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Summary: Background: This study was conducted to investigate the cascade involving DNA damage, senescence, and senescence-associated secretory phenotype (SASP) in experimental diabetes and in a four-year follow-up study in patients with pre-diabetes and type 2 diabetes. Methods: Kidney, lung, and liver were studied in 4 months diabetic db/db mice and age-matched controls for the presence of DNA damage and fibrosis. DNA damage (comet-tail-length and ɤH2Ax-positivity in white blood cells), urinary p21-excretion, and plasma IL-6 and TGF-β1 were determined from 115 healthy participants, 34 patients with pre-diabetes and 221 with type 2 diabetes. Urinary albumin-creatinine-ratio, lung function, and transient elastography of the liver were performed in a prospective follow-up study over 4 years. Findings: db/db mice showed an increased nuclear ɤH2AX signal in all tissues as compared to the background control. Markers for DNA damage, senescence, and SASP were increased in patients with diabetes. The presence of nephropathy, restrictive lung disease (RLD), and increased liver stiffness was in a cross-sectional design associated with increased markers for DNA damage, senescence, and SASP. The progression of nephropathy over 4 years was predicted by increased DNA damage, senescence, and SASP, while the progression of RLD was associated with increased DNA damage and IL-6 only. The progression of liver stiffness was not associated with any of these parameters. HbA1c was not predictive for progression. Interpretation: In db/db mice, the cascade of DNA damage is associated with diabetes-related complications. In patients with diabetes, the progression of complications in the kidney and lung is predicted by markers reflecting DNA damage, and senescence-triggered organ fibrosis. Funding: This work was supported by the German Research Foundation (DFG) in the CRC 1118 and CRC 1158, by the GRK DIAMICOM, by the German Center for Diabetes Research (DZD e.V.), and by the Ministry of Science, Research and the Arts, Baden-Württemberg (Kompetenznetzwerk Präventivmedizin).

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 (TM6SF2 EK ; 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 (TM6SF2 EK : n = 16) or without (TM6SF2 EE : n = 16) the heterozygous TM6SF2-polymorphism of similar age and body mass index, underwent Botnia-clamps with [6,6- 2 H 2 ]glucose to measure whole-body-, hepatic- and adipose tissue-insulin sensitivity. HCL was assessed with 1 H-magnetic-resonance-spectroscopy. A subset of both groups (n = 24) was re-evaluated after 5 years. Despite doubled HCL, TM6SF2 EK had similar hepatic- and adipose tissue-insulin sensitivity and 27% higher whole-body-insulin sensitivity than TM6SF2 EE . 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 TM6SF2 EE 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., Competing Interests: Declaration of competing interest M.R. is on scientific advisory boards of Boehringer-Ingelheim, Eli Lilly, NovoNordisk and Target RWE, and received investigator-initiated support from Boehringer Ingelheim, Nutricia/Danone and Sanofi–Aventis. All contributions to the manuscript by D.F.M. have been performed when affiliated to the German Diabetes Center, prior to current employment by Boehringer Ingelheim. All other authors have no potential conflicts of interest relevant to this article., (Copyright © 2023. Published by Elsevier B.V.)

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., Competing Interests: Declaration of competing interest AEB is a member of the International Carbohydrate Consortium and of the ILSI Europe Carbohydrate Task Force. All other authors have no conflict of interest., (Copyright © 2022. Published by Elsevier B.V.)

