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Allan A Vaag and Henning Beck-Nielsen

The effect of prolonged treatment with Acipimox on in vivo peripheral insulin sensitivity, and on glucose and lipid metabolism, was investigated in patients with NIDDM in a double-blind study. Twelve NIDDM patients were randomized to treatment with either placebo or Acipimox in pharmacological doses (250 mg×3) for three months. Fasting plasma glucose, insulin, C-peptide and HbA1c concentrations were unaffected after three months of acipimox treatment. However, fasting plasma non-esterifled fatty acid (NEFA) concentrations were twofold elevated after Acipimox treatment (1.34±0.09 vs 0.66±0.09 mmol/l; p<0.05). Despite this, repeated acute Acipimox administration after the three months' treatment period enhanced total insulin-stimulated glucose disposal to the same extent as acute Acipimox administration before the treatment period (367±59 vs 392±66 mg·m−2·min−1, NS; both p<0.05 vs placebo glucose disposal) (267±44 mg·m−2·min−1). In conclusion, insulin resistance or tachyphylaxis towards the effects of Acipimox on insulin stimulated glucose disposal was not induced during prolonged Acipimox treatment. The lack of improvement of blood glucose control in the patients with NIDDM may be due to the demonstrated rebound effect of lipolysis.

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Allan A Vaag, Aase Handberg, Peter Skøtt, Erik A Richter and Henning Beck-Nielsen

Vaag, AA, Handberg A, Skøtt P, Richter EA, Beck-Nielsen H. Glucose-fatty acid cycle operates in humans at the levels of both whole body and skeletal muscle during low and high physiological plasma insulin concentrations. Eur J Endocrinol 1994;130:70–9. ISSN 0804–4643

Plasma non-esterified fatty acid concentrations were elevated acutely (Intralipid + heparin infusion) in 14 normal humans in order to study the effects of fatty acids on whole-body basal and insulin-stimulated glucose metabolism, and on activities of skeletal muscle key enzymes. Whole-body glucose metabolism was assessed using [3-3H]glucose and indirect calorimetry. Biopsies were taken from the vastus lateralis muscle during basal and insulin-stimulated (3 h, 40 mU·m−2·min1) steady-state periods. Total peripheral glucose uptake was unaffected by Intralipid infusion in the basal state, whereas it decreased during Intralipid infusion in the hyperinsulinemic state (10.7±0.7 vs 8.7±0.8 mg · kg−1 fat-free mass · min−1, p < 0.02). Intralipid infusion decreased whole-body glucose oxidation in the basal state (1.3±0.2 vs 0.8±0.1 mg·kg−1 fat-free mass·min−1, p<0.001) and during hyperinsulinemia (3.6±0.2 vs 1.7±0.2 mg·kg−1 fat-free mass·min−1 p<0.001). Whole-body non-oxidative glucose uptake increased during Intralipid infusion in the basal state and was unaffected in the hyperinsulinemic state. The skeletal muscle pyruvate dehydrogenase activity ratio decreased in the basal state during Intralipid infusion (55±6 vs 43±5%, p<0.05), whereas no statistical significant decrease in the pyruvate dehydrogenase activity ratio was observed during insulin infusion (57±8 vs 47 ± 5%, NS). Insulin increased the activity of the active form of pyruvate dehydrogenase on the control day, but not during Intralipid infusion. Activities of phosphofructokinase and glycogen synthase were unaffected by Intralipid infusion. Plasma glucose concentrations were similar during Intralipid infusion and on the control day, whereas Intralipid infusion increased the muscle glucose content in the basal state (1.36±0.09 vs 1.77±0.12 mmol/kg dry wt, p<0.05) and in the hyperinsulinemic state (1.23 ± 0.09 vs 1.82 ± 0.16 mmol/kg dry wt, p <0.05). Insulin increased the muscle lactate content on the control day (6.50±0.95 vs 8.65±0.77 mmol/kg dry wt, p<0.05), but not during Intralipid infusion. In conclusion, the glucose–fatty acid cycle operates in humans in vivo at the levels of both whole body and skeletal muscle during both low and high physiological insulin concentrations.

