Association of dietary patterns with diabetes-related comorbidities varies among diabetes endotypes.

BACKGROUND AND AIMS: Differences of dietary pattern adherence across the novel diabetes endotypes are unknown. This study assessed adherence to pre-specified dietary patterns and their associations with cardiovascular risk factors, kidney function, and neuropathy among diabetes endotypes. METHODS AND RESULTS: The cross-sectional analysis included 765 individuals with recent-onset (67 %) and prevalent diabetes (33 %) from the German Diabetes Study (GDS) allocated into severe autoimmune diabetes (SAID, 35 %), severe insulin-deficient diabetes (SIDD, 3 %), severe insulin-resistant diabetes (SIRD, 5 %), mild obesity-related diabetes (MOD, 28 %), and mild age-related diabetes (MARD, 29 %). Adherence to a Mediterranean diet score (MDS), Dietary Approaches to Stop Hypertension (DASH) score, overall plant-based diet (PDI), healthful (hPDI) and unhealthful plant-based diet index (uPDI) was derived from a food frequency questionnaire and associated with cardiovascular risk factors, kidney function, and neuropathy using multivariable linear regression analysis. Differences in dietary pattern adherence between endotypes were assessed using generalized mixed models. People with MARD showed the highest, those with SIDD and MOD the lowest adherence to the hPDI. Adherence to the MDS, DASH, overall PDI, and hPDI was inversely associated with high-sensitivity C-reactive protein (hsCRP) among people with MARD (ß (95%CI): -9.18 % (-15.61; -2.26); -13.61 % (-24.17; -1.58); -19.15 % (-34.28; -0.53); -16.10 % (-28.81; -1.12), respectively). Adherence to the PDIs was associated with LDL cholesterol among people with SAID, SIRD, and MOD. CONCLUSIONS: Minor differences in dietary pattern adherence (in particular for hPDI) and associations with markers of diabetes-related complications (e.g. hsCRP) were observed between endotypes. So far, evidence is insufficient to derive endotype-specific dietary recommendations. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01055093.

Association of thyroid function with non-alcoholic fatty liver disease in recent-onset diabetes.

BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) has been linked to type 2 diabetes (T2D), but also to hypothyroidism. Nevertheless, the relationship between thyroid function and NAFLD in diabetes is less clear. This study investigated associations between free thyroxine (fT4) or thyroid-stimulating hormone (TSH) and NAFLD in recent-onset diabetes. METHODS: Participants with recent-onset type 1 diabetes (T1D, n = 358), T2D (n = 596) or without diabetes (CON, n = 175) of the German Diabetes Study (GDS), a prospective longitudinal cohort study, underwent Botnia clamp tests and assessment of fT4, TSH, fatty liver index (FLI) and in a representative subcohort 1 H-magnetic resonance spectroscopy. RESULTS: First, fT4 levels were similar between T1D and T2D (p = .55), but higher than in CON (T1D: p < .01; T2D: p < .001), while TSH concentrations were not different between all groups. Next, fT4 correlated negatively with FLI and positively with insulin sensitivity only in T2D (ß = -.110, p < .01; ß = .126, p < .05), specifically in males (ß = -.117, p < .05; ß = .162; p < .01) upon adjustments for age, sex and BMI. However, correlations between fT4 and FLI lost statistical significance after adjustment for insulin sensitivity (T2D: ß = -.021, p = 0.67; males with T2D: ß = -.033; p = .56). TSH was associated positively with FLI only in male T2D before (ß = .116, p < .05), but not after adjustments for age and BMI (ß = .052; p = .30). CONCLUSIONS: Steatosis risk correlates with lower thyroid function in T2D, which is mediated by insulin resistance and body mass, specifically in men, whereas no such relationship is present in T1D.

Homeostasis Model Assessment of ß-Cell Function for Diagnosis of Insulinoma.

