, and represents a new beta-cell secretory product whose normal physiological function remains to be determined. The use of molecular biology has also led to a better understanding of the molecular defects contributing to insulin resistance. Characterization of the insulin-receptor gene in patients with extreme forms of insulin resistance has resulted in the identification of mutations that impair its function and lead to tissue resistance to the action of insulin. Molecular biological approaches have also led to a better understanding of the regulation of glucose transport. They have revealed that there is a family of structurally related proteins encoded by distinct genes and expressed in a tissue-specific manner that are responsible for the transport of glucose across the plasma membrane. Moreover, they have shown that specific depletion of the glucose-transporter isoform that mediates insulin-stimulated glucose transport is responsible for decreased transport activity in adipose tissue in insulin-resistant states.

N epsilon-(carboxymethyl)lysine, N epsilon-(carboxymethyl)hydroxylysine, and the fluorescent cross-link pentosidine are formed by sequential glycation and oxidation reactions between reducing sugars and proteins. These compounds, termed glycoxidation products, accumulate in tissue collagen with age and at an accelerated rate in diabetes. Although glycoxidation products are present in only trace concentrations, even in diabetic collagen, studies on glycation and oxidation of model proteins in vitro suggest that these products are biomarkers of more extensive underlying glycative and oxidative damage to the protein. Possible sources of oxidative stress and damage to proteins in diabetes include free radicals generated by autoxidation reactions of sugars and sugar adducts to protein and by autoxidation of unsaturated lipids in plasma and membrane proteins. The oxidative stress may be amplified by a continuing cycle of metabolic stress, tissue damage, and cell death, leading to increased free radical production and compromised free radical inhibitory and scavenger systems, which further exacerbate the oxidative stress. Structural characterization of the cross-links and other products accumulating in collagen in diabetes is needed to gain a better understanding of the relationship between oxidative stress and the development of complications in diabetes. Such studies may lead to therapeutic approaches for limiting the damage from glycation and oxidation reactions and for complementing existing therapy for treatment of the complications of diabetes.

Islet amyloid polypeptide (IAPP) or amylin is a newly identified 37-amino acid COOH-terminal-amidated polypeptide that is the major protein constituent of amyloid deposits in insulinomas and amyloid deposits in pancreatic islets of non-insulin-dependent (type II) diabetic humans and adult diabetic cats. IAPP is stored with insulin in beta-cell secretory vesicles and is cosecreted with insulin in response to glucose and several secretagogues. IAPP has been demonstrated in normal pancreatic islets of many species, but IAPP-derived amyloid develops commonly in the islets of only a few species (e.g., humans and cats), especially in association with age-related diabetes. IAPP from the human and cat inherently contains a short amyloidogenic sequence that is not present in species that do not form islet amyloid. Studies in animals indicate that an aberration in the synthesis or processing of IAPP, leading to a local increase in concentration of IAPP in the islet, is also required to facilitate the conversion of IAPP to amyloid. The formation of islet amyloid may contribute to the development of type II diabetes by causing disruption of islet cells and by replacement of islets. It has also been proposed that an abnormality of IAPP homeostasis underlies the pathogenesis of type II diabetes. A significant causal relationship between IAPP and type II diabetes is based on reports that IAPP inhibits glucose-stimulated insulin release by beta-cells and that IAPP inhibits insulin-stimulated rates of glycogen synthesis and glucose uptake by skeletal muscle cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Islet amyloid polypeptide (IAPP) or amylin, a recently discovered minor secretory peptide of the beta-cell related to calcitonin gene-related peptide (CGRP), is a constituent of amyloid deposits in the islets of many non-insulin-dependent (type II) diabetic individuals and some elderly nondiabetic subjects. IAPP is synthesized as a small precursor at a level of approximately 1% that of insulin and is processed, amidated, stored in beta-granules, and released along with insulin and C-peptide. Analysis of its gene (located on chromosome 12) supports an evolutionary relationship to calcitonin and CGRP, peptides with which it shares some biological actions. Like CGRP, IAPP antagonizes the action of insulin mainly at the level of muscle glycogen synthesis, but the levels required for this effect seem to be considerably higher than reported circulating levels. No evidence for overproduction of IAPP in diabetic subjects has been found thus far, but much more work is necessary to define its normal secretory rates and clearance. Other proposed actions of IAPP include serum calcium-lowering effects and smooth muscle relaxation; the latter effect might promote the uptake of insulin into the circulation within the islets. Deposition of amyloid is species selective due to structural differences within the central part of the molecule and may be initiated intracellularly in type II diabetes by several mechanisms. No differences in the structure of IAPP or its precursor have been found in individuals with maturity-onset diabetes of the young or type II diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)

