Determination Of C-peptide Research Articles

Evaluation of early atherosclerosis markers in patients with nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is characterized by the excessive accumulation of fat in the liver cells. It is strongly associated with cardiovascular risk factors for atherosclerosis. Flow-mediated dilation (FMD) and carotid intima-media thickness (CIMT) are noninvasive methods for the evaluation of endothelium. They are considered early markers of atherogenesis. The aim of this study was to evaluate early atherosclerosis markers in patients with NAFLD. We examined 161 patients. All the patients underwent hepatic ultrasonography, transthoracic echocardiography, and brachial artery and carotid artery imaging. Fasting blood samples were drawn from all patients for the determination of lipids, insulin, C-peptide, and fasting blood glucose. HOMA-IR was calculated. Among the 161 patients, 44 had normal hepatic ultrasonography, 42 had stage 1 hepatosteatosis, 53 had stage 2 hepatosteatosis and 22 had stage 3 hepatosteatosis. FMD was reduced in patients with NAFLD as compared with the healthy controls (5.9 ± 3.1 vs. 9.6 ± 2.7%, P<0.001). There was a significant negative moderate correlation between ultrasonographic hepatosteatosis grade and FMD (r=-0.556, P<0.001). The mean CIMT was significantly increased in patients with NAFLD as compared with the controls (0.40 ± 0.19 vs. 0.27 ± 0.18, P<0.001). There was a significant positive weak correlation between ultrasonographic hepatosteatosis grade and mean CIMT (r=0.376, P<0.001). This study showed that NAFLD is associated with impaired CIMT and FMD, which are early markers of atherosclerosis. These findings may play a crucial role in understanding the pathophysiology of the atherosclerotic process in patients with NAFLD.

C-Peptide as a Remedy for Diabetic Microangiopathy?

Insulin, connecting peptide (C-peptide) is part of the proinsulin molecule from which it is cleaved by a serine protease within the pancreatic β-cells and subsequently released in equimolar amounts with insulin (1–3). Primarily, C-peptide, which is predominantly cleared by the kidney, was regarded a biologically inert byproduct of insulin secretion and an unneeded contaminant of commercial insulin preparations (1,4), neither affecting glucose metabolism nor lipolysis (5). In contrast, radioimmunological determination of C-peptide turned out to be a useful tool for diagnostic purposes in diabetes research at large, including the estimation of insulin production rates in healthy humans (6) and of residual insulin release in type 1 diabetic patients (7) as well as in vitro (8). From 1995 onwards the question of C-peptide’s biological activity was raised again, and it was assigned a multitude of physiological actions affecting renal, neural, and circulatory functions as well as a wide spectrum of signaling phenomena in vitro (9,10). These reviews raised the hope that C-peptide might find a role in treatment of diabetes-associated late complications, particularly diabetic microangiopathy. Any such proof would be of great clinical importance as the global …

Activated Hypothalamic Pituitary Adrenal Axis in Patients with Metabolic Syndrome

Metabolic syndrome (MetS) is correlated with the activity of hypothalamic-pituitary-adrenal axis (HPA), but the underlying mechanism still remains elusive. The aim of this study was to investigate the HPA axis function in patients with MetS. This case-control study included 159 people. They were divided into 2 groups. The first group included 73 healthy volunteers (control group: 19 males, 54 females, mean±SD: 49.9±7.5 years old, with BMI: 27.9±4.42 kg/m2) and the second group included 86 patients with MetS (case group: 48 males, 38 females, mean±SD: 52.2±7.6 years old, with BMI: 30.5±5.35 kg/m2). An oral glucose tolerance test (OGTT) was performed for all subjects after a 12-h overnight fast, and blood samples were obtained for determination of ACTH, cortisol, insulin, C-peptide, and glucose levels. Serum cortisol after an overnight dexamethasone suppression test was determined in both groups. Patients with MetS had serum cortisol levels after an overnight dexamethasone suppression test significantly higher than controls. During OGTT plasma ACTH levels were higher at all time points in patients with MetS compared to controls, whereas serum cortisol levels were comparable between the 2 groups. Plasma ACTH during OGTT was also correlated with most of the components of MetS. The HPA axis in patients with MetS seems to be more active as evidenced by the higher cortisol levels after the overnight dexamethasone suppression test and by the higher ACTH levels during OGTT. This functional hypercortisolism might be involved in the pathogenesis of the metabolic syndrome.

