Glucose Intolerance In Type Research Articles

Increased Insulin Secretion and Glucose Effectiveness in Obese Patients with Type 2 Diabetes following Bariatric Surgery.

β-cell dysfunction and insulin resistance are the main mechanisms causing glucose intolerance in type 2 diabetes (T2D). Bariatric surgeries, i.e., sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB), are procedures both known to induce weight loss, increase insulin action, and enhance β-cell function, but hepatic insulin extraction and glucose effectiveness may also play a role. To determine the contribution of these regulators on glucose tolerance after bariatric surgery, an oral glucose tolerance test (OGTT) was performed before and 2 months after surgery in 9 RYGB and 7 SG subjects. Eight healthy subjects served as metabolic controls. Plasma glucose, insulin, C-peptide, GLP-1, and GIP were measured during each OGTT. Insulin sensitivity and secretion, glucose effectiveness, and glucose rate of appearance were determined via oral minimal models. RYGB and SG resulted in similar weight reductions (13%, RYGB (p < 0.01); 14%, SG (p < 0.05)). Two months after surgery, insulin secretion (p < 0.05) and glucose effectiveness both improved equally in the two groups (11%, RYGB (p < 0.01); 8%, SG (p > 0.05)), whereas insulin sensitivity remained virtually unaltered. Bariatric surgery resulted in a comparable increase in the GLP-1 response during the OGTT, whereas GIP concentrations remained unaltered. Following surgery, oral glucose intake resulted in a comparable increase in hepatic insulin extraction, the response in both RYGB and SG patients significantly exceeding the response observed in the control subjects. These results demonstrate that the early improvement in glucose tolerance in obese T2D after RYGB and SG surgeries is attributable mainly to increased insulin secretion and glucose effectiveness, while insulin sensitivity seems to play only a minor role. This trial is registered with NCT02713555.

Epidermal Growth Factor Receptor in Hepatic Endothelial Cells Suppresses MCP-1-Dependent Monocyte Recruitment in Diabetes.

Insulin resistance is a compromised response to insulin in target tissues such as liver. Emerging evidence shows that vascular endothelial cells (ECs) are critical in mediating glucose metabolism. However, how liver ECs can regulate inflammation in the setting of insulin resistance is still unknown. Using genome-wide transcriptome analysis of ECs isolated from diabetic mice, we found enrichment of the genes involved in epidermal growth factor receptor (Egfr) signaling. In line with this, hepatic sinusoidal ECs in diabetic mice had elevated levels of Egfr expression. Interestingly, we found an increased number of hepatic myeloid cells, especially macrophages, and systemic glucose intolerance in Cdh5Cre/+Egfrfl/fl mice lacking Egfr in ECs compared with littermate control mice with type II diabetes. Egfr deficiency upregulated the expression of MCP-1 in hepatic sinusoidal ECs. This resulted in augmented monocyte recruitment and macrophage differentiation in Cdh5Cre/+Egfrfl/fl mice compared with littermate control mice as determined by a mouse model of parabiosis. Finally, MCP-1 neutralization and hepatic macrophage depletion in Cdh5Cre/+Egfrfl/fl mice resulted in a reduced number of hepatic macrophages and ameliorated glucose intolerance compared with the control groups. Collectively, these results demonstrate a protective endothelial Egfr signaling in reducing monocyte-mediated hepatic inflammation and glucose intolerance in type II diabetic mice.

Morus alba L. (Sangzhi) Alkaloids Promote Insulin Secretion, Restore Diabetic β-Cell Function by Preventing Dedifferentiation and Apoptosis.

