Variations in the four and a half LIM domains 1 gene (<Emphasis Type="Italic">FHL1</Emphasis>) are associated with fasting insulin and insulin sensitivity responses to regular exercise

Aims/hypothesis The expression of the four and a half LIM domains 1 gene (FHL1) is increased in the muscle of individuals who show an improvement in insulin sensitivity index (S _I) after 20 weeks of exercise training. The aim of the present study was to investigate associations between three FHL1 single nucleotide polymorphisms (SNPs) and variables derived from an IVGTT, both in the sedentary state and in response to exercise training, in participants in the HERITAGE Family Study. Materials and methods SNPs were typed using fluorescence polarisation methodology. Analyses were performed separately by sex and in black and white individuals. Results In black participants, no associations were found with any of the SNPs. In white women (n = 207), SNP rs9018 was associated with the disposition index (D _I), which is calculated as S _I generated from the MINMOD program (×10⁻⁴ min⁻¹[μU/ml]⁻¹) multiplied by acute insulin response to glucose (AIR_g; pmol/l × 10 min), and the glucose disappearance index (K _g) training responses (p = 0.016 and p = 0.008, respectively). In white men (n = 222), all SNPs were associated with fasting glucose levels (p ≤ 0.05) and SNP rs2180062 with the insulin sensitivity index (S _I) (p = 0.04) in the sedentary state. Two SNPs were associated with fasting insulin training response. Fasting insulin decreased to a greater extent in carriers of the rs2180062 C allele (p = 0.01) and rs9018 T allele (p = 0.04). With exercise training, S _I (×10⁻⁴ min⁻¹[μU/ml]⁻¹: 0.68 ± 0.20 vs −0.77 ± 0.44, p = 0.046), D _I (319 ± 123 vs –528 ± 260, p = 0.006) and K _g (per 100 min: 0.09 ± 0.04 vs −0.14 ± 0.8, p = 0.03) improved more in the C allele carriers at rs2180062 than in the T allele carriers. Conclusions/interpretation Fasting insulin and S _I responses to exercise training were associated with DNA sequence variation in FHL1 in white men. Whether these associations exist only in white men remains to be investigated. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users.     

Reducing glycaemic variability in type 1 diabetes self-management with a continuous glucose monitoring system based on wired enzyme technology

Aims/hypothesis  This study was designed to investigate the use and impact of a continuous glucose monitoring system (the FreeStyle Navigator) under home-use conditions in the self-management of type 1 diabetes. Methods  A 20 day masked phase, when real-time data and alarms were not available, was compared with a subsequent 40 day unmasked phase for a number of specified measures of glycaemic variability. HbA_1c (measured by DCA 2000) and a hypoglycaemia fear survey were recorded at the start and end of the study. Results  The study included 48 patients with type 1 diabetes (mean age 35.7 ± 10.9, range 18–61 years; diabetes duration 17.0 ± 9.5 years). Two patients did not complete the study for personal reasons. Comparing masked (all 20 days) and unmasked (last 20 days) phases, the following reductions were seen: time outside euglycaemia from 11.0 to 9.5 h/day (p = 0.002); glucose SD from 3.5 to 3.2 mmol/l (p < 0.001); hyperglycaemic time (>10.0 mmol/l) from 10.3 to 8.9 h/day (p = 0.0035); mean amplitude of glycaemic excursions (peak to nadir) down by 10% (p < 0.001); high blood glucose index down by 18% (p = 0.0014); and glycaemic risk assessment diabetes equation score down by 12% (p = 0.0013). Hypoglycaemic time (<3.9 mmol/l) decreased from 0.70 to 0.64 h/day without statistical significance (p > 0.05). Mean HbA_1c fell from 7.6 ± 1.1% at baseline to 7.1 ± 1.1% (p < 0.001). In the hypoglycaemia fear survey, the patients tended to take less snacks at night-time after wearing the sensor. Conclusions/interpretation  Home use of a continuous glucose monitoring system has a positive effect on the self-management of diabetes. Thus, continuous glucose monitoring may be a useful tool to decrease glycaemic variability.     

