Augmented Insulin Sensitivity Research Articles

Enhancing insulin sensitivity in type 2 diabetes mellitus using apelin-loaded small extracellular vesicles from Wharton’s jelly-derived mesenchymal stem cells: a novel therapeutic approach

BackgroundType 2 diabetes mellitus (T2DM), characterized by β-cell dysfunction and insulin resistance (IR), presents considerable treatment challenges. Apelin is an adipocyte-derived factor that shows promise in improving IR; however, it is limited by poor targeting and a short half-life. In the present study, engineered small extracellular vesicles (sEVs) derived from Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) loaded with apelin were used to address the limitations of the therapeutic application of apelin.MethodsWJ-MSCs were transduced to obtain engineered sEVs loaded with overexpressed apelin (apelin-MSC-sEVs) and the control sEVs (MSC-sEVs). T2DM mice were injected with apelin-MSC-sEVs and MSC-sEVs, and blood glucose monitoring, glucose and insulin tolerance tests, confocal microscopy, and immunocytochemical analysis were performed. IR models of 3T3-L1 adipocytes were employed to detect GLUT4 expression in each group using western blotting; the affected pathways were determined by measuring the changes in Akt and AMPK signaling and phosphorylation.ResultsUpon successful engineering, WJ-MSCs demonstrated significant overexpression of apelin. The genetic modification did not adversely impact the characteristics of sEVs, ranging from surface protein markers, morphology, to particle size, but generated apelin-overexpressed sEVs. Apelin-MSC-sEVs treatment resulted in notable enhancement of Akt and AMPK pathway activities within 3T3-L1 adipocytes and adipose tissues of T2DM mice. Furthermore, the apelin-loaded sEVs significantly reduced plasma glucose levels, increased pancreatic β-cell proliferation, improved insulin and glucose tolerance, and modulated pro-inflammatory cytokine profiles, compared to mice treated with the control sEVs.ConclusionOur study developed novel genetically engineered apelin-loaded sEVs derived from WJ-MSCs, and demonstrated their potent role in augmenting insulin sensitivity and regulating inflammatory responses, highlighting their therapeutic promise in T2DM management. The findings open new avenues for the development of clinically viable treatments for T2DM in humans using the apelin-loaded sEVs.

A Comprehensive Analysis of Visfatin Drug in Type 2 Diabetes, Insulin Resistance, and Cardiovascular Disease

This review paper aims to provide a comprehensive analysis of the role of the visfatin drug in managing Type 2 diabetes, insulin resistance, and cardiovascular disease. The study explores the mechanism of action of visfatin and its potential therapeutic effects on glucose metabolism, insulin sensitivity, and cardiovascular health. This study integrates pertinent research investigations, clinical experiments, and animal models to assess the effectiveness and safety of visfatin as a therapeutic alternative for these interrelated ailments. The results indicate that visfatin exhibits potential in ameliorating glycemic regulation, augmenting insulin sensitivity, and conceivably mitigating the likelihood of cardiovascular complications among patients afflicted with Type 2 diabetes and insulin resistance.

Functional Fiber Reduces Mice Obesity by Regulating Intestinal Microbiota.

Obesity may cause metabolic syndrome and has become a global public health problem, and dietary fibers (DF) could alleviate obesity and metabolic syndrome by regulating intestinal microbiota. We developed a functional fiber (FF) with a synthetic mixture of polysaccharides, high viscosity, water-binding capacity, swelling capacity, and fermentability. This study aimed to investigate the effect of FF on obesity and to determine its prevention of obesity by modulating the gut microbiota. Physiological, histological, and biochemical parameters, and gut microbiota composition were investigated in the following six groups: control group (Con), high-fat diet group (HFD), low-fat diet group (LFD, conversion of HFD to LFD), high-fat +8% FF group (8% FF), high-fat +12% FF group (12% FF), and high-fat +12% FF + antibiotic group (12% FF + AB). The results demonstrated that 12% FF could promote a reduction in body weight and epididymal adipocyte area, augment insulin sensitivity, and stimulate heat production from brown adipose tissue (BAT) (p < 0.05). Compared with the HFD, 12% FF could also significantly improve the intestinal morphological integrity, attenuate systemic inflammation, promote intestinal microbiota homeostasis, and stabilize the production of short-chain fatty acids (SCFAs) (p < 0.05). Consistent with the results of 12% FF, the LFD could significantly reduce the body weight and epididymal adipocyte area relative to the HFD (p < 0.05), but the LFD and HFD showed no significant difference (p > 0.05) in the level of inflammation and SCFAs. Meanwhile, 12% FF supplementation showed an increase (p < 0.05) in the abundance of the Bifidobacterium, Lactococcus, and Coprococcus genus in the intestine, which had a negative correlation with obesity and insulin resistance. Additionally, the treatment with antibiotics (12% FF + AB) could inhibit the effect of FF in the HFD. The Kyoto Encyclopedia of Genes and Genomes (KEGG) function prediction revealed that 12% FF could significantly inhibit the cyanogenic amino acid metabolic pathway and decrease the serum succinate concentration relative to the HFD group. The overall results indicate that 12% FF has the potential to reduce obesity through the beneficial regulation of the gut microbiota and metabolites.

