Serum Insulin Secretion Research Articles

Reg2 treatment is protective but the induced Reg2 autoantibody is destructive to the islets in NOD mice

Regenerating family protein 2 (Reg2) is a trophic factor which stimulates β-cell replication and resists islet destruction. However, Reg2 also serves as an islet autoantigen, which makes it complicated to judge the effectiveness in treating diabetes. How Reg2 treatment behaves in non-obese diabetic (NOD) mice is to be investigated. NOD mice were treated with recombinant Reg2 protein, Complete Freund’s adjuvant (CFA) + PBS and CFA+Reg2 vaccinations, CFA+PBS- and CFA+Reg2-immunized antisera, and single chain variable fragment (scFv)-Reg2 and mIgG2a-Reg2 antibodies. Glycemic level, bodyweight, serum Reg2 antibody titer, glucose tolerance, and insulin secretion were determined. Islet morphological characteristics, insulitis, cell apoptosis, islet cell components, and T cell infiltration were analyzed by histological examinations. The autoantigenicity of constructed Reg2C and Reg2X fragments was determined in healthy BALB/c mice, and the bioactivity in stimulating cell proliferation and survival was assessed in insulinoma MIN6 cells. Reg2 administration alleviated diabetes in NOD mice with improved glucose tolerance and insulin secretion but elevated serum Reg2 autoantibodies. Histomorphometry showed reduced inflammatory area, TUNEL signal and CD8 + T cell infiltration, and increased β-cell proportion in support of the islet-protective effect of Reg2 treatment. CFA+PBS and CFA+Reg2 immunizations prevented diabetic onset and alleviated insulitis while injections of the antisera offered mild protections. Antibody treatments accelerated diabetic onset without increasing the overall incidence. Reg2C fragment depletes antigenicity, but reserves protective activity in streptozotocin (STZ)-treated MIN6 cells. In conclusion, Reg2 treatment alleviates type 1 diabetes (T1D) by preserving islet β-cells, but induces Reg2 autoantibody production which poses a potential risk of accelerating diabetic progression.

Proanthocyanidins isolated from lotus seed skin mitigate glycolipid metabolism disorder through the p38/Nrf2/NF-κB signaling pathway.

Lotus seed skin extract is rich in flavonoids, making it a promising candidate for developing health products. In a previous study, we found that proanthocyanidins from lotus seed skin, particularly proanthocyanidin B1 (PB1), can indirectly activate the Nrf2 signaling pathway, exerting an antioxidant effect. In this study, we isolate proanthocyanidins from lotus seed skin (PLS) using ethanol extraction and RP-HPLC identification, and investigate its effects on glycolipid metabolism both in vivo and in vitro. Our results demonstrate that PLS reduces body weight in high-fat diet (HFD) mice by decreasing feed efficiency. PLS also normalizes serum glucose, insulin secretion, glycosylated hemoglobin (HbA1c), and intraperitoneal glucose tolerance (IPGTT). Furthermore, PLS significantly improves blood lipid parameters and inhibits the expressions of six proinflammatory factors, including IL-1α, IL-1β, IL-3, IL-6, IFN-γ and TNF-α in HFD mice. Additionally, analysis of fresh liver tissues reveals that PLS and PB1 induce the expressions of antioxidant proteins such as HO-1 and NQO1 by activating the p38-Nrf2 signaling pathway and inhibiting the NF-κB signaling pathway. In conclusion, proanthocyanidins from lotus seed skin regulate glycolipid metabolism disorders by targeting the p38/Nrf2/NF-κB signaling pathway. Our study offers a new approach for the high-value comprehensive utilization of lotus seed skin by-products and precise dietary intervention for metabolic syndrome.

OR24-6 Liver-Specific Inhibition of Sialic Acid Biosynthesis Improves Systemic Glucose Homeostasis in Mice

