Associations between inflammation-related biomarkers and depressive symptoms in individuals with recently diagnosed type 1 and type 2 diabetes.

Depressive disorders represent a frequent comorbidity of both type 1 (T1D) and type 2 diabetes (T2D). Inflammation-related processes have been implicated in the development of both diabetes and depression. This study aimed to investigate whether biomarkers of subclinical inflammation were associated with depressive symptoms in individuals with recently diagnosed diabetes and if such associations differed by diabetes type. This cross-sectional study was based on 295 individuals with T2D (67% men, mean age 53years) and 139 individuals with T1D (60% men, mean age 36years) of the German Diabetes Study. The main inclusion criterion was a known disease duration of <1year. Depressive symptoms were assessed with the Allgemeine Depressionsskala, Langversion (ADS-L) questionnaire, the German version of the Center for Epidemiological Studies Depression scale (CES-D) questionnaire. Associations between biomarkers of subclinical inflammation and the ADS-L as continuous score were assessed using multiple linear regression models adjusting for age, sex, body mass index, HbA1c, lipids, hypertension, medication and comorbidities. Serum high-sensitivity C-reactive protein (hsCRP) and the ratio of high-molecular-weight (HMW)/total adiponectin were positively associated with ADS-L in T2D (both P<0.01), but not in T1D. In contrast, serum levels of soluble intercellular adhesion molecule (sICAM)-1 were positively associated with ADS-L only in T1D (P=0.035). The latter association was significantly different between both diabetes types (Pinteraction=0.036). No associations were observed for interleukin (IL)-6, IL-18 and soluble E-selectin. Only the association between HMW/total adiponectin and ADS-L in T2D remained significant after correction for multiple testing. In conclusion, our study shows that the ratio HMW/total adiponectin is associated with depressive symptoms in individuals with recently diagnosed T2D. It also provides suggestive evidence that further biomarkers of subclinical inflammation and endothelial activation may be associated with depressive symptoms in individuals with recently diagnosed T1D and T2D.

Cohort profile: the German Diabetes Study (GDS).

BACKGROUND: The German Diabetes Study (GDS) is a prospective longitudinal cohort study describing the impact of subphenotypes on the course of the disease. GDS aims at identifying prognostic factors and mechanisms underlying the development of related comorbidities. STUDY DESIGN AND METHODS: The study comprises intensive phenotyping within 12 months after clinical diagnosis, at 5-year intervals for 20 years and annual telephone interviews in between. Dynamic tests, including glucagon, mixed meal, intravenous glucose tolerance and hyperinsulinemic clamp tests, serve to assess beta-cell function and tissue-specific insulin sensitivity. Magnetic resonance imaging and multinuclei spectroscopy allow quantifying whole-body fat distribution, tissue-specific lipid deposition and energy metabolism. Comprehensive analyses of microvascular (nerve, eye, kidney) and macrovascular (endothelial, cardiorespiratory) morphology and function enable identification and monitoring of comorbidities. The GDS biobank stores specimens from blood, stool, skeletal muscle, subcutaneous adipose tissue and skin for future analyses including multiomics, expression profiles and histology. Repeated questionnaires on socioeconomic conditions, patient-reported outcomes as quality of life, health-related behavior as physical activity and nutritional habits are a specific asset of GDS. This study will recruit 3000 patients and a group of humans without familiy history of diabetes. 237 type 1 and 456 type 2 diabetes patients have been already included.

Pancreatic adipose tissue infiltration, parenchymal steatosis and beta cell function in humans.