In 1960, immunoassays of insulin first demonstrated significant quantities of circulating hormone in non-insulin-dependent (type II) diabetes and for 30 yr have fostered debate as to whether a beta-cell abnormality plays an etiological role in this syndrome. Early efforts to determine the adequacy of islet beta-cell function showed that obesity and its associated insulin resistance were major confounding variables. Subsequently, it was recognized that glucose not only directly regulated insulin synthesis and secretion but moderated all other islet signals, including other substrates, hormones, and neural factors. When both obesity and glucose are taken into account, it becomes clear that patients with fasting hyperglycemia all have abnormal islet function. Type II diabetes is characterized by a defect in first-phase or acute glucose-induced insulin secretion and a deficiency in the ability of glucose to potentiate other islet nonglucose beta-cell secretagogues. The resulting hyperglycemia compensates for the defective glucose potentiation and maintains nearly normal basal insulin levels and insulin responses to nonglucose secretagogues but does not correct the defect in first-phase glucose-induced insulin release. Before the development of fasting hyperglycemia, only first-phase glucose-induced insulin secretion is obviously defective. This is because progressive islet failure is matched by rising glucose levels to maintain basal and second-phase insulin output. The relationship between islet function and fasting plasma glucose is steeply curvilinear, so that there is a 75% loss of beta-cell function by the time the diagnostic level of 140 mg/dl is exceeded. This new steady state is characterized by glucose overproduction and inefficient utilization. Insulin resistance is also present in most patients and contributes to the hyperglycemia by augmenting the glucose levels needed for compensation. Decompensation and absolute hypoinsulinemia occur when the renal threshold for glucose is exceeded and prevents further elevation of circulating glucose. The etiology of the islet beta-cell lesion is not known, but a hypothesis based on basal hyperproinsulinemia and islet amyloid deposits in the pancreas of type II diabetes is reviewed. The recent discovery of the islet amyloid polypeptide (IAPP) or amylin, which is the major constituent of islet amyloid deposits, is integrated into this hypothesis. It is suggested that pro-IAPP and proinsulin processing and mature peptide secretion normally occur together and that abnormal processing, secondary to or in conjunction with defects in hormone secretion, lead to progressive accumulation of intracellular IAPP and pro-IAPP, which in cats, monkeys, and humans form intracellular fibrils and amyloid deposits with a loss of beta-cell mass.(ABSTRACT TRUNCATED AT 400 WORDS)

Guanine nucleotide-binding proteins (G proteins) are critically important mediators of many signal-transduction systems. Several important sites regulating stimulus-secretion coupling and release of insulin from pancreatic beta-cells are modulated by G proteins. Gs mediates increases in intracellular cAMP associated with hormone-induced stimulation of insulin secretin. Gi mediates decreases in intracellular cAMP caused by inhibitors of insulin secretion, e.g., epinephrine, somatostatin, prostaglandin E2, and galanin. G proteins also regulate ion channels, phospholipases, and distal sites in exocytosis. Cholera and pertussis toxins irreversibly ADP ribosylate G proteins and are important tools that can be used both to manipulate G-protein-dependent modulators of insulin secretion and detect and quantify G proteins by electrophoretic techniques. The stage is set to pursue these initial observations in greater depth and ascertain whether G-protein research will provide important new insights into normal and abnormal regulation of insulin secretion.

The beta-cell is unique because its major agonists, i.e., insulin secretagogues, undergo metabolism instead of interacting with a receptor. This perspectives presents the hypothesis that the first part of a metabolic signal of a secretagogue is specific to the secretagogue and the beta-cell and can be envisioned as proximal. The second part, which occurs after transduction to more universal signaling mechanisms, is viewed as distal. Distal signaling and exocytosis in the beta-cell operate the same as in other cells. Aerobic glycolysis is required for glucose-induced insulin release. Because glyceraldehyde, which enters metabolism at the triose phosphates in the glycolytic pathway, is a potent insulin secretagogue but pyruvate, which is metabolized in the mitochondrion, is not an insulin secretagogue, the proximal signal for glucose-induced insulin release originates with an interaction between the central part of the glycolytic pathway and mitochondrial metabolism. The proximal message in leucine-induced insulin release originates with leucine allosterically activating glutamate dehydrogenase, which activates endogenous glutamate metabolism, and by the metabolism of leucine itself. The methyl ester of succinate is a potent experimental insulin secretagogue. It is puzzling why the glucose signal requires the interplay of glycolysis and mitochondrial metabolism, whereas the signals from leucine and succinate originate entirely from within the mitochondrion. Leucine-induced insulin release is suppressed and glucose-induced insulin release is activated in islets cultured at a high concentration of glucose. Conversely, leucine-induced insulin release is activated and glucose-induced insulin release is suppressed in islets cultured at low glucose.(ABSTRACT TRUNCATED AT 250 WORDS)

