Environmental pollutants and type 2 diabetes: a review of mechanisms that can disrupt beta cell function

The prevalence of diabetes mellitus is currently at epidemic proportions and it is estimated that it will increase even further over the next decades. Although genetic predisposition and lifestyle choices are commonly accepted reasons for the occurrence of type 2 diabetes, it has recently been suggested that environmental pollutants are additional risk factors for diabetes development and this review aims to give an overview of the current evidence for this. More specifically, because of the crucial role of pancreatic beta cells in the development and progression of type 2 diabetes, the present work summarises the known effects of several compounds on beta cell function with reference to mechanistic studies that have elucidated how these compounds interfere with the insulin secreting capacity of beta cells. Oestrogenic compounds, organophosphorus compounds, persistent organic pollutants and heavy metals are discussed, and a critical reflection on the relevance of the concentrations used in mechanistic studies relative to the levels found in the human population is given. It is clear that some environmental pollutants affect pancreatic beta cell function, as both epidemiological and experimental research is accumulating. This supports the need to develop a solid and structured platform to fully explore the diabetes-inducing potential of pollutants.     

Reduced beta cell function in offspring of mothers with young-onset type 2 diabetes

Aims/hypothesis Animal models indicate that even exposure to mild maternal hyperglycaemia in utero is detrimental to the beta cell function of the offspring, but evidence of this in humans is limited. In Europids who are diagnosed with type 2 diabetes before the age of 50 years, the risk of diabetes in the offspring of the diabetic mothers is greatly increased compared with the risk in those born to diabetic fathers. We hypothesised that offspring born to mothers with young-onset type 2 diabetes would have been exposed to mild hyperglycaemia in utero, so we studied the impact of this on their beta cell function.Subjects and methods We measured beta cell function using early insulin response (EIR) after oral glucose; insulin resistance using HOMA; and HbA_1c in 568 non-diabetic adult offspring born to parents with type 2 diabetes (mean age 55.8 years), split according to which parent was affected (in 327 it was the mother) and parental age of diagnosis: <50 years (n=117) or ≥50 years. To reduce the impact of genetic susceptibility, the offspring of affected fathers were used as control subjects.Results Offspring of mothers with young-onset type 2 diabetes had lower EIR (log EIR 4.32, 95% CI [4.14–4.51] vs 4.63 [4.43–4.83] p=0.02) and higher HbA_1c (4.89% [4.79–4.99] vs 4.68% [4.57–4.79] p=0.02) than the offspring of fathers with young-onset type 2 diabetes. Insulin sensitivity was similar in the two groups. There were no differences in EIR or HbA_1c between the offspring born to mothers and fathers who were diagnosed after the age of 50 years.Conclusions/interpretation We conclude that the offspring of mothers with young-onset type 2 diabetes have a reduction in beta cell function. This is consistent with exposure to mild maternal hyperglycaemia programming beta cell function.     

New therapies aimed at the preservation or restoration of beta cell function in type 1 diabetes

Type 1 diabetes is caused by an immune-mediated destruction of the insulin-secreting beta cells in the pancreas. The disease can become clinically apparent at any age. At diagnosis, there is invariably some residual beta cell function and more so in adults than in children. Recent studies--including one conducted mainly in Belgium--have provided proof of principle that short-term anti-T-cell antibody treatment is able to preserve residual beta cell function for at least 18 months. The resultant stabilizing effect on metabolic control is expected to delay or limit chronic complications in these patients. With a similar goal in mind, nonuremic C-peptide negative patients are offered beta cell transplantation. The outcome of these implants looks promising but their final applicability hinges on finding ways to induce immune tolerance to the donor beta cells. A widespread application, however, will only occur if the shortage of viable human donor cells can be overcome. Both xenotransplantation and stem cell therapy provide possible strategies to solve this problem and represent areas of intense investigation. The ultimate goal is prevention of clinical disease. Studies by the Belgian Diabetes Registry and others in first degree family members of type 1 diabetic patients have refined the identification of individuals at very high risk of hyperglycaemia so that new immunological treatments can be tested in the prediabetic phase.     

