Pancreatic islet renin angiotensin system: its novel roles in islet function and in diabetes mellitus

Several regulatory systems are implicated in the regulation of islet function and beta cell mass. Of great interest in this context are some endocrine, paracrine/autocrine, and intracrine regulators. These include, to name but a few, the gut peptides, growth factors, prostaglandins, and some vasoactive mediators such as nitric oxide, bradykinins, endothelins, and angiotensins. Apart from its potent vasoconstrictor actions, the renin-angiotensin system (RAS) that generates angiotensin II has several novel functions-stimulation and inhibition of cell proliferation; induction of apoptosis; generation of reactive oxygen species; regulation of hormone secretion; and proinflammatory and profibrogenic actions. In the pancreas, recent evidence supports the presence of an islet RAS, which is subject to activation by islet transplantation and diabetes. Such a local islet RAS, if activated, may drive islet fibrosis and reduce islet blood flow, oxygen tension, and insulin biosynthesis. Moreover, activation of an islet RAS may drive the synthesis of reactive oxygen species, cause oxidative stress-induced beta cell dysfunction and apoptosis, and thus contribute to the islet dysfunction seen in type 2 diabetes and after islet transplantation. Blockade of the RAS could contribute to the development of novel therapeutic strategies in the prevention and treatment of patients with diabetes and in islet transplantation.     

Heavy metals,islet function and diabetes development

Heavy metals have been known to possess many adverse health effects for a long time. Uncontrolled industrialization breaks out heavy metal pollution in the world. Heavy metal pollutants damage organ functions and disrupt physiological homeostasis. Diabetes mellitus is growing in prevalence worldwide. Several studies have indicated that the deficiency and efficiency of some essential trace metals may play a role in the islet function and development of diabetes mellitus. Some toxic metals have also been shown to be elevated in biological samples of diabetes mellitus patients. In the present work, we review the important roles of heavy metals in islet function and diabetes development in which the in vitro, in vivo, or human evidences are associated with exposure to zinc, arsenic, cadmium, mercury, and nickel. Through this work, we summarize the evidence which suggests that some heavy metals may play an important role in diabetes mellitus as environmental risk factors.     

Heavy metals, islet function and diabetes development

It has long been believed that heavy metals possess many adverse health effects. Uncontrolled industrialization has released heavy metal pollution in the world. Heavy metal pollutants damage organ functions and disrupt physiological homeostasis. Diabetes mellitus is growing in prevalence worldwide. Several studies have indicated that the deficiency and efficiency of some essential trace metals may play a role in the islet function and development of diabetes mellitus. Some toxic metals have also been shown to be elevated in biological samples of diabetes mellitus patients. In the present work, we review the important roles of heavy metals in islet function and diabetes development in which the in vitro, in vivo or human evidences are associated with exposure to zinc, arsenic, cadmium, mercury and nickel. Through this work, we summarize the evidence which suggests that some heavy metals may play an important role in diabetes mellitus as environmental risk factors.     

糖尿病患者胰岛自身抗体与β细胞功能的关系

目的 研究胰岛自身抗体与糖尿病（DM）临床表现，β细胞功能的关系。方法 分析733例住院DM患者的临床和生化特征。测定血清C肽，胰岛细胞抗体（ICA），谷氨酸脱羧酶抗体（GADA）和蛋白酪氨酸磷酸酶抗体（IA-2A）水平。结果 58例速发型1型DM中34.5%，GADA阳性，22.4%ICA阳性，27.3%IA-2A阳性，在临床初诊为2型DM的675例患者中，13.5%有一种以上抗体阳性，其中10.1%GADA阳性，2.7%ICA阳性，8.7%IA-2A阳性，在不同病程的成人隐匿性自身免疫性糖尿病（LADA）中自身抗体阳性率无明显变化。而病程2年以上的1型DM患者中则呈降低趋势，随着病程延长，患者均有空腹和餐后C肽水平降低，但下降的速度以1型DM最快，LADA次之，2型DM最慢，多因素逐步回归分析表明，GADA是导致空腹与餐后C肽水平降低的危险因素。结论 在速发型1型DM和LADA患者中GADA，ICA和IA-2A阳性率不同，联合抗体检测有助于诊断，LADA患者β细胞功能衰退较慢，保护残存β细胞可有利于延缓病情进展。     

Insulin requirement in non-insulin-dependent diabetes mellitus: relation to simple tests of islet B-cell function and insulin sensitivity