Exercise training reduces fatty acid availability and improves the insulin sensitivity of glucose metabolism

Aims/hypothesis It is not known whether the beneficial effects of exercise training on insulin sensitivity are due to changes in hepatic and peripheral insulin sensitivity or whether the changes in insulin sensitivity can be explained by adaptive changes in fatty acid metabolism, changes in visceral fat or changes in liver and muscle triacylglycerol content. We investigated the effects of 6 weeks of supervised exercise in sedentary men on these variables. Subjects and methods We randomised 17 sedentary overweight male subjects (age 50 ± 2.6 years, BMI 27.6 ± 0.5 kg/m²) to a 6-week exercise programme (n = 10) or control group (n = 7). The insulin sensitivity of palmitic acid production rate (Ra), glycerol Ra, endogenous glucose Ra (EGP), glucose uptake and glucose metabolic clearance rate were measured at 0 and 6 weeks with a two-step hyperinsulinaemic–euglycaemic clamp [step 1, 0.3 (low dose); step 2, 1.5 (high dose) mU kg⁻¹ min⁻¹]. In the exercise group subjects were studied >72 h after the last training session. Liver and skeletal muscle triacylglycerol content was measured by magnetic resonance spectroscopy and visceral adipose tissue by cross-sectional computer tomography scanning. Results After 6 weeks, fasting glycerol, palmitic acid Ra (p = 0.003, p = 0.042) and NEFA concentration (p = 0.005) were decreased in the exercise group with no change in the control group. The effects of low-dose insulin on EGP and of high-dose insulin on glucose uptake and metabolic clearance rate were enhanced in the exercise group but not in the control group (p = 0.026; p = 0.007 and p = 0.04). There was no change in muscle triacylglycerol and liver fat in either group. Conclusions/interpretation Decreased availability of circulating NEFA may contribute to the observed improvement in the insulin sensitivity of EGP and glucose uptake following 6 weeks of moderate exercise. Electronic supplementary material Supplementary material is available in the online version of this article at and is accessible to authorised users.     

A 10-s sprint performed prior to moderate-intensity exercise prevents early post-exercise fall in glycaemia in individuals with type 1 diabetes

Aims/hypothesis We investigated whether a 10-s maximal sprint effort performed immediately prior to moderate-intensity exercise provides another means to counter the rapid fall in glycaemia associated with moderate-intensity exercise in individuals with type 1 diabetes. Materials and methods Seven complication-free type 1 diabetic males (21.6 ± 3.6 years; mean±SD) with HbA_1c levels of 7.4 ± 0.7% injected their normal morning insulin dose and ate their usual breakfast. When post-meal glycaemia fell to ∼11 mmol/l, participants were asked to perform a 10-s all-out sprint (sprint trial) or to rest (control trial) immediately before cycling at 40% of peak rate of oxygen consumption for 20 min, with both trials conducted in a random counterbalanced order. Results Sprinting did not affect the rapid fall in glycaemia during the subsequent bout of moderate-intensity exercise (2.9 ± 0.4 mmol/l in 20 min; p = 0.00; mean±SE). However, during the following 45 min of recovery, glycaemia in the control trial decreased by 1.23 ± 0.60 mmol/l (p = 0.04) while remaining stable in the sprint trial, subsequently decreasing in this latter trial at a rate similar to that in the control trial. The large increase in noradrenaline (norepinephrine) (p = 0.005) and lactate levels (p = 0.0005) may have contributed to the early post-exercise stabilisation of glycaemia in the sprint trial. During recovery, adrenaline (epinephrine) and NEFA levels increased marginally in the sprint trial, but other counter-regulatory hormones did not change significantly (p < 0.05). Conclusions/interpretation A 10-s sprint performed immediately prior to moderate-intensity exercise prevents glycaemia from falling during early recovery from moderate-intensity exercise in individuals with type 1 diabetes.     

Four weeks of near-normalisation of blood glucose improves the insulin response to glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes

Objective  The incretin effect is attenuated in patients with type 2 diabetes mellitus, partly as a result of impaired beta cell responsiveness to glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). The aim of the present study was to investigate whether 4 weeks of near-normalisation of the blood glucose level could improve insulin responses to GIP and GLP-1 in patients with type 2 diabetes. Methods  Eight obese patients with type 2 diabetes with poor glycaemic control (HbA_1c 8.6 ± 1.3%), were investigated before and after 4 weeks of near-normalisation of blood glucose (mean blood glucose 7.4 ± 1.2 mmol/l) using insulin treatment. Before and after insulin treatment the participants underwent three hyperglycaemic clamps (15 mmol/l) with infusion of GLP-1, GIP or saline. Insulin responses were evaluated as the incremental area under the plasma C-peptide curve. Results  Before and after near-normalisation of blood glucose, the C-peptide responses did not differ during the early phase of insulin secretion (0–10 min). The late phase C-peptide response (10–120 min) increased during GIP infusion from 33.0 ± 8.5 to 103.9 ± 24.2 (nmol/l) × (110 min)⁻¹ (p < 0.05) and during GLP-1 infusion from 48.7 ± 11.8 to 126.6 ± 32.5 (nmol/l) × (110 min)⁻¹ (p < 0.05), whereas during saline infusion the late-phase response did not differ before vs after near-normalisation of blood glucose (40.2 ± 11.2 vs 46.5 ± 12.7 [nmol/l] × [110 min]⁻¹). Conclusions  Near-normalisation of blood glucose for 4 weeks improves beta cell responsiveness to both GLP-1 and GIP by a factor of three to four. No effect was found on beta cell responsiveness to glucose alone. ClinicalTrials.gov ID no.: NCT 00612950 Funding: This study was supported by The Novo Nordisk Foundation, The Medical Science Research Foundation for Copenhagen.     

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

Aims/hypothesis 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. Methods 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). Results 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. Conclusions/interpretation 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. ClinicalTrials.gov ID no.: NCT00612625     

Bivariate genome-wide scan for metabolic phenotypes in non-diabetic Chinese individuals from the Stanford, Asia and Pacific Program of Hypertension and Insulin Resistance Family Study

Aims/hypothesis Hypertension, obesity, impaired glucose tolerance and dyslipidaemia are metabolic abnormalities that often cluster together more often than expected by chance alone. Since these metabolic variables are highly heritable and are at least partially genetically determined, the clustering of defects in these traits implies that pleiotropic effects, where a common set of genes influences more than one trait simultaneously, are likely. Methods We conducted bivariate linkage analyses for highly correlated traits, aiming to dissect the genetic architecture affecting these traits, in 411 Chinese families participating in the Stanford Asia–Pacific Program of Hypertension and Insulin Resistance Study. Results We confirmed the pleiotropic effects of the locus at 37 cM on chromosome 20 on the following pairs: (1) fasting insulin and insulin AUC (empirical p = 0.0006); (2) fasting insulin and homeostasis model assessment of beta cell function (HOMA-beta) (empirical p = 0.0051); and (3) HOMA of insulin resistance (IR) and HOMA-beta (empirical p = 0.0044). In addition, the peak logarithm of the odds (LOD) scores of linkage between a chromosomal locus and a trait for the pair fasting insulin and HOMA-IR rose to 5.10 (equivalent LOD score in univariate analysis, LOD_[1] = 4.01, empirical p = 8.0 × 10⁻⁵) from 3.67 and 3.42 respectively for these two traits in univariate analysis. Additional significant linkage evidence, not shown in single-trait analysis, was identified at 45 cM on chromosome 16 for the pair 1 h insulin and the AUC for insulin, with a LOD score of 4.29 (or LOD_[1] = 3.27, empirical p = 2.0 × 10⁻⁴). This new locus is also likely to harbour the common genes regulating these two traits (p = 1.73 × 10⁻⁶). Conclusions/interpretation These data help provide a better understanding of the genomic structure underlying the metabolic syndrome. Y.-F. Chiu and L.-M. Chuang contributed equally to this study.     

Inappropriate suppression of glucagon during OGTT but not during isoglycaemic i.v. glucose infusion contributes to the reduced incretin effect in type 2 diabetes mellitus

