Mannogalactoglucan from mushrooms protects pancreatic islets via restoring UPR and promotes insulin secretion in TIDM mice

Type 1 diabetes mellitus(T1DM) lacks insulin secretion due to autoimmune deficiency of pancreaticβ-cells.Protecting pancreatic islets and enhancing insulin secretion has been therapeutic approaches.Mannogalactoglucan is the main type of polysaccharide from natural mushroom,which has potential medicinal prospects.Nevertheless,the antidiabetic property of mannogalactoglucan in T1DM has not been fully elucidated.In this study,we obtained the neutral fraction of alkali-soluble Armillaria mellea polysaccharide(AAMP-N) with the structure of mannogalactoglucan from the fruiting body of A.mellea and investigated the potential therapeutic value of AAMP-N in T1DM.We demonstrated that AAMP-N lowered blood glucose and improved diabetes symptoms in T1DM mice.AAMP-N activated unfolded protein response(UPR) signaling pathway to maintain ER protein folding homeostasis and promote insulin secretion in vivo.Besides that,AAMP-N promoted insulin synthesis via upregulating the expression of transcription factors,increased Ca^(2+) signals to stimulate intracellular insulin secretory vesicle transport via activating calcium/calmodulin-dependent kinase Ⅱ(CamkⅡ) and cAMP/PKA signals,and enhanced insulin secretory vesicle fusion with the plasma membrane via vesicle-associated membrane protein 2(VAMP2).Collectively,these studies demonstrated that the therapeutic potential of AAMP-N on pancreatic islets function,indicating that mannogalactoglucan could be natural nutraceutical used for the treatment of T1DM.

Neurotransmitters regulateβcells insulin secretion:A neglected factor

βcells are the main cells responsible for the hypoglycemic function of pancreatic islets,and the insulin secreted by these cells is the only hormone that lowers blood glucose levels in the human body.βcells are regulated by various factors,among which neurotransmitters make an important contribution.This paper discusses the effects of neurotransmitters secreted by various sympathetic and parasympathetic nerves onβcells and summarizes the mechanisms by which various neurotransmitters regulate insulin secretion.Many neurotransmitters do not have a single source and are not only released from nerve terminals but also synthesized byβcells themselves,allowing them to synergistically regulate insulin secretion.Almost all of these neurotransmitters depend on the presence of glucose to function,and their actions are mostly related to the Ca^(2+)and cAMP concentrations.Although neurotransmitters have been extensively studied,many of their mechanisms remain unclear and require further exploration by researchers.

Short-Term Effects of Liraglutide versus Vildagliptin on Insulin Secretion and Sensitivity in Type 2 Diabetes: A Single Blinded Randomized Controlled Trial (LIRAVIS Study)

Background: We aimed to evaluate the short-term metabolic effects of a GLP-1a, (liraglutide) versus a DPP-4i, (vildagliptin) in a group of sub-Saharan type 2 diabetes patients. Methods: We conducted a randomized controlled single blinded clinical trial in 14 uncontrolled type 2 diabetes patients (HbA1c ≥ 53 mmol/mol) with mean duration of diabetes of 8 [1 - 12] years and median age of 57 [49 - 61] years. Baseline treatment consisted of metformin in monotherapy or metformin plus sulfonylureas. Participants were randomly allocated to 2 groups of add-on 1.2 mg/day subcutaneous liraglutide in group 1 or 100 mg/day of oral vildagliptin in group 2 for 2 weeks. In all participants, insulin secretion in response to mixed meal tolerance test, insulin sensitivity by 80 mU/m2/min hyperinsulinemic-euglycemic clamp, body composition, and lipid profile were measured before and after intervention. Results: At the end of intervention, insulin sensitivity remained unchanged both with liraglutide from 6.6 [4.2 - 7.9] to 6.9 [4.3 - 10.8] mg/kg/min;p = 0.61 and vildagliptin from 7.1 [5.3 - 9.0] to 6.5 [5.6 - 9.4] mg/kg/min (p = 0.86). The area under the C-peptide curve varied from 5.5 [1.0 - 10.9] to 14.9 [10.8 - 17.2] nmol/L/120min, p = 0.09 in group 1 and from 1.1 [0.5 - 14.1] to 13.0 [9.6 - 16.9] nmol/L/120min (p = 0.17) in group 2. LDL Cholesterol levels decreased significantly with liraglutide from 0.85 g/L [0.51 - 1.02] to 0.54 g/L [0.50 - 0.73] (p = 0.04) but not with Vildagliptin. Body weight tended to decrease in group 1 (−0.6 kg) versus modest increase in group 2 (+1.1 kg). Conclusion: Short-term metabolic effects of Liraglutide and Vildagliptin add-on therapy are comparable in sub-Saharan type 2 diabetes patients with a more favorable trend for Liraglutide on body weight, lipid profile, and insulin secretion.