CONTEXT: Diagnosis of insulinoma is based on different criteria from the 72-hour fasting test according to current guidelines (Endocrine Society [ES], European [ENETS], and North American [NANETS] Neuroendocrine Tumor Societies), including assessment of ß-cell function by glucagon stimulation test. OBJECTIVE: This study tested whether the homeostasis model assessment of insulin secretion, including assessment of ß-cell function, (HOMA-B) at the end of the fasting test provides comparable efficacy for insulinoma diagnosis. METHODS: In 104 patients with suspected insulinoma, 72-hour fasting tests were performed with frequent assessment of glucose, insulin, and C-peptide in venous blood. HOMA-B values using insulin and C-peptide were calculated at the end of the fasting test, as defined by the lowest glucose concentration from each participant. RESULTS: HOMA-B was more than 6.5-fold higher in patients with (n = 23) than in those without (n = 81) insulinoma (insulin and C-peptide; both P < .001). HOMA-B (cutoff using insulin >253 a.u. and C-peptide >270 a.u.) had a sensitivity of 0.96, 0.78 to 1.00, and a specificity of 0.96 or greater (≥0.89-0.99) for insulinoma diagnosis. ES and ENETS/NANETS criteria reached a diagnostic sensitivity of less than or equal to 0.96 (≤0.78-1.00) and ≤0.83 (≤0.61-0.95) as well as specificity of ≤0.85 (≤0.76-0.92) and less than or equal to 1.00 (≤0.96-1.00) for insulin, and C-peptide, respectively. Using insulin for HOMA-B, sensitivity tended to be higher compared to ENETS/NANETS criteria (P = .063) and specificity was higher compared to ES criteria using insulin and C-peptide (both P < .005). CONCLUSION: HOMA-B, as calculated at the end of the fasting test employing defined cutoffs for insulin and C-peptide, provides excellent diagnostic efficacy, suggesting that it might represent an alternative and precise tool to diagnose insulinoma.

Precise glucose measurement in sodium fluoride-citrate plasma affects estimates of prevalence in diabetes and prediabetes.

OBJECTIVES: Estimates of glucose concentrations vary among types of blood samples, which impact on the assessment of diabetes prevalence. Guidelines recommend a conversion factor to calculate plasma glucose from measurements of glucose in whole blood. The American Diabetes Association recommends the use of blood drawing tubes containing sodium fluoride (NaF) and citrate, which have not yet been evaluated regarding possible differences in glucose concentration and conversion factors. Thus, we compared glucose measurements in NaF-citrate plasma and venous whole blood and estimated the impact of differences on diabetes and prediabetes prevalence. METHODS: Glucose differences were calculated by Bland-Altman analysis with pairwise comparison of glucose measurements from whole blood and NaF-citrate plasma (n=578) in clinical studies of the German Diabetes Center. Subsequently, we computed the impact of the glucose difference on diabetes and prediabetes prevalence in the population-based National Health and Nutrition Examination Survey (NHANES). RESULTS: Even upon conversion of whole blood to plasma glucose concentrations using the recommended conversion factor, mean glucose concentration difference remained 4.72 % higher in NaF-citrate plasma. Applying the higher glucose estimates, increases the population-based diabetes and prediabetes prevalence by 13.67 and 33.97 % or more than 7.2 and 13 million people in NHANES, respectively. Additional economic burden could be about 20 $ billion per year due to undiagnosed diabetes. CONCLUSIONS: The recommended conversion factor is not valid for NaF-citrate plasma. Systematic bias of glucose measurements due to sampling type leads to clinically relevant higher estimates of diabetes and prediabetes prevalence.

Correlates of Skeletal Muscle Mass and Differences Between Novel Subtypes in Recent-Onset Diabetes.

CONTEXT: Low skeletal muscle mass (SMM) is associated with long-standing diabetes but little is known about SMM in newly diagnosed diabetes. OBJECTIVE: We aimed to identify correlates of SMM in recent-onset diabetes and to compare SMM between novel diabetes subtypes. METHODS: SMM was normalized to body mass index (SMM/BMI) in 842 participants with known diabetes duration of less than 1 year from the German Diabetes Study (GDS). Cross-sectional associations between clinical variables, 79 biomarkers of inflammation, and SMM/BMI were assessed, and differences in SMM/BMI between novel diabetes subtypes were analyzed with different degrees of adjustment for confounders. RESULTS: Male sex and physical activity were positively associated with SMM/BMI, whereas associations of age, BMI, glycated hemoglobin A1c, homeostatic model assessment for ß-cell function, and estimated glomerular filtration rate with SMM/BMI were inverse (all P < .05; model r2 = 0.82). Twenty-three biomarkers of inflammation showed correlations with SMM/BMI after adjustment for sex and multiple testing (all P < .0006), but BMI largely explained these correlations. In a sex-adjusted analysis, individuals with severe autoimmune diabetes had a higher SMM/BMI whereas individuals with severe insulin-resistant diabetes and mild obesity-related diabetes had a lower SMM/BMI than all other subtypes combined. However, differences were attenuated after adjustment for the clustering variables. CONCLUSION: SMM/BMI differs between diabetes subtypes and may contribute to subtype differences in disease progression. Of note, clinical variables rather than biomarkers of inflammation explain most of the variation in SMM/BMI.