Allan Vaag, Department of Internal Medicine M, Odense University Hospital, Sdr. Boulevard, DK-5000, Odense C, Denmark

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Allan A Vaag, Jens J Holst, Aage Vølund and Henning Beck-Nielsen

Vaag AA, Holst JJ, Volund A, Beck-Nielsen H. Gut incretin hormones in identical twins discordant for non-insulin-dependent diabetes mellitus (NIDDM)—evidence for decreased glucagon-like peptide 1 secretion during oral glucose ingestion in NIDDM twins. Eur J Endocrinol 1996;135:425–32. ISSN 0804–4643

The incremental glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) responses (areas under curves; AUCs) were determined during a standard 180-min 75-g oral glucose tolerance test in a group of 12 identical twin pairs discordant for non-insulin-dependent diabetes mellitus (NIDDM) and 13 matched controls without family history of diabetes using highly sensitive and specific radioimmunoassay hormone assays. Data were analysed using multifactor analysis of variance (ANOVA) to identify and correct for possible covariates and to correct for multiple comparisons. Fasting plasma GLP-1 and GIP concentrations were similar in all groups. The twins with frank NIDDM had a decreased incremental GLP-1 response during oral glucose ingestion compared with controls without family history of diabetes (AUC±sem; 0.55 ± 0.14 vs 1.17 ± 0.25 (mmol/l) × min, p < 0.05). The incremental GLP-1 secretion in the non-diabetic twins was not significantly different from neither their NIDDM co-twins nor the controls without family history of diabetes. The incremental GIP responses were similar in all study groups. Gender was identified as the major independent covariate for incremental glucose, insulin, GIP and GLP-1 responses, with higher values of all parameters in females. Waist-to-hip ratio and body mass index (BMI) were identified as independent but oppositely directed covariates for the incremental GLP-1 responses (waist-to-hip ratio: r = 0.43, p < 0.02; BMI: r= −0.34, p = 0.06). Incremental GLP-1 responses correlated with incremental insulin responses in the combined study population (N = 37; R = 0.42, p = 0.01). In conclusion, a decreased intestinal GLP-1 secretion may contribute to the abnormal insulin secretion during oral glucose ingestion in NIDDM twins. However, decreased secretion of gut incretin hormones (GLP-1 or GIP) does not explain all of the defects of pancreatic insulin secretion in NIDDM patients/twins or in non-diabetic individuals (identical twins) with a genetic predisposition to NIDDM.

Allan Vaag, Odense University Hospital, Department of Endocrinology and Internal Medicine M, Sdr. Boulevard, Odense, DK-5000, Denmark

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Søren S Lund, Lise Tarnow, Merete Frandsen, Ulla M Smidt, Oluf Pedersen, Hans-Henrik Parving and Allan A Vaag

Free access

Søren S Lund, Lise Tarnow, Merete Frandsen, Ulla M Smidt, Oluf Pedersen, Hans-Henrik Parving and Allan A Vaag

Free access

Geeti P Arora, Richa G Thaman, Rashmi B Prasad, Peter Almgren, Charlotte Brøns, Leif C Groop and Allan A Vaag

Objective

The World Health Organization (WHO) has in 2013 changed the diagnostic criteria for gestational diabetes mellitus (GDM) to acknowledge the putative effect of mildly elevated fasting plasma glucose (FPG) levels on pregnancy outcomes. We aimed to determine the prevalence and risk factors of GDM comparing the previous WHO 1999 criteria to the WHO 2013 criteria in North India.

Methods

In a population-based screening programme, 5100 randomly selected North Indian women were studied using a cross-sectional design with a questionnaire, venous FPG and 2-h capillary plasma glucose (PG) after a 75 g oral glucose tolerance test performed between 24 and 28 weeks of pregnancy.

Results

The prevalence of GDM was 35% using WHO 2013 criteria vs 9% using WHO 1999 criteria. FPG measurements identified 94% of WHO 2013 GDM cases as opposed to 11% of WHO 1999 GDM cases. In contrast, 2-h PG measurements identified only 13% of WHO 2013 GDM cases compared with 96% of the WHO 1999 GDM cases. Using logistic regression with backward elimination, urban habitat, illiteracy, non-vegetarianism, increased BMI, Hindu religion and low adult height were all independent risk factors of GDM using the 1999 criteria, whereas only urban habitat, low adult height and increased age were independent risk factors of GDM using the 2013 criteria.