Aims/hypothesis We investigated glucagon responses during OGTT and isoglycaemic i.v. glucose infusion, respectively, to further elucidate the mechanisms behind the glucose intolerance in patients with type 2 diabetes. Materials and methods Ten patients (eight men) with type 2 diabetes (age: 64 [51–80] years; BMI: 23 [21–26] kg/m²; HbA_1c: 6.9 [6.2–8.7]%, values mean [range]) and ten control subjects matched for sex, age and BMI were studied. Blood was sampled on two separate days following a 4-h 50-g OGTT and an isoglycaemic i.v. glucose infusion, respectively. Results Isoglycaemia during the 2 days was obtained in both groups. In the control subjects no difference in glucagon suppression during the first 45 min of OGTT and isoglycaemic i.v. glucose infusion (−36 ± 12 vs −64 ± 23 mmol/l × 45 min; p = NS) was observed, whereas in the group of patients with type 2 diabetes significant glucagon suppression only occurred following isoglycaemic i.v. glucose infusion (−63 ± 21 vs 10 ± 16 mmol/l × 45 min; p = 0.002). The incretin effect was significantly reduced in patients with type 2 diabetes compared with control subjects, but no significant differences in the secretion of glucagon-like peptide-1 or glucose-dependent insulinotropic polypeptide between the two groups during OGTT or isoglycaemic i.v. glucose infusion, respectively, could explain this. Conclusions/interpretation Attenuated and delayed glucagon suppression in patients with type 2 diabetes occurs after oral ingestion of glucose, while isoglycaemic i.v. administration of glucose results in normal suppression of glucagon. We suggest that this phenomenon contributes both to the glucose intolerance and to the reduced incretin effect observed in patients with type 2 diabetes.     

Insulin secretory responses to rising and falling glucose concentrations are delayed in subjects with impaired glucose tolerance

Aims/hypothesis. We hypothesized that beta-cell responses to changes in glucose would not be normal in subjects with impaired glucose tolerance (IGT). Methods. Three groups of 6 subjects were studied: normal weight with normal glucose tolerance (control subjects); obese with normal glucose tolerance (Obese-NGT); and obese with IGT (Obese-IGT). All subjects had a graded glucose infusion protocol to increase (step-up) and then decrease (step-down) plasma glucose. We obtained average insulin-secretion rates (ISR) over the glucose range common to all three groups during step-up and step-down phases, minimal model indices of beta-cell function (f_b, f_d, f_s, T_up, T_down ), and insulin sensitivity (Si). Results. ISR differed significantly between step-up and -down phases only in Obese-IGT individuals. Basal (f_b) and stimulated (f_d, f_s) beta-cell sensitivity to glucose were similar in the three groups. Delays between glucose stimulus and beta-cell response during both step-up (T_up) and -down (T_down) phases were higher in Obese-IGT compared to Controls and Obese-NGT individuals. The product ISR × Si (10^–5·min^–2× l) was lower in Obese-IGT compared to Controls, both during step-up (919 ± 851 vs 3192 ± 1185, p < 0.05) and step-down (1455 ± 1203 vs 3625 ± 691, p < 0.05) phases. Consistently, the product f_s× Si (10^–14·min^–2· pmol^–1× l) was lower in Obese-IGT than in control subjects (27.6 ± 25.4 vs 103.1 ± 20.2, p < 0.05). Conclusion/interpretation. Subjects with IGT are not able to secrete insulin to compensate adequately for insulin resistance. They also show delays in the timing of the beta-cell response to glucose when glucose levels are either rising or falling. [Diabetologia (2002) 45: ▪–▪] Received: 30 July 2001 and in revised form: 21 November 2001     

Variants in KCNQ1 are associated with susceptibility to type 2 diabetes in the population of mainland China

Aims/hypothesis  Two recent genome-wide association studies have identified several novel type 2 diabetes susceptibility variants in intron 15 of the KCNQ1 gene. We aimed to evaluate the effects of the variants in KCNQ1 on type 2 diabetes and metabolic traits in the population of mainland China. Methods  Three candidate single nucleotide polymorphisms were genotyped in 1,912 individuals with type 2 diabetes and 2,041 normal controls using the ligase detection reaction method. Results  We confirmed the association of KCNQ1 with type 2 diabetes in the population of mainland China. Allele frequency ORs of the three single nucleotide polymorphisms (SNPs) were: rs2237892 (OR 1.19, 95% CI 1.08–1.31, p = 3.0 × 10⁻⁴); rs2237895 (OR 1.20, 95% CI 1.09–1.32, p = 1.9 × 10⁻⁴); and rs2237897 (OR 1.24, 95% CI 1.13–1.36, p = 3.9 × 10⁻⁵). We also found a significant difference in the distribution of the global haplotypes between the type 2 diabetes group and the normal control group (p = 2.6 × 10⁻⁵). In addition, in the control group SNP rs2237892 was marginally associated with increasing fasting plasma glucose and SNPs rs2237892 and rs2237897 were associated with HbA_1c. Furthermore, for all three variants, homozygous carriers of the diabetes-associated allele had significantly decreased BMI and waist circumferences. Conclusions/interpretation  Our investigation confirmed the effects of KCNQ1 variants on type 2 diabetes risk in the Chinese population. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorised users. Y. Liu and D. Z. Zhou contributed equally to this study.     

