Impact of physical fitness and exercise training on subcutaneous adipose tissue beiging markers in humans with and without diabetes and a high-fat diet-fed mouse model.

AIMS: Exercise training induces white adipose tissue (WAT) beiging and improves glucose homeostasis and mitochondrial function in rodents. This could be relevant for type 2 diabetes in humans, but the effect of physical fitness on beiging of subcutaneous WAT (scWAT) remains unclear. This translational study investigates if beiging of scWAT associates with physical fitness in healthy humans and recent-onset type 2 diabetes and if a voluntary running wheel intervention is sufficient to induce beiging in mice. MATERIALS AND METHODS: Gene expression levels of established beiging markers were measured in scWAT biopsies of humans with (n = 28) or without type 2 diabetes (n = 28), stratified by spiroergometry into low (L-FIT; n = 14 each) and high physical fitness (H-FIT; n = 14 each). High-fat diet-fed FVB/N mice underwent voluntary wheel running, treadmill training or no training (n = 8 each group). Following the training intervention, mitochondrial respiration and content of scWAT were assessed by high-resolution respirometry and citrate synthase activity, respectively. RESULTS: Secreted CD137 antigen (Tnfrsf9/Cd137) expression was three-fold higher in glucose-tolerant H-FIT than in L-FIT, but not different between H-FIT and L-FIT with type 2 diabetes. In mice, both training modalities increased Cd137 expression and enhanced mitochondrial content without changing respiration in scWAT. Treadmill but not voluntary wheel running led to improved whole-body insulin sensitivity. CONCLUSIONS: Higher physical fitness and different exercise interventions associated with higher gene expression levels of the beiging marker CD137 in healthy humans and mice on a high-fat diet. Humans with recent-onset type 2 diabetes show an impaired adipose tissue-specific response to physical activity.

Mechanosensing by ß1 integrin induces angiocrine signals for liver growth and survival.

Angiocrine signals derived from endothelial cells are an important component of intercellular communication and have a key role in organ growth, regeneration and disease1-4. These signals have been identified and studied in multiple organs, including the liver, pancreas, lung, heart, bone, bone marrow, central nervous system, retina and some cancers1-4. Here we use the developing liver as a model organ to study angiocrine signals5,6, and show that the growth rate of the liver correlates both spatially and temporally with blood perfusion to this organ. By manipulating blood flow through the liver vasculature, we demonstrate that vessel perfusion activates ß1 integrin and vascular endothelial growth factor receptor 3 (VEGFR3). Notably, both ß1 integrin and VEGFR3 are strictly required for normal production of hepatocyte growth factor, survival of hepatocytes and liver growth. Ex vivo perfusion of adult mouse liver and in vitro mechanical stretching of human hepatic endothelial cells illustrate that mechanotransduction alone is sufficient to turn on angiocrine signals. When the endothelial cells are mechanically stretched, angiocrine signals trigger in vitro proliferation and survival of primary human hepatocytes. Our findings uncover a signalling pathway in vascular endothelial cells that translates blood perfusion and mechanotransduction into organ growth and maintenance.

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.

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.

Relative validity of a glycemic index extended food-frequency questionnaire.

BACKGROUND AND AIMS: The dietary glycemic index (GI) and glycemic load (GL) are increasingly recognized as important for the prevention and management of diabetes mellitus. To extend the portfolio of assessment methods for large-scale epidemiological studies, we propose a GI-specific addition to an already established FFQ. METHODS AND RESULTS: The German version of the EPIC-FFQ was extended by GI-specific questions for major carbohydrate sources varying notably in GI (breakfast cereals, bread, pasta, rice, potato etc.). We performed relative validation analyses comparing the GI-extended FFQ to three to four 3-day weighted dietary records (3-d WDR) in 100 middle-aged individuals with diabetes mellitus participating in the German Diabetes Study (GDS). Level of agreement between the two methods was assessed by correlation and cross-classification analyses as well as Bland-Altman-Plots, conducted separately for women and men. Spearman correlation analysis for female participants suggested good agreement between the GI-extended FFQ and 3-d WDRs for energy adjusted dietary GL (r = 0.52, p = 0.0004). For both women and men, agreement with the estimations of dietary GI, GL (for men) and carbohydrates from low and higher-GI food sources from the GI-extended FFQ was acceptable (r: 0.28-0.45). Classification of the dietary GI and GL in the opposite quartile was <10% comparing the GI-extended FFQ and 3-d WDR. Bland-Altman plots suggested a tendency for an overestimation of the dietary GI from the GI-extended FFQ in the lower GI-ranges, particularly for men. CONCLUSION: Compared to the 3-d WDR, the GI-extended FFQ showed a moderate to good relative validity for parameters of carbohydrate quality.

