SUGAR-DIP trial: Oral medication strategy versus insulin for diabetes in pregnancy, study protocol for a multicentre, open-label, non-inferiority, randomised controlled trial

Introduction In women with gestational diabetes mellitus (GDM) requiring pharmacotherapy, insulin was the established first-line treatment. More recently, oral glucose lowering drugs (OGLDs) have gained popularity as a patient-friendly, less expensive and safe alternative. Monotherapy with metformin or glibenclamide (glyburide) is incorporated in several international guidelines. In women who do not reach sufficient glucose control with OGLD monotherapy, usually insulin is added, either with or without continuation of OGLDs. No reliable data from clinical trials, however, are available on the effectiveness of a treatment strategy using all three agents, metformin, glibenclamide and insulin, in a stepwise approach, compared with insulin-only therapy for improving pregnancy outcomes. In this trial, we aim to assess the clinical effectiveness, cost-effectiveness and patient experience of a stepwise combined OGLD treatment protocol, compared with conventional insulin-based therapy for GDM. Methods The SUGAR-DIP trial is an open-label, multicentre randomised controlled non-inferiority trial. Participants are women with GDM who do not reach target glycaemic control with modification of diet, between 16 and 34 weeks of gestation. Participants will be randomised to either treatment with OGLDs, starting with metformin and supplemented as needed with glibenclamide, or randomised to treatment with insulin. In women who do not reach target glycaemic control with combined metformin and glibenclamide, glibenclamide will be substituted with insulin, while continuing metformin. The primary outcome will be the incidence of large-for-gestational-age infants (birth weight >90th percentile). Secondary outcome measures are maternal diabetes-related endpoints, obstetric complications, neonatal complications and cost-effectiveness analysis. Outcomes will be analysed according to the intention-to-treat principle. Ethics and dissemination The study protocol was approved by the Ethics Committee of the Utrecht University Medical Centre. Approval by the boards of management for all participating hospitals will be obtained. Trial results will be submitted for publication in peer-reviewed journals

Salivary cortisol in the diagnosis of adrenal insufficiency: cost efficient and patient friendly

Saliva as a diagnostic tool is patient friendly and offers analytical advantages. Hormonal analysis of saliva is not influenced by changes in concentrations of binding globulins as the free concentration of the hormones is measured. Analysis of salivary cortisol is common practice in the diagnostic work-up of hypercortisolism. We investigated the potential role of measuring salivary cortisol when adrenal insufficiency (AI) is suspected, to reduce the numbers of ACTH stimulation tests. Over a period of 6 years, patients undergoing an ACTH stimulation test (tetracosactide, 250 μg) in our hospital were included. Plasma cortisol (Elecsys, Cobas, Roche Diagnostics) and salivary cortisol and cortisone (LC–MS/MS) were determined at t = 0, 30 and 60 min after stimulation. Based on peak plasma cortisol levels, AI was ruled out in 113 patients and was established in 16 patients. Patients without AI displayed maximal salivary cortisol concentrations of 12.6–123.4 nmol/L (95th percentile) after stimulation, as opposed to 0.5–15.2 nmol/L in AI patients. At t = 0 min, a minimal salivary cortisol concentration of 1.0 nmol/L was observed in patients without AI, whereas AI patients had a maximum concentration of 5.9 nmol/L. Using these cut-off values, 34% of the initial patient group could be diagnosed without an ACTH stimulation test (28% >5.9 nmol/L, 6% <1.0 nmol/L). A novel diagnostic algorithm, including early morning salivary cortisol analysis can reduce the numbers of ACTH stimulation tests in patients suspected of AI. This patient-friendly method can thereby reduce total health care costs

Medical and surgical treatment of postbariatric hypoglycaemia: retrospective data from daily practice

