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.

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.

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.

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.

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.

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.

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.

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.

An 8-week diet high in cereal fiber and coffee but free of red meat does not improve beta-cell function in patients with type 2 diabetes mellitus: a randomized controlled trial.

BACKGROUND: Higher dietary intake of fibers and coffee, but lower red meat intake is associated with reduced risk for type 2 diabetes in epidemiological studies. We hypothesized that a calorie-restricted diet, which is high in fiber and coffee, but free of red meat, improves beta-cell function in patients with T2D. METHODS: In a randomized parallel-group pilot trial, obese type 2 diabetes patients were randomly allocated to consume either a diet high in cereal fiber and coffee, but free of red meat (n = 17) (L-RISK) or a diet low in fiber, free of coffee but high in red meat (n = 20) (H-RISK) for 8 weeks. Insulin secretion was assessed from glucagon stimulation tests (GST) and mixed-meal tolerance tests (MMTT) before and after dietary intervention. RESULTS: Both diets resulted in comparable reduction of fasting concentrations of insulin (H-RISK -28% vs. L-RISK -32%, both p < 0.01), C-peptide (H-RISK -26% vs. L-RISK -30%, both p < 0.01) and blood glucose (H-RISK -6.8%, p < 0.05 vs. L-RISK -10%, p < 0.01). Gastric inhibitory peptide (GIP) secretion increased by 24% after 8 weeks in the L-RISK only (p < 0.01). However, GST and MMTT showed no differences in insulin secretion after intervention. CONCLUSIONS: Calorie restriction independent of the intake of fiber, coffee or meat failed to improve beta-cell function, but improved GIP secretion in obese patients with type 2 diabetes. TRIAL REGISTRATION: Registration at Clinicaltrials.gov, Identifier number: NCT01409330, Registered 4 August 2011 - Retrospectively registered.

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.

Acute dietary fat intake initiates alterations in energy metabolism and insulin resistance.

BACKGROUND: Dietary intake of saturated fat is a likely contributor to nonalcoholic fatty liver disease (NAFLD) and insulin resistance, but the mechanisms that initiate these abnormalities in humans remain unclear. We examined the effects of a single oral saturated fat load on insulin sensitivity, hepatic glucose metabolism, and lipid metabolism in humans. Similarly, initiating mechanisms were examined after an equivalent challenge in mice. METHODS: Fourteen lean, healthy individuals randomly received either palm oil (PO) or vehicle (VCL). Hepatic metabolism was analyzed using in vivo 13C/31P/1H and ex vivo 2H magnetic resonance spectroscopy before and during hyperinsulinemic-euglycemic clamps with isotope dilution. Mice underwent identical clamp procedures and hepatic transcriptome analyses. RESULTS: PO administration decreased whole-body, hepatic, and adipose tissue insulin sensitivity by 25%, 15%, and 34%, respectively. Hepatic triglyceride and ATP content rose by 35% and 16%, respectively. Hepatic gluconeogenesis increased by 70%, and net glycogenolysis declined by 20%. Mouse transcriptomics revealed that PO differentially regulates predicted upstream regulators and pathways, including LPS, members of the TLR and PPAR families, NF-κB, and TNF-related weak inducer of apoptosis (TWEAK). CONCLUSION: Saturated fat ingestion rapidly increases hepatic lipid storage, energy metabolism, and insulin resistance. This is accompanied by regulation of hepatic gene expression and signaling that may contribute to development of NAFLD.REGISTRATION. ClinicalTrials.gov NCT01736202. FUNDING: Germany: Ministry of Innovation, Science, and Research North Rhine-Westfalia, German Federal Ministry of Health, Federal Ministry of Education and Research, German Center for Diabetes Research, German Research Foundation, and German Diabetes Association. Portugal: Portuguese Foundation for Science and Technology, FEDER - European Regional Development Fund, Portuguese Foundation for Science and Technology, and Rede Nacional de Ressonância Magnética Nuclear.

Inflammatory markers are associated with cardiac autonomic dysfunction in recent-onset type 2 diabetes.

