Failure to adequately adapt reduced insulin sensitivity with increased insulin secretion in women with impaired glucose tolerance

Summary To study the islet adaptation to reduced insulin sensitivity in normal and glucose intolerant post-menopausal women, we performed a euglycaemic, hyperinsulinaemic clamp in 108 randomly selected women, aged 58–59 years. Of the 20 women with the lowest insulin sensitivity, 11 had impaired glucose tolerance (IGT) whereas 9 had normal glucose tolerance (NGT). These women together with 15 women with medium insulin sensitivity and 16 women with high insulin sensitivity and NGT were further examined with arginine stimulation at three glucose levels (fasting, 14 and >25 mmol/l). In NGT, the acute insulin response (AIR) to 5 g i. v. arginine at all three glucose levels and the slope_AIR, i. e. the glucose potentiation of insulin secretion, were markedly increased in the women with the lowest insulin sensitivity and NGT compared to those with medium or high insulin sensitivity. In contrast, in low insulin sensitivity, AIR was significantly lower in IGT than in NGT (at glucose 14 mmol/l p=0.015, and at >25 mmol/l p=0.048). The potentiation of AIR induced by low insulin sensitivity in women with NGT was reduced by 74% (AIR at 14 mmol/l glucose) and 57% (AIR at >25 mmol/l glucose), respectively, in women with IGT. Also the slope_AIR was lower in IGT than in NGT (p=0.025); the increase in slope_AIR due to low insulin sensitivity was abolished in IGT. In contrast, glucagon secretion was not different between women with IGT as opposed to NGT. We conclude that as long as there is an adequate beta-cell adaptation to low insulin sensitivity with increased insulin secretory capacity and glucose potentiation of insulin secretion, NGT persists.Abbreviations NIDDM Non-insulin-dependent diabetes mellitus - AIR acute insulin response - AGR acute glucagon response     

Abnormal insulin secretion and glucose metabolism in pancreatic islets from the spontaneously diabetic GK rat

Summary Insulin secretion and islet glucose metabolism were compared in pancreatic islets isolated from GK/Wistar (GK) rats with spontaneous Type 2 (non-insulin-dependent) diabetes mellitus and control Wistar rats. Islet insulin content was 24.5±3.1 U/ng islet DNA in GK rats and 28.8±2.5 U/ng islet DNA in control rats, with a mean (±SEM) islet DNA content of 17.3±1.7 and 26.5±3.4 ng (p < 0.05), respectively. Basal insulin secretion at 3.3 mmol/l glucose was 0.19±0.03 · ng islet DNA^–1· h^–1 in GK rat islets and 0.40±0.07 in control islets. Glucose (16.7 mmol/l) stimulated insulin release in GK rat islets only two-fold while in control islets five-fold. Glucose utilization at 16.7 mmol/l glucose, as measured by the formation of ³H₂O from [5-³ H]glucose, was 2.4 times higher in GK rat islets (3.1±0.7 pmol · ng islet DNA^–1 · h^–1) than in control islets (1.3±0.1 pmol · ng islet DNA^–1 · h^–1; p<0.05). In contrast, glucose oxidation, estimated as the production of ¹⁴CO₂ from [U-¹⁴C]glucose, was similar in both types of islets and corresponded to 15±2 and 30±3 % (p<0.001) of total glucose phosphorylated in GK and control islets, respectively. Glucose cycling, i. e. the rate of dephosphorylation of the total amount of glucose phosphorylated, (determined as production of labelled glucose from islets incubated with ³H₂O) was 16.4±3.4% in GK rat and 6.4±1.0% in control islets, respectively (p<0.01). We conclude that insulin secretion stimulated by glucose is markedly impaired in GK rat islets. Glucose metabolism is also altered in GK rat islets, with diminished ratio between oxidation and utilization of glucose, and increased glucose cycling, suggesting links between impaired glucose-induced insulin release and abnormal glucose metabolism.     

