Blood Glucose Homeostasis Research Articles

Retinoprotective effect of agmatine in streptozotocin-induced diabetic rat model: avenues for vascular and neuronal protection : Agmatine in diabetic retinopathy.

Diabetic retinopathy (DR) is the most common diabetic neurovascular complication, and the leading cause of preventable blindness among working-age individuals. Recently, agmatine, the endogenous decarboxylated L-arginine, has gained attention as a pleiotropic agent that modulates the diabetes-associated decline in quality of life, and exhibited varied protective biological effects. Diabetes was induced by a single streptozotocin (STZ, 50 mg/kg, i.p.) injection. When diabetes was verified, the animals were randomly allocated into three groups (16 rat each); diabetic, agmatine-treated diabetic (1 mg/kg, daily, for 12 weeks), and control group. Blood glucose homeostasis, retinal redox status, apoptotic parameters, nitric oxide synthase (NOS), nitric oxide (NO), vascular endothelial growth factor (VEGF), glutamate, glutamine, glutamine synthase (GS) activity, nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), and mitogen-activated protein kinase (MAPKs) pathways were assayed biochemically. Retinal vascular permeability was measured. Retinal morphology was evaluated by hematoxylin and eosin staining. Retinal N-methyl-D-aspartic acid receptor1 (NMDAR1) and glutamate aspartate transporter (GLAST) mRNA were quantified. Glucose transporter 1, pro-caspase3, and glial fibrillary acidic protein (GFAP) expression were quantified by immunohistochemistry. Chronic agmatine treatment abrogated STZ-induced retinal neurodegeneration features including gliosis, and neuronal apoptosis, restored retinal vascular permeability, mostly through antioxidant, anti-apoptotic capacity, abolishing glutamate excitotoxicity, modulating the activity of NMDARs, MAPKs/NFκB, and NOS/NO pathways. By restoring the molecular and functional background of retinal neurovascular homeostatic balance, agmatine would be appropriate therapeutic option acting upstream of the DR, impeding its progression.

Genetic activation of α-cell glucokinase in mice causes enhanced glucose-suppression of glucagon secretion during normal and diabetic states

ObjectiveWhile the molecular events controlling insulin secretion from β-cells have been documented in detail, the exact mechanisms governing glucagon release by α-cells are understood only partially. This is a critical knowledge gap, as the normal suppression of glucagon secretion by elevated glucose levels fails in type 2 diabetes (T2D) patients, contributing to hyperglycemia through stimulation of hepatic glucose production. A critical role of glycolytic flux in regulating glucagon secretion was supported by recent studies in which manipulation of the activity and expression of the glycolytic enzyme glucokinase altered the setpoint for glucose-suppression of glucagon secretion (GSGS). Given this precedent, we hypothesized that genetic activation of glucokinase specifically in α-cells would enhance GSGS and mitigate T2D hyperglucagonemia. MethodsWe derived an inducible, α-cell-specific glucokinase activating mutant mouse model (GckLoxPGck∗/LoxPGck∗; Gcg-CreERT2; henceforth referred to as “α-mutGCK”) in which the wild-type glucokinase gene (GCK) is conditionally replaced with a glucokinase mutant allele containing the ins454A activating mutation (Gck∗), a mutation that increases the affinity of glucokinase for glucose by almost 7-fold. The effects of α-cell GCK activation on glucose homeostasis, hormone secretion, islet morphology, and islet numbers were assessed using both in vivo and ex vivo assays. Additionally, the effect of α-cell GCK activation on GSGS was investigated under diabetogenic conditions of high-fat diet (HFD) feeding that dysregulate glucagon secretion. ResultsOur study shows that α-mutGCK mice have enhanced GSGS in vivo and ex vivo, independent of alterations in insulin levels and secretion, islet hormone content, islet morphology, or islet number. α-mutGCK mice maintained on HFD displayed improvements in glucagonemia compared to controls, which developed the expected obesity, glucose intolerance, elevated fasting blood glucose, hyperinsulinemia, and hyperglucagonemia. ConclusionsUsing our novel α-cell specific activation of GCK mouse model, we have provided additional support to demonstrate that the glycolytic enzyme glucokinase is a key determinant in glucose sensing within α-cells to regulate glucagon secretion. Our results contribute to our fundamental understanding of α-cell biology by providing greater insight into the regulation of glucagon secretion through α-cell intrinsic mechanisms via glucokinase. Furthermore, our HFD results underscore the potential of glucokinase as a druggable target which, given the ongoing development of allosteric glucokinase activators (GKAs) for T2D treatment, could help mitigate hyperglucagonemia and potentially improve blood glucose homeostasis.

