Alterations of the Ca2＋ signaling pathway in pancreatic beta-cells isolated from db/db mice

Upon glucose elevation, pancreatic beta-cells secrete insulin in a Ca2＋-dependent manner. In diabetic animal models, different aspects of the calcium signaling path- way in beta-cells are altered, but there is no consensus regarding their relative contributions to the development of beta-cell dysfunction. In this study, we compared the increase in cytosolic Ca2＊ （[Ca2＊]~） via Ca2＋ influx, Ca2＊ mobilization from endoplasmic reticulum （ER） calcium stores, and the removal of Ca2＋ via multiple mechanisms in beta-cells from both diabetic db/db mice and non- diabetic C57BL/6J mice. We refined our previous quan- titative model to describe the slow [Ca2＋]i recovery after depolarization in beta-cells from db/db mice. According to the model, the activity levels of the two subtypes of the sarco-endoplasmic reticulum Ca2＋-ATPase （SERCA） pump, SERCA2 and SERCA3, were severely down-reg- ulated in diabetic cells to 65% and 0% of the levels in normal cells. This down-regulation may lead to a reduc- tion in the Ca2＋ concentration in the ER, a compensatory up-regulation of the plasma membrane Na＋/Ca2＋ exchanger （NCX） and a reduction in depolarizationevoked Ca2＋ influx. As a result, the patterns of glucosestimulated calcium oscillations were significantly different in db/db diabetic beta-cells compared with normal cells. Overall, quantifying the changes in the calcium signaling pathway in db/db diabetic beta-cells will aid in the development of a disease model that could provide insight into the adaptive transformations of beta-cell function during diabetes development.

Exploring the genetic basis of childhood monogenic diabetes

Monogenic diabetes is caused by one or even more genetic variations,which may be uncommon yet have a significant influence and cause diabetes at an early age.Monogenic diabetes affects 1%to 5%of children,and early detection and genetically focused treatment of neonatal diabetes and maturity-onset diabetes of the young can significantly improve long-term health and well-being.The etiology of monogenic diabetes in childhood is primarily attributed to genetic variations affecting the regulatory genes responsible for beta-cell activity.In rare instances,mutations leading to severe insulin resistance can also result in the development of diabetes.Individuals diagnosed with specific types of monogenic diabetes,which are commonly found,can transition from insulin therapy to sulfonylureas,provided they maintain consistent regulation of their blood glucose levels.Scientists have successfully devised materials and methodologies to distinguish individuals with type 1 or 2 diabetes from those more prone to monogenic diabetes.Genetic screening with appropriate findings and interpretations is essential to establish a prognosis and to guide the choice of therapies and management of these interrelated ailments.This review aims to design a comprehensive literature summarizing genetic insights into monogenetic diabetes in children and adolescents as well as summarizing their diagnosis and management.

Relationship between Free Thyroxine and Islet Beta-cell Function in Euthyroid Subjects

Thyroid hormones have a specific effect on glucose-induced insulin secretion from the pancreas.We aimed to investigate the association between euthyroid hormones and islet betacell function in general population and non-treated type 2 diabetes mellitus(T2DM)patients.A total of 5089 euthyroid participants(including 4601 general population and 488 non-treated T2DM patients)were identified from a cross-sectional survey on the prevalence of metabolic diseases and risk factors in East China from February 2014 to June 2016.Anthropometric indices,biochemical parameters,and thyroid hormones were measured.Compared with general population,non-treated T2DM patients exhibited higher total thyroxine(TT4)and free thyroxine(FT4)levels but lower ratio of free triiodothyronine(T3):T4(P<0.01).HOMA-βhad prominently negative correlation with FT4 and positive relationship with free T3:T4 in both groups even after adjusting for age,body mass index(BMI)and smoking.When analyzed by quartiles of FT4 or free T3:T4,there were significantly decreased trend of HOMA-β going with the higher FT4 and lower free T3:T4 in both groups.Linear regression analysis showed that FT4 but not FT3 and free T3:T4 was negatively associated with HOMA-β no matter in general population or T2DM patients,which was independent of age,BMI,smoking,hypertension and lipid profiles.FT4 is independently and negatively associated with islet beta-cell function in euthyroid subjects.Thyroid hormone even in reference range could play an important role in the function of pancreatic islets.