Conclusions

Intervention studies are needed to justify the WHO 2013 GDM criteria increasing the prevalence four fold to include more than one third of North Indian pregnant women.

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Søren S Lund, Lise Tarnow, Merete Frandsen, Ulla M Smidt, Oluf Pedersen, Hans-Henrik Parving and Allan A Vaag

Objective

Non-obese patients with type 2 diabetes (T2DM) are characterized by predominant defective insulin secretion. However, in non-obese T2DM patients, metformin, targeting insulin resistance, is non-inferior to the prandial insulin secretagogue, repaglinide, controlling overall glycaemia (HbA1c). Whether the same apply for postprandial glucose and lipid metabolism is unknown. Here, we compared the effect of metformin versus repaglinide on postprandial metabolism in non-obese T2DM patients.

Design

Single-centre, double-masked, double-dummy, crossover study during 2×4 months involving 96 non-obese (body mass index≤27 kg/m2) insulin-naïve T2DM patients. At enrolment, patients stopped prior oral hypoglycaemic agents therapies and after a 1-month run-in period on diet-only treatment, patients were randomized to repaglinide (2 mg) thrice daily followed by metformin (1 g) twice daily or vice versa each during 4 months with 1-month washout between interventions.

Methods

Postprandial metabolism was evaluated by a standard test meal (3515 kJ; 54% fat, 13% protein and 33% carbohydrate) with blood sampling 0–6 h postprandially.

Results

Fasting levels and total area under the curve (AUC) for plasma glucose, triglycerides and free fatty acids (FFA) changed equally between treatments. In contrast, fasting levels and AUC of total cholesterol, low-density lipoprotein (LDL) cholesterol, non-high-density lipoprotein (non-HDL) cholesterol and serum insulin were lower during metformin than repaglinide (mean (95% confidence intervals), LDL cholesterol difference metformin versus repaglinide: AUC: −0.17 mmol/l (−0.26; −0.08)). AUC differences remained significant after adjusting for fasting levels.

Conclusions

In non-obese T2DM patients, metformin reduced postprandial levels of glycaemia, triglycerides and FFA similarly compared to the prandial insulin secretagogue, repaglinide. Furthermore, metformin reduced fasting and postprandial cholesterolaemia and insulinaemia compared with repaglinide. These data support prescription of metformin as the preferred drug in non-obese patients with T2DM targeting fasting and postprandial glucose and lipid metabolism.

Open access

Leo Niskanen, Lawrence A Leiter, Edward Franek, Jianping Weng, Taner Damci, Manuel Muñoz-Torres, Jean-Paul Donnet, Lars Endahl, Trine Vang Skjøth and Allan Vaag

Objective

Insulin degludec/insulin aspart (IDegAsp) is a soluble co-formulation of insulin degludec (70%) and insulin aspart (IAsp: 30%). Here, we compare the efficacy and safety of IDegAsp, an alternative IDegAsp formulation (AF: containing 45% IAsp), and biphasic IAsp 30 (BIAsp 30).

Design

Sixteen-week, open-label, randomised, treat-to-target trial.

Methods

Insulin-naive subjects with type 2 diabetes (18–75 years) and a HbA1c of 7–11% were randomised to twice-daily IDegAsp (n=61), AF (n=59) or BIAsp 30 (n=62), all in combination with metformin. Insulin was administered pre-breakfast and dinner (main evening meal) and titrated to pre-breakfast and pre-dinner plasma glucose (PG) targets of 4.0–6.0 mmol/l.

Results

Mean HbA1c after 16 weeks was comparable for IDegAsp, AF and BIAsp 30 (6.7, 6.6 and 6.7% respectively). With IDegAsp, 67% of subjects achieved HbA1c <7.0% without confirmed hypoglycaemia in the last 4 weeks of treatment compared with 53% (AF) and 40% (BIAsp 30). Mean fasting PG was significantly lower for IDegAsp vs BIAsp 30 (treatment difference (TD): −0.99 mmol/l (95% confidence interval: −1.68; 0.29)) and AF vs BIAsp 30 (TD: −0.88 mmol/l (−1.58; −0.18)). A significant, 58% lower rate of confirmed hypoglycaemia was found for IDegAsp vs BIAsp 30 (rate ratio (RR): 0.42 (0.23; 0.75)); rates were similar for AF vs BIAsp 30 (RR: 0.92 (0.54; 1.57)). IDegAsp and AF had numerically lower rates of nocturnal confirmed hypoglycaemia vs BIAsp 30 (RR: 0.33 (0.09; 1.14) and 0.66 (0.22; 1.93) respectively).

