Family history of diabetes mellitus determines insulin sensitivity and beta cell function in polycystic ovary syndrome

Objective: To examine the impact of family history of diabetes mellitus 2 (DM 2) on insulin sensitivity and secretion in lean women with polycystic ovary syndrome (PCOS). Thirteen healthy women (C), 14 PCOS without family history of DM 2 (FH-) and 8 PCOS with family history of DM 2 (FH+) were examined using euglycemic hyperinsulinemic clamp and an arginine secretion test (insulin and glucagon at fasting glycemia (AIR(FG) and AGR(FG)) and at hyperglycemia (AIR(14) and AGR(14)). FH+ women were more insulin resistant than FH- with lower insulin sensitivity index corrected per lean body mass (p 0.05). They had significantly higher triglycerides (p 0.05) and lower HDL-cholesterol (p 0.05) than C or FH- women. Concerning insulin secretion, AIR(FG) was increased in FH+ women comparing FH- women (p 0.05). Disposition indices derived from AIR(FG) or AIR(14) and insulin sensitivity index did not differ between FH+ or FH-. Thus, women with PCOS with the concomitant family history of DM 2 have lower insulin sensitivity than healthy control women. Insulin resistance observed in these women with PCOS is compensated by increased insulin secretion.     

Randomised prospective study for the effect of therapy on residual beta cell function in type-1 diabetes mellitus [ISRCTN70703138]

BACKGROUND: Newly diagnosed insulin-dependent diabetes mellitus is characterised by a temporary recovery of endogeneous insulin ("remission") after the beginning of medical treatment with subcutaneous insulin injections. Although most diabetologists think, that insulin reserve is related to reduced occurrence of diabetic long-term complications, such as eye, nerve and kidney disease, there is only one prospective controlled clinical study (the DCCT) addressing this question, however as secondary hypothesis. METHODS/DESIGN: Therefore, we composed a trial consisting of two cohorts with two therapeutic options within each cohort (conventional versus intensive therapy) and a three-year follow-up. In one group the patients are randomly assigned to the treatment regimes to test the statistical alternative hypothesis if variable insulin dosage is superior to fixed insulin injection in preserving insulin reserve measured by C-peptide in serum. Another group includes patients who prefer one of the two therapies, decline randomisation, but consent to follow-up. Apart from the determination of insulin reserve as a biological parameter a second primary endpoint was defined as 'therapeutic failure' according to the criteria of the European Association for the Study of Diabetes. Patients pass a training program to help them self-manage diabetes. A standardised protocol is being set up to minimize centre effects and bias of health care providers. Potential patient dependent bias will be investigated by questionnaires measuring psychic coping processes of people with diabetes. Management of visit dates is directly navigated by the database. Automated visit-reminders are mailed to patients and caregivers to optimise the number of visits on schedule. Data quality is regularly monitored and centres are informed on the results of continuous data management.     

Pancreatic beta cell allotransplant in double transgenic mouse model of type 1 diabetes mellitus

The purpose of this study was to evaluate the therapeutic response to intra-hepatic and intra-portal allotransplant with pancreatic beta cells in double transgenic mice (dTg) with autoimmune diabetes. The results showed an improvement in metabolic and somatic parameters and an increase in survival rate. Histopathology analysis revealed the presence of transplanted islets and the absence of the inflammatory infiltrate 5 days after the procedure and an increase in insulinemia. In the absence of immunosuppressive drugs, rejection of the transplanted islet seems to appear after 10 weeks, being marked by an increase in blood glucose level. A re-transplantation was performed in one mouse of each group and the glycemia levels recorded after the second transplant were less successful.     

Riboflavin metabolism in diabetes mellitus]

Riboflavin excretion with urine in children suffering from diabetes mellitus is found to be significantly higher in comparison with healthy adults, the riboflavin content in the serum being normal. The total riboflavin concentration in erythrocytes is substantially lower and administration of daily-required riboflavin doses does not increase this parameter. FAD-dependent glutathione reductase in erythrocyte hemolysates is approximately 1.5 times higher than that of healthy children and does not depend on the additional intake of polyvitamins. The seeming affinity of the enzyme with exogenous FAD in sick children is almost 40 times lower in comparison with this value in healthy children, that is why the FAD-effect value in diabetes mellitus children does not exceed 1.2. Peculiarities of the riboflavin metabolism at diabetes mellitus and possibility to use the investigated parameters as criteria of vitamin B2 supply are discussed.     