Evaluation of simple tests of islet B-cell function and insulin sensitivity as predictors of metabolic control was performed during 3 months of insulin withdrawal in 25 insulin-treated diabetic subjects. All patients had a glucagon stimulated plasma C-peptide concentration above 0.33 nmol/l and a fasting plasma C-peptide concentration above 0.20 nmol/l a few days before insulin withdrawal. Insulin sensitivity was measured as the glucose disappearance rate (k) during an intravenous insulin tolerance test. Two patients were considered insulin-requiring due to high fasting blood glucose levels (greater than 20 mmol/l) and two patients due to an increase in glycosylated haemoglobin of more than 1.1% (greater than approximately 3SD) in combination with weight loss. None of the remaining patients had a significant increase in glycosylated haemoglobin. An inverse correlation was found between stimulated C-peptide levels and insulin sensitivity (r = 0.41, p less than 0.05). Fasting and stimulated C-peptide concentrations of 0.40 and 0.70 nmol/l, respectively, separated non-insulin-requiring patients from a group consisting of both insulin- and non-insulin-requiring patients. At these C-peptide levels the predictive value of a positive test was 100% while the predictive value of a negative test was as low as 33% or 27% depending on whether fasting or stimulated C-peptide concentration was used. Including the k value in the prediction only increased the predictive values of negative tests to 40% and 33%, respectively.     

Autoantibodies to islet amyloid polypeptide in diabetes.

Islet amyloid polypeptide (IAPP) is the constituent peptide of amyloid in pancreatic islets of Type 2 diabetic patients and in insulinomas. Amyloid formation in Type 2 diabetes is associated with islet cell destruction which may promote formation of autoantibodies to IAPP. An ELISA method has been developed to detect IAPP autoantibodies and used to assay serum from 80 non-diabetic subjects, 49 Type 1 and 228 Type 2 diabetic patients, and 10 patients with insulinomas. Microtitre plates coated with IAPP 1-37 were used to detect antibody binding followed by an alkaline phosphatase conjugated anti-human IgG. ELISA binding decreased with sample dilution and with pre-incubation of the samples with IAPP. The optical density of the substrate reaction was compared with results from a standard serum from a non-diabetic subject (OD ratio). Elevated OD ratios were detected in some subjects from each patient group but the Type 2 diabetic group had significantly higher titres than the non-diabetic subjects (p less than 0.001). The OD ratio was elevated (greater than mean + 2SD non-diabetic group) in 15% of Type 2 and 18% of Type 1 diabetic patients and in 20% with insulinomas. IAPP antibody levels did not correlate with age or gender of subjects, or duration of diabetes. IAPP autoantibodies could be an additional marker for B-cell damage in diabetes.     

持续皮下胰岛素输注对2型糖尿病早期胰岛功能改善作用的临床研究

目的探讨初发的2型糖尿病患者,应用持续皮下胰岛素输注(CSII)或多次胰岛素皮下注射(MSII)的治疗,对胰岛β细胞功能和血糖的影响。方法CSII组采用持续皮下胰岛素输注形式,在3天内使血糖达标;MSII组采用小剂量起步,平均2~3周逐步将血糖调整到位的方法,观察治疗前后血糖、血浆C肽(C-P)空腹、餐后1小时、2小时及HbAlc的变化。结果两组的血糖及HbAlc较治疗前明显下降(P<0.05),而CSII组下降更为明显(P<0.05),且该组C-P空腹及餐后1小时值有所升高(P<0.05),胰岛素用量也较MSII组有所减少。结论对初诊的血糖较高的2型糖尿病患者尽早应用持续皮下胰岛素输注的方式,更有助于将血糖控制在理想水平及改善胰岛功能。     

Clinical time-course and characteristics of islet cell cytoplasmatic antibodies in childhood diabetes

