Insulin Secretion In Patients Research Articles

Effects of saxagliptin on β-cell stimulation and insulin secretion in patients with type 2 diabetes

To study the effect of dipeptidyl peptidase-4 (DPP-4) inhibition with saxagliptin on β-cell function as reflected by the stimulated insulin secretion rate after an enteral glucose load in patients with type 2 diabetes. Patients in this randomized, parallel-group, double-blind, placebo-controlled study were drug-naïve, aged 43-69 years, with baseline haemoglobin A1c (HbA1c) 5.9-8.1%. Twenty patients received saxagliptin 5 mg once daily; 16 received placebo. Patients were assessed at baseline and week 12 by intravenous hyperglycaemic clamp (0-180 min, fasting state), and intravenous-oral hyperglycaemic clamp (180-480 min, postprandial state) following oral ingestion of 75 g glucose. Primary and secondary endpoints were percent changes from baseline in insulin secretion during postprandial and fasting states, respectively. Insulin secretion was calculated by C-peptide deconvolution. After 12 weeks, saxagliptin significantly increased insulin secretion percent change from baseline during the postprandial state by an 18.5% adjusted difference versus placebo (p = 0.04), an improvement associated with increased peak plasma concentrations of intact glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. In the fasting state, saxagliptin significantly increased insulin secretion by a 27.9% adjusted difference versus placebo (p = 0.02). Saxagliptin also improved glucagon area under the curve in the postprandial state (adjusted difference -21.8% vs. placebo, p = 0.03). DPP-4 inhibition with saxagliptin improves pancreatic β-cell function in postprandial and fasting states, and decreases postprandial glucagon concentration. Given the magnitude of enhancement of the insulin response in the fasting state, further study into the effect of DPP-4 inhibition on the β-cell is warranted.

GAD autoantibody affinity in LADA patients

Background/Aims: The DIAMYD Phase II study tested whether GAD65 antigen-specific immune intervention could preserve endogenous insulin secretion in patients with latent autoimmune diabetes in adults (LADA). Forty-seven LADA patients received 2 subcutaneous injections of alum-formulated recombinant human GAD65 (4µg, 20µg, 100µg or 500µg) or placebo at intervals of 4 weeks and were followed thereafter for 30 months with respect to metabolic outcome. Here, we asked whether GAD autoantibody (GADA) affinity is affected by vaccination with rhGAD65 and associated with fasting C-peptide levels in LADA patients.

Correlation of glycated albumin but not hemoglobin A1c with endogenous insulin secretion in fulminant type 1 diabetes mellitus.

Aims/Introduction: Fulminant type 1 diabetes mellitus (FT1DM) develops as a result of very rapid and almost complete pancreatic β-cell destruction. We hypothesized that in patients with FT1DM who have less endogenous insulin secretion, disease progression is more rapid, and thus glycated albumin (GA) levels are lower. This study was designed to prove this hypothesis. The present study included 42 patients with FT1DM (24 men, 18 women) in whom glycated hemoglobin (HbA1c), GA and daily urinary C-peptide (CPR) were measured at the time of diagnosis. Patients with complications, such as liver disease, kidney disease, anemia, or who were pregnant were excluded. Urinary CPR (log transformed) was not correlated with HbA1c (R = 0.168, P = 0.287), but was positively correlated with GA (R = 0.336, P = 0.030). It was weakly, but not significantly, correlated with GA/HbA1c ratio (R = 0.281, P = 0.072). In patients with GA < 24.0%, urinary CPR was significantly lower than in patients with GA ≥ 24.0%. In addition, in patients with GA/HbA1c ratio <3.8, urinary CPR was significantly lower than in patients with GA/HbA1c ratio ≥ 3.8. Our findings suggest that in patients with FT1DM, GA at the time of diagnosis was correlated with endogenous insulin secretion. GA < 24.0% at the time of diagnosis is predictive for less endogenous insulin secretion in patients with FT1DM. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00050.x, 2010).

