Adipose tissue secretes factors that control various physiological systems. The fall in leptin during fasting mediates hyperphagia and suppresses thermogenesis, thyroid and reproductive hormones, and immune system. On the other hand, rising leptin levels in the fed state stimulate fatty acid oxidation, decrease appetite, and limit weight gain. These divergent effects of leptin occur through neuronal circuits in the hypothalamus and other brain areas. Leptin also regulates the activities of enzymes involved in lipid metabolism, e.g., AMP-activated protein kinase and stearoyl-CoA desaturase-1, and also interacts with insulin signaling in the brain. Adiponectin enhances fatty acid oxidation and insulin sensitivity, in part by stimulating AMP-activated protein kinase phosphorylation and activity in liver and muscle. Moreover, adiponectin decreases body fat by increasing energy expenditure and lipid catabolism. These effects involve peripheral and possibly central mechanisms. Adipose tissue mediates interconversion of steroid hormones and secretes proinflammatory cytokines, vasoactive peptides, and coagulation and complement proteins. Understanding the actions of these "adipocytokines" will provide insight into the pathogenesis and treatment of obesity and related diseases.

DNA sequences that regulate expression of the insulin gene are located within a region spanning approximately 400 bp that flank the transcription start site. This region, the insulin promoter, contains a number of cis-acting elements that bind transcription factors, some of which are expressed only in the beta-cell and a few other endocrine or neural cell types, while others have a widespread tissue distribution. The sequencing of the genome of a number of species has allowed us to examine the manner in which the insulin promoter has evolved over a 450 million-year period. The major findings are that the A-box sites that bind PDX-1 are among the most highly conserved regulatory sequences, and that the conservation of the C1, E1, and CRE sequences emphasize the importance of MafA, E47/beta2, and cAMP-associated regulation. The review also reveals that of all the insulin gene promoters studied, the rodent insulin promoters are considerably dissimilar to the human, leading to the conclusion that extreme care should be taken when extrapolating rodent-based data on the insulin gene to humans.

Initial attempts to unravel the molecular mechanism of insulin resistance have strongly suggested that a defect responsible for insulin resistance in the majority of patients lies at the postreceptor level of insulin signaling. Subsequent studies in insulin-resistant animal models and humans have consistently demonstrated a reduced strength of insulin signaling via the insulin receptor substrate (IRS)-1/phosphatidylinositol (PI) 3-kinase pathway, resulting in diminished glucose uptake and utilization in insulin target tissues. However, the nature of the triggering event(s) remains largely enigmatic. Two separate, but likely, complementary mechanisms have recently emerged as a potential explanation. First, it became apparent that serine phosphorylation of IRS proteins can reduce their ability to attract PI 3-kinase, thereby minimizing its activation. A number of serine kinases that phosphorylate serine residues of IRS-1 and weaken insulin signal transduction have been identified. Additionally, mitochondrial dysfunction has been suggested to trigger activation of several serine kinases, leading to a serine phosphorylation of IRS-1. Second, a distinct mechanism involving increased expression of p85alpha has also been found to play an important role in the pathogenesis of insulin resistance. Conceivably, a combination of both increased expression of p85alpha and increased serine phosphorylation of IRS-1 is needed to induce clinically apparent insulin resistance.

A substantial proportion of the transplanted islet mass fails to engraft due to death by apoptosis, and a number of strategies have been explored to inhibit beta-cell loss. Inhibition of extrinsic signals of apoptosis (i.e., cFLIP or A20) have been explored in experimental islet transplantation but have only shown limited impact. Similarly, strategies targeted at intrinsic signal inhibition (i.e., BCL-2) have not yet provided substantial improvement in islet engraftment. Recently, investigation of downstream apoptosis inhibitors that block the final common pathway (i.e., X-linked inhibitor of apoptosis protein [XIAP]) have demonstrated promise in both human and rodent models of engraftment. In addition, XIAP has enhanced long-term murine islet allograft survival. The complexities of both intrinsic and extrinsic apoptotic pathway inhibition are discussed in depth.