Roles of sulfonylurea receptor 1 and multidrug resistance protein 1 in modulating insulin secretion in human insulinoma

BACKGROUND:Sulfonylurea receptor 1(SUR1)and multidrug resistance protein 1(MRP1)are two prominent members of multidrug resistance proteins associated with insulin secretion. The aims of this study were to investigate their expression in insulinomas and their sole and synergistic effects in modulating abnormal insulin secretion. METHODS:Fasting glucose,insulin and C-peptide were measured in 11 insulinoma patients and 11 healthy controls. Prolonged oral glucose tolerance tests were performed in 6 insulinoma patients.Insulin content,SUR1 and MRP1 were detected in 11 insulinoma patients by immunohistochemistry. SUR1 and MRP1 were also detected in 6 insulinoma patients by immunofluorescence. RESULTS:Insulinoma patients presented the typical demons-trations of Whipple’s triad.Fasting glucose of each insulinoma patient was lower than 2.8 mmol/L,and simultaneous insulin and C-peptide were increased in insulinoma patients. Prolonged oral glucose tolerance tests showed that insulin secretion in insulinoma patients were also stimulated by high glucose.Immunohistochemistry and immunofluorescence staining showed that SUR1 increased,but MRP1 decreased in insulinoma compared with the adjacent islets. CONCLUSIONS:The hypersecretion of insulin in insulinomas might be,at least partially,due to the enrichment of SUR1. In contrast,MRP1,which is down-regulated in insulinomas, might reflect a negative feedback in insulin secretion.

Vascular endothelial growth factor B inhibits insulin secretion in MIN6 cells and reduces Ca2+ and cyclic adenosine monophosphate levels through PI3K/AKT pathway

BACKGROUND Type 2 diabetes(T2 D) is characterized by insufficient insulin secretion caused by defective pancreatic β-cell function or insulin resistance,resulting in an increase in blood glucose.However,the mechanism involved in this lack of insulin secretion is unclear.The level of vascular endothelial growth factor B(VEGF-B) is significantly increased in T2 D patients.The inactivation of VEGF-B could restore insulin sensitivity in db/db mice by reducing fatty acid accumulation.It is speculated that VEGF-B is related to pancreatic β-cell dysfunction and is an important factor affecting β-cell secretion of insulin.As an in vitro model of normal pancreatic β-cells,the MIN6 cell line can be used to analyze the mechanism of insulin secretion and related biological effects.AIM To study the role of VEGF-B in the insulin secretion signaling pathway in MIN6 cells and explore the effect of VEGF-B on blood glucose regulation.METHODS The MIN6 mouse pancreatic islet β-cell line was used as the model system.By administering exogenous VEGF-B protein or knocking down VEGF-B expression in MIN6 cells,we examined the effects of VEGF-B on insulin secretion,Ca2+ and cyclic adenosine monophosphate(cAMP) levels,and the insulin secretion signaling pathway.RESULTS Exogenous VEGF-B inhibited the secretion of insulin and simultaneously reduced the levels of Ca2+ and cAMP in MIN6 cells.Exogenous VEGF-B also reduced the expression of phospholipase C gamma 1(PLCγ1),phosphatidylinositol 3-kinase(PI3 K),serine/threonine kinase(AKT),and other proteins in the insulin secretion pathway.Upon knockdown of VEGF-B,MIN6 cells exhibited increased insulin secretion and Ca2+ and cAMP levels and upregulated expression of PLCγ1,PI3 K,AKT,and other proteins.CONCLUSION VEGF-B can regulate insulin secretion by modulating the levels of Ca2+ and cAMP.VEGF-B involvement in insulin secretion is related to the expression of PLCγ1,PI3 K,AKT,and other signaling proteins.These results provide theoretical support and an experimental basis for the study of VEGF-B in the pathogenesis of T2 D.