Quantification of Insulin Vesicle Dynamics, Fusion Events and Calcium Activity in Intact Mouse Islets

Proper regulation of glucose homeostasis requires the controlled secretion of insulin and glucagon by β- and α-cells, respectively, in the pancreatic islets. The secretion profiles of insulin and glucagon track in opposition to each other with respect to glucose stimulation. These two hormones work as counterregulatory partners to maintain blood glucose homeostasis and the misregulation of both is implicated in the onset of diabetes. Therefore, it is crucial to understand the mechanistic pathways that drive the regulation of both insulin and glucagon release in pancreatic islets. For this, we adopt a multi-pronged approach to investigate the dynamics and fusion events of insulin vesicles, and intracellular Ca2+ activity in β- and α-cells of mouse pancreatic islets. The dynamics of insulin vesicle motion and release were monitored by 2D confocal and 3D dual-view inverted selective plane illumination microscopy (diSPIM) time-lapse imaging on c-peptide-EGFP labeled MIN6 cells and intact islets of transgenic ins1 promoter driven c-peptide-superfolder GFP (c-peptide-sfGFP) expressing mice under different glucose conditions. insulin vesicle fusion events were also quantified with pH-sensitive Vamp2-pHluorin labeled vesicles in MIN6 cells using total internal reflection fluorescence (TIRF) microscopy. Quantification of α- and β-cell Ca2+ activities under glucose stimulation and various conditions were conducted in intact islets of transgenic GCG-iCre and INS-Cre-GCaMP6 mice, respectively, utilizing confocal and diSPIM imaging. in addition, we examine the effects of Complexin 2, a protein kinase A (PKA)-dependent SNARE binding protein, on the regulation of glucagon secretion, along with α-cell intracellular Ca2+ activity, in Complexin2 knockout mice islets. by stepwise delineation of the various mechanistic pathways, we aim to decipher the intricate coordination between the intrinsic, paracrine and juxtacrine mechanisms within individual islet cells for proper islet function.

A synthetic BRET-based optogenetic device for pulsatile transgene expression enabling glucose homeostasis in mice

Pulsing cellular dynamics in genetic circuits have been shown to provide critical capabilities to cells in stress response, signaling and development. Despite the fascinating discoveries made in the past few years, the mechanisms and functional capabilities of most pulsing systems remain unclear, and one of the critical challenges is the lack of a technology that allows pulsatile regulation of transgene expression both in vitro and in vivo. Here, we describe the development of a synthetic BRET-based transgene expression (LuminON) system based on a luminescent transcription factor, termed luminGAVPO, by fusing NanoLuc luciferase to the light-switchable transcription factor GAVPO. luminGAVPO allows pulsatile and quantitative activation of transgene expression via both chemogenetic and optogenetic approaches in mammalian cells and mice. Both the pulse amplitude and duration of transgene expression are highly tunable via adjustment of the amount of furimazine. We further demonstrated LuminON-mediated blood-glucose homeostasis in type 1 diabetic mice. We believe that the BRET-based LuminON system with the pulsatile dynamics of transgene expression provides a highly sensitive tool for precise manipulation in biological systems that has strong potential for application in diverse basic biological studies and gene- and cell-based precision therapies in the future.

Sitagliptin and fucoidan prevent apoptosis and reducing ER stress in diabetic rat testes.

Sitagliptin increases the levels of incretin hormones and stimulates a decrease in blood glucose levels, by blocking the DPP4 enzyme. We have very limited information about impact of sitagliptin on male genital system and relationship between sitagliptin/diabetes/ER. Fucoidan can be effective in blood glucose homeostasis. We goal to explain of the effect of sitagliptin and introduce an approach of fucoidan treatment in experimental diabetes in male rats. Fifty-eight Wistar albino rats were divided into C-control group and D-diabetes group: 60mg/kg streptozotocin intraperitoneal (i.p.); DS group: STZ+10mg/kg sitagliptin intragastric (i.g.); DF group: STZ+100mg/kg fucoidan i.p.; and DSF group: STZ+10mg/kg sitagliptin+100mg/kg fucoidan. A significant decrease was detected when DS, DF and DSF groups compared to group D in blood glucose levels, basement membrane thickness and also apoptotic cell/tubule index, pJNK, caspase 3, caspase 12, GRP78, CHOP and DPP4. Sitagliptin and fucoidan have been found to be effective in blood glucose homeostasis and reducing the expression of certain proteins that lead to apoptosis and especially the proteins in the ER stress pathway. Therefore, we think that both sitagliptin and fucoidan can be effective in preventing or eliminating histopathological damages in diabetic testicular tissues, and their treatment effects can be used more.

