Showing papers on "Insulin published in 2007"

Macrophage-specific PPARγ controls alternative activation and improves insulin resistance

Abstract: Obesity and insulin resistance, the cardinal features of metabolic syndrome, are closely associated with a state of low-grade inflammation. In adipose tissue chronic overnutrition leads to macrophage infiltration, resulting in local inflammation that potentiates insulin resistance. For instance, transgenic expression of Mcp1 (also known as chemokine ligand 2, Ccl2) in adipose tissue increases macrophage infiltration, inflammation and insulin resistance. Conversely, disruption of Mcp1 or its receptor Ccr2 impairs migration of macrophages into adipose tissue, thereby lowering adipose tissue inflammation and improving insulin sensitivity. These findings together suggest a correlation between macrophage content in adipose tissue and insulin resistance. However, resident macrophages in tissues display tremendous heterogeneity in their activities and functions, primarily reflecting their local metabolic and immune microenvironment. While Mcp1 directs recruitment of pro-inflammatory classically activated macrophages to sites of tissue damage, resident macrophages, such as those present in the adipose tissue of lean mice, display the alternatively activated phenotype. Despite their higher capacity to repair tissue, the precise role of alternatively activated macrophages in obesity-induced insulin resistance remains unknown. Using mice with macrophage-specific deletion of the peroxisome proliferator activated receptor-gamma (PPARgamma), we show here that PPARgamma is required for maturation of alternatively activated macrophages. Disruption of PPARgamma in myeloid cells impairs alternative macrophage activation, and predisposes these animals to development of diet-induced obesity, insulin resistance, and glucose intolerance. Furthermore, gene expression profiling revealed that downregulation of oxidative phosphorylation gene expression in skeletal muscle and liver leads to decreased insulin sensitivity in these tissues. Together, our findings suggest that resident alternatively activated macrophages have a beneficial role in regulating nutrient homeostasis and suggest that macrophage polarization towards the alternative state might be a useful strategy for treating type 2 diabetes.

Interleukin-1-receptor antagonist in type 2 diabetes mellitus.

Abstract: Background The expression of interleukin-1–receptor antagonist is reduced in pancreatic islets of patients with type 2 diabetes mellitus, and high glucose concentrations induce the production of interleukin-1β in human pancreatic beta cells, leading to impaired insulin secretion, decreased cell proliferation, and apoptosis. Methods In this double-blind, parallel-group trial involving 70 patients with type 2 diabetes, we randomly assigned 34 patients to receive 100 mg of anakinra (a recombinant human interleukin-1–receptor antagonist) subcutaneously once daily for 13 weeks and 36 patients to receive placebo. At baseline and at 13 weeks, all patients underwent an oral glucose-tolerance test, followed by an intravenous bolus of 0.3 g of glucose per kilogram of body weight, 0.5 mg of glucagon, and 5 g of arginine. In addition, 35 patients underwent a hyperinsulinemic–euglycemic clamp study. The primary end point was a change in the level of glycated hemoglobin, and secondary end points were changes in beta-cell function, insulin sensitivity, and inflammatory markers. Results At 13 weeks, in the anakinra group, the glycated hemoglobin level was 0.46 percentage point lower than in the placebo group (P = 0.03); C-peptide secretion was enhanced (P = 0.05), and there were reductions in the ratio of proinsulin to insulin (P = 0.005) and in levels of interleukin-6 (P<0.001) and C-reactive protein (P = 0.002). Insulin resistance, insulin-regulated gene expression in skeletal muscle, serum adipokine levels, and the body-mass index were similar in the two study groups. Symptomatic hypoglycemia was not observed, and there were no apparent drugrelated serious adverse events. Conclusions The blockade of interleukin-1 with anakinra improved glycemia and beta-cell secretory function and reduced markers of systemic inflammation. (ClinicalTrials.gov number, NCT00303394.)

Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes

Abstract: Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases of ageing such as type 2 diabetes. SIRT1, an NAD+-dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produce beneficial effects on glucose homeostasis and insulin sensitivity. Resveratrol, a polyphenolic SIRT1 activator, mimics the anti-ageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival. Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. These compounds bind to the SIRT1 enzyme-peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates. In diet-induced obese and genetically obese mice, these compounds improve insulin sensitivity, lower plasma glucose, and increase mitochondrial capacity. In Zucker fa/fa rats, hyperinsulinaemic-euglycaemic clamp studies demonstrate that SIRT1 activators improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver. Thus, SIRT1 activation is a promising new therapeutic approach for treating diseases of ageing such as type 2 diabetes.

