Classification of Diabetes Mellitus by Studies of C-Peptide Secretory Capacity

Residual pancreatic B-cell function was investigated in children with diabetes mellitus in whom classification of the type of disease was difficult at the first visit. Intravenous glucagon tests were performed at the first visit and subsequently, the C-peptide responses compared. Based on our data on a limited number of patients, we propose C-peptide concentrations of 3.0 to 3.5 ng/ml at the peak or at 6 min after injection of glucagon, as the critical level which distinguishes non-insulin dependent from insulin-dependent diabetes mellitus. However, the degree of obesity, clinical stage and other factors also need to be considered in the classification of diabetes mellitus.     

Metabolic response to beet fibre test meals

Test meals with 10.9 g dietary fibre from sugar beet and corresponding control meals were given to eight healthy subjects, aged 67 ± 9 years. The postprandial glucose, triglyceride, hormone and glycerol responses were monitored during 3 hours. After the beet fibre meal the insulin and C-peptide areas were reduced by 28 ( P < 0.01) and 22% ( P > 0.025), respectively, and the somatostatin levels increased by approximately 30% ( P > 0.05). Further, the maximum relative postprandial reduction of plasma glycerol levels was less evident after the fibre-rich meal than after the control meal (36 ± 4% v. 46 ± 4%, P < 0.05). There was no apparent difference in the overall glycaemic response between the meals. The triglyceride levels were similar after both test meals.
Suspension of beet fibre bread given to rats by oro-gastric intubation induced lower blood glucose response than a control bread at 15 and 30 min ( P < 0.001), respectively, but a similar insulin response.
The results suggest an effect of beet fibre on the rate of carbohydrate absorption, expressed as a lower insulin response in the healthy volunteers and a reduced glucose response in the rat.
The mechanism behind this effect in healthy subjects could possibly be mediated by an increased somatostatin response.     

Stimulation by hCRF of C-peptide release in type 2 diabetics during concomitant opioid receptor blockade

Summary Administration of synthetic human corticotropin-releasing factor (hCRF, 2 µg/kg body weight) during simultaneous application of the opioid antagonist naloxone (1.6 mg i.v. bolus, followed by an infusion at a rate of 1.2 mg/h) produced a significant increase in plasma C-peptide levels of six male Type 2 diabetic patients which even exceeded the postprandial values. This stimulatory effect of hCRF/naloxone on plasma C-peptide was less pronounced in six healthy men. hCRF alone did not provoke any reaction of plasma C-peptide in either group.The possibility of a paracrine, CRF-dependent mechanism in pancreatic islets which somehow involves inhibitory opioid receptors is preferentially discussed. Such a mechanism may underlie the stimulatory action of hCRF/naloxone on B cells and would explain the absent reaction of peripheral venous plasma C-peptide to hCRF alone as well as the amplifying effect of simultaneous opioid receptor blockade.Abbreviations ACTH adrenocorticotropic hormone - C-peptide connecting-peptide - CRF corticotropin-releasing factor - hCRF human CRF - oCRF ovine CRF - min minutes - S.D. standard deviation - S.E.M. standard error of the mean This study was supported by the Deutsche Forschungsgemeinschaft (Go 299/3-2)Dedicated to Professor Dr. N. Zöllner on the occasion of his 65th birthday     

Effect of C-peptide administration on whole body glucose utilization in STZ-induced diabetic rats

Recent studies suggest that C-peptide stimulates glucose transport in isolated skeletal muscle. In order to determine the effect of C-peptide on whole body glucose utilization, streptozotocin (60 mg kg^-1) (STZ)-induced diabetic and normal rats were studied using the euglycaemic clamp procedure and continuous infusion of somatostatin (1.0 μg kg^-1 min^-1) in pentobarbital-anaesthetized rats. Plasma insulin levels during the 6.0- and 30.0-mU kg^-1 min^-1 insulin infusions rose to 70–90 μU mL^-1 and 500–700 μU mL^-1, respectively. Blood glucose concentrations were clamped at 7.5–7.9 mmol L^-1 in the diabetic rats and at basal levels or 7.7 mmol L^-1 in the non-diabetic (normal) rats. Biosynthetic human C-peptide (0.5 nmol kg^-1 min^-1) was infused in 12 diabetic and 11 normal rats, resulting in concentrations of 26–41 nmol L^-1. The metabolic clearance rate of glucose (MCR) for the diabetic rats receiving C-peptide (12.0±1.0 mL kg^-1 min^-1) was significantly (P<0.01) higher than that in the diabetic rats given saline (6.3±0.7 mL kg^-1 min^-1) or a randomly scrambled C-peptide (7.8±1.3 mL kg^-1 min^-1) at low-dose insulin infusion but not at the high-dose insulin infusion. In normal rats C-peptide did not significantly increase the MCR for glucose. These results thus demonstrate that C-peptide has the capacity to increase glucose utilization in STZ-induced diabetic rats.     