Analysis of type 2 diabetes heterogeneity with a tree-like representation: insights from the prospective German Diabetes Study and the LURIC cohort.

BACKGROUND: Heterogeneity in type 2 diabetes can be represented by a tree-like graph structure by use of reversed graph-embedded dimensionality reduction. We aimed to examine whether this approach can be used to stratify key pathophysiological components and diabetes-related complications during longitudinal follow-up of individuals with recent-onset type 2 diabetes. METHODS: For this cohort analysis, 927 participants aged 18-69 years from the German Diabetes Study (GDS) with recent-onset type 2 diabetes were mapped onto a previously developed two-dimensional tree based on nine simple clinical and laboratory variables, residualised for age and sex. Insulin sensitivity was assessed by a hyperinsulinaemic-euglycaemic clamp, insulin secretion was assessed by intravenous glucose tolerance test, hepatic lipid content was assessed by 1 H magnetic resonance spectroscopy, serum interleukin (IL)-6 and IL-18 were assessed by ELISA, and peripheral and autonomic neuropathy were assessed by functional and clinical measures. Participants were followed up for up to 16 years. We also investigated heart failure and all-cause mortality in 794 individuals with type 2 diabetes undergoing invasive coronary diagnostics from the Ludwigshafen Risk and Cardiovascular Health (LURIC) cohort. FINDINGS: There were gradients of clamp-measured insulin sensitivity (both dimensions: p<0·0001) and insulin secretion (pdim1<0·0001, pdim2=0·00097) across the tree. Individuals in the region with the lowest insulin sensitivity had the highest hepatic lipid content (n=205, pdim1<0·0001, pdim2=0·037), pro-inflammatory biomarkers (IL-6: n=348, pdim1<0·0001, pdim2=0·013; IL-18: n=350, pdim1<0·0001, pdim2=0·38), and elevated cardiovascular risk (nevents=143, pdim1=0·14, pdim2<0·00081), whereas individuals positioned in the branch with the lowest insulin secretion were more prone to require insulin therapy (nevents=85, pdim1=0·032, pdim2=0·12) and had the highest risk of diabetic sensorimotor polyneuropathy (nevents=184, pdim1=0·012, pdim2=0·044) and cardiac autonomic neuropathy (nevents=118, pdim1=0·0094, pdim2=0·06). In the LURIC cohort, all-cause mortality was highest in the tree branch showing insulin resistance (nevents=488, pdim1=0·12, pdim2=0·0032). Significant gradients differentiated individuals having heart failure with preserved ejection fraction from those who had heart failure with reduced ejection fraction. INTERPRETATION: These data define the pathophysiological underpinnings of the tree structure, which has the potential to stratify diabetes-related complications on the basis of routinely available variables and thereby expand the toolbox of precision diabetes diagnosis. FUNDING: German Diabetes Center, German Federal Ministry of Health, Ministry of Culture and Science of the state of North Rhine-Westphalia, German Federal Ministry of Education and Research, German Diabetes Association, German Center for Diabetes Research, European Community, German Research Foundation, and Schmutzler Stiftung.

Association of a lifestyle score with cardiometabolic markers among individuals with diabetes: a cross-sectional study.

INTRODUCTION: To investigate the associations of a lifestyle score with various cardiovascular risk markers, indicators for fatty liver disease as well as MRI-determined total, subcutaneous and visceral adipose tissue mass in adults with new-onset diabetes. RESEARCH DESIGN AND METHODS: This cross-sectional analysis included 196 individuals with type 1 (median age: 35 years; median body mass index (BMI): 24 kg/m²) and 272 with type 2 diabetes (median age: 53 years; median BMI: 31 kg/m²) from the German Diabetes Study. A healthy lifestyle score was generated based on healthy diet, moderate alcohol consumption, recreational activity, non-smoking and non-obese BMI. These factors were summed to form a score ranging from 0 to 5. Multivariable linear and non-linear regression models were used. RESULTS: In total, 8.1% of the individuals adhered to none or one, 17.7% to two, 29.7% to three, 26.7% to four, and 17.7% to all five favorable lifestyle factors. High compared with low adherence to the lifestyle score was associated with more favorable outcome measures, including triglycerides (ß (95% CI) -49.1 mg/dL (-76.7; -21.4)), low-density lipoprotein (-16.7 mg/dL (-31.3; -2.0)), and high-density lipoprotein cholesterol (13.5 mg/dL (7.6; 19.4)), glycated hemoglobin (-0.5% (-0.8%; -0.1%)), high-sensitivity C reactive protein (-0.4 mg/dL (-0.6; -0.2)), as well as lower hepatic fat content (-8.3% (-11.9%; -4.7%)), and visceral adipose tissue mass (-1.8 dm³ (-2.9; -0.7)). The dose-response analyses showed that adherence to every additional healthy lifestyle factor was associated with more beneficial risk profiles. CONCLUSIONS: Adherence to each additional healthy lifestyle factor was beneficially associated with cardiovascular risk markers, indicators of fatty liver disease and adipose tissue mass. Strongest associations were observed for adherence to all healthy lifestyle factors in combination. TRIAL REGISTRATION NUMBER: NCT01055093.

