Merethe Hansen

Local administration of insulin‐like growth factor‐I (IGF‐I) stimulates tendon collagen synthesis in humans

Collagen is the predominant structural protein in tendons and ligaments, and can be controlled by hormonal changes. In animals, injections of insulin‐like growth factor I (IGF‐I) has been shown to increase collagen synthesis in tendons and ligaments and to improve structural tissue healing, but the effect of local IGF‐I administration on tendon collagen synthesis in human has not been studied. The purpose of this study was to study whether local injections of IGF‐I would have a stimulating effect on tendon collagen synthesis. Twelve healthy nonsmoking men [age 62 ± 1 years (mean ± SEM), BMI 27 ± 1] participated. Two injections of either human recombinant IGF‐I (0.1 mL Increlex©) or saline (control) into each patellar tendon were performed 24‐h apart, respectively. Tendon collagen fractional synthesis rate (FSR) was measured by stable isotope technique in the hours after the second injection. Simultaneously, interstitial peritendinous (IGF‐I) and [procollagen type I N‐terminal propeptide (PINP)], as a marker for type I collagen synthesis, were determined by microdialysis technique. Tendon collagen FSR and PINP were significantly higher in the IGF‐I leg compared with the control leg (P < 0.05). In conclusion, local IGF‐I administration can directly enhance tendon collagen synthesis both within and around the human tendon tissue.

Preoperative β‐cell function in patients with type 2 diabetes is important for the outcome of Roux‐en‐Y gastric bypass surgery

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.

Effect of administration of oral contraceptives on the synthesis and breakdown of myofibrillar proteins in young women

Oral contraceptive (OC) treatment has an inhibiting effect on protein synthesis in tendon and muscle connective tissue. We aimed to investigate whether OC influence myofibrillar protein turnover in young women. OC‐users (24±2 years; Lindynette®n=7, Cilest®n=4) and non‐OC‐users (controls, 24±4 years n=12) performed one‐legged kicking exercise. The next day, the myofibrillar protein fractional synthesis rate (FSR) was measured using stable isotopic tracers (13C‐proline) while the subjects were fed standardized nutrient drinks. Simultaneously, a marker for myofibrillar protein breakdown, 3‐methyl‐histidine (3‐MH), was measured in the interstitial fluid of the vastus lateralis. Measurements were performed in both legs. In general, myofibrillar protein FSR was lower in OC‐users (two‐way analysis of variance, P<0.05), although the difference seemed to depend on the OC type. Interstitial 3‐MH in the skeletal muscle was not different between groups and did not vary by OC type. Exercise did not change myofibrillar protein FSR or 3‐MH concentrations. Serum androstenedione and bioavailability of testosterone were lower in OC‐users. In conclusion, the results indicate that the use of OC has an inhibiting effect on myofibrillar protein synthesis and the magnitude of the effect may depend on the type of OC. In contrast, there was no effect of OC on myofibrillar protein breakdown in the fed state.

Adipose tissue mitochondrial respiration and lipolysis before and after a weight loss by diet and RYGB.

To study adipose tissue mitochondrial respiration and lipolysis following a massive weight loss.

GH/IGF-I axis and matrix adaptation of the musculotendinous tissue to exercise in humans

Exercise is not only associated with adaptive responses within skeletal muscle fibers but also with induction of collagen synthesis both in muscle and adjacent connective tissue. Additionally, exercise and training leads to activation of the systemic growth hormone/insulin‐like growth factor I axis (GH/IGF‐I), as well as increased local IGF‐I expression. Studies in humans with pathologically high levels of GH/IGF‐I, and in healthy humans who receive either weeks of GH administration or acute injection of IGF‐I into connective tissue, demonstrate increased expression and synthesis of collagen in muscle and tendon. These observations support a stimulatory effect of GH/IGF‐I on the connective tissue in muscle and tendon, which appears far more potent than the effect on contractile proteins of skeletal muscle. However, GH/IGF‐I may play an additional role in skeletal muscle by regulation of stem cells (satellite cells), as increased satellite cell numbers are found in human muscle with increased GH/IGF‐I levels, despite no change in myofibrillar protein synthesis. Although advanced age is associated with both a reduction in the GH/IGF‐I axis activity, and in skeletal muscle mass (sarcopenia) as well as in tendon connective tissue, there is no direct proof linking age‐related changes in the musculotendinous tissue to an impaired GH/IGF‐I axis.