AIMS/HYPOTHESIS: This study aimed to perform a comprehensive analysis of interlobular, intralobular and parenchymal pancreatic fat in order to assess their respective effects on beta cell function. METHODS: Fifty-six participants (normal glucose tolerance [NGT] (n = 28), impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) (n = 14) and patients with type 2 diabetes (n = 14)) underwent a frequent-sampling OGTT and non-invasive magnetic resonance imaging (MRI; whole-body and pancreatic) and proton magnetic resonance spectroscopy ((1)H-MRS; liver and pancreatic fat). Total pancreatic fat was assessed by a standard 2 cm(3) (1)H-MRS method, intralobular fat by 1 cm(3) (1)H-MRS that avoided interlobular fat within modified DIXON (mDIXON) water images, and parenchymal fat by a validated mDIXON-MRI fat-fraction method. RESULTS: Comparison of (1)H-MRS techniques revealed an inhomogeneous distribution of interlobular and intralobular adipose tissue, which increased with decreasing glucose tolerance. mDIXON-MRI measurements provided evidence against uniform steatosis, revealing regions of parenchymal tissue void of lipid accumulation in all participants. Total (r = 0.385, p < 0.01) and intralobular pancreas adipose tissue infiltration (r = 0.310, p < 0.05) positively associated with age, but not with fasting or 2 h glucose levels, BMI or visceral fat content (all p > 0.5). Furthermore, no associations were found between total and intralobular pancreatic adipose tissue infiltration and insulin secretion or beta cell function within NGT, IFG/IGT or patients with type 2 diabetes (all p > 0.2). CONCLUSIONS/INTERPRETATION: The pancreas does not appear to be another target organ for abnormal endocrine function because of ectopic parenchymal fat storage. No relationship was found between pancreatic adipose tissue infiltration and beta cell function, regardless of glucose tolerance status.

Low-energy diets differing in fibre, red meat and coffee intake equally improve insulin sensitivity in type 2 diabetes: a randomised feasibility trial.

AIMS/HYPOTHESIS: Epidemiological studies have found that a diet high in fibre and coffee, but low in red meat, reduces the risk for type 2 diabetes. We tested the hypothesis that these nutritional modifications differentially improve whole-body insulin sensitivity (primary outcome) and secretion. METHODS: Inclusion criteria were: age 18-69 years, BMI ≥ 30 kg/m(2), type 2 diabetes treated with diet, metformin or acarbose and known disease duration of ≤ 5 years. Exclusion criteria were: HbA1c >75 mmol/mol (9.0%), type 1 or secondary diabetes types and acute or chronic diseases including cancer. Patients taking any medication affecting the immune system or insulin sensitivity, other than metformin, were also excluded. Of 59 patients (randomised using randomisation blocks [four or six patients] with consecutive numbers), 37 (54% female) obese type 2 diabetic patients completed this controlled parallel-group 8-week low-energy dietary intervention. The participants consumed either a diet high in cereal fibre (whole grain wheat/rye: 30-50 g/day) and coffee (≥ 5 cups/day), and free of red meat (L-RISK, n = 17) or a diet low in fibre (≤ 10 g/day), coffee-free and high in red meat (≥ 150 g/day) diet (H-RISK, n = 20). Insulin sensitivity and secretion were assessed by hyperinsulinaemic-euglycaemic clamp and intravenous glucose tolerance tests with isotope dilution. Whole-body and organ fat contents were measured by magnetic resonance imaging and spectroscopy. RESULTS: Whole-body insulin sensitivity increased in both groups (mean [95% CI]) (H-RISK vs L-RISK: 0.8 [0.2, 1.4] vs 1.0 [0.4, 1.7]mg kg(-1) min(-1), p = 0.59), while body weight decreased (-4.8% [-6.1%, -3.5%] vs -4.6% [-6.0%, -3.3%], respectively). Hepatic insulin sensitivity remained unchanged, whereas hepatocellular lipid content fell in both groups (-7.0% [-9.6%, -4.5%] vs -6.7% [-9.5%, -3.9%]). Subcutaneous fat mass (-1,553 [-2,767, -340] cm(3) vs -751 [-2,047; 546] cm(3), respectively) visceral fat mass (-206 [-783, 371] cm(3) vs -241 [-856, 373] cm(3), respectively) and muscle fat content (-0.09% [-0.16%, -0.02%] vs -0.02% [-0.10%, 0.05%], respectively) decreased similarly. Insulin secretion remained unchanged, while the proinflammatory marker IL-18 decreased only after the L-RISK diet. CONCLUSIONS/INTERPRETATION: No evidence of a difference between both low-energy diets was identified. Thus, energy restriction per se seems to be key for improving insulin action in phases of active weight loss in obese type 2 diabetic patients, with a potential improvement of subclinical inflammation with the L-RISK diet. TRIAL REGISTRATION: Clinicaltrials.gov NCT01409330. FUNDING: This study was supported by the Ministry of Science and Research of the State of North Rhine-Westphalia (MIWF NRW), the German Federal Ministry of Health (BMG), the Federal Ministry for Research (BMBF) to the Center for Diabetes Research (DZD e.V.) and the Helmholtz Alliance Imaging and Curing Environmental Metabolic Diseases (ICEMED).