UK prospective diabetes study (UKPDS)

Summary The UK Prospective Diabetes Study (UKPDS) is a multi-centre, prospective, randomised, intervention trial of 5100 newly-diagnosed patients with Type 2 (non-insulin-dependent) diabetes mellitus which aims to determine whether improved blood glucose control will prevent complications and reduce the associated morbidity and mortality. Newly presenting Type 2 diabetic patients aged 25–65 years inclusive, median age 53 years, median body mass index 28 kg/m² and median fasting plasma glucose 11.3 mmol/l, were recruited and treated initially by diet. Ninety five percent remained hyperglycaemic (fasting plasma glucose > 6 mmol/l) and were randomly allocated to different therapies. In the main randomisation, those who were asymptomatic and had fasting plasma glucose under 15 mmol/l were allocated either to diet policy, or to active policy with either insulin or sulphonylurea aiming to reduce the fasting plasma glucose to under 6 mmol/l. Over 3 years, the median fasting plasma glucose in those allocated to diet policy was 8.9 mmol/l compared with 7.0 mmol/l in those allocated to active policy. The Hypertension in Diabetes Study has been included in a factorial design to assess whether improved blood pressure control will be advantageous. Patients with blood pressure 160/90 mm Hg were randomly allocated to tight control aiming for < 150/85 mm Hg with either an angiotensin-converting enzyme inhibitor or a Beta-blocker or to less tight control aiming for < 200/105 mm Hg. The endpoints of the studies are major clinical events which affect the life and well-being of patients, such as heart attacks, angina, strokes, amputations, blindness and renal failure. To date, 728 patients have had at least one clinical endpoint. Surrogate endpoints include indices of macrovascular and microvascular disease detected by ECG with Minnesota Coding, retinal colour photography and microalbuminuria. The studies also aim to evaluate potential risk factors for the development of diabetic complications such as smoking, obesity, central adiposity, plasma LDL-and HDL-cholesterol, triglyceride, insulin, urate and other biochemical variables. The studies are planned to terminate in 1994, with a median follow-up of 9 years (range 3–16 years) for the glucose study and 5 years (range 2–6 years) for the hypertension study.     

2型糖尿病患者治疗3年前后临床疗效对比分析

目的比较和分析2型糖尿病(T2DM)患者治疗3年前后的代谢和血压控制、胰岛B细胞功能变化及其与糖尿病并发症的关系。方法选择1993—2000年解放军第306医院糖尿病中心治疗3年的T2DM患者,测量身高、体重、腰围、臀围、卧立位血压,测定空腹及餐后2h血糖和胰岛素、糖化血红蛋白(HbA1c)、胆固醇(TC)、三酰甘油(TG)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)、肌酐(Cr)、尿微量白蛋白等和眼底检查,统计分析血糖、血脂和血压治疗达标率及相应的用药情况。结果T2DM患者治疗3年后应用的降血糖药物种类、降血压药物种类、调脂药物及胰岛素使用者的比例明显升高。HbA1c、HDL-C控制理想的病例从3年前的23%、69%升高到3年后的30%、76%;血压、TC、TG和LDL-C情况无明显改变;空腹及餐后胰岛素、胰岛素抵抗指数(HOMA-IR)明显下降,微量白蛋白尿的病例从3年前的15%增加到3年后的23%;眼底病变则由26%升高到33%。结论尽管T2DM患者使用降糖药、调脂药和胰岛素治疗的病例数明显增加,但3年治疗后代谢控制仍不满意,胰岛B细胞功能明显下降,眼底病和肾脏受损在加重,需要进一步重视T2DM治疗的全面达标。     

Prolonged exposure of pancreatic beta cells to raised glucose concentrations results in increased cellular content of islet amyloid polypeptide precursors