Novel therapies with precision mechanisms for type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) is one of the greatest health crises of our time and its prevalence is projected to increase by >50% globally by 2045. Currently, 10 classes of drugs are approved by the US Food and Drug Administration for the treatment of T2DM. Drugs in development for T2DM must show meaningful reductions in glycaemic parameters as well as cardiovascular safety. Results from an increasing number of cardiovascular outcome trials using modern T2DM therapeutics have shown a reduced risk of atherosclerotic cardiovascular disease, congestive heart failure and chronic kidney disease. Hence, guidelines have become increasingly evidence based and more patient centred, focusing on reaching individualized glycaemic goals while optimizing safety, non-glycaemic benefits and the prevention of complications. The bar has been raised for novel therapies under development for T2DM as they are now expected to achieve these aims and possibly even treat concurrent comorbidities. Indeed, the pharmaceutical pipeline for T2DM is fertile. Drugs that augment insulin sensitivity, stimulate insulin secretion or the incretin axis, or suppress hepatic glucose production are active in more than 7,000 global trials using new mechanisms of action. Our collective goal of being able to truly personalize medicine for T2DM has never been closer at hand.

Abstract 13039: Loss of Visceral Adipose Tissue Macrophage Subsets Induces Myocardial Infarction Induced Insulin Resistance: Role of Adiponectin

Introduction: Myocardial infarction (MI) is the major cause of morbidity and mortality in the western world. Insulin resistance is a major complication in patients with MI. Hypothesis: Loss of visceral adipose tissue (VAT) resident macrophages in MI results in diminished adiponectin production causing systemic insulin resistance. Methods: To understand if MI results in insulin resistance, we analyzed UPMC patient records and identified patients who had normal fasting blood glucose levels on average 15 days before ST elevation myocardial infarction (STEMI) and checked their fasting blood glucose levels 30 days after STEMI. To understand the mechanisms of MI-induced insulin resistance, we used a mouse model of coronary ligation in C57BL/6 mice and analyzed the features of insulin resistance by measuring serum insulin, serum adiponectin, AKT activation status in the liver and muscle. Results: We found that 50% of non-diabetic patients (fasting blood glucose levels 99±2.5 mg/ dl) developed hyperglycemia (141±13 mg/dl) after MI, suggesting that MI causes insulin resistance. Consistently, mice with MI had higher fasting blood insulin, and reduced p-Akt levels in the liver and skeletal muscles confirming insulin resistance. Concomitantly, mice and patients with MI had reduced number of visceral adipose tissue (VAT) resident macrophages. In line with this, MI resulted in marked reduction in the level of macrophage colony stimulating factor (M-CSF), a cytokine required for tissue resident macrophage survival. M-CSF supplementation in mice with MI improved insulin sensitivity and decreased inflammatory phenotype of VAT macrophages. Furthermore, the systemic level of adiponectin, which is reported to augment insulin sensitivity, was profoundly reduced in mice after MI. Specific depletion of VAT resident macrophages resulted in lower levels of adiponectin in the serum, indicating that this macrophage subset is necessary for adiponectin production by adipocytes. Conclusions: Our data demonstrate that diminished M-CSF levels after MI triggers apoptosis of VAT resident macrophages, resulting in reduced adiponectin secretion and systemic insulin resistance.

Insulin Resistance in Apolipoprotein M Knockout Mice is Mediated by the Protein Kinase Akt Signaling Pathway.