The effect of intense exercise on postprandial glucose homeostasis in Type II diabetic patients

Abstract Aims/hypothesis. The influence of postprandial high intensity exercise on glycaemia was studied in patients with Type II diabetes mellitus. Methods. Patients who were treated by diet only (n = 8) ate a standardised breakfast and 4 h later a standardised lunch. They were studied in the resting state (control day) and on another day (exercise day) when they did intermittent exercised at high intensity after breakfast) (4 bouts including 3 min at 56.5 ± 3.9 % V˙._{O2 max} (means ± SEM), 4 min at 98.3 ± 5.1 % V˙._{O2 max} and 6 min of rest). Responses were calculated as areas under the plasma concentration curve (AUC) during 4 h after either breakfast or lunch. Results. Breakfast-AUCs for glucose, insulin and C peptide were lower (p < 0.05) on the exercise day compared with the control day (glucose: 538 ± 94 vs 733 ± 64 mmol · l^–1· 240 min; insulin: 16 ± 4 vs 22 ± 3 pmol · ml^–1· 240 min; C peptide: 143 ± 22 vs 203 ± 29 pmol · ml^–1· 240 min). After breakfast glucose appearance was unaffected by exercise, whereas disappearance and clearance increased (p < 0.05). Muscle glycogen was diminished by exercise (p < 0.05). After lunch no differences were observed between experiments. Exercise-induced reductions in glucose, insulin and C peptide responses were similar (p > 0.05) in this study of intermittent, high intensity exercise and in a previous study of isocaloric but prolonged moderate (45 min at 53 ± 2 % V˙._{O2 max}) postprandial exercise. Conclusion/interpretation. Postprandial high intensity exercise does not deteriorate glucose homeostasis but reduces both glucose concentrations and insulin secretion. The effect of exercise is related to energy expenditure rather than to peak exercise intensity. Finally, postprandial exercise does not influence glucose homeostasis during a subsequent main meal. [Diabetologia (1999) 42: 1282–1292] Received: 7 May 1999 and in revised form: 5 July 1999     

TCF7L2 variants are associated with increased proinsulin/insulin ratios but not obesity traits in the Framingham Heart Study

Aims/hypothesis  Common variants in the TCF7L2 gene are associated with type 2 diabetes via impaired insulin secretion. One hypothesis is that variation in TCF7L2 impairs insulin processing in the beta cell. In contrast, the association of related TCF7L2 polymorphisms with obesity is controversial in that it has only been shown in cohorts susceptible to ascertainment bias. We reproduced the association of diabetes-associated variants with proinsulin/insulin ratios, and also examined the association of a TCF7L2 haplotype with obesity in the Framingham Heart Study (FHS). Methods  We genotyped the TCF7L2 single nucleotide polymorphisms rs7903146 and rs12255372 (previously associated with type 2 diabetes) and rs10885406 and rs7924080 (which tag haplotype A [HapA], a haplotype reported to be associated with obesity) in 2,512 FHS participants. We used age- and sex-adjusted linear mixed-effects models to test for association with glycaemic traits, proinsulin/insulin ratios and obesity measures. Results  As expected, the T risk allele of rs7903146 was associated with higher fasting plasma glucose (p = 0.01). T/T homozygotes had a 23.5% increase in the proinsulin/insulin ratio (p = 1 × 10⁻⁷) compared with C/C homozygotes. There was no association of HapA with BMI (p = 0.98), waist circumference (p = 0.89), subcutaneous adipose tissue (p = 0.32) or visceral adipose tissue (p = 0.92). Conclusions/interpretation  We confirmed that the risk allele of rs7903146 is associated with hyperglycaemia and a higher proinsulin/insulin ratio. We did not detect any association of the TCF7L2 HapA with adiposity measures, suggesting that this may have been a spurious association from ascertainment bias, possibly induced by the evaluation of obesity in separate groups of glycaemic cases and controls. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorised users.     