Aim: To evaluate medical and surgical treatment of postbariatric hypoglycaemia (PBH) in daily practice. Materials and Methods: Retrospective data were extracted from medical records from four hospitals. PBH was defined by neuroglycopenic symptoms together with a documented glucose <3.0 mmol/L in the postprandial setting after previous bariatric surgery. Data were scored semiquantitatively on efficacy and side effects by two reviewers independently. Duration of efficacy and of use were calculated. Results: In total, 120 patients were included with a median follow-up of 27 months with a mean baseline age of 41 years, total weight loss of 33% and glucose nadir 2.3 mmol/L. Pharmacotherapy consisted of acarbose, diazoxide, short- and long-acting octreotide and glucagon-like peptide-1 receptor agonist analogues (liraglutide and semaglutide) with an overall efficacy in 45%-75% of patients. Combination therapy with two drugs was used by 30 (25%) patients. The addition of a second drug was successful in over half of the patients. Long-acting octreotide and the glucagon-like peptide-1 receptor agonist analogues scored best in terms of efficacy and side effects with a median duration of use of 35 months for octreotide. Finally, 23 (19%) patients were referred for surgical intervention. Efficacy of the surgical procedures, pouch banding, G-tube placement in remnant stomach and Roux-en-Y gastric bypass reversal, pooled together, was 79% with a median duration of initial effect of 13 months. Conclusions: In daily practice, pharmacotherapy for PBH was successful in half to three quarters of patients. Combination therapy was often of value. One in five patients finally needed a surgical procedure, with overall good results

Vitamin D supplementation and testosterone concentrations in male human subjects

ObjectiveA possible association between serum 25-hydroxyvitamin D and testosterone levels has been reported; however, contradictory results have emerged. DesignTo investigate a causal link between vitamin D and testosterone status, we studied the effect of vitamin D supplementation on serum testosterone concentrations in three independent intervention studies including male patients with heart failure (study 1), male nursing home residents (study 2) and male non-Western immigrants in the Netherlands (study 3). MethodsIn study 1, 92 subjects were randomized to either vitamin D (2000IU cholecalciferol daily) or control. Blood was drawn at baseline, after 3 and 6weeks. In study 2, 49 vitamin D deficient subjects received either vitamin D (600IU daily) or placebo. Blood was drawn at baseline, after 8 and 16weeks. In study 3, 43 vitamin D deficient subjects received either vitamin D (1200IU daily) or placebo. Blood was drawn at baseline, after 8 and 16weeks. Serum 25-hydroxyvitamin D levels were measured using LC-MS/MS or radioimmunoassay. Testosterone levels were measured using a 2nd generation immunoassay. ResultsSerum 25-hydroxyvitamin D levels significantly increased in all treatment groups (median increase of 27, 30 and 36nmol/l in studies 1, 2 3, respectively) but not in the control groups. The documented increase in 25-hydroxyvitamin D levels, however, did not affect mean testosterone concentrations at the end of the study (median increase of 0, 05 and 0nmol/l in studies 1, 2 and 3, respectively). ConclusionsIn this post hoc analysis of three small clinical trials of limited duration in men with normal baseline testosterone concentrations, vitamin D supplementation was not associated with an increase in circulating testosterone concentration

Vitamin D supplementation and testosterone concentrations in male human subjects

ObjectiveA possible association between serum 25-hydroxyvitamin D and testosterone levels has been reported; however, contradictory results have emerged.DesignTo investigate a causal link between vitamin D and testosterone status, we studied the effect of vitamin D supplementation on serum testosterone concentrations in three independent intervention studies including male patients with heart failure (study 1), male nursing home residents (study 2) and male non-Western immigrants in the Netherlands (study 3).MethodsIn study 1, 92 subjects were randomized to either vitamin D (2000IU cholecalciferol daily) or control. Blood was drawn at baseline, after 3 and 6weeks. In study 2, 49 vitamin D deficient subjects received either vitamin D (600IU daily) or placebo. Blood was drawn at baseline, after 8 and 16weeks. In study 3, 43 vitamin D deficient subjects received either vitamin D (1200IU daily) or placebo. Blood was drawn at baseline, after 8 and 16weeks. Serum 25-hydroxyvitamin D levels were measured using LC-MS/MS or radioimmunoassay. Testosterone levels were measured using a 2nd generation immunoassay.ResultsSerum 25-hydroxyvitamin D levels significantly increased in all treatment groups (median increase of 27, 30 and 36nmol/l in studies 1, 2 3, respectively) but not in the control groups. The documented increase in 25-hydroxyvitamin D levels, however, did not affect mean testosterone concentrations at the end of the study (median increase of 0, 05 and 0nmol/l in studies 1, 2 and 3, respectively).ConclusionsIn this post hoc analysis of three small clinical trials of limited duration in men with normal baseline testosterone concentrations, vitamin D supplementation was not associated with an increase in circulating testosterone concentrations.</p

Medical and surgical treatment of postbariatric hypoglycemia:retrospective data from daily practice