BackgroundPrevious clinical studies have suggested that apolipoprotein M (apoM) is involved in glucose metabolism and plays a causative role in insulin sensitivity.ObjectiveThe potential mechanism of apoM on modulating glucose homeostasis is explored and differentially expressed genes are analyzed by employing ApoM deficient (ApoM-/-) and wild type (WT) mice.MethodsThe metabolism of glucose in the hepatic tissues of high-fat diet ApoM-/- and WT mice was measured by a glycomics approach. Bioinformatic analysis was applied for analyzing the levels of differentially expressed mRNAs in the liver tissues of these mice. The insulin sensitivity of ApoM-/- and WT mice was compared using the insulin tolerance test and the phosphorylation levels of protein kinase Akt (AKT) and insulin stimulation in different tissues were examined by Western blot.ResultsThe majority of the hepatic glucose metabolites exhibited lower concentration levels in the ApoM-/- mice compared with those of the WT mice. Gene Ontology (GO) classification and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis indicated that ApoM deficiency affected the genes associated with the metabolism of glucose. The insulin tolerance test suggested that insulin sensitivity was impaired in ApoM-/- mice. The phosphorylation levels of AKT in muscle and adipose tissues of ApoM-/- mice were significantly diminished in response to insulin stimulation compared with those noted in WT mice.Conclusion ApoM deficiency led to the disorders of glucose metabolism and altered genes related to glucose metabolism in mice liver. In vivo data indicated that apoM might augment insulin sensitivity by AKT-dependent mechanism.

Hepatic HAX-1 inactivation prevents metabolic diseases by enhancing mitochondrial activity and bile salt export

Increasing hepatic mitochondrial activity through pyruvate dehydrogenase and elevating enterohepatic bile acid recirculation are promising new approaches for metabolic disease therapy, but neither approach alone can completely ameliorate disease phenotype in high-fat diet-fed mice. This study showed that diet-induced hepatosteatosis, hyperlipidemia, and insulin resistance can be completely prevented in mice with liver-specific HCLS1-associated protein X-1 (HAX-1) inactivation. Mechanistically, we showed that HAX-1 interacts with inositol 1,4,5-trisphosphate receptor-1 (InsP3R1) in the liver, and its absence reduces InsP3R1 levels, thereby improving endoplasmic reticulum-mitochondria calcium homeostasis to prevent excess calcium overload and mitochondrial dysfunction. As a result, HAX-1 ablation activates pyruvate dehydrogenase and increases mitochondria utilization of glucose and fatty acids to prevent hepatosteatosis, hyperlipidemia, and insulin resistance. In contrast to the reduction of InsP3R1 levels, hepatic HAX-1 deficiency increases bile salt exporter protein levels, thereby promoting enterohepatic bile acid recirculation, leading to activation of bile acid-responsive genes in the intestinal ileum to augment insulin sensitivity and of cholesterol transport genes in the liver to suppress hyperlipidemia. The dual mechanisms of increased mitochondrial respiration and enterohepatic bile acid recirculation due to improvement of endoplasmic reticulum-mitochondria calcium homeostasis with hepatic HAX-1 inactivation suggest that this may be a potential therapeutic target for metabolic disease intervention.

Combined Soluble Fiber-Mediated Intestinal Microbiota Improve Insulin Sensitivity of Obese Mice.

Dietary fiber, an important regulator of intestinal microbiota, is a promising tool for preventing obesity and related metabolic disorders. However, the functional links between dietary fiber, intestinal microbiota, and obesity phenotype are still not fully understood. Combined soluble fiber (CSF) is a synthetic mixture of polysaccharides and displays high viscosity, water-binding capacity, swelling capacity, and fermentability. We found that supplementing high-fat diet (HFD) with 6% CSF significantly improved the insulin sensitivity of obese mice without affecting their body weight. Replacing the HFD with normal chow basal diet (NCD), the presence of CSF in the feed significantly enhanced satiety, decreased energy intake, promoted weight and fat loss, and augmented insulin sensitivity. CSF also improved the intestinal morphological integrity, attenuated systemic inflammation, promoted intestinal microbiota homeostasis, and stabilized the production of short-chain fatty acids (SCFAs) that was perturbed during HFD-induced obesity, and these stabilizing effects were more prominent when the basal diet was switched to NCD. The enrichment of bacteria of the S24-7 family and Allobaculum genus increased markedly in the intestine following 6% CSF supplementation- and correlated with decreased adiposity and insulin resistance. Five bacterial genera that were decreased by CSF, including Oscillospira, unclassified Lachonospitaceae, unclassified Clostridiales, unclassified Desulfovibrionaceae, and unclassified Ruminococcae, were subjected to co-occurrence network analysis and were positively correlated to adiposity and insulin resistance, indicating a key role in the microbial response to CSF. Thus, CSF has a potential to promote insulin sensitivity and even reduce obesity via beneficial regulation of the gut microecosystem.

