Addition of vildagliptin to insulin improves glycaemic control in type 2 diabetes

Aims/hypothesis Type 2 diabetes is difficult to manage in patients with a long history of disease requiring insulin therapy. Moreover, addition of most currently available oral antidiabetic agents increases the risk of hypoglycaemia. Vildagliptin is a dipeptidyl peptidase-IV inhibitor, which improves glycaemic control by increasing pancreatic beta cell responsiveness to glucose and suppressing inappropriate glucagon secretion. This study assessed the efficacy and tolerability of vildagliptin added to insulin therapy in patients with type 2 diabetes. Materials and methods This was a multicentre, 24-week, double-blind, randomised, placebo-controlled, parallel-group study in patients with type 2 diabetes that was inadequately controlled (HbA_1c = 7.5–11%) by insulin. Patients received vildagliptin (n = 144; 50 mg twice daily) or placebo (n = 152) while continuing insulin therapy. Results Baseline HbA_1c averaged 8.4 ± 0.1% in both groups. The adjusted mean change from baseline to endpoint (AMΔ) in HbA_1c was −0.5 ± 0.1% and −0.2 ± 0.1% in patients receiving vildagliptin or placebo, respectively, with a significant between-treatment difference (p = 0.01). In patients aged ≥65 years, the AMΔ HbA_1c was −0.7 ± 0.1% in the vildagliptin group vs −0.1 ± 0.1% in the placebo group (p < 0.001). The incidence of adverse events was similar in the vildagliptin (81.3%) and placebo (82.9%) groups. However, hypoglycaemic events were less common (p < 0.001) and less severe (p < 0.05) in patients receiving vildagliptin than in those receiving placebo. Conclusions/interpretation Vildagliptin decreases HbA_1c in patients whose type 2 diabetes is poorly controlled with high doses of insulin. Addition of vildagliptin to insulin therapy is also associated with reduced confirmed and severe hypoglycaemia. ClinicalTrials.gov ID no.: NCT 00099931. Electronic supplementary material The online version of this article (doi:) contains a complete list of investigators which is available to authorised users.     

N-terminal pro-B-type natriuretic peptide and functional capacity in patients with obstructive sleep apnea

The obstructive sleep apnea syndrome (OSAS) is associated with cardiovascular abnormalities including left ventricular hypertrophy, left ventricular diastolic dysfunction, and endothelial dysfunction. The present study evaluated whether N-terminal pro-B-type natriuretic peptide (NT-proBNP) and peak oxygen consumption (peak VO₂), both integral markers of cardiovascular function, are related to OSAS severity. In addition, we tested whether NT-proBNP levels depend on body composition in OSAS patients, similar to what has been reported in patients without OSAS. Eighty-nine patients with untreated OSAS underwent NT-proBNP measurement, dual X-ray absorptiometry, and cardiopulmonary exercise testing. In a representative subgroup (n = 32), transthoracic echocardiography was performed. The severity of OSAS was classified based on apnea–hypopnea index (AHI) values as mild (AHI 5–15 h⁻¹), moderate (AHI 15–30 h⁻¹), and severe (AHI >30 h⁻¹). OSAS was mild in 19 (21%), moderate in 21 (24%), and severe in 49 (55%) patients. NT-proBNP levels did not differ among patients with mild [30 (10–57)], moderate [37 (14–55)], and severe [24 (13–49) pg/ml; p = 0.8] OSAS and were not related to body mass index (r = 0.07; p = 0.5), percent lean body mass (r = −0.17; p = 0.1), and percent fat mass (r = 0.18; p = 0.1). Percent predicted peak VO₂ was on average normal and did not differ among patients with mild (115 ± 26), moderate (112 ± 23), and severe OSAS (106 ± 29%; p = 0.4). Body weight-indexed peak VO₂ did not differ among patients with mild (31.9 ± 10.3), moderate (32.1 ± 7.9), and severe OSAS (30.0 ± 9.9 ml kg⁻¹ min⁻¹; p = 0.6) either. Lower NT-proBNP (β = −0.2; p = 0.02) was independently but weakly associated with higher body weight-indexed peak VO₂. In the echocardiography subgroup, NT-proBNP was not significantly related to left ventricular mass index (r = 0.26; p = 0.2). In conclusion, NT-proBNP and peak VO₂ are not related to OSAS severity, and NT-proBNP poorly reflects left ventricular hypertrophy in OSAS. The lack of a relationship between NT-proBNP and OSAS severity is not due to a significant influence of body composition on NT-proBNP. There is an association between higher NT-proBNP and lower peak VO₂, indicating that NT-proBNP is a marker of cardiorespiratory fitness in patients with OSAS. However, the association is too weak to be clinically useful.     