Insulin Minimal Model Indexes and Secretion: Proper Handling of Uncertainty by a Bayesian Approach

The identification of the insulin minimal model (MM) for the estimation of insulin secretion rate (ISR) and physiological indexes (e.g. beta-cell sensitivity) requires the knowledge of C-peptide (CP) kinetics. The four parameters of the two-compartment model of CP kinetics in a given individual can be derived either from an additional bolus experiment or, more frequently, from a population model. However, in both situations, the CP kinetics is uncertain and, in MM identification, it should be treated as such. This paper shows how to handle CP kinetics uncertainty by using a Bayesian methodology. In seven subjects, MM indexes and ISR were estimated together with their confidence intervals, using either the bolus data or the population model to assess CP kinetics. The two main results that arise from the application of the new methodology are: (i) the use of the population model in place of the bolus data to determine CP kinetics does not affect, on average, the point estimates of ISR profile and MM parameters but only the confidence intervals which becomes wider (less than 50%); (ii) in both the bolus and population situation neglecting the uncertainty of CP kinetics, as done in MM literature so far, introduces no bias, on average, on point estimates of MM indexes but only an underestimation of confidence intervals.     

Die Kombinationstherapie Insulin/Sulfonylharnstoff in der Langzeittherapie des Typ-II-Diabetes nach „Sekundärversagen“

Summary In type 2 diabetes with secondary failure of sulfonylurea therapy good metabolic control can seldom be achieved by insulin therapy even with high insulin doses. Hyperinsulinemia however is a possible risk factor of cardiovascular disease in type 2 diabetes. Maintaining the effects of sulfonylurea action insulin should be added in as small amounts as possible to avoid hyperinsulinemia and to ameliorate hyperglycemia.16 type 2 diabetics with secondary failure were treated either with insulin alone (group A;n=8) or with 3.5 mg b.i.d glibenclamide plus small amounts of intermediate insulin (group B;n=8) in a randomised order. After the inpatient period outpatient control was performed monthly up to six months, later on four times a year up to two years.Both groups were comparable with regard to age, duration of diabetes, body weight and metabolic control. The daily insulin dose was 14±2 IU after one month and 19±2 IU after two years in group B. In contrast 30±3 IU and 43±5 IU respectively were needed in group A (p<0.001). All patients B were treated with one daily injection, all patients A needed two injections. Resulting in nearly identical metabolic control in group A basal insulin levels exceeded those in group B after two years significantly (28.6±3.7 vs. 18.6±1.6 mcU/ml;p<0.01). Endogenous C-peptide response was suppressed in group A compared to group B after inpatient period and after one month (0.12±0.01 vs. 0.49±0.15 and 0.09±0.04 vs. 0.13±0.08 pmol/ml;p<0.05). The combined therapy of insulin and sulfonylureas demonstrates the benefit of a prolonged sulfonylurea administration in the treatment of type 2 diabetes with secondary failure.As compared to common insulin therapy a small amount of exogenous insulin by one daily injection additionally to glibenclamide shows similar improvement in metabolic control. Hyperinsulinemia as a risk factor of macroangiopathy is markedly reduced in patients treated with combined therapy compared to those with insulin alone.