Improving insulin sensitivity, liver steatosis and fibrosis in type 2 diabetes by a food-based digital education-assisted lifestyle intervention program: a feasibility study.

PURPOSE: Recent trials demonstrated remission of type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) following formula diet-induced weight loss. To improve the outreach for populations in need, many mobile health apps targeting weight loss have been developed with limited scientific evaluation of these apps. The present feasibility study investigated the effects of a novel approach incorporating a regular 'whole food-based' low-calorie diet combined with app-based digital education and behavioral change program on glucose metabolism and disease management. METHODS: Twenty-four individuals with type 2 diabetes followed this approach supported by weekly coaching calls for 12 weeks. Phenotyping included bioimpedance analysis, mixed-meal tolerance test, magnetic resonance spectroscopy and transient elastography for assessing liver fat content and liver stiffness. RESULTS: Over 12 weeks, participants reduced their body weight by 9% (97 ± 13 to 88 ± 12 kg), body mass index (BMI; 33 ± 5 to 29 ± 4 kg/m2), total fat mass (31 ± 10 to 27 ± 10%) (all p < 0.01) and liver fat by 50% alongside with decreased liver stiffness. Target HbA1c (< 6.5%) was achieved by 38% and resolution of NAFLD (liver fat content < 5.6%) was observed in 30% of the participants. CONCLUSION: This novel approach combining digital education with a low-calorie diet results in effective improvements of body weight, glycemic control and NAFLD and could complement existing care for patients with type 2 diabetes. TRIAL REGISTRATION: NCT04509245.

1H-MRS of femoral red and yellow bone marrow fat composition and water content in healthy young men and women at 3 T.

OBJECTIVES: There is a discrepancy between studies suggesting that higher bone marrow fat saturation is associated with impaired health, and studies suggesting that erythropoiesis increases red bone marrow (RBM) fat saturation in young healthy individuals. Here, we seeked to elucidate these discrepancies by using long TE magnetic resonance spectroscopy (MRS) to study both yellow bone marrow (YBM) and RBM in the femur of healthy volunteers. MATERIALS AND METHODS: Thirty-three young healthy volunteers (17 females), age range 20-31 years, underwent long TE 1H MRS at 3.0 T of RBM and YBM fat composition in the left femur. The water content of the bone marrow depots was measured using short TE MRS. RESULTS: The female participants displayed a lower unsaturation in the sampled RBM volume (RBMV) than the males (P < 0.01) without displaying a concomitant difference in YBM (P = 0.42). They also showed a higher water content and broader spectral linewidths in RBM (P = 0.04). The water content in RBM strongly associated with broader spectral linewidths (R = 0.887, P ≪ 0.01) and inversely with RBMV fat unsaturation (R = - 0.365, P = 0.04). DISCUSSION: These results partly support the notion that females display higher rate of erythropoiesis and lower fat unsaturation in RBM.

Energy metabolism of white adipose tissue and insulin resistance in humans.

