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  • 1
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    1412-P: Preexisting Nonalcoholic Steatohepatitis Attenuates Improvement of Adipose Tissue OXPHOS Capacity after Weight-Loss Surgery
    American Diabetes Association ; 2022
    In:  Diabetes Vol. 71, No. Supplement_1 ( 2022-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 71, No. Supplement_1 ( 2022-06-01)
    Abstract: Impaired adipose tissue (AT) function closely associates with obesity, type 2 diabetes and nonalcoholic fatty liver disease (NAFLD) . Mitochondrial oxidative phosphorylation (OXPHOS) capacity of AT improves after weight loss surgery. However, it is not clear if the improvement is affected by the presence of NAFLD before surgery. We examined 52 severely obese people exhibiting no histological liver disease (OBE_CON) , simple steatosis (OBE_NAFL) or steatohepatitis (OBE_NASH) before (0 weeks) , 12 and 52 weeks after bariatric surgery. Whole-body insulin sensitivity was measured by hyperinsulinemic euglycemic clamps. OXPHOS capacity of subcutaneous AT was assessed by high-resolution respirometry. Transcript levels of TNFα in AT were quantified by RT-PCR. Before surgery, OBE_NASH presented with lower insulin sensitivity and higher HbA1c compared to OBE_CON and OBE_NAFL (all p & lt;0.05) whereas OXPHOS capacity in AT was comparable between the groups. Maximum coupled respiration declined at week 12 by 17% from week 0 in OBE_CON only (p & lt;0.05) . From 12 to 52 weeks, AT maximum coupled respiration markedly increased by 82 and 49% in OBE_CON and OBE_NAFL (both p & lt;0.001) but only by 28% in OBE_NASH (p=0.05; maximum coupled OXPHOS at week 52: OBE_CON vs. OBE_NASH p & lt;0.05) . The changes in AT maximum coupled respiration from 12 to 52 weeks correlated negatively with changes in AT TNFα levels in OBE_CON (β=-0.83, p & lt;0.001) and negatively with changes in systemic C-reactive protein levels in OBE_NASH (β=-0.34, p & lt;0.05) . Maximal noncoupled OXPHOS yielded similar changes and correlations. In conclusion, in severe obesity, weight loss-related improvements in AT OXPHOS capacity may be mediated to a great extent by reduced AT inflammation in people without liver disease; however, with pre-surgery manifestation of NASH and worsening of metabolic control, residual systemic subclinical inflammation may attenuate the improvement of AT OXPHOS capacity after bariatric surgery. Disclosure S.Kahl: None. G.Heilmann: None. I.Esposito: None. M.Schlensak: None. M.Roden: Advisory Panel; Eli Lilly and Company, Research Support; Boehringer Ingelheim International GmbH, Nutricia, Speaker's Bureau; Novo Nordisk. K.Strassburger: None. S.Gancheva: None. N.Saatmann: None. C.Granata: None. C.Herder: Research Support; Sanofi. K.Pafili: None. J.Puetzer-furmanczak: None. T.Sarabhai: None. Funding German Federal Ministry of Health; Ministry of Culture and Science of the State North Rhine-Westphalia;German Federal Ministry of Education and Research;European Funds for Regional Development (EFRE-0400191) ;EUREKA Eurostars-2 (E!113230DIA-PEP) ;German Science Foundation (CRC/SFB1116/2 B12; RTG/GRK 2576 vivid, Project 3) ;Schmutzler Stiftung
    Type of Medium: Online Resource
    ISSN: 0012-1797
    URL: Article
    DOI: 10.2337/db22-1412-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2022
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  • 2
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    Mechanisms of Insulin Resistance in Primary and Secondary Nonalcoholic Fatty Liver
    American Diabetes Association ; 2017
    In:  Diabetes Vol. 66, No. 8 ( 2017-08-01), p. 2241-2253
    Details
    In: Diabetes, American Diabetes Association, Vol. 66, No. 8 ( 2017-08-01), p. 2241-2253