利拉鲁肽联合二甲双胍对2型糖尿病合并肥胖患者胰岛β细胞功能以及内脏脂肪水平的影响

目的分析利拉鲁肽联合二甲双胍对2型糖尿病（T2DM）合并肥胖患者胰岛β细胞功能以及内脏脂肪水平的影响。 方法选取重庆两江新区第一人民医院2016年3月至2018年3月收治的194例T2DM合并肥胖患者,将其随机分为研究组、对照组,各97例,均给予为期16周的二甲双胍治疗,研究组加用利拉鲁肽皮下注射。比较两组患者治疗前后血糖、胰岛β细胞功能指数（HOMA-β）、内脏脂肪水平（VFL）等指标变化,总结利拉鲁肽在T2DM合并肥胖治疗中的临床价值。计数资料采用卡方检验,计量资料采用t检验。 结果研究组不良反应发生率为29.90﹪,对照组为23.71﹪,组间比较差异无统计学意义（χ²= 0.946,P > 0.05）。两组患者治疗后FPG、2 hPG、BMI均较治疗前下降,研究组治疗后FPG、2 hPG、BMI分别为（7.12±1.35）?mmol/?L、（9.03±2.66）?mmol/L、（26.32±1.60）kg/m²,均低于对照组的（7.83± 1.19）?mmol/L、（10.57±2.39）?mmol/?L、（27.74±1.66）kg/m²,差异有统计学意义（t = 3.886、4.241、6.066,P均?< 0.05）。两组患者治疗后HOMA-β较治疗前升高,HOMA-IR较治疗前下降,研究组治疗后HOMA-β为155.69±24.55,高于对照组的117.49±21.98,其HOMA-IR为2.30±0.71,低于后者的3.20±0.64,差异有统计学意义（t = 11.407、9.273,P均< 0.05）。两组患者治疗后VFL、脂肪率均较治疗前下降,研究组治疗后VFL、脂肪率低于对照组,且其治疗后肌肉含量较治疗前下降,差异有统计学意义（P < 0.05）。 结论在二甲双胍的基础上联合利拉鲁肽能够通过改善胰岛β细胞功能、减少内脏脂肪,达到改善T2DM合并肥胖患者的胰岛素抵抗的目的,是一种安全、有效的治疗方案。     

Red cell peroxide metabolism in diabetes mellitus

In a group of normal controls and in a group of diabetics subdivided for type we evaluated the following red blood cell parameters: superoxide dismutase (SOD), glutathione peroxidase (GSH.Px), catalase (C-ase), glutathione content (GSH) and membrane-protein-sulphydryl groups (P-SH). There was no difference in the enzymatic activities of superoxide dismutase, glutathione peroxidase and catalase in normals and in the diabetics. However, the erythrocyte GSH content as well as membrane P-SH groups discriminate the normals from diabetics and also the diabetics subdivided for type. None of these parameters was related to the erythrocyte filterability considered as a reflection of the red blood cell deformability. These findings reveal that the diabetic red blood cell is less protected from oxidant agents.     

Depressed cardiac myofilament function in human diabetes mellitus

Diabetes mellitus is associated with a distinct cardiomyopathy. Whether cardiac myofilament function is altered in human diabetes mellitus is unknown. Myocardial biopsies were obtained from seven diabetic patients and five control, nondiabetic patients undergoing coronary artery bypass surgery. Myofilament function was assessed by determination of the developed force-Ca2+ concentration relation in skinned cardiac cells from flash-frozen human biopsies. Separate control experiments revealed that flash freezing of biopsy specimens did not affect myofilament function. All patients in the diabetes mellitus cohort were classified as Type 2 diabetes mellitus patients, and most showed signs of diastolic dysfunction. Diabetes mellitus was associated with depressed myofilament function, that is, decreased Ca2+ sensitivity (29%, P < 0.05 vs. control) and a trend toward reduction of maximum Ca2+-saturated force (29%, P = 0.08 vs. control). The slope of the force-Ca2+ concentration relation (Hill coefficient) was not affected by diabetes, however. We conclude that human diabetes mellitus is associated with decreased cardiac myofilament function. Depressed cardiac myofilament Ca2+ responsiveness may underlie the decreased ventricular function characteristic of human diabetic cardiomyopathy.     

Potential interactions of zinc in the neuroendocrine-endocrine disturbances of diabetes mellitus type 2

An accumulation of evidence implicates leptin, insulin, glucocorticoids, proopiomelanocortin (POMC), and neuropeptide Y (NPY) interactions as being integral to metabolic control associated with neuroendocrine-endocrine functioning. Dysfunction of neuroendocrine-endocrine interactions contributes to the metabolic disturbances of diabetes mellitus type 2 (DM-2). Since Zn has a direct impact on the healthy functioning of hormonal and neuropeptide balance, it is possible that altered Zn status and metabolism in DM-2 are involved in some of the metabolic dysfunctions of DM-2.     