Fluid Therapy For Pediatric Patients With Diabetic Ketoacidosis: Current Perspectives.

Diabetic ketoacidosis (DKA) is a preventable life-threatening complication of type 1 diabetes. Fluids form a crucial component of DKA therapy, goals being the restoration of intravascular, interstitial and intracellular compartments. Hydration reduces hyperglycemia by decreased counter-regulatory hormones, enhanced renal glucose clearance and augmented insulin sensitivity. However, for the last several decades, fluids in DKA have been subject of intense debate owing to their possible role in causation of cerebral edema (CE). Rehydration protocols have been modified to prevent major osmotic shifts, correct electrolyte imbalances and avoid cerebral or pulmonary edema. In DKA, a conservative deficit assumption ranging from 6.5% to 8.5% is preferred. Normal saline (0.9%) has been the traditional fluid of choice, for both, volume resuscitation and deficit replacement in DKA. However, the risk of AKI with its liberal chloride content remains a contentious issue. On the other hand, balanced crystalloids with restricted chloride content need more exploration in children with DKA, both with respect to DKA resolution and AKI. Although fluids are an integral part of DKA management, a fine balance is needed to avoid under-hydration or over-hydration during DKA management. In this narrative review, we discuss the current perspectives on fluids in pediatric DKA.

The Effect of Alpha-Lipoic Acid on Liver Function and Metabolic Markers in Obese Patients with Non-Alcoholic Fatty Liver Disease: A Double - Blind Randomized Controlled Trial

Background: Insulin resistance has a pivotal role in the occurrence of impaired glucose tolerance and dyslipidemia in patients with Non-Alcoholic Fatty Liver Disease (NAFLD). There is evidence of possible beneficial effects of Alpha-Lipoic Acid (ALA) on insulin resistance and metabolic disorders. Objectives: This study aimed at examining the effects of ALA supplementation on liver enzymes, insulin sensitivity, glucose markers, and lipid profile in obese patients with NAFLD. Methods: In this double-blind placebo-controlled randomized clinical trial, 50 obese patients with NAFLD were randomly allocated to “ALA group” (received 1200 mg ALA as two capsules per day) or “Placebo group” (received placebo containing cornstarch as two capsules per day) for 12 weeks. Anthropometric measures, dietary intakes, liver enzymes as well as glucose markers and lipid profile were assessed at baseline and after 12 weeks of intervention. Results: Forty-five patients completed the study (ALA group = 23; placebo group = 22). Liver enzymes were not significantly altered by the intervention group. Alpha Lipoic Acid supplementation led to a significant attenuation in serum levels of insulin (13.4 ± 5.4 vs. 18.1 ± 8.6; P = 0.019) and triglyceride (146.9 ± 60.6 vs. 186.3 ± 54.2; P = 0.037) in comparison with the placebo group, yet did not affect other lipid profile parameters, Fasting Serum Glucose (FSG) and β-cell function index (HOMA-B) in patients with NAFLD. furthermore, quantitative insulin sensitivity check index (QUICKI) increased significantly in the ALA group compared to the placebo (0.329 ± 0.025 versus 0.317 ± 0.020; P = 0.033). Conclusions: Patients with NAFLD may benefit from ALA supplementation, at least partially through augmented insulin sensitivity and improvement of lipid profile.