Background: Morus alba L. (Sangzhi) alkaloids (SZ-A), extracted from the Chinese herb Morus alba L. (mulberry twig), have been shown to ameliorate hyperglycemia in type 2 diabetes and have been approved for diabetes treatment in the clinic. However, their versatile pharmacologic effects and regulatory mechanisms are not yet completely understood. Purpose: This study explored the protective effects of SZ-A on islet β cells and the underlying mechanism. Methods: Type 2 diabetic KKAy mice were orally administered SZ-A (100 or 200 mg/kg, once daily) for 11 weeks, and oral glucose tolerance, insulin tolerance, intraperitoneal glucose tolerance and hyperglycemia clamp tests were carried out to evaluate the potency of SZ-A in vivo. The morphology and β-cell dedifferentiation marker of KKAy mouse islets were detected via immunofluorescence. The effect of SZ-A on glucose-stimulated insulin secretion was investigated in both the islet β-cell line MIN6 and mouse primary islets. Potential regulatory signals and pathways in insulin secretion were explored, and cell proliferation assays and apoptosis TUNEL staining were performed on SZ-A-treated MIN6 cells. Results: SZ-A alleviated hyperglycemia and glucose intolerance in type 2 diabetic KKAy mice and improved the function and morphology of diabetic islets. In both MIN6 cells and primary islets, SZ-A promoted insulin secretion. At a normal glucose level, SZ-A decreased AMPKα phosphorylation, and at high glucose, SZ-A augmented the cytosolic calcium concentration. Additionally, SZ-A downregulated the β-cell dedifferentiation marker ALDH1A3 and upregulated β-cell identifying genes, such as Ins1, Ins2, Nkx2.2 and Pax4 in KKAy mice islets. At the same time, SZ-A attenuated glucolipotoxicity-induced apoptosis in MIN6 cells, and inhibited Erk1/2 phosphorylation and caspase 3 activity. The major active fractions of SZ-A, namely DNJ, FAG and DAB, participated in the above regulatory effects. Conclusion: Our findings suggest that SZ-A promotes insulin secretion in islet β cells and ameliorates β-cell dysfunction and mass reduction under diabetic conditions both in vivo and in vitro, providing additional supportive evidence for the clinical application of SZ-A.

Glucose Lowering Treatment Modalities of Type 2 Diabetes Mellitus.

This chapter gives an overview of present knowledge and clinical aspects of antidiabetic drugs according to the recently available research evidence and clinical expertise.Many agents are acting on eight groups of pathophysiological mechanisms, which is commonly called as "Ominous Octet" by DeFronzo. The muscle, liver and β-cell, the fat cell, gastrointestinal tract, α-cell, kidney, and brain play essential roles in the development of glucose intolerance in type 2 diabetic individuals (Defronzo, Diabetes 58:773-795, 2009).A treatment paradigm shift is seen in the initiation of anti-hyperglycemic agents from old friends (meglitinides or sulphonylürea) to newer agents effecting on GLP-1 RA or SGLT-2 inhibitors. It is mostly about the other protective positive effects of these agents for kidney, heart, etc. Although there are concerns for the long term safety profiles; they are used widely around the World. The delivery of patient-centered care, facilitating medication adherence, the importance of weight loss in obese patients, the importance of co-morbid conditions are the mainstays of selecting the optimal agent.

Chronotherapeutic effect of orexin antagonists on glucose metabolism in diabetic mice.

Disrupted sleep is associated with increased risk of type 2 diabetes. Central actions of orexin, mediated by orexin-1 and orexin-2 receptors, play a crucial role in the maintenance of wakefulness; accordingly, excessive activation of the orexin system causes insomnia. Resting-phase administration of dual orexin receptor antagonist (DORA) has been shown to improve sleep abnormalities and glucose intolerance in type 2 diabetic db/db mice, although the mechanism remains unknown. In the present study, to investigate the presence of functional link between sleep and glucose metabolism, the influences of orexin antagonists with or without sleep-promoting effects were compared on glucose metabolism in diabetic mice. In db/db mice, 2-SORA-MK1064 (an orexin-2 receptor antagonist) and DORA-12 (a DORA) acutely improved non-rapid eye movement sleep, whereas 1-SORA-1 (an orexin-1 receptor antagonist) had no effect. Chronic resting-phase administration of these drugs improved glucose intolerance, without affecting body weight, food intake, locomotor activity, and energy expenditure calculated from O2 consumption and CO2 production. The expression levels of pro-inflammatory factors in the liver were reduced by 2-SORA-MK1064 and DORA-12, but not 1-SORA-1, whereas those in the white adipose tissue were reduced by 1-SORA-1 and DORA-12 more efficiently than 2-SORA-MK1064. When administered chronically at awake phase, these drugs caused no effect. In streptozotocin-induced type 1-like diabetic mice, neither abnormality in sleep-wake behavior nor improvement of glucose intolerance by these drugs were observed. These results suggest that both 1-SORA-type (sleep-independent) and 2-SORA-type (possibly sleep-dependent) mechanisms can provide chronotherapeutic effects against type 2 diabetes associated with sleep disturbances in db/db mice.