GENERATION OF TRANSGENIC MICE FOR IN VIVO DETECTION OF INSULIN-CONTAINING GRANULE EXOCYTOSIS AND QUANTIFICATION OF INSULIN SECRETION

Insulin secretion is a complex and highly regulated process.Although much progress has been made in understanding the cellular mechanisms of insulin secretion and regulation,it remains unclear how conclusions from these studies apply to living animals.That few studies have been done to address these issues is largely due to the lack of suitable tools in detecting secretory events at high spatial and temporal resolution in vivo.When combined with genetically encoded biosensor,optical imaging is a powerful tool for visualization of molecular events in vivo.In this study,we generated a DNA construct encoding a secretory granule resident protein that is linked with two spectrally separate fluorescent proteins,a highly pH-sensitive green pHluorin on the intra-granular side and a red mCherry in the cytosol.Upon exocytosis of secretory granules,the dim pHluorin inside the acidic secretory granules became highly fluorescent outside the cells at neutral pH,while mCherry fluorescence remained constant in the process,thus allowing ratiometric quantification of insulin secretory events.Furthermore,mCherry fluorescence enabled tracking the movement of secretory granules in living cells.We validated this approach in insulin-secreting cells,and generated a transgenic mouse line expressing the optical sensor specifically in pancreaticβ-cells.The transgenic mice will be a useful tool for future investigations of molecular mechanism of insulin secretion in vitro and in vivo.

Leptin Regulated Insulin Secretion via Stimulating IRS2-associated Phosphoinositide 3-kinase Activity in the isolated Rat Pancreatic Islets

To investigate the molecular mechanism of leptin regulating insulin secretion through determining the regulation of insulin secretion and the insulin receptor substrate (IRS)-2-associated phosphoinositide 3-kinase (PI3K) activity by leptin in the isolated rat pancreatic islets, pancreatic islets were isolated from male SD rats by the collagenase method. The purified islets were incubated with leptin 2 nmol/L for 1 h in the presence of 5.6 mmol/L or 11.1 mmol/L glucose. Insulin release was measured using radioimmunoassay. IRS-2-associated activity of PI3K was determined by immunoprecipitate assay and Western blot. The results showed that in the presence of 5.6 mmol/L glucose, leptin had no significant effect on both insulin secretion and IRS-2-associated PI3K activity, but in the presence of 11.1 mmol/L glucose, insulin release was significantly inhibited after the islets were exposed to leptin for 1 h (P<0.01). PI3K inhibitor wortmannin blocked the inhibitory regulation of leptin on insulin release (P<0.05). Western Blot assay revealed that 2 nmol/L leptin could significantly increase the IRS-2-associated activity of PI3K by 51.5 % (P<0.05) in the presence of 11.1 mmol/L glucose. It was concluded that Leptin could significantly inhibit insulin secretion in the presence of 11.1 mmol/L glucose by stimulating IRS-2-associated activity of PI3K, which might be the molecular mechanism of leptin regulating insulin secretion.

Regulation of Insulin Secretion and Expression of SUR1 Gene by Chronic Exposure to Free Fatty Acids in Rat Pancreatic β Cells

To study the effects of free fatty acids on insulin secretion and expression of SUR1 gene in rat pancreatic B cells in vitro, and to explore the molecular mechanisms in lipotoxicity inducing insulin secretion dysfunction, pancreatic islet cells were isolated and digested from male SD rats. Purified islets were incubated with either 0.25 mmol/L palmitate or 0.125 mmol/L oleate for 48 h in vitro. Then islets were stimulated with either 5.6 mmol/L or 16.7 mmol/L glucose for 1 h. Insulin release was measured by using radioimmunoassay, and the expression of SUR1 gene mRNA was quantified by reserve transcription-polymerase chain reaction (RT-PCR). The islets exposed to both palmitate and oleate for 48 h showed an increased basal and a decreased glucose-indused insulin release as compared with control islets. Palmitate increased basal insulin secretion by 110 % (P<0.01), decreased glucose stimulated insulin secretion by 43 % (P<0.01); while oleate increased basal insulin secretion by 80 % (P<0.01) and decreased glucose stimulated insulin secretion by 32 % (P<0.05). RT-PCR showed that oleate significantly suppressed SUR1 gene expression by 64 % (P<0.01)as compared with the control group, while palmitate group manifested a light decrease of 15 % (P >0.05) of SUR1 gene expression. Our results suggested that chronic exposure to free fatty acids of pancreatic β cells inhibited glucose stimulated insulin secretion. Regulation of SUR1 gene expression may be involved in such effects, which may also be one of the molecular mechanisms in lipotoxocity inducing β cells secretion dysfunction.