How the immunoassay transformed C-peptide from a duckling into a swan

This edition of 'Then and now' re-examines Lise Heding's very highly cited paper 'Radioimmunological determination of human C-peptide in serum', which was published in Diabetologia in 1975. We show how this article and other related articles by Heding contributed to heightened respect for C-peptide (and transformation of Heding's research programme). Initially thought of as an inert discard, C-peptide in blood is now recognised as an excellent surrogate measure of insulin secretion under a wide range of conditions. The assay is especially valuable for acute ascertainment of the insulin secretory capabilities of patients with type 1 diabetes or of transplanted beta cells. The assay is also being used to monitor endogenous beta cell loss or in vivo expansion of beta cell mass over the long term. We conclude with two promising future applications: (1) measurements of C-peptide in blood (along with insulin, glucose, and HbA(1c)) at annual intervals as a potential approach to earlier diagnosis of diabetes; and (2) among many recent advances in recognising properties of C-peptide (including status as a candidate hormone), most promising is C-peptide as a possible therapy for diabetic neuropathy and nephropathy.

The Importance of HbA1c Control in Patients with Subclinical Hypothyroidism.

Goal:To investigate the correlation between TSH and HbA1c in the treatment of L-thyroxine in the process of glycemic control in patients with subclinical hypothyroidism.Patients and methods:The sample consisted of 100 patients, mean age 51.75±3.23 years, BMI=27.97±4.52 kg/m2, with SH (TSH>4.2 mU/L and normal serum T3 and T4). Laboratory diagnosis included the determination of free T3, free T4, thyroid antibodies, Tg, insulin, C-peptide and glucose during the OGTT, HbA1c, CRP and lipid levels. 20 patients with SH had prediabetes and 38 patients had DM. All patients were treated with low doses of L-thyroxine (25-50ug) and all were physically active.Results:After 6 months of treatment with L-thyroxine, the patients had normal or decreased TSH (5.85±0.92 vs. 3.54±0.55 mU/L), insulin levels (114.64±24.11 vs. 96.44±17.26 pmol/L) significantly reduced HbA1c (6.74±1.01 vs. 6.26±1.12) is reduced.Conclusion:The correlation between TSH and HbA1c was positive and significant (r=0.46). This indicates a significant effect of treatment with L-thyroxine on glycemic control in patients with subclinical hypothyroidism.

C-peptide in the classification of diabetes in children and adolescents

To report C-peptide results in newly diagnosed patients and the relation to clinical diagnosis of diabetes. A nation-wide cohort, the Better Diabetes Diagnosis study was used to determine serum C-peptide at diagnosis in 2734 children and adolescents. Clinical data were collected at diagnosis and follow-up. C-peptide was determined in a validated and controlled time-resolved fluoroimmunoassay. The clinical classification of diabetes, before any information on human leukocyte antigen, islet autoantibodies, or C-peptide was received, was type 1 diabetes (T1D) in 93%, type 2 diabetes (T2D) in 1.9%, maturity onset diabetes of the young (MODY) in 0.8%, secondary diabetes (0.6%), while 3.3% could not be classified. In a random, non-fasting serum sample at diagnosis, 56% of the patients had a C-peptide value >0.2 nmol/L. Children classified as T2D had the highest mean C-peptide (1.83 + 1.23 nmol/L) followed by MODY (1.04 ± 0.71 nmol/L) and T1D (0.28 ± 0.25 nmol/L). Only 1/1037 children who had C-peptide <0.2 nmol/L at diagnosis was classified with a type of diabetes other than T1D. Predictive value of C-peptide >1.0 nmol/L for the classification of either T2D or MODY was 0.46 [confidence interval 0.37-0.58]. More than half of children with newly diagnosed diabetes have clinically important residual beta-cell function. As the clinical diagnosis is not always straightforward, a random C-peptide taken at diagnosis may help to classify diabetes. There is an obvious use for C-peptide determinations to evaluate beta-cell function in children with diabetes.

Glucagon-like peptide-1 secretion in women with gestational diabetes mellitus during and after pregnancy.