Characterization of the peak at 2.06 ppm in (31) P magnetic resonance spectroscopy of human liver: phosphoenolpyruvate or phosphatidylcholine?

High field MR scanners can resolve a metabolite resonating at 2.06 ppm in the in vivo proton-decoupled liver (31) P MR spectrum. Traditionally this peak has been assigned to phosphoenolpyruvate (PEP), the key metabolite for gluconeogenesis. However, recent evidence supported the assignment to biliary phosphatidylcholine (PtdCh), which is produced in the liver and stored in the gall bladder. To elucidate the respective contributions of PtdCh and PEP to the in vivo resonance at 2.06 ppm (PEP-PtdCh), we made phantom measurements that confirmed that both biliary PtdCh and PEP resonate approximately at 2 ppm. The absolute quantification of PEP-PtdCh yielded concentrations ranging from 0.6 to 2.0 mmol/l, with mean coefficients of variation of 4.8% for intraday and 7.2% for interday reproducibility in healthy volunteers. The T1 relaxation time of PEP-PtdCh was 0.97 ± 0.30 s in the liver and 0.44 ± 0.11 s in the gallbladder. Ingestion of a mixed meal decreased the concentration of PtdCh-PEP by approximately 12%. In the retrospective analysis, PEP-PtdCh was 68% higher in the liver of subjects with gallbladder infiltration of the volume of interest (VOI) compared with those without gallbladder infiltration. PEP-PtdCh was also significantly higher in the liver of cholecystectomy patients compared with volunteers without gallbladder infiltration, which suggests increased intrahepatic bile fluid as a compensation for gall bladder removal. These results show that liver PtdCh is the major component of the resonance at 2.06 ppm and that careful VOI positioning is mandatory to avoid interference from the gallbladder.

Estimates of insulin sensitivity from the intravenous-glucose-modified-clamp test depend on suppression of lipolysis in type 2 diabetes: a randomised controlled trial.

AIMS/HYPOTHESIS: The combined IVGTT-hyperinsulinaemic-euglycaemic clamp (Botnia clamp) allows the assessment of insulin secretion and sensitivity in one experiment. It remains unclear whether this clamp yields results comparable with those of the standard hyperinsulinaemic-euglycaemic clamp (SHEC) in diabetes patients. We hypothesised that the IVGTT induces responses affecting insulin sensitivity assessment. METHODS: Of 22 randomised diet- or metformin-treated patients with well-controlled type 2 diabetes, 19 randomly underwent a Botnia clamp and an SHEC, spaced by 2 weeks, in one clinical research centre in a crossover study. The main outcomes were whole-body and hepatic insulin sensitivity as measured by the clamp and [6,6-(2)H2]glucose. Substrate utilisation was assessed from indirect calorimetry and beta cell function from insulin dynamics during IVGTT. RESULTS: The values of whole-body insulin sensitivity obtained from Botnia clamp and SHEC were correlated (r = 0.87, p < 0.001), but also revealed intra-individual variations. Hepatic insulin sensitivity did not differ between experiments during the clamp, but differed after IVGTT. The contribution of glucose oxidation to glucose disposal increased by 2.2 ± 0.3 and 1.2 ± 0.4 mg kg fat-free mass (FFM)(-1) min(-1) (Botnia and SHEC, p < 0.05), whereas lipid oxidation decreased by 0.8 ± 0.1 and 0.4 ± 0.1 mg kg FFM(-1) min(-1) (p < 0.05) from baseline. Differences in NEFA (r = -0.60, p < 0.01), but not C-peptide (r = -0.16, p = 0.52) or hepatic insulin sensitivity between IVGTT and placebo before the clamps correlated with individual variations of insulin sensitivity. CONCLUSIONS/INTERPRETATION: The Botnia clamp provides similar estimates of insulin sensitivity as SHEC in patients with type 2 diabetes, but changes in NEFA during IVGTT may affect insulin sensitivity and thereby the discrimination between insulin-sensitive and insulin-resistant individuals. TRIAL REGISTRATION: ClinicalTrials.gov NCT01397279 FUNDING: The study was funded by the Ministry of Science and Research of the State of North Rhine-Westphalia and the German Federal Ministry of Health, and supported in part by grants from the Federal Ministry for Research to the Centers for Diabetes Research, Helmholtz Alliance Imaging and Curing Environmental Metabolic Diseases and the Schmutzler-Stiftung.