1863-P: The Hepatic Role of Heat Shock Protein 72 in the Pathogenesis of Type 2 Diabetes

Cell stresses, such as ER stress or oxidative stress are considered to be key mediators in pathophysiology of type 2 diabetes. Heat shock protein (HSP) 72, a major inducible HSP against heat, serves to protect cells from those cellular stresses and works in protein quality control. Induction of HSP72 improves glucose intolerance in type 2 diabetic model mice. In this study, we investigated glucose metabolism in whole body HSP72 deficient (KO) mice. The effects of hepatic HSP72 induction in KO mice were also investigated. KO mice and control mice were subjected to a high-fat diet regimen. Metabolic parameters and pathophysiological examination were performed. HSP72 was overexpressed in mice by lenti-virus to investigate the role of HSP72 in liver. There were no significant differences in body weight and food intake between two groups. Fasting and random-fed blood glucose levels were significantly higher in KO mice than those in control mice. The fasting insulin level was significantly lower in KO mice. Upon glucose challenge, blood glucose levels were higher in KO mice. On insulin tolerance test, KO mice exhibited insulin resistant phenotype. Visceral fat mass was increased and hepatic steatosis was obvious in KO mice with increased SREBP-1c mRNA expression. Upon insulin stimulation, phosphorylation of Akt was decreased in KO liver, with increased activation of JNK. Hepatic gluconeogenesis was not suppressed in KO accompanied by increased gluconeogenic enzymes. When restoring HSP72 expression in liver by lenti-virus on KO mice, blood glucose, hepatic steatosis and gluconeogenesis were ameliorated. Interestingly, visceral fat size and macrophage infiltration were both reversed by hepatic HSP72 induction. Deficiency of HSP72 leads to type 2 diabetic phenotype. As induction of HSP72 in liver is beneficial to improve glucose homeostasis in KO, the abundance of HSP72 in liver is critical in diabetic pathophysiology, and appropriate HSP72 induction may serve as a target in the treatment of type 2 diabetes. Disclosure T. Kondo: None. S. Kitano: None. N. Miyakawa: None. T. Watanabe: None. R. Goto: None. K. Ono: None. M. Igata: None. J. Kawashima: None. H. Motoshima: None. T. Matsumura: None. E. Araki: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Novo Nordisk Inc., Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; Astellas Pharma Inc., Merck &amp; Co., Inc., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi. Funding Japan Society for the Promotion of Science

Double transcranial direct current stimulation of the brain increases cerebral energy levels and systemic glucose tolerance in men.

Transcranial direct current stimulation (tDCS) is a neuromodulatory method that has been tested experimentally and has already been used as an adjuvant therapeutic option to treat a number of neurological disorders and neuropsychiatric diseases. Beyond its well known local effects within the brain, tDCS also transiently promotes systemic glucose uptake and reduces the activity of the neurohormonal stress axes. We aimed to test whether the effects of a single tDCS application could be replicated upon double stimulation to persistently improve systemic glucose tolerance and stress axes activity in humans. In a single-blinded cross-over study, we examined 15 healthy male volunteers. Anodal tDCS vs sham was applied twice in series. Systemic glucose tolerance was investigated by the standard hyperinsulinaemic-euglycaemic glucose clamp procedure, and parameters of neurohormonal stress axes activity were measured. Because tDCS-induced brain energy consumption has been shown to be part of the mechanism underlying the assumed effects, we monitored the cerebral high-energy phosphates ATP and phosphocreatine by 31 phosphorus magnetic resonance spectroscopy. As hypothesised, analyses revealed that double anodal tDCS persistently increases glucose tolerance compared to sham. Moreover, we observed a significant rise in cerebral high-energy phosphate content upon double tDCS. Accordingly, the activity of the neurohormonal stress axes was reduced upon tDCS compared to sham. Our data demonstrate that double tDCS promotes systemic glucose uptake and reduces stress axes activity in healthy humans. These effects suggest that repetitive tDCS may be a future non-pharmacological option for combating glucose intolerance in type 2 diabetes patients.

