Natural history of pancreatic islet B-cell function in type 2 diabetes mellitus studied over six years by homeostasis model assessment

Islet B-cell function and insulin sensitivity were estimated with the aid of a mathematical model from repeated fasting plasma glucose and insulin measurements over a 6 year period in 131 patients with type 2 diabetes mellitus who could be managed satisfactorily on dietary therapy alone. They presented between the ages of 40 and 69 years, and were studied before and after one year of treatment, and then at regular intervals from 12 until 72 months later. A method of averaging the individual trends by means of a linear model regression technique was used to assess the progression of their diabetes. Dietary management over the first 12 months resulted in weight loss from 118% to 106% average body weight, and improved insulin sensitivity from 26% to 40% of normal (p less than 0.001). From 12 to 72 months, the fasting plasma glucose rose at a mean rate of 0.23 mmol/l per year (p less than 0.001) despite a rate of weight loss of 0.2% average body weight per year (p less than 0.01). The estimated islet B-cell function, expressed as a percentage of normal, decreased significantly (p less than 0.05) at a rate of 1.5% per year, with no statistically significant change in insulin sensitivity. Extrapolation suggests the reduction in B-cell function predated the departure of fasting plasma glucose from the normal range.     

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)     

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.     

高血糖状态对2型糖尿病患者胰岛β细胞分泌功能的影响

目的　了解葡萄糖毒性对胰岛 β细胞分泌功能的影响。 　方法　观察 118例 2型糖尿病 (T2DM)患者在不同血糖状态下 ,胰岛 β细胞分泌对口服葡萄糖耐量试验 (OGTT)和胰高血糖素刺激试验 (GST)的反应能力。　结果　胰岛 β细胞的分泌功能在OGTT随空腹血糖的升高而下降(P <0 0 1) ;在GST随血糖升高而增强 ,达 9mmol/L以上时维持在高水平。OGTT胰岛素释放倍数与胰岛素抵抗指数 (HOMA IR)呈负相关 (P <0 0 1) ,GST胰岛素释放倍数与胰岛 β细胞功能指数(HOMA β)呈正相关 (P <0 0 1)。 　结论　葡萄糖毒性干扰胰岛 β细胞功能的判断 ,血糖过高抑制OGTT时的胰岛素释放 ,GST受此影响小 ,能较客观反映胰岛 β细胞功能状态。     

The effect of intravenous metformin on glucose metabolism during hyperglycaemia in type 2 diabetes.

A stepped intravenous metformin infusion was used in conjunction with the hyperglycaemic clamp technique to study the dose-response relationship of plasma metformin concentration with hepatic glucose production and peripheral glucose disposal in nine patients with Type 2 diabetes. The study was of double-blind crossover design, using NaCl infusion as control. Plasma metformin concentrations spanning the therapeutic range (1.64 +/- 0.13 mg l-1 and 6.57 +/- 0.61 mg l-1) were achieved. No differences in peripheral glucose disposal were demonstrated when compared with NaCl infusion (3.4 +/- 0.1 vs 3.6 +/- 0.2 (+/- SE) mg kg-1 min-1 and 3.4 +/- 0.2 vs 3.3 +/- 0.2 mg kg-1 min-1, respectively). There was also no difference in basal hepatic glucose production during metformin and NaCl infusion (2.7 +/- 0.3 vs 2.8 +/- 0.2 mg kg-1 min-1). No acute effect of metformin on hepatic glucose production or peripheral glucose disposal was observed, implying that a chronic persistent effect is more important in these respects than immediate effects consequent upon changes in plasma drug level.     

UK Prospective Diabetes Study V. Characteristics of Newly presenting Type 2 Diabetic Patients: Estimated Insulin Sensitivity and Islet B-cell Function

In 713 newly diagnosed Caucasian diabetic patients aged 25–65 inclusive, insulin sensitivity and islet B-cell function were estimated from fasting plasma glucose and insulin concentrations by Homeostasis Model Assessment. Insulin sensitivity was reduced in obese subjects. It was also slightly lower in male than in female diabetic patients, in those who were sedentary and in those with high fasting plasma glucose concentrations. The estimated B-cell function was particularly impaired in patients with a high fasting plasma glucose and in those with normal rather than excess body weight. Whilst diabetes can present in normal weight patients with marked deficiency of B-cell function, presenting patients often have only a moderate impairment of B-cell function with markedly impaired insulin sensitivity secondary to obesity, physical inactivity, or being male.     

热量限制改善2型糖尿病患者胰岛素抵抗及胰岛功能的分子机制

2型糖尿病发生、发展的两大基本原因是胰岛素抵抗和胰岛β细胞功能紊乱.由于口服药物及胰岛素注射治疗所带来的不良反应及生活不便,2型糖尿病在临床上需要更方便而又安全的治疗方式.热量限制作为自然疗法中的一种,可以通过影响AMP活化蛋白激酶、自噬等改善2型糖尿病患者的胰岛素抵抗水平及胰岛功能.深入了解热量限制,改善2型糖尿病的分子机制,有助于转化到临床制定相应的治疗策略,延缓甚至阻止2型糖尿病的发生和发展.     