Quantitative liver 31P magnetic resonance spectroscopy at 3T on a clinical scanner.

PURPOSE: The aims of this study were (i) to establish a robust and fast method to quantify hepatocellular phosphorus compounds in molar concentration on a 3T clinical scanner, (ii) to evaluate its reproducibility, and (iii) to test its feasibility for a use in large cohort studies. METHOD: Proton-decoupled (31) P magnetic resonance spectroscopy of liver (31) P compounds were acquired on 85 healthy subjects employing image selected in-vivo spectroscopy localization in 13 min of acquisition at 3T. Absolute quantification was achieved using an external reference and double-matching phantoms (inorganic phosphates and adenosine triphosphate (ATP) solutions). Reproducibility of the method was also examined. RESULTS: This method showed a high intra- and interday as well as inter- and intraobserver reproducibility (r > 0.98; P < 0.001), with a high signal to noise ratio (SNR) (i.e., mean SNR of γ-ATP: 16). The mean liver concentrations of 85 healthy subjects were assessed to be 1.99 ± 0.51 and 2.74 ± 0.55 mmol/l of wet tissue volume for Pi and γ-ATP, respectively. CONCLUSION: This method reliably quantified molar concentrations of liver (31) P compounds on 85 subjects with a short total examination time (∼25 min) on a 3T clinical scanner. Thus, the current method can be readily utilized for a clinical study, such as a large cohort study.

Initial clinical application of modified Dixon with flexible echo times: hepatic and pancreatic fat assessments in comparison with (1)H MRS.

OBJECTS: Hepatic and pancreatic fat content become increasingly important for phenotyping of individuals with metabolic diseases. This study aimed to (1) evaluate hepatic fat fractions (HFF) and pancreatic fat fractions (PFF) using (1)H magnetic resonance spectroscopy (MRS) and the recently introduced fast mDixon method, and to examine body fat effects on HFF and PFF, (2) investigate regional differences in HFF and PFF by mDixon. MATERIALS AND METHODS: HFF and PFF were quantified by mDixon with two flexible echo times and by single voxel (1)H MRS in 24 healthy subjects. The regional differences of PFF within the pancreas were assessed with mDixon. Abdominal visceral and subcutaneous fat was assessed by T1-weighted MRI at 3T. RESULTS: Both methods correlated well for quantification of HFF (r = 0.98, p < 0.0001) and PFF (r = 0.80, p < 0.0001). However, mDixon showed a higher low limit in HFF and PFF. PFF showed no regional differences using mDixon. In addition, both visceral and subcutaneous fat correlated with pancreatic fat, while only visceral fat correlated with liver fat, employing both (1)H MRS and mDixon. CONCLUSION: The novel and fast two-point mDixon exhibits a good correlation with the gold-standard (1)H MRS for assessment of HFF and PFF, with limited sensitivity for assessing lower fat content.

Evaluation of the Influence of Sildenafil on the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Vericiguat in Healthy Adults.

BACKGROUND AND OBJECTIVE: Vericiguat is approved for the treatment of patients with heart failure with ejection fraction < 45%. Sildenafil, indicated for the treatment of erectile dysfunction, is a potential co-medication in male patients. This study investigated the safety and tolerability of co-administration of vericiguat and sildenafil in healthy volunteers. METHODS: This was a single-center, randomized, placebo-controlled, parallel-group study in 32 healthy white male volunteers. Participants received vericiguat 10 mg or placebo once daily for 16 days. Both groups received single doses of sildenafil (25 mg, 50 mg, and 100 mg) on days 13-15. Safety, hemodynamic changes, and pharmacokinetic effects were assessed. RESULTS: All subjects in the vericiguat group and seven (43.8%) in the placebo group reported one or more treatment-emergent adverse events, all of mild or moderate intensity. Decreases in seated blood pressure (≤ 5.4 mmHg) with the vericiguat-sildenafil combination compared with placebo-sildenafil were small and there was no evidence of a sildenafil dose-related effect. Standing blood pressure and standing and seated heart rate were similar between treatment groups. Co-administration of sildenafil did not affect vericiguat pharmacokinetics. A mild increase in sildenafil exposure (≤ 22%) when co-administered with vericiguat was observed. CONCLUSIONS: Adding single doses of sildenafil to vericiguat 10 mg once daily at steady state was well tolerated and produced a minimal reduction in seated blood pressure (≤ 5.4 mmHg) compared with administration of sildenafil alone. There was no effect of sildenafil on vericiguat pharmacokinetics, and an increase in sildenafil exposure with vericiguat co-administration was not clinically relevant. CLINICAL TRIAL REGISTRATION: EudraCT no. 2015-004997-14.