Hepatic mitochondrial oxidative phosphorylation is normal in obese patients with and without type 2 diabetes

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.

The Effect of Metformin on Glucose Homeostasis During Moderate Exercise

OBJECTIVE We investigated the role of metformin on glucose kinetics during moderate exercise. RESEARCH DESIGN AND METHODS Before, during, and after a 45-min bout of exercise at 60% VO2max, glucose kinetics were determined by isotope tracer technique in patients with type 2 diabetes mellitus with metformin treatment (DM2+Met) or without metformin treatment (DM2) and in healthy control subjects (CON) matched for BMI and age. Glucoregulatory hormones and metabolites were measured throughout the study. RESULTS Plasma glucose concentration was unchanged during exercise in CON but decreased in DM2. No significant change was found in DM2+Met. Hormones and metabolites showed no differences among the groups except for elevated exercise-induced concentrations of lactate in DM2 (area under the curve [AUC] 31 ± 1% vs. CON) and glucagon in DM2 (AUC 5 ± 1% vs. DM2+Met). Free fatty acid levels were lower in DM2+Met than in DM2 (AUC −14 ± 1%). Absolute values of the baseline glucose rate of appearance (Ra) were elevated in DM2 and DM2+Met, but the increase in glucose Ra relative to baseline was blunted in DM2 (19 ± 1%) and DM2+Met (18 ± 4%) compared with CON (46 ± 4%). Glucose rate of disappearance relative to baseline increased more in CON (31 ± 3%) than in DM2 (6 ± 1%) and DM2+Met (21 ± 2%), showing a small increase caused by metformin. Glucose metabolic clearance rate relative to baseline was similar during exercise in DM2 (33 ± 1%) and CON (35 ± 3%) but was improved in DM2+Met (37 ± 3%) compared with DM2. CONCLUSIONS Metformin has a positive effect on glucose homeostasis during exercise.

Increased post-operative cardiopulmonary fitness in gastric bypass patients is explained by weight loss

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 (VO2max) 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. VO2max increased (A: 21 ± 1 vs D: 29 mL/min/kg, P < 0.001), but absolute VO2max decreased (A: 2713 ± 126 vs 2609 ± 187 mL/min, P = 0.02) and VO2max 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 VO2max, RYGB patients do not adopt new exercise habits following surgery.

The Effect of Preoperative Type 2 Diabetes and Physical Fitness on Mental Health and Health-Related Quality of Life after Roux-en-Y Gastric Bypass.

Objective. To investigate the predictive value of type 2 diabetes and lack of physical activity for mental health and health-related quality of life after Roux-en-Y gastric bypass. Method. Forty severely obese patients undergoing Roux-en-Y gastric bypass were included in the GASMITO study. Information about physiological and psychological factors was prospectively assessed at four time points, two times prior to surgery and two times after surgery. Measures included oral and intravenous glucose tolerance tests, VO2max test, Symptoms Checklist (SCL-90), Short Form Health Survey 36 (SF-36), Body Image Questionnaire, and a questionnaire assessing sociodemographic factors and medical status. Results. Mean % excess weight loss was 65% (±12) at 18-month follow-up and 50% of the participants with diabetes experienced total remission. Also, significant improvements were observed with regard to physical fitness, mental distress, health-related quality of life, and weight-related body image (p < 0.05). The interaction between follow-up time and type 2 diabetes at baseline significantly predicted six of the thirteen psychological subscales (p < 0.05) and, across the follow-ups, physical fitness level made modest contributions to variations in mental symptoms and HRQOL but not weight-related body image. Conclusion. The results suggest that baseline difference in mental symptoms and physical HRQOL between diabetic and nondiabetic patients declines across follow-ups and resolves around the time of surgery.

Mitochondrial respiratory capacity remains stable despite a comprehensive and sustained increase in insulin sensitivity in obese patients undergoing gastric bypass surgery

It has been proposed, but not yet demonstrated by convincing evidence in published articles, that insulin resistance and mitochondrial respiratory function are causally related physiological phenomena. Here, we tested the prediction that weight loss–induced increase in insulin sensitivity will correlate with a corresponding change in mitochondrial respiratory capacity over the same time period.