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Objective: GDF15 has emerged as a stress‐induced hormone, acting on the brain to reduce food intake and body weight while affecting neuroendocrine function. Very high GDF15 levels are found in thalassaemia, where growth, energy balance and neuroendocrine function are impaired. We examined the relationships between GDF15 and anthropometric measures and endocrine status in β‐thalassaemia. Design: Cross sectional study. Patients: All β‐thalassaemia patients attending the thalassaemia unit of Colombo North Teaching Hospital for blood transfusions. Measurements: Anthropometric data, appetite scores, circulating GDF15, IGF, thyroid and reproductive hormone levels in 103 β‐thalassaemia patients were obtained. Results: GDF15 levels were markedly elevated in thalassaemia patients (24.2‐fold with β‐thalassaemia major compared with healthy controls). Among patients with β‐thalassaemia major, the relationship between GDF15 and body mass index (BMI) was curvilinear with all individuals with GDF15 levels above 24,000 pg/mL having a BMI below 20 kg/m2. After adjustment for BMI, age and Tanner stage, serum IGF1 concentrations correlated negatively with GDF15 in all thalassaemia patients (β = −.027, p =.02). We found a significant positive relationship between GDF15 and gonadotropin (in both sexes) and testosterone (in males). Conclusions: GDF15 levels were markedly elevated in patients with β‐thalassaemia and its association with BMI is consistent with the known effect of GDF15 to reduce body weight. The inverse association between GDF15 with IGF1 levels may reflect a neuroendocrine impact of GDF15 or an indirect effect via impaired nutritional state. The positive association with testosterone in males and gonadotropins in both sexes, was surprising and should prompt further GDF15 studies on the hypothalamic pituitary gonadal axis. [ABSTRACT FROM AUTHOR]

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%, bothp < 0.01), C-peptide (H-RISK -26% vs. L-RISK -30%, bothp < 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. [ABSTRACT FROM AUTHOR]

Understanding the role of insulin resistance (IR) in type 1 diabetes (T1D) may help to improve its treatment. Postprandial insulin secretion stimulates amino acid (AA) uptake and protein synthesis. Consequently, impaired insulin-mediated AA clearance could raise postprandial branched-chain AA (BCAA: valine (VAL), leucine (LEU), isoleucine (ILE)) levels and in turn contribute to BCAA-induced IR. We hypothesized that BCAA levels associate negatively with postprandial ß-cell function already in recent-onset T1D. In a cross-sectional study, volunteers of the German Diabetes-Study with T1D (n=10, diabetes duration <1 year) and excellent glycemic control (HbA1C 6.6±0.9%/48±9 mmol/mol), and age-, sex- and BMI- matched glucose tolerant humans (control, CON, n=10, HbA1C 5.1±0.3%/32±3 mmol/mol) underwent a mixed-meal tolerance test (MMT) to assess ß-cell function through disposition index (DI, the product of insulin sensitivity (IS) and acute insulin response to glucose) and postprandial IS (PREDIM index, predicted M-value). Adipose tissue (AT) IR index was calculated as fasting plasma levels of FFA (mmol*l-1) x insulin (pmol*l-1). Postprandial total BCAA, VAL and LEU levels were 25% higher in patients with T1D compared with CON (AUC 11167±5136 vs. 8410±3298, 14363±959 vs. 11754±3890, 11980±4317 vs. 8476±4257 µmol*l-1*3 h-1, p<0.05, respectively). PREDIM was lower in T1D (3.3±1.1 vs. CON 7.0±1.4 ml*min-1*m-2, p<0.01), while fasting and postprandial AT IR were not different. Persons with T1D showed an inverse relationship between BCAA concentrations and C-peptide levels (total BCAA: r=-0.76, p<0.01; VAL: r=-0.80, p<0.01; LEU: r=-0.71, p<0.05; ILE: r=-0.67, p<0.05) and DI (total BCAA: r=-0.71, p<0.05; VAL: r=-0.78, p<0.01; LEU: r=-0.75, p<0.01; ILE: r=-0.69, p<0.05). In conclusion, persons with even well-controlled recent-onset T1D exhibit elevated postprandial BCAA concentrations, likely due to impaired ß-cell function, which contribute to postprandial IR. Disclosure: Y. Karusheva: None. K. Strassburger: None. D.F. Markgraf: None. O.P. Zaharia: None. K. Bodis: None. A. Tura: None. G. Pacini: None. V. Burkart: None. J. Szendroedi: None. M. Roden: Advisory Panel; Self; Servier. Board Member; Self; Poxel SA. Consultant; Self; Eli Lilly and Company, Gilead Sciences, Inc., ProSciento, TARGET PharmaSolutions. Research Support; Self; Boehringer Ingelheim International GmbH, Novartis Pharma K.K., Sanofi US. Speaker's Bureau; Self; Novo Nordisk A/S. [ABSTRACT FROM AUTHOR]