Vericiguat is approved for the treatment of patients with heart failure with reduced ejection fraction. Sildenafil is a treatment for erectile dysfunction. This study investigated whether sildenafil was safe to use in individuals treated with vericiguat. In total, 32 healthy white male volunteers were randomly allocated to receive either vericiguat 10 mg or placebo once daily for 16 days. Both groups received single doses of sildenafil (25 mg, 50 mg, and 100 mg) on days 13­15. Co-administration of single doses of sildenafil and vericiguat 10 mg was well tolerated. All side effects were of mild or moderate intensity, and the addition of sildenafil to vericiguat had a minimal effect on blood pressure. Giving these drugs together did not alter the way either drug was absorbed, distributed, or eliminated by the body to a clinically relevant extent.

First randomized evaluation of safety, pharmacodynamics, and pharmacokinetics of BAY 1831865, an antibody targeting coagulation factor XI and factor XIa, in healthy men.

BACKGROUND: Bleeding is a clinically significant issue with all current anticoagulants. Safer antithrombotic strategies are required. OBJECTIVES: To investigate the safety, pharmacodynamics, and pharmacokinetics of BAY 1831865, a humanized, factor XI (FXI)-directed monoclonal antibody, after single intravenous (i.v.) or subcutaneous (s.c.) doses in healthy volunteers. PATIENTS/METHODS: In a first-in-human, phase I study, 70 volunteers were randomly assigned (4:1) to receive single-dose BAY 1831865 (3.5, 7, 17, 35, 75, or 150 mg i.v. or 150 mg s.c.) or placebo. Adverse events, pharmacodynamics, and pharmacokinetics were evaluated. RESULTS: In this study, no hemorrhage, or hypersensitivity or infusion-/injection-related reactions were reported. Drug-related adverse events occurred in 3 (5.4%) of 56 volunteers; all were mild and self-limited. Dose-dependent prolongation of activated partial thromboplastin time (aPTT) and inhibition of FXI clotting activity was observed with BAY 1831865 i.v. (geometric mean maximum ratio-to-baseline: aPTT, range, 1.09-3.11 vs. 1.05 with placebo; FXI, range, 0.70-0.04 vs. 0.91 with placebo). Onset of effect was rapid after i.v. administration, with duration of effect (up to 55 days) determined by dose. BAY 1831865 s.c. had similar pharmacodynamic effects but a slower onset of action. Terminal half-life increased continuously with increasing i.v. dose (range, 28-208 h), leading to strong and continuous increases in systemic exposure to BAY 1831865. Absolute bioavailability of BAY 1831865 s.c. was 47.2% (95% confidence interval, 30.2-73.7). CONCLUSIONS: BAY 1831865 i.v. or s.c. was well tolerated, with no evidence of bleeding in healthy volunteers. BAY 1831865 exhibited pronounced, sustained dose-dependent prolongation of aPTT and duration of FXI inhibition.

An Integrated Psychosomatic Treatment Program for People with Diabetes (psy-PAD).