Evidence that vildagliptin attenuates deterioration of glycaemic control during 2-year treatment of patients with type 2 diabetes and mild hyperglycaemia

Aim: To assess the 2‐year efficacy and tolerability of vildagliptin (50 mg once daily) in patients with type 2 diabetes (T2DM) and mild hyperglycaemia. Methods: This was a multicentre, randomized, double‐blind, placebo‐controlled trial comprising a 52‐week core study with a 4‐week, active treatment–free washout followed by a 52‐week extension study with another washout period conducted in 131 drug‐naïve patients with T2DM and mild hyperglycaemia [glycosylated haemoglobin (HbA_1c) 6.2–7.2%]. All patients received lifestyle counselling at each study visit. Efficacy and tolerability were assessed during visits at weeks 0 (core study baseline), 4, 8, 12, 16, 24, 32, 40 and 52 of active treatment; at week 56 (i.e. after the first washout period); at weeks 68, 80, 96 and 108 and at week 112 (i.e. after the second washout period). Standard meal tests were also performed at weeks 0, 24, 52, 56, 80, 108 and 112 to assess postprandial glycaemia and β‐cell function, which was quantified by glucose area under the curve (AUC_{0–2 h})/insulin secretory rate (ISR) AUC_{0–2 h} (ISR/G). Changes from baseline and between‐treatment differences (placebo‐adjusted changes from baseline during vildagliptin treatment) were analysed by ancova . Results: The placebo‐adjusted change from week 0 in HbA_1c was ?0.3 ± 0.1% after 1 year of vildagliptin treatment (p < 0.001) and ?0.5 ± 0.2% after 2 years (p = 0.008). The placebo‐adjusted change from core study baseline in fasting plasma glucose, in glucose AUC_{0–2 h} and in the β‐cell function parameter, ISR/G, tended to be greater after 2 years than after 1 year of treatment with vildagliptin. Even after a 4‐week washout, the placebo‐adjusted change from week 0 to week 112 in ISR/G was 3.2 ± 1.6 pmol/min/m²/mM (p = 0.058) and the placebo‐adjusted difference in the change from week 0 to week 112 in HbA_1c was ?0.3 ± 0.1% (p = 0.051). The incidences of adverse events (AEs), serious AEs and discontinuations because of AEs were similar in the two treatment groups, and hypoglycaemic episodes were reported by no patient receiving vildagliptin and by two patients receiving placebo. Conclusions: In drug‐naïve patients with mild hyperglycaemia, 2‐year treatment with vildagliptin 50 mg once daily attenuated the progressive loss of glycaemic control seen in patients receiving only lifestyle counselling (and placebo). This appears to be because of a corresponding attenuation of the deterioration of β‐cell function as assessed by ISR/G.     

Reduced intrahepatic fat content is associated with increased whole-body lipid oxidation in patients with type 1 diabetes

Aims/hypothesis Insulin resistance may be associated with ectopic fat accumulation potentially determined by reduced lipid oxidation. In patients with type 1 diabetes peripheral insulin resistance is associated with higher intramyocellular lipid content. We assessed whether these patients are also characterised by intrahepatic fat accumulation and abnormal fat oxidation. Methods Nineteen patients with type 1 diabetes (6 women, 13 men, age 35±7 years, BMI 23±3 kg/m², HbA₁c 8.7±1.4%) and 19 healthy matched individuals were studied by (1) euglycaemic–hyperinsulinaemic clamp combined with [6,6−²H₂]glucose infusion to assess whole–body glucose metabolism; (2) indirect calorimetry to assess glucose and lipid oxidation; and (3) localised ¹H−magnetic resonance spectroscopy of the liver to assess intrahepatic fat content. Results Patients with type 1 diabetes showed a reduced insulin−stimulated metabolic clearance rate of glucose (4.3±1.3 ml kg⁻¹ min⁻¹) in comparison with normal subjects (6.0±1.6 ml kg⁻¹ min⁻¹; p<0.001). Endogenous glucose production was higher in diabetic patients (p=0.001) and its suppression was impaired during insulin administration (66±30 vs 92±8%; p=0.047) in comparison with normal subjects. Plasma glucagon concentrations were not different between groups. The estimated hepatic insulin concentration was lower in diabetic patients than in normal subjects (p<0.05), as was the intrahepatic fat content (1.5±0.7% and 2.2±1.0% respectively; p<0.03), the latter in association with a reduced respiratory quotient (0.74±0.05 vs 0.84±0.06; p=0.01) and increased fasting lipid oxidation (1.5±0.5 vs 0.8±0.4 mg kg⁻¹ min⁻¹; p<0.01). Conclusions/interpretation In patients with type 1 diabetes, insulin resistance was not associated with increased intrahepatic fat accumulation. In fact, diabetic patients had reduced intrahepatic fat content, which was associated with increased fasting lipid oxidation. The unbalanced hepatic glucagon and insulin concentrations affecting patients with type 1 diabetes may be involved in this abnormality of intrahepatic lipid metabolism.     

