Michael Taulo Lund

Ceramide and diacylglycerol are linked to insulin resistance in rodents, but in humans the data are inconsistent. Insulin resistance is frequently observed with aging, but the role of ceramide and diacylglycerol is not clarified. Training improves metabolic health and, therefore, we aimed to elucidate the influence of age and high-intensity interval training (HIIT) on ceramide and diacylglycerol content in muscle. Fourteen young (33 ± 1) and 22 older (63 ± 1) overweight to obese subjects performed 6 weeks HIIT three times a week. Maximal oxygen uptake and body composition were measured and muscle biopsies and fasting blood samples were obtained. Muscle ceramide and diacylglycerol were measured by gas-liquid chromatography and proteins in insulin signaling, lipid and glucose metabolism were measured by Western blotting. Content of ceramide and diacylglycerol total, saturated, C16:0 and C18:0 fatty acids and C18:1 ceramide were higher in older compared to young. HIIT reduced saturated and C18:0 ceramides, while the content of the proteins involved in glucose (GLUT4, glycogen synthase, hexokinase II, AKT) and lipid metabolism (adipose triglyceride lipase, fatty acid binding protein) were increased after HIIT. We demonstrate a higher content of saturated ceramide and diacylglycerol fatty acids in the muscle of older subjects compared to young. Moreover, the content of saturated ceramides was reduced and muscle glucose metabolism improved at protein level after HIIT. This study highlights an increased content of saturated ceramides in aging which could be speculated to influence insulin sensitivity.

Key points: Hepatic insulin resistance in patients with obesity or type 2 diabetes has been suggested to result from hepatic mitochondrial dysfunction. High‐resolution respirometry (HRR) can be used to assess oxidative phosphorylation by measuring the mitochondrial oxygen consumption rate in the individual complexes of the mitochondria. By using HRR, the present study demonstrates no difference in hepatic mitochondrial oxidative phosphorylation among subjects with obesity with or without type 2 diabetes and non‐obese controls. Furthermore, the amount of mitochondria, assessed by the citrate synthase activity, is not different between the three groups. Together the present findings indicate that hepatic mitochondrial oxidative phosphorylation capacity is not impaired in patients with obesity or type 2 diabetes. Obese patients with type 2 diabetes (T2DM) and without type 2 diabetes (OB) are characterized by high hepatic lipid content and hepatic insulin resistance. This may be linked to impaired hepatic mitochondrial oxidative phosphorylation (OXPHOS) capacity. The aim of the present study was to investigate and compare hepatic mitochondrial OXPHOS capacity in T2DM, OB and non‐obese controls (CON). Seventeen obese patients (nine OB and eight T2DM) and six CON patients had perioperative liver biopsies taken. Samples were divided into three parts to measure (1) complex I, II and IV linked respiration, (2) citrate synthase (CS) activity and (3) lipid droplet (LD) size and area (% of total tissue area filled by LDs). State 3 respiration of complex I, II and IV and the CS activity did not differ in OB, T2DM and CON. LD size was significantly higher in T2DM compared with CON, and LD area tended (P = 0.10) to be higher in T2DM and OB compared with CON. The present findings indicate that hepatic OXPHOS capacity is not different in patients with markedly different weight and glycaemic control. Furthermore, the results do not support impaired hepatic mitochondrial respiratory capacity playing a major role in the development of obesity‐induced type 2 diabetes.

Roux‐en‐Y gastric bypass (RYGB) leads to a major weight loss in obese patients. However, given that most patients remain obese after the weight loss, regular exercise should be part of a healthier lifestyle. The primary aim of this study was to investigate the cardiopulmonary fitness in obese patients before and after RYGB. Thirty‐four patients had body composition and cardiopulmonary fitness (VO_2max) assessed and completed questionnaires regarding physical activity and function twice before RYGB (time points A and B) and 4 and 18 months after surgery (time points C and D). Weight loss was 37 ± 2 kg during the study period. VO_2max increased (A: 21 ± 1 vs D: 29 mL/min/kg, P < 0.001), but absolute VO_2max decreased (A: 2713 ± 126 vs 2609 ± 187 mL/min, P = 0.02) and VO_2max per kilogram fat free mass did not change. Self‐perceived limitations to perform exercise decreased and self‐perceived physical fitness increased after RYGB. Self‐reported low‐ and high‐intensity physical activity did not change. With weight loss, self‐rated fitness level increased and the limitations to perform exercise decreased in RYGB patients. Nevertheless, as shown by the lower absolute VO_2max, RYGB patients do not adopt new exercise habits following surgery.