Abstract Glycosylation is an important posttranslational modification that modulates protein expression and function. Sialic acid is the most abundant terminal monosaccharide of N-linked glycosylation in mammalian cells, and its biosynthesis is controlled by the rate-limited enzyme UDP-GlcNAc 2-epimerase/ManNac kinase (GNE). There is a positive association between the abundance of terminally sialylated plasma glycoproteins and the risk of type 2 diabetes (T2DM). The majority of glycosylated plasma proteins are liver-derived, and key hepatic receptors involved in glucose metabolism, such as the insulin receptor (IR) and glucagon receptor (GCGR), are terminally sialylated. Whether and how protein sialylation in the liver influences glucose homeostasis is unknown. To address this question we generated floxed GNE mice and at 4 weeks of age injected males with either AAV8 encoding a liver-specific targeted Cre recombinase or GFP, to yield mice lacking or normally expressing GNE in liver (GNELKO and GNELWT, respectively). Two weeks post AAV8 injection, GNELKO showed a >98% loss of GNE protein selectively in liver and drastic reductions in the sialylation of liver and plasma proteins detected by glycan-specific lectin-based analyses. Whereas body weights/body composition and plasma lipids were unaltered, GNELKO had lower fasting serum glucose and greater glucose tolerance and insulin sensitivity compared to GNELWT; serum insulin or glucose-stimulated insulin secretion were unchanged. In GNELKO mice hyperinsulinemic-euglycemic clamps displayed a loss of insulin suppression of hepatic glucose production, hepatic IRa and IRb subunit expression and Akt and GSK phosphorylation were decreased, and liver glycogen content was lowered >85%. However, there was also evidence of markedly impaired GCGR function in GNELKO mice, with serum glucagon levels raised 18-fold and attenuation of hepatic cAMP production, CREB phosphorylation and gluconeogenesis in response to glucagon. Regarding extrahepatic mechanisms, GNELKO mice displayed enhanced peripheral glucose disposal, and this was associated with increased IRb, Akt and GSK phosphorylation in skeletal muscle, and with serum FGF21 levels elevated by 406%. In additional studies, when invoked following 12 weeks of high fat diet feeding, liver GNE silencing caused dramatic improvements in glucose tolerance and insulin sensitivity. To evaluate the relevance of these findings to humans, liver GNE transcript levels were queried in a publicly available cohort, and they were higher in T2DM patients compared to non-diabetic controls in two independent cohorts (n= 54 and n=9 for Cohort I and n=4 and n=4 for Cohort II, respectively). Collectively these observations reveal that protein sialylation in the liver has dramatic impact on both insulin and glucagon action in the liver, and on peripheral glucose disposal. Further interrogation of the modulation of glucose control mechanisms by protein sialylation may lead to novel approaches to combatting glucose intolerance in T2DM and other conditions. Presentation: Monday, June 13, 2022 12:15 p.m. - 12:30 p.m.

Cisapride induced hypoglycemia via the KCNH6 potassium channel

Mutations in KCNH6 has been proved to cause hypoinsulinemia and diabetes in human and mice. Cisapride is a stomach-intestinal motility drug used to treat gastrointestinal dysfunction. Cisapride has been reported to be a potential inhibitor of the KCNH family, but it remained unclear whether cisapride inhibited KCNH6. Here, we discovered the role of cisapride on glucose metabolism, focusing on the KCNH6 potassium channel protein. Cisapride reduced blood glucose level and increased serum insulin secretion in wild-type (WT) mice fed standard normal chow/a high-fat diet or in db/db mice, especially when combined with tolbutamide. This effect was much stronger after 4 weeks of intraperitoneal injection. Whole-cell patch-clamp showed that cisapride inhibited KCNH6 currents in transfected HEK293 cells in a concentration-dependent manner. Cisapride induced an increased insulin secretion through the disruption of intracellular calcium homeostasis in a rat pancreatic β-cell line, INS-1E. Further experiments revealed that cisapride did not decrease blood glucose or increase serum insulin in KCNH6 β-cell knockout (Kcnh6-β-KO) mice when compared with WT mice. Cisapride also ameliorated glucose-stimulated insulin secretion (GSIS) in response to high glucose in WT but not Kcnh6-β-KO mice. Thus, our data reveal a novel way for the effect of KCNH6 in cisapride-induced hypoglycemia.

The effect of trimethylamine N-oxide on the metabolism of visceral white adipose tissue in spontaneously hypertensive rat

ABSTRACT Strong links have been reported among trimethylamine N-oxide (TMAO), visceral white adipose tissue (vWAT), and cardiometabolic diseases. However, the effects of TMAO on vWAT in hypertension remained incompletely explored. The impact of a chronic 22-week-long treatment with 1 g/L TMAO on vWAT, and its transcriptional and metabolic changes in spontaneously hypertensive rats (SHRs) were evaluated by serum cytokine measurements, histological analysis, fatty acid determinations, and co-expression network analyses. TMAO increased the serum interleukin-6 levels and insulin secretion in SHRs. The adipocyte size was diminished in the SHR 1 g/L TMAO group. In addition, one kind of monounsaturated fatty acids (cis-15-tetracosenoate) and four kinds of polyunsaturated fatty acids (cis-11,14,17-eicosatrienoic acid, docosatetraenoate, docosapentaenoate n-3, and docosapentaenoate n-6) were elevated by TMAO treatment. Three co-expression modules significantly related to TMAO treatment were identified and pathway enrichment analyses indicated that phagosome, lysosome, fatty acid metabolism, valine, leucine, and isoleucine degradation and metabolic pathways were the most significantly altered biological pathways. This study shed new light on the metabolic roles of TMAO on the vWAT of SHRs. TMAO regulated the metabolic status of vWAT, including reduced lipogenesis and an improved specific fatty acid composition. The mechanisms underlying these effects likely involve phagosome and lysosome pathways.

