Ferulic acid enhances insulin secretion by potentiating L-type Ca2+ channel activation / 中西医结合学报

OBJECTIVE@#To investigate the effect of ferulic acid, a natural compound, on pancreatic beta cell viability, Ca2+ channels, and insulin secretion.@*METHODS@#We studied the effects of ferulic acid on rat insulinoma cell line viability using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide viability assay. The whole-cell patch-clamp technique and enzyme-linked immunosorbent assay were also used to examine the action of ferulic acid on Ca2+ channels and insulin secretion, respectively.@*RESULTS@#Ferulic acid did not affect cell viability during exposures up to 72 h. The electrophysiological study demonstrated that ferulic acid rapidly and concentration-dependently increased L-type Ca2+ channel current, shifting its activation curve in the hyperpolarizing direction with a decreased slope factor, while the voltage dependence of inactivation was not affected. On the other hand, ferulic acid have no effect on T-type Ca2+ channels. Furthermore, ferulic acid significantly increased insulin secretion, an effect inhibited by nifedipine and Ca2+-free extracellular fluid, confirming that ferulic acid-induced insulin secretion in these cells was mediated by augmenting Ca2+ influx through L-type Ca2+ channel. Our data also suggest that this may be a direct, nongenomic action.@*CONCLUSION@#This is the first electrophysiological demonstration that acute ferulic acid treatment could increase L-type Ca2+ channel current in pancreatic β cells by enhancing its voltage dependence of activation, leading to insulin secretion.

Pancreatic β-cell dedifferentiation detected by flow cytometry / 中华内科杂志

Objective:To establish a method for detecting pancreatic β-cell dedifferentiation using flow cytometry.Methods:Experimental study. Min6 (mouse β cell line), αTC1-6 (mouse α cell line), HepG2 (human hepatocellular carcinoma cells) and mouse F9 cells (mouse teratocarcinoma cell) were cultured with conventional medium. Min6 cells were treated with interleukin-1β (IL-1β) in combined with tumor necrosis factor α (TNFα), or palmitic acid (PA) overnight and stained with anti-chromogranin A (ChgA), anti-insulin (Ins), anti-glucagon (Gcg), anti-SRY-box transcription factor 9 (Sox9) and anti-octamer binding transcription factor 4 (Oct4) antibodies, respectively. Flow cytometry was applied to detect the pression of ChgA, Ins, Gcg, Sox9, and Oct4 in the cells, respectively. Unpaired Student t test was used for statistical analysis. Results:Flow cytometry analyses showed that Ins and ChgA were highly expressed in Min6 cells, Gcg was highly expressed in αTC1-6, Sox9 was highly expressed in HepG2, and Oct4 was highly expressed in F9 cells, respectively (around 90%). Treatment of Min6 cells with IL-1β+TNFα significantly decreased Ins positive staining cells (92.775%±1.702% vs. 97.125%±0.246%, P=0.045), while increased Sox9 positive staining cells (41.675%±0.390% vs. 25.875%±3.348%, P=0.003). No significant changes in ChgA and Oct4 expression could be viewed (both P>0.05). PA treatment elevated the number of Gcg positive staining cells (54.500%±3.597% vs. 41.160%±3.007%, P=0.022). The levels of mRNA expression by qPCR of the above proteins were in consistent with the levels of protein expression by flow cytometry in Min6 cells. Conclusion:Flow cytometry can be used to detect proteins expressed in dedifferentiated models of β cells, which provides a new method for identify dedifferentiation of pancreatic β cells.

La controvertida participación del GLP-1 en los mecanismos fisiológicos desencadenados tras cirugía bariátrica / The controversial participation of GLP-1 in the physiological mechanisms unchained after bariatric surgery