Adipose tissue, when carried around in excessive amounts, predisposes to a large number of diseases. Epidemiological data show that the prevalence of obesity has significantly increased over the past 20 years and continues to do so at an alarming rate. Here, some molecular aspects of the key constituent of adipose tissue, the adipocyte, are reviewed. While the adipocyte has been studied for many years and remarkable insights have been gained about some processes, many areas of the physiology of the fat cell remain unexplored. Our understanding of how cellular events in the adipocyte affect the local environment through paracrine interactions and how systemic effects are achieved through endocrine interactions is rudimentary. While storage and release of lipids are major functions of adipocytes, the adipocyte also uses specific lipid molecules for intracellular signaling and uses a host of protein factors to communicate with essentially every organ system in the body. The intensity and complexity of these signals are highly regulated, differ in each fat pad, and are dramatically affected by various disease states.

The glucose-phosphorylating enzyme glucokinase has structural, kinetic, and molecular genetic features that are ideal for its primary role as glucose sensor in a network of neuro/endocrine sentinel cells that maintain glucose homeostasis in many vertebrates including humans. The glucokinase-containing, insulin-producing beta-cells of the pancreas take the prominent lead in this network, functioning in the aggregate as the master gland. The beta-cells are also conceptualized as the prototype for all other glucose sensor cells, which determines our current understanding of many extrapancreatic glucose sensors. About 99% of the enzyme resides, however, in the hepato-parenchymal cells and serves its second role in a high-capacity process of blood glucose clearance. Two examples strikingly illustrate how pivotal a position glucokinase has in the regulation of glucose metabolism: 1) activating and inactivating mutations of the enzyme cause hypo- and hyperglycemia syndromes in humans described collectively as "glucokinase disease" and fully explained by the glucose sensor paradigm, and 2) glucokinase activator drugs (GKAs) have been discovered that bind to an allosteric site and increase the kcat and lower the glucose S(0.5) of the enzyme. GKAs enhance glucose-stimulated insulin release from pancreatic islets and glucose disposition by the liver. They are now intensively explored to develop a novel treatment for diabetes. Future biophysical, molecular, genetic, and pharmacological studies hold much promise to unravel the evolving complexity of the glucokinase glucose sensor system.

Iatrogenic hypoglycemia is a problem for people with diabetes. It causes recurrent morbidity, and sometimes death, as well as a vicious cycle of recurrent hypoglycemia, precluding maintenance of euglycemia over a lifetime of diabetes. Improved therapeutic approaches that will minimize both hypo- and hyperglycemia will be based on insight into the pathophysiology of glucoregulation, specifically glucose counterregulation, in insulin-deficient (type 1 and advanced type 2) diabetes. In such patients, hypoglycemia is the result of the interplay of relative or absolute therapeutic insulin excess and compromised physiological (the syndrome of defective glucose counterregulation) and behavioral (the syndrome of hypoglycemia unawareness) defenses against falling plasma glucose concentrations. The concept of hypoglycemia-associated autonomic failure (HAAF) in diabetes posits that recent antecedent iatrogenic hypoglycemia causes both defective glucose counterregulation (by reducing epinephrine responses to a given level of subsequent hypoglycemia in the setting of absent decrements in insulin and absent increments in glucagon) and hypoglycemia unawareness (by reducing sympathoadrenal and the resulting neurogenic symptom responses to a given level of subsequent hypoglycemia) and thus a vicious cycle of recurrent hypoglycemia. The clinical impact of HAAF is well established in type 1 diabetes; it also affects those with advanced type 2 diabetes. It is now known to be largely reversible, by as little as 2-3 weeks of scrupulous avoidance of hypoglycemia, in most affected patients. However, the mechanisms of HAAF and its component syndromes are largely unknown. Loss of the glucagon secretory response, a key feature of defective glucose counterregulation, is plausibly explained by insulin deficiency, specifically loss of the decrement in intraislet insulin that normally signals glucagon secretion as glucose levels fall. Reduced neurogenic symptoms, a key feature of hypoglycemia unawareness, are largely the result of reduced sympathetic neural responses to falling glucose levels. The mechanism by which hypoglycemia shifts the glycemic thresholds for sympathoadrenal activation to lower plasma glucose concentrations, the key feature of both components of HAAF, is not known. It does not appear to be the result of the release of a systemic mediator (e.g., cortisol, epinephrine) during antecedent hypoglycemia or of increased blood-to-brain glucose transport (although increased transport of alternative fuels is conceivable). It is likely the result of alterations of brain metabolism. Although there is an array of clues, the specific alteration remains to be identified. While the research focus has been largely on the hypothalamus, hypoglycemia is now known to activate widespread brain regions, including the medial prefrontal cortex. The possibility that HAAF could be the result of posthypoglycemic brain glycogen supercompensation has also been raised. Finally, there appear to be diverse causes of HAAF. In addition to recent antecedent hypoglycemia, these include exercise- and sleep-related HAAF. Clearly, a unifying mechanism of HAAF would need to incorporate these causes as well. Pending the prevention and cure of diabetes, critical fundamental, translational, and outcomes research is needed if we are to eliminate hypoglycemia from the lives of people affected by diabetes.