Summary Most non-insulin dependent diabetic patients have amyloid deposits in their pancreatic islets. It is not known whether chronic hyperglycaemia contributes to the formation of amyloid fibrils from the islet amyloid polypeptide that is produced by the pancreatic beta cells. Since islet amyloid exhibits islet amyloid polypeptide precursors immunoreactivity, we examined whether sustained in vitro exposure to raised glucose increases the abundance of these precursors in human beta cells. After 6 days stimulation with 20 mmol/l glucose the cellular content of insulin but not islet amyloid polypeptide was decreased leading to an increase in the ratio of the latter over insulin (3.0 ± 0.6 vs 1.8 ± 0.3 after 6 mmol/l glucose culture, p < 0.05). Similar changes occurred in rat beta cells cultured for 3 days in the presence of 20 mmol/1 glucose plus 3-isobutyl-1-methylxanthine. Western blot analysis of cellular islet amyloid polypeptide after prolonged exposure to high glucose indicated the presence of higher proportions of its precursor- and intermediate forms. In human beta cells cultured in 20 mmol/l glucose, the major form corresponds to an intermediate species which exhibits an immunoreactivity for the N-flanking peptide, as is also the case in islet amyloid. We concluded that prolonged in vitro exposure of beta cells to raised glucose concentrations increases the relative proportion of islet amyloid polypeptide over insulin, as well as of its precursors over the mature form of islet amyloid polypeptide. [Diabetologia (1999) 42: 188–194] Received: 1 April 1998 and in final revised form: 13 October 1998     

Heterogeneous glycaemic and insulinaemic responses to oral glucose in non-diabetic men: interactions between duration of obesity,body fat distribution and family history of diabetes mellitus

Summary The interaction between environmental and genetic factors in the alterations of glucose-insulin homeostasis was studied in 104 non-diabetic men. Family history of diabetes mellitus was used as an index of genetic predisposition to diabetes. Body composition was measured by under-water weighing whereas subcutaneous and visceral adipose tissue areas were measured at the abdominal and femoral levels by computed tomography. The sample was first divided into two groups. The first group included subjects with normal glycaemic and insulinaemic responses during a 75 g oral glucose tolerance test. The second group was composed of subjects either with a high glucose response or high insulin response or both. Men included in the second group were different from the normal subjects for almost all body fatness variables. They also presented a prevalence of a positive family history of diabetes which was significantly higher than normal subjects. The second group was then divided into three distinct subgroups based on insulin and glucose responses of the subjects during the oral glucose tolerance test. Subjects with high insulin but normal glucose responses were characterized by significantly higher levels of total body fat and deep abdominal adipose tissue when compared to the normal group (p<0.05). Men with both high insulinaemic and glycaemic responses displayed higher body fatness values and higher deep and subcutaneous abdominal adipose tissue areas (p<0.05) in comparison with normal subjects. They also had a higher body mass index at age 20 years than control subjects and subjects with high insulin but normal glucose responses. In contrast, subjects with normal insulin but with high glucose responses were not different from the normal group with regard to body fat and adipose tissue areas. These results show the heterogeneous origin of altered glucose-insulin homeostasis in non-diabetic men. Finally, subjects in the altered glucose-insulin homeostasis group with no family history of diabetes displayed a higher body mass index at age 20 years (p<0.05) in comparison with subjects who had a positive family history of the disease. They also presented a greater abdominal-to-thigh fat ratio measured by computed tomography. These results suggest that in men with alterations of glucose-insulin homeostasis, the relationship of body fat distribution to glucose tolerance and plasma insulin levels is different in those with no family history of diabetes than in subjects with a positive family history of diabetes.     

Twenty-four-hour energy expenditure in Pima Indians with Type 2 (non-insulin-dependent) diabetes mellitus

Summary To assess the impact of Type 2 (non-insulin-dependent) diabetes mellitus on energy metabolism, 24-h energy expenditure, basal metabolic rate and sleeping metabolic rate were measured in a respiratory chamber in 151 Pima Indians, 102 with normal glucose tolerance (67 male/35 female, (mean ± SD) 28±7 years, 99±24 kg, 32±9% body fat) and in 49 with Type 2 diabetes (22 male/27 female, 35±11 years, 107±33 kg, 39±7% body fat), after at least 3 days on a weight maintaining diet. After adjustment for differences in fat-free mass, fat mass, age and sex, 24-h energy expenditure, basal metabolic rate and sleeping metabolic rate were significantly higher in diabetic patients than in control subjects (72 kcal/day, p<0.05; 99 kcal/day, p<0.005; 99 kcal/day, p<0.001 respectively). Spontaneous physical activity was similar in both groups whereas the thermic effect of food, calculated as the mean energy expenditure corrected for activity throughout the day above sleeping metabolic rate and expressed as a percentage of energy intake, was significantly lower in Type 2 diabetic patients (17.1±7.1 vs 19.8±5.6%, p<0.05). Adjusted values of 24-h energy expenditure, basal metabolic rate and sleeping metabolic rate were correlated with hepatic endogenous glucose production (r=0.22, p<0.05; r=0.22, p<0.05; r=0.31, p<0.01 respectively). Therefore, increased basal and sleeping metabolic rates, resulting in increased 24-h sedentary energy expenditure may play a role in the weight loss so often observed in Type 2 diabetic subjects in addition to the energy loss from glycosuria.     