RESUMEN: Numerosas hipótesis se invocan para explicar el efecto beneficioso sobre el metabolismo glucídico tras la cirugía bariátrica. Algunos autores abogan por la secreción y liberación de distintas sustancias con funciones endocrinas (enterohormonas). Una de las sustancias más señaladas como efector, con efectos contrastados pero datos controvertidos, es el GLP-1. Nuestro estudio se realizó en ratas Wistar macho sanas, para evitar la ausencia de factores de confusión como son la DMT2 y la obesidad. Para conocer el mapa de adaptación a la secreción de GLP-1 tras la cirugía, se designaron 5 grupos: dos grupos control (de ayuno y de estrés quirúrgico); y tres grupos quirúrgicos (gastrectomía vertical, resección del 50 % del intestino medio y el Bypass gástrico con montaje en Y de Roux). Después de tres meses se estudiaron mediante técnicas inmunohistoquímicas el patrón de síntesis de GLP-1 en las distintas porciones del intestino delgado. También se estudió la expresión de los receptores de membrana en las células de los islotes pancreáticos. Se observó la existencia de un significativo aumento del número de células secretoras en íleon, duodeno y yeyuno en los grupos quirúrgicos de técnicas mixtas (RYGB) y malabsortivas (RI50). Igualmente se observó una elevación de los receptores pancreáticos en las mismas técnicas frente a los controles. Nuestros datos indican que la secreción intestinal de GLP-1 y su sensibilidad a nivel pancreáticas están aumentada, como efecto adaptativo a la agresión mecánica del tubo y a la alteración del flujo de nutrientes tras la cirugía.

SUMMARY: Numerous hypotheses are invoked to explain the beneficial effect on glucose metabolism after bariatric surgery. Some authors advocate for the secretion and release of various substances with endocrine functions (enterohormones). One of the substances most marked as effector, with contrasting effects but controversial data, is Glucagon-like peptide-1 GLP-1. Our study was performed in healthy male Wistar rats, to avoid the absence of confounding factors such as DMT2 and obesity. In order to know the map of adaptation to GLP-1 secretion after surgery, five groups were designated: Two control groups (fasting and surgical stress); and three surgical groups (vertical sleeve gastrectomy, 50 % midgut resection and Roux-en-Y gastric bypass). After three months, the GLP-1 synthesis pattern was studied by immunohistochemical techniques in the different portions of the small digestive tract. The expression of membrane receptors in pancreatic islet cells was also studied. There was a significant increase in the number of secretory cells in ileum, duodenum and jejunum in mixed surgical (RYGB) and malabsorptive (RI50) groups. An elevation of pancreatic receptors was also observed in the same techniques against controls. Our data indicated that intestinal secretion of GLP1 and its sensitivity to the pancreatic level were increased, both to an adaptive effect to the mechanical aggression of the digestive tube and to the alteration of nutrient flow after surgery.

Myricetin Protects Against High Glucose-Induced β-Cell Apoptosis by Attenuating Endoplasmic Reticulum Stress via Inactivation of Cyclin-Dependent Kinase 5

BACKGROUND: Chronic hyperglycemia has deleterious effects on pancreatic β-cell function and turnover. Recent studies support the view that cyclin-dependent kinase 5 (CDK5) plays a role in β-cell failure under hyperglycemic conditions. However, little is known about how CDK5 impair β-cell function. Myricetin, a natural flavonoid, has therapeutic potential for the treatment of type 2 diabetes mellitus. In this study, we examined the effect of myricetin on high glucose (HG)-induced β-cell apoptosis and explored the relationship between myricetin and CDK5. METHODS: To address this question, we subjected INS-1 cells and isolated rat islets to HG conditions (30 mM) in the presence or absence of myricetin. Docking studies were conducted to validate the interaction between myricetin and CDK5. Gene expression and protein levels of endoplasmic reticulum (ER) stress markers were measured by real-time reverse transcription polymerase chain reaction and Western blot analysis. RESULTS: Activation of CDK5 in response to HG coupled with the induction of ER stress via the down regulation of sarcoendoplasmic reticulum calcium ATPase 2b (SERCA2b) gene expression and reduced the nuclear accumulation of pancreatic duodenal homeobox 1 (PDX1) leads to β-cell apoptosis. Docking study predicts that myricetin inhibit CDK5 activation by direct binding in the ATP-binding pocket. Myricetin counteracted the decrease in the levels of PDX1 and SERCA2b by HG. Moreover, myricetin attenuated HG-induced apoptosis in INS-1 cells and rat islets and reduce the mitochondrial dysfunction by decreasing reactive oxygen species production and mitochondrial membrane potential (Δψm) loss. CONCLUSION: Myricetin protects the β-cells against HG-induced apoptosis by inhibiting ER stress, possibly through inactivation of CDK5 and consequent upregulation of PDX1 and SERCA2b.