Antioxidant,anti-alpha-glucosidase and pancreatic beta-cell protective effects of methanolic extract of Ensete superbum Cheesm seeds

Objective: To investigate the antioxidant, anti-a-glucosidase and pancreatic b-cell protective potential of Ensete superbum(E. superbum) seeds.Methods: A variety of in vitro assays including radical scavenging, reducing power potential, phenolic content determination, a-glucosidase assay and pancreatic b-cell(1.4E7 cells) viability were employed for assessing the effect of methanolic extract of E. superbum seeds.Results: The radical scavenging and reducing power effects comparable with the standard rutin were obtained while the enzyme inhibitory activity of the extract was 68-fold better than the standard antidiabetic drug, acarbose. The seed extract of E. superbum was packed-full of polyphenols with mean percentage gallic acid equivalent value of(38.2 ± 1.8)(n = 3). The protection of pancreatic cells from massive onslaught of hydrogen peroxide was far superior to that obtained for rutin.Conclusions: The reputed antidiabetic therapeutic uses of the seeds extract of E. superbum may be justified on the basis of inhibition of carbohydrate enzymes, antioxidant effects and pancreatic b-cell protection.

Genetic perspectives on childhood monogenic diabetes:Diagnosis,management,and future directions

Monogenic diabetes is caused by one or even more genetic variations, which maybe uncommon yet have a significant influence and cause diabetes at an early age.Monogenic diabetes affects 1 to 5% of children, and early detection and geneticallyfocused treatment of neonatal diabetes and maturity-onset diabetes of theyoung can significantly improve long-term health and well-being. The etiology ofmonogenic diabetes in childhood is primarily attributed to genetic variationsaffecting the regulatory genes responsible for beta-cell activity. In rare instances,mutations leading to severe insulin resistance can also result in the developmentof diabetes. Individuals diagnosed with specific types of monogenic diabetes,which are commonly found, can transition from insulin therapy to sulfonylureas,provided they maintain consistent regulation of their blood glucose levels.Scientists have successfully devised materials and methodologies to distinguishindividuals with type 1 or 2 diabetes from those more prone to monogenicdiabetes. Genetic screening with appropriate findings and interpretations isessential to establish a prognosis and to guide the choice of therapies andmanagement of these interrelated ailments. This review aims to design a comprehensiveliterature summarizing genetic insights into monogenetic diabetes inchildren and adolescents as well as summarizing their diagnosis and management.

Adipose stem cell-based regenerative medicine for reversal of diabetic hyperglycemia

Diabetes mellitus(diabetes) is a devastating disease that affects millions of people globally and causes a myriad of complications that lead to both patient morbidity and mortality. Currently available therapies, including insulin injection and beta cell replacement through either pancreas or pancreatic islet transplantation, are limited by the availability of organs. Stem cells provide an alternative treatment option for beta cell replacement through selective differentiation of stem cells into cells that recognize glucose and produce and secrete insulin. Embryonic stem cells, albeit pluripotent, face a number of challenges, including ethical and political concerns and potential teratoma formation. Adipose tissue represents an alternative source of multipotent mesenchymal stem cells, which can be obtained using a relatively simple, non-invasive, and inexpensive method. Similarly to other adult mesenchymal stem cells, adipose-derived stem cells(ADSCs) are capable of differentiating into insulin-producing cells. They are also capable of vasculogenesis and angiogenesis, which facilitate engraftment of donor pancreatic islets when co-transplanted. Additionally, anti-inflammatory and immunomodulatory effects of ADSCs can protect donorislets during the early phase of transplantation and subsequently improve engraftment of donor islets into the recipient organ. Although ADSC-therapy is still in its infancy, the potential benefits of ADSCs are far reaching.

Intra-islet endothelial cell and β-cell crosstalk: Implication for islet cell transplantation

The intra-islet microvasculature is a critical interface between the blood and islet endocrine cells governing a number of cellular and pathophysiological processes associated with the pancreatic tissue. A growing body of evidence indicates a strong functional and physical interdependency of β-cells with endothelial cells(ECs), the building blocks of islet microvasculature. Intra-islet ECs, actively regulate vascular permeability and appear to play a role in fine-tuning blood glucose sensing and regulation. These cells also tend to behave as "guardians", controlling the expression and movement of a number of important immune mediators, thereby strongly contributing to the physiology of islets. This review will focus on the molecular signalling and crosstalk between the intra-islet ECs and β-cells and how their relationship can be a potential target for intervention strategies in islet pathology and islet transplantation.