BPN, a marine-derived PTP1B inhibitor, activates insulin signaling and improves insulin resistance in C2C12 myotubes

Insulin resistance is a key feature of type 2 diabetes mellitus (T2DM) and is characterized by defects in insulin signaling. Protein tyrosine phosphatase 1B (PTP1B) is a major negative regulator of insulin signaling cascade and has attracted intensive investigation in recent T2DM therapy study. BPN, a marine-derived bromophenol compound, was isolated from the red alga Rhodomela confervoides. This study investigated the effects of BPN on the insulin signaling pathway in insulin-resistant C2C12 myotubes by inhibiting PTP1B. Molecular docking study and analysis of small- molecule interaction with PTP1B all showed BPN inhibited PTP1B activity via binding to the catalytic site through hydrogen bonds. We then found that BPN permeated into C2C12 myotubes, on the one hand, activated insulin signaling in an insulin-independent manner in C2C12 cells; on the other hand, ameliorated palmitate-induced insulin resistance through augmenting insulin sensitivity. Moreover, our studies also showed that PTP1B inhibition by BPN increased glucose uptake in normal and insulin-resistant C2C12 myotubes through glucose transporter 4 (GLUT4) translocation. Taken together, BPN activates insulin signaling and alleviates insulin resistance and represents a potential candidate for further development as an antidiabetic agent.

The bradykinin-cGMP-PKG pathway augments insulin sensitivity via upregulation of MAPK phosphatase-5 and inhibition of JNK.

Bradykinin (BK) promotes insulin sensitivity and glucose uptake in adipocytes and other cell types. We demonstrated that in rat adipocytes BK enhances insulin-stimulated glucose transport via endothelial nitric oxide synthase, nitric oxide (NO) generation, and decreased activity of the mitogen-activated protein kinase (MAPK) JNK (c-Jun NH2-terminal kinase). In endothelial cells, NO increases soluble guanylate cyclase (sGC) activity, which, in turn, activates protein kinase G (PKG) by increasing cGMP levels. In this study, we investigated whether BK acts via the sGC-cGMP-PKG pathway to inhibit the negative effects of JNK on insulin signaling and glucose uptake in rat adipocytes. BK augmented cGMP concentrations. The BK-induced enhancement of insulin-stimulated glucose uptake was mimicked by the sGC activator YC-1 and a cell-permeable cGMP analog, CPT-cGMP, and inhibited by the sGC inhibitor ODQ and the PKG inhibitor KT 5823. Transfection of dominant-negative PKG reduced the BK augmentation of insulin-induced Akt phosphorylation. The activation of JNK and ERK1/2 by insulin was attenuated by BK, which was mediated by the sGC-cGMP-PKG pathway. Whereas insulin-stimulated phosphorylation of upstream activators of JNK and ERK, i.e., MKK4 and MEK1/2, was unaffected, BK augmented insulin-mediated induction of MKP-5 mRNA and protein levels. Furthermore, zaprinast, a phosphodiesterase inhibitor, enhanced cGMP and MKP-5 and prolonged the action of BK. These data indicate that BK enhances insulin action by inhibition of negative feedback by JNK and ERK via upregulation of MKP-5, mediated by the sGC-cGMP-PKG signaling pathway.

Bone morphogenetic protein-7 (BMP-7) augments insulin sensitivity in mice with type II diabetes mellitus by potentiating PI3K/AKT pathway.

A direct link between development of insulin resistance and the presence of chronic inflammation, in case of obesity exists, with cytokines playing an important role in glucose metabolism. Members of TGF-β superfamily, including bone morphogenetic proteins (BMPs), have been shown to be involved in islet morphogenesis, establishment of β-cell mass and adipose cell fate determination. Here, we demonstrate a novel and direct role of BMP-4 and -7 in the regulation of glucose homeostasis and insulin resistance. An age-dependent increase in serum BMP-4 and decrease in serum BMP-7 levels was observed in animal models of type II diabetes. In this study, BMP-7 and -4 have been demonstrated to have antagonistic effects on insulin signaling and thereby on glucose homeostasis. BMP-7 augmented glucose uptake in the insulin sensitive tissues such as the adipose and muscle by increasing Glut4 translocation to the plasma membrane through phosphorylation and activation of PDK1 and Akt, and phosphorylation and translocation of FoxO1 to the cytoplasm in liver/HepG2 cells. Restoration of BMP-7 levels in serum of diabetic animals resulted in decreased blood glucose levels in contrast to age matched untreated control groups, opening up a new therapeutic avenue for diabetes. On the contrary, BMP-4 inhibited insulin signaling through activation of PKC-θ isoform, and resulted in insulin resistance through the attenuation of insulin signaling. BMP-7 therefore is an attractive candidate for tackling a multifaceted disease such as diabetes, since it not only reduces body fat, but also strengthens insulin signaling, causing improved glucose uptake and ameliorating peripheral insulin resistance. © 2017 BioFactors, 43(2):195-209, 2017.