Effects of TM6SF2 rs58542926 polymorphism on hepatocellular lipids and insulin resistance in early type 2 diabetes.

BACKGROUND AND AIMS: Increased hepatocellular lipid content (HCL) is linked to insulin resistance, risk of type 2 diabetes and related complications. Conversely, a single-nucleotide polymorphism (TM6SF2EK; rs58542926) in the transmembrane 6 superfamily member 2-gene has been associated with nonalcoholic fatty liver disease (NAFLD), but lower cardiovascular risk. This case-control study tested the role of this polymorphism for tissue-specific insulin sensitivity during early course of diabetes. METHODS AND RESULTS: Males with recent-onset type 2 diabetes with (TM6SF2EK: n = 16) or without (TM6SF2EE: n = 16) the heterozygous TM6SF2-polymorphism of similar age and body mass index, underwent Botnia-clamps with [6,6-2H2]glucose to measure whole-body-, hepatic- and adipose tissue-insulin sensitivity. HCL was assessed with 1H-magnetic-resonance-spectroscopy. A subset of both groups (n = 24) was re-evaluated after 5 years. Despite doubled HCL, TM6SF2EK had similar hepatic- and adipose tissue-insulin sensitivity and 27% higher whole-body-insulin sensitivity than TM6SF2EE. After 5 years, whole-body-insulin sensitivity, HCL were similar between groups, while adipose tissue-insulin sensitivity decreased by 87% and 55% within both groups and circulating triacylglycerol increased in TM6SF2EE only. CONCLUSIONS: The TM6SF2-polymorphism rs58542926 dissociates HCL from insulin resistance in recent-onset type 2 diabetes, which is attenuated by disease duration. This suggests that diabetes-related metabolic alterations dominate over effects of the TM6SF2-polymorphism during early course of diabetes and NAFLD.

Intramyocellular Triglyceride Content During the Early Course of Type 1 and Type 2 Diabetes.

Intramyocellular lipid content (IMCL) is elevated in insulin-resistant humans, but it changes over time, and relationships with comorbidities remain unclear. We examined IMCL during the initial course of diabetes and its associations with complications. Participants of the German Diabetes Study (GDS) with recent-onset type 1 (n = 132) or type 2 diabetes (n = 139) and glucose-tolerant control subjects (n = 128) underwent 1H-MRS to measure IMCL and muscle volume, whole-body insulin sensitivity (hyperinsulinemic-euglycemic clamps; M-value), and cycling spiroergometry (VO2max). Subgroups underwent the same measurements after 5 years. At baseline, IMCL was ∼30% higher in type 2 diabetes than in other groups independently of age, sex, BMI, and muscle volume. In type 2 diabetes, the M-value was ∼36% and ∼62% lower compared with type 1 diabetes and control subjects, respectively. After 5 years, the M-value decreased by ∼29% in type 1 and ∼13% in type 2 diabetes, whereas IMCL remained unchanged. The correlation between IMCL and M-value in type 2 diabetes at baseline was modulated by VO2max. IMCL also associated with microalbuminuria, the Framingham risk score for cardiovascular disease, and cardiac autonomic neuropathy. Changes in IMCL within 5 years after diagnosis do not mirror the progression of insulin resistance in type 2 diabetes but associate with early diabetes-related complications. ARTICLE HIGHLIGHTS: Intramyocellular lipid content (IMCL) can be elevated in insulin-resistant humans, but its dynamics and association with comorbidities remain unclear. Independently of age, sex, body mass, and skeletal muscle volume, IMCL is higher in recent-onset type 2, but not type 1 diabetes, and remains unchanged within 5 years, despite worsening insulin resistance. A degree of physical fitness modulates the association between IMCL and insulin sensitivity in type 2 diabetes. Whereas higher IMCL associates with lower insulin sensitivity in people with lower physical fitness, there is no association between IMCL and insulin sensitivity in those with higher degree of physical fitness. IMCL associates with progression of microalbuminuria, cardiovascular disease risk, and cardiac autonomic neuropathy.