OBJECTIVE: Cardiovascular autonomic neuropathy is a common but underestimated diabetes-related disorder. Associations between cardiovascular autonomic dysfunction and subclinical inflammation, both risk factors of diabetic comorbidities and mortality, have been proposed in non-diabetic populations, while data for type 1 and type 2 diabetes are conflicting. Our aim was to investigate associations between inflammation-related biomarkers and cardiac autonomic dysfunction in patients with diabetes. METHODS: We characterised the associations between seven biomarkers of subclinical inflammation and cardiac autonomic dysfunction based on heart rate variability and cardiovascular autonomic reflex tests (CARTs) in 161 individuals with type 1 and 352 individuals with type 2 diabetes (time since diagnosis of diabetes <1 year). Analyses were adjusted for age, sex, anthropometric, metabolic and lifestyle factors, medication and cardiovascular comorbidities. RESULTS: In individuals with type 2 diabetes, higher serum interleukin (IL)-18 was associated with lower vagal activity (p≤0.015 for association with CARTs), whereas higher levels of total and high-molecular-weight adiponectin showed associations with very low frequency power, an indicator of reduced sympathetic activity (p≤0.014). Higher levels of soluble intercellular adhesion molecule-1 were associated with indicators of both lower vagal (p=0.025) and sympathetic (p=0.008) tone, soluble E-selectin with one indicator of lower vagal activity (p=0.047). Serum C-reactive protein and IL-6 were also related to cardiac autonomic dysfunction, but these associations were explained by confounding factors. No consistent associations were found in individuals with type 1 diabetes. CONCLUSIONS: Biomarkers of inflammation were differentially associated with diminished cardiac autonomic dysfunction in recent-onset type 2 diabetes.

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.

Specific Metabolic Profiles and Their Relationship to Insulin Resistance in Recent-Onset Type 1 and Type 2 Diabetes.

CONTEXT: Insulin resistance reflects the inadequate insulin-mediated use of metabolites and predicts type 2 diabetes (T2D) but is also frequently seen in long-standing type 1 diabetes (T1D) and represents a major cardiovascular risk factor. OBJECTIVE: We hypothesized that plasma metabolome profiles allow the identification of unique and common early biomarkers of insulin resistance in both diabetes types. DESIGN, SETTING, AND PATIENTS: Two hundred ninety-five plasma metabolites were analyzed by mass spectrometry from patients of the prospective observational German Diabetes Study with T2D (n = 244) or T1D (n = 127) and known diabetes duration of less than 1 year and glucose-tolerant persons (CON; n = 129). Abundance of metabolites was tested for association with insulin sensitivity as assessed by hyperinsulinemic-euglycemic clamps and related metabolic phenotypes. MAIN OUTCOMES MEASURES: Sixty-two metabolites with phenotype-specific patterns were identified using age, sex, and body mass index as covariates. RESULTS: Compared with CON, the metabolome of T2D and T1D showed similar alterations in various phosphatidylcholine species and amino acids. Only T2D exhibited differences in free fatty acids compared with CON. Pairwise comparison of metabolites revealed alterations of 28 and 49 metabolites in T1D and T2D, respectively, when compared with CON. Eleven metabolites allowed differentiation between both diabetes types and alanine, α-amino-adipic acid, isoleucin, and stearic acid showed an inverse association with insulin sensitivity in both T2D and T1D combined. CONCLUSION: Metabolome analyses from recent-onset T2D and T1D patients enables identification of defined diabetes type-specific differences and detection of biomarkers of insulin sensitivity. These analyses may help to identify novel clinical subphenotypes diabetes.

Adiponectin, markers of subclinical inflammation and nerve conduction in individuals with recently diagnosed type 1 and type 2 diabetes.

OBJECTIVE: Subclinical inflammation has been implicated in the development of diabetic sensorimotor polyneuropathy (DSPN), but studies using electrophysiological assessment as outcomes are scarce. Therefore, we aimed to investigate associations of biomarkers reflecting different aspects of subclinical inflammation with motor and sensory nerve conduction velocity (NCV) in individuals with diabetes. DESIGN AND METHODS: Motor and sensory NCV was assessed in individuals with recently diagnosed type 2 (n=352) or type 1 diabetes (n=161) from the baseline cohort of the observational German Diabetes Study. NCV sum scores were calculated for median, ulnar and peroneal motor as well as median, ulnar and sural sensory nerves. Associations between inflammation-related biomarkers, DSPN and NCV sum scores were estimated using multiple regression models. RESULTS: In type 2 diabetes, high serum interleukin (IL)-6 was associated with the presence of DSPN and reduced motor NCV. Moreover, higher levels of high-molecular weight (HMW) adiponectin, total adiponectin and their ratio were associated with prevalent DSPN and both diminished motor and sensory NCV, whereas no consistent associations were observed for C-reactive protein, IL18, soluble intercellular adhesion molecule-1 and E-selectin. In type 1 diabetes, only HMW and total adiponectin showed positive associations with motor NCV. CONCLUSIONS: Our results point to a link between IL6 and both DSPN and slowed motor NCV in recently diagnosed type 2 diabetes. The reverse associations between adiponectin and NCV in type 1 and type 2 diabetes are intriguing, and further studies should explore whether they may reflect differences in the pathogenesis of DSPN in both diabetes types.