Metformin Ameliorates Lipotoxic β-Cell Dysfunction through a Concentration-Dependent Dual Mechanism of Action

BACKGROUND: Chronic exposure to elevated levels of free fatty acids contributes to pancreatic β-cell dysfunction. Although it is well known that metformin induces cellular energy depletion and a concomitant activation of AMP-activated protein kinase (AMPK) through inhibition of the respiratory chain, previous studies have shown inconsistent results with regard to the action of metformin on pancreatic β-cells. We therefore examined the effects of metformin on pancreatic β-cells under lipotoxic stress.METHODS: NIT-1 cells and mouse islets were exposed to palmitate and treated with 0.05 and 0.5 mM metformin. Cell viability, glucose-stimulated insulin secretion, cellular adenosine triphosphate, reactive oxygen species (ROS) levels and Rho kinase (ROCK) activities were measured. The phosphorylation of AMPK was evaluated by Western blot analysis and mRNA levels of endoplasmic reticulum (ER) stress markers and NADPH oxidase (NOX) were measured by real-time quantitative polymerase chain reaction analysis.RESULTS: We found that metformin has protective effects on palmitate-induced β-cell dysfunction. Metformin at a concentration of 0.05 mM inhibits NOX and suppresses the palmitate-induced elevation of ER stress markers and ROS levels in a AMPK-independent manner, whereas 0.5 mM metformin inhibits ROCK activity and activates AMPK.CONCLUSION: This study suggests that the action of metformin on β-cell lipotoxicity was implemented by different molecular pathways depending on its concentration. Metformin at a usual therapeutic dose is supposed to alleviate lipotoxic β-cell dysfunction through inhibition of oxidative stress and ER stress.

Advances in predictors of clinical remission in intensive insulin therapy / 中国医师杂志

For patients with type 2 diabetes,early intensive insulin therapy can quickly correct hyperglycemia,improve high glucose toxicity,reduce insulin resistance,protect and even reverse partial residual β-cell function and prevent or delay the occurrence of chronic complications.Therefore,this method is more and more widely used in clinical practice.For the patients receiving intensive insulin therapy,it is of great significance to identify the patients who are prone to recurrence as early as possible through the influencing factors (especially the predictive indicators before treatment) and take timely intervention measures to improve the treatment rate of diabetes mellitus and the rate of glycemic control.

Molecular and cellular mechanisms underlying the Stem Cell Educator therapy for the clinical treatment of diabetes / 中国医师杂志

Multiple immune dysfunctions and shortage of islet beta cells are two key issues for type 1 (T1D) and type 2 (T2D) diabetes.International multi-center clinical studies and basic research have demonstrated the safety and clinical efficacy of Stem Cell Educator therapy for the treatment of T1D and T2D.CB-SC display multiple immune modulations on T cells,regulatory T cells (Tregs),and monocytes through various molecular mechanisms,such as cell-cell contacting,releasing soluble factors,and correcting the autoimmune memory.Recently,we found that platelet-releasing mitochondria exhibit the immune modulation and can migrate to pancreatic islets and be taken up by islet beta cells,leading to the proliferation and enhancement of islet beta cell functions.These findings reveal new mechanisms underlying Stem Cell Educator therapy and open up new avenues to improve the treatment of diabetes in clinics.

Immunomodulatory drugs in type 1 diabetes mellitus: current status and future prospects / 中国医师杂志

The pathophysiological nature of type 1 diabetes mellitus (T1DM) as an autoimmune disease provides the basis for immunotherapy.As an important therapeutic approach,immunomodulatory drugs are promising in the protection of pancreatic β-cells by effecting at various stages of autoimmune progression.In this review,we summarize the recent advances of immunomodulatory drugs in the prevention and treatment of T1DM and propose future directions.

Latent Autoimmune Diabetes in Adults: A Review on Clinical Implications and Management

Latent autoimmune diabetes in adults (LADA) is a heterogeneous disease characterized by a less intensive autoimmune process and a broad clinical phenotype compared to classical type 1 diabetes mellitus (T1DM), sharing features with both type 2 diabetes mellitus (T2DM) and T1DM. Since patients affected by LADA are initially insulin independent and recognizable only by testing for islet-cell autoantibodies, it could be difficult to identify LADA in clinical setting and a high misdiagnosis rate still remains among patients with T2DM. Ideally, islet-cell autoantibodies screening should be performed in subjects with newly diagnosed T2DM, ensuring a closer monitoring of those resulted positive and avoiding treatment of hyperglycaemia which might increase the rate of β-cells loss. Thus, since the autoimmune process in LADA seems to be slower than in classical T1DM, there is a wider window for new therapeutic interventions that may slow down β-cell failure. This review summarizes the current understanding of LADA, by evaluating data from most recent studies, the actual gaps in diagnosis and management. Finally, we critically highlight and discuss novel findings and future perspectives on the therapeutic approach in LADA.