Association of GCKR rs780094, alone or in combination with GCK rs1799884, with type 2 diabetes and related traits in a Han Chinese population

Aims/hypothesis  The GCKR rs780094 and GCK rs1799884 polymorphisms have been reported to be associated with dyslipidaemia and type 2 diabetes in white Europeans. The aim of this study was to replicate these associations in Han Chinese individuals and to identify the potential mechanisms underlying these associations. Methods  The single nucleotide polymorphisms rs780094 and rs1799884 were genotyped in a population-based sample of Han Chinese individuals (n = 3,210) and tested for association with risk of type 2 diabetes and related phenotypes. Results  The GCKR rs780094 A allele was marginally associated with reduced risk of type 2 diabetes (OR 0.85, 95% CI 0.73–1.00, p value under an additive model [p _(add)] = 0.05) and significantly associated with reduced risk of impaired fasting glucose (IFG) or type 2 diabetes (OR 0.86, 95% CI 0.77–0.96, p _[add] = 0.0032). It was also significantly associated with decreased fasting glucose and increased HOMA of beta cell function (HOMA-B) and fasting triacylglycerol levels (p _[add] = 0.0169–5.3 × 10⁻⁶), but not with HOMA of insulin sensitivity (HOMA-S). The associations with type 2 diabetes and IFG remained significant after adjustment for BMI, while adjustment for HOMA-B abolished the associations. The GCKR rs780094 was also associated with obesity and BMI, independently of its association with type 2 diabetes. The GCK rs1799884 A allele was significantly associated with decreased HOMA-B (p _[add] = 0.0005), but not with type 2 diabetes or IFG. Individuals with increasing numbers of risk alleles for both variants had significantly lower HOMA-B (p _[add] = 5.8 × 10⁻⁵) in the combined analysis. Conclusions/interpretation  Consistent with observations in white Europeans, the GCKR rs780094 polymorphism contributes to the risk of type 2 diabetes and dyslipidaemia in Han Chinese individuals. In addition, we showed that the effect on type 2 diabetes is probably mediated through impaired beta cell function rather than through obesity. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorised users. Q. Qi and Y. Wu contributed equally to this study.     

A comparison of twice-daily exenatide and biphasic insulin aspart in patients with type 2 diabetes who were suboptimally controlled with sulfonylurea and metformin: a non-inferiority study

Aims/hypothesis The aim of this 52-week, open-label, non-inferiority trial was to compare the safety and efficacy of exenatide (an incretin mimetic) with that of biphasic insulin aspart. Materials and methods Patients on metformin and a sulfonylurea were randomised to exenatide (n = 253; 5 μg twice daily for 4 weeks, 10 μg thereafter) or biphasic insulin aspart (n = 248; twice-daily doses titrated for optimal glucose control), while continuing with metformin and sulfonylurea treatment. Results Glycaemic control achieved with exenatide was non-inferior to that achieved with biphasic insulin aspart (mean±SEM, HbA_1c change: exenatide −1.04 ± 0.07%, biphasic insulin aspart −0.89 ± 0.06%; difference −0.15 [95% CI −0.32 to 0.01]%). Exenatide-treated patients lost weight, while patients treated with biphasic insulin aspart gained weight [between-group difference −5.4 (95% CI −5.9 to −5.0) kg]. Both treatments reduced fasting serum glucose (exenatide −1.8 ± 0.2 mmol/l, p < 0.001; biphasic insulin aspart −1.7 ± 0.2 mmol/l, p < 0.001). Greater reductions in postprandial glucose excursions following morning (p < 0.001), midday (p = 0.002) and evening meals (p < 0.001) were observed with exenatide. The withdrawal rate was 21.3% (54/253) for exenatide and 10.1% (25/248) for biphasic insulin aspart. Nausea (33% incidence, 3.5% discontinuation) was the most common adverse event observed with exenatide. Conclusions/interpretation Exenatide treatment resulted in HbA_1c reduction similar to biphasic insulin aspart and provided better postprandial glycaemic control, making it a potential alternative for the treatment of type 2 diabetes. Treatment with biphasic insulin aspart was associated with weight gain and lower risk of adverse gastrointestinal events. Although the availability of glucose-lowering agents associated with weight reduction may be considered a therapeutic advance, the long-term implications of progressive weight reduction observed with exenatide have yet to be defined. Electronic supplementary material A list of the site investigators is available as electronic supplementary material in the online version of this article at and is accessible to authorised users.     