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 [ABSTRACT FROM AUTHOR]

Increased levels of branched-chain amino acids (BCAA) associate with insulin resistance and type 2 diabetes (T2D), which could result from dietary habits, gut microbiome composition or direct effects on cellular energy metabolism. We hypothesized that reduced dietary intake of BCAA improves whole body insulin sensitivity and hyperinsulinemia in patients with T2D. In a randomized, placebo-controlled, double-blinded, cross over trial, 12 metabolically well-controlled patients with T2D received an isocaloric diet (protein: 1 g/kg body weight), containing either the complete amino acid set (BCAA+) or a 60% reduction in BCAA (BCAA-) for 1 week each. Effects on glucose homeostasis were assessed from mixed meal tolerance tests (MMT) and hyperinsulinemic-euglycemic clamps (HEC, M-value), and pathways affecting insulin signaling were analyzed in muscle and adipose tissue biopsies. Microbiome composition was assessed by next generation sequencing. After the BCAA- diet, MMT-derived insulin secretion was 28% lower compared to the BCAA+ diet (p<0.05). After the BCAA- diet, MMT-derived insulin sensitivity (PREDIM, the validated predicted HEC-derived M-value from meal data), turned 23% higher (p<0.01), whereas HEC-derived insulin sensitivity (M-value) remained unchanged. Respiratory control ratio was 1.7-fold higher in adipose tissue (p<0.05), but unchanged in skeletal muscle. Mechanistic target of rapamycin (mTOR) was downregulated by 13% in adipose tissue (p<0.05). BCAA- diet was associated with a 40% increase of fecal Bacteroidetes and a 11% decrease of Firmicutes (both p<0.05). In conclusion, a short-term dietary reduction of BCAA decreases insulin secretion, increases postprandial insulin sensitivity, which may relate to adipocyte mitochondrial efficiency and altered gut microbiome composition in patients with T2D. Disclosure: Y. Karusheva: None. T. van Gemert: None. K. Strassburger: None. D.F. Markgraf: Research Support; Self; Sanofi. T. Jelenik: None. L. Mastrototaro: None. M. Simon: None. O.P. Zaharia: None. K. Bodis: None. F. Bärenz: None. D. Schmoll: Employee; Self; Sanofi-Aventis Deutschland GmbH. V. Burkart: None. K. Muessig: None. J. Szendroedi: None. M. Roden: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Poxel SA, Servier. Board Member; Self; Eli Lilly and Company. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi. Speaker's Bureau; Self; Novo Nordisk Inc. Funding: Sanofi Aventis Deutschland GmbH [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The article focuses on metabolic responsiveness to training depends on insulin sensitivity and protein content of exosomes in insulin-resistant males. Topics include the high-intensity interval training (HIIT) improves cardiorespiratory fitness (VO2max), but its impact on metabolism remains unclear, and the hypothesized that 12-week HIIT increases insulin sensitivity in males with or without type 2 diabetes [T2D and NDM (nondiabetic humans)].

It has traditionally been suggested that the early development of diabetic sensorimotor polyneuropathy (DSPN) is characterized by predominant and progressive injury to small nerve fibres followed by large fibre impairment. We alternatively hypothesized that small and large fibre damage due to DSPN in type 1 and type 2 diabetes could develop in parallel and may not only be progressive but also reversible. Participants from the German Diabetes Study baseline cohort with recent-onset type 1/type 2 diabetes (n = 350/570) and age-matched glucose-tolerant control individuals (Control 1/Control 2: n = 114/190) were assessed using nerve conduction studies, thermal detection thresholds, vibration perception thresholds, neuropathy symptom scores, neuropathy disability scores and intraepidermal nerve fibre density (IENFD) in skin biopsies (type 1/type 2 diabetes: n = 102/226; Control 1/Control 2: n = 109/208). Subsets of participants with type 1/type 2 diabetes were followed for 5 years (n = 184/307; IENFD subset: n = 18/69). DSPN was defined by the Toronto Consensus criteria. At baseline, DSPN was present in 8.1% and 13.3% of the type 1 and type 2 diabetes groups, respectively. The most frequently abnormal tests in the lower limbs below or above the 2.5th and 97.5th centiles of the controls were the IENFD (13.7%) and individual nerve conduction studies (up to 9.4%) in type 1 diabetes participants and IENFD (21.8%), malleolar vibration perception thresholds (17.5%), and individual nerve conduction studies (up to 11.8%) in those with type 2 diabetes, whereas thermal detection threshold abnormalities did not differ between the control and diabetes groups. After 5 years, the highest progression rates from the normal to the abnormal range in type 2 diabetes participants were found for IENFD (18.8%) by -4.1 ± 2.8 fibres/mm, malleolar vibration perception threshold (18.6%) by 9.1 ± 20.2 µm and nerve conduction studies (15.0%) by 3.7 ± 1.5 points, while vice versa the highest regression rates were observed for neuropathy disability scores (11.2%) by -3.1 ± 1.3 points, sural nerve amplitudes (9.1%) by 4.7 ± 3.0 µV, IENFD (8.7%) by 1.4 ± 1.3 fibres/mm, and neuropathy symptom scores (8.2%) by -5.8 ± 1.6 points. In type 1 diabetes participants, no major progression was seen after 5 years, but subclinical DSPN regressed in 10.3%. These findings point to early parallel damage to both small and large nerve fibres in well-controlled recent-onset type 2 and, to a lesser extent, type 1 diabetes. After 5 years, peripheral nerve morphology and function and clinical measures progress to the abnormal range in type 2 diabetes, but initial nerve alterations are also reversible to a meaningful degree. [ABSTRACT FROM AUTHOR]