Heterogenous glucose-stimulated insulin secretion at single islet level

Insulin secretion by pancreatic islets plays a vital role in regulating blood glucose levels.Nevertheless,the mech-anism responsible for this dynamic insulin secretion has not been completely understood,particularly at the single islet level.In this study,we have successfully developed an easy microfluidic platform that allows for the exploration of dynamic glucose-stimulated insulin secretion(GSIS)at the single islet level.With the utilization of this platform,we evaluated dynamic GSIS from single islets isolated from both normal and diabetic rats.Our results demonstrate that islets can be categorized into three types based on their dynamic GSIS:Type Ⅰ exhibits a biphasic GSIS profile with a fast first phase and flat second phase;Type Ⅱ also has a biphasic GSIS profile with a fast first phase but a slow increased second phase;Type Ⅲ displays only a slowly increased second phase and lacks a fast first phase.RNA sequencing analysis demonstrated that the cell type and exocytosis-specific genes are consistent with the proportion of cells and insulin release kinetics among the three types of islets,respectively.Moreover,our findings suggest that high expression of Atp5pb is anti-correlated with the first phase of insulin secretion.Furthermore,we revealed that diabetic islets exhibit only the type Ⅰ GSIS response,indicating a deliberate impairment of the second phase of insulin secretion.Together,this device serves as a crucial tool in the research field of islets and diabetes,allowing researchers to investigate islet functional heterogeneity and identity at the single islet level.

Dietary Green Tea Extract and Antioxidants Improve Insulin Secretory Functions of Pancreatic β-Cells in Mild and Severe Experimental Rodent Model of Chronic Pancreatitis

Chronic pancreatitis (CP) is a progressive inflammatory disorder of the pancreas. It is predominantly idiopathic (with an unknown cause) in India and mostly due to alcohol in the West. Diabetes that occur secondary to chronic pancreatitis (T3c Diabetes) is often brittle, and is difficult to attain normoglycemia with conventional treatment requiring multiple doses of insulin. Mild and severe model of CP was induced in mice by repeated intraperitoneal injections of cerulein and L-arginine respectively with an intent to study islet dysfunction and develop therapeutic strategy in animal models of CP. Dietary intervention of epigallocatechin-3-gallate (EGCG) was tested in both the models of CP for its beneficial effects on insulin secretory functions. Pancreata collected upon euthanasia were used to study alterations in the morphology of pancreatic parenchyma and inflammation by staining with H&E and fibrotic changes by Masson’s trichrome and picrosirius staining. Insulin secretory functions of islets were evaluated to test the efficacy of the dietary intervention on β-cell functions. Intraperitoneal glucose tolerance test was performed to monitor the glucose homeostasis before and after the dietary intervention. Both the models resulted in CP with dispersed acini, inflammation and fibrosis. The loss of acini and extent of fibrosis was more in L-arginine model. 2-fold improvement in glucose-stimulated insulin secretory functions of islets was observed with 0.5% EGCG dietary intervention in cerulein model of CP and 1.6-fold in L-arginine model of CP. A further improvement in insulin secretion by 3.2-fold was observed with additional dietary supplements like N-acetyl cysteine, curcumin in combination with EGCG. Our results thus demonstrate and highlight the therapeutic potential of dietary green tea (EGCG) supplementation in reversing islet dysfunction and improving glucose homeostasis in experimental chronic pancreatitis in mice.

Effect of repaglinide and gliclazide on glycaemic control, early-phase insulin secretion and lipid profiles in newly diagnosed type 2 diabetics