Summary Circulating islet cell antibodies (ICA) were present in high frequency (80%) early after diagnosis and decreased in the time course of childhood diabetes mellitus. The complement fixing ability of islet cell antibodies (CF-ICA) in the course of the disease appeared to depend on the titre of ICA: the coefficient of correlation between ICA and CF-ICA titres was 0.79 and all ICA's with a titre over 16 were complement-fixing. Incubating fresh frozen human pancreatic sections thrice rather than once with the children's sera, increased the detectability of complement fixation by a factor 1.4 in all ICA-positive sera. Thus tested, the detection of complement fixation per se did not appear to have a separate pathogenic significance, as the fraction of complement fixing ICA's was almost constant throughout the clinical course. The presence of ICA-IgG subclasses also was dependent on the ICA titre: above a titre of 16 mostly all four subclasses could be detected. Incubating the pancreatic tissue thrice rather than once with ICA-positive sera resulted in enhanced detectability of ICA-IgG₁. Early in the course of childhood diabetes, including two prediabetic children, most of the IgG subclasses could be detected in ICA, but after a duration of one year IgG₁ alone was mainly seen. In two other children, having a family history of insulin-dependency, restriction to the IgG₂ subclass was found.     

Autologous islet cell transplantation to prevent surgical diabetes

Autologous islet transplantation (AIT) is performed to prevent surgical diabetes after total or semi-total pancreatectomy for the treatment of chronic pancreatitis with severe abdominal pain. In addition, AIT is used in cases of benign pancreatic tumors and pancreatic trauma. It has been shown that AIT results in better outcomes in terms of glycemic control compared with allogeneic islet transplantation. The reasons for the favorable outcomes of AIT are thought to be: (i) patients have no autoimmune diseases; (ii) the transplanted islets do not suffer allogeneic rejection; (iii) diabetogenic antirejection drugs are not required; (iv) pancreata do not undergo a cytokine storm as a result of periods of brain death; (v) the period of cold preservation of retrieved pancreata is short; (vi) the isolated islets are immediately transplanted without culture; and (vii) pancreata with pancreatitis may contain more progenitor cells. Further research into AIT would help improve the results of allogeneic islet transplantation. Conversely, the technical difficulties associated with islet isolation appear to be the largest hurdle for AIT; therefore, remote center islet isolation may prove to be key in the promotion of this treatment.     

Autoimmunity to islet proteins in children diagnosed with new-onset diabetes

Autoantibody and T cells reacting with islet proteins have been demonstrated in patients with type 1 diabetes. In recent years an increasing number of children have been clinically classified with type 2 (not ketosis prone, evidence of insulin resistance, presence of acanthosis nigricans, and obesity) or indeterminant diabetes (admixture of clinical features of types 1 and 2). In this study, we compared the islet cell autoantibody and T-cell responses to islet proteins in type 2 (n = 19) and indeterminant (n = 16) children (<18 yr of age) to classic type 1 (n = 37) diabetic patients. We observed that 37 of 37 type 1 diabetic children demonstrated autoantibody and/or T-cell reactivity to islet proteins. Fourteen of the 19 type 2 patients were positive for islet cell autoantibodies, and six of 14 were positive for T-cell responses to islet proteins. For the indeterminant patients, 11 of 16 of the patients were positive for autoantibodies, and six of 16 patients were positive for T-cell responses to islet proteins. These results demonstrate that autoimmunity to islet proteins is present in a high percentage of children classified as indeterminant or type 2 diabetes. Moreover, the presence of obesity or acanthosis nigracans does not reliably distinguish children with or without islet cell autoimmunity.     

Sensitivity and reproducibility of urinary C-peptide as estimate of islet B-cell function in insulin-treated diabetes

The aims of the present study were to evaluate the ability of urinary C-peptide determination to demonstrate presence of residual insulin secretion, and to evaluate the reproducibility of urinary C-peptide excretion in 125 insulin-treated diabetic patients. C-peptide was determined in two consecutive 24-h urine specimens and related to plasma C-peptide 6 min after the intravenous injection of 1 mg glucagon. The detection limit of C-peptide in plasma was defined analytically (greater than or equal to 0.02 nmol l-1) and from pancreatectomized patients (greater than or equal to 0.06 nmol l-1), and in urine only analytically (greater than or equal to 0.1 nmol l-1). If the analytical detection limit of plasma C-peptide was used as indicator of residual insulin secretion, islet B-cell function was preserved in all patients. In patients with stimulated plasma C-peptide levels from 0.02- less than 0.06 nmol l-1 no increase was found in plasma C-peptide values after stimulation with glucagon. This unresponsiveness of islet B-cells is in good agreement with the existence of a biological detection limit of C-peptide in plasma of 0.06 nmol l-1. Using this biological plasma C-peptide detection limit, 49 of 125 patients were without residual insulin secretion. In contrast to this, only 7 patients were diagnosed as C-peptide nonsecretors using the analytical detection limit of urinary C-peptide. Eighty-four per cent of patients considered to have Type 1 (insulin-dependent) diabetes with a duration of diabetes of more than 15 years had detectable C-peptide in the urine.(ABSTRACT TRUNCATED AT 250 WORDS)     