Twelve weeks treatment with the DPP‐4 inhibitor, sitagliptin, prevents degradation of peptide YY and improves glucose and non‐glucose induced insulin secretion in patients with type 2 diabetes mellitus

To examine the effects of 12 weeks of treatment with the DPP-4 inhibitor, sitagliptin, on gastrointestinal hormone responses to a standardized mixed meal and beta cell secretory capacity, measured as glucose and non-glucose induced insulin secretion during a hyperglycaemic clamp, in patients with type 2 diabetes. A double-blinded, placebo-controlled study over 12 weeks in which 24 patients with T2DM were randomized to receive either sitagliptin (Januvia) 100 mg qd or placebo as an add-on therapy to metformin. In week 0, 1 and 12 patients underwent a meal test and a 90-min 20 mM hyperglycaemic clamp with 5 g of l-arginine infusion. Main outcome measure was postprandial total glucagon-like peptide 1 (GLP-1) concentration. Additional measures were insulin and C-peptide, glycaemic control, intact and total peptide YY (PYY) and glucose-dependent insulinotropic polypeptide (GIP), and intact glucagon-like peptide 2 (GLP-2) and GLP-1. All patients [sitagliptin n = 12, age: 59.5 (39-64) years, HbA1c: 8.0 (7.3-10.0)%, BMI: 33.2 (29.3-39.4); placebo n = 12, age: 60 (31-72) years, HbA1c: 7.7 (7.1-9.8)%, BMI: 30.7 (25.7-40.5)] [median (range)] completed the trial. Sitagliptin treatment improved glycaemic control, had no effect on total GLP-1, GIP or intact GLP-2, but reduced total PYY and PYY(3- 36), and increased PYY(1- 36) and intact incretin hormones. Sitagliptin improved first and second phases of beta cell secretion and maximal secretory capacity. All effects were achieved after 1 week. No significant changes occurred in the placebo group. The postprandial responses of total GLP-1 and GIP and intact GLP-2 were unaltered. PYY degradation was prevented. Glucose and non-glucose induced beta cell secretion was improved. There was no difference in responses to sitagliptin between 1 and 12 weeks of treatment.

Effects of Intravenous Glucose Load on Insulin Secretion in Patients With Ketosis-Prone Diabetes During Near-Normoglycemia Remission

OBJECTIVEMost patients with ketosis-prone type 2 diabetes (KPD) discontinue insulin therapy and remain in near-normoglycemic remission. The aim of this study was to determine the effect of glucotoxicity on β-cell function during remission in obese patients with KPD.RESEARCH DESIGN AND METHODSAge- and BMI-matched obese African Americans with a history of KPD (n = 8), severe hyperglycemia but without ketosis (ketosis-resistant type 2 diabetes, n = 7), and obese control subjects (n = 13) underwent intravenous infusion of 10% dextrose at a rate of 200 mg per m2/min for 20 h. β-Cell function was assessed by changes in insulin and C-peptide concentrations during dextrose infusion and by changes in acute insulin response (AIR) and first-phase insulin release (FPIR) to arginine stimulation before and after dextrose infusion.RESULTSThe mean ± SD time to discontinue insulin therapy was 7.1 ± 1.7 weeks in KPD and 9.6 ± 2.3 weeks in ketosis-resistant type 2 diabetes (NS). During a 20-h dextrose infusion, changes in insulin, C-peptide, and the C-peptide–to–glucose ratio were similar among diabetic and control groups. During dextrose infusion, subjects with ketosis-resistant type 2 diabetes had greater areas under the curve for blood glucose than subjects with KPD and control subjects (P < 0.05). The AIR and FPIR to arginine stimulation as well as glucose potentiation to arginine assessed before and after dextrose infusion were not different among the study groups.CONCLUSIONSNear-normoglycemia remission in obese African American patients with KPD and ketosis-resistant type 2 diabetes is associated with a remarkable recovery in basal and stimulated insulin secretion. At near-normoglycemia remission, patients with KPD displayed a pattern of insulin secretion similar to that of patients with ketosis-resistant type 2 diabetes and obese nondiabetic subjects.

