We performed the largest randomized, placebo-controlled clinical trial to date (N = 112, 12-week intervention) to investigate the effects and safety of resveratrol supplementation on liver fat content and cardiometabolic risk parameters in overweight and obese and insulin-resistant subjects. At baseline the variability in liver fat content was very large, ranging from 0.09% to 37.55% (median, 7.12%; interquartile range, 3.85%-12.94%). Mean (SD) liver fat content was 9.22 (6.85) % in the placebo group and 9.91 (7.76) % in the resveratrol group. During the study liver fat content decreased in the placebo group (-0.7%) but not in the resveratrol group (-0.03%) (differences between groups: P = .018 for the intention-to-treat [ITT] population; N = 54, resveratrol, N = 54, placebo and P = .0077 for the per protocol [PP] population). No effects of resveratrol supplementation on cardiometabolic risk parameters were observed. Resveratrol supplementation was well tolerated and safe. In conclusion, these data suggest that resveratrol supplementation is safe and that it does not considerably impact liver fat content or cardiometabolic risk parameters in humans.

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There is increasing evidence for a role of the metabolic syndrome (MetS) during development of distal sensorimotor polyneuropathy (DSPN). We hypothesized that MetS components are differentially associated with measures of DSPN in individuals with normal glucose tolerance (NGT) and early type 2 diabetes (T2D). Electrophysiological and quantitative sensory testing was performed in 180 participants with NGT and 355 with recent-onset T2D (known diabetes duration <1 year) matched for age from the German Diabetes Study (NGT/T2D [mean±SD]: age: 43.9±14.0/45.1±7.7 years; sex: 61/65% male; BMI: 26.8±5.0/32.3±6.5 kg/m²; HbA1c: 5.2±0.3/6.5±1.0%). Intraepidermal nerve fiber density (IENFD) was assessed in 218 individuals (NGT/T2D: n=117/101). Subsets of participants were followed for 5 years (NGT/T2D: n=48/53). MetS was defined according to International Diabetes Federation (2006) and DSPN according to Toronto consensus criteria (2011). After adjustment for age, sex, height, smoking and HbA1c, a lower IENFD was associated with higher weight (β=-0.306), number of MetS components (NMetSC; β=-0.222) and presence of central obesity (β=-0.292), while higher malleolar vibration perception threshold was associated with weight (β=0.219) in NGT (P<0.05), but not in T2D. Median motor nerve conduction velocity and sural sensory nerve action potential were inversely associated with weight (β=-0.182/-0.286), NMetSC (β=-0.127/-0.128), presence of central obesity (β=-0.163/-0.165), and MetS (β=-0.169/-0.203) in T2D (P<0.05). Higher weight predicted the presence of DSPN at 5 years (β=0.652, P=0.001) in NGT, while increasing NMetSC and MetS prevalence predicted a decline in IENFD over 5 years (β=-0.533/-0.388, P=0.001/0.013) in T2D. This suggests that obesity indices can predict DSPN over 5 years in NGT, while MetS and its components are differentially associated with measures of DSPN in early, well-controlled type 2 diabetes compared with NGT. Disclosure G.Sipola: None. A.Strom: None. M.Bombrich: None. R.Wagner: Advisory Panel; Daiichi Sankyo, Speaker's Bureau; Novo Nordisk, Sanofi. D.Ziegler: None. M.Roden: Advisory Panel; Eli Lilly and Company, Consultant; TARGET PharmaSolutions, Inc., Research Support; Boehringer-Ingelheim, Novo Nordisk, Novartis, Sanofi. G.J.Bönhof: None. Gds group: n/a. Funding German Federal Ministry of Health; Ministry of Innovation, Science, Research and Technology of the state North Rhine-Westphalia; German Federal Ministry of Education and Research

<p>Intramyocellular lipid content (IMCL) is elevated in insulin-resistant humans, but its 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 controls (n=128) underwent 1H-magnetic resonance spectroscopy 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, M-value was ~36% and ~62% lower compared to type 1 diabetes and controls, respectively. After 5 years, M-value decreased by ~29% in type 1 and ~13% in type 2 diabetes, whereas IMCL remained unchanged. The correlation of IMCL and M-value in type 2 diabetes at baseline was modulated by VO2max. IMCL also associated with microalbuminuria, Framingham risk score for cardiovascular disease and cardiac autonomic neuropathy. Changes in IMCL within 5 years after diagnosis do not mirror progression of insulin resistance in type 2 diabetes but associate with early diabetes-related complications.</p>

<p>Intramyocellular lipid content (IMCL) is elevated in insulin-resistant humans, but its 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 controls (n=128) underwent 1H-magnetic resonance spectroscopy 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, M-value was ~36% and ~62% lower compared to type 1 diabetes and controls, respectively. After 5 years, M-value decreased by ~29% in type 1 and ~13% in type 2 diabetes, whereas IMCL remained unchanged. The correlation of IMCL and M-value in type 2 diabetes at baseline was modulated by VO2max. IMCL also associated with microalbuminuria, Framingham risk score for cardiovascular disease and cardiac autonomic neuropathy. Changes in IMCL within 5 years after diagnosis do not mirror progression of insulin resistance in type 2 diabetes but associate with early diabetes-related complications.</p>