Mathematical Model for the Dynamics of Glucose, Insulin and β-Cell Mass under the Effect of Trauma, Excitement and Stress

In this work, we presented a mathematical model for the dynamics of glucose, insulin and beta-cell mass under the influence of trauma, excitement and/or stress, the model is an improvement on the work by?[1]. We defined and incorporated a parameter??to represent the effectiveness of epinephrine in suppressing insulin secretion and a parameter?Ge?representing epinephrine induced glucose increase as the factors that affect glucose and insulin homeostasis. The model which consists of a system of three nonlinear ordinary differential equations was used to investigate the effect of epinephrine on glucose, insulin and beta-cell mass dynamics. The result of the study showed that;In the presence of epinephrine, the blood glucose increased and the blood insulin decreased due to suppression by the hormone, despite the fact that there is an increase in beta-cell mass the system remained extremely hyperglycemic. Furthermore, the result of the numerical experiment carried out indicated that frequent epinephrine secretion into the blood induced prolong and extreme hyperglycemia. Frequent epinephrine secretion increases the risk of diabetes in humans. In view of the findings of this study, we recommend that there should be massive and continuous health education, especially for communities living in the areas where the stated agents (trauma, excitement and stress) of epinephrine secretion are common.

Pancreatic fat and β-cell function in overweight/obese children with nonalcoholic fatty liver disease

AIM: To analyze the associations of pancreatic fat with other fat depots and β-cell function in pediatric nonalcoholic fatty liver disease(NAFLD).METHODS: We examined 158 overweight/obese children and adolescents, 80 with NAFLD [hepatic fat fraction(HFF) ≥ 5%] and 78 without fatty liver. Visceral adipose tissue(VAT), pancreatic fat fraction(PFF) and HFF were determined by magnetic resonance imaging. Estimates of insulin sensitivity were calculated using the homeostasis model assessment of insulin resistance(HOMA-IR), defined by fasting insulin and fasting glucose and whole-body insulin sensitivity index(WBISI), based on mean values of insulin and glucose obtained from oral glucose tolerance test and the corresponding fasting values. Patients were considered to have prediabetes if they had either:(1) impaired fasting glucose, defined as a fasting glucose level ≥ 100 mg/d L to < 126 mg/d L;(2) impaired glucose tolerance, defined as a 2 h glucose concentration between ≥ 140 mg/d L and < 200 mg/d L; or(3) hemoglobin A1 c value of ≥ 5.7% to < 6.5%.RESULTS: PFF was significantly higher in NAFLD patients compared with subjects without liver involvement. PFF was significantly associated with HFF and VAT, as well as fasting insulin, C peptide, HOMA-IR, and WBISI. The association between PFF and HFF was no longer significant after adjusting for age, gender, Tanner stage, body mass index(BMI)-SD score, and VAT. In multiple regression analysis withWBISI or HOMA-IR as the dependent variables, against the covariates age, gender, Tanner stage, BMI-SD score, VAT, PFF, and HFF, the only variable significantly associated with WBISI(standardized coefficient B,-0.398; P = 0.001) as well as HOMA-IR(0.353; P = 0.003) was HFF. Children with prediabetes had higher PFF and HFF than those without. PFF and HFF were significantly associated with prediabetes after adjustment for clinical variables. When all fat depots where included in the same model, only HFF remained significantly associated with prediabetes(OR = 3.38; 95%CI: 1.10-10.4; P = 0.034).CONCLUSION: In overweight/obese children with NAFLD, pancreatic fat is increased compared with those without liver involvement. However, only liver fat is independently related to prediabetes.