Toll-like receptor 9 negatively regulates pancreatic islet beta cell growth and function in a mouse model of type 1 diabetes

Aims/hypothesis

Innate immune effectors interact with the environment to contribute to the pathogenesis of the autoimmune disease, type 1 diabetes. Although recent studies have suggested that innate immune Toll-like receptors (TLRs) are involved in tissue development, little is known about the role of TLRs in tissue development, compared with autoimmunity. We aimed to fill the knowledge gap by investigating the role of TLR9 in the development and function of islet beta cells in type 1 diabetes, using NOD mice.

Methods

We generated Tlr9^?/? NOD mice and examined them for type 1 diabetes development and beta cell function, including insulin secretion and glucose tolerance. We assessed islet and beta cell number and characterised CD140a expression on beta cells by flow cytometry. We also tested beta cell function in Tlr9^?/? C57BL/6 mice. Finally, we used TLR9 antagonists to block TLR9 signalling in wild-type NOD mice to verify the role of TLR9 in beta cell development and function.

Results

TLR9 deficiency promoted pancreatic islet development and beta cell differentiation, leading to enhanced glucose tolerance, improved insulin sensitivity and enhanced first-phase insulin secretory response. This was, in part, mediated by upregulation of CD140a (also known as platelet-derived growth factor receptor-α [PDGFRα]). In the absence of TLR9, induced by either genetic targeting or treatment with TLR9 antagonists, which had similar effects on ontogenesis and function of beta cells, NOD mice were protected from diabetes.

Conclusions/interpretation

Our study links TLR9 and the CD140a pathway in regulating islet beta cell development and function and indicates a potential therapeutic target for diabetes prevention and/or treatment.

     

Fasting and meal-stimulated residual beta cell function is positively associated with serum concentrations of proinflammatory cytokines and negatively associated with anti-inflammatory and regulatory cytokines in patients with longer term type 1 diabetes

Aims/hypothesis

Cytokines may promote or inhibit disease progression in type 1 diabetes. We investigated whether systemic proinflammatory, anti-inflammatory and regulatory cytokines associated differently with fasting and meal-stimulated beta cell function in patients with longer term type 1 diabetes.

Methods

The beta cell function of 118 patients with type 1 diabetes of duration of 0.75–4.97 years was tested using a standardised liquid mixed meal test (MMT). Serum samples obtained at ?5 to 120 min were analysed by multiplex bead-based technology for proinflammatory (IL-6, TNF-α), anti-inflammatory (IL-1 receptor antagonist [IL-1RA]) and regulatory (IL-10, TGF-β_1–3) cytokines, and by standard procedures for C-peptide. Differences in beta cell function between patient groups were assessed using stepwise multiple regression analysis adjusting for sex, age, duration of diabetes, BMI, HbA_1c and fasting blood glucose.

Results

High fasting systemic concentrations of the proinflammatory cytokines IL-6 and TNF-α were associated with increased fasting and stimulated C-peptide concentrations even after adjustment for confounders (p?<?0.03). Interestingly, increased concentrations of anti-inflammatory/regulatory IL-1RA, IL-10, TGF-β₁ and TGF-β₂ were associated with lower fasting and stimulated C-peptide levels (p?<?0.04), losing significance on adjustment for anthropometric variables. During the MMT, circulating concentrations of IL-6 and TNF-α increased (p?<?0.001) while those of IL-10 and TGF-β₁ decreased (p?<?0.02) and IL-1RA and TGF-β₂ remained unchanged.

Conclusions/interpretation

The association between better preserved beta cell function in longer term type 1 diabetes and increased systemic proinflammatory cytokines and decreased anti-inflammatory and regulatory cytokines is suggestive of ongoing inflammatory disease activity that might be perpetuated by the remaining beta cells. These findings should be considered when designing immune intervention studies aimed at patients with longer term type 1 diabetes and residual beta cell function.     