Studying the Hypothalamic Insulin Signal to Peripheral Glucose Intolerance with a Continuous Drug Infusion System into the Mouse Brain.

Insulin regulates systematic metabolism in the hypothalamus and the peripheral insulin response. An inflammatory reaction in peripheral adipose tissues contributes to type 2 diabetes mellitus (T2DM) development and appetite regulation in the hypothalamus. Chemokine CCL5 and C-C chemokine receptor type 5 (CCR5) levels have been suggested to mediate arteriosclerosis and glucose intolerance in type 2 diabetes mellitus (T2DM). In addition, CCL5 plays a neuroendocrine role in the hypothalamus by regulating food intake and body temperature, thus, prompting us to investigate its function in hypothalamic insulin signaling and the regulation of peripheral glucose metabolism.The micro-osmotic pump brain infusion system is a quick and precise way to manipulate CCL5 function and study its effect in the brain. It also provides a convenient alternative approach to generating a transgenic knockout animal. In this system, CCL5 signaling was blocked by intracerebroventricular (ICV) infusion of its antagonist, MetCCL5, using a micro-osmotic pump. The peripheral glucose metabolism and insulin responsiveness was detected by the Oral Glucose Tolerance Test (OGTT) and Insulin Tolerance Test (ITT). Insulin signaling activity was then analyzed by protein blot from tissue samples derived from the animals.After 7-14 days of MetCCL5 infusion, the glucose metabolism and insulin responsiveness was impaired in mice, as seen in the results of the OGTT and ITT. The IRS-1 serine302 phosphorylation was increased and the Akt activity was reduced in mice hypothalamic neurons following CCL5 inhibition. Altogether, our data suggest that blocking CCL5 in the mouse brain increases the phosphorylation of IRS-1 S302 and interrupts hypothalamic insulin signaling, leading to a decrease in insulin function in peripheral tissues as well as the impairment of glucose metabolism.

Studying the Hypothalamic Insulin Signal to Peripheral Glucose Intolerance with a Continuous Drug Infusion System into the Mouse Brain

Insulin regulates systematic metabolism in the hypothalamus and the peripheral insulin response. An inflammatory reaction in peripheral adipose tissues contributes to type 2 diabetes mellitus (T2DM) development and appetite regulation in the hypothalamus. Chemokine CCL5 and C-C chemokine receptor type 5 (CCR5) levels have been suggested to mediate arteriosclerosis and glucose intolerance in type 2 diabetes mellitus (T2DM). In addition, CCL5 plays a neuroendocrine role in the hypothalamus by regulating food intake and body temperature, thus, prompting us to investigate its function in hypothalamic insulin signaling and the regulation of peripheral glucose metabolism. The micro-osmotic pump brain infusion system is a quick and precise way to manipulate CCL5 function and study its effect in the brain. It also provides a convenient alternative approach to generating a transgenic knockout animal. In this system, CCL5 signaling was blocked by intracerebroventricular (ICV) infusion of its antagonist, MetCCL5, using a micro-osmotic pump. The peripheral glucose metabolism and insulin responsiveness was detected by the Oral Glucose Tolerance Test (OGTT) and Insulin Tolerance Test (ITT). Insulin signaling activity was then analyzed by protein blot from tissue samples derived from the animals. After 7-14 days of MetCCL5 infusion, the glucose metabolism and insulin responsiveness was impaired in mice, as seen in the results of the OGTT and ITT. The IRS-1 serine302 phosphorylation was increased and the Akt activity was reduced in mice hypothalamic neurons following CCL5 inhibition. Altogether, our data suggest that blocking CCL5 in the mouse brain increases the phosphorylation of IRS-1 S302 and interrupts hypothalamic insulin signaling, leading to a decrease in insulin function in peripheral tissues as well as the impairment of glucose metabolism.