Adipocyte JAK2 mediates growth hormone-induced hepatic insulin resistance.

For nearly 100 years, growth hormone (GH) has been known to affect insulin sensitivity and risk of diabetes. However, the tissue governing the effects of GH signaling on insulin and glucose homeostasis remains unknown. Excess GH reduces fat mass and insulin sensitivity. Conversely, GH insensitivity (GHI) is associated with increased adiposity, augmented insulin sensitivity, and protection from diabetes. Here, we induce adipocyte-specific GHI through conditional deletion of Jak2 (JAK2A), an obligate transducer of GH signaling. Similar to whole-body GHI, JAK2A mice had increased adiposity and extreme insulin sensitivity. Loss of adipocyte Jak2 augmented hepatic insulin sensitivity and conferred resistance to diet-induced metabolic stress without overt changes in circulating fatty acids. While GH injections induced hepatic insulin resistance in control mice, the diabetogenic action was absent in JAK2A mice. Adipocyte GH signaling directly impinged on both adipose and hepatic insulin signal transduction. Collectively, our results show that adipose tissue governs the effects of GH on insulin and glucose homeostasis. Further, we show that JAK2 mediates liver insulin sensitivity via an extrahepatic, adipose tissue-dependent mechanism.

Catabolism and safety of supplemental L-arginine in animals.

L-arginine (Arg) is utilized via multiple pathways to synthesize protein and low-molecular-weight bioactive substances (e.g., nitric oxide, creatine, and polyamines) with enormous physiological importance. Furthermore, Arg regulates cell signaling pathways and gene expression to improve cardiovascular function, augment insulin sensitivity, enhance lean tissue mass, and reduce obesity in humans. Despite its versatile roles, the use of Arg as a dietary supplement is limited due to the lack of data to address concerns over its safety in humans. Data from animal studies are reviewed to assess arginine catabolism and the safety of long-term Arg supplementation. The arginase pathway was responsible for catabolism of 76-85 and 81-96% Arg in extraintestinal tissues of pigs and rats, respectively. Dietary supplementation with Arg-HCl or the Arg base [315- and 630-mg Arg/(kg BWd) for 91d] had no adverse effects on male or female pigs. Similarly, no safety issues were observed for male or female rats receiving supplementation with 1.8- and 3.6-g Arg/(kg BWd) for at least 91d. Intravenous administration of Arg-HCl to gestating sheep at 81 and 180mg Arg/(kg BWd) is safe for at least 82 and 40d, respectively. Animals fed conventional diets can well tolerate large amounts of supplemental Arg [up to 630-mg Arg/(kg BWd) in pigs or 3.6-g Arg/(kg BWd) in rats] for 91d, which are equivalent to 573-mg Arg/(kg BWd) for humans. Collectively, these results can help guide studies to determine the safety of long-term oral administration of Arg in humans.

Liver-specific expression of carboxylesterase 1g/esterase-x reduces hepatic steatosis, counteracts dyslipidemia and improves insulin signaling

Ces1g/Es-x deficiency in mice results in weight gain, insulin resistance, fatty liver and hyperlipidemia through upregulation of de novo lipogenesis and oversecretion of triacylglycerol (TG)-rich lipoproteins. Here, we show that restoration of Ces1g/Es-x expression only in the liver significantly reduced hepatic TG concentration accompanied by decreased size of lipid droplets, reduced secretion of very low-density lipoproteins and improved insulin-mediated signal transduction in the liver. Collectively, these results demonstrate that hepatic Ces1g/Es-x plays a critical role in limiting hepatic steatosis, very low-density lipoprotein assembly and in augmenting insulin sensitivity.

RETRACTED: Grizzly Bears Exhibit Augmented Insulin Sensitivity while Obese Prior to a Reversible Insulin Resistance during Hibernation

The confluence of obesity and diabetes as a worldwide epidemic necessitates the discovery of new therapies. Success in this endeavor requires translatable preclinical studies, which traditionally employ rodent models. As an alternative approach, we explored hibernation where obesity is a natural adaptation to survive months of fasting. Here we report thatgrizzly bears exhibit seasonal tripartite insulin responsiveness such that obese animals augment insulin sensitivity but only weeks later enter hibernation-specific insulin resistance (IR) and subsequently reinitiate responsiveness upon awakening. Preparation for hibernation is characterized by adiposity coupled to increased insulin sensitivity via modified PTEN/AKT signaling specifically in adipose tissue, suggesting a state of "healthy" obesity analogous to humans with PTEN haploinsufficiency. Collectively, we show that bears reversibly cope with homeostatic perturbations considered detrimental to humans and describe a mechanism whereby IR functions not as a late-stage metabolic adaptation to obesity, but rather a gatekeeper of the fed-fasting transition.