Type 1 and type 2 diabetes are characterized by progressive beta-cell failure. Apoptosis is probably the main form of beta-cell death in both forms of the disease. It has been suggested that the mechanisms leading to nutrient- and cytokine-induced beta-cell death in type 2 and type 1 diabetes, respectively, share the activation of a final common pathway involving interleukin (IL)-1beta, nuclear factor (NF)-kappaB, and Fas. We review herein the similarities and differences between the mechanisms of beta-cell death in type 1 and type 2 diabetes. In the insulitis lesion in type 1 diabetes, invading immune cells produce cytokines, such as IL-1beta, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma. IL-1beta and/or TNF-alpha plus IFN-gamma induce beta-cell apoptosis via the activation of beta-cell gene networks under the control of the transcription factors NF-kappaB and STAT-1. NF-kappaB activation leads to production of nitric oxide (NO) and chemokines and depletion of endoplasmic reticulum (ER) calcium. The execution of beta-cell death occurs through activation of mitogen-activated protein kinases, via triggering of ER stress and by the release of mitochondrial death signals. Chronic exposure to elevated levels of glucose and free fatty acids (FFAs) causes beta-cell dysfunction and may induce beta-cell apoptosis in type 2 diabetes. Exposure to high glucose has dual effects, triggering initially "glucose hypersensitization" and later apoptosis, via different mechanisms. High glucose, however, does not induce or activate IL-1beta, NF-kappaB, or inducible nitric oxide synthase in rat or human beta-cells in vitro or in vivo in Psammomys obesus. FFAs may cause beta-cell apoptosis via ER stress, which is NF-kappaB and NO independent. Thus, cytokines and nutrients trigger beta-cell death by fundamentally different mechanisms, namely an NF-kappaB-dependent mechanism that culminates in caspase-3 activation for cytokines and an NF-kappaB-independent mechanism for nutrients. This argues against a unifying hypothesis for the mechanisms of beta-cell death in type 1 and type 2 diabetes and suggests that different approaches will be required to prevent beta-cell death in type 1 and type 2 diabetes.

Whether autoimmunity results primarily from a defect of the immune system, target organ dysfunction, or both remains an open issue in most human autoimmune diseases. The highly multigenic background on which diabetes develops in the NOD mouse and in the human suggests that numerous gene variants associate in contributing to activation of autoimmunity to beta-cells. Both immune genes and islet-related genes are involved. The presence of beta-cells is required for initiation of diabetes autoimmunity to proceed. Available experiments in the NOD mouse and epidemiological evidence in the human point to proinsulin as a key autoantigen in diabetes. The functional importance of insulin, the high number of autoantigens characterized at different stages of diabetes, and their clustering within beta-cell subparticles point to the islet as a starting point in the initiation phase of the disease. Genes that direct the autoimmune reaction toward the beta-cell target, autoantigens that are recognized by autoreactive B- and T-cells along the autoimmune process, the importance of beta-cells in the activation of autoreactive lymphocytes, and the expression level of key beta-cell molecules along diabetes development are successively considered in this review.