Obesity-associated improvements in metabolic profile through expansion of adipose tissue

Abstract: Excess caloric intake can lead to insulin resistance. The underlying reasons are complex but likely related to ectopic lipid deposition in nonadipose tissue. We hypothesized that the inability to appropriately expand subcutaneous adipose tissue may be an underlying reason for insulin resistance and beta cell failure. Mice lacking leptin while overexpressing adiponectin showed normalized glucose and insulin levels and dramatically improved glucose as well as positively affected serum triglyceride levels. Therefore, modestly increasing the levels of circulating full-length adiponectin completely rescued the diabetic phenotype in ob/ob mice. They displayed increased expression of PPARgamma target genes and a reduction in macrophage infiltration in adipose tissue and systemic inflammation. As a result, the transgenic mice were morbidly obese, with significantly higher levels of adipose tissue than their ob/ob littermates, leading to an interesting dichotomy of increased fat mass associated with improvement in insulin sensitivity. Based on these data, we propose that adiponectin acts as a peripheral "starvation" signal promoting the storage of triglycerides preferentially in adipose tissue. As a consequence, reduced triglyceride levels in the liver and muscle convey improved systemic insulin sensitivity. These mice therefore represent what we believe is a novel model of morbid obesity associated with an improved metabolic profile.

Prediction of Incident Diabetes Mellitus in Middle-aged Adults: The Framingham Offspring Study

Abstract: Background Prediction rules for type 2 diabetes mellitus (T2DM) have been developed, but we lack consensus for the most effective approach. Methods We estimated the 7-year risk of T2DM in middle-aged participants who had an oral glucose tolerance test at baseline. There were 160 cases of new T2DM, and regression models were used to predict new T2DM, starting with characteristics known to the subject (personal model, ie, age, sex, parental history of diabetes, and body mass index [calculated as the weight in kilograms divided by height in meters squared]), adding simple clinical measurements that included metabolic syndrome traits (simple clinical model), and, finally, assessing complex clinical models that included (1) 2-hour post–oral glucose tolerance test glucose, fasting insulin, and C-reactive protein levels; (2) the Gutt insulin sensitivity index; or (3) the homeostasis model insulin resistance and the homeostasis model insulin resistance β-cell sensitivity indexes. Discrimination was assessed with area under the receiver operating characteristic curves (AROCs). Results The personal model variables, except sex, were statistically significant predictors of T2DM (AROC, 0.72). In the simple clinical model, parental history of diabetes and obesity remained significant predictors, along with hypertension, low levels of high-density lipoprotein cholesterol, elevated triglyceride levels, and impaired fasting glucose findings but not a large waist circumference (AROC, 0.85). Complex clinical models showed no further improvement in model discriminations (AROC, 0.850-0.854) and were not superior to the simple clinical model. Conclusion Parental diabetes, obesity, and metabolic syndrome traits effectively predict T2DM risk in a middle-aged white population sample and were used to develop a simple T2DM prediction algorithm to estimate risk of new T2DM during a 7-year follow-up interval.

Meal Simulation Model of the Glucose-Insulin System

Abstract: A simulation model of the glucose-insulin system in the postprandial state can be useful in several circumstances, including testing of glucose sensors, insulin infusion algorithms and decision support systems for diabetes. Here, we present a new simulation model in normal humans that describes the physiological events that occur after a meal, by employing the quantitative knowledge that has become available in recent years. Model parameters were set to fit the mean data of a large normal subject database that underwent a triple tracer meal protocol which provided quasi-model-independent estimates of major glucose and insulin fluxes, e.g., meal rate of appearance, endogenous glucose production, utilization of glucose, insulin secretion. By decomposing the system into subsystems, we have developed parametric models of each subsystem by using a forcing function strategy. Model results are shown in describing both a single meal and normal daily life (breakfast, lunch, dinner) in normal. The same strategy is also applied on a smaller database for extending the model to type 2 diabetes.