Deficiency of Sphingosine-1-Phosphate Reduces the Expression of Prohibitin and Causes β-Cell Impairment via Mitochondrial Dysregulation

BACKGROUND: Emerging evidence suggests that sphingolipids may be involved in type 2 diabetes. However, the exact signaling defect through which disordered sphingolipid metabolism induces β-cell dysfunction remains unknown. The current study demonstrated that sphingosine-1-phosphate (S1P), the product of sphingosine kinase (SphK), is an essential factor for maintaining β-cell function and survival via regulation of mitochondrial action, as mediated by prohibitin (PHB). METHODS: We examined β-cell function and viability, as measured by mitochondrial function, in mouse insulinoma 6 (MIN6) cells in response to manipulation of cellular S1P and PHB levels. RESULTS: Lack of S1P induced by sphingosine kinase inhibitor (SphKi) treatment caused β-cell dysfunction and apoptosis, with repression of mitochondrial function shown by decreases in cellular adenosine triphosphate content, the oxygen consumption rate, the expression of oxidative phosphorylation complexes, the mitochondrial membrane potential, and the expression of key regulators of mitochondrial dynamics (mitochondrial dynamin-like GTPase [OPA1] and mitofusin 1 [MFN1]). Supplementation of S1P led to the recovery of mitochondrial function and greatly improved β-cell function and viability. Knockdown of SphK2 using small interfering RNA induced mitochondrial dysfunction, decreased glucose-stimulated insulin secretion (GSIS), and reduced the expression of PHB, an essential regulator of mitochondrial metabolism. PHB deficiency significantly reduced GSIS and induced mitochondrial dysfunction, and co-treatment with S1P did not reverse these trends. CONCLUSION: Altogether, these data suggest that S1P is an essential factor in the maintenance of β-cell function and survival through its regulation of mitochondrial action and PHB expression.

Pathophysiology of Type 2 Diabetes in Koreans

The pathophysiology of type 2 diabetes is characterized by variable degrees of insulin resistance and impaired insulin secretion. Both genetic and environmental factors serve as etiologic factors. Recent genetic studies have identified at least 83 variants associated with diabetes. A significant number of these loci are thought to be involved in insulin secretion, either through β-cell development or β-cell dysfunction. Environmental factors have changed rapidly during the past half century, and the increased prevalence of obesity and diabetes can be attributed to these changes. Environmental factors may affect epigenetic changes and alter susceptibility to diabetes. A recent epidemiologic study revealed that Korean patients with type 2 diabetes already had impaired insulin secretion and insulin resistance 10 years before the onset of diabetes. Those who developed diabetes showed impaired β-cell compensation with an abrupt decrease in insulin secretion during the last 2 years before diabetes developed. The retrograde trajectory of the disposition index differed according to the baseline subgroups of insulin secretion and insulin sensitivity. We hope that obtaining a more detailed understanding of the perturbations in the major pathophysiologic process of diabetes on the individual level will eventually lead to the implementation of precision medicine and improved patient outcomes.

Pioglitazone Attenuates Palmitate-Induced Inflammation and Endoplasmic Reticulum Stress in Pancreatic β-Cells

BACKGROUND: The nuclear receptor peroxisome proliferator-activator gamma (PPARγ) is a useful therapeutic target for obesity and diabetes, but its role in protecting β-cell function and viability is unclear. METHODS: To identify the potential functions of PPARγ in β-cells, we treated mouse insulinoma 6 (MIN6) cells with the PPARγ agonist pioglitazone in conditions of lipotoxicity, endoplasmic reticulum (ER) stress, and inflammation. RESULTS: Palmitate-treated cells incubated with pioglitazone exhibited significant improvements in glucose-stimulated insulin secretion and the repression of apoptosis, as shown by decreased caspase-3 cleavage and poly (adenosine diphosphate [ADP]-ribose) polymerase activity. Pioglitazone also reversed the palmitate-induced expression of inflammatory cytokines (tumor necrosis factor α, interleukin 6 [IL-6], and IL-1β) and ER stress markers (phosphor-eukaryotic translation initiation factor 2α, glucose-regulated protein 78 [GRP78], cleaved-activating transcription factor 6 [ATF6], and C/EBP homologous protein [CHOP]), and pioglitazone significantly attenuated inflammation and ER stress in lipopolysaccharide- or tunicamycin-treated MIN6 cells. The protective effect of pioglitazone was also tested in pancreatic islets from high-fat-fed KK-Ay mice administered 0.02% (wt/wt) pioglitazone or vehicle for 6 weeks. Pioglitazone remarkably reduced the expression of ATF6α, GRP78, and monocyte chemoattractant protein-1, prevented α-cell infiltration into the pancreatic islets, and upregulated glucose transporter 2 (Glut2) expression in β-cells. Moreover, the preservation of β-cells by pioglitazone was accompanied by a significant reduction of blood glucose levels. CONCLUSION: Altogether, these results support the proposal that PPARγ agonists not only suppress insulin resistance, but also prevent β-cell impairment via protection against ER stress and inflammation. The activation of PPARγ might be a new therapeutic approach for improving β-cell survival and insulin secretion in patients with diabetes mellitus