Islet cell dysfunction in patients with chronic pancreatitis

Chronic pancreatitis(CP)is characterized by progressive inflammation and fibrosis of the pancreas that eventually leads to pancreatic exocrine and endocrine insufficiency.Diabetes in the background of CP is very difficult to manage due to high glycemic variability and concomitant malabsorption.Progressive beta cell loss leading to insulin deficiency is the cardinal mechanism underlying diabetes development in CP.Alpha cell dysfunction leading to deranged glucagon secretion has been described in different studies using a variety of stimuli in CP.However,the emerging evidence is varied probably because of dependence on the study procedure,the study population as well as on the stage of the disease.The mechanism behind islet cell dysfunction in CP is multifactorial.The intra-islet alpha and beta cell regulation of each other is often lost.Moreover,secretion of the incretin hormones such as glucagon like peptide-1 and glucose-dependent insulinotropic polypeptide is dysregulated.This significantly contributes to islet cell disturbances.Persistent and progressive inflammation with changes in the function of other cells such as islet delta cells and pancreatic polypeptide cells are also implicated in CP.In addition,the different surgical procedures performed in patients with CP and antihyperglycemic drugs used to treat diabetes associated with CP also affect islet cell function.Hence,different factors such as chronic inflammation,dysregulated incretin axis,surgical interventions and anti-diabetic drugs all affect islet cell function in patients with CP.Newer therapies targeting alpha cell function and beta cell regeneration would be useful in the management of pancreatic diabetes in the near future.

Long-term case study of a Wuzhishan miniature pig with diabetes

Background:Miniature pigs are attractive animal models for exploring diabetes because they are similar to humans in terms of physiological structure and metabolism.However,little is known about the complications of diabetes in pigs.Methods:In this study,a 28-month observation of a Wuzhishan miniature pig with streptozotocin(STZ)-induced(120 mg/kg)diabetes was conducted,to investigate diabetes-related complications and the possibility of self-recovery in miniature pigs.Blood glucose,serum and urinary biochemistry was measured,and histopathologic examinations of eyes,kidney and pancreas were made.Results:During the observation,diabetic complications of eyes and kidney were observed.The eye complications included bilateral cataracts in the 15th month and degeneration of inner retina and microaneurysm in the 28th month.Kidney complications included glomerular mesangial expansion,focal segmental glomerular sclerosis,and renal tubular epithelial degeneration,but no proteinuria was observed.By 28 months after the application of STZ,with no treatment given,blood glucose had recovered and the number of pancreatic islet beta-cells had increased significantly.Conclusions:We showed that the STZ-induced diabetes model in miniature pigs could accurately mimic the pathological changes of human diabetes,and that pancreatic islet beta-cell regeneration did occur in an adult miniature pig,providing a new means for exploring diabetic complications and pancreatic islet beta-cell regeneration.

Pancreatic fat and β-cell function in overweight/obesechildren with nonalcoholic fatty liver disease

AIM: To analyze the associations of pancreatic fat with other fat depots and β-cell function in pediatric nonalcoholic fatty liver disease(NAFLD).METHODS: We examined 158 overweight/obese children and adolescents, 80 with NAFLD [hepatic fat fraction(HFF) ≥ 5%] and 78 without fatty liver. Visceral adipose tissue(VAT), pancreatic fat fraction(PFF) and HFF were determined by magnetic resonance imaging. Estimates of insulin sensitivity were calculated using the homeostasis model assessment of insulin resistance(HOMA-IR), defined by fasting insulin and fasting glucose and whole-body insulin sensitivity index(WBISI), based on mean values of insulin and glucose obtained from oral glucose tolerance test and the corresponding fasting values. Patients were considered to have prediabetes if they had either:(1) impaired fasting glucose, defined as a fasting glucose level ≥ 100 mg/d L to < 126 mg/d L;(2) impaired glucose tolerance, defined as a 2 h glucose concentration between ≥ 140 mg/d L and < 200 mg/d L; or(3) hemoglobin A1 c value of ≥ 5.7% to < 6.5%.RESULTS: PFF was significantly higher in NAFLD patients compared with subjects without liver involvement. PFF was significantly associated with HFF and VAT, as well as fasting insulin, C peptide, HOMA-IR, and WBISI. The association between PFF and HFF was no longer significant after adjusting for age, gender, Tanner stage, body mass index(BMI)-SD score, and VAT. In multiple regression analysis withWBISI or HOMA-IR as the dependent variables, against the covariates age, gender, Tanner stage, BMI-SD score, VAT, PFF, and HFF, the only variable significantly associated with WBISI(standardized coefficient B,-0.398; P = 0.001) as well as HOMA-IR(0.353; P = 0.003) was HFF. Children with prediabetes had higher PFF and HFF than those without. PFF and HFF were significantly associated with prediabetes after adjustment for clinical variables. When all fat depots where included in the same model, only HFF remained significantly associated with prediabetes(OR = 3.38; 95%CI: 1.10-10.4; P = 0.034).CONCLUSION: In overweight/obese children with NAFLD, pancreatic fat is increased compared with those without liver involvement. However, only liver fat is independently related to prediabetes.