LADA和2型糖尿病一级亲属胰岛β细胞功能的变化

目的 探讨成人隐匿性自身免疫性糖尿病（LADA）和2型糖尿病（T2DM）一级亲属胰岛β细胞功能的变化。方法 对24例健康对照（NC）、28例谷氨酸脱羧酶抗体（GAD-Ab）阳性LADA一级亲属、14例羧基肽酶H抗体（CPH—Ab）阳性LADA一级亲属，15例T2DM一级亲属行纳格列奈-OGTT，比较其反映B细胞功能的相关指标。结果 ①GAD-Ab阳性LADA一级亲属的胰岛素释放峰值、30min时的△I／△G、IRR、MVI、AUCIns较NC组降低（P〈0．05～0．01）；其HOMA—IR高于NC组（P〈0．05）；②T2DM一级亲属组的HOMA—IR高于NC组（P〈0．05）；③LADA一级亲属组中抗体阳性者的胰岛素释放峰值、30min时的△I／△G、IRR及MVI较阴性者降低更明显；后者的HOMA—IR大于NC组（P〈0．05）。结论 LADA一级亲属存在明显的早期相胰岛分泌与储备功能减退及IR，其中抗体阳性者以胰岛分泌功能缺陷为主伴IR，抗体阴性者以IR为主伴胰岛分泌功能缺陷；T2DM一级亲属存在明显的IR。     

初诊2型糖尿病患者血清总骨钙素水平对胰岛β细胞功能的影响

目的 分析初诊2型糖尿病患者不同总骨钙素水平组间的胰岛素抵抗指标及胰岛β细胞分泌功能指标差异及其相关性,探讨总骨钙素与胰岛功能的关系。方法 选取2016年12月至2018年10月于北京大学国际医院内分泌科门诊及住院的初诊2型糖尿病患者216例,根据患者总骨钙素水平分为4组,比较不同血清总骨钙素水平组间胰岛素抵抗指标及胰岛β细胞分泌功能之间的差异及上述指标间的相关性。结果 4组间甲状旁腺素水平比较差异有统计学意义（P<0.05）,低骨钙素水平组甲状旁腺素水平较低（F=3.55,P<0.05）。女性患者,骨钙素水平与稳态模型评估β指数（homeostasis model assessment β,HOMA-β）及葡萄糖处置指数（disposition index 0,DI0）水平呈显著正相关（r=0.41,P<0.05;r=0.45,P<0.05）。60岁以上男性患者,骨钙素水平与HOMA-β及DI0水平呈显著正相关（r=0.34,P<0.05;r=0.32,P<0.05）。多元线性回归分析结果显示,女性及60岁以上男性2型糖尿病患者低骨钙素水平与胰岛β细胞分泌功能降低独立相关（P<0.05）。结论 对于初诊女性及60岁以上男性2型糖尿病患者,低骨钙素水平可能与胰岛β细胞分泌功能降低独立相关,这为2型糖尿病的发病机制及治疗提供了新的研究方向。     

微小RNA在2型糖尿病相关机制中的研究进展

2型糖尿病及其慢性并发症严重威胁人类健康,但其确切发病机制并不十分清楚.微小RNA是一种非编码单链RNA,参与2型糖尿病等多种疾病的发生.微小RNA在胰岛素抵抗、胰岛功能缺陷这两个2型糖尿病主要病理生理过程及其并发症发生中的重要作用引发越来越多的关注.     

Early and longer term effects of gastric bypass surgery on tissue-specific insulin sensitivity and beta cell function in morbidly obese patients with and without type 2 diabetes

Aims/hypothesis

Bariatric surgery consistently induces remission of type 2 diabetes. We tested whether there are diabetes-specific mechanisms in addition to weight loss.