Diabetes is a severe chronic disease that affects approximately 200 million individuals worldwide, with extremely debilitating effects and considerably high health care costs. The two major classes of diabetes, known as type 1 (previously known as insulin-dependent or juvenile-onset diabetes) and type 2 (non-insulin-dependent diabetes), share common symptoms such as hyperglycemia and the development of long-term complications, but they differ in many aspects, including their etiopathogenesis. New insights suggest that overlapping factors, formerly considered typical hallmarks of each specific type, can coexist in the same diabetic patient, making it difficult to support a sharp distinction between the two classes and, more importantly, to adopt appropriate therapeutic solutions. In type 1 and type 2 diabetic subjects, but even more in patients with combined types, multiple genetic factors play a role in determining susceptibility or resistance to the disease, and perhaps also the time of onset, the severity of the symptoms, the possibility of developing complications and, ultimately, the response to therapy. In this review, the therapeutic treatments currently under investigation, as well as the curative strategies envisioned for future applications, are reanalyzed considering the multifaceted and complex aspects of a continuum that can be just defined as "diabetes."

Metabolic and immune systems are the most fundamental requirements for survival, and many metabolic and immune response pathways or nutrient- and pathogen-sensing systems have been evolutionarily highly conserved. Consequently, metabolic and immune pathways are also highly integrated and interdependent. In the past decade, it became apparent that this interface plays a critical role in the pathogenesis of chronic metabolic diseases, particularly obesity and type 2 diabetes. Importantly, the inflammatory component in obesity and diabetes is now firmly established with the discovery of causal links between inflammatory mediators, such as tumor necrosis factor (TNF)-alpha and insulin receptor signaling and the elucidation of the underlying molecular mechanisms, such as c-Jun NH2-terminal kinase (JNK)- and inhibitor of nuclear factor-kappaB kinase-mediated transcriptional and posttranslational modifications that inhibit insulin action. More recently, obesity-induced endoplasmic reticulum stress has been demonstrated to underlie the initiation of obesity-induced JNK activation, inflammatory responses, and generation of peripheral insulin resistance. This article will review the link between stress, inflammation, and metabolic disease, particularly type 2 diabetes, and discuss the mechanistic and therapeutic opportunities that emerge from this platform by focusing on JNK and endoplasmic reticulum stress responses.

Diabetes is classified clinically into two types: type 1 and type 2 diabetes. Type 1 diabetes is an autoimmune diabetes, whereas, in contrast, type 2 diabetes is nonautoimmune. However, there is a group of phenotypic adult type 2 diabetic patients ( approximately 10%) who have islet autoantibodies similar to type 1 diabetes. These patients are said to have latent autoimmune diabetes in adults (LADA) or type 1.5 diabetes. T-cells reacting with islet proteins have been demonstrated in type 1 and type 1.5 diabetic patients. In contrast, classic autoantibody-negative type 2 diabetic patients are also negative for T-cell responses to islet proteins. Therefore, we questioned whether type 1 and type 1.5 diabetes are similar or different autoimmune diseases. We have investigated the immunological and metabolic differences between type 1, type 1.5, and classic type 2 diabetic patients. We have identified autoantibody differences, differences in islet proteins recognized by T-cells, and differences in insulin resistance. We have also identified a small group of patients who have T-cells responsive to islet proteins but who are autoantibody negative. These patients appear to be similar to type 1.5 patients in having decreased stimulated C-peptide values. These immunological differences between type 1 and type 1.5 diabetes suggest at least partially distinct disease processes.