Gestational diabetes mellitus (GDM) predisposes women to future development of Type 2 diabetes mellitus (DM2) and the two conditions share similar metabolic alterations. Recent observations suggest that a defective glucose stimulated insulin secretion by glucagon-like peptide-1 (GLP- 1) plays a role in the pathogenesis of DM2. Whether such a defect is impaired in GDM remains to be ascertained. We have determined GLP-1 secretion in response to oral glucose tolerance test (OGTT) in GDM and normal glucose tolerance (NGT) during and after pregnancy. 100-g-3h OGTT was performed in 12 GDM and 16 NGT women at 27.3 ± 4.1 weeks of gestation, for determination of plasma GLP-1, glucose, insulin, and C-peptide. Insulin sensitivity (ISI) and insulin secretion (first and second phase); as well as ISI-secretion index (ISSI) were also derived. NGT and GDM women were comparable for age pre-pregnancy body mass index (BMI) and weight gain. GDM had higher glucose area under the curve (AUC): 27,575.5 ± 3448 vs 20,685.88 ± 2715 mg/dl min (p<0.01), but lower first-phase insulin secretion (993.12±367 vs 1376.61 ± 423, p<0.05) and ISSI compared to controls (3873.23 ± 1185 vs 6232.13 ± 1734, p<0.001). When we examined GLP-1 mean levels in relation to mean glycemic values, GLP-1 secretion was inappropriately low with respect to mean glycemic values in GDM compared to NGT. At follow-up, AUCGLP-1 was significantly lower in post-partum GDM compared to post-partum NGT women (2542 ± 273 vs 10,092 ± 7367 pmol·l-1·min-1, p<0.05, respectively). Our study suggests that GLP-1 secretion in GDM women is inadequate for the prevailing glycemic levels both in pregnancy and post partum. Moreover, we cannot exclude that other important aspects of the incretin effect may be involved in GDM development.

Identification of insulin secretory defects and insulin resistance during oral glucose tolerance test in a cohort of cystic fibrosis patients

Cystic fibrosis (CF)-related diabetes is a leading complication of CF and is associated with pulmonary and nutritional deterioration, years before an evident hyperglycemia, possibly because of insulin deficiency and resistance. To evaluate glucose tolerance, insulin secretion, and insulin sensitivity by a widely applicable method suitable for accurate and prospective measurements in a CF population. A total of 165 CF subjects (80 females) aged 17±5 years and 18 age- and sex-matched healthy controls (CON) received an oral glucose tolerance test with glucose, insulin and C-peptide determinations. Insulin sensitivity was defined on the basis of glucose and insulin concentrations using the oral glucose insulin sensitivity index, whereas β-cell function was determined on the basis of a model relating insulin secretion (C-peptide profile) to glucose concentration. Fifteen percent of CF patients had glucose intolerance and 6% had diabetes without fasting hyperglycemia and 3% had diabetes with fasting hyperglycemia. β-cell function was reduced in CF patients compared with CON (70.0±4.1 vs 117.9±11.6 pmol/min per m(2) per mM, P<0.001) and decreased significantly with age by -2.7 pmol/min per m(2) per mM per year (confidence interval (CI) -4.5 to -0.82), i.e. almost 4% yearly. The early insulin secretion index was also reduced. Insulin sensitivity was similar to CON. CF patients who attained glucose tolerance comparable to CON had lower β-cell function and higher insulin sensitivity. The major alteration in insulin secretion and insulin sensitivity of CF patients is slowly declining β-cell function, consisting of delayed and reduced responsiveness to hyperglycemia, that in CF patients with normal glucose tolerance may be compensated by an increased insulin sensitivity.

Inhibition of DPP-4 with Vildagliptin Improved Insulin Secretion in Response to Oral as well as “Isoglycemic” Intravenous Glucose without Numerically Changing the Incretin Effect in Patients with Type 2 Diabetes

Dipeptidyl peptidase-4 (DPP-4) inhibitors block the degradation of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. The aim of the present study was to quantitatively assess the incretin effect after treatment with the DPP-4 inhibitor vildagliptin (V) or placebo (P) in patients with type 2 diabetes. Twenty-one patients (three women, 18 men) with type 2 diabetes previously treated with metformin (mean age, 59 yr; body mass index, 28.6 kg/m(2); glycosylated hemoglobin, 7.3%) were studied in a two-period crossover design. They received 100 mg V once daily or P for 13 d in randomized order. The incretin effect was measured on d 12 (75-g oral glucose) and d 13 ("isoglycemic" iv glucose) based on insulin and C-peptide determinations and insulin secretion rates (ISR). V relative to P treatment significantly increased intact incretin concentrations after oral glucose and insulin secretory responses to both oral glucose and isoglycemic iv glucose (e.g. AUC(ISR oral), by 32.7%, P = 0.0006; AUC(ISR iv), by 33.1%, P = 0.01). The numerical incretin effect was not changed (IE(ISR), V vs. P, 35.7 ± 4.9 and 34.6 ± 4.0%, P = 0.80). DPP-4 inhibition augmented insulin secretory responses both after oral glucose and during isoglycemic iv glucose infusions, with no net change in the incretin effect. Thus, slight variations in basal incretin levels may be more important than previously thought. Or, DPP-4 inhibitor-induced change in the incretin-related environment of islets may persist overnight, augmenting insulin secretory responses to iv glucose as well. Alternatively, yet unidentified mediators of DPP-4 inhibition may have caused these effects.

