Determinants of low bone turnover in type 2 diabetes (T2DM) are poorly understood. To investigate the relationship between markers of bone turnover, glycaemic control, disease duration and calciotropic hormones in T2DM we assessed baseline biochemical data from the DiabOS Study, a prospective multicenter observational cohort study. In a cross-sectional study-design data from 110 postmenopausal women and men aged 50–75 years diagnosed with T2DM for at least 3 years and 92 non-diabetic controls were evaluated. Biochemical markers of bone formation (N-terminal propeptide of type I procollagen [PINP]), bone-specific alkaline phosphatase [BAP]) and resorption (C-terminal cross-linking telopeptide of type I collagen [CTX]), measures of calcium homeostasis (intact parathormone [iPTH], 25-Hydroxyvitamin D, calcium, magnesium) and glycaemic control were assessed. After adjustment for age, gender and body mass index (BMI), patients with T2DM had lower serum levels of PINP (p < 0.001), CTX (p < 0.001), iPTH (p = 0.03) and magnesium (p < 0.001) compared to controls. Serum calcium, creatinine, 25-Hydroxyvitamin D and sclerostin did not differ between both groups. In multivariate linear regression analyses only serum iPTH remained an independent determinant of bone turnover markers in T2DM (PINP: p = 0.02; CTX: p < 0.001 and BAP: p < 0.01), whereas glycated haemoglobin (HbA1c), disease duration, age and BMI were not associated with bone turnover. In conclusion low bone turnover in T2DM is associated with low iPTH. The underlying mechanism remains to be elucidated.

Anti-diabetic drugs are widely used and are essential for adequate glycemic control in patients with type 2 diabetes. Recently, marketed anti-diabetic drugs include incretin-based therapies (GLP-1 receptor agonists and DPP-4 inhibitors) and sodium-glucose co-transporter 2 (SGLT2) inhibitors. In contrast to well-known detrimental effects of thiazolidinediones on bone metabolism and fracture risk, clinical data on the safety of incretin-based therapies is limited. Based on meta-analyses of trials investigating the glycemic-lowering effect of GLP-1 receptor agonists and DPP4 inhibitors, it seems that incretin-based therapies are not associated with an increase in fracture risk. Sodium-glucose co-transporter 2 inhibitors may alter calcium and phosphate homeostasis as a result of secondary hyperparathyroidism induced by increased phosphate reabsorption. Although these changes may suggest detrimental effects of SGLT-2 inhibitors on skeletal integrity, treatment-related direct effects on bone metabolism seem unlikely. Observed changes in BMD, however, seem to result from increased bone turnover in the early phase of drug-induced weight loss. Fracture risk, which is observed in older patients with impaired renal function and elevated cardiovascular disease risk treated with SGLT2 inhibitors, seems to be independent of direct effects on bone but more likely to be associated with falls and changes in hydration status secondary to osmotic diuresis.

Objective: Growth hormone (GH) has a strong lipolytic action and its secretion is increased during exercise. Data on fuel metabolism and its hormonal regulation during prolonged exercise in patients with growth hormone deficiency (GHD) is scarce. This study aimed at evaluating the hormonal and metabolic response during aerobic exercise in GHD patients.Design: Ten patients with confirmed GHD and 10 healthy control individuals (CI) matched for age, sex, BMI, and waist performed a spiroergometric test to determine exercise capacity (VO2max). Throughout a subsequent 120-minute exercise on an ergometer at 50% of individual VO2max free fatty acids (FFA), glucose, GH, cortisol, catecholamines and insulin were measured. Additionally substrate oxidation assessed by indirect calorimetry was determined at begin and end of exercise.Results: Exercise capacity was lower in GHD compared to CI (VO2max 35.5 +/- 7.4 vs 41.5 +/- 5.5 ml/min * kg, p = 0.05). GH area under the curve (AUC-GH), peak-GH and peak-FFA were lower in GHD patients during exercise compared to CI (AUC-GH 100 +/- 93.2 vs 908.6 +/- 623.7 ng * min/ml, p < 0.001; peak-GH 1.5 +/- 1.53 vs 12.57 +/- 9.36 ng/ml, p < 0.001, peak-FFA 1.01 +/- 0.43 vs 1.51 +/- 0.56 mmol/l, p = 0.036, respectively). There were no significant differences for insulin, cortisol, catecholamines and glucose. Fat oxidation at the end of exercise was higher in CI compared to GHD patients (295.7 +/- 73.9 vs 187.82 +/- 103.8 kcal/h, p = 0.025).Conclusion: A reduced availability of FFA during a 2-hour aerobic exercise and a reduced fat oxidation at the end of exercise may contribute to the decreased exercise capacity in GHD patients. Catecholamines and cortisol do not compensate for the lack of the lipolytic action of GH in patients with GHD. (C) 2016 Elsevier Ltd. All rights reserved.