Astragalus polysaccharide improves type 2 diabetes mellitus in rats by protecting islet β cells / 第二军医大学学报

Objective To explore the effect of Astragalus polysaccharides (APS) on the function and quantity of islet β cells in rats with type 2 diabetes mellitus (T2DM). Methods SD rats were randomly divided into normal control group, T2DM model group and APS treatment group, with 8 rats in each group. The T2DM rats in the T2DM model group was induced by the combination of high fat diet and streptozotocin, and the rats in the APS treatment group was treated with APS (700 mg·kg-1·d-1, content of APS being 70%). The rats were sacrificed after 8 weeks of drug intervention, and the serum samples were collected to measure fasting blood glucose (FBG), triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and fasting insulin (FINS), and to calculate insulin secretion index (HOMA-β value). Pancreas tissues were extracted and stained with Hematoxylin-Eosin to observe the pancreatic histopathological characteristics, and the quantity of islet β cells was observed and calculated with immuno-histochemical method. Results (1) Compared with the normal control group, the rats in T2DM model group had significant increases in the FBG, TG and LDL-C, and significant decreases in the HDL-C, FINS and HOMA-β (P<0.05); compared with the T2DM model group, the rats in APS treatment group had significant decreases in the FBG, TG and LDL-C (P<0.05), and significant increases in the FINS and HOMA-β (P<0.05). (2) Compared with the normal control group, the rats in T2DM model group showed a significant atrophy of the islet accompanied by loss of granular and vacuolar degeneration, and the number of the islet β cells was significantly reduced (P<0.05); compared with the T2DM model group, the rats in APS treatment group showed a significant increase in the islet volume accompanied by improvement of islet degranulation and vacuolar degeneration, and had a significant increase in the number of islet β cells (P<0.05). Conclusion APS can improve the glucose and lipid metabolisms of the T2DM rats, which may be caused by increasing insulin secretion through the protective effect on pancreatic islet β cells.

In Vitro Effect of Fatty Acids Identified in the Plasma of Obese Adolescents on the Function of Pancreatic β-Cells

BACKGROUND: The increase in circulating free fatty acid (FFA) levels is a major factor that induces malfunction in pancreatic β-cells. We evaluated the effect of FFAs reconstituted according to the profile of circulating fatty acids found in obese adolescents on the viability and function of the murine insulinoma cell line (mouse insulinoma [MIN6]). METHODS: From fatty acids obtained commercially, plasma-FFA profiles of three different youth populations were reconstituted: obese with metabolic syndrome; obese without metabolic syndrome; and normal weight without metabolic syndrome. MIN6 cells were treated for 24 or 48 hours with the three FFA profiles, and glucose-stimulated insulin secretion, cell viability, mitochondrial function and antioxidant activity were evaluated. RESULTS: The high FFA content and high polyunsaturated ω6/ω3 ratio, present in plasma of obese adolescents with metabolic syndrome had a toxic effect on MIN6 cell viability and function, increasing oxidative stress and decreasing glucose-dependent insulin secretion. CONCLUSION: These results could help to guide nutritional management of obese young individuals, encouraging the increase of ω-3-rich food consumption in order to reduce the likelihood of deterioration of β-cells and the possible development of type 2 diabetes mellitus.