Copper addition prevents the inhibitory effects of interleukin 1-β on rat pancreatic islets

Summary Since copper [Cu(II)] is a necessary cofactor for both intra-mitochondrial enzymes involved in energy production and hydroxyl scavenger enzymes, two hypothesised mechanisms for action of interleukin-Iβ (IL-1β), we studied whether CU(II) addition could prevent the inhibitory effect of IL-1β on insulin release and glucose oxidation in rat pancreatic islets. Islets were incubated with or without 50 U/ml IL-1β, in the presence or absence of various concentrations of Cu(II)-GHL (Cu(II) complexed with glycyl-l-histidyl-l-lysine, a tripeptide known to enhance copper uptake into cultured cells). CuSO₄ (1–1000 ng/ml) was used as a control for Cu(II) effect when present as an inorganic salt. At the end of the incubation period, insulin secretion was evaluated in the presence of either 2.8 mmol/l (basal insulin secretion) or 16.7 mmol/l glucose (glucose-induced release). In control islets basal insulin secretion was 92.0±11.4 pg · islet⁻¹ h⁻¹ (mean ± SEM,n=7) and glucose-induced release was 2824.0±249.0 pg · islet⁻¹ h⁻¹. In islets pre-exposed to 50 U/ml IL-1β, basal insulin release was not significantly affected but glucose-induced insulin release was greatly reduced (841.2±76.9,n=7,p<0.005). In islets incubated with IL-1β and Cu-GHL (0.4 μmol/l, maximal effect) basal secretion was 119.0±13.1 pg · islet⁻¹ h⁻¹ and glucose-induced release was 2797.2±242.2, (n=7,p<0.01 in respect to islets exposed to IL-1β alone). In contrast to data obtained with Cu(II)-GHL, increasing concentrations of CuSO4 (up to 10 μmol/l) did not influence the inhibitory effect of IL-1β on glucose-stimulated insulin release. Glucose oxidation (in the presence of 16.7 mmol/l glucose) was 31.5±2.4 pmol · islet⁻¹·90min⁻¹ in control islets and 7.0±0.9 (p<0.01) in IL-1β-exposed islets. In islets exposed to IL-1β and Cu-GHL glucose oxidation was similar to control islets (31.9±1.9). In contrast, Cu-GHL did not prevent the IL-1β-induced increase in nitric oxide production. Nitrite levels were 5±1.7, 26±5 and to 29±4 pmol · islet⁻¹·48 h⁻¹ (mean ± SEM,n=5) in the culture medium from control IL-1β and IL-1β+Cu-GHL exposed islets, respectively. These data indicate that the Cu(II) complexed to GHL is able to prevent the inhibitory effects of IL-1β on insulin secretion and glucose oxidation, but not on NO production. The mechanism of action of Cu-GHL is still unclear, but it might restore the activity of the enzymatic systems inhibited by IL-1β. [Diabetologia (1995) 38∶39–45]     

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.     

Evidence for direct action of alloxan to induce insulin resistance at the cellular level

Summary To determine whether long-term insulin deficiency alters insulin movement across the endothelium, plasma and lymph dynamics were assessed in dogs after alloxan (50 mg/kg; n = 8) or saline injection (n = 6). Glucose tolerance (K_G) and acute insulin response were assessed by glucose injection before and 18 days after treatment. Two days later, hyperglycaemic (16.7 mmol/l) hyperinsulinaemic (60 pmol · min⁻¹· kg⁻¹) glucose clamps were carried out in a subset of dogs (n = 5 for each group), with simultaneous sampling of arterial blood and hindlimb lymph. Alloxan induced fasting hyperglycaemia (12.9 ± 2.3 vs 5.7 ± 0.2 mmol/l; p = 0.018 vs pre-treatment) and variable insulinopenia (62 ± 14 vs 107 ± 19 pmol/l; p = 0.079). The acute insulin response, however, was suppressed by alloxan (integrated insulin from 0–10 min: 155 ± 113 vs 2745 ± 541 pmol · l⁻¹· 10 min⁻¹; p = 0.0027), resulting in pronounced glucose intolerance (K_G: 0.99 ± 0.19 vs 3.14 ± 0.38 min⁻¹; p = 0.0002 vs dogs treated with saline). During clamps, steady state arterial insulin was higher in dogs treated with alloxan (688 ± 60 vs 502 ± 38 pmol/l; p = 0.023) due to a 25 % reduction in insulin clearance (p = 0.045). Lymph insulin concentrations were also raised (361 ± 15 vs 266 ± 27 pmol/l; p = 0.023), such that the lymph to arterial ratio was unchanged by alloxan (0.539 ± 0.022 vs 0.533 ± 0.033; p = 0.87). Despite higher lymph insulin, glucose uptake (R_d) was significantly diminished after injection of alloxan (45.4 ± 2.5 vs 64.3 ± 6.5 μmol · min⁻¹· kg⁻¹; p = 0.042). This was reflected in resistance of target tissues to the lymph insulin signal (ΔR_d/Δlymph insulin: 3.389 ± 1.093 vs 11.635 ± 2.057 · 10⁻⁶· l · min⁻¹· kg^–1· pmol⁻¹· l⁻¹; p = 0.012) which correlated strongly with the K_G (r = 0.86; p = 0.0001). In conclusion, alloxan induces insulinopenic diabetes, with glucose intolerance and insulin resistance at the target tissue level. Alloxan treatment, however, does not alter lymph insulin kinetics, indicating that insulin resistance of Type 1 (insulin-dependent) diabetes mellitus reflects direct impairment at the cellular level. [Diabetologia (1998) 41: 1327–1336] Received: 3 November 1997 and in final revised form: 2 June 1998     