Reducing VEGFB expression regulates the balance of glucose and lipid metabolism in mice via VEGFR1.

In recent years, studies have demonstrated that vascular endothelial growth factor B (VEGFB) can affect the metabolism of fatty acids and glucose, and it is expected to become a target for the diagnosis and treatment of metabolic diseases such as obesity and diabetes. At present, the specific mechanism that VEGFB regulates lipid and glucose metabolism balance is not completely understood. The present study used systemic VEGFB gene-knockout mice to investigate the effects of downregulation of the VEGFB gene on lipid metabolism and insulin secretion, and to explore the mechanism of the VEGFB pathway involved in the regulation of glucose and lipid metabolism. The morphological changes in the liver and pancreas of mice after VEGFB gene deletion were observed under a light microscope and a scanning electron microscope, and the effects of VEGFB gene deletion on lipid metabolism and blood glucose balance were detected by a serological technique. The detection indexes included total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol. Simultaneously, fasting blood glucose, glycosylated hemoglobin A1c (HbA1c), fasting insulin and glucagon were measured. Insulin sensitivity was assessed by using the insulin tolerance tests and glucose tolerance tests, and function of β-cell islets was evaluated by using the insulin resistance index (HOMA-IR) and pancreatic β-cell secretion index (HOMA-β). Τhe protein expression changes of vascular endothelial growth factor receptor 1 (VEGFR1) and vascular endothelial growth factor receptor 2 (VEGFR2) in mouse islets were detected by western blotting and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) after the VEGFB gene was knocked down to analyze the mechanism of VEGFB that may be involved in glucose and lipid metabolism. It was observed that after VEGFB was knocked down, mouse hepatocytes exhibited steatosis and increased secretory vesicles in islet cells. The lipid metabolism indexes such as TG, TC and LDL increased significantly; however, the levels of FBS, postprandial blood glucose and HbA1c decreased, whereas the glucose tolerance increased. Serum insulin secretion increased and HOMA-IR decreased since VEGFB was knocked down. Western blotting and RT-qPCR results revealed that the expression levels of VEGFR1 and neuropilin-1 decreased after the VEGFB gene was knocked down, while the expression levels of VEGFA and VEGFR2 increased. The absence of VEGFB may be involved in the regulation of glucose and lipid metabolism in mice by activating the VEGFA/VEGFR2 signaling pathway. VEGFB is expected to become a new target for the treatment of metabolic diseases such as obesity and diabetes. At present, the mechanism of VEGFB involved in regulating lipid metabolism and glucose metabolism is not completely clear. It was identified that downregulating VEGFB improved lipid metabolism and insulin resistance. The role of VEGFB/VEGFR1 pathway and other family members in regulating glucose and lipid metabolism was detected, which provided a theoretical and experimental basis for VEGFB to affect the regulation of glucose and lipid metabolism balance.

Chemical Profile of Launaea nudicaulis Ethanolic Extract and Its Antidiabetic Effect in Streptozotocin-Induced Rats.

Launaea nudicaulis is used in folk medicine worldwide to treat several diseases. The present study aimed to assess the antidiabetic activity of L. nudicaulis ethanolic extract and its effect on diabetic complications in streptozotocin-induced hyperglycemic rats. The extract was orally administrated at 250 and 500 mg/kg/day for 5-weeks and compared to glibenclamide as a reference drug at a dose of 5 mg/kg/day. Administration of the extract exhibited a potential hypoglycemic effect manifested by a significant depletion of serum blood glucose concurrent with a significant elevation in serum insulin secretion. After 5-weeks, extract at 250 and 500 mg/kg/day decreased blood glucose levels by about 53.8 and 68.1%, respectively, compared to the initial values (p ≤ 0.05). The extract at the two dosages prevented weight loss of rats from the 2nd week till the end of the experiment, compared to diabetic control rats. The extract further exhibited marked improvement in diabetic complications including liver, kidney and testis performance, oxidative stress, and relative weight of vital organs, with respect to diabetic control. Histopathological examinations confirmed the previous biochemical analysis, where the extract showed a protective effect on the pancreas, liver, kidney, and testis that degenerated in diabetic control rats. To characterize extract composition, UPLC-ESI–qTOF-MS identified 85 chromatographic peaks belonging to flavonoids, phenolics, acyl glycerols, nitrogenous compounds, and fatty acids, with four novel phenolics reported. The potential anti-diabetic effect warrants its inclusion in further studies and or isolation of the main bioactive agent(s).