Uncoupling Exercise Bioenergetics From Systemic Metabolic Homeostasis by Conditional Inactivation of Baf60 in Skeletal Muscle.

Impaired skeletal muscle energy metabolism is linked to the pathogenesis of insulin resistance and glucose intolerance in type 2 diabetes. The contractile and metabolic properties of myofibers exhibit a high degree of heterogeneity and plasticity. The regulatory circuitry underpinning skeletal muscle energy metabolism is critically linked to exercise endurance and systemic homeostasis. Recent work has identified the Baf60 subunits of the SWI/SNF chromatin-remodeling complex as powerful regulators of the metabolic gene programs. However, their role in integrating myofiber energy metabolism with exercise endurance and metabolic physiology remains largely unknown. In this study, we conditionally inactivated Baf60a, Baf60c, or both in mature skeletal myocytes to delineate their contribution to muscle bioenergetics and metabolic physiology. Our work revealed functional redundancy between Baf60a and Baf60c in maintaining oxidative and glycolytic metabolism in skeletal myofibers and exercise endurance. Unexpectedly, mice lacking these two factors in skeletal muscle were protected from diet-induced and age-associated metabolic disorders. Transcriptional profiling analysis identified the muscle thermogenic gene program and myokine secretion as key pathways that integrate myofiber metabolism with systemic energy balance. As such, Baf60 deficiency in skeletal muscle illustrates a surprising disconnect between exercise endurance and systemic metabolic homeostasis.

Altered amyloid precursor protein processing regulates glucose uptake and oxidation in cultured rodent myotubes.

Aims/hypothesisImpaired glucose uptake in skeletal muscle is an important contributor to glucose intolerance in type 2 diabetes. The aspartate protease, beta-site APP-cleaving enzyme 1 (BACE1), a critical regulator of amyloid precursor protein (APP) processing, modulates in vivo glucose disposal and insulin sensitivity in mice. Insulin-independent pathways to stimulate glucose uptake and GLUT4 translocation may offer alternative therapeutic avenues for the treatment of diabetes. We therefore addressed whether BACE1 activity, via APP processing, in skeletal muscle modifies glucose uptake and oxidation independently of insulin.MethodsSkeletal muscle cell lines were used to investigate the effects of BACE1 and α-secretase inhibition and BACE1 and APP overexpression on glucose uptake, GLUT4 cell surface translocation, glucose oxidation and cellular respiration.ResultsIn the absence of insulin, reduction of BACE1 activity increased glucose uptake and oxidation, GLUT4myc cell surface translocation, and basal rate of oxygen consumption. In contrast, overexpressing BACE1 in C2C12 myotubes decreased glucose uptake, glucose oxidation and oxygen consumption rate. APP overexpression increased and α-secretase inhibition decreased glucose uptake in C2C12 myotubes. The increase in glucose uptake elicited by BACE1 inhibition is dependent on phosphoinositide 3-kinase (PI3K) and mimicked by soluble APPα (sAPPα).Conclusions/interpretationInhibition of muscle BACE1 activity increases insulin-independent, PI3K-dependent glucose uptake and cell surface translocation of GLUT4. As APP overexpression raises basal glucose uptake, and direct application of sAPPα increases PI3K–protein kinase B signalling and glucose uptake in myotubes, we suggest that α-secretase-dependent shedding of sAPPα regulates insulin-independent glucose uptake in skeletal muscle.