The Role of microsomal triglyceride transfer protein and dietary cholesterol in chylomicron production in diabetes

Aims/hypothesis. The aim of this study was to examine factors involved in chylomicron production in the streptozotocin diabetic rat, our hypothesis being that the synthesis of the chylomicron is abnormal in diabetes. Methods. Diabetic rats (n = 20) were paired with control rats (n = 20). Cholesterol emulsion was given by gavage and the lymph duct was cannulated. Lymph was collected for 4 h. Chylomicrons were prepared from the lymph by ultracentrifugation. Lymph apolipoprotein B48 was isolated by gradient gel electrophoresis and quantified by densitometric scanning. Intestinal microsomal triglycerol transfer protein mRNA was measured by solution hybridisation nuclease protection, using a rat specific [³²P]-labelled cRNA probe. Results. Serum triglyceride and cholesterol were greatly increased in diabetic compared with control animals (258 ± 77 and 8.9 ± 6.4 mg/ml vs 1.04 ± 0.37 and 0.54 ± 0.03 mg/ml, p < 0.0001). Lymph chylomicron triglyceride and cholesterol were also higher in diabetic rats (29.4 ± 27.3 and 0.28 ± 0.3 mg/h vs 16.8 ± 10.6 and 0.18 ± 0.09 mg/h, p < 0.05). Lymph chylomicron apo B48 was similar in the two groups. Intestinal microsomal triglycerol transfer protein mRNA was higher in the diabetic rats (12.6 ± 3.2 vs 3.8 ± 3.0 amol/μg RNA, p < 0.0001) and there was a positive correlation between lymph triglyceride and microsomal triglycerol transfer protein mRNA in the whole group (r = 0.65, p < 0.01). Conclusion/interpretation. The study shows that microsomal triglycerol transfer protein mRNA is raised in diabetes without an increase in apolipoprotein B48 in the lymph suggesting that microsomal triglycerol transfer protein regulates chylomicron triglyceride content but not particle number. [Diabetologia (1999) 42: 944–948] Received: 9 December 1998 and in revised form: 6 April 1999     

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.     

Improved postprandial glycaemic controls with insulin Aspart in type 2 diabetic patients treated with insulin

The effect on postprandial blood glucose control of an immediately pre-meal injection of the rapid acting insulin analogue Aspart (IAsp) was compared with that of human insulin Actrapid injected immediately or 30 before a test meal in insulin-treated type 2 diabetic patients with residual β-cell function. In a double-blind, double dummy crossover design, patients attended three study days where the following insulin injections in combination with placebo were given in a random order: IAsp (0.15 IU/kg body weight) immediately before the meal, or insulin Actrapid (0.15 IU/kg) immediately (Act-₀) or 30 minutes before (Act-₃₀) a test meal. We studied 25 insulin-requiring type 2 diabetic patients, including 14 males and 11 females, with a mean age of 59.7 years (range, 43–71), body mass index 28.3 kg/m² (range, 21.9–35.0), HbA_1c 8.5% (range, 6.8–10.0), glucagon-stimulated C-peptide 1.0 nmol/l (range, 0.3–2.5) and diabetes duration 12.5 years (range, 3.0–26.0). Twenty-two patients completed the study A significantly improved postprandial glucose control was demonstrated with IAsp as compared to Act₀, based on a significantly smaller postprandial blood glucose excursion (IAsp, 899 ± 609 (SD) mmol/l · min versus Act₀, 1102 ± 497 mmol/l min, p < 0.01) and supported by a significantly lower maximum serum glucose concentration (C_max) up to 360 min after dosing (IAsp, 10.8 ± 2.2 mmol/l vs. Act₀, 12.0 ±2.4 mmol/l, p < 0.02). No difference was demonstrated with a meal and Actrapid injected 30 minutes before the meal (AUC_glucose IAsp, 899 ± 609 mmol/l min vs. Act-₃₀, 868 ± 374 mmol/l min; C_max IAsp, 10.8 ± 2.2 mmol/l vs. Act-₃₀, 11.1 ± 1.8 mmol/l). No concerns about the safety of IAsp were raised. Immediate pre-meal administration of the rapid-acting insulin analogue Aspart in patients with type 2 diabetes resulted in an improved postprandial glucose control compared to Actrapid injected immediately before the meal, but showed similar control compared to Actrapid injected 30 minutes before the meal. These results indicate that the improved glucose control previously demonstrated with insulin Aspart compared to human insulin in healthy subjects and type 1 diabetic patients also applies to insulin-treated type 2 diabetic patients. Received: 3 December 1999 / Accepted in revised form: 3 March 2000     