老年糖尿病患者胰岛细胞抗体测定及其与β细胞功能的关系

目的观察老年糖尿病患者胰岛细胞抗体(ICA)与β细胞功能的关系.方法用ICA法测定80例老年糖尿病患者ICA并与48例健康老年人对照,同时测定糖耐量试验、胰岛素、C肽释放试验.结果 (1)老年糖尿病患者ICA阳性率为13.75%,显著高于对照组(P＜0.05).(2)ICA阳性患者空腹及餐后血糖均高于ICA阴性患者,但无统计学差异.(3)ICA阳性患者餐后1 h、2 h的胰岛素、C肽均低于ICA阴性患者(均P＜0.05).结论老年糖尿病ICA阳性患者β细胞功能损伤较ICA阴性患者严重.     

Association between vascular measures and cognitive function in type 2 diabetes

AimTo examine correlation between vascular measures and cognitive performance in type 2 diabetes (T2D).MethodsThis was a cross-sectional study on patients (N = 1167) aged ≥45 years attending Diabetes Centre in a tertiary hospital and primary care polyclinic. The following vascular measures were measured: systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), pulse pressure (PP), pulse wave velocity (PWV) and augmentation index (AI). Cognition was assessed by Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Multiple linear regression was used to examine relationships between vascular measures and cognition, adjusting for demographics, education, depression, clinical covariates and presence of APOE _Ɛ4 allele.ResultsIn unadjusted analyses, all the vascular measures, except for MAP, were associated with RBANS total score. In fully adjusted analyses, the association with RBANS total score persisted for peripheral PP, aortic PP and aortic DBP with βs −0.05 (95%CI -0.07 to −0.02; p = 0.001), −0.04 (95%CI −0.06 to −0.01; p = 0.002) and 0.05 (95%CI 0.00 to 0.09; p = 0.033). Association between peripheral and aortic PP and RBANS total score was unaffected by age-stratification (age <60 and ≥60 years). In contrast, significant association between aortic DBP and RBANS total score was only observed for those ≥60 years. Peripheral and aortic PP (which estimate pulsatility) are negatively associated with attention, visuospatial/constructional and language ability.ConclusionsPeripheral and aortic PP, and aortic DBP were independently correlated with cognitive performance globally and in multiple domains. Further research should be conducted to establish the clinical relevance and importance.     

Comparison of indices of islet B-cell function in type 2 diabetes in relation to insulin effectiveness and clinical outcome.

The most appropriate way to estimate islet B-cell function in Type 2 diabetes is unclear, and this has led to many different techniques of measurement being used. We have examined the associations to two fasting and four glucose-stimulated indices of islet B-cell function in members of a group of 249 Type 2 patients, seeking correlations with concurrent glucose tolerance and antilipolytic effect, and with subsequent clinical outcome. The six B-cell indices were interrelated to variable degrees (rs -0.21 to +0.92). Early glucose-stimulated insulin output (incremental 1st-phase insulin area) was not significantly positively correlated with the fasting plasma concentration of immunoreactive insulin at any time. Fasting immunoreactive insulin and 'minimal model' islet B-cell parameters were poorly related to the rate constant for glucose clearance and the degree of antilipolysis (rs values between -0.13 and +0.40). Homeostatic model assessment of the fasting islet B-cell function was more consistently related to these metabolic effects. Incremental first-phase insulin area was the islet B-cell index most consistently related to metabolic abnormalities (rs up to +0.56), and to subsequent need for oral hypoglycaemic or exogenous insulin therapy. No index of islet B-cell function was consistently associated with the subsequent development of diabetic tissue damage.     