Effect of human umbilical cord-derived mesenchymal stem cells on type 2 diabetic rats and its mechanism / 中华内分泌代谢杂志

Objective To observe the effect of human umbilical cord-derived mesenchymal stem cells (hMSCs) on type 2 diabetic rats, and to explore the possible mechanism. Methods Type 2 diabetic rats were induced by high-fat diet combined with a low dosage of streptozotocin ( STZ, 25 mg/ kg). After 3 × 106 hMSCs suspended in 1 ml PBS or 1ml 10-fold concentrated hMSC supernatant were intravenously infused into the rats via the tail vein, the blood glucose levels were measured every day. One week later, intraperitoneal glucose tolerance test and insulin tolerance test were performed to evaluate the effects of hMSCs on diabetic rats. Pancreatic tissues were collected for insulin/ glucagon immunofluorescence staining. Results After hMSCs infusion, blood glucose level and homeostasis model of assessment for insulin resistance index were significantly decreased in type 2 diabetic rats(both P<0. 01). The glucose tolerance and insulin tolerance were greatly alleviated by hMSCs(all P<0. 01). Intravenously infused 1ml 10-fold concentrated hMSC supernatant showed a similar result to hMSCs. Conclusion In type 2 diabetic rats, hMSCs are able to effectively lower the blood glucose level, improve insulin sensitivity, and increase the number of β cells, which seems to be mediated by their secreted molecules.

Mesenchymal stem cells in diabetes treatment: Progress and perspectives / 解放军医学杂志

Diabetes is a chronic metabolic disorder caused by relative or absolute insulin deficient or reduced sensitivity of target cells to insulin. Mesenchymal stem cells (MSCs) are adult stem cells with multiple differentiation potential, self-renewable and immunoregulatory properties. Accumulating evidences from clinic or animal experiments recent years showed that MSCs infusion could ameliorate hyperglycemia in diabetes. The research progress of MSCs in diabetes treatment is summarized and a corresponding perspective is herewith proposed in present paper.

Comparative effects on type 2 diabetes of mesenchymal stem cells derived from bone marrow and adipose tissue / 解放军医学杂志

Objective To compare the effects on type 2 diabetes of mesenchymal stem cells (MSCs) derived from bone marrow and adipose tissue. Methods Thirty type 2 diabetic rat models were established by an eight weeks high-fat diet (HFD) with a low dose streptozotocin (STZ, 25mg/kg), and randomly assigned into three groups (10 each): diabetes group (T2DM), bone marrow MSCs transplantation group (BMSC) and adipose tissue MSCs transplantation group (ADSC). Ten normal rats were set as control. MSCs were isolated from bone marrow or inguinal adipose tissue of normal rats. One week after STZ injection, 3 106 MSCs suspended in 1ml PBS were infused into rats via tail vein. The blood glucose was measured every day after MSCs transplantation, the intraperitoneal glucose tolerance test (IPGTT) and intraperitoneal insulin tolerance test (IPITT) were performed the 7th day after transplantation to evaluate the effects of MSCs on diabetic rats. Pancreatic tissues were collected for insulin/glucagon immunofluorescence staining. Results After MSCs transplantation, the blood glucose decreased gradually and continuously in type 2 diabetic rats, with glucose tolerance and insulin sensitivity improved greatly. The improved insulin sensitivity was further confirmed by a decreased HOMA-IR (homeostasis model of assessment for insulin resistance) index and increased pancreas islet β-cells (P<0.05). However, no significant differences were observed between BMSC and ADSC group. Conclusion Both BMSC and ADSC have the same effect on type 2 diabetic rats, so the ADSC will be the ideal stem cells for treatment of type 2 diabetes.

Characteristics of plasma glucose and insulin secretion after a glucose load and prediction of islet beta cell function in obese children / 天津医药