Herrn Professor Dr. N. Zöllner zum 65. Geburtstag gewidmet     

C肽对高糖状态下人脐静脉内皮细胞体外表达eNOS的影响

目的 :探讨在高糖状态下C肽对人脐静脉内皮细胞 (HUVEC)体外表达内皮型一氧化氮合酶 (eNOS)的影响。方法 :将培养成功的HUVEC在不同浓度的C肽和葡萄糖环境下孵育72h ,提取细胞总RNA ,应用半定量逆转录聚合酶链反应 (SQ -RT -PCR)法 ,检测eNOSmRNA表达的情况。结果 :生理浓度葡萄糖 (5 5mmol/L)状态下 ,低浓度的C肽 (0 3nmol/L)使HUVECeNOSmRNA表达减弱(P<0.01) ,生理浓度 (3nmol/L)和高浓度(30nmol/L)的C肽可使eNOSmRNA的表达明显增强(P<0.01) ;高浓度葡萄糖(33.3mmol/L)状态使HU VECeNOSmRNA表达减弱(P<0.01) ,加入生理浓度或高浓度C肽后 ,eNOSmRNA表达增强(P<0.01)。结论 :HUVEC体外eNOSmRNA表达可受C肽浓度影响 ;高浓度或生理浓度C肽可缓解高糖对HUVECeNOS表达的抑制作用。提示C肽可能对防治糖尿病大血管病变具有重要作用     

初诊2型糖尿病短期胰岛素治疗前后C肽水平的变化

目的通过观察初诊2型糖尿病患者短期胰岛素治疗前后C肽水平的变化,了解短期胰岛素治疗能否改善胰岛β细胞功能。方法对146例初诊断2型糖尿病患者(空腹血糖≥12mmol/L,未接受过其他治疗的患者)进行1～3月的短期胰岛素治疗,使血糖在短期内得到较好的控制,比较治疗前后标准馒头餐C肽释放试验的C肽水平变化。结果经过短期胰岛素治疗,所有病例血糖得到了良好控制,3个月后复查C肽释放试验,空腹及餐后30min、60min、120min和180min的C肽水平较治疗前均明显升高(P<0.001),恢复到了2型糖尿病自然病程中较为早期的水平。结论初诊2型糖尿病短期胰岛素治疗,可以使血糖在短期内达到良好控制,C肽水平明显提高,胰岛β细胞分泌功能明显得到改善。     

格雷夫斯病患者糖代谢特点及其影响因素分析

目的　了解格雷夫斯病(Graves′disease ,GD)患者胰岛素、C肽变化与糖耐量的关系。方法　未经治疗的格雷夫斯病患者6 5例,行口服葡萄糖耐量 胰岛素释放试验后,用化学发光法测血清胰岛素、C肽值并与正常对照比较。结果　格雷夫斯病组除空腹外其余各点血糖值明显增高(P <0 .0 0 1) ,基础免疫活性胰岛素正常,葡萄糖刺激后明显增高(P <0 . 0 0 2 7) ,总血清胰岛素/总血糖(∑IRI/∑BG)在弥漫性甲状腺肿伴格雷夫斯病组明显增加,游离三碘甲状腺原氨酸(FT3 )与多个时点血清胰岛素、C肽呈显著负相关。结论　格雷夫斯病在治疗前存在高血糖与高胰岛素血症并存的胰岛素抵抗状态。     

Serum C-peptide as a key contributor to lipid-related residual cardiovascular risk in the elderly

ObjectivesThe serum levels of C-peptide, an important risk factor for cardiovascular disease (CVD), increase with age. This study aimed to investigate the association between serum C-peptide and increased risk for CVD with altered lipid metabolism in the elderly.MethodsThis was a population-based cross-sectional study that included 3091 elderly participants aged ≥65 years. Serum C-peptide and lipid levels were measured according to standard protocols. Sampling weights were used to estimate the characteristics of study participants. Stratified analysis of covariance was used to evaluate the changes in the serum lipid levels according to quartiles of serum C-peptide levels, and the linear trend was assessed using a linear model. The logistic regression model was carried out to determine the association between the serum C-peptide levels and serum lipid levels.ResultsThe results of the analysis of covariance stratified by sex and serum insulin level showed that the serum triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C) levels were significantly associated with changes in the serum C-peptide levels, independent of the serum insulin level. The logistic regression analyses indicated that the serum C-peptide levels were positively associated with the serum TG levels, and negatively associated with the serum HDL-C levels. A significant dose-response association was obtained in both men and women.ConclusionsSerum C-peptide levels were strongly associated with increased serum TG and reduced HDL-C levels in the elderly. Our results suggest that serum C-peptide increases the risk of CVD via a pathway that increases TG or decreases HDL-C levels.