Glycated Albumin and Glycated Hemoglobin Are Influenced Differently by Endogenous Insulin Secretion in Patients With Type 2 Diabetes

OBJECTIVEGlycated albumin (GA) relative to A1C is a useful marker of short-term glycemic control. We investigated whether endogenous insulin secretion in type 2 diabetes has different effects on GA and A1C levels.RESEARCH DESIGN AND METHODSA1C, GA, and GA-to-A1C ratio were compared in 202 type 2 diabetic patients by type of treatment. Effect of β-cell function determined by homeostasis model assessment (HOMA-%β) on GA-to-A1C ratio was examined. In addition, GA-to-A1C ratio was compared between type 2 diabetic patients and 16 patients with type 1 diabetes.RESULTSIn type 2 diabetic patients, GA-to-A1C ratio was significantly higher in those treated with insulin than in those treated with diet or oral hypoglycemic agents. HOMA-%β showed a significant inverse correlation with GA-to-A1C ratio. This ratio was higher in type 1 diabetic patients than in type 2 diabetic patients.CONCLUSIONSIn diabetic patients with decreased insulin secretion, serum GA levels are higher relative to A1C.

Decreased insulin secretion in patients receiving tacrolimus as GVHD prophylaxis after allogeneic hematopoietic SCT

Decreased insulin secretion in patients receiving tacrolimus as GVHD prophylaxis after allogeneic hematopoietic SCT

Relation of free and specifically bound leptin to insulin secretion in patients with impaired glucose tolerance (IGT).

Impaired glucose tolerance (IGT) is frequently associated with an increased fat mass and an altered fat distribution. The adipocyte derived hormone, leptin has been shown to interact with insulin at various levels and may be intimately involved in this process. However, only limited data concerning the interaction of insulin, glucose tolerance and leptin are available and no data exist on the potential influence of bound vs. free circulating leptin. We therefore studied free and bound leptin in 136 patients (77 males, 59 females) with IGT, in relation to plasma glucose, insulin, proinsulin and C-peptide levels as well as serum free and bound leptin concentrations during an oral glucose tolerance test (oGTT). The expected positive relation of free serum leptin levels with body mass index (BMI) was found. Free leptin concentrations were higher in women than in men. Analysis in tertiles revealed a significant relation between free leptin (16-58, 60-160, and 169-932 pmol/l) and mean fasting insulin levels (65, 93, and 100 pmol/l). This relationship remained significant in a multiple regression analysis with BMI and gender as covariates. Similar independent relationships to leptin serum levels were observed for HbA1c and plasma C peptide levels and the proinsulin/insulin ratio but not for plasma glucose and proinsulin levels. These data suggest a fine tuning of leptin by small changes in circulating insulin levels observed in impaired glucose tolerance.

GAD Treatment and Insulin Secretion in Recent-Onset Type 1 Diabetes

The 65-kD isoform of glutamic acid decarboxylase (GAD) is a major autoantigen in patients with type 1 diabetes mellitus. This trial assessed the ability of alum-formulated GAD (GAD-alum) to reverse recent-onset type 1 diabetes in patients 10 to 18 years of age. We randomly assigned 70 patients with type 1 diabetes who had fasting C-peptide levels above 0.1 nmol per liter (0.3 ng per milliliter) and GAD autoantibodies, recruited within 18 months after receiving the diagnosis of diabetes, to receive subcutaneous injections of 20 microg of GAD-alum (35 patients) or placebo (alum alone, 35 patients) on study days 1 and 30. At day 1 and months 3, 9, 15, 21, and 30, patients underwent a mixed-meal tolerance test to stimulate residual insulin secretion (measured as the C-peptide level). The effect of GAD-alum on the immune system was also studied. Insulin secretion gradually decreased in both study groups. The study treatment had no significant effect on change in fasting C-peptide level after 15 months (the primary end point). Fasting C-peptide levels declined from baseline levels significantly less over 30 months in the GAD-alum group than in the placebo group (-0.21 vs. -0.27 nmol per liter [-0.62 vs. -0.81 ng per milliliter], P=0.045), as did stimulated secretion measured as the area under the curve (-0.72 vs. -1.02 nmol per liter per 2 hours [-2.20 vs. -3.08 ng per milliliter per 2 hours], P=0.04). No protective effect was seen in patients treated 6 months or more after receiving the diagnosis. Adverse events appeared to be mild and similar in frequency between the two groups. The GAD-alum treatment induced a GAD-specific immune response. GAD-alum may contribute to the preservation of residual insulin secretion in patients with recent-onset type 1 diabetes, although it did not change the insulin requirement. (ClinicalTrials.gov number, NCT00435981.)