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 [ABSTRACT FROM AUTHOR]

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 [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) is associated with abnormal mitochondrial capacity. While oxidative capacity can be increased in steatosis, hepatic ATP decreases in long-standing diabetes. However, longitudinal studies on diabetes-related NAFLD and its relationship to hepatic energy metabolism are lacking. This prospective study comprised volunteers with type 1 (T1DM, n = 30) and type 2 (T2DM, n = 37) diabetes. At diagnosis and 5 years later, we used 1H/31P magnetic resonance spectroscopy to measure hepatocellular lipid (HCL), γATP and inorganic phosphate (Pi) concentrations, and to assess adipose tissue volumes. Insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamps. At diagnosis, individuals with T2DM had higher HCL and adipose tissue volumes, but lower whole-body insulin sensitivity than those with T1DM, despite comparable glycemic control. NAFLD was present in 38% of individuals with T2DM and 7% with T1DM. After 5 years, visceral adipose tissue only increased in individuals with T2DM, while HCL almost doubled in this group (p < 0.001), resulting in a 70% prevalence of NAFLD (independent of diabetes treatment). Changes in HCL correlated with adipose tissue volume and insulin resistance (r = 0.50 and r = 0.44, both p < 0.05). Pi decreased by 17% and 10% in individuals with T2DM and T1DM (p < 0.05), respectively. In T1DM, HCL did not change, whereas γATP decreased by 10% and correlated negatively with glycated hemoglobin (r = -0.56, p < 0.05). The rapid increase in HCL during the early course of T2DM likely results from enlarging adipose tissue volume and insulin resistance in response to impaired hepatic mitochondrial adaptation. The decrease of phosphorus metabolites in T1DM may be due to pharmacological insulin supply. Previous studies suggested that the impaired function of mitochondria, the power plants of cells, can promote fatty liver and type 2 diabetes mellitus. This study now shows that during the first 5 years of type 2 diabetes the increase in body fat content rapidly leads to a doubling of liver fat content, whereas the energy metabolism of the patients' livers progressively declines. These data suggest that fat tissue mass and liver mitochondria have an important role in the development of fatty liver disease in humans with diabetes. NCT01055093 [Display omitted] • Hepatic lipids increase 2-fold in the early course of type 2 diabetes. • Patients with type 1 diabetes do not develop steatosis in first 5 years after diagnosis. • Adipose tissue mass and insulin resistance drive the development of steatosis. • Phosphorus metabolites decline in type 1 diabetes due to low portal insulin supply. [ABSTRACT FROM AUTHOR]

A novel clustering approach identified five subgroups of diabetes with distinct progression trajectories of complications. We hypothesized that these subgroups differ in multiple biomarkers of inflammation. Serum levels of 74 biomarkers of inflammation were measured in 414 individuals with recent adult-onset diabetes from the German Diabetes Study (GDS) allocated to five subgroups based on data-driven cluster analysis. Pairwise differences between subgroups for biomarkers were assessed with generalized linear mixed models before (model 1) and after (model 2) adjustment for the clustering variables. Participants were assigned to five subgroups: severe autoimmune diabetes (21%), severe insulin-deficient diabetes (SIDD) (3%), severe insulin-resistant diabetes (SIRD) (9%), mild obesity-related diabetes (32%), and mild age-related diabetes (35%). In model 1, 23 biomarkers showed one or more pairwise differences between subgroups (Bonferroni-corrected P < 0.0007). Biomarker levels were generally highest in SIRD and lowest in SIDD. All 23 biomarkers correlated with one or more of the clustering variables. In model 2, three biomarkers (CASP-8, EN-RAGE, IL-6) showed at least one pairwise difference between subgroups (e.g., lower CASP8, EN-RAGE, and IL-6 in SIDD vs. all other subgroups, all P < 0.0007). Thus, novel diabetes subgroups show multiple differences in biomarkers of inflammation, underlining a prominent role of inflammatory pathways in particular in SIRD. [ABSTRACT FROM AUTHOR]