Aim: To evaluate medical and surgical treatment of postbariatric hypoglycaemia (PBH) in daily practice. Materials and Methods: Retrospective data were extracted from medical records from four hospitals. PBH was defined by neuroglycopenic symptoms together with a documented glucose <3.0 mmol/L in the postprandial setting after previous bariatric surgery. Data were scored semiquantitatively on efficacy and side effects by two reviewers independently. Duration of efficacy and of use were calculated. Results: In total, 120 patients were included with a median follow-up of 27 months with a mean baseline age of 41 years, total weight loss of 33% and glucose nadir 2.3 mmol/L. Pharmacotherapy consisted of acarbose, diazoxide, short- and long-acting octreotide and glucagon-like peptide-1 receptor agonist analogues (liraglutide and semaglutide) with an overall efficacy in 45%-75% of patients. Combination therapy with two drugs was used by 30 (25%) patients. The addition of a second drug was successful in over half of the patients. Long-acting octreotide and the glucagon-like peptide-1 receptor agonist analogues scored best in terms of efficacy and side effects with a median duration of use of 35 months for octreotide. Finally, 23 (19%) patients were referred for surgical intervention. Efficacy of the surgical procedures, pouch banding, G-tube placement in remnant stomach and Roux-en-Y gastric bypass reversal, pooled together, was 79% with a median duration of initial effect of 13 months. Conclusions: In daily practice, pharmacotherapy for PBH was successful in half to three quarters of patients. Combination therapy was often of value. One in five patients finally needed a surgical procedure, with overall good results

Relative importance of four functional measures as predictors of 15-year mortality in the older Dutch population

Abstract Background Decreased physical function is known to raise mortality risk. Little is known about how different physical function measures compare in predicting mortality risk in older men and women. The objective of this study was to compare four, objective and self-reported, physical function measures in predicting 15-year mortality risk in older men and women. Methods Data were used from the Longitudinal Aging Study Amsterdam (LASA), an ongoing cohort study in a population-based sample of the older Dutch population, sampled from municipal records. The 1995–96 cycle, including 727 men and 778 women aged 65–88 years, was considered as the baseline. Mortality was followed up through September 1, 2011. Physical function measures were: lower-body performance (chair stands test, walk test and tandem stand); handgrip strength (grip strength dynamometer); lung function (peak expiratory flow rate); functional limitations (self-report of difficulties in performing six activities of daily living). Cox proportional hazard models were used to determine the predictive value of each physical function measure for 15-year mortality risk, adjusted for demographic, lifestyle and health variables as potential confounders. Results 1031 participants (68.5%) had died. After adjustments for confounders, in models assessing single functional measures, peak flow was the strongest predictor of all-cause mortality in men (HR 1.76, CI 1.38–2.26, CI) and lower-body performance in women (HR 1.97,CI 1.40–2.76, CI). In a model including all four functional measures only peak flow was statistically significant in predicting mortality in both genders (men HR 1.54,CI 1.18–2.01 and women HR 1.45,CI 1.08–1.94). In women, lower-body performance (HR 1.66, CI 1.15–2.41) followed by grip strength (HR 1.38, CI 1.02–1.89), and in men, functional limitations (HR 1.43, CI 1.14–1.8) were the other significant predictors of all-cause mortality. Conclusion Both objective and self-reported measures of physical functioning predicted all-cause mortality in a representative sample of the older Dutch population to different extents in men and women. Peak flow contributed important unique predictive value for mortality in both men and women. In women, however, lower-body performance tests had better predictive ability. A second-best predictor in men was self-reported functional limitations. Peak flow, and possibly one of the other measures, may be used in clinical practice for assessment in the context of time constraints

Vitamin D supplementation and testosterone concentrations in male human subjects

ObjectiveA possible association between serum 25-hydroxyvitamin D and testosterone levels has been reported; however, contradictory results have emerged. DesignTo investigate a causal link between vitamin D and testosterone status, we studied the effect of vitamin D supplementation on serum testosterone concentrations in three independent intervention studies including male patients with heart failure (study 1), male nursing home residents (study 2) and male non-Western immigrants in the Netherlands (study 3). MethodsIn study 1, 92 subjects were randomized to either vitamin D (2000IU cholecalciferol daily) or control. Blood was drawn at baseline, after 3 and 6weeks. In study 2, 49 vitamin D deficient subjects received either vitamin D (600IU daily) or placebo. Blood was drawn at baseline, after 8 and 16weeks. In study 3, 43 vitamin D deficient subjects received either vitamin D (1200IU daily) or placebo. Blood was drawn at baseline, after 8 and 16weeks. Serum 25-hydroxyvitamin D levels were measured using LC-MS/MS or radioimmunoassay. Testosterone levels were measured using a 2nd generation immunoassay. ResultsSerum 25-hydroxyvitamin D levels significantly increased in all treatment groups (median increase of 27, 30 and 36nmol/l in studies 1, 2 3, respectively) but not in the control groups. The documented increase in 25-hydroxyvitamin D levels, however, did not affect mean testosterone concentrations at the end of the study (median increase of 0, 05 and 0nmol/l in studies 1, 2 and 3, respectively). ConclusionsIn this post hoc analysis of three small clinical trials of limited duration in men with normal baseline testosterone concentrations, vitamin D supplementation was not associated with an increase in circulating testosterone concentrations