The Role of Markers of Low-Grade Inflammation for the Early Time Course of Glycemic Control, Glucose Disappearance Rate, and ß-Cell Function in Recently Diagnosed Type 1 and Type 2 Diabetes.

OBJECTIVE: Inflammatory processes are involved in the progression of insulin resistance and ß-cell dysfunction in individuals with prediabetes and contribute to the development of diabetes. We hypothesized that higher levels of biomarkers of low-grade inflammation are associated with the early progression of recently diagnosed diabetes. RESEARCH DESIGN AND METHODS: Within the prospective German Diabetes Study, patients with recently diagnosed type 1 (n = 42) and type 2 (n = 94) diabetes underwent detailed metabolic characterization within the first year after diagnosis and 2 years thereafter. Associations between changes in markers of low-grade inflammation with changes in glycemic control, ß-cell function, and glucose disappearance rate were assessed using multivariable linear regression analysis. Associations were adjusted for age, sex, BMI, smoking status, and 2-year changes in BMI, smoking status, and glucose-lowering medication. RESULTS: Patients with type 1 and type 2 diabetes exhibited good glucometabolic control at baseline (mean HbA1c 7.08 ± 1.58% [54 ± 17 mmol/mol] and 6.43 ± 0.98% [47 ± 11 mmol/mol], respectively) and 2 years thereafter (mean HbA1c 7.03 ± 1.20% [53 ± 13 mmol/mol] and 6.62 ± 1.14% [49 ± 13], respectively). Two-year increases of high-sensitivity C-reactive protein, soluble E-selectin (sE-selectin), and soluble intercellular adhesion molecule-1 in type 2 diabetes and of IL-18 in type 1 diabetes were associated with 2-year increases of HbA1c. Additionally, 2-year increases of sE-selectin were associated with 2-year decreases of prehepatic ß-cell function in type 2 diabetes (all P < 0.05). CONCLUSIONS: These data indicate that with the clinical onset of diabetes, low-grade inflammation relates to worsening of glycemia and that endothelial activation may contribute to decreasing ß-cell function.

Effect of Low-Energy Diets Differing in Fiber, Red Meat, and Coffee Intake on Cardiac Autonomic Function in Obese Individuals With Type 2 Diabetes.

OBJECTIVE: The autonomic nervous system (ANS) regulates both the cardiovascular system and energy balance and is disturbed in diabetes and obesity. The effect of different approaches of caloric restriction on ANS function has not been assessed in individuals with diabetes. Thus, we sought to determine whether low-energy diets differing in fiber, red meat, and coffee intake exert differential effects on cardiac autonomic function. RESEARCH DESIGN AND METHODS: In this randomized parallel-group pilot trial, obese patients with type 2 diabetes were randomly allocated to consume either a diet high in cereal fiber, free of red meat, and high in coffee (n = 13) or a diet low in fiber, high in red meat, and coffee free (n = 15) over 8 weeks. Eight measures of heart rate variability (HRV) indicating vagal and/or sympathetic modulation over 3 h and inflammatory markers were determined during a hyperinsulinemic-euglycemic clamp. RESULTS: After 8 weeks, both dietary interventions resulted in a mean weight loss of 5-6 kg, a mean decline in heart rate of 4-6 bpm, and improvement in vagally mediated HRV. However, the changes in HRV parameters from baseline to 8 weeks did not differ between the groups. In the entire study cohort, incremental HRV from baseline to 8 weeks was associated with enhanced oxidative glucose utilization (P < 0.05), but not with insulin sensitivity and inflammatory markers. CONCLUSIONS: In obese patients with type 2 diabetes, energy restriction per se over 8 weeks contributed to improved cardiac vagal function in relation to improved oxidative glucose utilization. This preliminary finding should be verified in a confirmatory trial.