    Abstract: Nonalcoholic fatty liver disease is associated with hepatic insulin resistance and may result primarily from increased hepatic de novo lipogenesis (PRIM) or secondarily from adipose tissue lipolysis (SEC). We studied mice with hepatocyte- or adipocyte-specific SREBP-1c overexpression as models of PRIM and SEC. PRIM mice featured increased lipogenic gene expression in the liver and adipose tissue. Their selective, liver-specific insulin resistance was associated with increased C18:1-diacylglycerol content and protein kinase Cε translocation. SEC mice had decreased lipogenesis mediated by hepatic cholesterol responsive element–binding protein and featured portal/lobular inflammation along with total, whole-body insulin resistance. Hepatic mitochondrial respiration transiently increased and declined with aging along with higher muscle reactive oxygen species production. In conclusion, hepatic insulin resistance originates from lipotoxicity but not from lower mitochondrial capacity, which can even transiently adapt to increased peripheral lipolysis. Peripheral insulin resistance is prevented during increased hepatic lipogenesis only if adipose tissue lipid storage capacity is preserved.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db16-1147
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2017
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  • 3
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    1816-P: Hepatic Mitochondrial Alterations in a Murine Model of Combined Diabetes and Fatty Liver Disease
    American Diabetes Association ; 2020
    In:  Diabetes Vol. 69, No. Supplement_1 ( 2020-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 69, No. Supplement_1 ( 2020-06-01)
    Abstract: Nonalcoholic fatty liver disease (NAFLD) is tightly associated with obesity and type 2 diabetes. There is evidence that mitochondrial function is altered in both diseases. Here, we examined hepatic mitochondria during different stages of NAFLD in mice with experimental diabetes. Two-days old male C57BL/6j mice received 200 µg streptozotocin (STAM) or vehicle (CTRL). From 4 weeks on, they were on high-fat diet for either 4 w or 8 w to induce steatosis or nonalcoholic steatohepatitis (NASH). Liver histology was performed to quantify steatosis, inflammation and fibrosis. Mitochondrial respiration was assessed in liver tissues using high-resolution respirometry with different substrate protocols. Citrate synthase activity (CSA) served as a surrogate marker for mitochondrial content. Immunoblotting was used to quantify mitochondrial complexes. Compared to CTRL, STAM mice showed 140% and 54% higher blood glucose and liver/body weight. Hepatic steatosis increased from 2% to 15% at 4 w and decreased to 5% at 8 w. NAFLD activity score was 0.25 in CTRL and increased to 2.5 at 4 w and 8 w in STAM. STAM mice had lower CSA, indicating lower mitochondrial content at both time points, whereas complex III protein content was decreased only at 8 w. Of note, maximal uncoupled β-oxidation-associated respiration, normalized to CSA, was 1.7- and 2.7-fold higher in livers of STAM mice after 4 w and 8 w, respectively, as compared to CTRL. In conclusion, combined diabetes and NASH decreased mitochondrial content but resulted in greater maximal oxidative capacity per mitochondrion, possibly reflecting an adaptation of mitochondrial function during NAFLD progression in adult mice. Disclosure B. Dewidar: None. C. Englisch: None. D. Pesta: None. E. Rohbeck: None. C. Ress: None. I. Esposito: 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 and Ministry of Culture and Science of the State North Rhine-Westphalia; German Federal Ministry of Education and Research by the European Regional Development Fund (KomIT, EFRE-0400191); German Research Foundation (DFG; SFB 1116/2)
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db20-1816-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2020
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  • 4
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    Specific Hepatic Sphingolipids Relate to Insulin Resistance, Oxidative Stress, and Inflammation in Nonalcoholic Steatohepatitis
    American Diabetes Association ; 2018
    In:  Diabetes Care Vol. 41, No. 6 ( 2018-06-01), p. 1235-1243
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 41, No. 6 ( 2018-06-01), p. 1235-1243