BACKGROUND: Insulin resistance not only occurs in obesity, but also in lipodystrophy. Although adipose tissue mass affects metabolic fluxes and participates in interorgan crosstalk, the role of energy metabolism within white adipose tissue for insulin resistance is less clear. MATERIALS AND METHODS: A Medline search identified in vivo studies in humans on energy and lipid metabolism in subcutaneous (SAT) and visceral adipose tissue (VAT). Studies in adipocyte cultures and transgenic animal models were included for the better understanding of the link between abnormal energy metabolism in adipose tissue and insulin resistance. RESULTS: The current literature indicates that higher lipolysis and lower lipogenesis in VAT compared to SAT enhance portal delivery of lipid metabolites (glycerol and fatty acids) to the liver. Thus, the lower lipolysis and higher lipogenesis in SAT favour storage of excess lipids and allow for protection of insulin-sensitive tissues from lipotoxic effects. In insulin-resistant humans, enhanced lipolysis and impaired lipogenesis in adipose tissue lead to release of cytokines and lipid metabolites, ultimately promoting insulin resistance. Adipose tissue of insulin-resistant humans also displays lower expression of proteins involved in mitochondrial function. In turn, this leads to lower availability of mitochondria-derived energy sources for lipogenesis in adipose tissue. CONCLUSIONS: Abnormal mitochondrial function in human white adipose tissue likely contributes to the secretion of lipid metabolites and lactate, which are linked to insulin resistance in peripheral tissues. However, the relevance of adipose tissue energy metabolism for the regulation of human insulin sensitivity remains to be further elucidated.

Patterns of cutaneous nerve fibre loss and regeneration in type 2 diabetes with painful and painless polyneuropathy.

AIMS/HYPOTHESIS: The determinants and mechanisms of the development of diabetic sensorimotor polyneuropathy as a painful (DSPN+p) or painless (DSPN-p) entity remain unclear. We examined the degree of cutaneous nerve fibre loss and regeneration in individuals with type 2 diabetes with DSPN+p or DSPN-p compared with individuals with recent-onset type 2 diabetes and corresponding healthy volunteers. METHODS: In this cross-sectional study, skin biopsies taken from the distal lateral calf were obtained from individuals with recent-onset type 2 diabetes (n = 32) from the German Diabetes Study, with DSPN+p (n = 34) and DSPN-p (n = 32) from the PROPANE study, and volunteers with normal glucose tolerance (n = 50). Double immunofluorescence staining for protein gene product 9.5 (PGP9.5) (pan-neuronal marker) and growth-associated protein 43 (GAP-43) (nerve regeneration marker) was applied to assess intraepidermal nerve fibre density (IENFD) and length (IENFL) and dermal nerve fibre length (DNFL). DSPN was diagnosed using the modified Toronto Consensus (2011) criteria, while neuropathic pain was assessed using an 11-point Numerical Rating Scale. RESULTS: After adjustment for age, sex, BMI and HbA1c, IENFD and IENFL were reduced for both markers in individuals with recent-onset diabetes and both DSPN groups compared with control participants (all p < 0.05), but did not differ between the DSPN groups. The DNFL GAP-43/PGP9.5 ratio was higher in the DSPN+p and DSPN-p groups compared with control participants (1.18 ± 0.28 and 1.07 ± 0.10 vs 1.02 ± 0.10; p ≤ 0.05) and in the DSPN + p group compared with DSPN-p (p < 0.05). Correlation analyses showed distinct inverse associations between the DNFL GAP-43/PGP9.5 ratio and PGP9.5 positive IENFD as well as DNFL (IENFD: ß = -0.569, DNFL: ß = -0.639; both p < 0.0001) in individuals with type 2 diabetes, but not in the control group. A similar pattern was found for correlations between the DNFL GAP-43/PGP9.5 ratio and peripheral nerve function tests. CONCLUSIONS/INTERPRETATION: Dermal nerve fibre regeneration is enhanced in DSPN, particularly in DSPN+p, and increases with advancing intraepidermal nerve fibre loss. These data suggest that, despite progressive epidermal fibre loss, dermal nerve repair is preserved, particularly in DSPN+p, but fails to adequately counteract epidermal neurodegenerative processes.

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.

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.