Islet cell autoantibodies are strongly associated with the development of type 1 diabetes. The appearance of autoantibodies to one or several of the autoantigens-GAD65, IA-2, or insulin-signals an autoimmune pathogenesis of beta-cell killing. A beta-cell attack may be best reflected by the emergence of autoantibodies dependent on the genotype risk factors, isotype, and subtype of the autoantibodies as well as their epitope specificity. It is speculated that progression to beta-cell loss and clinical onset of type 1 diabetes is reflected in a developing pattern of epitope-specific autoantibodies. Although the appearance of autoantibodies does not follow a distinct pattern, the presence of multiple autoantibodies has the highest positive predictive value for type 1 diabetes. In the absence of reliable T-cell tests, dissection of autoantibody responses in subjects of genetic risk should prove useful in identifying triggers of islet autoimmunity by examining seroconversion and maturation of the autoantibody response that may mark time to onset of type 1 diabetes. The complexity of the disease process is exemplified by multiple clinical phenotypes, including autoimmune diabetes masquerading as type 2 diabetes in youth and adults. Autoantibodies may also provide prognostic information in clinically heterogeneous patient populations when examined longitudinally.

Type 1 and type 2 diabetes frequently co-occur in the same families, suggesting common genetic susceptibility. Such mixed family history is associated with an intermediate phenotype of diabetes: insulin resistance and cardiovascular complications in type 1 diabetic patients and lower BMI and less cardiovascular complications as well as lower C-peptide concentrations in type 2 diabetic patients. GAD antibody positivity is more common in type 2 diabetic patients from mixed families than from common type 2 diabetes families. The mixed family history is associated with more type 1-like genetic (HLA and insulin gene) and phenotypic characteristics in type 2 diabetic patients, especially in the GAD antibody-positive subgroup. Leaving out the extreme ends of diabetes phenotypes, young children progressing rapidly to total insulin deficiency and strongly insulin-resistant subjects mostly with non-Europid ethnic origin, a large proportion of diabetic patients may have both type 1 and type 2 processes contributing to their diabetic phenotype.

Despite extensive and ongoing investigations of the immune mechanisms of autoimmune diabetes in humans and animal models, there is much less information about the natural history of insulin secretion before and after the clinical presentation of type 1 diabetes and the factors that may affect its course. Studies of insulin production previously published and from the Diabetes Prevention Trial (DPT)-1 suggest that there is progressive impairment in insulin secretory responses but the reserve in response to physiological stimuli may be significant at the time of diagnosis, although maximal responses are more significantly impaired. Other factors, including insulin resistance, may play a role in the timing of clinical presentation along this continuum. The factors that predict the occurrence and rapidity of decline in beta-cell function are still largely unknown, but most studies have identified islet cell autoantibodies as predictors of future decline and age as a determinant of residual insulin production at diagnosis. Historical as well as recent clinical experience has emphasized the importance of residual insulin production for glycemic control and prevention of end-organ complications. Understanding the modifiers and predictors of beta-cell function would allow targeting immunological approaches to those individuals most likely to benefit from therapy.

The natural history of autoimmune type 1 diabetes in children is associated with the appearance of islet autoantibodies early in life, which is influenced by genetic and environmental factors. Once islet autoantibodies have developed, the progression to diabetes in antibody-positive individuals is determined by the age of antibody appearance and by the magnitude of the autoimmunity, in turn related to the age of the subject. Characteristics that describe the magnitude of the autoimmunity can stage progression to type 1 diabetes in islet autoantibody-positive subjects regardless of genetic background or age.