Methods

We studied 25 morbidly obese patients (BMI 51.7?±?1.5?kg/m² [mean?±?SEM]), 13 with non-insulin-treated type 2 diabetes (HbA_1c 7.1?±?0.5% [54?±?5?mmol/mol]), before and at 2?weeks and 1?year after Roux-en-Y gastric bypass (RYGB). Lean (n?=?8, BMI 23.0?±?0.5?kg/m²) and obese (n?=?14) volunteers who were BMI-matched (36.0?±?1.2) to RYGB patients at 1?year after surgery served as controls. We measured insulin-stimulated glucose disposal (M) and substrate utilisation (euglycaemic clamp/indirect calorimetry), endogenous glucose production (EGP) by 6,6-[²H₂]glucose, lipolysis (rate of appearance of [²H₅]glycerol) and beta cell function (acute insulin response to i.v. glucose [AIR] as determined by C-peptide deconvolution).

Results

At baseline, all obese groups showed typical metabolic abnormalities, with M, glucose oxidation and non-oxidative disposal impaired, and EGP, lipolysis, lipid oxidation and energy expenditure increased. Early after RYGB plasma glucose and insulin levels, and energy expenditure had decreased, while lipid oxidation increased, with M, EGP and AIR unchanged. At 1?year post-RYGB (BMI 34.4?±?1.1?kg/m²), all diabetic patients were off glucose-lowering treatment and mean HbA_1c was 5.4?±?0.14% (36?±?2?mmol/mol) (p?=?0.03 vs baseline); AIR also improved significantly. In all RYGB patients, M, substrate oxidation, EGP, energy expenditure and lipolysis improved in proportion to weight loss, and were therefore similar to values in obese controls, but still different from those in lean controls.

Conclusions/interpretation

In morbidly obese patients, RYGB has metabolic effects on liver, adipose tissue, muscle insulin sensitivity and pattern of substrate utilisation; these effects can be explained by energy intake restriction and weight loss, the former prevailing early after surgery, the latter being dominant in the longer term.     

Preferable effect of pravastatin compared to atorvastatin on beta cell function in Japanese early-state type 2 diabetes with hypercholesterolemia

While a large numbers of clinical trials using various kinds of statins has been reported, a possible preventive effect on new onset of type 2 diabetes mellitus was shown only by the subanalysis of The West of Scotland Coronary Prevention Study (WOSCOPS) using pravastatin. The aim of this study was to investigate whether pravastatin has a preferable effect on glucose tolerance among statins. An open-label prospective cross-over trial was performed to compare the effect of pravastatin (10 mg/day) or atorvastatin (10 mg/day) in Japanese early-state type 2 diabetes mellitus with hypercholesterolemia. The analyzed study subjects were treated with pravastatin (10 mg/day, n = 12) or atorvastatin (10 mg/day, n = 12) for 12 weeks. After a 4-week-washout period, the drugs were switched and treatment was continued for another 12 weeks. Oral glucose tolerance test (OGTT) was performed to evaluate several parameters including the appropriateness of beta cell function for the individual insulin sensitivity (disposition index: product of a validated secretion parameter and sensitivity) at the end of each therapy. HbA(1c) and 2 h-glucose levels during OGTT in the pravastatin treatment were significantly lower than atorvastatin treatment. Disposition index after pravastatin treatment was significantly higher than after atorvastatin treatment. In conclusion, our study suggests that pravastatin has a favorable effect on pancreatic beta cell function compared with atorvastatin.     

Relation of genetic polymorphisms in microRNAs with diastolic and systolic function in type 2 diabetes mellitus