The plasma C-peptide and insulin responses to stimulation with intravenous glucagon and a mixed meal in well-controlled Type 2 (non-insulin-dependent) diabetes mellitus: dependency on acutely established hyperglycaemia

Summary The dose-response relationships between acutely established hyperglycaemia and the plasma C-peptide and insulin responses to i. v. stimulation with 1 mg of glucagon and a standard mixed meal were investigated in 10 patients with well-controlled Type 2 (non-insulin dependent) diabetes mellitus. Hyperglycaemia was maintained for 90 min before stimulation using a hyperglycaemic clamp technique. Each test was performed on different steady state blood glucose levels of 6 mmol/l, 12 mmol/l, and 20 mmol/l, respectively. The plasma C-peptide and insulin responses after glucagon and the meal were potentiated markedly at each level of prestimulatory hyperglycaemia. After glucagon injection, the relative glucose potentiation of the insulin response was significantly higher than the relative glucose potentiation of the C-peptide response at each level of hyperglycaemia (p<0.01). This difference may be explained by a higher fractional hepatic removal of insulin at normoglycaemia, since the molar ratio between the incremental C-peptide and insulin responses after glucagon stimulation was higher at prestimulatory normoglycaemia (4.85 (3.65–12.05)) than at the prestimulatory blood glucose concentrations 12 mmol/l (2.41 (2.05–4.09)) (p< 0.01) and 20 mmol/l (2.24 (1.37–3.62)) (p<0.01). In conclusion, the islet B-cell responses to glucagon and a standard mixed meal are potentiated to a high degree by acutely established prestirnulatory hyperglycaemia in patients with well-controlled Type 2 diabetes. Acute prestirnulatory hyperglycaemia is also associated with a markedly reduced incremental C-peptide/insulin ratio after glucagon stimulation in such patients. Measurement of the insulin response after i. v. glucagon injection at acute hyperglycaemia compared with the response at normoglycaemia therefore seriously overestimates the relative glucose potentiation of pancreatic B-cell responsiveness in patients with well-controlled Type 2 diabetes.     

Circulating zonulin levels in newly diagnosed Chinese type 2 diabetes patients

AimsStudies suggest that type 2 diabetes mellitus is associated with increased gut permeability. Human zonulin is the only physiological mediator discovered to date that is known to regulate gut permeability reversibly by disassembling intestinal tight junctions. However, the relationship between zonulin and type 2 diabetes remains to be defined, and no Chinese population-based data were reported. The aim of this study was to investigate the association between serum zonulin levels and type 2 diabetes in a Chinese Han population.Methods143 newly diagnosed type 2 diabetes patients, 124 patients with impaired glucose tolerance and 121 subjects with normal glucose tolerance were enrolled in this study. Serum zonulin was measured by ELISA.ResultsPatients with type 2 diabetes had higher serum zonulin levels than impaired or normal glucose tolerant subjects. Serum zonulin correlated with body mass index, waist-to-hip ratio, triglyceride, total cholesterol, HDL-C, fasting plasma glucose, 2 h plasma glucose, HbA1c, tumor necrosis factor α, interleukin 6, HOMA-IR and QUICK index using correlation analysis (p < 0.05 for all). Multivariate stepwise regression analysis showed that zonulin levels were independently associated with insulin resistance (β = 0.024, p = 0.005). In logistic regression analysis, zonulin levels were an independent predictor of type 2 diabetes (OR = 1.080, p = 0.037).ConclusionsSerum zonulin levels are significantly elevated in newly diagnosed Chinese Type 2 diabetes patients, and are associated with dyslipidemia, inflammation and insulin resistance, indicating a potential role of zonulin in the pathophysiology of type 2 diabetes in Chinese.     

胰岛素与口服降糖药对新诊断2型糖尿病患者β细胞功能的影响

目的比较胰岛素（Ins）与口服降糖药（OHA）治疗对新诊断2型糖尿病（T2DM）患者胰岛β细胞功能的影响。方法64例新诊断T2DM患者随机分为Ins组和OHA治疗组。定期检测PG、Ins、C-P水平及其他相关指标,用HOMA-β、HOMA-IR及△I30／△G30来评价胰岛功能变化。结果（1）随访至6个月时,两组上述指标均元统计学差异（P均〉0．05）。（2）随访至12个月时,与OHA组比,Ins组HOMA-β及△I30／△G30较治疗前显著上升（P〈0．05）。两组HOMA-IR无统计学差异（P〉0．05）。结论与0HA相比,早期Ins治疗能更好地保护B细胞功能。     