Effect of Frey's procedure on islet cell function in patients with chronic calcific pancreatitis

Background: Frey’s procedure involves both drainage and resection of the pancreas in subjects with chronic calcific pancreatitis(CCP). The procedure may affect the pancreatic endocrine function after surgery. The present study was to evaluate the effect of Frey’s procedure on both beta and alpha cell function in CCP patients.Methods: Thirty CCP patients who underwent Frey’s procedure were included. According to the glycemic status, patients were divided into the diabetes mellitus(DM), prediabetes, and normal glucose tolerance(NGT) groups. Islet cell function was assessed before and 3 months after surgery.Results: At baseline, there was a significant difference in beta cell function among the three groups [NGT group 1.71(1.64–2.07) vs prediabetes group1.50(0.83–1.61) vs DM group 0.33(0.12–0.55), P < 0.0001], but the insulin resistance was not different among them. Post glucose hyperglucagonemia representing alphacell dysfunction during oral glucose tolerance test was present in all of them, but showed no significant difference [NGT group 0.15(0.06–0.31) vs prediabetes group 0.32(0.05–0.70) vs DM group 0.07(0.02–0.18), P = 0.20]. Frey’s procedure did not change beta cell function and insulin resistance. However, alphacell dysfunction deteriorated after surgery [0.10(0.03–0.27) vs 0.33(0.09–0.68), P = 0.004].Conclusions: Although Frey’s procedure does not affect the beta cell function and insulin resistance in CCP patients, the alpha-cell dysfunction deteriorates after surgery.

Metabolically healthy obesity:Is it really healthy for type 2 diabetes mellitus?

Metabolically healthy obese(MHO)individuals are reported to have a lower risk of developing cardiovascular diseases in comparison with individuals with metabolic syndrome.However,the association between MHO and type 2 diabetes(T2DM)is still controversial.Some studies indicated that MHO is a favorable phenotype for T2DM,but more studies showed that MHO individuals have an increased risk of developing T2DM compared with metabolically healthy normalweight individuals,especially among those who would acquire metabolically unhealthy obesity.This has been supported by finding insulin resistance and lowgrade inflammatory responses in MHO individuals with a tendency for impaired beta-cell dysfunction.Studies also showed that liver fat accumulation increased the risk of incidence of T2DM in MHO.Here,we reviewed current literature on the relationship between MHO and T2DM,discussed the determinants for the development of diabetes in MHO,and summarized the measures for the prevention of T2DM in MHO.

Autophagy induced by glibenclamide serves as a defense against apoptosis in INS-1 rat insulinoma cells

Glibenclamide, a blocker of ATP-sensitive potassium channels, has been found to induce apoptosis in some cell types, including pancreatic beta-cells. Since autophagy plays doubleedged roles in pancreatic beta-cell survival, frequently through cross-talking with apoptosis, we investigated if glibenclamide induced autophagy in INS-1 rat insulinoma cells and the influence of autophagy on apoptosis. Mammalian target of rapamycin (mTOR) is a negative regulator of autophagy. As one of the substrates of mTOR, p70 S6 kinase (p70 S6K) is phosphorylated upon mTOR activation. Our results showed that glibenclamide induced an elevated protein level of the autophagy marker LC3-II, while decreasing phosphorylated p70 S6K, indicative of inhibition on mTOR signaling in INS-1 cells. Furthermore, inhibiting glibenclamide-induced autophagy via knocking down the autophagy essential gene Atg7 decreased cell viability and increased apoptosis in INS-1 cells. Our results indicate that glibenclamide induces autophagy in INS-1 cells, and that autophagy activation is exerting a protective activity against apoptosis.