The effect of meal frequency on biochemical cardiometabolic factors: A systematic review and meta-analysis of randomized controlled trials

Although several randomized controlled trials (RCTs) have supported the beneficial effects of higher meal frequency (MF) on cardiometabolic risk factors, the putative effects of higher MF on health remain inconclusive. This study systematically reviewed the evidence from RCTs of the effect of higher compared with lower MF on the blood lipid profile, glucose homeostasis, and adipokines. PubMed, Scopus, ISI Web of Science, and the Cochrane database were searched up to October 2020 to retrieve relevant RCTs. A DerSimonian and Laird random effects model was used to pool mean differences and 95% CI for each outcome. The quality of studies and evidence was assessed through standard methods. Twenty-one RCTs (686 participants) were included in this meta-analysis. Overall results showed a significant improvement in total cholesterol [weighted mean difference (WMD)=-6.08mg/dl; 95% CI:-10.68,-1.48; P=0.01; I2=88%], and low-density cholesterol (LDL-C) (WMD=-6.82mg/dl; 95% CI:-10.97,-1.60; P=0.009; I2=85.7%), while LDL-C to high-density cholesterol ratio (LDL-C: HDL-C) increased (WMD=0.22; 95% CI: 0.07, 0.36; P=0.003; I2=0.0%) in higher MF vs. lower MF. No significant effects were found on measures of glycemic control, apolipoproteins-A1 and B, or leptin. In subgroup analyses, higher MF significantly reduced serum triglyceride (TG), and increased HDL-C, compared with lower MF in interventions>12 weeks, and decreased serum TC and LDL-C in healthy participants. A significant reduction in LDL-C also was observed in studies where the same foods given both arms, simply divided into different feeding occasions, and in feeding studies, following higher MF compared to lower MF. Our meta-analysis found that higher, compared with lower MF may improve total cholesterol, and LDL-C. The intervention does not affect measures of glycemic control, apolipoproteins-A1 and B, or leptin. However, the GRADE ratings of low credibility of the currently available evidence highlights the need for more high-quality studies in order to reach a firm conclusion.

Efficient induction of pancreatic alpha cells from human induced pluripotent stem cells by controlling the timing for BMP antagonism and activation of retinoic acid signaling

Diabetes mellitus is caused by breakdown of blood glucose homeostasis, which is maintained by an exquisite balance between insulin and glucagon produced respectively by pancreatic beta cells and alpha cells. However, little is known about the mechanism of inducing glucagon secretion from human alpha cells. Many methods for generating pancreatic beta cells from human pluripotent stem cells (hPSCs) have been reported, but only two papers have reported generation of pancreatic alpha cells from hPSCs. Because NKX6.1 has been suggested as a very important gene for determining cell fate between pancreatic beta and alpha cells, we searched for the factors affecting expression of NKX6.1 in our beta cell differentiation protocols. We found that BMP antagonism and activation of retinoic acid signaling at stage 2 (from definitive endoderm to primitive gut tube) effectively suppressed NKX6.1 expression at later stages. Using two different hPSCs lines, treatment with BMP signaling inhibitor (LDN193189) and retinoic acid agonist (EC23) at Stage 2 reduced NKX6.1 expression and allowed differentiation of almost all cells into pancreatic alpha cells in vivo after transplantation under a kidney capsule. Our study demonstrated that the cell fate of pancreatic cells can be controlled by adjusting the expression level of NKX6.1 with proper timing of BMP antagonism and activation of retinoic acid signaling during the pancreatic differentiation process. Our method is useful for efficient induction of pancreatic alpha cells from hPSCs.