Non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and liver fibrosis emerge as progressive liver diseases that accompany metabolic syndrome usually characterized by obesity, insulin resistance and type 2 diabetes. Currently no FDA approved treatments exist for the treatment of NASH and liver fibrosis, which requires a better knowledge of the underlying molecular mechanisms. TSC22D4 belongs to the TSC-22 protein family, the members of which are regulated by inflammatory and stress signals. Interestingly, patients with type 2 diabetes, with NAFLD as well as with NASH all have elevated levels of hepatic TSC22D4 expression. Previous studies with targeted deletion of TSC22D4 specifically in hepatocytes showed that TSC22D4 not only acts as a critical controller of diabetic hyperglycemia, but also contributes to NAFLD/NASH progression. To gain better insight into the development of progressive liver diseases, here we studied the function of TSC22D4 in hepatic stellate cells (HSCs), which play a key role in the pathogenesis of liver fibrosis. Our results indicated that TSC22D4 contributes to TGFβ1-mediated activation of HSCs and promotes their proliferation and migration. RNA-Sequencing analysis revealed that TSC22D4 initiates transcriptional events associated with HSC activation. Overall, our findings establish TSC22D4 as a key hub in the development of liver fibrosis, acting across different cellular compartments. Combinatorial TSC22D4 targeting in both hepatocytes and HSC may thus show superior efficacy against progressive liver disease., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background & Aims: 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., Methods: 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 1 H/ 31 P 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., Results: 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)., Conclusions: 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., Lay Summary: 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., Clinical Trial Number: NCT01055093., Competing Interests: Conflict of interest MR is on scientific advisory boards of Allergan, Astra-Zeneca, Bristol-Myers Squibb, Eli Lilly, Gilead Sciences, Inventiva, Intercept Pharma, Novartis, NovoNordisk, Servier Laboratories, Target Pharmasolutions, and Terra Firma and receives investigator-initiated support from Boehringer Ingelheim, Nutricia/Danone and Sanofi–Aventis.. YKu, OPZ, PB, YKa, VB, JHH and JS declare no competing interests. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Epidemiological studies have shown that increased circulating branched-chain amino acids (BCAAs) are associated with insulin resistance and type 2 diabetes (T2D). This may result from altered energy metabolism or dietary habits., Objective: We hypothesized that a lower intake of BCAAs improves tissue-specific insulin sensitivity., Methods: This randomized, placebo-controlled, double-blinded, crossover trial examined well-controlled T2D patients receiving isocaloric diets (protein: 1 g/kg body weight) for 4 wk. Protein requirements were covered by commercially available food supplemented ≤60% by an AA mixture either containing all AAs or lacking BCAAs. The dietary intervention ensured sufficient BCAA supply above the recommended minimum daily intake. The patients underwent the mixed meal tolerance test (MMT), hyperinsulinemic-euglycemic clamps (HECs), and skeletal muscle and white adipose tissue biopsies to assess insulin signaling., Results: After the BCAA- diet, BCAAs were reduced by 17% during fasting (P < 0.001), by 13% during HEC (P < 0.01), and by 62% during the MMT (P < 0.001). Under clamp conditions, whole-body and hepatic insulin sensitivity did not differ between diets. After the BCAA- diet, however, the oral glucose sensitivity index was 24% (P < 0.01) and circulating fibroblast-growth factor 21 was 21% higher (P < 0.05), whereas meal-derived insulin secretion was 28% lower (P < 0.05). Adipose tissue expression of the mechanistic target of rapamycin was 13% lower, whereas the mitochondrial respiratory control ratio was 1.7-fold higher (both P < 0.05). The fecal microbiome was enriched in Bacteroidetes but depleted of Firmicutes., Conclusions: Short-term dietary reduction of BCAAs decreases postprandial insulin secretion and improves white adipose tissue metabolism and gut microbiome composition. Longer-term studies will be needed to evaluate the safety and metabolic efficacy in diabetes patients.This trial was registered at clinicaltrials.gov as NCT03261362., (Copyright © American Society for Nutrition 2019.)