Plasma pancreatic polypeptide levels are associated with differences in body fat distribution in human subjects

Aims/hypothesis Pancreatic polypeptide (PP) is produced by the F-cells of the pancreas, and its plasma concentration has been used as a marker of parasympathetic activity. Recent work in rodents suggests that there is both sympathetic and parasympathetic innervation of white adipose tissue and that parasympathetic activity is anabolic resulting in lipid accumulation. We have examined whether in humans increased PP levels are associated with increased intra-abdominal fat (IAF), and thereby insulin resistance. Materials and methods We measured PP levels in 177 non-diabetic subjects (75 male/102 female; age 32–75 years) 3 min after an i.v. glucose bolus during a frequently sampled intravenous glucose tolerance test. IAF and s.c. fat (SCF) areas were measured by CT scan. The insulin sensitivity index (S _I) was quantified using Bergman’s minimal model. Results PP levels were higher in men than in women (96.2 ± 72.2 vs 76.1 ± 55.0 pg/ml, mean ± SD, p = 0.037), as was IAF area (124.7 ± 67.4 vs 83.0 ± 57.7 cm², p < 0.001). While PP levels were significantly associated with IAF (r = 0.16, p = 0.031), WHR (r = 0.30, p < 0.001) and age (r = 0.37, p < 0.01), they were not associated with SCF (r = 0.02, p = 0.829). The association between PP and IAF was not independent of age and/or sex. S _I was negatively associated with PP levels (r = −0.17, p = 0.026) and IAF area (r = −0.65, p < 0.001). The association between S _I and PP disappeared after adjusting for IAF area, indicating that S _I was not a major determinant of PP levels. Conclusions/interpretation In humans, age and sex may modulate the association between plasma PP level and IAF area, suggesting that they may be determinants of parasympathetic activity and thus IAF accumulation.     

Long-term physical training in female Type 1 (insulin-dependent) diabetic patients: absence of significant effect on glycaemic control and lipoprotein levels

Summary No objective evidence has been presented to support the beneficial effect of physical training on glycaemic control in Type 1 (insulin-dependent) diabetic patients trained two to three times a week for several months. In the present study we examined the possibility that a daily exercise programme would be more suitable for improving glycaemic control. Thirteen patients completed a 5-month study; 6 were randomized to exercise training (20 min daily bicycle exercise) and 7 served as non-exercising controls. The training resulted in an 8% increase in maximal oxygen uptake (p < 0.05). No change in glycaemic control occurred during the study period in either group. In addition, serum lipid and lipoprotein levels were followed. Total cholesterol decreased during the study period irrespective of training. No effect was noted on the levels of LDL, VLDL, HDL and HDL₂ cholesterol. A significant training effect was obtained in the HDL₃ subfraction (−10%,p < 0.05). Total triglycerides were unchanged, but a decrease in the level of LDL triglycerides was observed with training (−12%,p < 0.01). It is concluded that, in female Type 1 diabetic patients, daily physical training for several months does not improve glycaemic control and results only in minor changes in serum lipoprotein profiles.     

Does exercise affect the antioxidant system in patients with ankylosing spondylitis?

We aimed to investigate the effect of regular supervised exercise program on functinal status, disease activity, and total antioxidant status (TAS) level in patients with ankylosing spondylitis (AS). Thirty-two patients (mean age: 44 years) with AS were included in the study and divided into two groups. Group 1, the exercise group (n = 16), attended a supervised exercise program that consisted of aerobic, strengthening, and stretching exercises for 1 h a day, five times a week for 3 weeks. Group 2, the control group, received a home exercise program (n:16). Bath AS Activity Index (BASDAI) and Bath AS Functional Index (BASFI) were calculated and serum TAS levels were measured for each patient at 0 and 3 weeks. There was no significant difference in patients' baseline characteristics (age, disease duration, BASFI, and BASDAI scores) between exercise and control groups. In the exercise group, there were significant improvements between pre-exercise and post-exercise assessments in BASFI (2.8 ± 1,8; 1.7 ± 1,40, p = 0.004) and BASDAI scores (2.1 ± 1.7; 1.2 ± 1.3, p = 0.01). Mean TAS levels were significantly decreased after supervised exercise program (1.48 ± 0.16 mmol/L; 1.36 ± 0.20 mmol/L, p = 0.03). In the control group, BASFI score (2.4 ± 1.7; 2.9 ± 2.1, p = 0.19), BASDAI score (2.6 ± 2.2; 3.1 ± 2.6, p = 0.33), and mean TAS levels (1.38 ± 0.23 mmol/L; 1.39 ± 0.20 mmol/L, p = 0.66) did not differ significantly between 0 and 3 weeks. Short-term, supervised exercise program improved functional status and decreased disease activity. However, the mechanism of this beneficial clinical effect does not seem to be through antioxidant activity.     