Research on mapping diabetes-susceptibility genes is dependent on several factors, including the existence of a single major gene for susceptibility, genetic homogeneity, and the existence of appropriate clinical material. The power to detect susceptibility genes is dependent on the risks in relatives and the distance of genetic markers from the susceptibility genes. For insulin-dependent diabetes mellitus (IDDM), the best-fitting risk models are those with a single major locus with residual polygenic factors. The major locus effect is likely represented by genes in the HLA complex, because specific genotypes have been found to affect IDDM risk significantly. Thus, mapping the remaining polygenic IDDM susceptibility factors--each of small effect--is a difficult and long task. For non-insulin-dependent diabetes mellitus (NIDDM), the likely risk models result in few genes with moderate effect. Models of NIDDM have significant residual polygenic variation remaining, reflecting the importance of multiple loci with small effect, environmental effects, or genetic heterogeneity; however, the prospects for mapping genes that provide at least moderate susceptibility for NIDDM now appear promising.

Our understanding of the role of HLA genes associated with insulin-dependent diabetes mellitus (IDDM) is in disarray, despite recent improvements in the definition of specific alleles and haplotypes. Some genes are highly associated with IDDM, other genes are associated with resistance to IDDM, and some highly associated susceptibility genes are markedly influenced by trans-associated synergistic effects (DR3/4 heterozygotes) or protective effects (DR2/4 heterozygotes). This plethora of genetic associations has spawned the notion that there are many contributing susceptibility genes, which, in turn, has led to the search for shared structural features among different genes on IDDM-associated haplotypes. From a more mechanistic point of view, however, the wide range of variable IDDM associations, with both cis- and trans-encoded protective and/or synergistic effects, suggests a different approach. This article proposes a hypothesis in which the different HLA associations with IDDM can be simply explained by a single unifying concept: a hierarchy of affinities determines the interaction between a diabetogenic peptide and different class II molecules, and an individual is susceptible to IDDM if the class II molecule in that individual with the highest affinity for such a peptide is a DQ beta susceptibility gene. The explicit formulation of this proposal and its genetic implications provide an explanation for HLA-encoded dominant "protection" and for some of the more subtle genetic observations related to cis and trans influences in IDDM susceptibility.

The insulin receptor is a multifunctional protein encoded by a modular gene. Certain discrete domains within the insulin-receptor structure subserve specific functional properties. In some instances, these discrete domains are encoded by individual exons. This organizational model of the insulin receptor predicts the existence of divergent signaling pathways facilitating specific bioeffects. Some of these signaling pathways are shared with the closely related insulinlike growth factor I receptor (convergent pathways), whereas others are different (divergent). The concept of discrete functional domains also provides several mechanisms whereby inactive insulin receptors (no kinase activity) can inhibit the function of normal receptors. The ability of kinase-inactive insulin receptors to inhibit the signaling function of normal insulin receptors may be an operative mechanism in certain insulin-resistant states.

Transgenic mouse technology has gained recognition as an important tool for examining many fundamental biological questions in vivo. Recently, transgenic mouse techniques have been applied to the study of type I (insulin-dependent) diabetes. These studies have been particularly informative in elucidating 1) mechanisms whereby immune tolerance is maintained to antigens on rare specialized cells such as the pancreatic beta-cell, 2) disease susceptibility and resistance genes, and 3) potentially important immune effector mechanisms. In this article, we discuss these studies, their impact on understanding of the pathogenesis of type I diabetes, and the potential of the transgenic mouse approach for future research.

This perspective deals with prediction of overt diabetic nephropathy in patients with insulin-dependent diabetes mellitus (IDDM). The role of elevated urinary albumin excretion rate (microalbuminuria) in predicting diabetic nephropathy has been emphasized by new follow-up studies. Development of severe kidney impairment was seen in a large percentage of patients with microalbuminuria, but with more intensive care for diabetic patients, this percentage may be falling. Herein, I analyzed alternatives to microalbuminuria in predicting kidney disease in diabetes. 1) Parental predisposition to hypertension is not seen in all studies and therefore may not be a decisive factor, and it cannot be used in prediction of nephropathy. 2) Prediabetic blood pressure may predict nephropathy in certain non-insulin-dependent diabetic patients, but elevated blood pressure seems to develop after early microalbuminuria and is likely to be an aggravating factor in established microalbuminuria in IDDM patients. 3) At the clinical diagnosis of IDDM, diabetic nephropathy cannot be predicted. 4) Glycemic control is poor in normoalbuminuric patients with later development of microalbuminuria, and multiple glycosylated hemoglobin measurements are therefore important. 5) In diabetes, glomerular hyperfiltration is associated with late nephropathy, but it alone cannot be the decisive factor, because hyperfiltration in nondiabetic individuals does not produce kidney disease, according to new long-term follow-up studies. 6) Studies of glomerular structure and ultrastructure have not yet documented predictive values for overt nephropathy, but further studies are in progress. 7) Isolated blood pressure elevation without microabuminuria (probably representing essential hypertension in diabetes) has not been predictive. 8) It is clear that elevation of serum creatinine is a very late and insensitive parameter, occurring only with pronounced proteinuria.(ABSTRACT TRUNCATED AT 250 WORDS)