Fatty Liver: A Novel Component of the Metabolic Syndrome

Abstract: Although the epidemic of obesity has been accompanied by an increase in the prevalence of the metabolic syndrome, not all obese develop the syndrome and even lean individuals can be insulin resistant. Both lean and obese insulin resistant individuals have an excess of fat in the liver which is not attributable to alcohol or other known causes of liver disease, a condition defined as nonalcoholic fatty liver disease (NAFLD) by gastroenterologists. The fatty liver is insulin resistant. Liver fat is highly significantly and linearly correlated with all components of the metabolic syndrome independent of obesity. Overproduction of glucose, VLDL, CRP, and coagulation factors by the fatty liver could contribute to the excess risk of cardiovascular disease associated with the metabolic syndrome and NAFLD. Both of the latter conditions also increase the risk of type 2 diabetes and advanced liver disease. The reason why some deposit fat in the liver whereas others do not is poorly understood. Individuals with a fatty liver are more likely to have excess intraabdominal fat and inflammatory changes in adipose tissue. Intervention studies have shown that liver fat can be decreased by weight loss, PPARgamma agonists, and insulin therapy.

Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes

Abstract: Genetic variants in the gene encoding for transcription factor-7-like 2 (TCF7L2) have been associated with type 2 diabetes (T2D) and impaired beta cell function, but the mechanisms have remained unknown. We therefore studied prospectively the ability of common variants in TCF7L2 to predict future T2D and explored the mechanisms by which they would do this. Scandinavian subjects followed for up to 22 years were genotyped for 3 SNPs (rs7903146, rs12255372, and rs10885406) in TCF7L2, and a subset of them underwent extensive metabolic studies. Expression of TCF7L2 was related to genotype and metabolic parameters in human islets. The CT/TT genotypes of SNP rs7903146 strongly predicted future T2D in 2 independent cohorts (Swedish and Finnish). The risk T allele was associated with impaired insulin secretion, incretin effects, and enhanced rate of hepatic glucose production. TCF7L2 expression in human islets was increased 5-fold in T2D, particularly in carriers of the TT genotype. Overexpression of TCF7L2 in human islets reduced glucose-stimulated insulin secretion. In conclusion, the increased risk of T2D conferred by variants in TCF7L2 involves the enteroinsular axis, enhanced expression of the gene in islets, and impaired insulin secretion.

Cardiovascular actions of insulin.

Abstract: Insulin has important vascular actions to stimulate production of nitric oxide from endothelium. This leads to capillary recruitment, vasodilation, increased blood flow, and subsequent augmentation of glucose disposal in classical insulin target tissues (e.g., skeletal muscle). Phosphatidylinositol 3-kinase-dependent insulin-signaling pathways regulating endothelial production of nitric oxide share striking parallels with metabolic insulin-signaling pathways. Distinct MAPK-dependent insulin-signaling pathways (largely unrelated to metabolic actions of insulin) regulate secretion of the vasoconstrictor endothelin-1 from endothelium. These and other cardiovascular actions of insulin contribute to coupling metabolic and hemodynamic homeostasis under healthy conditions. Cardiovascular diseases are the leading cause of morbidity and mortality in insulin-resistant individuals. Insulin resistance is typically defined as decreased sensitivity and/or responsiveness to metabolic actions of insulin. This cardinal feature of diabetes, obesity, and dyslipidemia is also a prominent component of hypertension, coronary heart disease, and atherosclerosis that are all characterized by endothelial dysfunction. Conversely, endothelial dysfunction is often present in metabolic diseases. Insulin resistance is characterized by pathway-specific impairment in phosphatidylinositol 3-kinase-dependent signaling that in vascular endothelium contributes to a reciprocal relationship between insulin resistance and endothelial dysfunction. The clinical relevance of this coupling is highlighted by the findings that specific therapeutic interventions targeting insulin resistance often also ameliorate endothelial dysfunction (and vice versa). In this review, we discuss molecular mechanisms underlying cardiovascular actions of insulin, the reciprocal relationships between insulin resistance and endothelial dysfunction, and implications for developing beneficial therapeutic strategies that simultaneously target metabolic and cardiovascular diseases.