Correlation between Serum 25-Hydroxyvitamin D3 and Abnormal Insulin Secretion in Patients with Type 2 Diabetes Mellitus

To investigate the correlation between serum 25-hydroxyvitamin D3 and abnormal insulin secretion in patients with type 2 diabetes mellitus. Eight type 2 diabetes mellitus patients treated from January 2018 to November 2020 (observation group) and another 80 healthy volunteers receiving physical examination in the same period (control group) were included. Fasting venous blood sample was collected to detect serum 25-hydroxyvitamin D3, fasting blood glucose, glycosylated hemoglobin, fasting insulin, insulin resistance index and insulin secretion index. According to insulin secretion index, observation group was divided into normal and abnormal insulin secretion groups and their serum 25-hydroxyvitamin D3, fasting blood glucose, glycosylated hemoglobin, fasting insulin and insulin resistance index were compared. Based on serum 25-hydroxyvitamin D3 level, observation group was divided into serum 25-hydroxyvitamin D3 positive and negative groups and their fasting blood glucose, glycosylated hemoglobin, fasting insulin, insulin resistance index and insulin secretion index were compared. The correlations of serum 25-hydroxyvitamin D3 with fasting blood glucose, glycosylated hemoglobin, fasting insulin, insulin resistance index and insulin secretion index were analyzed. Observation group had lower serum 25-hydroxyvitamin D3 level and insulin secretion index and higher fasting blood glucose, glycosylated hemoglobin, fasting insulin and insulin resistance index than those of control group (p<0.05). Abnormal insulin secretion group had lower serum 25-hydroxyvitamin D3 level and higher fasting blood glucose, fasting insulin and insulin resistance index than those of normal insulin secretion group (p<0.05). Serum 25-hydroxyvitamin D3 positive group had higher fasting blood glucose, glycosylated hemoglobin, fasting insulin and insulin resistance index and lower insulin secretion index than those of serum 25-hydroxyvitamin D3 negative group (p<0.05). Serum 25-hydroxyvitamin D3 was negatively correlated with fasting blood glucose, glycosylated hemoglobin, fasting insulin and insulin resistance index, but positively correlated with insulin secretion index. In type 2 diabetes mellitus patients, the expression of serum 25-hydroxyvitamin D3 is down-regulated, which is closely related to abnormal insulin secretion. Serum 25-hydroxyvitamin D3 can be used to determine the insulin secretion function of type 2 diabetes mellitus patients.

Slightly Elevated Serum Ionic Fluoride Levels Inhibit Insulin Secretion and Increase Glucose Levels in a General Japanese Population: a Cross-sectional Study.

A cross-sectional study was performed to investigate the relationships between serum fluoride levels, glucose levels, and insulin secretion in a general population. A total of 330 healthy subjects (167 men; 163 women) aged between 40 and 69years were examined. Lifestyle information was obtained using questionnaires. Blood samples were collected in the early morning, and biochemical parameters and glucose indices were measured. Serum ionic fluoride (SIF) levels were assessed using a highly sensitive method. Relationships between glucose indices and SIF levels were investigated using a multiple linear regression analysis. SIF levels positively correlated with fasting plasma glucose (FPG) and glycohemoglobin (HbA1c) levels in both sexes. In women, SIF levels negatively correlated with homeostasis model assessment insulin secretion (HOMA-β) levels. In men, the proportion of regular drinkers negatively correlated with HOMA-β, but not SIF levels. Although SIF levels < 1μmol/L were associated with reduced insulin secretion and increased FPG levels, the risk of diabetes was not elevated. These results suggest that increased SIF levels caused by a large fluoride intake and compromised renal function combined with poor lifestyle choices elevate the risk of diabetes. Further studies are warranted to elucidate the effects of fluoride on glucose metabolism.