Glucose-responsive beta cells in islets isolated from a patient with long-standing type 1 diabetes mellitus

To the Editor: The heterogeneous nature of the autoimmune process in type 1 diabetes mellitus can, on occasion, result in the preservation of beta cells in patients with longstanding disease [1]. The detection of low levels of basal C-peptide secretion in these patients suggests some beta cell secretory capacity [2]. Whether these residual beta cells are functionally intact, however, remains unanswered. Here we report in vitro observations on islets isolated from a cadaveric donor who had had type 1 diabetes mellitus for 13 years. The objectives were to isolate islets from the pancreas to determine islet hormone secretion profiles and cellular electrophysiological responses, and to compare these variables with data from islets from non-diabetic donors. In addition, we compared the pancreatic histology of this donor pancreas with that of other type 1 diabetic mellitus donors with established or newly diagnosed disease. The donor, a white female, was 19 years old at diagnosis, weighed 73.8 kg (BMI 28 kg/m) and had no family history of diabetes. She was treated with gliclazide and metformin. Seven weeks after diagnosis, despite maximal doses of oral therapy, she developed ketonuria and had a fasting blood glucose of 24 mmol/l. She therefore started insulin treatment (0.27 U/kg insulin twice daily). This was increased to 0.6 U/kg using a basal bolus regimen over a 6 month period. She underwent four admissions for severe diabetic ketoacidosis. Unfortunately no serum samples were taken for determination of C-peptide or antibody status at any time. Samples taken at the time of death showed HLA-DR3 and -4 positivity. The donor’s pancreas was retrieved for research with the informed consent of the family and with the approval of the local ethics committee. Islets were isolated using established protocols [3]. An islet count was omitted as poor dithizone uptake was predicted. Islets that were visibly structurally intact were hand-picked from the purified digest for the secretion experiments and the residual islets were retained for morphological analysis. The islets used for the functional experiments were therefore not a true representation of the whole isolated population. Insulin and glucagon secretion was measured from batches of 15 islets (in quadruplicates) pre-incubated in 1 mmol/l glucose for 1 h followed by incubation for 1 h at 1, 6 or 20 mmol/l glucose. The hormone contents of islets and supernatant fractions were determined by radioimmunoassay [4]. Membrane capacitance, as a measure of insulin granule exocytosis, was recorded from isolated alpha and beta cells using the patch-clamp technique [5]. Pancreatic tissue samples taken from the body and tail regions of this donor pancreas and from the donor pancreases of three additional type 1 diabetic patients (diabetes duration >10 years, n=2; diabetes duration <48 h, n=1; tissue retrieval at post mortem was approved by the local ethics committee) were prepared for light and electron microscopy [6]; they were J. N. Walker : P. R. V. Johnson : S. J. Hughes Nuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, Oxford, UK

Relationship between pancreatic beta-cell function and body mass index and age in patients with newly diagnosed type 2 diabetes

Objective To investigate relationship between insulin sensitivity and beta-cell function with body mass index (BMI) and age in patients with newly diagnosed type 2 diabetes mellitus (T2DM).Methods Totally, 304 patients with T2DM newly-diagnosed at admission to the first hospital affiliated to Nanjing Medical University, Jiangsu province, during 2006 to 2007 were recruited in the study. The patients were divided into three groups based on WHO criteria of obesity in Asia Pacific Region in 2003, 68 cases with normal weight ( 18. 5≤ BMI ＜ 23.0), 69 in overweight (23.0 ≤ BMI ＜ 25.0), and 167 in obesity (BMI≥25.0). Fasting serum glucose, glycesylated hemoglobin Alc (HbAlc) and lipids were measured for all the subjects, as well as oral glucose tolerance test (OGTr), C-peptide releasing tests and determination of serum insulin performed. Homeostasis model assessment of insulin resistance index (HOMA-IR), insulinogenic index (AI30/AG30) and modified beta-cell function index (MBCI) werecalculated to evaluate their insulin sensitivity and beta-cell function of the islets. All these parameters werecompared between the three groups and subgroups. Results HOMA-IR and MBCI were significantly higherin T2DM patients with obesity than those in the groups with normal weight and over-weight ( P < 0. 05 ).AI30/AG30 in obesity group was significantly higher than that in the group with normal weight (P <0. 05).Multiple linear regression analysis showed that BMI independently correlated with HOMA-IR ( P < O. 05 ).Sub-group analysis showed that △I30/△G30 and MBCI were significantly higher in those aged 60 years and over with obesity than those in the groups aged less than 60 years ( P ＜ 0. 05 ). Conclusions Non-obese patients with newly diagnosed T2DM have more severe impaired insulin secretion than that in obese ones,and their insulin resistance increases with BMI. Age has no significant correlation with pancreatic beta-cell function or insulin sensitivity. Key words: Diabetes mellitns,type 2; Body mass index; Insulin resistance; Pancreatic β cell function; Age factors