Objective: The rs738409(G) single nucleotide polymorphism (SNP) in the patatin-like phospholipase domain-containing 3 (PNPLA3) gene associates with increased risk and progression of nonalcoholic fatty liver disease (NAFLD). As the recently described severe insulin-resistant diabetes (SIRD) cluster specifically relates to NAFLD, this study examined whether this SNP differently associates with hepatic lipid content (hepatocellular lipids [HCL]) and insulin sensitivity in recent-onset diabetes.Research Design and Methods: A total of 917 participants in the German Diabetes Study (GDS) underwent genotyping, hyperinsulinemic-euglycemic clamps with stable isotopic tracer dilution, and MRS.Results: The G allele associated positively with HCL (β = 0.36, P < 0.01), independent of age, sex, and BMI across the whole cohort, but not in the individual clusters. Those with SIRD exhibited lowest whole-body insulin sensitivity compared with those with severe insulin-deficient (SIDD), moderate obesity-related (MOD), moderate age-related (MARD), and severe autoimmune diabetes (SAID) clusters (all P < 0.001). Interestingly, the SIRD group presented with higher prevalence of the rs738409(G) SNP compared with other clusters and the glucose-tolerant control group (P < 0.05). HCL was higher in the SIRD group (median 13.6% [1st quartile 5.8; 3rd quartile 19.1] compared with the MOD (6.4 % [2.1; 12.4], P < 0.05), MARD (3.0% [1.0; 7.9], P < 0.001), SAID (0.4% [0.0; 1.5], P < 0.001), and glucose-tolerant (0.9% [0.4; 4.9), P < 0.001) group. Although the PNPLA3 polymorphism did not directly associate with whole-body insulin sensitivity in SIRD, the G-allele carriers had higher circulating free fatty acid concentrations and greater adipose tissue insulin resistance compared with noncarriers (both P < 0.001).Conclusions: Members of the SIRD cluster are more frequently carriers of the rs738409(G) variant. The SNP-associated adipose tissue insulin resistance and excessive lipolysis may contribute to their NAFLD. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Altered mitochondrial dynamics may contribute to impaired mitochondrial function and insulin sensitivity in type 2 diabetes (T2D). High intensity interval training (HIIT) can induce mitochondrial biogenesis in healthy humans, but its impact on mitochondrial remodeling in insulin resistant states is still unclear. To this end, this study examined the effect of HIIT on mitochondrial function and dynamics in T2D as well as in insulin resistant (IR) and sensitive (IS) glucose tolerant humans to elucidate the interplay between mitochondrial turnover and muscle insulin sensitivity. Twenty T2D, 11 IR and 12 IS humans age- and BMI-matched (HbA1c in %: 7.2 ± 0.2, 5.4 ± 0.1, 5.5 ± 0.1; M-value in mg*kg-1*min-1: 3.0 ± 0.4, 4.1 ± 0.3, 7.4 ± 0.4) performed a 12-week HIIT cycling protocol for 3 days/week. Before the intervention (baseline) and 72 h after the last exercise bout, whole-body insulin sensitivity was measured by hyperinsulinemic-euglycemic clamps, whereas mitochondrial respiration and dynamics were assessed by high resolution respirometry and immunoblotting of skeletal muscle biopsies. After HIIT, all participants showed improved cardiorespiratory fitness and increased muscle maximal oxygen uptake (p<0.001 vs. baseline), whereas insulin sensitivity increased only in T2D and IR (M-value; 4.3 ± 0.5 and 5.7 ± 0.6; p<0.01 vs. baseline). Moreover, HIIT doubled muscle citrate synthase activity in all groups, while biomarkers of mitochondrial fission (p<0.01), fusion (p<0.001) and mitophagy (p<0.001 for phospho-Parkin(Ser65) and p<0.05 for phospho-Pink(Thr257)) increased only in T2D. In conclusion, this study suggests that mitochondrial fusion and fission synergically respond to chronic exercise training and likely contribute to the exercise training response of insulin sensitivity at least in overt T2D. Targeting these mechanisms might help to better understand muscle insulin resistance and to identify novel therapeutic strategies for tailored prevention and treatment of T2D. Disclosure: L. Mastrototaro: None. M. Apostolopoulou: None. D. Pesta: None. K. Strassburger: None. Y. Karusheva: None. S. Gancheva: None. J. Szendroedi: None. M. Roden: Advisory Panel; Self; Allergan plc, Bristol-Myers Squibb Company, Novo Nordisk A/S, Research Support; Self; Boehringer Ingelheim International GmbH, Danone Nutricia, Sanofi-Aventis Deutschland GmbH. [ABSTRACT FROM AUTHOR]