BACKGROUND: Many people with diabetes have permanently elevated blood sugar concentrations and a high level of diabetes-related psychological stress, also called "diabetes distress." In clinical practice, diabetes distress is often an impediment to successful self-management. psy-PAD is a psychodynamically oriented short-term therapy program whose goal is to reduce diabetes distress and improve glycemic control. METHODS: A randomized controlled trial was conducted with 143 patients with either type 1 or type 2 diabetes who were being treated in eleven specialized diabetological practices. psy-PAD in the intervention group (eight sessions) was compared with optimized standard care as the control condition. The inclusion criteria were HbA1c ≥ 7.5% combined with diabetes distress (PAID >35, or doctor's determination). The primary endpoint was the HbA1c at six months (t1). Diabetes-related distress (PAID), depressive symptoms (HADS-D, PHQ-9), anxiety symptoms (HADS-A), health-related quality of life (SF-36), panic (short form of the PHQ-D), body mass index (BMI), and triglyceride levels were secondary endpoints. Follow-ups were conducted at six (t1) and 12 months (t2) (trial registration: DRKS00003247). RESULTS: The intergroup comparison at t1 revealed a significant, clinically relevant reduction of HbA1c by -0.53 percentage points (95% confidence interval [-0.89; -0.16], p = 0.005). The secondary analyses revealed relevant differences in the point estimators for diabetes distress at t1 and t2, depressive symptoms at t2 and BMI at t1. CONCLUSION: For people with diabetes and diabetes distress who do not achieve satisfactory glycemic control despite intensive treatment in specialized diabetological practices, integrated psychosomatic-psychotherapeutic treatment can lower blood sugar levels over the intermediate term and also reduce diabetes distress and depressive symptoms over a one-year period.

Hepatic energy metabolism in a family with a glucokinase gene mutation and dysglycemia.

Carriers heterozygous for the D124N (c.370, GAC > AAC in exon 4) variant of GCK not only exhibit reduced insulin-secretion, but also impaired adipose insulin sensitivity, which may shift fatty acids towards the liver. This could contribute to increased hepatic lipid-accumulation and alterations of liver energy metabolism resulting in dysglycemia. ClinicalTrial.gov registration no: NCT01055093.

Blood glucose testing and primary prevention of diabetes mellitus type 2--evaluation of the effect of evidence based patient information.

BACKGROUND: Evidence-based patient information (EBPI) has been recognised as important tool for informed choice in particular in the matter of preventive options. An objective, on the best scientific evidence-based consumer information about subthreshold elevated blood glucose levels (impaired fasting glucose and impaired glucose tolerance) and primary prevention of diabetes, is not available yet. Thus we developed a web-based EBPI and aim to evaluate its effects on informed decision making in people 50 years or older. METHODS/DESIGN: We conduct a web-based randomised-controlled trial to evaluate the effect of information about elevated blood glucose levels and diabetes primary prevention on five specific outcomes: (i) knowledge of elevated blood glucose level-related issues (primary outcome); (ii) attitudes to a metabolic testing; (iii) intention to undergo a metabolic testing; (iv) decision conflict; (v) satisfaction with the information. The intervention group receives a specially developed EBPI about subthreshold elevated blood glucose levels and diabetes primary prevention, the control group information about this topic, available in the internet.The study population consists of people between 50 and 69 years of age without known diabetes. Participants will be recruited via the internet page of the cooperating health insurance company, Techniker Krankenkasse (TK), and the internet page of the German Diabetes Centre. Outcomes will be measured through online questionnaires. We expect better informed participants in the intervention group. DISCUSSION: The design of this study may be a prototype for other web-based prevention information and their evaluation. TRIAL REGISTRATION: Current Controlled Trial: ISRCTN22060616.

The Effects of Weak and Strong CYP3A Induction by Rifampicin on the Pharmacokinetics of Five Progestins and Ethinylestradiol Compared to Midazolam.

It is known that co-administration of CYP3A inducers may decrease the effectiveness of oral contraceptives containing progestins as mono-preparations or combined with ethinylestradiol. In a randomized clinical drug-drug interaction study, we investigated the effects of CYP3A induction on the pharmacokinetics of commonly used progestins and ethinylestradiol. Rifampicin was used to induce CYP3A. The progestins chosen as victim drugs were levonorgestrel, norethindrone, desogestrel, and dienogest as mono-products, and drospirenone combined with ethinylestradiol. Postmenopausal women (n = 12-14 per treatment group) received, in fixed sequence, a single dose of the victim drug plus midazolam without rifampicin, with rifampicin 10 mg/day (weak induction), and with rifampicin 600 mg/day (strong induction). The effects on progestin exposure were compared with the effects on midazolam exposure (as a benchmark). Unbound concentrations were evaluated for drugs binding to sex hormone binding globulin. Weak CYP3A induction, as confirmed by a mean decrease in midazolam exposure by 46%, resulted in minor changes in progestin exposure (mean decreases: 15-37%). Strong CYP3A induction, in contrast, resulted in mean decreases by 57-90% (mean decrease in midazolam exposure: 86%). Namely, the magnitude of the observed induction effects varied from weak to strong. Our data might provide an impetus to revisit the currently applied clinical recommendations for oral contraceptives, especially for levonorgestrel and norethindrone-containing products, and they might give an indication as to which progestin could be used, if requested, by women taking weak CYP3A inducers-although it is acknowledged that the exact exposure-response relationship for contraceptive efficacy is currently unclear for most progestins.