Pioglitazone attenuates fatty acid–induced oxidative stress and apoptosis in pancreatic β‐cells

Thiazolidinediones (TZDs), ligands for peroxisome proliferator-activated receptor gamma, are antidiabetic agents that improve hyperglycemia by decreasing insulin resistance in obese diabetic animal models and patients with type 2 diabetes. We have studied whether pioglitazone, a TZD, can exert a direct effect against pancreatic beta-cell lipoapoptosis. MIN6 cells were cultured in medium containing either 5.6 (low glucose) or 25 mM glucose (high glucose) in the presence or absence of 0.5 mM palmitate for 48 h. We examined the effect of 10 microM pioglitazone on MIN6 cells on glucose-stimulated insulin secretion, cellular ATP, uncoupling protein-2 (UCP-2) mRNA expression, intracellular triglyceride content, reactive oxygen species production, the number of apoptotic cells and nuclear factor-kappaB (NF-kappaB) activity. Pioglitazone recovered partly impaired glucose-stimulated insulin secretion and cellular ATP in MIN6 cell exposed to high glucose with 0.5 mM palmitate. Pioglitazone suppressed intracellular triglyceride accumulation in cells exposed to high glucose with 0.5 mM palmitate. Palmitate-induced upregulation of UCP-2 mRNA levels was suppressed by pioglitazone in a dose-dependent manner. Pioglitazone decreased palmitate-induced reactive oxygen species production in MIN6 cells by 24% and in mouse islet cells by 53%. Pioglitazone also decreased palmitate-induced NF-kappaB activity by 40% and protected beta-cells from palmitate-induced apoptosis by 22% in MIN6 cell. Pioglitazone attenuated fatty acid-induced oxidative stress and apoptosis in pancreatic beta-cells. TZDs might be used as a mean for maintaining beta-cell survival and preserving capacity of insulin secretion in patients with diabetes mellitus.

Transition from insulin to sulfonylurea in a child with diabetes due to a mutation in KCNJ11 encoding Kir6.2—initial and long-term response to sulfonylurea therapy

Mutations in the KCNJ11 gene encoding the adenosine triphosphate (ATP)-sensitive potassium channel (K(ATP)) subunit Kir6.2 are the most frequent cause of diabetes in infancy. Sulfonylurea (SU) treatment restores insulin secretion in patients with KCNJ11 mutations. We report a 9-year-old boy who presented at the age of three months with diabetic ketoacidosis. Results Sequencing of the KCNJ11 gene revealed an R201H mutation. Therefore, he was transferred from insulin to oral SU therapy. He required a high-threshold dose before insulin could be discontinued. After transition, a subsequent dose reduction was necessary to avoid hypoglycemia. Improved sustained metabolic control without complications was achieved on a low SU maintenance dose twice daily over 36 months. SU therapy is safe for patients with diabetes due to KCNJ11 mutations. The mechanism of a threshold dose and the twice-daily requirement needs further attention.