Histidine Augments the Suppression of Hepatic Glucose Production by Central Insulin Action

Glucose intolerance in type 2 diabetes is related to enhanced hepatic glucose production (HGP) due to the increased expression of hepatic gluconeogenic enzymes. Previously, we revealed that hepatic STAT3 decreases the expression of hepatic gluconeogenic enzymes and suppresses HGP. Here, we show that increased plasma histidine results in hepatic STAT3 activation. Intravenous and intracerebroventricular (ICV) administration of histidine-activated hepatic STAT3 reduced G6Pase protein and mRNA levels and augmented HGP suppression by insulin. This suppression of hepatic gluconeogenesis by histidine was abolished by hepatic STAT3 deficiency or hepatic Kupffer cell depletion. Inhibition of HGP by histidine was also blocked by ICV administration of a histamine H1 receptor antagonist. Therefore, histidine activates hepatic STAT3 and suppresses HGP via central histamine action. Hepatic STAT3 phosphorylation after histidine ICV administration was attenuated in histamine H1 receptor knockout (Hrh1KO) mice but not in neuron-specific insulin receptor knockout (NIRKO) mice. Conversely, hepatic STAT3 phosphorylation after insulin ICV administration was attenuated in NIRKO but not in Hrh1KO mice. These findings suggest that central histidine action is independent of central insulin action, while both have additive effects on HGP suppression. Our results indicate that central histidine/histamine-mediated suppression of HGP is a potential target for the treatment of type 2 diabetes.

Voluntary exercise at young stage prevents glucose intolerance in type 2 diabetic rats

PurposeTo investigate the effects of voluntary exercise at young stage on whole‐body metabolism and glucose tolerance in type 2 diabetic rats.MethodsOtsuka Long‐Evans Tokushima Fatty (OLETF) rats as an animal model of type 2 diabetes and their counterparts (Long‐Evans Tokushima Otsuka; LETO) were used. Twenty male OLETF and LETO rats were divided into three groups, respectively: Sedentary (SED, n=8), Wheel Running (WR, n=6), or Wheel Running‐Sedentary (WS, n=6) group. WR and WS groups were allowed to access a running wheel freely from 5 to 25 week‐old. In WS group, however, a running wheel was locked from 15 to 25 week‐old and rats could not run in the wheel. At 25 week‐old, resting oxygen consumption (VO2 rest) of each rat was measured in a metabolic chamber. Subsequently an intraperitoneal glucose tolerance test (IPGTT) was performed.ResultsThere were no significant differences in the areas under the curve of IPGTT (AUC) and VO2 rest (ml/kg/min) among three LETO groups. In OLETF rats, AUC in WR and WS groups were significantly lower than SED group, with AUC being lower for WR group. Moreover, VO2 rest of OLETF in WR and WS groups were significantly higher than SED group.ConclusionOur data suggest that voluntary exercise at young stage improves resting metabolism and prevents glucose intolerance in grown‐up type 2 diabetic rats, and these effects remained following exercise cessation.

Atypical protein kinase C in cardiometabolic abnormalities

To review the aberrations of insulin signaling to atypical protein kinase C (aPKC) in muscle and liver that generate cardiovascular risk factors, including obesity, hypertriglyceridemia, hypercholesterolemia, insulin resistance and glucose intolerance in type 2 diabetes mellitus (T2DM), and obesity-associated metabolic syndrome (MetSyn). aPKC and Akt mediate the insulin effects on glucose transport in muscle and synthesis of lipids, cytokines and glucose in liver. In T2DM, whereas Akt and aPKC activation are diminished in muscle, and hepatic Akt activation is diminished, hepatic aPKC activation is conserved. Imbalance between muscle and hepatic aPKC activation (and expression of PKC-ι in humans) by insulin results from differential downregulation of insulin receptor substrates that control phosphatidylinositol-3-kinase. Conserved activation of hepatic aPKC in hyperinsulinemic states of T2DM, obesity and MetSyn is problematic, as excessive activation of aPKC-dependent lipogenic, gluconeogenic and proinflammatory pathways increases the cardiovascular risk factors. Indeed, selective inhibition of hepatic aPKC by adenoviral-mediated expression of kinase-inactive aPKC, or newly developed small-molecule biochemicals, dramatically improves abdominal obesity, hepatosteatosis, hypertriglyceridemia, hypercholesterolemia, insulin resistance and glucose intolerance in murine models of obesity and T2DM. Hepatic aPKC is a unifying target for treating multiple clinical abnormalities that increase the cardiovascular risk in insulin-resistant states of obesity, MetSyn and T2DM.