Astragaloside IV as Potential Antioxidant Against Diabetic Ketoacidosis in Juvenile Mice Through Activating JNK/Nrf2 Signaling Pathway

Astragaloside IV (AS IV) has antioxidative and anti-apoptotic properties, however, its effects on juvenile mice with diabetic ketoacidosis (DKA) have not been determined. This study aims to explore the effect and mechanism of Astragaloside IV (AS-IV) on juvenile mice with DKA. DKA model was established through intraperitoneal injection of streptozotocin (STZ) and alloxan (ALX). DKA mice were divided into Control group, DKA group, DKA+AS-IV group, DKA+AS-IV+SP600125 group, DKA+AS-IV+Anisomycin group, DKA+AS-IV+GV248 group and DKA+AS-IV+GV248-Nrf2 group. To verify the implication of JNK signal pathway, JNK inhibitor SP600125 and activator Anisomycin were injected. The effects of AS-IV on antioxidant capacity and pathologies of pancreatic tissues in DKA juvenile mice were assessed. The expression of JNK/Nrf2 signal pathway was measured by Western blot. DKA juvenile mouse models were successfully established, evidenced by elevated blood glucose and blood ketone, suppressed insulin and pH value, and notable injuries in pancreatic tissues. Gavage of AS-IV can enhance antioxidant capacity of pancreatic tissue and ameliorate injuries in pancreatic tissues. AS-IV increased insulin level, in addition to suppressing blood glucose in DKA juvenile mice. In pancreatic tissues of DKA juvenile mice, protein level of p-JNK/JNK in pancreatic tissue and Nrf2 in the nuclei were increased after administration of AS-IV. Inhibition on JNK/Nrf2 signal pathway would impair the favorable effect of AS-IV on DKA juvenile mice, while antioxidant capacity, insulin level and blood glucose were improved in DKA juvenile mice injected an activator of JNK/Nrf2 pathway. Collectively, AS-IV can enhance the antioxidant capacity of DKA juvenile mice to decrease blood glucose and to increase serum insulin secretion. The mechanism of action may be realized through the JNK/Nrf2 pathway.

Dacryodes edulis (G. Don) H.J. Lam modulates glucose metabolism, cholinergic activities and Nrf2 expression, while suppressing oxidative stress and dyslipidemia in diabetic rats

Ethnopharmacological relevanceDacryodes edulis L. is an evergreen tree indigenous to western and eastern Africa which is utilized for nutritional and medicinal purposes. Folklorically, different parts of the tree are used in treating and managing diabetes and its complications. AimsThe antidiabetic effect of the butanol fraction of D. edulis ethanol extract (BFDE) was studied in fructose-streptozotocin induced type 2 diabetic rats. MethodsThe ethanol extract was fractionated to yield the hexane, dichloromethane, ethyl acetate, butanol and aqueous fractions. The in vitro antidiabetic activities of the fractions were determined by their ability to inhibit α-glucosidase activity. BDFE was the most active and showed no cytotoxic effect while stimulating glucose uptake in 3T3-L1 adipocytes. Thus, selected for in vivo study. Diabetic rats were grouped into 4. The negative control group was administered water only, another group was treated with metformin (200 mg/kg bodyweight), while the other groups were administered BDFE at 150 and 300 mg/kg bodyweight respectively. Two other groups consisting of normal rats were given water and BFDE (300 mg/kg bodyweight) respectively, with the former serving as normal control. After 6 weeks of intervention, the rats were humanely sacrificed using appropriate anaesthesia. ResultsTreatment with the fraction significantly (p < 0.05) reduced the blood glucose level of the diabetic rats, with concomitant increase in serum insulin secretion. It also caused significant (p < 0.05) elevation of reduced glutathione level, superoxide dismutase, catalase, α-amylase, and ATPase activities, with concomitant depletion in myeloperoxidase activity, NO and MDA levels of the serum and pancreas. The pancreatic morphology and β-cell function were significantly improved in BFDE-treated rats, with restoration of the pancreatic capillary networks. Treatment with BFDE significantly (p < 0.05) inhibited the activities of glycogen phosphorylase, fructose 1,6 biphosphatase, glucose 6 phosphatase, and acetylcholinesterase, while suppressing the expression of Nrf2. HPLC analysis revealed the presence of gallic acid, vanillic acid, vanillin, and (−)-epicatechin in the fraction. ConclusionThese results portray the antidiabetic and antioxidative properties of BFDE, which may be a synergistic consequence of the identified phenolics.

Association of serum lipids with β-cell function in obese children and adolescents.

Few data are available on the association between serum lipids and insulin secretion (ISEC) in children. We evaluated the association of triglycerides (TG), HDL cholesterol (HDL-C) and LDL cholesterol (LDL-C) with ISEC in 1150 non-diabetic obese children and adolescents using multivariable robust median regression. The following models were employed: (1) IGI or incAUCR as the ISEC response variable; (2) QUICKI, OGIS, the Stumvoll index or the Matsuda insulin sensitivity index as the insulin sensitivity (ISEN) predictor; (3) TG, HDL-C and LDL-C as the predictors of interest; (4) 120-min glucose, age, sex and body mass index as confounders. LDL-C and TG were not associated with ISEC in any model. In three out of four IGI models, an increase of 1 interquartile range (IQR) of HDL-C was associated with a decrease of median incAUCR ranging from −9 (robust 95% CI −17 to −2) to −8 (−14 to −1) pmol/mmol. In two out of four incAUCR models, an increase of 1 IQR of HDL-C was associated with a decrease of median IGI ranging from −8 (−15 to −1) to −7 (−11 to −2) pmol/mmol. TG and LDL-C are not associated and HDL-C is inversely associated with ISEC in obese children and adolescents.