Near normalisation of blood glucose improves the potentiating effect of GLP-1 on glucose-induced insulin secretion in patients with type 2 diabetes

The ability of glucagon-like peptide-1 (GLP-1) to enhance beta cell responsiveness to i.v. glucose is impaired in patients with type 2 diabetes mellitus compared with healthy individuals. We investigated whether 4 weeks of near normalisation of blood glucose (BG) improves the potentiation of glucose-stimulated insulin secretion by GLP-1. Nine obese patients with type 2 diabetes and inadequate glycaemic control (HbA(1c) 8.0+/-0.4%) were investigated before and after 4 weeks of near normalisation of BG using insulin treatment (mean diurnal blood glucose 6.4+/-0.3 mmol/l, HbA(1c) 6.6+/-0.3%). Nine matched healthy participants were also studied. Beta cell function was investigated before and after insulin treatment using stepwise glucose infusions and infusion of saline or GLP-1 (1.0 pmol kg(-1) min(-1)), resulting in supraphysiological total GLP-1 concentrations of approximately 200 pmol/l. The responsiveness to glucose or glucose+GLP-1 was expressed as the slope of the linear regression line relating insulin secretion rate (ISR) and plasma glucose concentration (pmol kg(-1) min(-1) [mmol/l](-1)). In the diabetic participants, the slopes during glucose+saline infusion did not differ before and after insulin treatment (0.33+/-0.07 and 0.39+/-0.04, respectively; p=NS). In contrast, near normalisation of blood glucose improved beta cell sensitivity to glucose during glucose+GLP-1 infusion (1.27+/-0.2 before vs 1.73+/-0.31 after; p<0.01). In the healthy participants, the slopes during the glucose+saline and glucose+GLP-1 infusions were 1.01+/-0.14 and 4.79+/-0.53, respectively. A supraphysiological dose of GLP-1 enhances beta cell responses to glucose in patients with type 2 diabetes, and 4 weeks of near normalisation of blood glucose further improves this effect.

A possible association between primary aldosteronism and a lower β-cell function

Primary aldosteronism (PA) is the most common secondary cause of hypertension and recently has been implicated as a cause of impaired glucose tolerance. We investigated the glucose insulin sensitivity and insulin secretion in patients with idiopathic primary aldosteronism. Thirty PA patients and 60 essential hypertensive (EH) patients as controls were included, matched (1: 2) by their body mass index (BMI) (29.9 +/- 4.3 versus 29.8 +/- 5.8 m/kg), age (53.7 +/- 9.4 versus 59.9 +/- 8.6 years old) and gender (male/female: 8/22 versus 17/43). In all patients, we measured insulin, total cholesterol, triglycerides, C-peptide and fasting glucose levels. Homeostasis model assessment for insulin resistance (HOMA-IR) and HOMA of pancreatic beta-cell function (HOMA-betaF) indexes were calculated. We also evaluated the response to spironolactone in 19 PA patients. PA patients had higher levels of glucose (5.2 +/- 0.7 versus 4.9 +/- 0.7 mmol/l; P = 0.017). Insulin levels (10.7 +/- 6.5 versus 11.5 +/- 5.8 uUI/ml, P = 0.525) and HOMA-IR (2.51 +/- 1.59 versus 2.45 +/- 1.29 uUI/ml x mmol/l, P = 0.854) were similar in both groups. HOMA-betaF index (138.9 +/- 89.8 versus 179.8 +/- 100.2%, P = 0.049) and C-peptide (0.83 +/- 0.63 versus 1.56 +/- 0.84 ng/dl, P = 0.0001) were lower in PA patients. Potassium was normal in both groups. Negative correlations between serum aldosterone/plasma renin activity (SA/PRA) ratio and HOMA-betaF, and between C-peptide and SA levels were found in all patients. After the spironolactone treatment, we found an increase of C-peptide and insulin levels without changes in HOMA-IR or HOMA-betaF. Our results showed differences in glucose metabolism between PA patients and those with hypertension suggesting that these findings could probably be determined by a lower beta-cell function influenced by aldosterone. These findings highlight the importance of aldosterone in glucose metabolism.