Objective To investigate the characteristics of plasma glucose, insulin secretion and changes of insulin resistance (IR) after a glucose load in obese children, and to predict islet β-cell function. Methods A total of 635 obese children were classified into normal glucose tolerance (NGT) group (n=483), impaired glucose regulation (IGR) group (n=112) and type 2 diabetes mellitus (DM) group (n=40) based on their glucose levels. Subjects were also divided into G1 group (23 kg/m2≤BMI<30 kg/m2, n=393) and G2 group (BMI≥30 kg/m2, n=242) based on their different BMI levels. Level of fast plasma glucose (FPG, 0.5 h-PG, 1 h-PG, 2 h-PG and 3 h-PG) and insulin (FINS, 0.5 h-INS, 1 h-INS, 2 h-INS and 3 h-INS) were measured 0 h, 0.5 h, 1 h, 2 h and 3 h after a glucose load. Insulin resistance index (HOMA-IR), whole body insulin sensitivity index (WBISI), function of pancreatic beta-cell (HOMA-β), first-phase insulin secretion index (ΔI30/ΔG30) and area under curve of insulin (AUCI) were calculated and compared between groups. Results The value of insulin at each time point was significantly higher in IGR group than that of NGT group. The values of insulin at 0.5 h, 1 h, and 2 h were significantly lower in DM group than those of IGR group, respectively (all P<0.05). Compared with NGT group, AUCI, HOMA-IR and HOMA-β increased, but WBISI and ΔI30/ΔG30 decreased in IGR group (all P<0.05). HOMA-IR increased but WBISI, HOMA-βandΔI30/ΔG30 decreased in DM group (all P<0.05). Compared with IGR group, AUCI, HOMA-βandΔI30/ΔG30 decreased in DM group (all P<0.05). Values of FINS, AUCI, HOMA-IR, 2h-PG and HOMA-βwere significantly higher in G2 group than those of G1 group, but WBISI decreased (all P<0.05). There were no significant differences in FPG and ΔI30/ΔG30 between these two groups. Conclusion From NGT, IGR to DM, the peak of insulin secretion is postponed, insulin resistance is getting heavier and the compensation of insulin secretion after a glucose load is increased first and then decreased.

The influence of cholecystokinin-octopeptide on oxidative stess in islet beta cells injured by free fat acids / 重庆医学

Objective To observe the effect of cholecystokinin-octopeptide(CCK-8) on oxidative stress and cell proliferation in mice islet β cells (NIT-1 cells) injured by high concentration free fat acids .Methods In vitro cultured NIT-1 cells were divided into 3 groups ,they were control group ,FFAs group (add 0 .25 mmol/mL of oleinic acid + 0 .25 mmol/mL of palmic acid) and CCK-8 group (add FFAs and 1 × 10 - 8 mmol/L of CCK-8 simultaneously) .Cell morphologies were observed ;NIT-1 cells proliferations were detected by M TT method ,and apoptosis rates were measured by flow cytometry ;The levels of T-AOC ,GSH-Px ,CAT ,SOD and MDA in supernatant were also measured .Results There were less cell debris in CCK-8 group than FFAs group(all P< 0 .01) ;the OD570 value of CCK-8 group was significant higher than FFAs group(P< 0 .01) ,and the 72 h CCK-8 group was higher than 48 h CCK-8 group(P< 0 .01) .Compared with FFAs group ,the levels of CAT ,T-AOC ,SOD and GSH-Px in CCK-8 group were in-creased and the concentration of MDA was decreased obviously(P< 0 .05) ,the levels of CAT ,SOD in 72 h CCK-8 group were high-er than 48 h CCK-8 group ,MDA was lower than 48 h CCK-8 group(P< 0 .05) .Conclusion CCK-8 could protect islet β cells injury from FFAs through anti-oxidative stress mechanism and promote NIT-1 cells proliferation .

Hyperinsulinemic Hypoglycemia in Infancy: Current Concepts in Diagnosis and Management.

Purpose: Molecular basis of various forms of hyperinsulinemic hypoglycemia, involving defects in key genes regulating insulin secretion, are being increasingly reported. However, the management of medically unresponsive hyperinsulinism still remains a challenge as current facilities for genetic diagnosis and appropriate imaging are limited only to very few centers in the world. We aim to provide an overview of spectrum of clinical presentation, diagnosis and management of hyperinsulinism. Methods: We searched the Cochrane library, MEDLINE and EMBASE databases, and reference lists of identified studies. Conclusions: Analysis of blood samples, collected at the time of hypoglycemic episodes, for intermediary metabolites and hormones is critical for diagnosis and treatment. Increased awareness among clinicians about infants “at-risk” of hypoglycemia, and recent advances in genetic diagnosis have made remarkable contribution to the diagnosis and management of hyperinsulinism. Newer drugs like lanreotide (long acting somatostatin analogue) and sirolimus (mammalian target of rapamycin (mTOR) inhibitor) appears promising as patients with diffuse disease can be treated successfully without subtotal pancreatectomy, minimizing the long-term sequelae of diabetes and pancreatic insufficiency. Newer insights in understanding the molecular and histological basis and improvements in imaging and surgical techniques will modify the approach to patients with congenital hyperinsulinism.