Wu-Mei-wan protects pancreatic \u03b2 cells by inhibiting NLRP3 Inflammasome activation in diabetic mice

BackgroundWu-Mei-Wan (WMW) is a traditional Chinese herbal formulation that is clinically prescribed to treat diabetes mellitus in China. WMW has been shown to alleviate damage in pancreatic β cells, but the underlying mechanism remains unclear. This study aims to explore how WMW plays a protective role in pancreatic islets.MethodsDrug testing and mechanism analyses were performed on mice treated with three concentrations of WMW (4800, 9600, and 19,200 mg/kg/bw) for four consecutive weeks. Blood was collected from both db/db and wild-type mice to determine fasting blood glucose (FBG) and serum insulin levels. The expression of proteins related to apoptosis, cysteinyl aspartate-specific proteinase 12 (caspase-12) and B-cell leukemia 2 (Bcl-2), was measured by western blot. Interleukin-1β (IL-1β), interleukin-18 (IL-18), monocyte chemoattractant protein-1α (MCP-1α), and tumor necrosis factor-α (TNF-α) in the pancreas were tested with enzyme-linked immunosorbent assay (ELISA). Immunohistochemistry staining of F4/80 was performed to measure the pancreatic infiltration of macrophages. Western blot and immunofluorescence staining of the NLRP3 inflammasome were used to measure the expression of proteins related to apoptosis and inflammation.ResultsWMW dose-dependently reduced FBG and promoted serum insulin secretion in db/db mice compared to the wild-type controls. WMW protected pancreatic β cells with a pattern of decreasing caspase-12 and increasing Bcl-2 expression. WMW also reversed the upregulated production of IL-1β, IL-18, MCP-1α, and macrophage-specific surface glycoprotein F4/80 in diabetic mice. In addition, the protein expression levels of NLRP3 inflammasome components NLRP3, ASC, and caspase-1 (P20) were higher in db/db mice than in wild-type controls.ConclusionsWMW inhibits the activation of the NLRP3 inflammasome to protect pancreatic β cells and prevent type 2 diabetes mellitus development.

Insulin stimulus-secretion coupling is triggered by a novel thiazolidinedione/sulfonylurea hybrid in rat pancreatic islets.

New compounds with promising antidiabetic activity were synthesized. For the first time, a portion of the glibenclamide molecule was bound to a part of the core structure of thiazolidinedione to evaluate insulin secretagogue activity. Following studies in our laboratory, 4-{2-[2-(3,4-dichlorophenyl)-4-oxo-1,3-thiazolidin-3-yl]ethyl}benzene-1-sulfonamide (DTEBS) was selected to evaluate glycemia using the glucose tolerance test and insulin secretagogue activity by E.L.I.S.A. The mechanism of action of this compound was studied by 45 Ca2+ influx and whole-cell patch-clamp in rat pancreatic isolated islets. Furthermore, AGE formation in vitro was investigated. We herein show that this novel hybrid compound (DTEBS) exhibits an insulinogenic index and a profile of serum insulin secretion able to maintain glucose homeostasis. Its mechanism of action is mediated by ATP-sensitive potassium channels (KATP) and L-type voltage-dependent calcium channels (VDCC) and by activating protein kinase C and A (PKC and PKA). In addition, the stimulatory action of the compound on calcium influx and insulin secretion indicates that the potentiation of voltage-sensitive K+ currents (Kv) is due to the repolarization phase of the action potential after secretagogue excitation-secretion in pancreatic islets. Furthermore, under these experimental conditions, the compound did not induce toxicity and the in vitro late response of the compound to protein glycation reinforces its use to prevent complications of diabetes. DTEBS exerts an insulin secretagogue effect by triggering KATP, VDCC, and Kv ionic currents, possibly via PKC and PKA pathway signal transduction, in beta-cells. Furthermore, DTEBS may hold potential for delaying the late complications of diabetes.