Metabolic surgery-induced changes of the growth hormone system relate to improved adipose tissue function.

AIMS: Body weight loss improves insulin resistance and growth hormone secretion in obesity, which may be regulated by leptin according to preclinical studies. How changes in leptin, lipids and insulin sensitivity after bariatric (metabolic) surgery affect the human growth hormone system is yet unclear. PARTICIPANTS AND METHODS: People with obesity (OBE, n = 79, BMI 50.8 ± 6.3 kg/m2) were studied before, 2, 12, 24 and 52 weeks after metabolic surgery and compared to lean healthy humans (control; CON, n = 24, BMI 24.3 ± 3.1 kg/m2). Tissue-specific insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamps with D-[6,6-2H2]glucose. Fasting leptin, growth hormone (GH), insulin-like growth factor 1 (IGF-1) and IGF-binding proteins (IGFBP1, IGFBP3) were measured using ELISA. RESULTS: At baseline, OBE exhibited higher glycemia and leptinemia as well as pronounced peripheral, adipose tissue and hepatic insulin resistance compared to CON. GH and IGFBP1 were lower, while IGF1 was comparable between groups. At 52 weeks, OBE had lost 33% body weight and doubled their peripheral insulin sensitivity, which was paralleled by continuous increases in GH, IGF-1 and IGFBP1 as well as decrease in leptin. The rise in GH correlated with reductions in free fatty acids, adipose tissue insulin resistance and insulinemia, but not with changes in body weight, peripheral insulin sensitivity, glycemia or leptinemia. The rise in IGF-1 correlated with reduction in high-sensitive C-reactive protein. CONCLUSION: Reversal of alterations of the GH-IGF-1 axis after surgically-induced weight loss is unlikely related to improved leptin secretion and/or insulin sensitivity, but is rather associated with restored adipose tissue function and reduced low-grade inflammation.

Serum neurofilament light chain: a novel biomarker for early diabetic sensorimotor polyneuropathy.

AIMS/HYPOTHESIS: No established blood-based biomarker exists to monitor diabetic sensorimotor polyneuropathy (DSPN) and evaluate treatment response. The neurofilament light chain (NFL), a blood biomarker of neuroaxonal damage in several neurodegenerative diseases, represents a potential biomarker for DSPN. We hypothesised that higher serum NFL levels are associated with prevalent DSPN and nerve dysfunction in individuals recently diagnosed with diabetes. METHODS: This cross-sectional study included 423 adults with type 1 and type 2 diabetes and known diabetes duration of less than 1 year from the prospective observational German Diabetes Study cohort. NFL was measured in serum samples of fasting participants in a multiplex approach using proximity extension assay technology. DSPN was assessed by neurological examination, nerve conduction studies and quantitative sensory testing. Associations of serum NFL with DSPN (defined according to the Toronto Consensus criteria) were estimated using Poisson regression, while multivariable linear and quantile regression models were used to assess associations with nerve function measures. In exploratory analyses, other biomarkers in the multiplex panel were also analysed similarly to NFL. RESULTS: DSPN was found in 16% of the study sample. Serum NFL levels increased with age. After adjustment for age, sex, waist circumference, height, HbA1c, known diabetes duration, diabetes type, cholesterol, eGFR, hypertension, CVD, use of lipid-lowering drugs and use of non-steroidal anti-inflammatory drugs, higher serum NFL levels were associated with DSPN (RR [95% CI] per 1-normalised protein expression increase, 1.92 [1.50, 2.45], p<0.0001), slower motor (all p<0.0001) and sensory (all p≤0.03) nerve conduction velocities, lower sural sensory nerve action potential (p=0.0004) and higher thermal detection threshold to warm stimuli (p=0.023 and p=0.004 for hand and foot, respectively). There was no evidence for associations between other neurological biomarkers and DSPN or nerve function measures. CONCLUSIONS/INTERPRETATION: Our findings in individuals recently diagnosed with diabetes provide new evidence associating higher serum NFL levels with DSPN and peripheral nerve dysfunction. The present study advocates NFL as a potential biomarker for DSPN.

Mitochondrial respiration is decreased in visceral but not subcutaneous adipose tissue in obese individuals with fatty liver disease.