The effect of portal and peripheral insulin delivery on carbohydrate and lipid metabolism in a miniature pig model of human IDDM

Summary A pig model of insulin-dependent diabetes was used to examine the importance of the portal-systemic insulin gradient for whole-body metabolic control. Six pigs had jugular vein, portal vein, and carotid artery cannulae implanted before being made diabetic (150 mg kg^{− 1} streptozotocin). Each animal received 4 weeks of portal and 4 weeks of peripheral insulin delivery in random order. The blood glucose target range was 5–10 mmol · l^{− 1}, and serum fructosamine and fasting and postprandial blood glucose concentrations were not different between peripheral and portal insulin infusion. Insulin requirement was not different between the 4 week infusion periods, but fasting peripheral insulin levels after peripheral delivery (124 ± 16 (mean ± SEM) pmol · l^{− 1}) were significantly higher (p < 0.05) than in portally infused (73.8 ± 5.4 pmol · l^{− 1}) or pre-diabetic control animals (68.4 ± 3.6 pmol · l^{− 1}). Basal hepatic glucose output was also higher (p < 0.05) in peripherally (4.2 ± 0.4 mg · kg^{− 1}· min^{− 1}) than in portally infused animals (2.9 ± 0.4 mg · kg^{− 1}· min^{− 1}) or controls (3.0 ± 0.3 mg · kg^{− 1}· min^{− 1}). Clamp glucose metabolic clearance rate was, however, not different between the peripheral and portal insulin delivery routes (8.1 ± 1.0 vs 9.0 ± 0.7 ml · kg^{− 1}· min^{− 1}), although both were significantly lower (p < 0.05) than that measured in prediabetic control animals (11.7 ± 1.0 ml · kg^{− 1}· min^{− 1}). Lipid profiles and subfractions were similar in all three groups. It is concluded that the portal route of delivery is superior to the peripheral in maintaining more appropriate insulin concentrations and control of hepatic glucose output, although in the absence of euglycaemia it is still associated with significant metabolic abnormalities. [Diabetologia (1997) 40: 1125–1134] Received: 25 February 1997 and in revised form: 23 May 1997     

Glucagon-like peptide 1 abolishes the postprandial rise in triglyceride concentrations and lowers levels of non-esterified fatty acids in humans

Aims/hypothesis Diabetic dyslipidaemia contributes to the excess morbidity and mortality in patients with type 2 diabetes. Exogenous glucagon-like peptide 1 (GLP-1) lowers postprandial glycaemia predominantly by slowing gastric emptying. Therefore, the effects of GLP-1 on postprandial lipid levels and gastric emptying were assessed. Methods 14 healthy male volunteers were studied with an i.v. infusion of GLP-1 (1.2 pmol kg⁻¹ min⁻¹) or placebo over 390 min in the fasting state. A solid test meal was served and gastric emptying was determined using a ¹³C-labelled sodium octanoate breath test. Venous blood was drawn frequently for measurement of glucose, insulin, C-peptide, glucagon, GLP-1, triglycerides and NEFA. Results GLP-1 administration lowered fasting and postprandial glycaemia (p<0.0001). Gastric emptying was delayed by GLP-1 compared with placebo (p<0.0001). During GLP-1 administration, insulin secretory responses were higher in the fasting state but lower after meal ingestion. After meal ingestion, triglyceride plasma levels increased by 0.33±0.14 mmol/l in the placebo experiments (p<0.0001). In contrast, the postprandial increase in triglyceride levels was completely abolished by GLP-1 (change in triglycerides, −0.023±0.045 mmol/l; p<0.05). During GLP-1 infusion, plasma concentrations of NEFA were suppressed by 39% in the fasting state (p<0.01) and by 31±5% after meal ingestion (p<0.01). Conclusions/interpretation GLP-1 improves postprandial lipidaemia, presumably as a result of delayed gastric emptying and insulin-mediated inhibition of lipolysis. Thus, by lowering both glucose and lipid concentrations, GLP-1 administration may reduce the cardiovascular risk in patients with type 2 diabetes.     