Effect of Thai Folklore Recipe from Abutilon indicum and Mimosa pudica in Streptozotocin-Induced Diabetic Rats

Context: Abutilon indicum and Mimosa pudica were a folklore recipe in Northeastern of Thailand. The recipe was reported that claim to diabetic treatment. Aims: The studies were evaluated to hypoglycemic effect, serum insulin secretion and blood biochemistry in streptozotocin (STZ)-induced diabetic rats. Materials and Methods: The recipe were composed of whole plants from A. indicum and M. Pudica (1:1 w/w) powder. The pound plants were macerated with aqueous (AMA), hydro-ethanol (AMHE) and 80% ethanol (AME) to crude extracts. The AMA, AMHE and AME at the doses of 125, 250 and 500 mg/kg body weight (b.w.) were administered orally daily in diabetic rats during eight weeks. Fasting blood glucose levels (FBG) were measured at weekly. The serum insulin levels and blood biochemical data including blood urea nitrogen (BUN), creatinine (CREA), total protein (TP), albumin (Alb), serum aspartate aminotransferase (AST), serum alanine aminotransferase (ALT), alkaline phosphatase (ALP), triglycerides (TG), total cholesterol (TC), high-density lipoprotein (HDL) and low-density lipoprotein (LDL) were estimated at the end of experiment. Results: All doses of the extracts were showed significantly (p<0.05) decreasing percent age of FBG in diabetic rats. Especially, AME 125 mg/ kg b.w. was showed more potent significantly (p<0.05) decreasing percentage of FBG at week of 2, 5, 7 and 8. The serum insulin levels of all doses administered with the extracts were significantly (p< 0.05) higher than diabetic control group. On the other hand, all doses of the extracts were significantly (p< 0.05) decreasing ALT and ALP lower than diabetic control group. While, AMA and AMHE at the doses of 250 and 500 mg/kg b.w. were increased HDL, but decreased TC, TG and LDL. Conclusion: The study was proved to diabetic treatment and improvement of diabetic stage and blood biochemical parameters. In addition, the experiment was confirmed to folklore traditional use.

Serum adiponectin and insulin secretion: A direct or inverse association?

We investigated the association between serum high molecular weight (HMW) adiponectin and insulin secretion in a population‐based study, with or without adjustment for insulin sensitivity. A total of 488 participants (263 women) were included in the present study. Insulin secretion was estimated using the homeostasis model assessment of β‐cell function ± adjustment for insulin resistance using the disposition index. Multivariate analysis showed that HMW adiponectin was significantly and inversely associated with homeostasis model assessment of β‐cell function (partial regression coefficient −0.19, 95% confidence interval −0.28, −0.10, P < 0.0001). However, HMW adiponectin was significantly and positively associated with disposition index (partial regression coefficient 0.15, 95% confidence interval 0.06, 0.24, P = 0.0016). The present study showed that a positive association between HMW adiponectin levels and insulin secretion evaluated using an index incorporating adjustment for insulin resistance was identified, and vice versa using an index that did not adjust for insulin resistance.

Higher Fasting and Postprandial Free Fatty Acid Levels Are Associated With Higher Muscle Insulin Resistance and Lower Insulin Secretion in Young Non-Obese Women

BackgroundTo assess the relationship of the shape of glucose concentration curve during a standardized meal test to serum free fatty acid (FFA) concentrations, insulin resistance and insulin secretion in young non-obese women.MethodsThirty-five young women had a standardized meal for breakfast with measurement of glucose, insulin and FFA concentrations at 0 (fasting), 30, 60 and 120 min; the areas under the concentration curves were calculated (AUCg, AUCi and AUCffa, respectively). Meal-induced insulin response (MIR) was calculated as the ratio between the incremental insulin and glucose concentrations during the first 30 min of meal tests. In two women (group A), post-breakfast glucose (PBG) returned to levels below fasting plasma glucose (FPG) at 30 min; in 15 and 11 women, PBG returned to levels below FPG at 60 and 120 min (groups B and C, respectively). In the remaining seven women (group D), PBG never fell below FPG.ResultsDespite no difference in fasting insulin and AUCi, fasting FFA, AUCg and AUCffa were the lowest in group A, increased linearly from group B to C and plateaued in group D, whereas MIR might be the highest in group A, decreased from group B to C and plateaued in group D.ConclusionYoung women whose PBG returned to FPG more slowly had higher muscle insulin resistance and lower MIR associated with higher fasting and postprandial FFA levels compared with young women whose PBG returned to baseline more quickly.

Glucose tolerance and insulin responsiveness in Gitelman syndrome patients.