The G-allele in the single-nucleotide polymorphism (SNP) rs738409 in the patatin-like phospholipase domain containing 3 (PNPLA3) gene associates with increased risk of nonalcoholic fatty liver disease (NAFLD) and its progression. As the recently-described severe insulin resistant diabetes (SIRD) cluster specifically relates to NAFLD, the present study examined whether this SNP differently associates with insulin sensitivity and hepatic lipid content (HCL) in clusters of new-onset diabetes patients. Participants (n=917) of the prospective German Diabetes Study underwent genotyping, hyperinsulinemic-euglycemic clamps and magnetic resonance spectroscopy. SIRD had the lowest whole-body insulin sensitivity compared to severe insulin deficient (SIDD), moderate obesity-related (MOD), moderate age-related (MARD) and severe autoimmune diabetes clusters (SAID; all p<0.001). Interestingly, SIRD presented with higher prevalence of the G-allele compared to other clusters and the glucose tolerant controls (p<0.05). Also, HCL was higher in SIRD [13.6 (5.8;19.1)%] compared to MOD [6.4 (2.1;12.4)%], MARD [3.0 (1.0;7.9)%], SAID [0.4 (0.0;1.5)%] and the glucose tolerant group [0.9 (0.4;4.9)%] (all p<0.05). Although the PNPLA3 polymorphism did not directly associate with whole-body insulin sensitivity or HCL in SIRD, G-allele carriers of this cluster had higher free fatty acids and greater adipose-tissue insulin resistance than non-carriers. In conclusion, SIRD patients are more frequently carriers of the G-allele which is associated with adipose-tissue insulin resistance and lipolysis. Together, these alterations may mutually accelerate NAFLD and progression of SIRD. Disclosure: O.P. Zaharia: None. K. Strassburger: None. B. Knebel: None. Y. Kupriyanova: None. Y. Karusheva: None. K. Bodis: None. M. Wolkersdorfer: None. D.F. Markgraf: None. V. Burkart: None. J. Hwang: None. J. Kotzka: None. H. Al-Hasani: Consultant; Self; Bayer AG. J. Szendroedi: None. M. Roden: Advisory Panel; Self; Servier. Board Member; Self; Poxel SA. Consultant; Self; Eli Lilly and Company, Gilead Sciences, Inc., ProSciento, TARGET PharmaSolutions. Research Support; Self; Boehringer Ingelheim International GmbH, Novartis Pharma K.K., Sanofi US. Speaker's Bureau; Self; Novo Nordisk A/S. Funding: German Federal Ministry of Health; Ministry of Culture and Science of North Rhine-Westphalia; German Federal Ministry of Education and Research; German Center for Diabetes Research [ABSTRACT FROM AUTHOR]

Small extracellular vesicles (SEV) are secreted into circulation after acute exercise suggesting a new mode of tissue crosstalk. High intensity interval training (HIIT) leads to improved insulin sensitivity and oxidative capacity in patients with type 2 diabetes. As the impact of HIIT on SEV release is unknown, this study examined its effects on number and proteome of SEV in insulin sensitive (IS) and insulin resistant (IR) humans to identify biomarkers for the early prediction of individual responses of insulin sensitivity to exercising. Eight T2D, 8 glucose tolerant IR and 6 IS humans with similar age and BMI (HbA1c in %: 7.4 ± 0.4, 5.3 ± 0.1, 5.5 ± 0.1; M-value in mg*kg-1*min-1: 1.8 ± 0.4, 4.1 ± 0.4, 7.2 ± 0.5) performed a 12-weeks HIIT cycling protocol for 3 days/week. Before the intervention (baseline) and 72 h after the last exercise bout, whole-body insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamps and serum samples were collected to isolate SEV by size exclusion chromatography. SEV size and number were measured by Nanoparticle Tracking Analysis and proteomic profiling was done by mass spectrometry using data independent acquisition. After 12 weeks of HIIT, T2D and IR improved their insulin sensitivity (M-value: T2D 3.5 ± 0.8, IR 6.2 ± 0.7; p<0.01 vs. baseline) and increased the number of circulating SEV by 52 ± 19% and 58 ± 21% (p<0.05 vs. baseline). Quantitative proteomic analysis of SEV revealed that HIIT regulated 258 proteins (118 in T2D, 125 in IR, 89 in IS) with an enrichment of proteins related to glycolysis in T2D, to antioxidative metabolism in IR and to lipid metabolism in IS. In conclusion, HIIT increases SEV number, but differently affects SEV mass and proteome in IS and IR humans, suggesting that SEV cargo could contribute to the individual response of insulin sensitivity to HIIT. Detailed characterization of SEV cargo can help to better understand the mechanisms of tissue crosstalk in the adaptation to exercise training and to develop novel exercise mimetics. Disclosure: L. Mastrototaro: None. M. Apostolopoulou: None. S. Hartwig: None. D. Pesta: None. K. Strassburger: None. E. DeFilippo: None. Y. Karusheva: None. S. Gancheva: None. D.F. Markgraf: None. S. Lehr: None. K. Mussig: None. H. Al-Hasani: Consultant; Self; Bayer AG. J. Szendroedi: None. M. Roden: Advisory Panel; Self; Servier. Board Member; Self; Poxel SA. Consultant; Self; Eli Lilly and Company, Gilead Sciences, Inc., ProSciento, TARGET PharmaSolutions. Research Support; Self; Boehringer Ingelheim International GmbH, Novartis Pharma K.K., Sanofi US. Speaker's Bureau; Self; Novo Nordisk A/S. [ABSTRACT FROM AUTHOR]