International Comparison of C-Peptide Measurements

C-peptide measurement has been widely used as a marker of insulin secretion in patients with diabetes. We assessed the comparability of C-peptide results obtained with different methods and by different laboratories and determined whether C-peptide results could be harmonized by normalization with a WHO reference reagent or with plasma. We sent 16 different heparin plasma samples to 15 laboratories in 7 countries. The samples were analyzed with 10 different assay methods. A WHO C-peptide standard was also sent to each laboratory and used to determine the feasibility of normalizing results. To assess the impact of calibrator matrix on the comparability of results, we also used the mean results of all laboratories for 4 of the samples to normalize the remaining sample results. Between-laboratory variability increased with increasing C-peptide concentrations. Normalization of results with WHO reference reagents did not improve comparability, but normalization with samples significantly improved comparability among laboratories and methods. The 95% confidence interval estimate for the SD for the lab/method effect (0.0-0.061) using sample-normalized values did not overlap with the 95% CI estimate with the raw data (0.090-0.225). C-peptide results generated by different methods and different laboratories do not always agree, especially at higher concentrations of C-peptide. These data support the concept of using a single laboratory for multisite studies and support efforts to harmonize C-peptide measurements by use of calibrators prepared in the sample matrix.

Role of vitamin D in the pathogenesis of type 2 diabetes mellitus

Vitamin D deficiency has been shown to alter insulin synthesis and secretion in both humans and animal models. It has been reported that vitamin D deficiency may predispose to glucose intolerance, altered insulin secretion and type 2 diabetes mellitus. Vitamin D replenishment improves glycaemia and insulin secretion in patients with type 2 diabetes with established hypovitaminosis D, thereby suggesting a role for vitamin D in the pathogenesis of type 2 diabetes mellitus. The presence of vitamin D receptors (VDR) and vitamin D-binding proteins (DBP) in pancreatic tissue and the relationship between certain allelic variations in the VDR and DBP genes with glucose tolerance and insulin secretion have further supported this hypothesis. The mechanism of action of vitamin D in type 2 diabetes is thought to be mediated not only through regulation of plasma calcium levels, which regulate insulin synthesis and secretion, but also through a direct action on pancreatic beta-cell function. Therefore, owing to its increasing relevance, this review focuses on the role of vitamin D in the pathogenesis of type 2 diabetes mellitus.

The comparison of second phase insulin secretion in patients treated with repaglinide or gliclazide

Summary Aims Sulfonylurea with long half-life such as gliclazide has sustained stimulation on insulin secretion compared to repaglinide which has short half-life for only about 1 h. In this hospital cohort, randomized, cross-over study, we used modified low dose graded glucose infusion test (M-LDGGI) to evaluate second phase insulin secretion after 4 months of treatment with either gliclazide or repaglinide. Methods Sixteen fresh type 2 diabetes with age of 49.5 ± 2.6 years old and BMI of 25.3 ± 0.9 kg/m 2 were included. After titration and maintain dose stage, all cases were randomized to the repaglinide or gliclazide treatment for 4 months. At the end of each treatment period, an M-LDGGI was done. Results The general linear model repeated measurement was used to evaluate the plasma glucose, insulin and insulin/glucose curve during M-LDGGI. Although the plasma insulin and insulin/glucose ratios were higher at 40 min and 100–120 min, they did not reach statistically significant. The area under curve of the plasma glucose, insulin and insulin/glucose ratio was also used to evaluate the secretory capacity of beta cell. Although the AUC of the ratio of plasma insulin/plasma glucose seems to be more evident than the curves, they are still not significantly different with each other. Conclusions In conclusion, although non-significant, better second phase insulin secretion could be noted with treatment of repaglinide than gliclazide for 4 months. Further study with longer duration and larger study cohort are needed to solve this interesting and important question.