Combined clofibrate-chlorpropamide therapy in diabetes insipidus complicated with diabetes mellitus]

The authors observed the incidence of diabetes mellitus and diabetes insipidus in three cases. The combined clofibrat-chlorpropamide treatment proved to be successful. They succeeded in ceasing the daily insuline by giving the two drugs together. The daily diuresis diminished considerably in all three patients. The authors advise the combined clofibrat-chlorpropamide treatment in the incidence of the two diseases. This is especially reasonable when there is a disturbance in the lipoid metabolism.     

Toward beta cell replacement for diabetes

The discovery of insulin more than 90 years ago introduced a life‐saving treatment for patients with type 1 diabetes, and since then, significant progress has been made in clinical care for all forms of diabetes. However, no method of insulin delivery matches the ability of the human pancreas to reliably and automatically maintain glucose levels within a tight range. Transplantation of human islets or of an intact pancreas can in principle cure diabetes, but this approach is generally reserved for cases with simultaneous transplantation of a kidney, where immunosuppression is already a requirement. Recent advances in cell reprogramming and beta cell differentiation now allow the generation of personalized stem cells, providing an unlimited source of beta cells for research and for developing autologous cell therapies. In this review, we will discuss the utility of stem cell‐derived beta cells to investigate the mechanisms of beta cell failure in diabetes, and the challenges to develop beta cell replacement therapies. These challenges include appropriate quality controls of the cells being used, the ability to generate beta cell grafts of stable cellular composition, and in the case of type 1 diabetes, protecting implanted cells from autoimmune destruction without compromising other aspects of the immune system or the functionality of the graft. Such novel treatments will need to match or exceed the relative safety and efficacy of available care for diabetes.     

Nitric oxide and superoxide dismutase modulate endothelial progenitor cell function in type 2 diabetes mellitus

Background

The renin-angiotensin aldosterone system (RAAS) plays an important role in regulating the blood pressure and the genetic polymorphisms of RAAS genes has been extensively studied in relation to the cardiovascular diseases in various populations with conflicting results. The aim of this study was to determine the association of five genetic polymorphisms (A6G and A20C of angiotensinogen (AGT), MboI of renin, Gly460Trp of aldosterone synthase and Lys173Arg of adducin) of RAAS genes in Malaysian essential hypertensive and type 2 diabetic subjects.

Methods

RAAS gene polymorphisms were determined using mutagenically separated PCR and PCR-RFLP method in a total of 270 subjects consisting of 70 hypertensive subjects without type 2 diabetes mellitus (T2DM), 60 T2DM, 65 hypertensive subjects with T2DM and 75 control subjects.

Results

There was significant difference found in age, body mass index, systolic/diastolic blood pressure, fasting plasma glucose and high density lipoprotein cholesterol levels between the hypertensive subjects with or without T2DM and control subjects. No statistically significant differences between groups were found in the allele frequency and genotype distribution for A20C variant of AGT gene, MboI of renin, Gly460Trp of aldosterone and Lys173Arg of adducin (p > 0.05). However, the results for A6G of AGT gene revealed significant differences in allele and genotype frequencies in essential hypertension with or without T2DM (p < 0.001).

Conclusion

Among the five polymorphisms of RAAS genes only A6G variant of AGT gene was significantly associated in Malaysian essential hypertensive and type 2 diabetic subjects. Therefore, A6G polymorphism of the AGT gene could be a potential genetic marker for increased susceptibility to essential hypertension with or without T2DMin Malaysian subjects.     

Viruses and cytokines: evidence for multiple roles in pancreatic beta cell destruction in type 1 insulin-dependent diabetes mellitus

Insulin-dependent (type 1) diabetes mellitus (IDDM) is due to the selective autoimmune-mediated destruction of pancreatic beta cells possibly initiated by viruses. To elucidate the possible role of viruses and cytokines in the pathogenesis of IDDM, we have examined the effect of reovirus infection on beta cell major histocompatibility complex (MHC) expression and the effect of interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha) on beta cell function in vitro. Infection of RIN-m5F (rat insulinoma) cells with reovirus-1 or reovirus-3 was associated with a tenfold increase in class 1 MHC protein and mRNA expression. Reovirus infection did not induced the expression of class 11 MHC by RIN-m5F cells. Exposure of reovirus to ultraviolet light almost completely abolished its ability to induce class 1 MHC protein expression on infected cells. Murine islets cultured for 3 days with IFN-gamma and/or TNF-alpha had a significantly reduced insulin response to glucose, which was more marked with a combination of the cytokines. During 6 days of culture in IFN-gamma plus TNF-alpha islets underwent noticeable degeneration associated with an 80% reduction in insulin content. These findings together with previous data suggest viruses and cytokines may have multiple roles in beta cell destruction, indirectly through enhanced MHC protein expression and directly through functional impairment and loss of viability.     