Effects of pyridoxamine (K-163) on glucose intolerance and obesity in high-fat diet C57BL/6J mice

Advanced glycation end products (AGEs) contribute to the pathogenesis of diabetes-associated complications. Previously, we reported the possible effect of pyridoxamine (K-163), an AGE inhibitor, on improvement of glucose intolerance in type 2 diabetes mellitus KK-A y/Ta mice. Recently, AGEs and oxidative stress have been shown to induce insulin resistance. The objective of the present study is to examine the effect of pyridoxamine on glucose intolerance and oxidative stress. C57BL/6J mice were divided into 3 groups as follows: low-fat diet, high-fat diet, and high-fat diet with pyridoxamine treatment. Body and adipose tissue weight, serum insulin, hydrogen peroxide, malondialdehyde and AGE, and urinary 8-hydroxy-2′-deoxyguanosine levels were measured. Nicotinamide adenine dinucleotide phosphate subunits, antioxidant enzymes, and adipocytokine messenger RNA expressions in the adipose tissues were evaluated. Akt/protein kinase B activity and glucose transporter 4 translocation in skeletal muscle were also evaluated. Body and adipose tissue weights of the pyridoxamine treatment group were significantly decreased compared with those of the high-fat diet group. Pyridoxamine attenuated serum hydrogen peroxide, malondialdehyde and AGE, and urinary 8-hydroxy-2′-deoxyguanosine and nicotinamide adenine dinucleotide phosphate oxidase expression; increased antioxidant enzyme expression; and improved dysregulation of adipocytokines in adipose tissues. Pyridoxamine improved blood glucose levels after glucose injection and fasting hyperinsulinemia. Suppressed Akt/protein kinase B activity and glucose transporter 4 translocation in skeletal muscle in high-fat diet mice were improved by pyridoxamine treatment. It appears that the antioxidative effect of pyridoxamine is associated with improvement of glucose intolerance and obesity in C57BL/6J mice fed a high-fat diet. We assume that pyridoxamine may be useful in the treatment of the obesity-associated metabolic syndrome.

Involvement of NF‐kappaB in the Cross Talk Between the Renin‐Angiotensin System and Insulin Signaling in Skeletal Muscle in Burn Injury

Upregulation of the renin angiotensin system (RAS) is involved in impaired insulin signaling and glucose intolerance in type 2 diabetes and burn injury. We showed that losartan, an AT1 receptor blocker, improved insulin signaling and glucose tolerance in burn‐injured rats. It has been shown that NF‐kappaB activation may play an important role in angiotensin II induced skeletal muscle insulin resistance. Our aim was to examine the possible mechanism of the cross talk between the RAS and insulin signaling systems in skeletal muscle in burn injury. To assess the involvement of NF‐kappaB, we measured the levels of IkappaB, an inhibitor of NF‐kappaB, in rectus abdominus muscle three days after sham or burn injury. A 30% body surface area burn was induced in male Sprague‐Dawley rats by immersion of the dorsum into 90C water for 15s. Losartan (30 mg/kg/day) or placebo (water) was given by gavage for three days post‐burn. The level of IkappaB decreased in burned rats given placebo but returned to sham placebo levels in burned rats given losartan. These data suggest that NF‐kappaB may be involved in the cross talk between the renin‐angiotensin system and insulin signaling in skeletal muscle in burn injured rats.

Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus.