Comment on: Nathan DM, Buse JB, Davidson MB et al. (2006) Management of hyperglycaemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 49: 1711–1721

Glucose-responsive insulin secretion is frequently impaired prior to the onset of type 2 diabetes [1]. In addition, considering the reduced pancreatic beta cell mass in patients with type 2 diabetes [2], defects in insulin secretion appear heterogeneous in this patient group. In some patients, only postprandial insulin secretion appears impaired, whilst in others, basal insulin secretion is also affected. However, postprandial insulin secretion is impaired in almost all patients with type 2 diabetes. In the recently published consensus statement from the American Diabetes Association [3] and the European Association for the Study of Diabetes [4] concerning the initiation and adjustment of therapy for managing hyperglycaemia in type 2 diabetes, initial insulin therapy is aimed at increasing basal insulin supply with intermediateor long-acting insulins. Such a regimen cannot completely mimic a physiological pattern of insulin secretion. Consequently, postprandial glycaemic control tends to be inadequate, and a risk exists of fasting hypoglycaemia. Furthermore, the postprandial hyperglycaemia observed in patients with early-stage or mild type 2 diabetes increased the risk of microangiopathy or arteriosclerosis in two largescale clinical studies of type 2 diabetes, the United Kingdom Prospective Diabetes Study [5] and the DECODE study [6]. It has also been suggested that therapy focused on lowering postprandial glucose, rather than fasting glucose, may be superior for lowering HbA1c [7] and glucose variability (spike) [8]. Insulin preparations have been developed to provide insulin replacement that more closely reflects physiological insulin secretion; the introduction of rapid-acting insulin analogues and long-acting soluble insulin analogues has been a further step in this direction. Rapid-acting insulin analogues have been particularly effective at targeting postprandial hyperglycaemia [8]. They can, therefore, effectively reduce postprandial plasma glucose, even if administered immediately before a meal, and also minimise the risk of hypoglycaemia prior to the next meal [8]. The exact contribution of postprandial and fasting glucose increments to overall hyperglycaemia remains controversial. Monnier et al. reported that postprandial glucose excursion contributes up to ∼70% of the glucose load in patients with diabetes whose HbA1c levels are <7.3%, whereas the contribution of fasting hyperglycaemia increases gradually as diabetes worsens [9]. However, even in patients whose glycaemic control is poor, studies have demonstrated that treatment targeting postprandial hyperglycaemia, which improves glucose-responsive insulin secretion in patients with glucose desensitisation, improves both postprandial and also morning fasting plasma glucose (FPG) in such patients [10–12]. We hypothesised that mealtime dosing with rapid-acting insulin analogues strictly controls postprandial and daytime plasma glucose levels, and thereby improves glucose desensitisation and glucose-responsive insulin secretion. To test these hypotheses, we recently evaluated the effect of a mealtime, rapid-acting insulin analogue on the minimum early morning FPG levels (nadir FPG) in 40 Japanese Diabetologia (2007) 50:229–230 DOI 10.1007/s00125-006-0524-9

Elevated circulating adiponectin in type 1 diabetes is associated with long diabetes duration

To study circulating adiponectin concentrations in relation to diabetes duration and endogenous insulin secretion in patients with type 1 diabetes. Patients with haemoglobin A1c (HbA1c) < 6% (reference range 3.6-5.4%) were selected for the study. Twenty-two men and 24 women [age 41.3 +/- 13.8 years (mean +/- SD), diabetes duration 4 months to 52 years] participated. Healthy controls (15 women and nine men, age 41.3 +/- 13.0 years) were also included. Overnight fasting serum samples were analysed for adiponectin, HbA1c, C-peptide and lipoproteins. Significant positive associations were found between adiponectin concentrations and diabetes duration in univariate and multiple regression analyses. Serum adiponectin averaged 9.7 +/- 5.3 [median 8.1, interquartile range (IQR) 3.6] mg/l in patients with diabetes duration less than 10 years and 17.8 +/- 10.7 (median 14.7, IQR 7.5) mg/l in patients with longer duration (P = 0.0001). Among the patients, 24 were without detectable (< 100 pmol/l) and 22 with detectable C-peptide levels (185 +/- 91 pmol/l). C-peptide levels in controls averaged 492 +/- 177 pmol/l. HbA1c was 5.7 +/- 0.6% in patients without detectable C-peptide and 5.6 +/- 0.4% in patients with detectable C-peptide (ns). Serum adiponectin was higher in patients without detectable C-peptide than in patients with detectable C-peptide [17.3 +/- 11.1 vs. 10.6 +/- 5.8 mg/l (P < 0.005)] and in the controls [10.1 +/- 2.9 mg/l (P < 0.001 vs. patients without detectable C-peptide)]. The increase in circulating adiponectin concentrations in patients with type 1 diabetes appears to be strongly associated with long diabetes duration, irrespective of the metabolic control. Among other factors, a putative role for residual beta-cell function in the regulation of circulating adiponectin levels can be considered but we did not find sufficient evidence for this in the present study.