Efficacy and tolerability of vildagliptin in drug-naïve patients with type 2 diabetes and mild hyperglycaemia*

Aim: This study was conducted to assess efficacy and tolerability of vildagliptin in drug‐naïve patients with type 2 diabetes and mild hyperglycaemia. Methods: Multicentre, double‐blind, randomized, placebo‐controlled, parallel‐group study of 52‐week treatment with vildagliptin (50 mg q.d.) in 306 drug‐naïve patients with type 2 diabetes (A1C = 6.2–7.5%). A1C, fasting plasma glucose (FPG) and measures of prandial glucose control and beta‐cell function determined during standard meal tests were assessed. Results: Baseline A1C and FPG averaged 6.7% and 7.1 mmol/l, respectively, in patients randomized to vildagliptin (n = 156) and 6.8% and 7.2 mmol/l in those randomized to placebo (n = 150). A1C decreased modestly in vildagliptin‐treated patients (Δ = ?0.2 ± 0.1%) and increased in patients receiving placebo (Δ = 0.1 ± 0.1%). The between‐group difference (vildagliptin ? placebo) in adjusted mean change (AMΔ) in A1C was ?0.3 ± 0.1% (p < 0.001). FPG increased in patients receiving placebo (Δ = 0.5 ± 0.1 mmol/l) and to a significantly lesser extent in vildagliptin‐treated patients (between‐group difference in AMΔ FPG = ?0.4 ± 0.2 mmol/l, p = 0.032). Relative to placebo, 2‐h postprandial glucose (PPG) decreased (?0.9 ± 0.4 mmol/l, p = 0.012), and insulin secretory rate (ISR) relative to glucose [ISR area under the curve (AUC)_{0–2 h}/glucose AUC_{0–2 h}] increased (+5.0 ± 1.2 pmol/min/m²/mM, p < 0.001). Mean body weight decreased by 0.5 ± 0.3 kg in vildagliptin‐treated patients and by 0.2 ± 0.3 kg in patients receiving placebo. The side‐effect profile of vildagliptin was similar to that of placebo, and one hypoglycaemic episode occurred in one patient receiving placebo. Conclusions: In drug‐naïve patients with mild hyperglycaemia, relative to placebo, 52‐week treatment with vildagliptin 50 mg q.d. significantly decreases A1C, FPG and PPG and improves beta‐cell function without weight gain or hypoglycaemia.     

A Palaeolithic diet improves glucose tolerance more than a Mediterranean-like diet in individuals with ischaemic heart disease

Aims/hypothesis Most studies of diet in glucose intolerance and type 2 diabetes have focused on intakes of fat, carbohydrate, fibre, fruits and vegetables. Instead, we aimed to compare diets that were available during human evolution with more recently introduced ones. Methods Twenty-nine patients with ischaemic heart disease plus either glucose intolerance or type 2 diabetes were randomised to receive (1) a Palaeolithic (‘Old Stone Age’) diet (n = 14), based on lean meat, fish, fruits, vegetables, root vegetables, eggs and nuts; or (2) a Consensus (Mediterranean-like) diet (n = 15), based on whole grains, low-fat dairy products, vegetables, fruits, fish, oils and margarines. Primary outcome variables were changes in weight, waist circumference and plasma glucose AUC (AUC Glucose_0–120) and plasma insulin AUC (AUC Insulin_0–120) in OGTTs. Results Over 12 weeks, there was a 26% decrease of AUC Glucose_0–120 (p = 0.0001) in the Palaeolithic group and a 7% decrease (p = 0.08) in the Consensus group. The larger (p = 0.001) improvement in the Palaeolithic group was independent (p = 0.0008) of change in waist circumference (−5.6 cm in the Palaeolithic group, −2.9 cm in the Consensus group; p = 0.03). In the study population as a whole, there was no relationship between change in AUC Glucose_0–120 and changes in weight (r = −0.06, p = 0.9) or waist circumference (r = 0.01, p = 1.0). There was a tendency for a larger decrease of AUC Insulin_0–120 in the Palaeolithic group, but because of the strong association between change in AUC Insulin_0–120 and change in waist circumference (r = 0.64, p = 0.0003), this did not remain after multivariate analysis. Conclusions/interpretation A Palaeolithic diet may improve glucose tolerance independently of decreased waist circumference. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users.     