Recent studies identified distinct endotypes of diabetes with differences in metabolic features and in risk for diabetes-related comorbidities. Of note, persons allocated to the severe insulin resistant diabetes (SIRD) endotype, who show increased prevalence of nonalcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD), are more frequently carriers of the G-allele in the single-nucleotide polymorphism (SNP) rs738409 in the patatin-like phospholipase domain containing 3 (PNPLA3) gene. This SNP associates with increased risk of NAFLD yet the association between the presence of the PNPLA3 SNP and CKD remains controversial. The present study examined whether this SNP differently associates with CKD in endotypes of recent-onset diabetes. Participants with newly diagnosed diabetes (n=707) from the prospective German Diabetes Study underwent k-means clustering, genotyping, magnetic resonance spectroscopy to determine hepatocellular lipid content (HCL) and laboratory analyses to calculate the glomerular filtration rates (eGFR). SIRD had the lowest eGFR and highest HCL compared to severe insulin deficient, moderate obesity-related, moderate age-related and severe autoimmune diabetes clusters (all p&lt;0.05). HCL was negatively associated with eGFR (r=-0.287, p&lt;0.01) across all groups. Further stratification by PNPLA3 G-allele carrier status did not reveal any association between HCL and eGFR in any of the diabetes types, irrespective of G-allele carrier status. However, with declining eGFR the proportion of G-allele carriers increased from 44% for eGFR &gt;60 ml/min to 52% for eGFR &lt;60 ml/min (p&lt;0.05). In conclusion, increased hepatic lipid content is associated with reduced kidney function across all diabetes endotypes. This association is independent of the presence of the PNPLA3 polymorphism in newly diagnosed diabetes, but there might be role for PNPLA3 for the severity of CKD. Disclosure O.P. Zaharia: None. K. Strassburger: None. B. Knebel: None. Y. Kupriyanova: None. J. Kotzka: None. K. Bódis: None. M. Schön: None. M. Bombrich: None. C. Möser: None. K. Prystupa: Other Relationship; Berlin-Chemie AG. H. Al-Hasani: None. V. Schrauwen-Hinderling: None. K. Jandeleit-Dahm: None. R. Wagner: Speaker's Bureau; Novo Nordisk, Sanofi. Advisory Panel; Daiichi Sankyo. M. Roden: Advisory Panel; Eli Lilly and Company. Research Support; Boehringer-Ingelheim, Novo Nordisk, Novartis. Consultant; TARGET PharmaSolutions, Inc. Research Support; Sanofi. Funding German Research Foundation; European Foundation for the Study of Diabetes; German Diabetes Association; German Federal Ministry of Education and Research; Heinrich Heine University

Increased hepatocellular lipid content (HCL) is generally linked to insulin resistance, which contributes to greater risk of type 2 diabetes and cardiovascular 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. Thus, this case-control study tested the role of this polymorphism for tissue-specific insulin sensitivity during the early course of diabetes. Males with recent-onset type 2 diabetes with (TM6SF2EK: n=16) or without (TM6SF2EE: n=16) the heterozygous TM6SF2 polymorphism of similar age and BMI, underwent Botnia-clamps with [6,6-2H2]glucose to measure whole-body, hepatic and adipose tissue insulin sensitivity. HCL and liver fibrosis were assessed with 1H-magnetic resonance spectroscopy and non-invasive tests (FIB4, APRI, AST/ALT), respectively. 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 even 27% higher whole-body insulin sensitivity than TM6SF2EE. The novel diabetes endotypes were equally distributed among both groups. After 5 years, whole-body insulin sensitivity, HCL and liver fibrosis indices were similar, while adipose tissue insulin sensitivity decreased by 87% and 55% both in TM6SF2EK and TM6SF2EE and circulating triacylglycerol increased in TM6SF2EE only. The TM6SF2 gene polymorphism rs58542926 dissociates ectopic fat content from insulin resistance in recent-onset type 2 diabetes, which is however attenuated by disease duration. This suggests that diabetes-related metabolic alterations dominate over the effects of the TM6SF2 gene polymorphism during the early course of diabetes and NAFLD. Disclosure K.Bódis: None. R.Guthoff: Other Relationship; Alimera, Bayer Inc., Novartis, Allergan. V.Schrauwen-hinderling: None. H.Al-hasani: None. V.Burkart: None. J.Szendroedi: None. R.Wagner: Advisory Panel; Daiichi Sankyo, Speaker's Bureau; Novo Nordisk, Sanofi. D.F.Markgraf: Employee; Boehringer Ingelheim Pharma GmbH&Co.KG. M.Roden: Advisory Panel; Eli Lilly and Company, Consultant; TARGET PharmaSolutions, Inc., Research Support; Boehringer-Ingelheim, Novo Nordisk, Novartis, Sanofi. M.Bombrich: None. M.Schön: None. B.Knebel: None. O.P.Zaharia: None. G.J.Bönhof: None. Y.Karusheva: None. Y.Kupriyanova: None. J.Kotzka: None.

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