The interrelation between FGF23 and glucose metabolism in humans

Aims: Different studies point to a link between glucose metabolism and Fibroblast Growth Factor 23 (FGF23), an osteocyte-derived phosphaturic hormone. We aimed to investigate in humans the effect of (I) a glucose load and (II) a hyperinsulinemic-euglycemic clamp on FGF23 concentrations and conversely (III) the effect of a diet-induced increase in FGF23 concentration on glucose and insulin concentrations. Methods: Plasma cFGF23 concentrations were measured during: I. an oral glucose tolerance test in eight adults with impaired glucose tolerance and vitamin D deficiency and II. a hyperinsulinemic-euglycemic clamp in nine healthy adults. III. Serum glucose and insulin concentrations were measured in nine healthy adults receiving a single-day phosphate-enriched or -restricted diet. Results: I. A glucose load decreased FGF23 and phosphate concentrations. II. The hyperinsulinemic-euglycemic clamp decreased phosphate concentrations, but did not affect FGF23 concentrations. III. Fasting insulin and glucose concentrations remained unchanged after a diet-induced increase in FGF23 concentration. Conclusions: An oral glucose load in vitamin D deficient patients with impaired glucose metabolism decreased FGF23 concentrations, which cannot be attributed to changes in insulin concentration. Thus, bone may react rapidly after glucose loading by alternating FGF23 secretion. A diet-induced increase in FGF23 concentrations did not affect fasting glucose or insulin levels

Effect of moderate-dose vitamin D supplementation on insulin sensitivity in vitamin D-deficient non-Western immigrants in the Netherlands: a randomized placebo-controlled trial

Background: Low serum 25-hydroxyvitamin D [25(OH)D] concentrations have been associated with insulin resistance, the metabolic syndrome, and type 2 diabetes. Because many non-Western immigrants in the Netherlands are vitamin D deficient, obese, and at high risk of diabetes, vitamin D supplementation may contribute to prevent diabetes and insulin resistance. Objective: We examined the effect of vitamin D supplementation on insulin sensitivity and β cell function in overweight, vitamin D-deficient, non-Western immigrants at high risk of diabetes. Design: The study was a 16-wk, randomized, placebo-controlled trial. A total of 130 non-Western immigrants with prediabetes (fasting glucose concentration >5.5 mmol/L or random glucose concentration from 7.8 to 11.1 mmol/L) and vitamin D deficiency (serum 25[OH]D concentration <50 nmol/L) were randomly assigned after stratification by sex to receive either cholecalciferol (1200 IU/d) or a placebo for 16 wk. All participants received 500 mg Ca/d as calcium carbonate. The primary outcome was the difference in the area under the curve of insulin and glucose after a 75-g oral-glucose-tolerance test after 4 mo of treatment. Secondary outcomes were insulin-sensitivity variables, β cell-function variables, and metabolic syndrome. Results: Mean serum 25(OH)D concentrations increased significantly in the vitamin D compared with placebo groups. After 4 mo of therapy, the mean between-group difference was 38 nmol/L (95% CI: 32.1, 43.9 nmol/L; P < 0.001). There was no significant effect on insulin sensitivity and β cell function. In a post hoc analysis, when patients with diabetes at baseline were excluded, a significant increase in the insulinogenic index was observed in participants who obtained a 25(OH)D concentration ≥60 nmol/L (P = 0.040). Conclusions: Vitamin D supplementation in non-Western vitamin D-deficient immigrants with prediabetes did not improve insulin sensitivity or β cell function or change the incidence of metabolic syndrome. However, after the exclusion of diabetic subjects, an improvement in the insulinogenic index was observed in participants who obtained a 25(OH)D concentration ≥60 nmol/L. © 2014 American Society for Nutrition