BACKGROUND & AIMS: Adipose tissue dysfunction is involved in the development of insulin resistance and is responsible for excessive lipid delivery to other organs such as the liver. We tested the hypothesis that impaired mitochondrial function is a common feature of subcutaneous (SAT) and visceral adipose tissue (VAT), but may differently contribute to adipose tissue insulin resistance (IR) in obesity, non-alcoholic fatty liver (NAFL) and steatohepatitis (NASH). METHODS: In this cross-sectional study, we analyzed tissue-specific insulin sensitivity using stable isotope dilution and hyperinsulinemic-normoglycemic clamp tests. We also assessed mitochondrial respiration, mRNA and protein expression, and tissue morphology in biopsies of SAT and VAT from obese humans without NAFL, with NAFL or with NASH (n = 22/group). RESULTS: Compared to individuals without liver disease, persons with NAFL and NASH had about 30% (p = 0.010) and 33% (p = 0.002) lower maximal mitochondrial respiration, respectively, in VAT, but not in SAT. The lower maximal mitochondrial respiration of VAT was associated with lower adipose tissue insulin sensitivity (ß = 0.985, p = 0.041) and with increased VAT protein expression of tumor necrosis factor A across all groups (ß = -0.085, p = 0.040). VAT from individuals with NASH was characterized by lower expression of oxidative phosphorylation complex IV (p = 0.042) and higher mRNA expression of the macrophage marker CD68 (p = 0.002) than VAT from participants without NAFL. CONCLUSIONS: Humans with non-alcoholic fatty liver disease have distinct abnormalities of VAT energy metabolism, which correlate with adipose tissue dysfunction and may favor progression of NAFL to NASH. LAY SUMMARY: Adipose tissue (commonly called body fat) can be found under the skin (subcutaneous) or around internal organs (visceral). Dysfunction of adipose tissue can cause insulin resistance and lead to excess delivery of fat to other organs such as the liver. Herein, we show that dysfunction specifically in visceral adipose tissue was associated with fatty liver disease. CLINICAL TRIAL NUMBER: NCT01477957.

Metabolic Factors Predict Changes in Endothelial Function During the Early Course of Type 1 and Type 2 Diabetes.

CONTEXT: Endothelial dysfunction may occur early in the development of cardiovascular and metabolic diseases; however, it remains often underestimated and studies rarely discriminate between diabetes types. We have examined endothelial function and its determinants during the early course of type 1 and type 2 diabetes. METHODS: Caucasian participants of the prospective German Diabetes Study (GDS) with known diabetes duration <1 year (n = 398) or without diabetes, but of similar age, body mass index (BMI) and sex distribution (n = 109), underwent measurements of flow-mediated dilation (FMD) and nitroglycerin-mediated dilatation (NMD). Whole-body insulin sensitivity (M-value) was assessed by hyperinsulinemic-euglycemic clamps and physical fitness (VO2max) by spiroergometry. A subset of individuals with type 1 or type 2 diabetes (n = 108) was re-evaluated after 5 years. RESULTS: At baseline, neither FMD nor NMD differed between people with diabetes and the matched glucose-tolerant groups. At the 5-year follow-up, decline in FMD (-13.9%, P = .013) of persons with type 2 diabetes was independent of age, sex, and BMI, but associated with baseline adipose tissue insulin resistance and indices of liver fibrosis. The M-value decreased in both type 1 and type 2 diabetes groups by 24% and 15% (both P < .001, respectively) over 5 years. Higher HbA1c, lower M-value, and lower VO2max at baseline was associated with lower FMD in both type 1 and type 2 diabetes. CONCLUSION: Endothelial function decreases during the early course of type 2 diabetes. In addition to age and BMI, insulin sensitivity at diagnosis was the best predictor of progressive impairment in endothelial function in type 2 diabetes.

Socio-economic inequalities in glycaemic control in recently diagnosed adults with type 1 and type 2 diabetes.

BACKGROUND AND AIMS: It is unclear whether socio-economic status (SES) is associated with glycaemic control in people with recently diagnosed diabetes. The aim was to investigate whether SES is related to haemoglobin A1c (HbA1c) during the first year after diagnosis in people with type 1 and type 2 diabetes and if metabolic, quality of care or mental factors may explain the association. METHODS: In the German Diabetes Study, people with type 1 (n = 274, median age 36 [25th; 75th percentile: 28; 48] years) and type 2 diabetes (n = 424, 54 [47; 60] years) underwent detailed metabolic characterisation within the first year after diagnosis. SES was documented using a standardised questionnaire. Associations between SES and HbA1c were assessed using multivariable linear regression and restricted cubic spline regression analyses. Additional covariables were patient characteristics, laboratory measurements, health behaviour, quality of care and depression variables. Models were separately fitted for diabetes type, SES and its dimensions (income, education, occupation). RESULTS: Higher SES score was associated with lower HbA1c (-0.7 mmol/mol per unit increase in SES, 95% CI: -1.1; -0.2 mmol/mol [-0.1%, 95% CI: -0.1; 0.0%]) in people with type 1 diabetes. Included covariates did not attenuate this association. In people with type 2 diabetes, effect estimates were close to zero indicating no relevant difference. CONCLUSION: Socio-economic inequalities in HbA1c already exist during the first year after diagnosis in people with type 1 diabetes. The absence of association between glycaemic control and SES in type 2 diabetes could be due to the lower complexity of diabetes therapy compared to type 1 diabetes.