Key points: Roux‐en‐Y gastric bypass surgery leads to remission of type 2 diabetes in the majority of patients suffering from the disease. The gut hormone glucagon‐like peptide‐1 is believed to be of major importance for the remission process. The present project demonstrates a marked difference in the chance of remission of type 2 diabetes in patients with low or high preoperative β‐cell function in spite of a similar post‐surgery increase in postprandial glucagon‐like peptide‐1 release. Furthermore, post‐surgery intravenous glucose administration, which does not stimulate release of glucagon‐like peptide‐1, leads to increased insulin secretion in the patients with the best preoperative β‐cell function. Together the present findings indicate that patients with type 2 diabetes with high preoperative β‐cell function experience a glucagon‐like peptide‐1‐independent increase in β‐cell function after gastric bypass surgery. The majority of the patients with type 2 diabetes (T2DM) show remission after Roux‐en‐Y gastric bypass (RYGB). This is the result of increased postoperative insulin sensitivity and β‐cell secretion. The aim of the present study was to elucidate the importance of the preoperative β‐cell function in T2DM for the chance of remission after RYGB. Fifteen patients with and 18 without T2DM had 25 g oral (OGTT) and intravenous (IVGTT) glucose tolerance tests performed at inclusion, after a diet‐induced weight loss, and 4 and 18 months after RYGB. Postoperative first phase insulin secretion rate (ISR) during the IVGTT and β‐cell glucose sensitivity during the OGTT increased in T2DM. Postoperative insulin sensitivity and the disposition index (DI) markedly increased in both groups. By stratifying the T2DM into two groups according to highest (T2DM_high) and lowest (T2DM_low) baseline DI, a restoration of first phase ISR and β‐cell glucose sensitivity were seen only in T2DM_high. Remission of type 2 diabetes was 71 and 38% in T2DM_high and T2DM_low, respectively. Postoperative postprandial GLP‐1 concentrations increased markedly, but did not differ between the groups. Our findings emphasize the importance of the preoperative of β‐cell function for remission of diabetes after RYGB.

Aim: After both oral and intravenous glucose administration, peripheral insulin concentrations are lower in trained compared with untrained humans. Part of this is explained by an adaptation within the β‐cell. The insulin secretion rate is higher after oral compared with intravenous glucose administration due to the release of glucagon‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP) enhancing the glucose‐induced insulin secretion (the incretin effect). Our aim was to investigate whether GIP or GLP‐1 release or the incretin effect was different in trained compared with untrained humans after oral and intravenous glucose administration.Methods: A 3½‐h oral glucose tolerance test was performed in eleven trained and ten untrained, young, healthy men. On a separate day, an isoglycaemic intravenous glucose infusion was performed matching the individual glucose concentrations obtained during the oral glucose tolerance test. Blood samples for insulin, C‐peptide, GIP and GLP‐1 analyses were obtained frequently during both tests, and the insulin secretion rate, incretin effect and insulin clearance were calculated.Results: Plasma GIP and GLP‐1 concentrations, the incretin effect and the insulin clearance did not differ, and plasma glucose, insulin and C‐peptide concentrations and the insulin secretion rate were lower in trained compared with untrained subjects during both tests.Conclusion: With no difference in incretin effect and insulin clearance between the two groups, the lower plasma insulin concentrations found in trained compared with untrained, young, healthy men are most likely explained by lower β‐cell sensitivity to glucose and enhanced glucose uptake in skeletal muscle in the former group.

Postprandial insulin release is lower in healthy aerobically trained (T) compared to untrained (UT) individuals. This may be mediated by a lower release of the two incretin hormones [glucagon like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)] in T. The aim of this study was to assess and compare gut hormone response and satiety changes after a liquid meal intake in young, healthy T and UT males. Postprandial gut hormone release and subjective feelings of hunger, satiety, fullness and prospective food consumption were assessed before and frequently for the following 3 h after a 200 ml liquid meal (1,260 kJ and 27, 41 and 32 energy % as protein, carbohydrates and fat, respectively) in ten T and ten UT young, healthy male subjects. The insulin and GIP responses were markedly lower in T than UT and correlated during the first 30 min after the liquid meal. Baseline GLP-1 concentration was higher in T versus UT, but the response in the following 3 h after a liquid meal was similar in T and UT. Satiety measures did not differ between groups throughout the test. It is possible that in aerobically T subjects, a lower GIP release is partly responsible for a lower postprandial incretin stimulated insulin secretion.