Emerging evidence suggests that obesity and insulin resistance play a role in the development of diabetic cardiac autonomic neuropathy (CAN) characterized by reduced heart rate variability (HRV). In this context we assessed the relationship of 127 biomarkers of lipid metabolism (11 acylcarnitines, 39 free fatty acids, 12 sphingomyelins, 56 phosphatidylcholines, and 9 lysophosphatidylcholines) in plasma using mass spectrometry with HRV indices in individuals with recent-onset type 1 (T1D) or type 2 diabetes (T2D) from the baseline cohort (known diabetes duration (DD) ≤1 year) of the German Diabetes Study (T1D/T2D [mean±SD]: n=126/243; age: 34.5±12.9/53.4±11.0 years; BMI: 24.7±4.3/31.7±6.0 kg/m²; DD: 211±93/198±90 days; HbA1c: 6.8±1.4/6.5±0.9 %). Time domain and frequency domain HRV indices were derived from NN intervals recorded during a 3 h hyperinsulinemic-euglycemic clamp. After adjustment for age, sex, and BMI as well as Bonferroni correction including seven HRV parameters and the number of metabolites of the corresponding lipid class, higher levels of three free fatty acids (myristic acid: β=-0.14, p=0.049; palmitic acid: β=-0.19, p=0.007; palmitoleic acid: β=-0.15, p=0.048), eight phosphatidylcholines (e.g., phosphatidylcholine diacyl (PC aa) C32:0: β=-0.28, p<0.001; phosphatidylcholine acyl-alkyl C34:3: β=-0.20, p<0.004), and two sphingomyelins (sphingomyelin C16:0: β=-0.15, p=0.028; sphingomyelin C16:1: β=-0.18, p=0.020) were inversely associated with the standard deviation of NN intervals (SDNN) in recent-onset T2D but not T1D. PC aa C32:0 was inversely associated with both low (LF) and high frequency (HF) power spectrum in T2D (LF: β=-0.23, p=0.001; HF: β=-0.23, p=0.001). In conclusion, the link between higher plasma levels of specific lipid metabolites and early cardiac autonomic dysfunction in recent-onset type 2 diabetes suggests that plasma lipid panels could be useful to improve the prediction of the development or progression of CAN. Disclosure: G.J. Bönhof: None. A. Strom: None. K. Strassburger: None. B. Knebel: None. J. Kotzka: None. H. Al-Hasani: Consultant; Self; Bayer AG. J. Szendroedi: None. O.P. Zaharia: None. Y. Karusheva: None. M. Roden: Advisory Panel; Self; Servier. Board Member; Self; Poxel SA. Consultant; Self; Eli Lilly and Company, Gilead Sciences, Inc., ProSciento, TARGET PharmaSolutions. Research Support; Self; Boehringer Ingelheim International GmbH, Novartis Pharma K.K., Sanofi US. Speaker's Bureau; Self; Novo Nordisk A/S. D. Ziegler: None. [ABSTRACT FROM AUTHOR]

Background: The development of anti-inflammatory therapies for renal function loss in patients with diabetes requires identification of specific biomarkers which might differ by diabetes type. This study aimed to investigate associations between a novel panel of biomarkers of inflammation and estimated glomerular filtration rate (eGFR) in patients with type 1 diabetes (T1D) and type 2 diabetes (T2D). Methods: This study was based on 145 participants with T1D (mean age 33.8 years, 60.7% males) and 250 participants with T2D (mean age 55.3 years, 66.4% males) from the observational prospective German Diabetes Study (GDS), which includes adults with a diabetes duration <1 year. A panel of 74 biomarkers of inflammation was measured in serum of fasted participants using the proximity extension assay technology. eGFR was calculated from serum creatinine and cystatin C using the CKD-EPI equation. Associations between each biomarker and eGFR were assessed using multiple linear regression adjusting for age, sex, BMI, HbA1c, diabetes duration, lipids, hypertension and use of NSAIDs and glucose-lowering drugs. Results: Baseline eGFR was higher in T1D compared to T2D (mean (SD) 101.8 (15.3) vs. 89.3 (15.6) mL/min/1.73 m2; P<0.0001). After correction for multiple testing, 6 and 24 biomarkers were inversely associated with eGFR in T1D and T2D, respectively (all P<0.05). TNFB was T1D-specific, while ADA, CD40, CD244, CCL3, CCL20, CCL25, CX3CL1, CXCL9, CSF1, CST5, FGF23, FGF5, IL-15RA, IL12B, MMP10, NT3, SCF, TGFα and uPA were T2D-specific. CCL23, CD5, IL10RB, PDL1 and TNFRSF9 were associated with eGFR in both diabetes types. Conclusion: We identified novel inflammatory biomarkers, independently associated with eGFR in adults with recently diagnosed T1D and T2D. As a next step, these biomarkers shall be evaluated as potential predictors of incident and progressive diabetic nephropathy. Disclosure: H. Maalmi: None. C. Herder: Research Support; Self; Sanofi-Aventis. K. Strassburger: None. S. Urner: None. K. Jandeleit-Dahm: None. O.P. Zaharia: None. Y. Karusheva: None. K. Bodis: None. W. Rathmann: Advisory Panel; Self; AstraZeneca. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc. Research Support; Self; Novo Nordisk Inc. Speaker's Bureau; Self; Eli Lilly and Company, Novo Nordisk Inc. D.F. Markgraf: None. V. Burkart: None. J. Szendroedi: None. M. Roden: Advisory Panel; Self; Servier. Board Member; Self; Poxel SA. Consultant; Self; Eli Lilly and Company, Gilead Sciences, Inc., ProSciento, TARGET PharmaSolutions. Research Support; Self; Boehringer Ingelheim International GmbH, Novartis Pharma K.K., Sanofi US. Speaker's Bureau; Self; Novo Nordisk A/S. [ABSTRACT FROM AUTHOR]