Comparison of diabetes distress and depression screening results of emerging adults with type 1 diabetes onset at different ages: findings from the German early-onset T1D study and the German Diabetes Study (GDS).

BACKGROUND: Diabetes distress is increasingly considered one of the most important psychosocial issues in the care of people with type 1 diabetes (T1D). We analyse whether diabetes distress and depression screening results of emerging adults are associated with the age at T1D onset. METHODS: Data were taken from two cohort studies conducted at the German Diabetes Center, Düsseldorf, Germany. The 18-30-year-old participants had an age at onset either before the age of 5 years (childhood-onset long-term T1D study group, N = 749) or during adulthood (adult-onset short-term T1D study group from the German Diabetes Study (GDS), N = 163). Diabetes distress and depression screening were analysed by means of the 20-item Problem Areas in Diabetes (PAID-20) scale and the nine-item depression module from the Patient Health Questionnaire (PHQ-9). The average causal effect of age at onset was estimated by a doubly robust causal inference method. RESULTS: The PAID-20 total scores were increased in the adult-onset study group [potential outcome mean (POM) 32.1 (95% confidence interval 28.0; 36.1) points] compared to the childhood-onset study group [POM 21.0 (19.6; 22.4) points, difference 11.1 (6.9; 15.3) points, p<0.001] adjusted for age, sex and haemoglobin A1c (HbA1c) levels. Moreover, more participants in the adult-onset group [POM 34.5 (24.9; 44.2) %] than in the childhood-onset group [POM 16.3 (13.3; 19.2) %] screened positive for diabetes distress [adjusted difference 18.3 (8.3; 28.2) %, p<0.001]. The PHQ-9 total score [difference 0.3 (-1.1; 1.7) points, p=0.660] and the proportion of participants with a positive screening result for depression [difference 0.0 (-12.7; 12.8) %, p=0.994] did not differ between the groups in the adjusted analyses. CONCLUSIONS: Emerging adults with short-term type 1 diabetes screened positive for diabetes distress more often than adults with type 1 diabetes onset during early childhood when age, sex and HbA1c values were considered confounding factors. Accounting for age at onset or the duration of diabetes may help explain the heterogeneity in the data when psychological factors are examined.

Reduced Insulin Clearance Differently Relates to Increased Liver Lipid Content and Worse Glycemic Control in Recent-Onset Type 2 and Type 1 Diabetes.

OBJECTIVE: Diabetes may feature impaired insulin kinetics, which could be aggravated by altered hepatic metabolism and glycemic control. Thus, we examined insulin clearance and its possible determinants in individuals with recent-onset diabetes. RESEARCH DESIGN AND METHODS: Participants of the German Diabetes Study (GDS) with type 1 diabetes (T1D) (n = 306), type 2 diabetes (T2D) (n = 489), or normal glucose tolerance (control [CON]) (n = 167) underwent hyperinsulinemic-euglycemic clamps for assessment of whole-body insulin sensitivity (M value) and insulin clearance (ICCLAMP). Insulin clearance rates were further calculated during intravenous glucose tolerance tests (ICIVGTT) and mixed-meal tests (ICMMT). Hepatocellular lipid content (HCL) was quantified with 1H-MRS. RESULTS: Both T1D and T2D groups had lower ICCLAMP (0.12 ± 0.07 and 0.21 ± 0.06 vs. 0.28 ± 0.14 arbitrary units [a.u.], respectively, all P < 0.05) and ICMMT (0.71 ± 0.35 and 0.99 ± 0.33 vs. 1.20 ± 0.36 a.u., all P < 0.05) than CON. In T1D, ICCLAMP, ICIVGTT, and ICMMT correlated negatively with HbA1c (all P < 0.05). M value correlated positively with ICIVGTT in CON and T2D (r = 0.199 and r = 0.178, P < 0.05) and with ICMMT in CON (r = 0.176, P < 0.05). HCL negatively associated with ICIVGTT and ICMMT in T2D (r = -0.005 and r = -0.037) and CON (r = -0.127 and r = -0.058, all P < 0.05). In line, T2D or CON subjects with steatosis featured lower ICMMT than those without steatosis (both P < 0.05). CONCLUSIONS: Insulin clearance is reduced in both T1D and T2D within the first year after diagnosis but correlates negatively with liver lipid content rather in T2D. Moreover, insulin clearance differently associates with glycemic control and insulin sensitivity in each diabetes type, which may suggest specific mechanisms affecting insulin kinetics.