Developmental changes of oxalate excretion in enterally fed preterm infants

Summary  To further substantiate gestational age-related changes in oxalate excretion, we studied urinary oxalate excretion in 66 preterm infants born at 23.4–34.7 weeks of gestation. Spot urine of 66 preterm infants was analysed by ion chromatography as soon as they were completely orally fed with enriched breast milk and/or special preterm milk formula (days 7 to 57 of postnatal life). Infants with evidence of renal, gastrointestinal, muscular or metabolic disease were not included. Newborns on parenteral nutrition were excluded. Oxalate/creatinine ratios (Ox/Cr) decreased with gestational age (three age groups: group 1, 23 0/7–28 0/7; group 2, 28 1/7–32 0/7; and group 3, 32 1/7–35 0/7 weeks of gestation). The mean Ox/Cr was highest in group 1 (398.2 mmol/mol ± 116.8; n = 21). Differences between groups 1 + 3 were statistically significant; p = 0.001; those between groups 1 + 2 and between groups 2 + 3 were not. Ox/Cr correlated inversely with gestational and maturational age (r = −0.41, p = 0.001; r = −0.33, p = 0.007) and positively with postnatal age (r = 0.32, p = 0.008). It correlated inversely with birth weight as well as actual weight at sample collection (r = −0.46 and −0.44, p < 0.001). Ox/Cr was significantly linked to energy and carbohydrate intake (r = 0.3 and 0.4, p = 0.03 and 0.001). These results were independent of sex. In the present study we show that urinary oxalate excretion in preterm infants depends on gestational age. Competing interests: None declared The authors B. Bohnhorst and A. M. Das contributed equally.     

Six months of aerobic exercise does not improve microvascular function in type 2 diabetes mellitus

Aims/hypothesis Adults with type 2 diabetes mellitus have impaired microvascular function. It has been hypothesised that microvascular function may be restored through regular exercise. The aim of this study was to investigate whether 6 months of regular aerobic exercise would improve microvascular function in adults with type 2 diabetes. Materials and methods Fifty-nine patients with type 2 diabetes (32 males, age 62.9±7.6 years, HbA_1c 6.8±0.9%) were randomised to either a 6-month aerobic exercise programme (30 min, three times a week, 70–80% of maximal heart rate) or a ‘standard care’ control group. Before and after the intervention period, microvascular function was assessed as the maximum skin hyperaemia to local heating and endothelial and non-endothelial responsiveness following the iontophoretic application of acetylcholine and sodium nitroprusside. Maximal oxygen uptake, as an index of aerobic fitness, was assessed using a maximal exercise test. Results No significant improvement was seen in the exercise group compared with the control group for any of the variables measured: maximal oxygen uptake (control pre: 1.73±0.53 [means±SD] vs post: 1.67±0.40; exercise pre: 1.75±0.56 vs post: 1.87±0.62 l/min, p=0.10); insulin sensitivity (insulin tolerance test) (control pre: −0.17±0.06 vs post: −0.17±0.06; exercise pre: −0.16±0.1 vs post: −0.17±0.07 mmol l⁻¹ min⁻¹, p=0.97); maximal hyperaemia (control pre: 1.49±0.43 vs post: 1.52±0.57; exercise pre: 1.42±0.36 vs post: 1.47±0.33 V, p=0.85); peak response to acetylcholine (control pre: 1.37±0.47 vs post: 1.28±0.37; exercise pre: 1.27±0.44 vs post: 1.44±0.23 V, p=0.19) or to sodium nitroprusside (control pre: 1.09±0.50 vs post: 1.10±0.39; exercise pre: 1.12±0.28 vs post: 1.13±0.40 V, p=0.98). Conclusions/interpretation In this group of type 2 diabetic patients with good glycaemic control a 6-month aerobic exercise programme did not improve microvascular function or aerobic fitness.     

Pharmacokinetics of intravenous amiodarone and its electrocardiographic effects on healthy Japanese subjects

The aim of this phase I, dose-escalating study was to evaluate the pharmacokinetics, electrocardiographic effect and safety of amiodarone after a single intravenous administration in Japanese subjects. Thirty-two healthy Japanese male volunteers (20–32 years) were randomized to three single-dose groups (1.25, 2.5 and 5.0 mg/kg). In each group, six (1.25 mg/kg) or ten (2.5 and 5.0 mg/kg) subjects received a single 15-min infusion of intravenous amiodarone, and two subjects received glucose solution as control. The pharmacokinetic profile, blood pressure and electrocardiographic analyses were obtained on a timely basis after up to 77 days. The maximum plasma concentration (C _max) and area under the concentration-time curve (AUC_0–96) for amiodarone 1.25, 2.5 and 5.0 mg/kg displayed dose-dependent characteristics: mean C _max was 2,920 ± 610, 7,140 ± 1,480 and 13,660 ± 3,410 ng/ml, respectively; the mean AUC_0-96 was 3,600 ± 700, 8,100 ± 1,600 and 16,600 ± 4,300 ng h/ml, respectively. A long serum half-life (>14 days) was observed for amiodarone and desethylamiodarone. PR intervals were prolonged at 15 min (0.16 ± 0.0.1 vs. 0.15 ± 0.01 s, p = 0.03) and 18 min (0.17 ± 0.01 vs. 0.15 ± 0.01 s, p = 0.03) with the 5.0 mg/kg dose compared with baseline. No other significant changes in electrocardiographic parameters, pulse rate or blood pressure were observed. A needle-pain-induced vasovagal effect appeared in a volunteer, and three volunteers experienced pain at the drug infusion site. After a single infusion of amiodarone at doses of 1.25–5.0 mg/kg, serum concentrations increased in a dose-dependent manner. A single intravenous amiodarone dose barely affected the electrocardiographic parameters and was well tolerated.     