Impaired Hepatic Mitochondrial Capacity in Nonalcoholic Steatohepatitis Associated With Type 2 Diabetes.

OBJECTIVE: Individuals with type 2 diabetes are at higher risk of progression of nonalcoholic fatty liver (steatosis) to steatohepatitis (NASH), fibrosis, and cirrhosis. The hepatic metabolism of obese individuals adapts by upregulation of mitochondrial capacity, which may be lost during the progression of steatosis. However, the role of type 2 diabetes with regard to hepatic mitochondrial function in NASH remains unclear. RESEARCH DESIGN AND METHODS: We therefore examined obese individuals with histologically proven NASH without (OBE) (n = 30; BMI 52 ± 9 kg/m2) or with type 2 diabetes (T2D) (n = 15; 51 ± 7 kg/m2) as well as healthy individuals without liver disease (CON) (n = 14; 25 ± 2 kg/m2). Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamps with d-[6,6-2H2]glucose. Liver biopsies were used for assessing mitochondrial capacity by high-resolution respirometry and protein expression. RESULTS: T2D and OBE had comparable hepatic fat content, lobular inflammation, and fibrosis. Oxidative capacity in liver tissue normalized for citrate synthase activity was 59% greater in OBE than in CON, whereas T2D presented with 33% lower complex II-linked oxidative capacity than OBE and higher H2O2 production than CON. Interestingly, those with NASH and hepatic fibrosis score ≥1 had lower oxidative capacity and antioxidant defense than those without fibrosis. CONCLUSIONS: Loss of hepatic mitochondrial adaptation characterizes NASH and type 2 diabetes or hepatic fibrosis and may thereby favor accelerated disease progression.

BOND study: a randomised double-blind, placebo-controlled trial over 12 months to assess the effects of benfotiamine on morphometric, neurophysiological and clinical measures in patients with type 2 diabetes with symptomatic polyneuropathy.

INTRODUCTION: Diabetic sensorimotor polyneuropathy (DSPN) affects approximately 30% of people with diabetes, while around half of cases are symptomatic. Currently, there are only few pathogenetically oriented pharmacotherapies for DSPN, one of which is benfotiamine, a prodrug of thiamine with a high bioavailability and favourable safety profile. While benfotiamine has shown positive effects in preclinical and short-term clinical studies, no long-term clinical trials are available to demonstrate disease-modifying effects on DSPN using a comprehensive set of disease-related endpoints. METHODS AND ANALYSIS: The benfotiamine on morphometric, neurophysiological and clinical measures in patients with type 2 diabetes trial is a randomised double-blind, placebo-controlled parallel group monocentric phase II clinical trial to assess the effects of treatment with benfotiamine compared with placebo in participants with type 2 diabetes and mild to moderate symptomatic DSPN. Sixty participants will be 1:1 randomised to treatment with benfotiamine 300 mg or placebo two times a day over 12 months. The primary endpoint will be the change in corneal nerve fibre length assessed by corneal confocal microscopy (CCM) after 12 months of benfotiamine treatment compared with placebo. Secondary endpoints will include other CCM measures, skin biopsy and function indices, variables from somatic and autonomic nerve function tests, clinical examination and questionnaires, general health, health-related quality of life, cost, safety and blood tests. ETHICS AND DISSEMINATION: The trial was approved by the competent authority and the local independent ethics committee. Trial results will be published in peer-reviewed journals, conference abstracts, and via online and print media. TRIAL REGISTRATION NUMBER: DRKS00014832.

Physical Fitness and Cardiovascular Risk Factors in Novel Diabetes Subgroups.