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.

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.

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.

Branched-Chain Amino Acids Associate Negatively With Postprandial Insulin Secretion in Recent-Onset Diabetes.

CONTEXT: In addition to unfavorable effects on insulin sensitivity, elevated plasma branched-chain amino acids (BCAA) stimulate insulin secretion, which, over the long-term, could impair pancreatic ß-cell function. OBJECTIVE: To investigate cross-sectional and prospective associations between circulating BCAA and postprandial ß-cell function in recently diagnosed type 1 and type 2 diabetes. METHODS: The study included individuals with well-controlled type 1 and type 2 diabetes (known diabetes duration <12 months) and glucose-tolerant participants (controls) of similar age, sex, and body mass index (n = 10/group) who underwent mixed meal tolerance tests. Plasma BCAA levels were quantified by gas chromatography-mass spectrometry, postprandial ß-cell function was assessed from serum C-peptide levels, and insulin sensitivity was determined from PREDIM index (PREDIcted M-value). RESULTS: In type 1 diabetes, postprandial total BCAA, valine, and leucine levels were 25%, 18%, and 19% higher vs control, and total as well as individual postprandial BCAA were related inversely to C-peptide levels. In type 2 diabetes, postprandial isoleucine was 16% higher vs the respective controls, while neither total nor individual BCAA correlated with C-peptide levels. Whole-body insulin sensitivity was lower in both diabetes groups than in corresponding controls. CONCLUSION: Insulin deficiency associates with sustained high BCAA concentrations, which could contribute to exhausting the insulin secretory reserve in early type 1 diabetes.

Impact of mixed meal tolerance test composition on measures of beta-cell function in type 2 diabetes.

BACKGROUND: Application of mixed meal tolerance tests (MMTT) to measure beta-cell function in long-term studies is limited by modification of the commercial products occurring over time. This study assessed the intra-individual reliability of MMTTs and compared the effects of liquid meals differing in macronutrient composition on the estimation of beta-cell function in type 2 diabetes (T2DM). METHODS: To test the reliability of MMTTs, 10 people with T2DM (age 58 ± 11 years, body mass index 30.0 ± 4.9 kg/m2) received Boost® high Protein 20 g protein three times. For comparing different meals, another 10 persons with T2DM (58 ± 5 years, 31.9 ± 5.3 kg/m2) ingested either Boost® high Protein 20 g protein or the isocaloric Boost® high Protein 15 g protein containing 35% less protein and 18% more carbohydrates. C-peptide, insulin and glucose release were assessed from the incremental area under the concentration time curve (iAUC) and the intra- and inter-individual variation of these parameters from the coefficients of variations (CV). RESULTS: Repetitive ingestion of one meal revealed intra-individual CVs for the iAUCs of C-peptide, insulin and glucose, which were at least 3-times lower than the inter-individual variation of these parameters (18.2%, 19.7% and 18.9% vs. 74.2%, 70.5% and 207.7%) indicating a good reliability. Ingestion of two different meals resulted in comparable intra-individual CVs of the iAUCs of C-peptide and insulin (16.9%, 20.5%). CONCLUSION: MMTTs provide reliable estimation of beta-cell function in people with T2DM. Furthermore, moderate differences in the protein and carbohydrate contents in a standardized liquid meal do not result in relevant changes of C-peptide and insulin responses. TRIAL REGISTRATION: Clinicaltrials.gov, Identifier number: NCT01055093. Registered 22 January 2010 - Retrospectively registered, https://www.clinicaltrials.gov/ct2/show/study/NCT01055093.