The Metabolic State of Diabetic Monkeys Is Regulated by Fibroblast Growth Factor-21

Abstract: Fibroblast growth factor (FGF)-21 has been recently characterized as a potent metabolic regulator. Systemic administration of FGF-21 reduced plasma glucose and triglycerides to near normal levels in genetically compromised diabetic rodents. Importantly, these effects were durable and did not come at the expense of weight gain, hypoglycemia, or mitogenicity. To explore the therapeutic properties of FGF-21 in a nongenetically modified primate species, and thus demonstrate the potential for efficacy in humans, we evaluated its bioactivity in diabetic nonhuman primates. When administered daily for 6 wk to diabetic rhesus monkeys, FGF-21 caused a dramatic decline in fasting plasma glucose, fructosamine, triglycerides, insulin, and glucagon. Of significant importance in regard to safety, hypoglycemia was not observed at any point during the study. FGF-21 administration also led to significant improvements in lipoprotein profiles, including lowering of low-density lipoprotein cholesterol and raising of high-density lipoprotein cholesterol, beneficial changes in the circulating levels of several cardiovascular risk markers/factors, and the induction of a small but significant weight loss. These data support the development of FGF-21 for the treatment of diabetes and other metabolic diseases.

Addition of biphasic, prandial, or basal insulin to oral therapy in type 2 diabetes

Abstract: A b s t r ac t At 1 year, mean glycated hemoglobin levels were similar in the biphasic group (7.3%) and the prandial group (7.2%) (P = 0.08) but higher in the basal group (7.6%, P<0.001 for both comparisons). The respective proportions of patients with a gly- cated hemoglobin level of 6.5% or less were 17.0%, 23.9%, and 8.1%; respective mean numbers of hypoglycemic events per patient per year were 5.7, 12.0, and 2.3; and respective mean weight gains were 4.7 kg, 5.7 kg, and 1.9 kg. Rates of adverse events were similar among the three groups. Conclusions A single analogue-insulin formulation added to metformin and sulfonylurea resulted in a glycated hemoglobin level of 6.5% or less in a minority of patients at 1 year. The addition of biphasic or prandial insulin aspart reduced levels more than the addition of basal insulin detemir but was associated with greater risks of hypogly- cemia and weight gain. (Current Controlled Trials number, ISRCTN51125379.)

β-Cell Failure in Diabetes and Preservation by Clinical Treatment

Abstract: There is a progressive deterioration in beta-cell function and mass in type 2 diabetics. It was found that islet function was about 50% of normal at the time of diagnosis, and a reduction in beta-cell mass of about 60% was shown at necropsy. The reduction of beta-cell mass is attributable to accelerated apoptosis. The major factors for progressive loss of beta-cell function and mass are glucotoxicity, lipotoxicity, proinflammatory cytokines, leptin, and islet cell amyloid. Impaired beta-cell function and possibly beta-cell mass appear to be reversible, particularly at early stages of the disease where the limiting threshold for reversibility of decreased beta-cell mass has probably not been passed. Among the interventions to preserve or "rejuvenate" beta-cells, short-term intensive insulin therapy of newly diagnosed type 2 diabetes will improve beta-cell function, usually leading to a temporary remission time. Another intervention is the induction of beta-cell "rest" by selective activation of ATP-sensitive K+ (K(ATP)) channels, using drugs such as diazoxide. A third type of intervention is the use of antiapoptotic drugs, such as the thiazolidinediones (TZDs), and incretin mimetics and enhancers, which have demonstrated significant clinical evidence of effects on human beta-cell function. The TZDs improve insulin secretory capacity, decrease beta-cell apoptosis, and reduce islet cell amyloid with maintenance of neogenesis. The TZDs have indirect effects on beta-cells by being insulin sensitizers. The direct effects are via peroxisome proliferator-activated receptor gamma activation in pancreatic islets, with TZDs consistently improving basal beta-cell function. These beneficial effects are sustained in some individuals with time. There are several trials on prevention of diabetes with TZDs. Incretin hormones, which are released from the gastrointestinal tract in response to nutrient ingestion to enhance glucose-dependent insulin secretion from the pancreas, aid the overall maintenance of glucose homeostasis through slowing of gastric emptying, inhibition of glucagon secretion, and control of body weight. From the two major incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), only the first one or its mimetics or enhancers can be used for treatment because the diabetic beta-cell is resistant to GIP action. Because of the rapid inactivation of GLP-1 by dipeptidyl peptidase (DPP)-IV, several incretin analogs were developed: GLP-1 receptor agonists (incretin mimetics) exenatide (synthetic exendin-4) and liraglutide, by conjugation of GLP-1 to circulating albumin. The acute effect of GLP-1 and GLP-1 receptor agonists on beta-cells is stimulation of glucose-dependent insulin release, followed by enhancement of insulin biosynthesis and stimulation of insulin gene transcription. The chronic action is stimulating beta-cell proliferation, induction of islet neogenesis, and inhibition of beta-cell apoptosis, thus promoting expansion of beta-cell mass, as observed in rodent diabetes and in cultured beta-cells. Exenatide and liraglutide enhanced postprandial beta-cell function. The inhibition of the activity of the DPP-IV enzyme enhances endogenous GLP-1 action in vivo, mediated not only by GLP-1 but also by other mediators. In preclinical studies, oral active DPP-IV inhibitors (sitagliptin and vildagliptin) also promoted beta-cell proliferation, neogenesis, and inhibition of apoptosis in rodents. Meal tolerance tests showed improvement in postprandial beta-cell function. Obviously, it is difficult to estimate the protective effects of incretin mimetics and enhancers on beta-cells in humans, and there is no clinical evidence that these drugs really have protective effects on beta-cells.

Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity

Abstract: A subset of neurons in the brain, known as 'glucose-excited' neurons, depolarize and increase their firing rate in response to increases in extracellular glucose. Similar to insulin secretion by pancreatic beta-cells, glucose excitation of neurons is driven by ATP-mediated closure of ATP-sensitive potassium (K(ATP)) channels. Although beta-cell-like glucose sensing in neurons is well established, its physiological relevance and contribution to disease states such as type 2 diabetes remain unknown. To address these issues, we disrupted glucose sensing in glucose-excited pro-opiomelanocortin (POMC) neurons via transgenic expression of a mutant Kir6.2 subunit (encoded by the Kcnj11 gene) that prevents ATP-mediated closure of K(ATP) channels. Here we show that this genetic manipulation impaired the whole-body response to a systemic glucose load, demonstrating a role for glucose sensing by POMC neurons in the overall physiological control of blood glucose. We also found that glucose sensing by POMC neurons became defective in obese mice on a high-fat diet, suggesting that loss of glucose sensing by neurons has a role in the development of type 2 diabetes. The mechanism for obesity-induced loss of glucose sensing in POMC neurons involves uncoupling protein 2 (UCP2), a mitochondrial protein that impairs glucose-stimulated ATP production. UCP2 negatively regulates glucose sensing in POMC neurons. We found that genetic deletion of Ucp2 prevents obesity-induced loss of glucose sensing, and that acute pharmacological inhibition of UCP2 reverses loss of glucose sensing. We conclude that obesity-induced, UCP2-mediated loss of glucose sensing in glucose-excited neurons might have a pathogenic role in the development of type 2 diabetes.

Interleukin-1beta-induced insulin resistance in adipocytes through down-regulation of insulin receptor substrate-1 expression.

Abstract: Inflammation is associated with obesity and insulin resistance. Proinflammatory cytokines produced by adipose tissue in obesity could alter insulin signaling and action. Recent studies have shown a relationship between IL-1beta level and metabolic syndrome or type 2 diabetes. However, the ability of IL-1beta to alter insulin signaling and action remains to be explored. We demonstrated that IL-1beta slightly increased Glut 1 translocation and basal glucose uptake in 3T3-L1 adipocytes. Importantly, we found that prolonged IL-1beta treatment reduced the insulin-induced glucose uptake, whereas an acute treatment had no effect. Chronic treatment with IL-1beta slightly decreased the expression of Glut 4 and markedly inhibited its translocation to the plasma membrane in response to insulin. This inhibitory effect was due to a decrease in the amount of insulin receptor substrate (IRS)-1 but not IRS-2 expression in both 3T3-L1 and human adipocytes. The decrease in IRS-1 amount resulted in a reduction in its tyrosine phosphorylation and the alteration of insulin-induced protein kinase B activation and AS160 phosphorylation. Pharmacological inhibition of ERK totally inhibited IL-1beta-induced down-regulation of IRS-1 mRNA. Moreover, IRS-1 protein expression and insulin-induced protein kinase B activation, AS160 phosphorylation, and Glut 4 translocation were partially recovered after treatment with the ERK inhibitor. These results demonstrate that IL-1beta reduces IRS-1 expression at a transcriptional level through a mechanism that is ERK dependent and at a posttranscriptional level independently of ERK activation. By targeting IRS-1, IL-1beta is capable of impairing insulin signaling and action, and could thus participate in concert with other cytokines, in the development of insulin resistance in adipocytes.