This article reviews evidence for a pivotal role of glucokinase as glucose sensor of the pancreatic beta-cells. Glucokinase explains the capacity, hexose specificity, affinities, sigmoidicity, and anomeric preference of pancreatic islet glycolysis, and because stimulation of glucose metabolism is a prerequisite of glucose stimulation of insulin release, glucokinase also explains many characteristics of this beta-cell function. Glucokinase of the beta-cell is induced or activated by glucose in contrast to liver glucokinase, which is regulated by insulin. Tissue-specific regulation corresponds with observations that liver and pancreatic beta-cell glucokinase are structurally distinct. Glucokinase could play a glucose-sensor role in hepatocytes as well, and certain forms of diabetes mellitus might be due to glucokinase deficiencies in pancreatic beta-cells, hepatocytes, or both.

Glucokinase is expressed in both the liver and the pancreatic beta-cell and plays a key role in the metabolism of glucose by both tissues. Expression of this enzyme is differentially regulated; hepatic glucokinase is stimulated by insulin and repressed by cAMP, whereas beta-cell glucokinase activity is increased by glucose. Recently, the glucokinase gene has been characterized and was found to contain two different transcription control regions. One region regulates transcription of the gene in the liver, whereas the other region, which lies at least 12 kilobases further upstream, controls transcription in the pancreatic beta-cell. The finding of two different transcription control regions in a single glucokinase gene provides a genetic basis for the tissue-specific differential regulation of glucokinase and will serve as the basis for further studies to identify and characterize the different regulatory elements and factors in the liver and beta-cell, which are presumably involved. Comparison of different glucokinase cDNAs isolated from hepatic, insulinoma, and islet cDNA libraries indicates that at least three glucokinase isoforms are generated by differential RNA processing of the glucokinase gene transcripts. Whether any of these glucokinase isoforms are functionally unique remains to be determined.

The concept of pancreatic beta-cell mass is fundamental to the understanding of normal metabolism, the pathogenesis of diabetes, and the transplantation of beta-cell tissue. The amount of beta-cell tissue present in the pancreas is a major determinant of the quantity of insulin that can be secreted, and its mass will vary according to the size of the individual and the degree of insulin resistance present. Not all insulin-producing cells are the same, and the dimensions of this heterogeneity remain to be defined. Pancreatic beta-cell mass is markedly reduced in insulin-dependent diabetes mellitus and moderately reduced in non-insulin-dependent diabetes mellitus. In both forms of diabetes, there are qualitative and quantitative abnormalities of insulin secretion that cannot be explained entirely by changes in beta-cell mass. The amount of beta-cell tissue needed for successful transplantation has only been partially defined. Segmental (approximately 50% of the pancreas) transplantation can normalize plasma glucose levels in humans. Difficulty obtaining sufficient amounts of beta-cell tissue is expected to remain a barrier to successful islet transplantation for the immediate future. More should be learned about the function and fate of grafted islet cells.

The hyperglycemic patient remains persistently at risk for infectious complications. Whether ascribable to diabetes mellitus, to the administration of glucocorticoids, or to the infusion of hyperalimentation fluids, hyperglycemia may impair several mechanisms of humoral host defense, including such varied neutrophil functions as adhesion, chemotaxis, and phagocytosis. In addition, binding of glucose to the biochemically active site of the third component of complement C3 inhibits the attachment of this protein to the microbial surface and thereby impairs opsonization. Last, several pathogens frequently encountered in hyperglycemic patients possess unique mechanisms of virulence that flourish in the hyperglycemic environment. Most notable in this regard is the yeast Candida albicans, which expresses a glucose-inducible protein that is structurally and functionally homologous to a complement receptor on mammalian phagocytes. This protein promotes adhesion in the yeast and subverts phagocytosis by the host. Thus, hyperglycemia serves as a central mechanism in the predisposition of hyperglycemic patients to infection.