Effect of Fucoidan on the Regulation of Antioxidant Enzymes in Hepatorenal Tissues of Streptozotocin-Induced Diabetic Rats

Accumulation of reactive oxygen species resulting from hyperglycemia and inadequate endogenous antioxidants are responsible for the complications of diabetes. Accumulation of reactive oxygen species in the cells stimulates apoptosis, which hampers the cell architecture and functions of vital organs. This study investigates the effect of fucoidan from Sargassum wightii, a potent antioxidant with a regulatory effect on blood glucose homeostasis, in the liver and kidney of diabetic rats. Diabetes was induced in rats by administrating streptozotocin 50 mg/kg for 3 consecutive days through intraperitoneal injection. 30 male Wistar rats were divided into five groups consisting of six animals in each group and they were Group A: Control group, Group B: Diabetic group, Group C: Diabetic rats treated with metformin hydrochloride 250 mg/kg, Group D: Diabetic rats treated with fucoidan 50 mg/kg, and Group E: Diabetic rats treated with fucoidan 100 mg/kg. Fucoidan was administrated orally for 4 w after the induction of diabetes. Superoxide dismutase activity was low in the liver of the diabetic group and it showed 58.5 % activity, compared with the control group. Fucoidan administration elevated superoxide dismutase and it was 66.5 % and 80.6 % respectively in fucoidan 50 mg/kg and fucoidan 100 mg/kg groups, compared with the control group while in the metformin group 93.4 % activity was seen. A similar variation in the superoxide dismutase was observed in the kidney; wherein, administration of fucoidan restored the superoxide dismutase activity and it was 62.9 % in the fucoidan 50 mg/kg group and 79.5 % in the fucoidan 100 mg/kg group, compared with the control group while in diabetic group 49.4 % and metformin group 94.2 % activity were observed. The other tested antioxidant enzymes such as catalase, glutathione peroxidase and glutathione S transferase also showed marked regain in a dose-dependent manner upon administration of fucoidan. This study inferred that the administration of fucoidan in streptozotocininduced diabetic rats improved the antioxidant enzyme activity by moderating the accumulation of reactive oxygen species and reduced the pathophysiology.

Effect of Vitamin D Supplementation on Blood Glucose Homeostasis, BMI and Lipid Profile in Diabetic Patients with Vitamin D Deficiency

Effect of Vitamin D Supplementation on Blood Glucose Homeostasis, BMI and Lipid Profile in Diabetic Patients with Vitamin D Deficiency

Constructing a Smartphone-Controlled Semiautomatic Theranostic System for Glucose Homeostasis in Diabetic Mice.

With the development of mobile communication technology, smartphones have been used in point-of-care technologies (POCTs) as an important part of telemedicine. Using a multidisciplinary design principle coupling electrical engineering, software development, synthetic biology, and optogenetics, the investigators developed a smartphone-controlled semiautomatic theranostic system that regulates blood glucose homeostasis in diabetic mice in an ultraremote-control manner. The present chapter describes how the investigators tailor-designed the implant architecture "HydrogeLED," which is capable of coharboring a designer-cell-carrying alginate hydrogel and wirelessly powered far-red light LEDs. Using diabetes mellitus as a model disease, the in vivo expression of insulin or human glucagon-like peptide 1 (shGLP-1) from HydrogeLED implants could be controlled not only by pre-set ECNU-TeleMed programs, but also by a custom-engineered Bluetooth-active glucometer in a semiautomatic and glycemia-dependent manner. As a result, blood glucose homeostasis was semiautomatically maintained in diabetic mice through the smartphone-controlled semiautomatic theranostic system. By combining digital signals with optogenetically engineered cells, the present study provides a new method for the integrated diagnosis and treatment of diseases.

Repurposing New Use for Old Drug Chloroquine against Metabolic Syndrome: A Review on Animal and Human Evidence

Chloroquine (CQ) and hydroxychloroquine (HCQ) are traditional anti-malarial drugs that have been repurposed for new therapeutic uses in many diseases due to their simple usage and cost-effectiveness. The pleiotropic effects of CQ and HCQ in regulating blood pressure, glucose homeostasis, lipid, and carbohydrate metabolism have been previously described in vivo and in humans, thus suggesting their role in metabolic syndrome (MetS) prevention. The anti-hyperglycaemic, anti-hyperlipidaemic, cardioprotective, anti-hypertensive, and anti-obesity effects of CQ and HCQ might be elicited through reduction of inflammatory response and oxidative stress, improvement of endothelial function, activation of insulin signalling pathway, inhibition of lipogenesis and autophagy, as well as regulation of adipokines and apoptosis. In conclusion, the current state of knowledge supported the repurposing of CQ and HCQ usage in the management of MetS.