Common genetic variation in the melatonin receptor 1B gene (MTNR1B) is associated with decreased early-phase insulin response

Aims/hypothesis  We investigated whether variation in MTNR1B, which was recently identified as a common genetic determinant of fasting glucose levels in healthy, diabetes-free individuals, is associated with measures of beta cell function and whole-body insulin sensitivity. Methods  We studied 1,276 healthy individuals of European ancestry at 19 centres of the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study. Whole-body insulin sensitivity was assessed by euglycaemic–hyperinsulinaemic clamp and indices of beta cell function were derived from a 75 g oral glucose tolerance test (including 30 min insulin response and glucose sensitivity). We studied rs10830963 in MTNR1B using additive genetic models, adjusting for age, sex and recruitment centre. Results  The minor (G) allele of rs10830963 in MTNR1B (frequency 0.30 in HapMap Centre d’Etude du Polymorphisme [Utah residents with northern and western European ancestry] [CEU]; 0.29 in RISC participants) was associated with higher levels of fasting plasma glucose (standardised beta [95% CI] 0.17 [0.085, 0.25] per G allele, p = 5.8 × 10⁻⁵), consistent with recent observations. In addition, the G-allele was significantly associated with lower early insulin response (−0.19 [−0.28, −0.10], p = 1.7 × 10⁻⁵), as well as with decreased beta cell glucose sensitivity (−0.11 [−0.20, −0.027], p = 0.010). No associations were observed with clamp-assessed insulin sensitivity (p = 0.15) or different measures of body size (p > 0.7 for all). Conclusions/interpretation  Genetic variation in MTNR1B is associated with defective early insulin response and decreased beta cell glucose sensitivity, which may contribute to the higher glucose levels of non-diabetic individuals carrying the minor G allele of rs10830963 in MTNR1B. Electronic supplementary material  The online version of this article (doi:) contains a list of the members of the RISC Consortium, which is available to authorised users.     

Ischemic preconditioning improves stability of intestinal anastomoses in rats

Background  The aim of our study was to establish whether ischemic preconditioning (IPC) directly before performing a small bowel anastomosis has an effect on anastomotic stability and healing. Material and methods  Forty male Wistar rats were randomized to five groups: control (CO, n = 8) with preparation of the superior mesenteric artery (SMA) but without IPC. IPC groups had different intervals of ischemia (occlusion of the SMA) and reperfusion: 10 min ischemia and 20 min reperfusion (IPC10/20, n = 7), 10 min ischemia and 30 min reperfusion (IPC10/30, n = 8), 15 min ischemia and 20 min reperfusion (IPC15/20, n = 8), and 15 min ischemia and 30 min reperfusion (IPC15/30, n = 9). On the fourth postoperative day, the animals were relaparotomized: bursting pressure, hydroxyproline concentration, and histological ischemia mucosal injury scale of the anastomosis were assessed. Results  Four days after operation, the mean bursting pressure was 73 ± 6 mmHg in the control group, whereas it was significantly higher in IPC10/20 (113 ± 11 mmHg; p = 0.018), IPC10/30 (110 ± 13 mmHg; p = 0.001), and IPC15/30 (124 ± 9 mmHg; p = 0.003). IPC15/20 did not show a significant difference (63 ± 2 mmHg; p = 0.4). We did not find a significant effect regarding hydroxyproline concentration, but IPC diminished mucosal injury. Conclusions  IPC directly before performing a small bowel anastomosis has a time-dependent beneficial effect on anastomotic stability, thus indicating a new clinical approach to improve the healing process of intestinal anastomosis.