In humans, both type 1 and type 2 diabetes exemplify genetically heterogeneous complex diseases in which epigenetic factors contribute to underlying genetic susceptibility. Extended human pedigrees often show inheritance of both diabetes types. A common pathophysiological denominator in both disease forms is pancreatic beta-cell exposure to proinflammatory cytokines. Hence, it is intuitive that systemically expressed genes regulating beta-cell ability to withstand chronic diabetogenic stress may represent a component of shared susceptibility to both major disease forms. In this review, the authors assemble evidence from genetic experiments using animal models developing clearly distinct diabetes syndromes to inquire whether some degree of overlap in genes contributing susceptibility can be demonstrated. The conclusion is that although overlap exists in the pathophysiological insults leading to beta-cell destruction in the currently studied rodent models, the genetic bases seem quite distinct.

Type 2 diabetes is characterized by insulin resistance and progressive beta-cell failure. Deficient insulin secretion, with increased proportions of insulin precursor molecules, is a common feature of type 2 diabetes; this could result from inappropriate beta-cell function and/or reduced beta-cell mass. Most studies using tissues from diabetic patients are retrospective, providing only limited information on the relative contribution of beta-cell dysfunction versus decreased beta-cell mass to the "beta-cell failure" of type 2 diabetes. The gerbil Psammomys obesus is a good model to address questions related to the role of insulin resistance and beta-cell failure in nutritionally induced diabetes. Upon a change from its natural low-calorie diet to the calorie-rich laboratory food, P. obesus develops moderate obesity associated with postprandial hyperglycemia. Continued dietary load, superimposed on its innate insulin resistance, results in depletion of pancreatic insulin stores, with increased proportions of insulin precursor molecules in the pancreas and the blood. Inadequate response of the preproinsulin gene to the increased insulin needs is an important cause of diabetes progression. Changes in beta-cell mass do not correlate with pancreatic insulin stores and are unlikely to play a role in disease initiation and progression. The major culprit is the inappropriate insulin production with depletion of insulin stores as a consequence. Similar mechanisms could operate during the evolution of type 2 diabetes in humans.

Type 1 diabetes is perceived as a chronic immune-mediated disease with a subclinical prodromal period characterized by selective loss of insulin-producing beta-cells in the pancreatic islets in genetically susceptible subjects. A series of evidence supports a critical role of exogenous factors in the development of type 1 diabetes, such as 1) the fact that <10% of individuals with HLA-conferred diabetes susceptibility do progress to clinical disease, 2) a pairwise concordance of type 1 diabetes of <40% among monozygotic twins, 3) a more than 10-fold difference in the disease incidence among Caucasians living in Europe, 4) a several-fold increase in the incidence over the last 50 years, and 5) migration studies indicating that the disease incidence has increased in population groups who have moved from a low-incidence to a high-incidence region. This article discusses the trigger-booster hypothesis claiming that the diabetic disease process is triggered by an exogenous factor with definite seasonal variation and driven by one or several other environmental determinants. In addition, there are a series of modifying factors affecting the fate and pace of the process. Accordingly, progression to clinical type 1 diabetes typically requires the unfortunate combination of genetic disease susceptibility, a diabetogenic trigger, and a high exposure to a driving antigen.

Inflammatory mechanisms play a key role in the pathogenesis of type 1 diabetes. Individuals who progress to type 2 diabetes display features of low-grade inflammation years in advance of disease onset. This low-grade inflammation has been proposed to be involved in the pathogenetic processes causing type 2 diabetes. Mediators of inflammation such as tumor necrosis factor-alpha, interleukin (IL)-1beta, the IL-6 family of cytokines, IL-18, and certain chemokines have been proposed to be involved in the events causing both forms of diabetes. IL-6 has in addition to its immunoregulatory actions been proposed to affect glucose homeostasis and metabolism directly and indirectly by action on skeletal muscle cells, adipocytes, hepatocytes, pancreatic beta-cells, and neuroendocrine cells. Here we argue that IL-6 action-in part regulated by variance in the IL-6 and IL-6alpha receptor genes-contributes to, but is probably neither necessary nor sufficient for, the development of both type 1 and type 2 diabetes. Thus, the two types of diabetes are also in this respect less apart than apparent. However, the mechanisms are not clear, and we therefore propose future directions for studies in this field.