Search

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]

Objective: To evaluate whether the sodium-glucose cotransporter 2 inhibitor empagliflozin (EMPA) reduces liver fat content (LFC) in recent-onset and metabolically well-controlled type 2 diabetes (T2D).Research Design and Methods: Patients with T2D (n = 84) (HbA1c 6.6 ± 0.5% [49 ± 10 mmol/mol], known disease duration 39 ± 27 months) were randomly assigned to 24 weeks of treatment with 25 mg daily EMPA or placebo. The primary end point was the difference of the change in LFC as measured with magnetic resonance methods from 0 (baseline) to 24 weeks between groups. Tissue-specific insulin sensitivity (secondary outcome) was assessed by two-step clamps using an isotope dilution technique. Exploratory analysis comprised circulating surrogate markers of insulin sensitivity and liver function. Statistical comparison was done by ANCOVA adjusted for respective baseline values, age, sex, and BMI.Results: EMPA treatment resulted in a placebo-corrected absolute change of -1.8% (95% CI -3.4, -0.2; P = 0.02) and relative change in LFC of -22% (-36, -7; P = 0.009) from baseline to end of treatment, corresponding to a 2.3-fold greater reduction. Weight loss occurred only with EMPA (placebo-corrected change -2.5 kg [-3.7, -1.4]; P < 0.001), while no placebo-corrected change in tissue-specific insulin sensitivity was observed. EMPA treatment also led to placebo-corrected changes in uric acid (-74 mol/L [-108, -42]; P < 0.001) and high-molecular-weight adiponectin (36% [16, 60]; P < 0.001) levels from 0 to 24 weeks.Conclusions: EMPA effectively reduces hepatic fat in patients with T2D with excellent glycemic control and short known disease duration. Interestingly, EMPA also decreases circulating uric acid and raises adiponectin levels despite unchanged insulin sensitivity. EMPA could therefore contribute to the early treatment of nonalcoholic fatty liver disease in T2D. [ABSTRACT FROM AUTHOR]

Objective: Both impaired cardiorespiratory fitness (CRF) and heart rate variability (HRV) are predictors of mortality, but their relative roles in recent-onset diabetes are unknown. We determined to which extent CRF and HRV are reduced and interrelated in recent-onset diabetes.Research Design and Methods: Participants from the German Diabetes Study with type 1 (n = 163) or type 2 (n = 188) diabetes with known diabetes duration <1 year and two age-matched glucose-tolerant control groups (n = 40 each) underwent spiroergometry and HRV assessment during a hyperinsulinemic-euglycemic clamp.Results: Compared with control subjects, patients with type 2 diabetes showed reduced VO2max (median [1st-3rd quartiles] 19.3 [16.5-22.9] vs. 25.6 [20.7-29.9] mL/kg body weight/min; P < 0.05), diminished VCO2max (23.0 [19.1-26.8] vs. 30.9 [24.5-34.4] mL/kg body weight/min; P < 0.05), blunted heart rate recovery after 2 min (-29.0 [-35.0 to -23.0] vs. -36.0 [-42.8 to -28.0] beats/min; P < 0.05), and reduced HRV in four of nine indices, whereas patients with type 1 diabetes had unaltered CRF but reduced HRV in three of nine indices (P < 0.05), indicating diminished vagal and sympathetic HRV modulation. HRV measures correlated with VO2max in patients with type 1 diabetes (r >0.34; P < 0.05) but not in those with type 2 diabetes.Conclusions: CRF is reduced in recently diagnosed type 2 diabetes but preserved in type 1 diabetes, whereas cardiac autonomic function is reduced in both diabetes types but is strongly associated with CRF only in type 1 diabetes. These results support the therapeutic concept of promoting physical fitness in the early course of diabetes. [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]

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: Both impaired cardiorespiratory fitness (CRF) and heart rate variability (HRV) are predictors of mortality, but their relative roles in recent-onset diabetes are unknown. We determined to which extent CRF and HRV are reduced and interrelated in recent-onset diabetes., Research Design and Methods: Participants from the German Diabetes Study with type 1 (n = 163) or type 2 (n = 188) diabetes with known diabetes duration <1 year and two age-matched glucose-tolerant control groups (n = 40 each) underwent spiroergometry and HRV assessment during a hyperinsulinemic-euglycemic clamp., Results: Compared with control subjects, patients with type 2 diabetes showed reduced VO 2max (median [1st-3rd quartiles] 19.3 [16.5-22.9] vs. 25.6 [20.7-29.9] mL/kg body weight/min; P < 0.05), diminished VCO 2max (23.0 [19.1-26.8] vs. 30.9 [24.5-34.4] mL/kg body weight/min; P < 0.05), blunted heart rate recovery after 2 min (-29.0 [-35.0 to -23.0] vs. -36.0 [-42.8 to -28.0] beats/min; P < 0.05), and reduced HRV in four of nine indices, whereas patients with type 1 diabetes had unaltered CRF but reduced HRV in three of nine indices (P < 0.05), indicating diminished vagal and sympathetic HRV modulation. HRV measures correlated with VO 2max in patients with type 1 diabetes (r >0.34; P < 0.05) but not in those with type 2 diabetes., Conclusions: CRF is reduced in recently diagnosed type 2 diabetes but preserved in type 1 diabetes, whereas cardiac autonomic function is reduced in both diabetes types but is strongly associated with CRF only in type 1 diabetes. These results support the therapeutic concept of promoting physical fitness in the early course of diabetes., (© 2017 by the American Diabetes Association.)