Embryonic stem cell therapy for diabetes mellitus

There is a compelling need to develop novel therapies for diabetes mellitus. Recent successes in the transplantation of islets of Langerhans are seen as a major breakthrough. However, there is huge disparity between potential recipients and the availability of donor tissue. Human embryonic stem cells induced to form pancreatic beta cells could provide a replenishable supply of tissue. Early studies on the spontaneous differentiation of mouse embryonic stem cells have laid the foundation for a more directed approach based on recapitulating the events that occur during the development of the pancreas in the mouse. A high yield of definitive endoderm has been achieved, and although beta-like cells can be generated in a step-wise manner, the efficiency is still low and the final product is not fully differentiated. Future challenges include generating fully functional islet cells under Xeno-free and chemically defined conditions and circumventing the need for immunosuppression.     

利拉鲁肽联合二甲双胍对肥胖合并2型糖尿病患者糖脂代谢、胰岛β细胞功能及体脂的影响探究

目的探讨利拉鲁肽联合二甲双胍对肥胖合并2型糖尿病患者糖脂代谢、胰岛β细胞功能及体脂的影响。 方法选择成都市郫都区第二人民医院2017年1月至2018年12月收治的肥胖合并2型糖尿病患者141例作为研究对象,按照随机数字表法分为利拉鲁肽组47例、二甲双胍组47例与联合组47例。利拉鲁肽组采用利拉鲁肽治疗,二甲双胍组采用二甲双胍治疗,联合组采用利拉鲁肽联合二甲双胍治疗。三组疗程均为3个月。比较三组治疗前后糖代谢、脂代谢、胰岛β细胞功能和体重指数（BMI）变化,及不良反应,治疗前后比较采用配对t检验,三组间比较采用F检验,两组间比较采用LSD-t检验。 结果三组治疗后FPG、HbA1c和2hPG水平较治疗前降低,差异具有统计学意义（P均< 0.05）;联合组治疗后FPG（6.57±0.39）?mmol/L、HbA1c（7.03±0.42）%和2hPG（8.78±0.45）mmol/L低于利拉鲁肽组（7.03±0.32）mmol/ L、（7.68±0.35）%、（9.56±0.65）mmol/L（t = 6.251、8.151、6.764,P均?< 0.05）和二甲双胍组（7.06±0.39）mmol/L、（7.76±0.46）%、（9.70±0.81）?mmol/L,差异具有统计学意义（t = 6.091、8.034、6.807,P均< 0.05）。三组治疗后HDL-C水平较治疗前升高,而TC、LDL-C和TG水平较治疗前降低,差异具有统计学意义（P均< 0.05）;联合组治疗后HDL-C （1.56±0.13） mmol/ L高于利拉鲁肽组（1.29±0.14） mmol/ L（t = 9.689,P < 0.05）和二甲双胍组（1.32±0.15） mmol/ L,差异具有统计学意义（t = 8.289,P < 0.05）;而联合组TC（4.35±0.38） mmol/L、LDL-C（2.79±0.21）mmol/L和TG（2.15±0.26） mmol/ L低于利拉鲁肽组（5.18±0.43）mmol/L、（3.19±0.15）mmol/L、（2.65±0.17） mmol/L（t = 9.916、10.626、11.035,P < 0.05）和二甲双胍组（5.15±0.34）mmol/L、（3.23±0.25）mmol/ L、（2.68±0.23） mmol/ L,差异具有统计学意义（t = 10.756、9.239、10.467,P均< 0.05）。三组治疗后HOMA-β较治疗前升高,差异具有统计学意义（P < 0.05）;联合组治疗后HOMA-β（4.87±0.28）高于利拉鲁肽组（4.15±0.36）和二甲双胍组（4.08±0.41）,差异具有统计学意义（t = 10.823,10.909,P均< 0.05）。三组治疗后BMI较治疗前降低,差异具有统计学意义（P < 0.05）;联合组治疗后BMI （28.08±0.37）kg/m²低于利拉鲁肽组（29.73±0.49）kg/m²和二甲双胍组（29.61±0.43）kg/m²,差异具有统计学意义（t = 18.423,18.490,P均< 0.05）。 结论利拉鲁肽联合二甲双胍对肥胖合并2型糖尿病患者效果良好,可改善患者糖脂代谢和胰岛β细胞功能,降低体质指数,值得临床借鉴。