ABSTRACT 652

Background and aims: Metformin is a biguanide anti-hyperglycemic agent used in type 2 diabetes to augment insulin sensitivity without lowering glucose concentration below normal. Aims: Metformin, a widely used and promising antidiabetic agent, became a new threat for childhood intoxication. Methods: In this report we present seven cases with metformin ingestion of doses ranging from 3.4 g to 85 g (Table). Results: We would like to emphasize two adolescent girls of 85 g and 70 g metformin intake, much higher than previous cases in literature. 85 g metformin combined with 10 g nateglinid lead to intractable MALA, multiorgan failure, and exitus. The patient with 70 g intake benefited from hemodialysis and hyperbaric oxygen treatment. Conclusions: Metformin intoxication associated lactic acidosis is a potentially fatal condition, which should be urgently treated with prolonged hemodialysis. The primary goal of hemodialysis is clearance of lactate. Hyperbaric oxygen therapy may be administered in selected patients to induce aerobic respiration. Organ failure and shock during MALA predict poor outcome.

Higher Insulin Sensitivity and Impaired Insulin Secretion in Cachetic Solid Ehrlich Tumour-Bearing Mice

Insulin secretion is mainly regulated by blood glucose concentration. On the other hand, changes in peripheral insulin sensitivity induce compensatory adaptations in pancreatic β-cells to maintain normoglycaemia. Tumour presence causes dramatic alterations in glucose homeostasis and insulin secretion because of the high glucose consumption by the tumour cells. Here, we investigated insulin secretion in solid Ehrlich tumour-bearing mice in association with cachexia. For that, male adult Swiss mice were subcutaneously inoculated with solid Ehrlich tumour cells and sacrificed at 14 days after tumour implantation (SET), while control mice received saline alone (CTL). Insulin secretion, following different stimuli, glucose tolerance, and insulin sensitivity as well as the expression of key proteins involved in insulin secretion was assessed. The SET group showed decreased glycaemia, insulinaemia, hepatic glycogen and body weight, and increased plasma free fatty acids and triglycerides, characteristics of cancer cachexia. A very interesting finding in this study was the development of higher glucose tolerance and insulin sensitivity in SET group. The dose-response curve of insulin secretion to increasing glucose concentrations (2.8-22.2 mM) showed an EC50 of 10 mM glucose for CTL mice and 13 mM glucose for SET mice. Insulin secretion was significantly reduced in SET islets at 30 mM KCl, 100 μM carbachol, 20 mM arginine, and 20 mM leucine. Moreover, AKT, PKA, PKC, and AchRM3 expressions were reduced by 17% to 24% in SET animals. These results, mainly the augmented insulin sensitivity, show that SET is an interesting model to study alterations in pancreatic function and carbohydrate metabolism in cancer cachexia.

Multifunctional Cyclic d,l-α-Peptide Architectures Stimulate Non-Insulin Dependent Glucose Uptake in Skeletal Muscle Cells and Protect Them Against Oxidative Stress

Oxidative stress directly correlates with the early onset of vascular complications and the progression of peripheral insulin resistance in diabetes. Accordingly, exogenous antioxidants augment insulin sensitivity in type 2 diabetic patients and ameliorate its clinical signs. Herein, we explored the unique structural and functional properties of the abiotic cyclic D,L-α-peptide architecture as a new scaffold for developing multifunctional agents to catalytically decompose ROS and stimulate glucose uptake. We showed that His-rich cyclic D,L-α-peptide 1 is very stable under high H2O2 concentrations, effectively self-assembles to peptide nanotubes, and increases the uptake of glucose by increasing the translocation of GLUT1 and GLUT4. It also penetrates cells and protects them against oxidative stress induced under hyperglycemic conditions at a much lower concentration than α-lipoic acid (ALA). In vivo studies are now required to probe the mode of action and efficacy of these abiotic cyclic D,L-α-peptides as a novel class of antihyperglycemic compounds.