Beta-cell dysfunction is the primary contributor to the early postpartum diabetes among Chinese women with history of gestational diabetes mellitus

Background Women with a history of gestational diabetes mellitus （GDM） are at higher risk of future development of diabetes. This study investigated the risk factors associated with early postpartum abnormal glucose regulation （AGR） among Chinese women with a history of GDM. Methods A total of 186 women with a history of GDM were screened for early postpartum AGR at 6-8 weeks after delivery. Those with AGR were given lifestyle intervention therapy and reevaluated in 6-12 months. The demographic, anthropometric, prenatal and delivery data were recorded. The plasma high-sensitivity C-reactive protein （HsCRP） and lipid concentration were measured, and insulin secretion were analyzed. Insulinogenic index △ins30＇/△BG30＇, the homeostasis model assessment index （HOMA）-B, and HOMA-IR were calculated. Multiple regression analysis was performed to identify the risk factors. Results Of the GDM women 28.0% （52/186） had AGR at 6-8 weeks after delivery; 45.2% （17/40） of these AGR women reminded abnormal after 6-12 month lifestyle intervention. Compared to the women who reverted to normal, women with consistent AGR showed significantly lower fasting insulin concentration, lower △ins30＇/△BG30＇ as well as lower HOMA-B. No significant differences in age, body mass index （BMI）, waist circumference, blood pressure, lipid level HsCRP and HOMA-IR were observed between the two groups. Pre-pregnancy BMI ≥25 kg/m^2, fasting glucose level ≥5.6 mmol/L and/or 75 g oral glucose tolerance test （OGTT） 2 hours glucose level ≥11.1 mmol/L during pregnancy were predictors for the AGR at 6-8 weeks after delivery. △ins30＇/△BG30≤1.05 was a significant risk contributor to the consistent early postpartum AGR. Conclusion There is a high incidence of early postpartum AGR among Chinese woman with prior GDM. Beta-cell dysfunction, rather than insulin resistance or inflammation, is the predominant contributor to the early onset and consistent AGR after delivery.

Associations of insulin resistance and beta-cell function with abnormal lipid profile in newly diagnosed diabetes

Background:Abnormal lipids are strong predictors of cardiovascular disease in type 1 diabetes mellitus(T1DM)and type 2 diabetes mellitus(T2DM).However,the potential associations of insulin resistance(IR)and beta-cell function(BCF)with abnormal lipids in newly diagnosed T1DM or T2DM patients are not fully understood.Methods:A cross-sectional survey of 15,928 participants was conducted.Homeostasis model assessment and postprandial C-peptide levels were used to estimate IR and BCF.A restricted cubic spline(RCS)nested in binary logistic regression was used to examine the associations of IR and BCF with abnormal lipids.Results:High triglyceride(TG),low high-density lipoprotein cholesterol,and high low-density lipoprotein cholesterol(LDL-C)accounted for 49.7%,47.8%,and 59.2%of the participants,respectively.In multivariable analysis,high IR was associated with an increased risk of high TGs(P for trend<0.001)in T1DM and is associated with an elevated risk of high TG and low HDL-C(all P for trend<0.01)in T2DM.Low BCF was not associated with risks of dyslipidemia in patients with T1DM or T2DM after adjustment for potential confounders.Conclusion:High IR had different associations with the risk of dyslipidemia in newly diagnosed T1DM and T2DM patients,suggesting that early treatment that improves IR may benefit abnormal lipid metabolism.

Effects of Chinese medicine Tongxinluo on hyperglycemia and beta-cell damage in streptozotocin-induced diabetic rats

Background Oxidative stress has been implicated in the onset and progression of diabetes. Tongxinluo is a traditional Chinese medicine with potent antioxidant properties. The aim of this study was to test the hypothesis that pretreatment with Tongxinluo has similar effects as melatonin on preventing hyperglycemia and beta-cell damage in a rat model of streptozotocin （STZ）-induced diabetes. Methods Forty male Sprague Dawley rats were randomly assigned to four groups （n=10 each）： normal control （NC） group; STZ group （70 mg/kg, i.p.）; Tongxinluo （1.0 g-kg-^-d-1） pretreated （TXL＋STZ） group and melatonin （200 iJg-kg-~.d-1） pretreated （MLT＋STZ） group. Tongxinluo and melatonin were administered by gavage beginning 8 days before STZ injection and continuing until the end of the study （15 days after STZ administration）. Blood glucose levels and body weights, malondialdehyde （MDA）, and reduced glutathione （GSH） levels were measured, and immunofluorescence studies were performed in all of the groups. Results Pretreatment with Tongxinluo, as with melatonin, attenuated severe hyperglycemia and weight loss induced by STZ.. In pancreatic homogenates, MDA levels were significantly lower and GSH levels were significantly higher in Tongxinluo pretreated group and in melatonin pretreated group than those in STZ group. Values of insulin staining were significantly improved in Tongxinluo pretreated group and in melatonin pretreated group as compared with those in STZ group. Conclusions Tongxinluo, as melatonin, prevented hyperglycemia and beta-cell destruction induced by STZ in rats through reducing oxidative stress in pancreatic tissues. Tongxinluo may provide an alternative therapy for the prevention and treatment of diabetes.