The pancreatic islet: a micro-organ in control.

The islets of Langerhans constitute the endocrine pancreas which regulates blood glucose homeostasis and their dysfunction results in diabetes. Each of the pancreatic islets constitutes an entire micro-organ with intricate cell to cell interactions and that is well vascularized and innervated. An important therapeutic advantage in islet transplant is that pancreatic islets maintain their organ integrity when isolated and transplanted to patients with severe diabetes. Once transplanted, the islet micro-organs actively contribute to their own vascularization and start to function immediately. Hence, in terms of organ transplantation, the application of pancreatic islets will be a decisive clinical tool for future diabetes care (credit: Tilo Moede).

O-linked N-acetylglucosamine transferase (OGT) regulates pancreatic α-cell function in mice

The nutrient sensor O-GlcNAc transferase (OGT) catalyzes posttranslational addition of O-GlcNAc onto target proteins, influencing signaling pathways in response to cellular nutrient levels. OGT is highly expressed in pancreatic glucagon-secreting cells (α-cells), which secrete glucagon in response to hypoglycemia. The objective of this study was to determine whether OGT is necessary for the regulation of α-cell mass and function in vivo. We utilized genetic manipulation to produce two α-cell specific OGT-knockout models: a constitutive glucagon-Cre (αOGTKO) and an inducible glucagon-Cre (i-αOGTKO), which effectively delete OGT in α-cells. Using approaches including immunoblotting, immunofluorescent imaging, and metabolic phenotyping in vivo, we provide the first insight on the role of O-GlcNAcylation in α-cell mass and function. αOGTKO mice demonstrated normal glucose tolerance and insulin sensitivity but displayed significantly lower glucagon levels during both fed and fasted states. αOGTKO mice exhibited significantly lower α-cell glucagon content and α-cell mass at 6 months of age. In fasting, αOGTKO mice showed impaired pyruvate stimulated gluconeogenesis in vivo and reduced glucagon secretion in vitro. i-αOGTKO mice showed similarly reduced blood glucagon levels, defective in vitro glucagon secretion, and normal α-cell mass. Interestingly, both αOGTKO and i-αOGTKO mice had no deficiency in maintaining blood glucose homeostasis under fed or fasting conditions, despite impairment in α-cell mass and function, and glucagon content. In conclusion, these studies provide a first look at the role of OGT signaling in the α-cell, its effect on α-cell mass, and its importance in regulating glucagon secretion in hypoglycemic conditions.

Possible regulation of liver glycogen structure through the gut-liver axis by resistant starch: a review

Liver glycogen α particles in diabetic patients are fragile relative to those in healthy individuals, and restoring these fragile glycogen particles to a normal state shows potential to contribute to the remission of diabetes. Resistant starch (RS) is beneficial for diabetes management through its interactions with the gut microbiota. However, its effects on glycogen fragility are not fully understood. This review aims to summarize the recent understanding of the interactions between RS and the human gut microbiota and the possible connections to liver glycogen biosynthesis to elucidate its role in the development of glycogen fragility. RS might regulate glycogen fragility in diabetes by modulating the postprandial glycemic response and glycogen biosynthesis pathways. Before RS can be applied to repair fragile glycogen, more work should be done to better understand in vivo RS structures and identify the factor binding glycogen β particles together. This review contains important information on the connections between glycogen fragility and RS-gut microbiota interactions, which could help to better understand the health benefits of RS consumption.

Role of small leucine zipper protein in hepatic gluconeogenesis and metabolic disorder.