Background Both repaglinide and gliclazide are insulin secretagogues widely used in the treatment of type 2 diabetes.They stimulate insulin secretion through distinct mechanisms and may benefit patients from different aspects.The present study was to evaluate the effects of repaglinide or gliclazide on glycaemic control,insulin secretion,and lipid profiles in type 2 diabetes patients.Methods A total of 47 newly diagnosed type 2 diabetes patients were randomized 1：1 to receive a 4-week treatment with repaglinide or gliclazide.The standard mixed meal tolerance test was performed before and after the treatment.Plasma glucose （PG）,insulin concentration,and lipid profiles were measured.The area under insulin concentration curve （AUCins） and the early-phase insulin secretion index （△I30/△G3o） were calculated.Results After the trial,fasting and postprandial PG and postprandial insulin improved significantly in both groups （P〈0.05）.The maximum insulin concentration occurred earlier in the repaglinide group than that in the gliclazide group.AUCins increased in both groups （P 〈0.05）,but no significant difference was found between groups.△I30/△G30 increased in both groups （P 〈0.05）,especially in the repaglinide group （P 〈0.05）.Triglyceride and total cholesterol decreased significantly in the repaglinide group in some time points,while no significant change was observed in the gliclazide group.Conclusions Repaglinide and gliclazide had similar effects on glycaemic control and total insulin secretion,while repaglinide had more effects on improvements in β-cell function and lipid metabolism.

Use of First-phase Insulin Secretion in Early Diagnosis of Thyroid Diabetes and Type 2 Diabetes Mellitus

Background：A relationship between hyperthyroidism and insulin secretion in type 2 diabetes mellitus （T2DM） has been reported.Therefore,this study explored the use of first-phase insulin secretion in the differential diagnosis of thyroid diabetes （TDM） and T2DM.Methods：In total,101 patients with hyperthyroidism were divided into hyperthyroidism with normal glucose tolerance （TNGT）,hyperthyroidism with impaired glucose regulation （TIGR）,and diabetes （TDM） groups.Furthermore,96 patients without hyperthyroidism were recruited as control groups （normal glucose tolerance [NGT],impaired glucose regulation [IGR],and T2DM）.The following parameters were evaluated：homeostasis model assessment （HOMA）-IR,HOMA-β,modified β-cell function index （MBCI）,peak insulin/fasting insulin （IP/I0）,AUCins-OGTT,and AUCins-OGTr/AUCglu-OGTT from the oral glucose tolerance test （OGTT） insulin release test were utilized to assess the second-phase insulin secretion,while the IP/I0,AIR0＇-10＇,and AUCins-IVGTT from the intravenous glucose tolerance test （IVGTT） insulin release test were used to assess the first-phase insulin secretion.Results：In the OGTT,the HOMA-β values of the TNGT and TDM groups were higher than those of the NGT and T2DM groups （all P 〈 0.05）.In the hyperthyroidism groups,the MBCI of the TDM group was lower than that of the TNGT and TIGR groups （all P 〈 0.05）.Among the control groups,the MBCI values of the IGR and T2DM groups were lower than that of the normal glucose tolerance （NGT） group （all P 〈 0.05）.In the IVGTT,insulin secretion peaked for all groups at 2-4 min,except for the T2DM group,which showed a low plateau and no secretion peak.The IPvalues of the TNGT,TIGR,and TDM groups were higher than those of the NGT,IGR,and T2DM groups （all P 〈 0.05）.The IP/I0,AIR0＇-10＇,and AUCins-IVGTT values of the TDM group were higher than those of the T2DM group but were lower than those of the TNGT,TIGR,NGR,and IGR groups （all P 〈 0.05）.Compared with the other five groups,the IP/I0 AIR0＇-10＇,and AUCins-IVGTT values of the T2DM group were significantly decreased （all P 〈 0.05）.The IP/I0 and AUCins-IVGTT values of the TNGT group were higher than those of the NGT group （all P 〈 0.05）.Conclusions：β-cell function in TDM patients is superior to that in T2DM patients.First-phase insulin secretion could be used as an early diagnostic marker to differentiate TDM and T2DM.

P-glycoprotein regulating biphasic insulin secretion in rat pancreatic beta cells