Reduced Muscle Strength Is Associated With Insulin Resistance in Type 2 Diabetes Patients With Osteoarthritis.

CONTEXT: Type 2 diabetes is associated with a greater risk for musculoskeletal disorders, yet its impact on joint function remains unclear. OBJECTIVE: We hypothesized that patients with type 2 diabetes and osteoarthritis would exhibit musculoskeletal impairment, which would associate with insulin resistance and distinct microRNA profiles. METHODS: Participants of the German Diabetes Study with type 2 diabetes (T2D, n = 39) or normal glucose tolerance (CON, n = 27), both with (+OA) or without osteoarthritis (-OA) underwent intravenous glucose tolerance and hyperinsulinemic-euglycemic clamp tests. Musculoskeletal function was assessed by isometric knee extension strength (KES), grip strength, range of motion (ROM), and balance skills, while neural function was measured by nerve conductance velocity (NCV). Arthritis-related symptoms were quantified using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire, serum arthritis-related microRNA using quantitative polymerase chain reaction. RESULTS: Insulin sensitivity was lower in T2D+OA vs T2D-OA (4.4 ±â€…2.0 vs 5.7 ±â€…3.0 mg* kg-1*min-1) and in CON+OA vs CON-OA (8.1 ±â€…2.0 vs 12.0 ±â€…2.6 mg*kg-1,*min-1, both P < .05). In T2D+OA, KES and ROM were 60% and 22% lower than in CON+OA, respectively (both P < .05). Insulin sensitivity correlated positively with KES (r = 0.41, P < .05) among T2D, and negatively with symptom severity in CON and T2D (r = -0.60 and r = -0.46, respectively, P < .05). CON+OA and T2D+OA had inferior balance skills than CON-OA, whereas NCV was comparable in T2D+OA and T2D-OA. Expression of arthritis-related microRNAs was upregulated in T2D compared to CON, but downregulated in CON+OA compared to CON-OA (P < .05), and did not differ between T2D+OA and T2D-OA. CONCLUSION: Musculoskeletal impairment and osteoarthritis-related symptoms are associated with insulin resistance. Type 2 diabetes can mask changes in arthritis-related microRNA profiles.

NDUFB6 Polymorphism Is Associated With Physical Activity-Mediated Metabolic Changes in Type 2 Diabetes.

The rs540467 SNP in the NDUFB6 gene, encoding a mitochondrial complex I subunit, has been shown to modulate adaptations to exercise training. Interaction effects with diabetes mellitus remain unclear. We assessed associations of habitual physical activity (PA) levels with metabolic variables and examined a possible modifying effect of the rs540467 SNP. Volunteers with type 2 (n=242), type 1 diabetes (n=250) or normal glucose tolerance (control; n=139) were studied at diagnosis and subgroups with type 1 (n=96) and type 2 diabetes (n=95) after 5 years. Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamps, oxygen uptake at the ventilator threshold (VO2AT) by spiroergometry and PA by questionnaires. Translational studies investigated insulin signaling and mitochondrial function in Ndufb6 siRNA-treated C2C12 myotubes, with electronic pulse stimulation (EPS) to simulate exercising. PA levels were 10 and 6%, VO2AT was 31% and 8% lower in type 2 and type 1 diabetes compared to control. Within 5 years, 36% of people with type 2 diabetes did not improve their insulin sensitivity despite increasing PA levels. The NDUFB6 rs540467 SNP modifies PA-mediated changes in insulin sensitivity, body composition and liver fat estimates in type 2 diabetes. Silencing Ndufb6 in myotubes reduced mitochondrial respiration and prevented rescue from palmitate-induced insulin resistance after EPS. A substantial proportion of humans with type 2 diabetes fails to respond to rising PA with increasing insulin sensitivity. This may at least partly relate to a polymorphism of the NDUFB6 gene, which may contribute to modulating mitochondrial function. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT01055093. The trial was retrospectively registered on 25th of January 2010.