Insulin resistance in muscle and liver and β-cell failure represent the core pathophysiologic defects in type 2 diabetes. It now is recognized that the β-cell failure occurs much earlier and is more severe than previously thought. Subjects in the upper tertile of impaired glucose tolerance (IGT) are maximally/near-maximally insulin resistant and have lost over 80% of their β-cell function. In addition to the muscle, liver, and β-cell (triumvirate), the fat cell (accelerated lipolysis), gastrointestinal tract (incretin deficiency/resistance), α-cell (hyperglucagonemia), kidney (increased glucose reabsorption), and brain (insulin resistance) all play important roles in the development of glucose intolerance in type 2 diabetic individuals. Collectively, these eight players comprise the ominous octet and dictate that: 1 ) multiple drugs used in combination will be required to correct the multiple pathophysiological defects, 2 ) treatment should be based upon reversal of known pathogenic abnormalities and not simply on reducing the A1C, and 3 ) therapy must be started early to prevent/slow the progressive β-cell failure that already is well established in IGT subjects. A treatment paradigm shift is recommended in which combination therapy is initiated with diet/exercise, metformin (which improves insulin sensitivity and has antiatherogenic effects), a thiazolidinedione (TZD) (which improves insulin sensitivity, preserves β-cell function, and exerts antiatherogenic effects), and exenatide (which preserves β-cell function and promotes weight loss). Sulfonylureas are not recommended because, after an initial improvement in glycemic control, they are associated with a progressive rise in A1C and progressive loss of β-cell function. The natural history of type 2 diabetes has been well described in multiple populations (1–16) (rev. in (17,18). Individuals destined to develop type 2 diabetes inherit a set of genes from their parents that make their tissues resistant to insulin (1,16,19–24). In liver, the insulin resistance is manifested by …

Insulin secretion and insulin sensitivity at different stages of glucose tolerance: a cross-sectional study of Japanese type 2 diabetes

To evaluate the factors causing glucose intolerance in type 2 diabetes in Japan, insulin secretion and insulin sensitivity were compared across the range of glucose tolerance. Subjects were divided into 3 groups: normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and type 2 diabetes (DM) according to the criteria of the World Health Organization (WHO). We examined insulin secretion and insulin sensitivity using fasting blood glucose and insulin levels and 75 g oral glucose tolerance test (OGTT). We used homeostasis model assessment (HOMA) β-cell and insulinogenic index (30 minutes) to estimate insulin secretion and HOMA-insulin resistance (IR) and insulin sensitivity index (ISI) composite for insulin sensitivity. Although insulin resistance plays an important role in the development of diabetes in many ethnic populations, the differences in insulin sensitivity between NGT and IGT and between IGT and DM are small in Japanese patients. On the other hand, as glucose intolerance increases, insulin secretion decreases most remarkably both between NGT and IGT and between IGT and DM in Japanese patients. Decreasing insulin secretion and decreasing insulin sensitivity both occur in developing type 2 diabetes in Japanese patients, but decreased basal and early-phase insulin secretion had more pronounced contribution to glucose tolerance than the indices of insulin sensitivity. Japanese type 2 diabetic patients are characterized by a larger decrease in insulin secretion and show less attribution of insulin resistance.

Adjuvant-induced improvement of glucose intolerance in type 2 diabetic KK-Ay mice through interleukin-1 and tumor necrosis factor-alpha.

We reported that administration of complete Freund's adjuvant (CFA) improved glucose tolerance test (GTT) results in obese diabetic KK-Ay mice. In this study, we investigated its mechanism. An injection with CFA remarkably improved GTT for more than a week in KK-Ay mice, although insulin response was not changed compared with saline controls. The hypoglycemic effect of insulin was significantly, but partially, potentiated in the CFA-treated mice compared with the controls, suggesting that CFA stimulated insulin-mediated and non-insulin-mediated glucose disposal. Improvement in the GTT with CFA was partially transferable to nontreated mice by peritoneal exudative cells, but not spleen or lymph node cells. Pretreatment with anti-interleukin (IL)-1 alpha and -1 beta antibodies or anti-tumor necrosis factor (TNF)-alpha antibody significantly abrogated the improvement in the GTT with CFA. The results indicate that CFA-induced improvement in glucose intolerance in KK-Ay mice was mediated at least by IL-1 and TNF-alpha.

Role of non-esterified fatty acids in the pathogenesis of type 2 diabetes mellitus.

Over 30 years after the original description of Randle's cycle, the mechanisms by which elevated circulating non-esterified fatty acids might be causally related to glucose intolerance in Type 2 diabetes mellitus remain uncertain. This review examines the evidence that elevated plasma NEFA can inhibit glucose-stimulated insulin secretion by pancreatic beta-cells and impair glucose- and insulin-stimulated glucose disposal by peripheral tissues. Experimental evidence beginning to examine the mechanisms of these phenomena is discussed.