Allan Vaag and Sørens Lund
This review addresses the apparent disconnect between international guideline recommendations, real-life clinical practice and the results of clinical trials, with regard to the initiation of insulin using basal (long-acting) or premixed insulin analogues in patients with type 2 diabetes (T2D). English language guidelines vary considerably with respect to recommended glycaemic targets, the selection of human vs analogue insulin, and choice of insulin regimen. Randomised trials directly comparing insulin initiation between basal and premixed analogues are scarce, and hard endpoint outcome data are inadequate. The evidence presented suggests that a major component of the HbA1c not being attained in every day clinical practice may be a result of factors that are not adequately addressed in forced titration trials of highly motivated patients, including failure to comply with complex treatment and monitoring regimens. Enforced intensification of unrealistic complex treatment regimens and glycaemic targets may theoretically worsen the psychological well-being in some patients. More simple and sustainable treatment regimens and guidelines are urgently needed. As for the use of insulin in T2D, there is limited evidence to convincingly support that initiation of insulin using basal insulin analogues is superior to initiation using premixed insulin analogues. While awaiting improved clinical efficacy and cost-effectiveness data, practical guidance from national and international diabetes organisations should consider more carefully the importance of: i) being clear and consistent; and ii) the early implementation of sustainable and cost-effective insulin treatment regimens with an emphasis on optimising treatment ease of use and patient compliance.
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.
Bianca Hemmingsen, Søren S Lund, Jørn Wetterslev and Allan Vaag
This article is a narrative review of the current evidence of the effects on cardiovascular disease (CVD) of oral hypoglycaemic agents that increase insulin sensitivity in patients with type 2 diabetes (T2D). In overweight T2D patients, metformin has been demonstrated to reduce CVD risk, and this beneficial effect may be conserved with the combination of metformin and insulin treatment. However, the effect of glitazones on CVD is uncertain. There is conflicting evidence from large randomized trials to support a protective effect against CVD of lowering blood glucose per se but a systematic review with meta-analysis is lacking. It may be reasonable to aim for an intervention targeting multiple CVD risk factors such as dyslipidaemia, hypertension and albuminuria in T2D patients.
Steen B Haugaard, Huiling Mu, Allan Vaag and Sten Madsbad
It remains unknown whether sex impacts on intramyocellular triglyceride (IMTG) in obesity, as has been shown in non-obese subjects, and, if so, whether this may have implications on the association between IMTG and insulin sensitivity.
Subject and methods
A muscle biopsy from vastus lateralis was obtained in 27 obese women (body mass index (BMI)=35.5±0.8 kg/m2; mean±s.e.m., percentage of body fat (PBF)=44±1, n=7 impaired fasting glucose, n=7 type 2 diabetes), 20 obese men (BMI=35.8±0.8 kg/m2; PBF=33±1, n=4 impaired-fasting-glucose; n=6 type 2 diabetes) and 12 lean sedentary healthy individuals (controls; n=7 women, BMI=21.8±0.7 kg/m2, PBF=20±2; n=5 men, BMI=23.6±0.5 kg/m2, PBF=13±2). IMTG was determined by chromatography.
IMTG was increased twofold in obese women compared to obese men, lean men and lean women respectively (21.9±2.4 mg/g wet weight, 10.9±1.5, 9.8±2.1 and 10.9±2.4 mg/g, P<0.001). Among obese subjects of either gender IMTG did not increase along with reduced glycaemic control in terms of impaired fasting glucose and diabetes. Plasma insulin levels, which were similar among obese women with different glycaemic control levels, but much lower in lean women, paralleled the changes in IMTG among women. PBF was associated with IMTG in all subjects (P<0.001). In a linear model, sex (P<0.05) and PBF (P<0.05) independently explained variation in IMTG. Plasma free fatty acids (FFA) correlated with IMTG in all subjects (P<0.005).
Obese women display twice as much IMTG as obese men matched for BMI. Increased IMTG could be a pathophysiological element or a mere physiological phenomenon in feminine obesity ensuing prior to impaired glycaemic control, but associated with increased body fat, circulating FFA and insulin.