Diabetes associated cell stress and dysfunction: role of mitochondrial and non-mitochondrial ROS production and activity.

Abstract: It is now widely accepted, given the current weight of experimental evidence, that reactive oxygen species (ROS) contribute to cell and tissue dysfunction and damage caused by glucolipotoxicity in diabetes. The source of ROS in the insulin secreting pancreatic β-cells and in the cells which are targets for insulin action has been considered to be the mitochondrial electron transport chain. While this source is undoubtably important, we provide additional information and evidence for NADPH oxidase-dependent generation of ROS both in pancreatic β-cells and in insulin sensitive cells. While mitochondrial ROS generation may be important for regulation of mitochondrial uncoupling protein (UCP) activity and thus disruption of cellular energy metabolism, the NADPH oxidase associated ROS may alter parameters of signal transduction, insulin secretion, insulin action and cell proliferation or cell death. Thus NADPH oxidase may be a useful target for intervention strategies based on reversing the negative impact of glucolipotoxicity in diabetes.

Brain-derived neurotrophic factor (BDNF) and type 2 diabetes

Abstract: Decreased levels of brain-derived neurotrophic factor (BDNF) have been implicated in the pathogenesis of Alzheimer’s disease and depression. These disorders are associated with type 2 diabetes, and animal models suggest that BDNF plays a role in insulin resistance. We therefore explored whether BDNF plays a role in human glucose metabolism. We included (Study 1) 233 humans divided into four groups depending on presence or absence of type 2 diabetes and presence or absence of obesity; and (Study 2) seven healthy volunteers who underwent both a hyperglycaemic and a hyperinsulinaemic–euglycaemic clamp. Plasma levels of BDNF in Study 1 were decreased in humans with type 2 diabetes independently of obesity. Plasma BDNF was inversely associated with fasting plasma glucose, but not with insulin. No association was found between the BDNF G196A (Val66Met) polymorphism and diabetes or obesity. In Study 2 an output of BDNF from the human brain was detected at basal conditions. This output was inhibited when blood glucose levels were elevated. In contrast, when plasma insulin was increased while maintaining normal blood glucose, the cerebral output of BDNF was not inhibited, indicating that high levels of glucose, but not insulin, inhibit the output of BDNF from the human brain. Low levels of BDNF accompany impaired glucose metabolism. Decreased BDNF may be a pathogenetic factor involved not only in dementia and depression, but also in type 2 diabetes, potentially explaining the clustering of these conditions in epidemiological studies.

Randomized study of basal-bolus insulin therapy in the inpatient management of patients with type 2 diabetes (RABBIT 2 trial).

Abstract: OBJECTIVE —We sought to study the optimal management of hyperglycemia in non–intensive care unit patients with type 2 diabetes, as few studies thus far have focused on the subject. RESEARCH DESIGN AND METHODS —We conducted a prospective, multicenter, randomized trial to compare the efficacy and safety of a basal-bolus insulin regimen with that of sliding-scale regular insulin (SSI) in patients with type 2 diabetes. A total of 130 insulin-naive patients were randomized to receive glargine and glulisine ( n = 65) or a standard SSI protocol ( n = 65). Glargine was given once daily and glulisine before meals at a starting dose of 0.4 units · kg −1 · day −1 for blood glucose 140–200 mg/dl or 0.5 units · kg −1 · day −1 for blood glucose 201–400 mg/dl. SSI was given four times per day for blood glucose >140 mg/dl. RESULTS —The mean admission blood glucose was 229 ± 6 mg/dl and A1C 8.8 ± 2%. A blood glucose target of P 240 mg/dl. There were no differences in the rate of hypoglycemia or length of hospital stay. CONCLUSIONS —Treatment with insulin glargine and glulisine resulted in significant improvement in glycemic control compared with that achieved with the use of SSI alone. Our study indicates that a basal-bolus insulin regimen is preferred over SSI in the management of non–critically ill, hospitalized patients with type 2 diabetes.