Growth hormone replacement therapy (GHRT) increases exercise capacity and insulin resistance while it decreases fat mass in growth hormone-deficient patients (GHD). Ectopic lipids (intramyocellular (IMCL) and intrahepatocellular lipids (IHCL) are related to insulin resistance. The effect of GHRT on ectopic lipids is unknown. It is hypothesized that exercise-induced utilization of ectopic lipids is significantly decreased in GHD patients and normalized by GHRT. GHD (4 females, 6 males) and age/gender/waist-matched control subjects (CS) were studied. VO 2max was assessed on a treadmill and insulin sensitivity determined by a two-step hyperinsulinaemic-euglycaemic clamp. Visceral (VAT) and subcutaneous (SAT) fat were quantified by MR-imaging. IHCL and IMCL were measured before and after a 2 h exercise at 50–60% of VO 2max using MR-spectroscopy (∆IMCL, ∆IHCL). Identical investigations were performed after 6 months of GHRT. VO 2max was similar in GHD and CS and significantly increased after GHRT; GHRT significantly decreased SAT and VAT. 2 h-exercise resulted in a decrease in IMCL (significant in CS and GHRT) and a significant increase in IHCL in CS and GHD pre and post GHRT. GHRT didn’t significantly impact on ∆IMCL and ∆IHCL. We conclude that aerobic exercise affects ectopic lipids in patients and controls. GHRT increases exercise capacity without influencing ectopic lipids.

Type 2 diabetes is associated with increased fracture risk and the mechanisms underlying the detrimental effects of diabetes on skeletal health are only partially understood. Antidiabetic drugs are indispensable for glycemic control in most type 2 diabetics, however, they may, at least in part, modulate fracture risk in exposed patients. Preclinical and clinical data clearly demonstrate an unfavorable effect of thiazolidinediones on the skeleton with impaired osteoblast function and activated osteoclastogenesis. The negative effect of thiazolidinediones on osteoblastogenesis includes decreased activity of osteoblast-specific transcription factors (e.g. Runx2, Dlx5, osterix) and decreased activity of osteoblast-specific signaling pathways (e.g. Wnt, TGF-β/BMP, IGF-1). In contrast, metformin has a positive effect on osteoblast differentiation due to increased activity of Runx2 via the AMPK/USF-1/SHP regulatory cascade resulting in a neutral or potentially protective effect on bone. Recently marketed antidiabetic drugs include incretin-based therapies (GLP-1 receptor agonists, DPP-4 inhibitors) and sodium-glucose co-transporter 2 (SGLT2)-inhibitors. Preclinical studies indicate that incretins (GIP, GLP-1, and GLP-2) play an important role in the regulation of bone turnover. Clinical safety data are limited, however, meta-analyses of trials investigating the glycemic-lowering effect of both, GLP-1 receptor agonists and DPP4-inhibitors, suggest a neutral effect of incretin-based therapies on fracture risk. For SGLT2-inhibitors recent data indicate that due to their mode of action they may alter calcium and phosphate homeostasis (secondary hyperparathyroidism induced by increased phosphate reabsorption) and thereby potentially affect bone mass and fracture risk. Clinical studies are needed to elucidate the effect of SGLT2-inhibitors on bone metabolism. Meanwhile SGLT2-inhibitors should be used with caution in patients with high fracture risk, which is specifically true for the use of thiazolidinediones.

Clinical EndocrinologyVolume 83, Issue 4 p. 593-595 Letter to the Editor Effect of Growth hormone replacement therapy on soluble Klotho in patients with Growth hormone deficiency Rebecca Locher, Rebecca Locher Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital of Zurich, Zurich, Switzerland Division of Endocrinology and Diabetes, Cantonal Hospital of Graubünden, Chur, SwitzerlandSearch for more papers by this authorAndrea Egger, Andrea Egger Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital of Berne, Inselspital Berne, Berne, Switzerland Division of Internal Medicine, University Hospital of Basel, Basel, SwitzerlandSearch for more papers by this authorCornelia Zwimpfer, Cornelia Zwimpfer Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital of Zurich, Zurich, Switzerland Search for more papers by this authorLisa Sze, Lisa Sze Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital of Zurich, Zurich, Switzerland Division of Endocrinology, Diabetes and Osteology, Cantonal Hospital of St. Gallen, St. Gallen, SwitzerlandSearch for more papers by this authorChristoph Schmid, Christoph Schmid Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital of Zurich, Zurich, Switzerland Search for more papers by this authorEmanuel Christ, Emanuel Christ [email protected] Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital of Berne, Inselspital Berne, Berne, SwitzerlandSearch for more papers by this author Rebecca Locher, Rebecca Locher Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital of Zurich, Zurich, Switzerland Division of Endocrinology and Diabetes, Cantonal Hospital of Graubünden, Chur, SwitzerlandSearch for more papers by this authorAndrea Egger, Andrea Egger Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital of Berne, Inselspital Berne, Berne, Switzerland Division of Internal Medicine, University Hospital of Basel, Basel, SwitzerlandSearch for more papers by this authorCornelia Zwimpfer, Cornelia Zwimpfer Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital of Zurich, Zurich, Switzerland Search for more papers by this authorLisa Sze, Lisa Sze Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital of Zurich, Zurich, Switzerland Division of Endocrinology, Diabetes and Osteology, Cantonal Hospital of St. Gallen, St. Gallen, SwitzerlandSearch for more papers by this authorChristoph Schmid, Christoph Schmid Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital of Zurich, Zurich, Switzerland Search for more papers by this authorEmanuel Christ, Emanuel Christ [email protected] Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital of Berne, Inselspital Berne, Berne, SwitzerlandSearch for more papers by this author First published: 18 February 2015 https://doi.org/10.1111/cen.12756Citations: 6Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article.Citing Literature Volume83, Issue4October 2015Pages 593-595 RelatedInformation