Conclusions

IDegAsp provided comparable overall glycaemic control to BIAsp 30 with a significantly lower rate of hypoglycaemia.

Free access

Leo Niskanen, Lawrence A Leiter, Edward Franek, Jianping Weng, Taner Damci, Manuel Muñoz-Torres, Jean-Paul Donnet, Lars Endahl, Trine Vang Skjøth and Allan Vaag

The journal and the authors apologise for errors in Table 2 of this article that was published in the August issue (vol 167, pp 287–294). The n values were incorrectly published. The correct values are presented below and the table is published in full below.

Table 2

Observed mean changes from baseline HbA1c, FPG and body weight. Data are observed as mean (s.d.) for all randomised subjects (full analysis set).

nBaselineaWeek 16bChange from baseline
HbA1c (%)
 IDegAsp618.5 (1.2)6.7 (1.0)−1.8 (1.1)c
 AF598.5 (0.9)6.6 (0.6)−1.9 (1.1)c
 BIAsp 30628.6 (1.0)6.7 (0.7)−1.8 (0.9)c
FPG (mmol/l)
 IDegAsp6111.5 (2.6)6.4 (2.2)−5.1 (2.9)
 AF5911.8 (2.9)6.5 (1.9)−5.3 (3.0)
 BIAsp 306211.7 (3.1)7.5 (2.1)−4.3 (3.0)
Body Weight (kg)
 IDegAsp6187.5 (16.3)88.6 (16.9)1.1 (2.8)
 AF5984.9 (14.3)85.6 (14.9)0.7 (2.5)
 BIAsp 306291.8 (13.5)93.2 (13.1)1.4 (3.2)

Values at randomisation.

Last observation carried forward.

% points.

Free access

Søren S Lund, Lise Tarnow, Coen D A Stehouwer, Casper G Schalkwijk, Tom Teerlink, Jørgen Gram, Kaj Winther, Merete Frandsen, Ulla M Smidt, Oluf Pedersen, Hans-Henrik Parving and Allan A Vaag

Objective

In patients with type 2 diabetes mellitus (T2DM), biomarkers reflecting inflammation and endothelial dysfunction have been linked to cardiovascular disease (CVD biomarkers) and metabolic regulation. In T2DM patients, metformin and insulin secretagogues have demonstrated equal anti-hyperglycaemic potency. Here, we report the effect of metformin versus an insulin secretagogue, repaglinide, on CVD biomarkers in non-obese T2DM patients.

Design and methods

Single-centre, double-masked, double-dummy, crossover study during 2×4 months involving 96 non-obese (body mass index≤27 kg/m2) insulin-naïve T2DM patients. At enrolment, previous oral hypoglycaemic agents were stopped and the patients entered a 1-month run-in on diet-only treatment. Hereafter, patients were randomized to either 2 mg repaglinide thrice daily followed by 1 g metformin twice daily or vice versa each during 4 months with a 1-month washout between interventions.

Results

Levels of tumour necrosis factor-α, plasminogen activator inhibitor-1 antigen, tissue-type plasminogen activator antigen, von Willebrand factor, soluble intercellular adhesion molecule-1 and soluble E-selectin were significantly lower during metformin versus repaglinide treatments. In contrast, Amadori albumin and heart rate were higher during metformin versus repaglinide. Levels of interleukin-6, fibrinogen, soluble vascular cell adhesion molecule-1, asymmetric dimethylarginine and advanced glycation end products as well as glycaemic levels (previously reported) and 24-h blood pressure were similar between treatments. Adjustment for known macrovascular disease did not affect the between-treatment effects.

Conclusions

In non-obese T2DM patients, metformin was more effective in reducing selected biomarkers reflecting inflammation and endothelial dysfunction compared with repaglinide despite similar glycaemic levels between treatments.