Cellular Mechanisms for Insulin Resistance in Normal Pregnancy and Gestational Diabetes

Abstract: The incidence of gestational diabetes mellitus (GDM) has doubled over the last 6–8 years and is paralleling the obesity epidemic. GDM carries long-term implications for the subsequent development of type 2 diabetes in the mother and increased risk for obesity and glucose intolerance in the offspring. Insulin resistance exists before pregnancy in women with a history of GDM but worsens during gestation. Insulin secretion is inadequate to compensate for the insulin resistance, leading to hyperglycemia that is detected by routine glucose screening in pregnancy. Thus, chronic insulin resistance is a central component of the pathophysiology of GDM. Human pregnancy is characterized by a series of metabolic changes that promote adipose tissue accretion in early gestation, followed by insulin resistance and facilitated lipolysis in late pregnancy. In early pregnancy, insulin secretion increases, while insulin sensitivity is unchanged, decreased, or may even increase (1,2). However, in late gestation, maternal adipose tissue depots decline, while postprandial free fatty acid (FFA) levels increase and insulin-mediated glucose disposal worsens by 40–60% compared with prepregnancy (2). The ability of insulin to suppress whole-body lipolysis is also reduced during late pregnancy (3), and this is further reduced in GDM subjects (4), contributing to greater postprandial increases in FFAs, increased hepatic glucose production, and severe insulin resistance (2,5–7). Although various placental hormones have been suggested to reprogram maternal physiology to meet fetal needs, the cellular mechanisms for this complex transition remain obscure (8). Further, the critical molecular mechanisms involved in increasing maternal lipid flux in obese women throughout pregnancy that may underlie skeletal muscle insulin resistance and increased fetal fuels are just beginning to be investigated. Skeletal muscle is the principal site of whole-body glucose disposal, and along with adipose tissue, becomes severely insulin resistant during the latter half of pregnancy. Normal …

Glucose Regulation in Young Adults with Very Low Birth Weight

Abstract: BACKGROUND The association between small size at birth and impaired glucose regulation later in life is well established in persons born at term. Preterm birth with very low birth weight (<1500 g) is also associated with insulin resistance in childhood. If insulin resistance persists into adulthood, preterm birth with very low birth weight also may be associated with an increased risk of disease in adulthood. We assessed glucose tolerance and insulin sensitivity and measured serum lipid levels and blood pressure in young adults with very low birth weight. METHODS We performed a standard 75-g oral glucose-tolerance test, measuring insulin and glucose concentrations at baseline and at 120 minutes in 163 young adults (age range, 18 to 27 years) with very low birth weight and in 169 subjects who had been born at term and were not small for gestational age. The two groups were similar with regard to age, sex, and birth hospital. We measured blood pressure and serum lipid levels, and in 150 very-low-birth-weight subjects and 136 subjects born at term, we also measured body composition by means of dual-energy x-ray absorptiometry. RESULTS As compared with the subjects born at term, the very-low-birth-weight subjects had a 6.7% increase in the 2-hour glucose concentration (95% confidence interval [CI], 0.8 to 12.9), a 16.7% increase in the fasting insulin concentration (95% CI, 4.6 to 30.2), a 40.0% increase in the 2-hour insulin concentration (95% CI, 17.5 to 66.8), an 18.9% increase in the insulin-resistance index determined by homeostatic model assessment (95% CI, 5.7 to 33.7), and an increase of 4.8 mm Hg in systolic blood pressure (95% CI, 2.1 to 7.4). Adjustment for the lower lean body mass in the very-low-birth-weight subjects did not attenuate these relationships. CONCLUSIONS Young adults with a very low birth weight have higher indexes of insulin resistance and glucose intolerance and higher blood pressure than those born at term.

Alginate/chitosan nanoparticles are effective for oral insulin delivery.

Abstract: To evaluate the pharmacological activity of insulin-loaded alginate/chitosan nanoparticles following oral dosage in diabetic rats. Nanoparticles were prepared by ionotropic pre-gelation of an alginate core followed by chitosan polyelectrolyte complexation. In vivo activity was evaluated by measuring the decrease in blood glucose concentrations in streptozotocin induced, diabetic rats after oral administration and flourescein (FITC)-labelled insulin tracked by confocal microscopy. Nanoparticles were negatively charged and had a mean size of 750 nm, suitable for uptake within the gastrointestinal tract due to their nanosize range and mucoadhesive properties. The insulin association efficiency was over 70% and insulin was released in a pH-dependent manner under simulated gastrointestinal conditions. Orally delivered nanoparticles lowered basal serum glucose levels by more than 40% with 50 and 100 IU/kg doses sustaining hypoglycemia for over 18 h. Pharmacological availability was 6.8 and 3.4% for the 50 and 100 IU/kg doses respectively, a significant increase over 1.6%, determined for oral insulin alone in solution and over other related studies at the same dose levels. Confocal microscopic examinations of FITC-labelled insulin nanoparticles showed clear adhesion to rat intestinal epithelium, and internalization of insulin within the intestinal mucosa. The results indicate that the encapsulation of insulin into mucoadhesive nanoparticles was a key factor in the improvement of its oral absorption and oral bioactivity.