Russell L Esterline, Allan Vaag, Jan Oscarsson and Jiten Vora
Type 2 diabetes (T2D) is associated with inhibition of autophagic and lysosomal housekeeping processes that detrimentally affect key organ functioning; a process likely to be exacerbated by conventional insulin-driven anabolic therapies. We propose that the cardio-renal benefits demonstrated with sodium–glucose cotransporter-2 inhibitor (SGLT2i) treatment in T2D partly may be explained by their ability to drive consistent, overnight periods of increased catabolism brought about by constant glucosuria. Key steps driving this catabolic mechanism include: a raised glucagon/insulin ratio initially depleting glycogen in the liver and ultimately activating gluconeogenesis utilizing circulating amino acids (AAs); a general fuel switch from glucose to free fatty acids (accompanied by a change in mitochondrial morphology from a fission to a sustained fusion state driven by a decrease in AA levels); a decrease in circulating AAs and insulin driving inhibition of mammalian target of rapamycin complex 1 (mTORC1), which enhances autophagy/lysosomal degradation of dysfunctional organelles, eventually causing a change in mitochondrial morphology from a fission to a sustained fusion state. Resumption of eating in the morning restores anabolic biogenesis of new and fully functional organelles and proteins. Restoration of diurnal metabolic rhythms and flexibility by SGLT2is may have therapeutic implications beyond those already demonstrated for the cardio-renal axis and may therefore affect other non-diabetes disease states.
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
Sara G Vienberg, Charlotte Brøns, Emma Nilsson, Arne Astrup, Allan Vaag and Birgitte Andersen
Fibroblast growth factor 21 (FGF21) is a metabolic factor involved in glucose and lipid metabolism. However, little is known about the physiological role of FGF21 during a dietary challenge in humans.
Research design and methods
Twenty healthy low birth weight (LBW) with known risk of type 2 diabetes and 26 control (normal birth weight (NBW)) young men were subjected to 5 days of high-fat (HF) overfeeding (+50%). Basal and clamp insulin-stimulated serum FGF21 levels were examined before and after the diet, and FGF21 mRNA expression was measured in muscle and fat biopsies respectively.
Five days of HF overfeeding diet significantly (P<0.001) increased fasting serum FGF21 levels in both the groups (P<0.001). Furthermore, insulin infusion additionally increased serum FGF21 levels to a similar extent in both the groups. Basal mRNA expression of FGF21 in muscle was near the detection limit and not present in fat in both the groups before and after the dietary challenge. However, insulin significantly (P<0.001) increased FGF21 mRNA in both muscle and fat in both the groups during both diets.
Short-term HF overfeeding markedly increased serum FGF21 levels in healthy young men with and without LBW but failed to increase muscle or fat FGF21 mRNA levels. This suggests that the liver may be responsible for the rise of serum FGF21 levels during overfeeding. In contrast, the increase in serum FGF21 levels during insulin infusion may arise from increased transcription in muscle and fat. We speculate that increased serum FGF21 levels during HF overfeeding may be a compensatory response to increase fatty acid oxidation and energy expenditure.
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
Charlotte Brøns, Pernille N Saltbæk, Martin Friedrichsen, Yan Chen and Allan Vaag
Sleep disturbances and alterations of diurnal endocrine rhythms are associated with increased risk of type 2 diabetes (T2D). We previously showed that young men born small for gestational age (SGA) and with increased risk of T2D have elevated fat and decreased glucose oxidation rates during nighttime. In this study, we investigated whether SGA men have an altered diurnal profile of hormones, substrates and inflammatory markers implicated in T2D pathophysiology compared with matched individuals born appropriate for gestational age (AGA).
We collected hourly blood samples for 24 h, to measure levels of glucose, free fatty acids (FFA), triglycerides (TG), insulin, C-peptide, leptin, resistin, ghrelin, plasminogen activator inhibitor-1 (PAI-1), incretins (GLP-1 and GIP), and inflammatory markers (TNF-α and IL-6) in 13 young men born SGA and 11 young men born AGA.
Repeated measurements analyses were used to analyze the diurnal variations and differences between groups. The SGA subjects had increased 24-h glucose (P=0.03), glucagon (P=0.03) and resistin (P=0.003) levels with no difference in diurnal rhythms compared with AGA controls. We found significant diurnal variations in levels of blood glucose, plasma TG, FFA, insulin, C-peptide, GLP-1, GIP, leptin, visfatin, TNF-α, IL-6 and PAI-1. The variation in FFA levels differed between the groups during the evening. Plasma ghrelin and glucagon levels did not display diurnal variations.
Young men born SGA exhibit elevated 24-h blood glucose, and plasma glucagon and resistin levels with no major differences in diurnal rhythms of these or other key metabolic hormones, substrates or inflammatory markers implicated in the origin of adiposity and T2D.