Background and aimsType 2 diabetes mellitus (T2DM) has high risk of developing cardiac dysfunction, increasing of either cardiovascular death or hospitalization for heart failure. MicroRNAs (miRNA) affect cardiac function of T2DM. The aim of this study was to investigate the relationships between five miRNA single nucleotide polymorphisms (SNP) and diastolic and systolic function of T2DM.Methods and resultsThree hundred untreated T2DM subjects were included. Each subject underwent SNP genotyping, conventional echocardiography, tissue doppler imaging, and speckle tracking imaging. The effects of miRNA SNPs on diastolic and systolic function were evaluated. The diastolic function of T2DM subjects with miR-133a-1-rs8089787 wild genotype or let-7f-rs10877887 variant genotype was lower than those with miR-133a-1-rs8089787 variant genotype or let-7f-rs10877887 wild genotype, manifesting as higher left atrial volume index, lower mean E′, and higher E/E’ (P < 0.05). There were no significant effects of miR-133a-2-rs13040413, let-7a-1-rs13293512 and miR-27a-rs895819 on the diastolic function of T2DM subjects (P > 0.05). These five miRNA SNPs had no effect on the systolic function of T2DM subjects (P > 0.05).ConclusionsMiRNA-133a-1-rs8089787 and let-7f-rs10877887 were associated with impaired cardiac diastolic function in T2DM. The findings may be a promising therapeutic targets for preventing diastolic dysfunction in T2DM.     

阿格列汀对经二甲双胍治疗的肥胖2型糖尿病患者肺功能的影响

目的观察阿格列汀对经二甲双胍治疗的肥胖2型糖尿病患者肺功能的影响,并评估该方案的有效性与安全性。方法选取肥胖的2型糖尿病患者100例(均为二甲双胍500 mg bid,po控制不佳),随机分为观察组(50例)和对照组(50例)。对照组给予二甲双胍(1000 mg bid,po),观察组为二甲双胍(500 mg bid,po)联合阿格列汀(25 mg qd,po),两组患者规范治疗24 w,比较两组患者治疗前后肺活量(VC)、用力肺活量(FVC)、肺总量(TCL)、一秒用力呼气流量(FEV1)、一秒率(FEV_1/FVC)、最大自主通气量(MVV)、最大呼气峰流速(PEF)、肺一氧化碳弥散量(DLCO)、肺单位体积一氧化碳弥散量(DLCO/VA)、外周血清超氧化物歧化酶(Superioxide dismutase,SOD)、活性氧类物质(Reactive oxygen species,ROS)、谷胱甘肽过氧化物酶(Glutathione peroxidase,GSH-Px)活性及其丙二醛(Malondialdehyde,MDA)浓度、体重指数、腰围、糖化血红蛋白(Hb A1c)、空腹血糖(FBG),餐后2 h血糖(2h PBG)的变化情况,并记录治疗过程中的不良反应。结果治疗后两组患者的VC、FVC、TLC、FEV1、FEV1/FVC、PEF、MVV、DLCO、DLCO/VA均高于治疗前(P0.05),治疗后对照组患者上述指标均低于观察组(P0.05)。治疗后,两组ROS、MDA、FBG、2h PBG、Hb A1c、体重指数、腰围,较治疗前均降低,有统计学差异(P0.05),治疗后观察组上述指标明显低于对照组,差异有统计学意义(P0.05);治疗后,SOD、GSH-Px活性较治疗前升高,差异有统计学意义(P0.05),治疗后观察组上述指标明显高于对照组,有统计学差异(P0.05),且治疗过程中两组的不良反应无统计学差异(P0.05)。结论阿格列汀联合二甲双胍可改善肥胖2型糖尿病患者的肺功能,改善外周血清氧化与抗氧化物质的失衡,同时能降低患者的体重指数、腰围等指标,且不增加低血糖风险,值得临床广泛推广。     

肥胖对2型糖尿病患者临床特征及心脏结构功能的影响

目的 探讨肥胖对2型糖尿病患者心脏结构和功能的影响. 方法 符合WHO1999年糖尿病诊断标准的住院2型糖尿病患者270例.根据2000年亚太地区肥胖诊断标准将所有患者分为非肥胖组和肥胖组.使用M型超声心动图检测升主动脉内径(AOD)、左房内径(LAD)、左室收缩期内径(LVDs)、左室舒张期内径(LVDd)、室间隔厚度(IVS)、左室后壁厚度(LVPW)、左室短轴缩短率(FS)、射血分数(EF),采用多普勒超声检测二尖瓣E峰与A峰比值(E/A). 结果 (1)肥胖组体质量、体表面积、舒张压、空腹胰岛素、餐后胰岛素、空腹C肽、胰岛素抵抗指数(HOMA-IR)及三酰甘油高于非肥胖组,非肥胖组糖化血红蛋白及空腹血糖高于肥胖组;(2)肥胖组LAD.IVS、LVPW、左心室质量及E/A比值＜1的发生率高于非肥胖组;(3)多元逐步回归分析:非肥胖组EF与体质量指数呈负相关;肥胖组EF与收缩压呈正相关,与胆固醇、左心室质量(LVM)、空腹胰岛素呈负相关.结论 肥胖糖尿病患者存在明显左心肥大、左心舒张功能异常,与胰岛素抵抗、高三酰甘油血症并存.     