The nuclear receptor LXR is a glucose sensor

Abstract: The liver has a central role in glucose homeostasis, as it has the distinctive ability to produce and consume glucose. On feeding, glucose influx triggers gene expression changes in hepatocytes to suppress endogenous glucose production and convert excess glucose into glycogen or fatty acids to be stored in adipose tissue. This process is controlled by insulin, although debate exists as to whether insulin acts directly or indirectly on the liver. In addition to stimulating pancreatic insulin release, glucose also regulates the activity of ChREBP, a transcription factor that modulates lipogenesis. Here we describe another mechanism whereby glucose determines its own fate: we show that glucose binds and stimulates the transcriptional activity of the liver X receptor (LXR), a nuclear receptor that coordinates hepatic lipid metabolism. d-Glucose and d-glucose-6-phosphate are direct agonists of both LXR-alpha and LXR-beta. Glucose activates LXR at physiological concentrations expected in the liver and induces expression of LXR target genes with efficacy similar to that of oxysterols, the known LXR ligands. Cholesterol homeostasis genes that require LXR for expression are upregulated in liver and intestine of fasted mice re-fed with a glucose diet, indicating that glucose is an endogenous LXR ligand. Our results identify LXR as a transcriptional switch that integrates hepatic glucose metabolism and fatty acid synthesis.

Insulin gene mutations as a cause of permanent neonatal diabetes

Abstract: We report 10 heterozygous mutations in the human insulin gene in 16 probands with neonatal diabetes. A combination of linkage and a candidate gene approach in a family with four diabetic members led to the identification of the initial INS gene mutation. The mutations are inherited in an autosomal dominant manner in this and two other small families whereas the mutations in the other 13 patients are de novo. Diabetes presented in probands at a median age of 9 weeks, usually with diabetic ketoacidosis or marked hyperglycemia, was not associated with β cell autoantibodies, and was treated from diagnosis with insulin. The mutations are in critical regions of the preproinsulin molecule, and we predict that they prevent normal folding and progression of proinsulin in the insulin secretory pathway. The abnormally folded proinsulin molecule may induce the unfolded protein response and undergo degradation in the endoplasmic reticulum, leading to severe endoplasmic reticulum stress and potentially β cell death by apoptosis. This process has been described in both the Akita and Munich mouse models that have dominant-acting missense mutations in the Ins2 gene, leading to loss of β cell function and mass. One of the human mutations we report here is identical to that in the Akita mouse. The identification of insulin mutations as a cause of neonatal diabetes will facilitate the diagnosis and possibly, in time, treatment of this disorder.

Reactive Oxygen Species as a Signal in Glucose-Stimulated Insulin Secretion

Abstract: One of the unique features of beta-cells is their relatively low expression of many antioxidant enzymes. This could render beta-cells susceptible to oxidative damage but may also provide a system that is sensitive to reactive oxygen species as signals. In isolated mouse islets and INS-1(832/13) cells, glucose increases intracellular accumulation of H2O2. In both models, insulin secretion could be stimulated by provision of either exogenous H2O2 or diethyl maleate, which raises intracellular H2O2 levels. Provision of exogenous H2O2 scavengers, including cell permeable catalase and N-acetyl-L-cysteine, inhibited glucose-stimulated H2O2 accumulation and insulin secretion (GSIS). In contrast, cell permeable superoxide dismutase, which metabolizes superoxide into H2O2, had no effect on GSIS. Because oxidative stress is an important risk factor for beta-cell dysfunction in diabetes, the relationship between glucose-induced H2O2 generation and GSIS was investigated under various oxidative stress conditions. Acute exposure of isolated mouse islets or INS-1(832/13) cells to oxidative stressors, including arsenite, 4-hydroxynonenal, and methylglyoxal, led to decreased GSIS. This impaired GSIS was associated with increases in a battery of endogenous antioxidant enzymes. Taken together, these findings suggest that H2O2 derived from glucose metabolism is one of the metabolic signals for insulin secretion, whereas oxidative stress may disturb its signaling function.