German Diabetes Study - Baseline data of retinal layer thickness measured by SD-OCT in early diabetes mellitus.

PURPOSE: Recent studies highlighted that early diabetic neurodegeneration is present before microvascular changes are visible. Retinal neurodegeneration can decrease retinal layer thickness. We aimed to determine whether decreased retinal layer thickness is present already in the early time course of disease. METHODS: A cross-sectional analysis of patients and healthy adults from the German Diabetes Study (GDS, ClinicalTrials.gov Identifier number: CT01055093, https://clinicaltrials.gov/ct2/show/NCT01055093). Inclusion criteria were a diagnosis of diabetes mellitus (DM) within the last 12 months. Retinal layers thickness in the nasal pericentral segment was measured by spectral domain ocular coherence tomography (SD-OCT). For statistical analysis proc mixed (sas-version 9.4) was used. RESULTS: One hundred and seventy-eight eyes of 89 patients with type 1 DM (58 males, age 36 ± 11 years, BMI 25.5 ± 4.2 kg/m²) and 242 eyes of 121 patients with type 2 DM (84 males, age 53 ± 10 years, BMI 31.9 ± 6.3 kg/m²) with a disease duration of less than 1 year were compared to 76 eyes of 38 controls (27 males, age 41 ± 16 years, BMI 27.3 ± 6.4 kg/m²). Analysis of retinal layer thickness and visual function did not reveal a significant difference between patients and controls. CONCLUSION: In the early course of DM potential, neurodegeneration does not relate to measureable changes of retinal layer thickness.

Correlates of Insulin-Stimulated Glucose Disposal in Recent-Onset Type 1 and Type 2 Diabetes.

CONTEXT AND OBJECTIVE: Not only type 2 diabetes (T2D), but also type 1 diabetes (T1D), can be associated with insulin resistance, as assessed using insulin-stimulated whole-body glucose disposal (M-value). We hypothesized that different factors would affect the M-value at the onset of T1D and T2D. DESIGN AND PATIENTS: We examined 132 patients with T1D or T2D matched for sex, age, and body mass index with a known diabetes duration of <12 months. Multivariable linear regression analyses were applied to test the associations between glycemic control, blood lipid levels, adiponectin, and proinflammatory immune mediators and the M-value, obtained from the hyperinsulinemic-euglycemic clamp. RESULTS: Despite comparable age, body mass index, and near-normoglycemic control, the mean M-value was lower in those with T2D than in those with T1D. Patients with T1D had a lower waist/hip ratio and serum triglycerides but higher serum adiponectin than patients with T2D. However, the circulating proinflammatory markers were not different. Even with adjustments for glucose-lowering treatments, the fasting blood glucose correlated negatively with the M-value in both groups. However, gamma-glutamyl transferase-independently of any treatments-correlated negatively only in T2D. In contrast, serum adiponectin correlated positively with the M-values. CONCLUSIONS: Fasting glycemia correlated with insulin-stimulated glucose disposal in both diabetes types. However, altered liver and adipose tissue function were associated with insulin-stimulated glucose disposal only in T2D, underpinning the specific differences between these diabetes types.

Circulating triacylglycerols but not pancreatic fat associate with insulin secretion in healthy humans.