2型糖尿病胰岛细胞胰岛素抵抗的机制

胰岛素抵抗是2型糖尿病(T2DM)主要病理生理机制之一.肝脏、肌肉和脂肪组织存在胰岛素抵抗.近年来研究显示,胰岛α细胞与β细胞也存在胰岛素抵抗.高糖、高游离脂肪酸(FFA)、氧化应激、炎性反应均可导致胰岛素抵抗:高糖作用可下调胰岛α、β细胞磷脂酰肌醇3激酶(PI3K)/蛋白激酶B(PKB)途径;高FFA抑制胰岛素受体底物(IRS)及PI3K活性;氧化应激使胰岛α、β细胞的IRS表达下降;炎性因子可干扰IRS/PI3K信号通路.     

瑞格列奈与甘精胰岛素联合治疗新诊断2型糖尿病的疗效观察

目的：比较新诊断2型糖尿病患者应用胰岛素促泌剂瑞格列奈单一治疗及联合长效胰岛素甘精胰岛素治疗12周后血糖水平的差异。方法纳入2012年1月~2013年1月北京军区总医院新诊断2型糖尿病患者48例,随机分为单药治疗组（n=24）及联合治疗组（n=24）,单药治疗组仅餐前口服瑞格列奈（初始计量0.5 mg）,联合治疗组除餐前服用瑞格列奈外,每晚8 pm皮下注射甘精胰岛素（初始计量6 u）。根据血糖水平调整用药剂量,治疗12周后观察两组空腹静脉血糖（FBG）水平、餐后2小时血糖（2 hPBG）水平、糖化血红蛋白（HbA1c）水平及血糖达标时间。结果与单药治疗组相比,联合治疗组FBG[（5.9±1.6）mmol/L vs.（6.8±1.5）mmol/L]、2 hPBG[（8.8±0.9）mmol/L vs.（9.2±0.8）mmol/L]、HBA1c[（7.4±0.5）% vs.（7.8±1.3）%]均更低,且血糖达标时间明显缩短[（6.1±1.3）d vs.（8.9±2.5）d]。结论胰岛素促泌剂与长效胰岛素联合治疗2型糖尿病初始治疗较单独应用胰岛素促泌剂效果更好,并能促使血糖尽快达标。     

Residual B-cell function in type 1 (insulin-dependent) diabetes mellitus: Its relation to clinical and metabolic features

Summary The aim of the present study was to investigate whether or not residual B-cell function could be related to insulin sensitivity as well as to duration of disease, insulin requirement, and indices of metabolic control in a population of Type 1 (insulin-dependent) diabetic patients. A positive correlation was found between fasting C-peptide and age at onset of diabetes, whereas a negative relationship occurred between C-peptide and duration of disease. Fasting C-peptide negatively correlated also to mean daily plasma glucose, 24-h glycosuria, and fasting free fatty acid concentration. Moreover, a negative correlation was found between C-peptide and daily insulin requirement. Conversely, a positive relationship occurred between C-peptide levels and the parameter we used for estimating insulin sensitivity, i.e. glucose disappearance rate after i.v. insulin injection. These results once more emphasize the importance of residual B-cell function in Type 1 (insulin-dependent) diabetes mellitus, and suggest that the residual endogenous insulin secretion might play an important role in glucose homeostasis of Type 1 diabetes by influencing the sensitivity to insulin. Supported by grant No. 83/02132.04 fromConsiglio Nazionale delle Ricerche (CNR), Roma, Italy.     

新诊断2型糖尿病患者血清铁蛋白与糖、脂代谢及胰岛功能的关系

目的 比较不同血清铁蛋白(SF)水平的新诊断2型糖尿病(T2DM)患者糖、脂代谢及胰岛功能,分析其与SF的关系.方法 以新诊断T2DM患者115例为观察对象,按SF浓度分为高SF组40例(SF≥274.66 μg/L)与正常SF组75例(21.80 μg/L≤SF< 274.66 μg/L).测量两组患者的身高、体重、腰围、臀围,检测空腹血糖、餐后2h血糖(2 hPG)、HbA1c、空腹胰岛素(FINS)、总胆固醇、甘油三酯、高密度脂蛋白-胆固醇(HDL-C)、低密度脂蛋白-胆固醇(LDL-C),计算体重指数、腰臀比、稳态模型评估-胰岛素抵抗指数(HOMA-IR)、稳态模型评估-胰岛β细胞功能指数(HOMA-β)、定量胰岛素敏感性指数(QUICKI)和处置指数,并进行Spearman相关性及多元线性回归分析.结果 高SF组体重指数、FINS、甘油三酯、HOMA-IR高于正常SF组(t=2.470、2.631、2.316、2.879,P均<0.05),HDL-C、QUICKI低于正常SF组(t=-2.030、-2.623,P均<0.05);SF水平与体重指数、腰臀比、空腹血糖、2 hPG、HOMA-IR、甘油三酯均呈正相关(r=0.191 ～0.303,P均<0.05),与HDL-C、QUICKI、处置指数呈负相关(r=-0.221、-0.261、-0.293,P均<0.05);多元线性回归分析显示体重指数、处置指数和甘油三酯是SF的独立相关因素(β=0.041、-0.443、0.270,P均<0.05).结论 高SF水平的新诊断T2DM患者其糖、脂代谢紊乱及胰岛素抵抗程度较正常SF的T2DM患者更严重,SF可能通过增加胰岛素抵抗,促进T2DM的发生和发展.     