Background Intrahepatocellular (IHCL) and intramyocellular (IMCL) lipids are ectopic lipid stores. Aerobic exercise results in IMCL utilization in subjects over a broad range of exercise capacity. IMCL and IHCL have been related to impaired insulin action at the skeletal muscle and hepatic level, respectively. The acute effect of aerobic exercise on IHCL is unknown. Possible regulatory factors include exercise capacity, insulin sensitivity and fat availability subcutaneous and visceral fat mass). Aim To concomitantly investigate the effect of aerobic exercise on IHCL and IMCL in healthy subjects, using Magnetic Resonance spectroscopy. Methods Normal weight, healthy subjects were included. Visit 1 consisted of a determination of VO2max on a treadmill. Visit 2 comprised the assessment of hepatic and peripheral insulin sensitivity by a two-step hyperinsulinaemic euglycaemic clamp. At Visit 3, subcutaneous and visceral fat mass were assessed by whole body MRI, IHCL and IMCL before and after a 2-hours aerobic exercise (50% of VO2max) using 1H-MR-spectroscopy. Results Eighteen volunteers (12M, 6F) were enrolled in the study (age, 37.6±3.2 years, mean±SEM; VO2max, 53.4±2.9 mL/kg/min). Two hours aerobic exercise resulted in a significant decrease in IMCL (−22.6±3.3, % from baseline) and increase in IHCL (+34.9±7.6, % from baseline). There was no significant correlation between the exercise-induced changes in IMCL and IHCL and exercise capacity, subcutaneous and visceral fat mass and hepatic or peripheral insulin sensitivity. Conclusions IMCL and IHCL are flexible ectopic lipid stores that are acutely influenced by physical exercise, albeit in different directions. Trial Registration ClinicalTrial.gov NCT00491582

Carnosine (β-alanyl- l -histidine) is found in high concentrations in skeletal muscle and chronic β-alanine (BA) supplementation can increase carnosine content. This placebo-controlled, double-blind study compared two different 8-week BA dosing regimens on the time course of muscle carnosine loading and 8-week washout, leading to a BA dose–response study with serial muscle carnosine assessments throughout. Thirty-one young males were randomized into three BA dosing groups: (1) high–low: 3.2 g BA/day for 4 weeks, followed by 1.6 g BA/day for 4 weeks; (2) low–low: 1.6 g BA/day for 8 weeks; and (3) placebo. Muscle carnosine in tibialis - anterior (TA) and gastrocnemius (GA) muscles was measured by 1 H-MRS at weeks 0, 2, 4, 8, 12 and 16. Flushing symptoms and blood clinical chemistry were trivial in all three groups and there were no muscle carnosine changes in the placebo group. During the first 4 weeks, the increase for high–low (TA 2.04 mmol/kg ww , GA 1.75 mmol/kg ww ) was ~twofold greater than low–low (TA 1.12 mmol/kg ww , GA 0.80 mmol/kg ww ). 1.6 g BA/day significantly increased muscle carnosine within 2 weeks and induced continual rises in already augmented muscle carnosine stores (week 4–8, high–low regime). The dose–response showed a carnosine increase of 2.01 mmol/kg ww per 100 g of consumed BA, which was only dependent upon the total accumulated BA consumed (within a daily intake range of 1.6–3.2 g BA/day). Washout rates were gradual (0.18 mmol/kg ww and 0.43 mmol/kg ww /week; ~2%/week). In summary, the absolute increase in muscle carnosine is only dependent upon the total BA consumed and is not dependent upon baseline muscle carnosine, the muscle type, or the daily amount of supplemented BA.

Intramyocellular lipids (IMCL) are flexible fuel stores that are depleted by physical exercise and replenished by fat intake. IMCL or their degradation products are thought to interfere with insulin signaling thereby contributing to insulin resistance. From a practical point of view it is desirable to deplete IMCL prior to replenishing them. So far, it is not clear for how long and at which intensity subjects have to exercise in order to deplete IMCL. We therefore aimed at developing a standardized exercise protocol that is applicable to subjects over a broad range of exercise capacity and insulin sensitivity and allows measuring reliably reduced IMCL levels.