Cluster analysis using age, BMI, glycemia and homeostasis model estimates (HOMA-IR, -B) revealed distinct risk profiles for progression of diabetic nephropathy in large cohorts, but its relevance for other diabetes-related comorbidities remains unclear. We aimed to (i) examine whether intensified phenotyping would confirm the results of this cluster analysis and (ii) test the hypothesis that liver fat content (HCL), as marker of nonalcoholic fatty liver disease (NAFLD), differs among clusters at diabetes diagnosis and during follow-up. Thus, this cluster analysis was applied to recent-onset patients with non-autoimmune diabetes of the German Diabetes Study. This identified 286 mild age-related (MARD, 44%), 268 mild obesity-related (MOD, 42%), 66 severe insulin-resistant (SIRD, 10%) and 27 severe insulin-deficient (SIDD, 4%) diabetes patients. Furthermore, whole-body insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamps, HCL by magnetic resonance spectroscopy and hepatic fibrosis by a noninvasive score (NAFLD-FS). Congruently, whole-body insulin sensitivity was lowest in SIRD compared to MOD, SIDD and MARD (4.3±2.0 vs. 5.6±2.4, 6.5±2.6, 7.6±2.8 mg*kg-¹*min-¹, all p<0.05). In SIRD, HCL (14±4%) was higher than in SIDD (5±2%), MOD (9±1%) and MARD (7±1%) (all p<0.05). In SIRD, HCL negatively correlated with whole-body insulin sensitivity (r=-0.27, p<0.05). NAFLD-FS was highest in SIRD (0.4) compared to SIDD (-2.9), MOD (-0.8) and MARD (-0.8) (all p<0.05). At the 5-year follow-up (n=159), whole-body insulin sensitivity remained lowest in SIRD (p<0.05 vs. all clusters) with no difference in changes between clusters. Also, significant fibrosis (NAFLD-FS >0.6) was highest in SIRD (21%) compared to SIDD (0%), MOD (16%) and MARD (11%). In conclusion, patients of the SIRD cluster exhibit higher prevalence of steatosis at diagnosis and increased risk of NAFLD progression over 5 years. Disclosure: O.P. Zaharia: None. K. Strassburger: None. Y. Kupriyanova: None. Y. Karusheva: None. S. Antoniou: None. K. Bodis: None. O. Asplund: Research Support; Self; Eli Lilly and Company. V. Burkart: None. K. Muessig: None. J. Hwang: None. O. Kuss: None. L. Groop: None. E. Ahlqvist: None. J. Szendroedi: None. M. Roden: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Poxel SA, Servier. Board Member; Self; Eli Lilly and Company. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi. Speaker's Bureau; Self; Novo Nordisk Inc. Funding: German Ministry of Culture and Science of the State of North Rhine-Westphalia; German Federal Ministry of Health; German Federal Ministry of Education and Research [ABSTRACT FROM AUTHOR]