CONTEXT: Physical inactivity promotes insulin resistance and increases the risk of diabetes and cardiovascular disease. Recently introduced clustering based on simple clinical measures identified diabetes subgroups (clusters) with different risks of diabetes-related comorbidities and complications. OBJECTIVE: This study aims to determine differences in physical fitness and cardiovascular risk between diabetes subgroups and a glucose-tolerant control group (CON). We hypothesized that the severe insulin-resistant diabetes (SIRD) subgroup would be associated with lower physical fitness and increased cardiovascular risk. METHODS: The physical fitness and cardiovascular risk of 746 participants with recent-onset diabetes (diabetes duration of < 12 months, aged 18-69 years) and 74 CONs of the German Diabetes Study (GDS), a prospective longitudinal cohort study, were analyzed. Main outcome measures included physical fitness (VO2max from spiroerogometry), endothelial function (flow- and nitroglycerin-mediated dilation), and cardiovascular risk scores (Framingham Risk Scores for Coronary Heart Disease [FRS-CHD] and Atherosclerotic CardioVascular Disease [ASCVD] risk score). RESULTS: VO2max was lower in SIRD than in CON, severe autoimmune diabetes (SAID) (both P < .001), and mild age-related diabetes (MARD) (P < .01) subgroups, but not different compared to severe insulin-deficient diabetes (SIDD) (P = .98) and moderate obesity-related diabetes (MOD) subgroups (P = .07) after adjustment for age, sex, and body mass index. Endothelial function was similar among all groups, whereas SAID had lower FRS-CHD and ASCVD than SIRD, MOD, and MARD (all P < .001). CONCLUSION: Despite comparable endothelial function across all groups, SIRD showed the lowest physical fitness. Of note, SAID had the lowest cardiovascular risk within the first year after diabetes diagnosis compared to the other diabetes subgroups.

Differences in the prevalence of erectile dysfunction between novel subgroups of recent-onset diabetes.

AIMS/HYPOTHESIS: In men with diabetes, the prevalence of erectile dysfunction increases with advanced age and longer diabetes duration and is substantially higher in men with type 2 diabetes than those with type 1 diabetes. This study aimed to evaluate the prevalence of erectile dysfunction among the five novel subgroups of recent-onset diabetes and determine the strength of associations between diabetes subgroups and erectile dysfunction. METHODS: A total of 351 men with recent-onset diabetes (<1 year) from the German Diabetes Study baseline cohort and 124 men without diabetes were included in this cross-sectional study. Erectile dysfunction was assessed with the International Index of Erectile Function (IIEF) questionnaire. Poisson regression models were used to estimate associations between diabetes subgroups (each subgroup tested against the four other subgroups as reference) and erectile dysfunction (dependent binary variable), adjusting for variables used to define diabetes subgroups, high-sensitivity C-reactive protein and depression. RESULTS: The prevalence of erectile dysfunction was markedly higher in men with diabetes than in men without diabetes (23% vs 11%, p = 0.004). Among men with diabetes, the prevalence of erectile dysfunction was highest in men with severe insulin-resistant diabetes (SIRD) (52%), lowest in men with severe autoimmune diabetes (SAID) (7%), and intermediate in men with severe insulin-deficient diabetes (SIDD), mild obesity-related diabetes (MOD) and mild age-related diabetes (MARD) (31%, 18% and 29%, respectively). Men with SIRD had an adjusted RR of 1.93 (95% CI 1.04, 3.58) for prevalent erectile dysfunction (p = 0.038). Similarly, men with SIDD had an adjusted RR of 3.27 (95% CI 1.18, 9.10) (p = 0.023). In contrast, men with SAID and those with MARD had unadjusted RRs of 0.26 (95% CI 0.11, 0.58) (p = 0.001) and 1.52 (95% CI 1.04, 2.22) (p = 0.027), respectively. However, these associations did not remain statistically significant after adjustment. CONCLUSIONS/INTERPRETATION: The high RRs for erectile dysfunction in men with recent-onset SIRD and SIDD point to both insulin resistance and insulin deficiency as major contributing factors to this complication, suggesting different mechanisms underlying erectile dysfunction in these subgroups.

Metabolic responsiveness to training depends on insulin sensitivity and protein content of exosomes in insulin-resistant males.

High-intensity interval training (HIIT) improves cardiorespiratory fitness (VO2max), but its impact on metabolism remains unclear. We hypothesized that 12-week HIIT increases insulin sensitivity in males with or without type 2 diabetes [T2D and NDM (nondiabetic humans)]. However, despite identically higher VO2max, mainly insulin-resistant (IR) persons (T2D and IR NDM) showed distinct alterations of circulating small extracellular vesicles (SEVs) along with lower inhibitory metabolic (protein kinase Cε activity) or inflammatory (nuclear factor κB) signaling in muscle of T2D or IR NDM, respectively. This is related to the specific alterations in SEV proteome reflecting down-regulation of the phospholipase C pathway (T2D) and up-regulated antioxidant capacity (IR NDM). Thus, SEV cargo may contribute to modulating the individual metabolic responsiveness to exercise training in humans.