An Empirical Approach to Derive Water T<inf>1</inf> from Multiparametric MR Images Using an Automated Pipeline and Comparison With Liver Stiffness

Background: Water T1 of the liver has been shown to be promising in discriminating the progressive forms of fatty liver diseases, inflammation, and fibrosis, yet proper correction for iron and lipid is required. Purpose: To examine the feasibility of an empirical approach for iron and lipid correction when measuring imaging-based T1 and to validate this approach by spectroscopy on in vivo data. Study Type: Retrospective. Population: Next to mixed lipid-iron phantoms, individuals with different hepatic lipid content were investigated, including people with type 1 diabetes (N = 15, %female = 15.6, age = 43.5 ± 14.0), or type 2 diabetes mellitus (N = 21, %female = 28.9, age = 59.8 ± 9.7) and healthy volunteers (N = 9, %female = 11.1, age = 58.0 ± 8.1). Field Strength/Sequences: 3 T, balanced steady-state free precession MOdified Look-Locker Inversion recovery (MOLLI), multi- and dual-echo gradient echo Dixon, gradient echo magnetic resonance elastography (MRE). Assessment: T1 values were measured in phantoms to determine the respective correction factors. The correction was tested in vivo and validated by proton magnetic resonance spectroscopy (1H-MRS). The quantification of liver T1 based on automatic segmentation was compared to the T1 values based on manual segmentation. The association of T1 with MRE-derived liver stiffness was evaluated. Statistical Tests: Bland–Altman plots and intraclass correlation coefficients (ICCs) were used for MOLLI vs. 1H-MRS agreement and to compare liver T1 values from automatic vs. manual segmentation. Pearson's r correlation coefficients for T1 with hepatic lipids and liver stiffness were determined. A P-value of 0.05 was considered statistically significant. Results: MOLLI T1 values after correction were found in better agreement with the 1H-MRS-derived water T1 (ICC = 0.60 [0.37; 0.76]) in comparison with the uncorrected T1 values (ICC = 0.18 [-0.09; 0.44]). Automatic quantification yielded similar liver T1 values (ICC = 0.9995 [0.9991; 0.9997]) as with manual segmentation. A significant correlation of T1 with liver stiffness (r = 0.43 [0.11; 0.67]) was found. A marked and significant reduction in the correlation strength of T1 with liver stiffness (r = 0.05 [-0.28; 0.38], P = 0.77) was found after correction for hepatic lipid content. Data Conclusion: Imaging-based correction factors enable accurate estimation of water T1 in vivo. Level of Evidence: 1. Technical Efficacy: Stage 1

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

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

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

Empagliflozin Effectively Lowers Liver Fat Content in Well-Controlled Type 2 Diabetes: A Randomized, Double-Blind, Phase 4, Placebo-Controlled Trial

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 ( = 84) (HbA 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 of -1.8% (95% CI -3.4, -0.2%; = 0.02) and relative change in LFC of -22% (-36, -7%; = 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 kg]; < 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 mol/L]; < 0.001) and high-molecular-weight adiponectin (36% [16, 60%]; < 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

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 (p$_{dim1}$<0·0001, p$_{dim2}$=0·00097) across the tree. Individuals in the region with the lowest insulin sensitivity had the highest hepatic lipid content (n=205, p$_{dim1}$<0·0001, p$_{dim2}$=0·037), pro-inflammatory biomarkers (IL-6: n=348, p$_{dim1}$<0·0001, p$_{dim2}$=0·013; IL-18: n=350, p$_{dim1}$<0·0001, p$_{dim2}$=0·38), and elevated cardiovascular risk (n$_{events}$=143, p$_{dim1}$=0·14, p$_{dim2}$<0·00081), whereas individuals positioned in the branch with the lowest insulin secretion were more prone to require insulin therapy (n$_{events}$=85, p$_{dim1}$=0·032, p$_{dim2}$=0·12) and had the highest risk of diabetic sensorimotor polyneuropathy (n$_{events}$=184, p$_{dim1}$=0·012, p$_{dim2}$=0·044) and cardiac autonomic neuropathy (n$_{events}$=118, p$_{dim1}$=0·0094, p$_{dim2}$=0·06). In the LURIC cohort, all-cause mortality was highest in the tree branch showing insulin resistance (n$_{events}$=488, p$_{dim1}$=0·12, p$_{dim2}$=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

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 (T2D) can be represented by a tree-like structure using reversed graph-embedded dimensionality reduction. We examined whether this approach stratifies key pathophysiological components and diabetes-related complications during longitudinal follow-up of recent-onset T2D.Methods: Participants (n=927) of the German Diabetes Study (GDS) with recent-onset T2D were mapped onto a previously developed two-dimensional tree based on nine simple clinical and laboratory variables, residualized for age and sex. Insulin sensitivity was assessed by hyperinsulinaemic-euglycaemic clamp, insulin secretion by intravenous glucose tolerance test, hepatic lipid content (HLC) by 1H magnetic resonance spectroscopy, serum interleukin (IL)-6 and IL-18 by ELISA as well as peripheral and autonomic neuropathy by functional and clinical measures. Participants were followed-up for up to 16 years. In the Ludwigshafen Risk and Cardiovascular Health (LURIC) cohort in persons with diabetes undergoing invasive coronary diagnostics (n=794), we also investigated heart failure and all-cause mortality.Findings: There were gradients of clamp-measured insulin sensitivity (both dimensions: p&lt;0·001) and insulin secretion (both dimensions: p&lt;0·001) across the tree. Individuals in the region with the lowest insulin sensitivity had the highest HLC (pdim1&lt;0·001, pdim2=0·037), proinflammatory biomarkers (IL-6: pdim1&lt;0·001, pdim2=0·013; IL-18: pdim1&lt;0·001, pdim2=0·376) and elevated cardiovascular hazard (nevents=143, pdim1=0·144, pdim2&lt;0·001), whereas persons positioned in the branch with the lowest insulin secretion were more prone to require insulin therapy (nevents=85, pdim1=0·032, pdim2=0·116) and had the highest risk of peripheral (nevents=184, pdim1=0·012, pdim2=0·044) and autonomic neuropathy (nevents=118, pdim1=0·009, pdim2=0·060). In the LURIC cohort, mortality was highest in the tree branch exhibiting insulin resistance (nevents=448, pdim1=0·120, pdim2=0·003). Significant gradients differentiated persons having heart failure with preserved from those with reduced ejection fraction.Interpretation: These data define the pathophysiological underpinnings of the tree structure, with the potential to stratify diabetes-related complications based on routinely available variables and thereby extend the toolbox of precision diabetes diagnosis