Knockdown of the gene encoding transmembrane 6 superfamily member 2 protein (TM6SF2) in mice increases hepatocellular lipid content (HCL) and decreases very low-density lipoprotein secretion. Humans with TM6SF2 mutations are at higher risk of nonalcoholic fatty liver disease, but lower risk of cardiovascular disease. The relevance of TM6SF2 mutations for HCL and insulin sensitivity in type 2 diabetes is less clear. This study aimed at elucidating the relevance of the E167K (SNP rs58542926) mutation in the gene encoding TM6SF2 for HCL, hepatic insulin sensitivity and whole-body insulin sensitivity in type 2 diabetes. We compared male patients with recently diagnosed type 2 diabetes with (n=16) or without (n=16) E167K mutation, matched for age and BMI (50±1 vs. 48±3 years; 32±1 vs. 32±2 kg/m2) from the German Diabetes Study. Whole-body and hepatic insulin sensitivity were assessed by Botnia-clamp tests with [6,6-2H2]glucose, HCL by 1H magnetic resonance spectroscopy and hepatic fibrosis by the fibrosis-4 index (FIB4). Patients with and without TM6SF2 mutation had comparable levels of HbA1c (6.2±0.2 vs. 5.9±0.1%) and serum triglycerides (136±14 vs. 149±14 mg/dl). Carriers of TM6SF2 mutation had higher HCL (9.0±1.9 vs. 4.6±0.4%, p<0.05) and whole-body insulin sensitivity (7.1±0.6 vs. 5.4±0.2 mg/(kg*min), p<0.05), but similar hepatic insulin sensitivity (1.6±0.1 vs. 1.6±0.1 mg/(kg*min)) and fibrosis score (1.2±0.1 vs. 1.0±0.1). In conclusion, the E167K mutation of the TM6SF2 gene dissociates liver steatosis from whole-body insulin sensitivity. This may result from favored trapping of triglycerides within the liver, which would in turn protect peripheral tissues from insulin resistance induced by liver-derived lipids. Disclosure: K. Bodis: None. J. Szendroedi: None. J.M. Ahlers: None. Y. Karusheva: None. O.P. Zaharia: None. S. Antoniou: None. B. Knebel: None. Y. Kupriyanova: None. J. Hwang: None. V. Burkart: None. K. Muessig: None. H. Al-Hasani: None. M. Roden: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Poxel SA, Servier. Board Member; Self; Eli Lilly and Company. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi. Speaker's Bureau; Self; Novo Nordisk Inc. D.F. Markgraf: Research Support; Self; Sanofi. [ABSTRACT FROM AUTHOR]

Hepatic insulin metabolism in patients with newly diagnosed diabetes is not yet understood. Insulin clearance seems to be decreased in patients with obesity, visceral adiposity and type 2 diabetes (T2D), but data compared to glucose tolerant humans have been inconclusive. To this end, persons with type 1 diabetes (T1D; n=124) or type 2 diabetes (T2D; n=401) and glucose-tolerant humans (CON; n=245) underwent hyperinsulinemic-euglycemic clamps to assess insulin sensitivity (IS) and whole-body insulin clearance (ICWBIC, ml x kg-1 x min-1). Hepatic insulin clearance was also calculated from the ratio of the areas under the curve of plasma C-peptide and insulin (0-60 min) during intravenous glucose-tolerance test (IVGTT, 0-60 min) and mixed meal tolerance test (MMTT, 0-180 min). Hepatocellular lipid content (HCL) was measured by 1H-magnetic resonance spectroscopy. Analyses were adjusted for age, sex and BMI. In T1D, ICIVGTT (1.71±1.1 vs. 2.3±0.3 and 3.2±0.3, all p<0.05) as well as ICMMT (1.6±0.7 vs. 2.0±0.4 and 2.1±0.3, all p<0.05) were lowest compared to T2D and CON respectively and correlated negatively with HbA1c (r=-0.242 and r=-0.279, both p<0.05). In T2D, ICIVGTT was positively correlated with HbA1c (r=0.178, p<0.05) as well as with IS (r=0.242, p<0.05). T2D patients with hepatic steatosis (n=73) had lower ICIVGTT, ICWBIC as well as ICMMT (2.2±0.31 vs. 2.4±0.31, 1.4±0.4 vs. 1.5±0.4 and 1.9 ±0.3 vs. 2.1±0.2 respectively, (i.e., differences of 8%, 9% and 7%, all p<0.05) compared to T2D without steatosis (n=53). CON with steatosis also had lower ICIVGTT (n=103, 2.1±0.2 vs. 2.3±0.35, p<0.05). ICMMT positively correlated with IS (r=0.338 and r=0.187, both p<0.05) in T1D and T2D, but not in CON. In conclusion, glycemic control likely impairs insulin clearance particularly in T1D patients, whereas steatosis affects insulin clearance in T2D and in glucose tolerant humans. Disclosure: S. Antoniou: None. O.P. Zaharia: None. K. Strassburger: None. Y. Karusheva: None. K. Bodis: None. Y. Kupriyanova: None. V. Burkart: None. K. Muessig: None. A. Gastaldelli: Consultant; Self; A. Menarini Diagnostics, Eli Lilly and Company, Genentech, Inc., Gilead Sciences, Inc., Inventiva Pharma. M. Roden: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Poxel SA, Servier. Board Member; Self; Eli Lilly and Company. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi. Speaker's Bureau; Self; Novo Nordisk Inc. J. Szendroedi: None. [ABSTRACT FROM AUTHOR]