ObjectiveImpaired glucose metabolism and insulin sensitivity have been reported in patients with Gitelman syndrome (GS), but insulin secretion and the related mechanisms are not well understood.Design and methodsThe serum glucose levels, insulin secretion and insulin sensitivity were evaluated in patients with GS (n = 28), patients with type 2 diabetes mellitus (DM) and healthy individuals (n = 20 in both groups) using an oral glucose tolerance test. Serum and urine sodium, potassium and creatinine levels were measured at 0, 30, 60, 120 and 180 min after an oral glucose load was administered.ResultsThe areas under the serum glucose curves were higher in the GS patients than those in the healthy controls (17.4 ± 5.1 mmol·h/L vs 14.5 ± 2.8 mmol·h/L, P = 0.02) but lower than those in the DM patients (24.8 ± 5.3 mmol·h/L, P < 0.001). The areas under the serum insulin curves and the insulin secretion indexes in GS patients were higher than those in DM patients and lower than those in healthy subjects. The insulin secretion-sensitivity index of GS patients was between that of healthy subjects and DM patients, but the insulin sensitivity indices were not different among the three groups. After one hour of glucose administration, the serum potassium level significantly decreased from baseline, and the urinary potassium-to-creatinine ratio increased gradually and peaked at 2 h.ConclusionsGlucose metabolism and insulin secretion were impaired in GS patients, but insulin sensitivity was comparable between GS patients and patients with type 2 DM. After administration of an oral glucose load, the plasma potassium level decreased in GS patients due to the increased excretion of potassium in the urine.

Allantoin ameliorates chemically-induced pancreatic β-cell damage through activation of the imidazoline I3 receptors.

Objective. Allantoin is the primary active compound in yams (Dioscorea spp.). Recently, allantoin has been demonstrated to activate imidazoline 3 (I3) receptors located in pancreatic tissues. Thus, the present study aimed to investigate the role of allantoin in the effect to improve damage induced in pancreatic β-cells by streptozotocin (STZ) via the I3 receptors.Research Design and Methods. The effect of allantoin on STZ-induced apoptosis in pancreatic β-cells was examined using the ApoTox-Glo triplex assay, live/dead cell double staining assay, flow cytometric analysis, and Western blottings. The potential mechanism was investigated using KU14R: an I3 receptor antagonist, and U73122: a phospholipase C (PLC) inhibitor. The effects of allantoin on serum glucose and insulin secretion were measured in STZ-treated rats.Results. Allantoin attenuated apoptosis and cytotoxicity and increased the viability of STZ-induced β-cells in a dose-dependent manner; this effect was suppressed by KU14R and U73112. Allantoin decreased the level of caspase-3 and increased the level of phosphorylated B-cell lymphoma 2 (Bcl-2) expression detected by Western blotting. The improvement in β-cells viability was confirmed using flow cytometry analysis. Daily injection of allantoin for 8 days in STZ-treated rats significantly lowered plasma glucose and increased plasma insulin levels. This action was inhibited by treatment with KU14R.Conclusion. Allantoin ameliorates the damage of β-cells induced by STZ. The blockade by pharmacological inhibitors indicated that allantoin can activate the I3 receptors through a PLC-related pathway to decrease this damage. Therefore, allantoin and related analogs may be effective in the therapy for β-cell damage.

Vitamin D intake associates with insulin resistance in type 2 diabetes, but not in latent autoimmune diabetes in adults

This study aimed to evaluate the relationship between vitamin D (vitD) intake and serum concentrations and insulin secretion (assessed by C-peptide serum concentration)/insulin resistance (determined by estimated glucose disposal rate [eGDR]) in patients with latent autoimmune diabetes in adults (LADA) and type 2 diabetes (T2DM). C-peptide, serum vitD, lipid profile, insulin, glucose, and glycosylated hemoglobin (HbA1c) were assessed; vitD intake was determined; and eGDR was calculated. Groups were compared using the Student t or Mann-Whitney U test. Correlations were performed between insulin secretion, insulin resistance, and vitD, and linear regression models were adjusted for confounding variables. Of 107 patients included, age was 55.3 ± 11.84 years old, and time since diabetes diagnosis was 13.23 ± 5.96 years. There were significant intergroup differences in age, body mass index (BMI), hip measurements, glucose, and HbA1c. The correlation between vitD intake and C-peptide for the whole group was significant (r = 0.213; P = .032) as well as for vitD deficiency/sufficiency in T2DM (P = .042), whereas neither was significant in eGDR. After adjustment for age, HbA1c, disease progression, physical activity, solar exposure, sex, and BMI, vitD intake was only significant in T2DM (P = .028). In serum vitD, only the correlation between eGDR and vitD in T2DM was significant and intragroup when comparing vitD sufficiency. After adjustments, significance was lost. Patients with LADA had lower intake of vitD, poorer metabolic control, lower BMI, and younger age compared to T2DM patients. There was no association between serum vitD or vitD intake and insulin secretion when analyzed by group, although vitD intake was associated with insulin resistance in T2DM, but not LADA.