Carcinoembryonic antigen-related cell adhesion molecule 1: a link between insulin and lipid metabolism.

OBJECTIVE—Liver-specific inactivation of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) by a dominant-negative transgene (l-SACC1 mice) impaired insulin clearance, caused insulin resistance, and increased hepatic lipogenesis. To discern whether this phenotype reflects a physiological function of CEACAM1 rather than the effect of the dominant-negative transgene, we characterized the metabolic phenotype of mice with null mutation of the Ceacam1 gene (Cc1−/−).RESEARCH DESIGN AND METHODS—Mice were originally generated on a mixed C57BL/6x129sv genetic background and then backcrossed 12 times onto the C57BL/6 background. More than 70 male mice of each of the Cc1−/− and wild-type Cc1+/+ groups were subjected to metabolic analyses, including insulin tolerance, hyperinsulinemic-euglycemic clamp studies, insulin secretion in response to glucose, and determination of fasting serum insulin, C-peptide, triglyceride, and free fatty acid levels.RESULTS—Like l-SACC1, Cc1−/− mice exhibited impairment of insulin clearance and hyperinsulinemia, which caused insulin resistance beginning at 2 months of age, when the mutation was maintained on a mixed C57BL/6x129sv background, but not until 5–6 months of age on a homogeneous inbred C57BL/6 genetic background. Hyperinsulinemic-euglycemic clamp studies revealed that the inbred Cc1−/− mice developed insulin resistance primarily in liver. Despite substantial expression of CEACAM1 in pancreatic β-cells, insulin secretion in response to glucose in vivo and in isolated islets was normal in Cc1−/− mice (inbred and outbred strains).CONCLUSIONS—Intact insulin secretion in response to glucose and impairment of insulin clearance in l-SACC1 and Cc1−/− mice suggest that the principal role of CEACAM1 in insulin action is to mediate insulin clearance in liver.

Glucagon-like peptide 1 (GLP-1) suppresses ghrelin levels in humans via increased insulin secretion

Introduction Ghrelin is an orexigenic peptide predominantly secreted by the stomach. Ghrelin plasma levels rise before meal ingestion and sharply decline afterwards, but the mechanisms controlling ghrelin secretion are largely unknown. Since meal ingestion also elicits the secretion of the incretin hormone glucagon-like peptide 1 (GLP-1), we examined whether exogenous GLP-1 administration reduces ghrelin secretion in humans. Patients and methods 14 healthy male volunteers were given intravenous infusions of GLP-1(1.2 pmol·kg − 1 min − 1 ) or placebo over 390 min. After 30 min, a solid test meal was served. Venous blood was drawn frequently for the determination of glucose, insulin, C-peptide, GLP-1 and ghrelin. Results During the infusion of exogenous GLP-1 and placebo, GLP-1 plasma concentrations reached steady-state levels of 139 ± 15 pmol/l and 12 ± 2 pmol/l, respectively ( p < 0.0001). During placebo infusion, ghrelin levels were significantly reduced in the immediate postprandial period ( p < 0.001), and rose again afterwards. GLP-1 administration prevented the initial postprandial decline in ghrelin levels, possibly as a result of delayed gastric emptying, and significantly reduced ghrelin levels 150 and 360 min after meal ingestion ( p < 0.05). The patterns of ghrelin concentrations in the experiments with GLP-1 and placebo administration were inversely related to the respective plasma levels of insulin and C-peptide. Conclusions GLP-1 reduces the rise in ghrelin levels in the late postprandial period at supraphysiological plasma levels. Most likely, these effects are indirectly mediated through its insulinotropic action. The GLP-1-induced suppression of ghrelin secretion might be involved in its anorexic effects.