Factors that positively or negatively mediate the effects of age on working memory across the adult life span

Working memory abilities significantly decrease with advancing age; hence, the search for factors that may increase or mitigate this decline is critical. Several factors have been identified that influence working memory; however, their effects have been mainly assessed separately and rarely together with other factors in the same sample. We examined 120 variables to search for factors that jointly act as mediators of working memory decay across the adult life span. A sample of 1652 healthy adults was assessed in spatial and verbal working memory domains. Structural equation modeling analyses were conducted to search for potential mediators that intervened between age and working memory. Only 14 and 10 variables reliably mediated spatial and verbal working memory, respectively. Factors from several domains remained in the models, such as individual characteristics, physiological traits, consumption habits, and regular activities. These factors are sufficiently powerful to influence working memory decline when they jointly interact, as in everyday living.     

2型糖尿病和非酒精性脂肪肝病患者的胰岛素抵抗和胰岛β细胞功能

目的 探讨2型糖尿病(T2DM)和非酒精性脂肪肝病(NAFLD)患者胰岛β细胞功能和胰岛素抵抗的特征.方法 206例研究对象根据是否有T2DM和NAFLD分为4组,采用肝脏胰岛素抵抗指数(HIR)、HOMA胰岛素抵抗指数(HOMA-IR)及Matsuda指数(MSI)评估胰岛素抵抗性,采用HOMA-β、早相及晚相胰岛素分泌指数评估胰岛β细胞功能.结果 NAFLD组和T2DM伴NAFLD组的HIR均显著高于对照组和T2DM组(4.13±0.64,4.03±0.69比3.52±0.78,3.53±0.64,P<0.05),T2DM伴NAFLD组的HOMA-IR显著高于T2DM和NAFLD组(3.35±2.69比2.31±1.39,2.40±1.55,P<0.05);NAFLD组的早相胰岛素分泌指标显著低于对照组(2.13±0.17比2.61±0.13,P<0.05),而T2DM组和T2DM伴NAFLD组的HOMA-β、早相及晚相胰岛素分泌指标均明显低于对照组(P<0.05).结论 NAFLD患者主要表现为肝脏胰岛素抵抗,其胰岛β细胞早相胰岛素分泌受损;T2DM患者存在胰岛素抵抗,其胰岛β细胞早、晚相胰岛素分泌功能均受损.当患者既有T2DM又有NAFLD时,胰岛素抵抗将更严重.     

Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol

Aims/hypothesis  

Type 2 diabetes is regarded as inevitably progressive, with irreversible beta cell failure. The hypothesis was tested that both beta cell failure and insulin resistance can be reversed by dietary restriction of energy intake.     

The required beta cell research for improving treatment of type 2 diabetes

In healthy individuals, insulin resistance is associated with physiological conditions such as pregnancy or body weight gain and triggers an increase in beta cell number and insulin secretion capacity to preserve normoglycaemia. Failure of this beta cell compensation capacity is a fundamental cause of diabetic hyperglycaemia. Incomplete understanding of the molecular mechanisms controlling the plasticity of adult beta cells mechanisms and how these cells fail during the pathogenesis of diabetes strongly limits the ability to develop new beta cell‐specific therapies. Here, current knowledge of the signalling pathways controlling beta cell plasticity is reviewed, and possible directions for future research are discussed.