Hepatic gluconeogenesis is the central pathway for glucose generation in the body. The imbalance between glucose synthesis and uptake leads to metabolic diseases such as obesity, diabetes, and cardiovascular diseases. Small leucine zipper protein (sLZIP) is an isoform of LZIP and it mainly functions as a transcription factor. Although sLZIP is known to regulate the transcription of genes involved in various cellular processes, the role of sLZIP in hepatic glucose metabolism is not known. In this study, we investigated the regulatory role of sLZIP in hepatic gluconeogenesis and its involvement in metabolic disorder. We found that sLZIP expression was elevated during glucose starvation, leading to the promotion of phosphoenolpyruvate carboxylase and glucose-6-phosphatase expression in hepatocytes. However, sLZIP knockdown suppressed the expression of the gluconeogenic enzymes under low glucose conditions. sLZIP also enhanced glucose production in the human liver cells and mouse primary hepatic cells. Fasting-induced cyclic adenosine monophosphate impeded sLZIP degradation. Results of glucose and pyruvate tolerance tests showed that sLZIP transgenic mice exhibited abnormal blood glucose metabolism. These findings suggest that sLZIP is a novel regulator of gluconeogenic enzyme expression and plays a role in blood glucose homeostasis during starvation.

The importance of glycogen molecular structure for blood glucose control.

SummaryType 2 diabetes incidence continues to increase rapidly. This disease is characterized by a breakdown in blood glucose homeostasis. The impairment of glycemic control is linked to the structure of glycogen, a highly branched glucose polymer. Liver glycogen, a major controller of blood sugar, comprises small β particles which can link together to form larger α particles. These degrade to glucose more slowly than β particles, enabling a controlled release of blood glucose. The α particles in diabetic mice are however easily broken down into β particles, which degrade more quickly. Because this may lead to higher blood glucose, understanding this diabetes-associated breakdown of α-particle molecular structure may help in the development of diabetes therapeutics. We review the extraction of liver glycogen, its molecular structure, and how this structure is affected by diabetes and then use this knowledge to make postulates to guide the development of strategies to help mitigate type 2 diabetes.

Peripheral and central regulation of insulin by the intestine and microbiome.

Blood glucose and insulin homeostasis is disrupted during the progression of type 2 diabetes. Insulin levels and action are regulated by both peripheral and central responses that involve the intestine and microbiome. The intestine and its microbiota process nutrients and generate molecules that influence blood glucose and insulin. Peripheral insulin regulation is regulated by gut-segment-dependent nutrient sensing and microbial factors such as short-chain fatty acids and bile acids that engage G-protein-coupled receptors. Innate immune sensing of gut-derived bacterial cell wall components and lipopolysaccharides also alter insulin homeostasis. These bacterial metabolites and postbiotics influence insulin secretion and insulin clearance in part by altering endocrine responses such as glucagon-like peptide-1. Gut-derived bacterial factors can promote inflammation and insulin resistance, but other postbiotics can be insulin sensitizers. In parallel, activation of small intestinal sirtuin 1 increases insulin sensitivity by reversing high fat-induced hypothalamic insulin resistance through a gut-brain neuronal axis, whereas high fat-feeding alters small intestinal microbiome and increases taurochenodeoxycholic acid in the plasma and the dorsal vagal complex to induce insulin resistance. In summary, emerging evidence indicates that intestinal molecular signaling involving nutrient sensing and the host-microbe symbiosis alters insulin homeostasis and action. Gut-derived host endocrine and paracrine factors as well as microbial metabolites act on the liver, pancreas, and the brain, and in parallel on the gut-brain neuronal axis. Understanding common nodes of peripheral and central insulin homeostasis and action may reveal new ways to target the intestinal host-microbe relationship in obesity, metabolic disease, and type 2 diabetes.

Novel GLP-1 analog supaglutide improves glucose homeostasis in diabetic monkeys.

Glucagon-like peptide 1 (GLP-1) is an insulinotropic hormone and plays an important role in regulating glucose homeostasis. GLP-1 has a short half-life (t1/2 < 2 min) due to degrading enzyme dipeptidyl peptidase-IV and rapid kidney clearance, which limits its clinical application as a therapeutic reagent. We demonstrated recently that supaglutide, a novel GLP-1 mimetic generated by recombinant fusion protein techniques, exerted hypoglycemic and β-cell trophic effects in type 2 diabetes db/db mice. In the present study, we examined supaglutide's therapeutic efficacy and pharmacokinetics in diabetic rhesus monkeys. We found that a single subcutaneous injection of supaglutide of tested doses transiently and significantly reduced blood glucose levels in a dose-dependent fashion in the diabetic monkeys. During a 4-week intervention period, treatment of supaglutide of weekly dosing dose-dependently decreased fasting and random blood glucose levels. This was associated with significantly declined plasma fructosamine levels. The repeated administration of supaglutide remarkably also decreased body weight in a dose-dependent fashion accompanied by decreased food intake. Intravenous glucose tolerance test results showed that supaglutide improved glucose tolerance. The intervention also showed enhanced glucose-stimulated insulin secretion and improved lipid profile in diabetic rhesus monkeys. These results reveal that supaglutide exerts beneficial effects in regulating blood glucose and lipid homeostasis in diabetic rhesus monkeys.