Depressive disorders represent a frequent comorbidity of both type 1 (T1D) and type 2 diabetes (T2D). Inflammation-related processes have been implicated in the development of both diabetes and depression. This study aimed to investigate whether biomarkers of subclinical inflammation were associated with depressive symptoms in individuals with recently diagnosed diabetes and if such associations differed by diabetes type. This cross-sectional study was based on 295 individuals with T2D (67% men, mean age 53years) and 139 individuals with T1D (60% men, mean age 36years) of the German Diabetes Study. The main inclusion criterion was a known disease duration of <1year. Depressive symptoms were assessed with the Allgemeine Depressionsskala, Langversion (ADS-L) questionnaire, the German version of the Center for Epidemiological Studies Depression scale (CES-D) questionnaire. Associations between biomarkers of subclinical inflammation and the ADS-L as continuous score were assessed using multiple linear regression models adjusting for age, sex, body mass index, HbA1c, lipids, hypertension, medication and comorbidities. Serum high-sensitivity C-reactive protein (hsCRP) and the ratio of high-molecular-weight (HMW)/total adiponectin were positively associated with ADS-L in T2D (both P<0.01), but not in T1D. In contrast, serum levels of soluble intercellular adhesion molecule (sICAM)-1 were positively associated with ADS-L only in T1D (P=0.035). The latter association was significantly different between both diabetes types (P interaction =0.036). No associations were observed for interleukin (IL)-6, IL-18 and soluble E-selectin. Only the association between HMW/total adiponectin and ADS-L in T2D remained significant after correction for multiple testing. In conclusion, our study shows that the ratio HMW/total adiponectin is associated with depressive symptoms in individuals with recently diagnosed T2D. It also provides suggestive evidence that further biomarkers of subclinical inflammation and endothelial activation may be associated with depressive symptoms in individuals with recently diagnosed T1D and T2D., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Impaired energy metabolism is a possible mechanism that contributes to insulin resistance and ectopic fat storage., Objective: We examined whether meal ingestion differently affects hepatic phosphorus metabolites in insulin-sensitive and insulin-resistant humans., Design: Young, lean, insulin-sensitive humans (CONs) [mean ± SD body mass index (BMI; in kg/m(2)): 23.2 ± 1.5]; insulin-resistant, glucose-tolerant, obese humans (OBEs) (BMI: 34.3 ± 1.7); and type 2 diabetes patients (T2Ds) (BMI: 32.0 ± 2.4) were studied (n = 10/group). T2Ds (61 ± 7 y old) were older (P < 0.001) than were OBEs (31 ± 7 y old) and CONs (28 ± 3 y old). We quantified hepatic γATP, inorganic phosphate (Pi), and the fat content [hepatocellular lipids (HCLs)] with the use of (31)P/(1)H magnetic resonance spectroscopy before and at 160 and 240 min after a high-caloric mixed meal. In a subset of volunteers, we measured the skeletal muscle oxidative capacity with the use of high-resolution respirometry. Whole-body insulin sensitivity (M value) was assessed with the use of hyperinsulinemic-euglycemic clamps., Results: OBEs and T2Ds were similarly insulin resistant (M value: 3.5 ± 1.4 and 1.9 ± 2.5 mg · kg(-1) · min(-1), respectively; P = 0.9) and had 12-fold (P = 0.01) and 17-fold (P = 0.002) higher HCLs, respectively, than those of lean persons. Despite comparable fasting hepatic γATP concentrations, the maximum postprandial increase of γATP was 6-fold higher in OBEs (0.7 ± 0.2 mmol/L; P = 0.03) but only tended to be higher in T2Ds (0.6 ± 0.2 mmol/L; P = 0.09) than in CONs (0.1 ± 0.1 mmol/L). However, in the fasted state, muscle complex I activity was 53% lower (P = 0.01) in T2Ds but not in OBEs (P = 0.15) than in CONs., Conclusions: Young, obese, nondiabetic humans exhibit augmented postprandial hepatic energy metabolism, whereas elderly T2Ds have impaired fasting muscle energy metabolism. These findings support the concept of a differential and tissue-specific regulation of energy metabolism, which can occur independently of insulin resistance. This trial was registered at clinicaltrials.gov as NCT01229059., (© 2015 American Society for Nutrition.)