Idiopathic deep venous thrombosis and arterial endothelial dysfunction in the elderly

Arterial and venous thrombosis have always been regarded as different pathologies and epidemiological studies have examined the association between venous thrombosis and indicators of atherosclerosis and/or arterial thromboembolic events. We measured the flow-mediated dilation (FMD), a well-known marker of arterial endothelial dysfunction, in young–middle-aged and old-aged patients with and without unprovoked deep venous thrombosis (DVT). The aim of this study was to investigate whether DVT was a significant predictor for impaired FMD, considering all the patients and young–middle-aged (age < 65 years) and old-aged (age ≥ 65 years) patients separately. FMD was measured in the brachial artery on a population of 120 subjects with the same atherosclerosis risk factors, 68 male and 52 female, 70 young–middle-aged subjects (mean age ± SD 49.5 ± 10.5 years) and 50 old-aged subjects (76.2 ± 7.7 years). Patients with DVT showed a significant decrease of FMD compared to patients without DVT (6.8 ± 5.5% vs. 10.9 ± 3.5%, p < 0.001). Moreover, old-aged patients showed a significant decrease of FMD compared to the young–middle-aged subjects (7.4 ± 4.1% vs. 9.8 ± 5.3%, p = 0.005). In the whole study population, DVT was strongly associated with FMD (risk factors adjusted β = −4.14, p < 0.001). A significant interaction between age and the presence of DVT on predicting FMD was found (p = 0.003) suggesting a differential behavior of DVT as predictor of FMD. In young–middle-aged group, multivariate model confirmed that DVT was the most significant predictor of continuous FMD (β = −6.06, p < 0.001). On the contrary, DVT was no more a predictor of FMD in the old age group (β = −0.73, p=0.556). Furthermore, old-aged patients without DVT showed a statistically significant decrease of FMD compared to the young–middle-aged subjects without DVT (8.2±2.1% vs. 12.6±2.7%, p<0.001) and old-aged patients with DVT showed a not statistically significant decrease of the FMD compared to the young–middle-aged patients with DVT (6.7±5.3% vs. 6.8±5.7%, p = 0.932). In conclusion, young–middle-aged patients with spontaneous DVT show an impaired FMD, whereas this impairment in old-aged subjects is evident independently from the presence or absence of DVT. Aging per se may be associated with physiologic abnormalities in the systemic arteries and with endothelial dysfunction.     

Arrhythmia phenotype in mouse models of human long QT

Enhanced dispersion of repolarization (DR) was proposed as a unifying mechanism, central to arrhythmia genesis in the long QT (LQT) syndrome. In mammalian hearts, K⁺ channels are heterogeneously expressed across the ventricles resulting in ‘intrinsic’ DR that may worsen in long QT. DR was shown to be central to the arrhythmia phenotype of transgenic mice with LQT caused by loss of function of the dominant mouse K⁺ currents. Here, we investigated the arrhythmia phenotype of mice with targeted deletions of KCNE1 and KCNH2 genes which encode for minK/IsK and Merg1 (mouse homolog of human ERG) proteins resulting in loss of function of I_Ks and I_Kr, respectively. Both currents are important human K⁺ currents associated with LQT5 and LQT2. Loss of minK, a protein subunit that interacts with KvLQT1, results in a marked reduction of I_Ks giving rise to the Jervell and Lange–Nielsen syndrome and the reduced KCNH2 gene reduces MERG and I_Kr. Hearts were perfused, stained with di-4-ANEPPS and optically mapped to compare action potential durations (APDs) and arrhythmia phenotype in homozygous minK (minK^−/−) and heterozygous Merg1 (Merg^+/−) deletions and littermate control mice. MinK^−/− mice has similar APDs and no arrhythmias (n = 4). Merg^+/− mice had prolonged APDs (from 20 ± 6 to 32 ± 9 ms at the base, p < 0.01; from 18 ± 5 to 25 ± 9 ms at the apex, p < 0.01; n = 8), longer refractory periods (RP) (36 ± 14 to 63 ± 27 at the base, p < 0.01 and 34 ± 5 to 53 ± 21 ms at the apex, p < 0.03; n = 8), higher DR 10.4 ± 4.1 vs. 14 ± 2.3 ms, p < 0.02) and similar conduction velocities (n = 8). Programmed stimulation exposed a higher propensity to VT in Merg^+/− mice (60% vs. 10%). A comparison of mouse models of LQT based on K⁺ channel mutations important to human and mouse repolarization emphasizes DR as a major determinant of arrhythmia vulnerability.     

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