Background A 65-kD mdrl （multi-drug resistance protein 1, P-glycoprotein）-Iike protein has been suggested to be the regulatory protein to the chloride channel protein 3 （CIC-3） mediating insulin granules acidification and release in mouse pancreatic beta cells. But the protein has not been deeply investigated. In this study, we identified existence of the 65-kda protein in rat islets and preliminarily explored its biological functions. Methods Total RNAs of rat kidneys served as positive controls, and pancreas, islets and INS-1 cells were extracted for reverse-transcript PCR （RT-PCR）, respectively. The cDNAs were run with specific primers selected from the mRNA of abcblb encoding P-glycoprotein. All PCR products were visualized in agarose gel electrophoresis and sequenced. Homogenates of rat islets and INS-1 cells were applied to SDS-PAGE. P-glycoprotein was detected by a specific monoclonal antibody, C219. Biphasic insulin release was measured in static incubations of rat islets with radioimmunology assay. Results Compared with positive control, expression of the P-glycoprotein mRNA segments were detected in the islets, INS-1 cells and pancreas. Sequence analysis confirmed that the PCR products were matched with mRNA of P-glycoprotein. A 65-kda protein was recognized by the antibody in the islets homogenate but not in that of INS-1 cells in Western-blotting. Instead, the homogenate of INS-1 cells contained a 160-kda protein recognized by the antibody. Insulin secretion of rat islets were stimulated by high glucose （16.7mmol/L）, and showed biphasic curve during 60-minute incubation. After co-incubation with cyclosporine A （CsA）, specific inhibitor to P-glycoprotein, the second phase of insulin secretion was reduced significantly while the first phase was not influenced. Conclusions The 65-kda protein expressed in rat islets is most likely a mini-P-glycoprotein. It may play a key role regulating biphasic insulin release.

Regulation of leptin on insulin secretion and sulfonulurea receptor 1 transcription level in isolated rats pancreatic islets

Objective To investigate the regulation of leptin on insulin secretion and expression of ATP-sensitive potassium channel subunit sulfonulurea receptor 1 (SUR1) mRNA, and to determine whether the effects of leptin are mediated through known intracellular signaling transduction.Methods Pancreatic islets were isolated by the collagenase method from male SD rats. The purified islets were incubated with different concentrations of leptin for 2 h in the presence of different concentrations of glucose. Insulin release was measured using radioimmunoassay. Expression of SUR1 mRNA was detected by RT-PCR.Results In the presence of leptin 2 nmol/L, insulin release was significantly inhibited at either 11.1 or 16.7 mmol/L glucose concentration (both P<0.05), but insulin release was not altered at glucose of 5. 6 mmol/L physiological concentration. The dose-response experiment showed that the maximal effect of leptin on insulin secretion achieved at 2 nmol/L. Exposure of islets to 2 nmol/L leptin induced a significant increase of SUR1 transcription levels by 71% (P<0. 01) at 11.1 mmol/L glucose and by 56% (P<0. 05) at 16. 7 mmol/L glucose concentration. Selective phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor wortmannin significantly prevented the leptin effect on insulin secretion and SUR1 mRNA expression.Conclusions Regulatory effects of leptin on insulin secretion could be biphasic at different concentrations of glucose and leptin. The stimulatory regulation of SUR1 transcription levels may be mediated through activation of PI 3-kinase pathway, which may be a possible mechanism of leptin in regulating insulin secretion.

Effects of supraphysiologic concentration glucose on pancreatic duodenal homeobox-1 expression and insulin secretion in rats

The islet transcription factor pancreatic duodenal homeobox-1 （PDX-1, also known as insulin promoter factor-1 or IPF-1） is an orphan homeodomain protein that plays an important role in the development, proliferation, differentiation and maturation of pancreatic cells. It is initially detected in the part of the dorsal and ventral primitive gut epithelium that later develops into the pancreas in embryonic period. In adults, its expression is found predominantly in the differentiated islet beta-cells. A recent study shows that PDX-1 is a major islet transcription factor which activates insulin gene transcription.1 Glucose-induced insulin biosynthesis is concerned with some motifs in insulin gene promoter, and PDX-1 activates insulin gene transcription and biosynthesis through binding to these motifs. Targeted inactivation of PDX-1 gene in the mice as well as its mutation in humans2 results in agenesis of the pancreas.

Surrogate markers and predictors of endogenous insulin secretion in children and adolescents with type 1 diabetes

Background No studies have examined endogenous insulin secretion in pediatric patients with type 1 diabetes in China using the gold-standard mixed-meal tolerance test.Because the latter is labor-intensive,we examined simpler surrogate markers of endogenous insulin secretion in Chinese youth,as previously reported for a European population.Methods Participants were 57 children and adolescents with type 1 diabetes aged 4.4-16.8 years(56% females).We per-formed 120-minute mixed-meal tolerance tests with serum C-peptide(CP)measurements every 30 minutes.Severe insulin deficiency(SID)was defined as CP peak<0.2 nmol/L.Urine CP and creatinine levels were measured at 0 and 120 minutes.Results Twenty-five(44%)patients had SID.Fasting CP levels missed one case(96% sensitivity)with no false posi-tives(100% specificity).While the 120-minute urine CP/creatinine had 100% sensitivity,it yielded markedly lower speci-ficity(63%).Every 1-year increase in diabetes duration and 1-year decrease in age at diagnosis were associated with 37%(P<0.001)and 20%(P=0.005)reductions in serum CP area-under-the-curve,respectively.Thus,86% of children aged<5 years had SID compared to none among patients aged ≥11 years.Conclusions Simple fasting CP measurements could be used to detect most SID cases in Chinese youth with type 1 diabe-tes.Fasting CP is a far more reliable measure of endogenous insulin secretion than the more commonly used insulin dose.Therefore,it could more precisely determine insulin secretory capacity to target those who could benefit,if treatments to preserve residual insulin secretion are developed.