The utility of the C‐peptide in the phenotyping of patients candidates for pancreas transplantation

It is not unusual for simultaneous pancreas and kidney transplantation (SPK) to be performed in patients with type 2 diabetes (T2D), clinically classified as having type 1 diabetes (T1D). C-peptide determination is useful to identify these patients. We describe the prevalence and characteristics of patients with C-peptide levels >3 ng/mL, classified with T2D in 172 patients referred for SPK from 1998-2006. Nine patients (5.2%) fulfilled this criteria (mean free C-peptide 9.08 ng/mL) and were older at diabetes onset (23.5 vs. 12 yr, p < 0.001) and at assessment (42.2 vs. 37.6 yr, p = 0.047) with shorter time between diabetes onset and renal failure (17.8 vs. 22.7 yr, p = 0.3) compared with T1D patients (mean free C-peptide 0.24 ng/mL). In our experience the prevalence of T2D in candidates for SPK is not negligible. Despite some clinical differences with T1D these T2D patients can phenotypically be confounded with T1D in the absence of C-peptide determination.

Subclinical abnormalities of glucose metabolism in Brazilian women with a history of gestational diabetes mellitus

To evaluate insulin release and insulin sensitivity in women with prior gestational diabetes mellitus (GDM) to gain a better understanding of type 2 diabetes pathogenesis. GDM women were individually matched for age, body mass index, and waist/hip ratio with those who were normal glucose tolerant in a previous pregnancy (NGT). All women presented with normal glucose tolerance. Twenty pairs were submitted to the oral glucose tolerance test (OGTT) with plasma glucose, insulin, and C-peptide determinations. Of the 20 pairs, 18 participated in hyperglycemic (10.0 mmol/l) clamp experiments with frequent plasma glucose and insulin determinations, allowing us to calculate first- and second-phase insulin release and the insulin sensitivity index. GDM and NGT women were compared using Student's t-test, the Mann-Whitney U-test, Friedman's non-parametric test, and the two proportion test for independent groups. GDM women showed higher glycosylated hemoglobin values; at OGTT, they showed late insulin peak with increased plasma insulin levels only during the second hour, and a similar plasma C-peptide response despite a higher plasma glucose curve; during hyperglycemic clamp procedures, they showed similar biphasic insulin release and insulin sensitivity index. Considering that a woman with previous GDM had a defect in insulin release and/or insulin sensitivity, if its magnitude was at least 25% lower than that of the matched NGT woman, 43.8% showed impairment of first-phase insulin release and 55.6% insulin resistance. GDM women showed some degree of glucose intolerance. It is therefore necessary to follow them for a longer time.

Effects of taurine in glucose and taurine administration

Taurine has several biological processes such as hypoglycemic action, antioxidation, detoxification, etc. To assess the effect of taurine administration on the guinea pigs with hyperglycemia, blood glucose, C-peptide levels together with morphologic alterations in the pancreatic ultrastructure were investigated in terms of hypoglycemic action and malondialdehyde and total sulfhydryl group levels with regard to oxidation-antioxidation relation. Animals were divided into four groups of six. Glucose supplementation group was administrated a single dose of glucose (400 mg/kg, i.p.) injection. Glucose and taurine supplementation group was administrated glucose treatment (a single dose, 400 mg/kg, i.p.) following taurine (a single dose, 200 mg/kg, i.p.). Taurine and glucose supplementation group was administered taurine treatment (a single dose, 200 mg/kg, i.p.) following glucose treatment (a single dose, 400 mg/kg, i.p.). Control animals received no treatment. Blood samples were collected at the end of the experiments for the determination of glucose, C-peptide (indicator of insulin secretion), lipid peroxidation (thiobarbituric acid reactive substances), and total sulfhydryl groups levels. Pancreatic tissue samples were then collected and processed for transmission electron microscopy. The findings showed that glucose supplementation following taurine administration significantly decreased blood glucose level by increasing C-peptide level and the pancreatic secretion stimulated morphologically and insignificantly changed thiobarbituric acid reactive substances and total sulfhydryl group levels. These observations suggest that taurine administration may be useful in hyperglycemia because of its hypoglycemic and protective effects.

Secretion, degradation, and elimination of glucagon-like peptide 1 and gastric inhibitory polypeptide in patients with chronic renal insufficiency and healthy control subjects.

Glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) are important factors in the pathogenesis of type 2 diabetes and have a promising therapeutic potential. Alterations of their secretion, in vivo degradation, and elimination in patients with chronic renal insufficiency (CRI) have not yet been characterized. Ten patients with CRI (aged 47 +/- 15 years, BMI 24.5 +/- 2.2 kg/m(2), and serum creatinine 2.18 +/- 0.86 mg/dl) and 10 matched healthy control subjects (aged 44 +/- 12 years, BMI 24.9 +/- 3.4 kg/m(2), and serum creatinine 0.89 +/- 0.10 mg/dl) were included. On separate occasions, an oral glucose tolerance test (75 g), an intravenous infusion of GLP-1 (0.5 pmol. kg(-1). min(-1) over 30 min), and an intravenous infusion of GIP (1.0 pmol. kg(-1). min(-1) over 30 min) were performed. Venous blood samples were drawn for the determination of glucose (glucose oxidase), insulin, C-peptide, GLP-1 (total and intact), and GIP (total and intact; specific immunoassays). Plasma levels of GIP (3-42) and GLP-1 (9-36 amide) were calculated. Statistics were performed using repeated-measures and one-way ANOVA. After the oral glucose load, plasma concentrations of intact GLP-1 and intact GIP reached similar levels in both groups (P = 0.31 and P = 0.87, respectively). The concentrations of GIP (3-42) and GLP-1 (9-36 amide) were significantly higher in the patients than in the control subjects (P = 0.0021 and P = 0.027, respectively). During and after the exogenous infusion, GLP-1 (9-36 amide) and GIP (3-42) reached higher plasma concentrations in the CRI patients than in the control subjects (P < 0.001 and P = 0.0033, respectively), whereas the plasma levels of intact GLP-1 and GIP were not different between the groups (P = 0.29 and P = 0.27, respectively). Plasma half-lives were 3.4 +/- 0.6 and 2.3 +/- 0.4 min for intact GLP-1 (P = 0.13) and 5.3 +/- 0.8 and 3.3 +/- 0.4 min for the GLP-1 metabolite (P = 0.029) for CRI patients vs. healthy control subjects, respectively. Plasma half-lives of intact GIP were 6.9 +/- 1.4 and 5.0 +/- 1.2 min (P = 0.31) and 38.1 +/- 6.0 and 22.4 +/- 3.0 min for the GIP metabolite (P = 0.032) for CRI patients vs. healthy control subjects, respectively. Insulin concentrations tended to be lower in the patients during all experiments, whereas C-peptide levels tended to be elevated. These data underline the importance of the kidneys for the final elimination of GIP and GLP-1. The initial dipeptidyl peptidase IV-mediated degradation of both hormones is almost unaffected by impairments in renal function. Delayed elimination of GLP-1 and GIP in renal insufficiency may influence the pharmacokinetics and pharmacodynamics of dipeptidyl peptidase IV-resistant incretin derivatives to be used for the treatment of patients with type 2 diabetes.

Blood glucose control in healthy subject and patients receiving intravenous glucose infusion or total parenteral nutrition using glucagon-like peptide 1

Aims: It was the aim of the study to examine whether the insulinotropic gut hormone GLP-1 is able to control or even normalise glycaemia in healthy subjects receiving intravenous glucose infusions and in severely ill patients hyperglycaemic during total parenteral nutrition. Patients and methods: Eight healthy subjects and nine patients were examined. The volunteers received, in six separate experiments in randomised order, intravenous glucose at doses of 0, 2 and 5mg kg −1 min −1, each with intravenous GLP-1 or placebo for 6 h. Patients were selected on the basis of hyperglycaemia (>150 mg/dl) during complete parenteral nutrition with glucose (3.2±1.4 mg kg −1 min −1), amino acids ( n=8; 0.9±0.2 mg kg −1 min −1), with or without lipid emulsions. Four hours (8 a.m. to 12 a.m. on parenteral nutrition plus NaCl as placebo) were compared to 4 h (12 a.m. to 4 p.m.) with additional GLP-1 administered intravenously. The dose of GLP-1 was 1.2 pmol kg −1 min −1. Blood was drawn for the determination of glucose, insulin, C-peptide, GLP-1, glucagon, and free fatty acids. Results: Glycaemia was raised dose-dependently by glucose infusions in healthy volunteers ( p<0.0001). GLP-1 (∼100–150 pmol/l) stimulated insulin and reduced glucagon secretion and reduced glucose concentrations into the normoglycaemic fasting range (all p<0.05). In hyperglycaemic patients, glucose concentrations during the placebo period averaged 211±24 mg/dl. This level was reduced to 159±25 mg/dl with GLP-1 ( p<0.0001), accompanied by a rise in insulin ( p=0.0002) and C-peptide ( p<0.0001), and by trend towards a reduction in glucagon ( p=0.08) and free fatty acids ( p=0.02). GLP-1 was well tolerated. Conclusions: Hyperglycaemia during parenteral nutrition can be controlled by exogenous GLP-1, e.g. the natural peptide (available today), whereas the chronic therapy of Type 2 diabetes requires GLP-1 derivatives with longer duration of action.