酮症倾向的糖尿病患者胰岛自身抗体与胰岛功能的意义

目的探讨酮症倾向糖尿病（KPD）患者临床特征、自身抗体检出情况及胰岛8细胞功能。方法检测78例KPD患者血清谷氨酸脱羧酶抗体（GAD-Ab）、胰岛细胞抗体（ICA）、胰岛素自身抗体（IAA）、GP。任一抗体阳性为A＋，3种抗体均阴性为A-，空腹FGP≥0．333nmol／L为8＋，反之为β-。根据结果78例KPD患者分4组：A＋β＋；A＋β-；A—β＋；A-β-。比较各组的临床特征、自身抗体及胰岛功能。结果A-β＋组发病年龄最大，BMI、合并高血压和肥胖的百分率、TG、TC、TC—P和餐后C-P较高；A＋β-组发病年龄最轻，BMI、合并高血压和肥胖的百分率、C-P水平最低；A＋β＋组和A—β-组临床特征介于A＋β-组和A-β-组之间。结论KPD临床特点不同，自身免疫抗体和胰岛β细胞功能差异显著，提示应根据不同临床特点采取不同的治疗。     

The role of islet secretory function in the development of diabetes in the GK Wistar rat

Summary Insulin secretion and glucose metabolism were compared in islets isolated from GK Wistar rats (a non-obese, spontaneous model of non-insulin-dependent diabetes mellitus) and control Wistars aged 8 and 14 weeks. By 8 weeks of age, GK Wistar rats were clearly diabetic as indicated by non-fasting plasma glucose concentrations and impaired glucose tolerance. Islet insulin content was not significantly different to controls at either age. In islets from 14-week-old GK Wistar rats glucose-stimulated insulin release (6–16 mmol/l glucose) was significantly reduced to 25–50% of controls in static incubations (p<0.001). In perifusion, glucose-stimulated insulin release was reduced by 90% for first phase (p<0.01) and by 75% for second phase (p<0.05). The responses to arginine and 2 Ketoisocaproate in islets were similar to those in controls. In contrast, islets isolated from 8-week-old GK Wistar rats exhibited no significant reduction in glucose-stimulated insulin secretion in static incubations. In perifusion, although both first and second phases of glucose-stimulated insulin release were slightly reduced, these were not significantly different to controls. Islets from 8-week-old GK Wistar rats failed however to respond to stimulation by glyceraldehyde. Raising the medium glucose concentration to 16 mmol/l significantly increased rates of glucose utilisation ([³H] H₂O production from 5-[³H] glucose) and oxidation ([¹⁴C] CO₂ production from U-[¹⁴C] glucose) in islets isolated from 8-week-old control and GK Wistar rats, respectively. The rates of oxidation were not significantly different at stimulatory glucose concentrations whereas the rates of utilisation were significantly higher in islets from the diabetic animals (p<0.05). Production of [³H] H₂O from 2-[³H] glycerol metabolism was increased (p<0.05) at 2 mmol/l glucose but was not significantly different to controls at 16 mmol/l glucose in islets from 8-week-old GK Wistar rats. This data would suggest that abnormalities in islet function are present in 8-week-old diabetic animals although these do not seriously impair glucose-stimulated insulin release from isolated islets. This in turn would indicate that a defect in the glucose signalling pathway in beta cells is not a primary cause of the diabetes of GK Wistar rats and that deterioration of the secretory response is the consequence of some factor associated with the diabetic condition.Abbreviations KIC 2 Ketoisocaproate - BSA bovine serum albumin - GLUT glucose transporter     

Relationship of islet function to insulin action in human obesity

To analyze B-cell mechanisms in obesity, we measured the relationship (slope of potentiation) between glucose levels and acute insulin responses (AIR) to isoproterenol or arginine in nondiabetic subjects ranging from lean to markedly obese. Obese men (n = 9) had higher AIRs to isoproterenol than lean men (n = 11) at basal glucose levels [52 +/- 9 (SEM) vs. 32 +/- 5 microU/mL; P less than 0.05], and the difference increased as the ambient glucose level was raised (at 230 mg/dL; 263 +/- 22 vs. 140 +/- 21 microU/mL; P less than 0.0008). The individuals' slopes of glucose potentiation of AIR to isoproterenol were positively correlated with their excess weight (r = 0.72; P less than 0.001). Similar results were found when arginine was used as the secretagogue in other men and in women; the slope of potentiation was positively correlated with excess weight in both men and women (both P less than 0.005), although the effect of excess weight on slope was 51% greater among men (P less than 0.03). An independent measurement of insulin sensitivity (the Bergman SI) was made in the women. The potentiation slope was inversely correlated with SI (P less than 0.0001), indicating that the effect of obesity on insulin secretion is correlated with insulin resistance. These results characterize one mechanism contributing to the hyperinsulinemia of obesity and highlight the importance of considering the prevailing insulin sensitivity when assessing islet function.