Increased postprandial responses of GLP-1 and GIP in patients with chronic pancreatitis and steatorrhea following pancreatic enzyme substitution

We aimed to investigate how assimilation of nutrients affects the postprandial responses of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) and to evaluate the effect of pancreatic enzyme substitution (PES) on insulin secretion in patients with chronic pancreatitis (CP) and pancreatic exocrine insufficiency (PEI). Eight male patients with CP and PEI were studied. Blood was sampled frequently on two separate days after ingestion of a liquid meal with and without PES, respectively. Eight healthy male subjects served as a control group. beta-Cell responsiveness was estimated as changes in insulin secretion rates in response to changes in postprandial plasma glucose (PG). There was no difference in the PG incremental area under curve (AUC) for patients with and without PES [406 +/- 100 vs. 425 +/- 80 mM.4 h (mean +/- SE), P = 0.8]. The response of total GLP-1 was higher after PES (AUC: 7.8 +/- 1.2 vs. 5.3 +/- 0.6 nM.4 h, P = 0.01), as was the response of total GIP (AUC: 32.7 +/- 7.5 vs. 21.1 +/- 8.3 nM.4 h, P = 0.01). Concurrently, both plasma insulin, plasma C-peptide, and total insulin secretion increased after PES (AUC: 17.7 +/- 4.2 vs. 13.6 +/- 2.9 nM.4 h, P = 0.02; 237 +/- 31.4 vs. 200 +/- 27.4 nM.4 h, P = 0.005; and 595 +/- 82 vs. 497 +/- 80 pmol.kg(-1).4 h, P = 0.01, respectively). beta-Cell responsiveness to glucose was not significantly different on the two study days for patients with CP. These results suggest that the secretion of GLP-1 and GIP is under influence of the digestion and absorption of nutrients in the small intestine and that PES increases insulin secretion.

Effects of Duration of Type 2 Diabetes Mellitus on Insulin Secretion

To gain insight into the effects of duration of type 2 diabetes on insulin secretion in patients with type 2 diabetes mellitus. C-peptide concentrations were measured every 2 years before and after intravenous injection of 1 mg of glucagon in 89 patients with type 2 diabetes (51 men and 38 women) as part of the Rochester Diabetic Neuropathy Study in those subjects who participated in follow-up (median, 12 years; range, 6 to 14). Although insulin secretion decreased over time (P<0.001) in the group as a whole, both the pattern and the rate of decline in C-peptide concentration differed considerably among the study subjects. Insulin secretion, whether measured as fasting C-peptide, 6-minute C-peptide, or postglucagon increment in C-peptide concentrations, declined with increasing duration of diabetes in approximately half of the patients but either increased or remained essentially constant over time in the other half. The decrease in insulin secretion was not associated with a deterioration in glycemic control because hemoglobin A1c also declined (P<0.005) during the same interval. We conclude that insulin secretion decreases over time in many patients with type 2 diabetes. Because the rate of decline is variable, the predictive value of any single measurement is limited. These data indicate that although a decrease in insulin secretion over time is characteristic of type 2 diabetes mellitus, it is not inevitable.