Gastric inhibitory polypeptide does not inhibit gastric emptying in humans

The insulinotropic gut hormone gastric inhibitory polypeptide (GIP) has been demonstrated to inhibit gastric acid secretion and was proposed to possess "enterogastrone" activity. GIP effects on gastric emptying have not yet been studied. Fifteen healthy male volunteers (23.9 +/- 3.3 yr, body mass index 23.7 +/- 2.3 kg/m(2)) were studied with the intravenous infusion of GIP (2 pmol.kg(-1).min(-1)) or placebo, each administered to the volunteers on separate occasions from -30 to 360 min in the fasting state. At 0 min, a solid test meal (250 kcal containing [(13)C]sodium octanoate) was served. Gastric emptying was calculated from the (13)CO(2) exhalation rates in breath samples collected over 360 min. Venous blood was drawn in 30-min intervals for the determination of glucose, insulin, C-peptide, and GIP (total and intact). Statistical calculations were made by use of repeated-measures ANOVA and one-way ANOVA. During the infusion, GIP rose to steady-state concentrations of 159 +/- 15 pmol/l for total and 34 +/- 4 pmol/l for intact GIP (P < 0.0001). Meal ingestion further increased GIP concentrations in both groups, reaching peak levels of 265 +/- 20 and 82 +/- 9 pmol/l for total and 67 +/- 7 and 31 +/- 9 pmol/l for intact GIP during the administration of GIP and placebo, respectively (P < 0.0001). There were no differences in glucose, insulin, and C-peptide between the experiments with the infusion of GIP or placebo. Gastric half-emptying times were 120 +/- 9 and 120 +/- 18 min (P = 1.0, with GIP and placebo, respectively). The time pattern of gastric emptying was similar in the two groups (P = 0.98). Endogenous GIP secretion, as derived from the incremental area under the curve of plasma GIP concentrations in the placebo experiments, did not correlate to gastric half-emptying times (r(2) = 0.15, P = 0.15 for intact GIP; r(2) = 0.21, P = 0.086 for total GIP). We conclude that gastric emptying does not appear to be influenced by GIP. The secretion of GIP after meal ingestion is not suppressed by its exogenous administration. The lack of effect of GIP on gastric emptying underlines the differences between GIP and the second incretin glucagon-like peptide 1.

Similar insulin secretory response to a gastric inhibitory polypeptide bolus injection at euglycemia in first-degree relatives of patients with type 2 diabetes and control subjects

Insulin secretion following the intravenous infusion of gastric inhibitory polypeptide (GIP) is diminished in patients with type 2 diabetes and at least a subgroup of their first-degree relatives at hyperglycemic clamp conditions. Therefore, we studied the effects of an intravenous bolus administration of GIP at normoglycemic conditions in the fasting state. Ten healthy control subjects were studied with an intravenous bolus administration of placebo, and of 7, 20, and 60 pmol GIP/kg body weight (BW), respectively. Forty-five first-degree relatives of patients with type 2 diabetes and 33 matched control subjects were studied with (1) a 75-g oral glucose tolerance test (OGTT) and (2) an intravenous bolus injection of 20 pmol GIP/kg BW with blood samples drawn over 30 minutes for determination of plasma glucose, insulin, C-peptide, and GIP. Statistical analysis applied repeated-measures analysis of variance (ANOVA) and Duncan’s post hoc tests. Insulin secretion was stimulated after the administration of 20 and of 60 pmol GIP/kg BW in the dose-response experiments ( P < .0001). GIP administration (20 pmol/kg BW) led to a significant rise of insulin and C-peptide concentrations in the first-degree relatives and control subjects ( P < .0001), but there was difference between groups ( P = .64 and P = .87, respectively). Also expressed as increments over baseline, no differences were apparent (Δ insulin, 7.6 ± 1.2 and 7.6 ± 1.6 mU/L, P = .99; Δ C-peptide, 0.35 ± 0.06 and 0.38 ± 0.08 ng/mL, P = .75). Integrated insulin and C-peptide responses after GIP administration significantly correlated with the respective insulin and C-peptide responses after glucose ingestion (insulin, r = 0.78, P < .0001; C-peptide, r = 0.35, P = .0015). We conclude that a reduced insulinotropic effect of GIP in first-degree relatives of patients with type 2 diabetes cannot be observed at euglycemia. Therefore, a reduced GIP-induced insulin secretion in patients with type 2 diabetes and their first-degree relatives at hyperglycemia is more likely due to a general defect of B-cell function than to a specific defect of the GIP action.