BACKGROUND: Loss of adequate insulin secretion for the prevailing insulin resistance is critical for the development of type 2 diabetes and has been suggested to result from circulating lipids (triacylglycerols [TG] or free fatty acids) and/or adipocytokines or from ectopic lipid storage in the pancreas. This study aimed to address whether circulating lipids, adipocytokines or pancreatic fat primarily associates with lower insulin secretion. SUBJECTS/METHODS: Nondiabetic persons (n=73), recruited from the general population, underwent clinical examinations, fasting blood drawing to measure TG and adipocytokines and oral glucose tolerance testing (OGTT) to assess basal and dynamic insulin secretion and sensitivity indices. Magnetic resonance imaging and 1H-magnetic resonance spectroscopy were used to measure body fat distribution and ectopic fat content in liver and pancreas. RESULTS: In age-, sex- and BMI-adjusted analyses, total and high-molecular-weight adiponectin were the strongest negative predictors of fasting beta-cell function (BCF; ß=-0.403, p=0.0003 and ß=-0.237, p=0.01, respectively) and adaptation index (AI; ß=-0.210, p=0.006 and ß=-0.133, p=0.02, respectively). Circulating TG, but not pancreatic fat content, related positively to BCF (ß=0.375, p<0.0001) and AI (ß=0.192, p=0.003). Similar results were obtained for the disposition index (DI). CONCLUSIONS: The association of serum lipids and adiponectin with beta-cell function may represent a compensatory response to adapt for lower insulin sensitivity in nondiabetic humans.

Amino Acid and Fatty Acid Levels Affect Hepatic Phosphorus Metabolite Content in Metabolically Healthy Humans.

Objective: Hepatic energy metabolism negatively relates to insulin resistance and liver fat content in patients with type 2 diabetes, but its role in metabolically healthy humans is unclear. We hypothesized that intrahepatocellular γ-adenosine triphosphate (γATP) and inorganic phosphate (Pi) concentrations exhibit similar associations with insulin sensitivity in nondiabetic, nonobese volunteers. Design: A total of 76 participants underwent a four-point sampling, 75-g oral glucose tolerance test (OGTT), as well as in vivo31P/1H magnetic resonance spectroscopy. In 62 of them, targeted plasma metabolomic profiling was performed. Pearson correlation analyses were performed for the dependent variables γATP and Pi. Results: Adjusted for age, sex, and body mass index (BMI), hepatic γATP and Pi related to 2-hour OGTT glucose (r = 0.25 and r = 0.27, both P < 0.05), and Pi further associated with nonesterified fatty acids (NEFAs; r = 0.28, P < 0.05). However, neither γATP nor Pi correlated with several measures of insulin sensitivity. Hepatic γATP correlated with circulating leucine (r = 0.42, P < 0.001) and Pi with C16:1 fatty acids palmitoleic acid and C16:1w5 (r = 0.28 and 0.30, respectively, P < 0.01), as well as with δ-9-desaturase index (r = 0.33, P < 0.05). Only the association of γATP with leucine remained important after correction for multiple testing. Leucine and palmitoleic acid, together with age, sex, and BMI, accounted for 26% and for 15% of the variabilities in γATP and Pi, respectively. Conclusions: Specific circulating amino acids and NEFAs, but not measures of insulin sensitivity, partly affect hepatic phosphorus metabolites, suggesting mutual interaction between hepatic energy metabolism and circulating metabolites in nondiabetic humans.

Characterization of circulating leukocytes and correlation of leukocyte subsets with metabolic parameters 1 and 5 years after diabetes diagnosis.

AIMS: Infiltration of pancreatic islets with different leukocyte subtypes likely contributes to deterioration of glycemia in diabetes mellitus. Different subsets of leukocytes have been previously associated with type 1 or type 2 diabetes. This study aimed at examining these subsets at different stages of diabetes progression and possible relationships with metabolic parameters. METHODS: A total of 206 patients, 76 with type 1 and 130 with type 2 diabetes, were studied within the first year of diabetes diagnosis. In addition, 31 patients with type 1 and 73 with type 2 diabetes were examined at 5 years after diagnosis. Whole body insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamps; insulin secretion by glucagon stimulation tests and white blood cells were analyzed by flow cytometry. RESULTS: The percentage of peripheral CD8+ cells was 15% lower in patients with type 1 diabetes at 5 years than in patients at diabetes onset and correlated positively with fasting glycemia, total cholesterol and high-sensitive C-reactive protein (hsCRP) (all r > 0.37, p < 0.05), but not with insulin secretion. Patients with type 2 diabetes had 7% higher percentages of CD4+ cells after 5 years than those at diagnosis. CD4+ cells correlated with hsCRP (r = 0.36, p < 0.05), whereas CD8+ cytotoxic T-cells did not correlate with any metabolic parameter. CONCLUSION: CD8+ T-cells associate with worse glycemia, lipidemia and inflammation after 5 years of type 1 diabetes, whereas CD4+ T-cells associate with increased inflammation after 5 years upon onset of type 2 diabetes.