Liraglutide prevents high glucose level induced insulinoma cells apoptosis by targeting autophagy

Background The pathophysiology of type 2 diabetes is progressive pancreatic beta cell failure with consequential reduced insulin secretion. Glucotoxicity results in the reduction of beta cell mass in type 2 diabetes by inducing apoptosis. Autophagy is essential for the maintenance of normal islet architecture and plays a crucial role in maintaining the intracellular insulin content by accelerating the insulin degradation rate in beta cells. Recently more attention has been paid to the effect of autophagy in type 2 diabetes. The regulatory pathway of autophagy in controlling pancreatic beta cells is still not clear. The aim of our study was to evaluate whether liraglutide can inhibit apoptosis and modulate autophagy in vitro in insulinoma cells （INS-1 cells）. Methods INS-1 cells were incubated for 24 hours in the presence or absence of high levels of glucose, liraglutide （a long-acting human glucagon-like peptide-1 analogue）, or 3-methyadenine （3-MA）. Cell viability was measured using the Cell Counting Kit-8 （CCK8） viability assay. Autophagy of INS-1 cells was tested by monodansylcadaverine （MDC） staining, an autophagy fluorescent compound used for the labeling of autophagic vacuoles, and by Western blotting of microtubule-associated protein I light chain 3 （LC3）, a biochemical markers of autophagic initiation. Results The viability of INS-1 cells was reduced after treatment with high levels of glucose. The viability of INS-1 cells was reduced and apoptosis was increased when autophagy was inhibited. The viability of INS-1 cells was significantly increased by adding liraglutide to supplement high glucose level medium compared with the cells treated with high glucose levels alone. Conclusions Apoptosis and autophagy were increased in rat INS-1 cells when treated with high level of glucose, and the viability of INS-1 cells was significantly reduced by inhibiting autophagy. Liraglutide protected INS-1 cells from high glucose level-induced apoptosis that is accompanied by a significant increase of autophagy, suggesting that liraglutide plays a role in beta cell apoptosis by targeting autophagy. Thus, autophagy may be a new target for the prevention or treatment of diabetes.

The involvement of interleukin-22 in the expression of pancreatic beta cell regenerative Reg genes

Background:In Type 1 diabetes,the insulin-producingβ-cells within the pancreatic islets of Langerhans are destroyed.We showed previously that immunotherapy with Bacillus Calmette-Guerin(BCG)or complete Freund’s adjuvant(CFA)of non-obese diabetic(NOD)mice can prevent disease process and pancreaticβ-cell loss.This was associated with increased islet Regenerating(Reg)genes expression,and elevated IL-22-producing Th17 T-cells in the pancreas.Results:We hypothesized that IL-22 was responsible for the increased Reg gene expression in the pancreas.We therefore quantified the Reg1,Reg2,and Reg3δ(INGAP)mRNA expression in isolated pre-diabetic NOD islets treated with IL-22.We measured IL-22,and IL-22 receptor(R)-αmRNA expression in the pancreas and spleen of pre-diabetic and diabetic NOD mice.Our results showed:1)Reg1 and Reg2 mRNA abundance to be significantly increased in IL-22-treated islets in vitro;2)IL-22 mRNA expression in the pre-diabetic mouse pancreas increased with time following CFA treatment;3)a reduced expression of IL-22Rαfollowing CFA treatment;4)a down-regulation in Reg1 and Reg2 mRNA expression in the pancreas of pre-diabetic mice injected with an IL-22 neutralizing antibody;and 5)an increased isletβ-cell DNA synthesis in vitro in the presence of IL-22.Conclusions:We conclude that IL-22 may contribute to the regeneration ofβ-cells by up-regulating Regenerating Reg1 and Reg2 genes in the islets.