TAp63 is correlated with chronic inflammation in patients with newly diagnosed type 2 diabetes mellitus

Aims

To investigate TAp63 expression in patients with type 2 diabetes mellitus (T2DM) and the potential correlations between TAp63 and proinflammatory cytokines production and other clinical parameters.

A randomized crossover study of sulphonylurea and insulin treatment in patients with type 2 diabetes poorly controlled on dietary therapy

In 13 non-obese patients with Type 2 diabetes mellitus who failed to achieve adequate blood glucose control on dietary treatment (fasting blood glucose 13.4 +/- 2.7 (+/- SD) mmol l-1, glycosylated haemoglobin 13.0 +/- 1.7%), the effects of 6 months insulin or sulphonylurea therapy on blood glucose control and lipid metabolism were compared in a randomized crossover study. Three patients, who showed a clear improvement on insulin (median glycosylated haemoglobin fell from 14.7 to 8.6%), withdrew from the study prematurely because of subjective and objective signs of hyperglycaemia after crossover from insulin to sulphonylurea. Daily dose after 6 months was 2000 mg tolbutamide (n = 3), 18 +/- 1 mg glibenclamide (n = 7), or 34 +/- 3 U insulin. On insulin, fasting (8.0 +/- 1.9 mmol l-1) and postprandial blood glucose (10.4 +/- 2.7 mmol l-1), and glycosylated haemoglobin (9.5 +/- 1.1%) were lower than on sulphonylurea (11.0 +/- 3.4 mmol l-1, 14.4 +/- 4.8 mmol l-1 and 11.0 +/- 2.5%, respectively, p less than 0.05 in each case). Median increase in body weight was greater on insulin (4.2 vs 1.1 kg, p less than 0.05). Six patients experienced improved well-being on insulin compared with sulphonylurea. Median plasma non-esterified fatty acids decreased from 825 mumol l-1 to 476 mumol l-1 (sulphonylurea) and 642 mumol l-1 (insulin, both p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

miR-375与2型糖尿病

miR-375是一类特异性高表达于胰腺组织的非编码小RNA.研究表明,miR-375直接调控多种胰岛组织中特异性转录因子的表达,参与调控多种基因及信号转导通路,影响糖、脂代谢,在2型糖尿病的发生、发展中起一定作用.miR-375对胰岛β细胞分化、胰岛素分泌及糖、脂代谢的调控作用可能为2型糖尿病的早期干预和治疗提供新方向.     

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.     

C-peptide concentrations in patients with type 2 diabetes treated with insulin

AimsTo determine beta cell reserves of patients with type 2 diabetes who are treated with insulin by using fasting C-peptide concentrations and to investigate the clinical features related to C-peptide concentrations.Materials and methodsPatients with type 2 diabetes, who were using insulin as monotherapy or in combination therapy, were divided into three groups; those with an insufficient beta cell reserve (C-peptide: <0.5 ng/mL), borderline reserve (C-peptide: 0.5–2 ng/mL) and sufficient reserve (C-peptide:> 2 ng/mL).ResultsIn the 249 patients (mean age, 61.77 ± 9.34 years; 40.6% male), the mean duration of diabetes was 13.9 ± 8.43 years. The mean HbA1c concentrations, fasting glucose and C-peptide concentrations were 8.88 ± 1.87%, 184.29 ± 77.88 mg/dL and 1.95 ± 1.37 ng/mL, respectively. Fifty-seven percent of patients (n = 142) had a borderline beta cell reserve and 37% (n = 92) had high C-peptide concentrations. Only 6% of patients (n = 15) had an insufficient beta cell reserve. C-peptide levels were positively correlated with waist circumference (r: 0.282; p = 0.001), hip circumference (r: 0.251; p = 0.001), body mass index (r: 0.279; p = 0.001), fasting glucose concentrations (r: 0.309; p = 0.001) and triglyceride concentrations (r: 0.358; p = 0.001).ConclusionIn this study, almost all patients with type 2 diabetes using insulin were found to have sufficient or borderline beta cell reserves and insulin resistance-related parameters were prominent in those with adequate beta cell reserve.Clinical trials noNCT04005261