Epidemiology of renal involvement in newly-diagnosed middle-aged and elderly diabetic patients. Cross-sectional data from the population-based study “Diabetes Care in General Practice”, Denmark

Summary We report on a study in which 487 Danish general practitioners participated with the purpose of including all newly-diagnosed diabetic patients aged 40 years or more from a well-defined catchment population during a welldefined time period. A, total of 1267 diabetic patients with a median age of 65.3 years were included. Renal involvement was assessed from the albumin/creatinine ratio in a morning urine sample. Albumin/creatinie ratio was <2/2<20/≥20 mg/mmol in 59.8/33.6/6.6% of male and 66.6/28.8/4.6% of female patients. The level of albumin/creatinine ratio increased with age and the observed overall male predominance was almost confined to diabetic patients with an albumin/creatinine ratio of 5 mg/mmol or greater. By taking into account the confounding effect of age and sex, a positive association between smoking and albumin/creatinine ratio was disclosed. Moreover, high systolic blood pressure, hypertriglyceridaemia, hypercholesterolaemia (males only) and high HbA_1c, but not body mass index or diastolic blood pressure were identified as correlates of elevated albumin/creatinine ratio. Glucosuria was positively correlated with albumin/creatinine ratio even when the influence of HbA_1c, sex and age was taken into account. A positive correlation between serum creatinine and albumin/creatinine ratio was seen in males, but not in females. In addition, renal involvement was associated with the presence of peripheral angiopathy and diabetic retinopathy and with high resting heart rate. The cross-sectional data presented highlight the importance of reducing the overall burden of modifiable risk factors in newly-diagnosed Type 2 diabetic patients.     

Molecular screening of the glucokinase gene in familial Type 2 (non-insulin-dependent) diabetes mellitus

Summary The glucokinase locus has been implicated by linkage studies in several Caucasian pedigrees with early onset, autosomal dominant diabetes, and mutations have been identified in a large number of these pedigrees. Although mutations have been reported in some pedigrees with late onset Type 2 (non-insulin-dependent) diabetes mellitus, linkage studies of typical familial Type 2 diabetes did not suggest a major role for this locus. Nonetheless, linkage studies were consistent with the hypothesis that mutations of the glucokinase gene were responsible for the pathogenesis of Type 2 diabetes in a minority of pedigrees or one gene in a polygenic disorder. To systematically address this hypothesis, we examined 60 diabetic members of 18 pedigrees ascertained for two or more Type 2 diabetic siblings and eight unrelated diabetic spouses. Initially, the coding regions from each of the 11 glucokinase exons were examined by the sensitive technique of single strand conformation polymorphism analysis to screen for single nucleotide substitutions. Subsequently, we also sequenced each exon from an affected member of the single pedigree in which a glucokinase allele was most likely to segregate with diabetes. Single strand conformation polymorphism analysis detected only three variants, none of which altered the amino acid sequence. No coding or splice site mutations were detected. Likewise, no additional mutations were detected upon direct sequence analysis. However, additional screening of promoter and 3′ untranslated regions detected a variant pattern in the untranslated region of exon 10 which appeared to segregate with diabetes and impaired glucose tolerance in one pedigree. Sequence analysis demonstrated the deletion of a cytosine in exon 10 at position 906, but this deletion was not associated with Type 2 diabetes among unrelated spouses, was not linked to diabetes, and was not associated with significant elevations of fasting glucose or insulin among non-diabetic pedigree members. Similarly, two common variants in the islet promoter did not segregate with diabetes. We conclude that among typical familial Type 2 diabetes in a population representative of Northern European Caucasians, glucokinase mutations are an unlikely cause of diabetes. [Diabetologia (1994) 37: 182–187] Received: 10 June 1993 and in revised form: 20 August 1993     

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.