Annexin A6 Is Critical to Maintain Glucose Homeostasis and Survival During Liver Regeneration in Mice.

Liver regeneration requires the organized and sequential activation of events that lead to restoration of hepatic mass. During this process, other vital liver functions need to be preserved, such as maintenance of blood glucose homeostasis, balancing the degradation of hepatic glycogen stores, and gluconeogenesis (GNG). Under metabolic stress, alanine is the main hepatic gluconeogenic substrate, and its availability is the rate-limiting step in this pathway. Na+ -coupled neutral amino acid transporters (SNATs) 2 and 4 are believed to facilitate hepatic alanine uptake. In previous studies, we demonstrated that a member of the Ca2+ -dependent phospholipid binding annexins, Annexin A6 (AnxA6), regulates membrane trafficking along endo- and exocytic pathways. Yet, although AnxA6 is abundantly expressed in the liver, its function in hepatic physiology remains unknown. In this study, we investigated the potential contribution of AnxA6 in liver regeneration. Utilizing AnxA6 knockout mice (AnxA6-/- ), we challenged liver function after partial hepatectomy (PHx), inducing acute proliferative and metabolic stress. Biochemical and immunofluorescent approaches were used to dissect AnxA6-/- mice liver proliferation and energetic metabolism. Most strikingly, AnxA6-/- mice exhibited low survival after PHx. This was associated with an irreversible and progressive drop of blood glucose levels. Whereas exogenous glucose administration or restoration of hepatic AnxA6 expression rescued AnxA6-/- mice survival after PHx, the sustained hypoglycemia in partially hepatectomized AnxA6-/- mice was the consequence of an impaired alanine-dependent GNG in AnxA6-/- hepatocytes. Mechanistically, cytoplasmic SNAT4 failed to recycle to the sinusoidal plasma membrane of AnxA6-/- hepatocytes 48hours after PHx, impairing alanine uptake and, consequently, glucose production. We conclude that the lack of AnxA6 compromises alanine-dependent GNG and liver regeneration in mice.

Chronic CNS-mediated cardiometabolic actions of leptin: potential role of sex differences.

Previous studies using male rodents showed the adipocyte-derived hormone leptin acts in the brain to regulate cardiovascular function, energy balance, and glucose homeostasis. The importance of sex differences in cardiometabolic responses to leptin, however, is still unclear. We examined potential sex differences in leptin's chronic central nervous system (CNS)-mediated actions on blood pressure (BP), heart rate (HR), appetite, and glucose homeostasis in normal and type 1 diabetic rats. Female and male Sprague-Dawley (SD) rats were instrumented with intracerebroventricular cannulas for continuous 7-day leptin infusion (15 µg/day), and BP and HR were measured by telemetry 24 h/day. At baseline, females had lower mean arterial pressure (MAP) (96 ± 3 vs. 104 ± 4 mmHg, P < 0.05) but higher HR (375 ± 5 vs. 335 ± 5 beats/min, P < 0.05) compared with males. After leptin treatment, we observed similar increases in BP (∼3 mmHg) and HR (∼25 beats/min) in both sexes. Females had significantly lower body weight (BW, 283 ± 2 vs. 417 ± 7 g, P < 0.05) and caloric intake (162 ± 20 vs. 192 ± 9 kcal/kg of body wt, P < 0.05) compared with males, and leptin infusion reduced BW (-10%) and caloric intake (-62%) similarly in both sexes. In rats with streptozotocin-induced diabetes (n = 5/sex), intracerebroventricular leptin treatment for 7 days completely normalized glucose levels. The same dose of leptin administered intraperitoneally did not alter MAP, HR, glucose levels, or caloric intake in normal or diabetic rats. These results show that leptin's CNS effects on BP, HR, glucose regulation, and energy homeostasis are similar in male and female rats. Therefore, our results provide no evidence for sex differences in leptin's brain-mediated cardiovascular or metabolic actions.