Randomness in the Hybrid Modeling and Simulation of Insulin Secretion Pathways in Pancreatic Islets

Insulin secreted by pancreatic islet ˇ-cells is the principal regulating hormone of glucose metabolism.Disruption of insulin secretion may cause glucose to accumulate in the blood, and result in diabetes mellitus.Although deterministic models of the insulin secretion pathway have been developed, the stochastic aspect of this biological pathway has not been explored. The first step in this direction presented here is a hybrid model of the insulin secretion pathway, in which the delayed rectifying KCchannels are treated as stochastic events. This hybrid model can not only reproduce the oscillation dynamics as the deterministic model does, but can also capture stochastic dynamics that the deterministic model does not. To measure the insulin oscillation system behavior, a probability-based measure is proposed and applied to test the effectiveness of a new remedy.

Muscadine or amla extracts standardized to ellagic acid content ameliorate glucolipotoxicity associatedβ-cell dysfunction via inhibition of IL-1βand improved insulin secretion

Glucolipotocixity induces IL-1βsecretion which impairs pancreaticβ-cell insulin secretion.Ellagic acid and urolithin A have strong anti-inflammatory effect on cells.Muscadine and amla are very good sources of ellagic acid.The present study examined the effect of ellagic acid,ellagic acid-rich muscadine or amla extract,or urolothin A on inflammation inβcells under glucolipotoxic conditions.Rat NIT-1βcells were incubated in glucolipotoxic conditions(33.3 mM glucose,250μM palmitic acid or 33.3 mM glucose+250μM palmitic acid with or without ellagic acid,ellagic acid-rich muscadine or amla extracts standardized to its ellagic acid content,or urolithin A).Inflammatory status was evidenced by ELISA analysis of insulin and IL-1βsecretion.Ellagic acid-rich muscadine or amla extracts dose-dependently stimulated insulin secretion and down-regulated IL-1βbetter than pure ellagic acid,or urolithin A.Urolithin A did not statistically stimulate insulin secretion and did not inhibit IL-1β.

The correlation between serum uric acid level and early- phase insulin secretion in subjects with normal glucose regulation

Objective To investigate the correlation between serum uric acid(SUA)level and early-phase insulin secretion in subjects with normal glucose regulation(NGR).Methods Totally 367 community NGR residents confirmed by a 75g oral glucose tolerance test were enrolled.

Improvement of glucose metabolism in middle-aged mice on a high-fat diet by whole-grain highland barley is related to low methionine levels

Methionine restriction(MR)is an effective dietary strategy to regulate energy metabolism and alleviate oxidative stress and inflammation in the body,especially in the middle-aged and elderly population.However,the high methionine content of meat products makes this dietary strategy impossible to combine with protein supplementation and MR.Highland barley(HB),a low-methionine cereal,not only provides the body with protein but also has improved glucose metabolism and antioxidant and anti-inflammatory properties.Therefore,this study evaluated the feasibility of HB as a source of methionine-restricted dietary protein and the potential mechanisms.Middle-aged C57BL/6J mice were fed a control diet(CON),a high-fat diet(HFD),a whole-grain HB high-fat diet(HBHF),or a HBHF+methionine diet(HBHFmet)for 25 weeks.The results showed that the HBHF could keep the body weight,fasting glucose,insulin,homeostasis model assessment of insulin resistance(HOMA-IR),blood lipids,inflammation,and oxidative stress of HFD mice at normal levels.Compared with the HFD groups,HBHF inhibited pancreatic cell apoptosis and improved insulin secretion while improving hepatic and skeletal muscle glucose metabolism.However,these efficacies were attenuated in HBHFmet group mice.These findings suggest that HBHF has an MR strategy.