    Abstract: Insulin resistance and nonalcoholic fatty liver disease have been linked to several lipid metabolites in animals, but their role in humans remains unclear. This study examined the relationship of sphingolipids with hepatic and peripheral metabolism in 21 insulin-resistant obese patients without (NAFL−) or with (NAFL+) nonalcoholic fatty liver and nonalcoholic steatohepatitis (NASH) and 7 healthy lean individuals undergoing tissue biopsies during bariatric or elective abdominal surgery. RESEARCH DESIGN AND METHODS Hyperinsulinemic-euglycemic clamps with d-[6,6-2H2]glucose were performed to quantify tissue-specific insulin sensitivity. Hepatic oxidative capacity, lipid peroxidation, and the phosphorylated-to-total c-Jun N-terminal kinase (pJNK-to-tJNK) ratio were measured to assess mitochondrial function, oxidative stress, and inflammatory activity. RESULTS Hepatic total ceramides were higher by 50% and 33% in NASH compared with NAFL+ and NAFL−, respectively. Only in NASH were hepatic dihydroceramides (16:0, 22:0, and 24:1) and lactosylceramides increased. Serum total ceramides and dihydroceramides (hepatic dihydroceramides 22:0 and 24:1) correlated negatively with whole-body but not with hepatic insulin sensitivity. Hepatic maximal respiration related positively to serum lactosylceramide subspecies, hepatic sphinganine, and lactosylceramide 14:0. Liver lipid peroxides (total ceramides, sphingomyelin 22:0) and the pJNK-to-tJNK ratio (ceramide 24:0; hexosylceramides 22:0, 24:0, and 24:1) all positively correlated with the respective hepatic sphingolipids. CONCLUSIONS Sphingolipid species are not only increased in insulin-resistant humans with NASH but also correlate with hepatic oxidative stress and inflammation, suggesting that these lipids may play a role during progression of simple steatosis to NASH in humans.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc17-1318
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2018
    detail.hit.zdb_id: 1490520-6
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  • 5
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    Impaired Hepatic Mitochondrial Capacity in Nonalcoholic Steatohepatitis Associated With Type 2 Diabetes
    American Diabetes Association ; 2022
    In:  Diabetes Care Vol. 45, No. 4 ( 2022-04-01), p. 928-937
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 45, No. 4 ( 2022-04-01), p. 928-937
    Abstract: Individuals with type 2 diabetes are at higher risk of progression of nonalcoholic fatty liver (steatosis) to steatohepatitis (NASH), fibrosis, and cirrhosis. The hepatic metabolism of obese individuals adapts by upregulation of mitochondrial capacity, which may be lost during the progression of steatosis. However, the role of type 2 diabetes with regard to hepatic mitochondrial function in NASH remains unclear. RESEARCH DESIGN AND METHODS We therefore examined obese individuals with histologically proven NASH without (OBE) (n = 30; BMI 52 ± 9 kg/m2) or with type 2 diabetes (T2D) (n = 15; 51 ± 7 kg/m2) as well as healthy individuals without liver disease (CON) (n = 14; 25 ± 2 kg/m2). Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamps with d-[6,6-2H2]glucose. Liver biopsies were used for assessing mitochondrial capacity by high-resolution respirometry and protein expression. RESULTS T2D and OBE had comparable hepatic fat content, lobular inflammation, and fibrosis. Oxidative capacity in liver tissue normalized for citrate synthase activity was 59% greater in OBE than in CON, whereas T2D presented with 33% lower complex II–linked oxidative capacity than OBE and higher H2O2 production than CON. Interestingly, those with NASH and hepatic fibrosis score ≥1 had lower oxidative capacity and antioxidant defense than those without fibrosis. CONCLUSIONS Loss of hepatic mitochondrial adaptation characterizes NASH and type 2 diabetes or hepatic fibrosis and may thereby favor accelerated disease progression.
    Type of Medium: Online Resource
    ISSN: 0149-5992
    URL: Article
    DOI: 10.2337/dc21-1758
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2022
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  • 6
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    1212-P: Adipose Tissue Mitochondrial Function in Humans with Varying Liver Histology
    American Diabetes Association ; 2021
    In:  Diabetes Vol. 70, No. Supplement_1 ( 2021-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 70, No. Supplement_1 ( 2021-06-01)
    Abstract: Adipose dysfunction may drive the development of insulin resistance, type 2 diabetes (T2D) and nonalcoholic (NA) fatty liver disease (NAFLD), comprising NA fatty liver and steatohepatitis (NAFL and NASH). Possible underlying mechanism comprise impaired lipid storage or mitochondrial oxidation favoring increased fatty acid flux to other tissues. Thus, we examined subcutaneous (SAT) and visceral adipose tissue (VAT) mitochondrial capacity in humans with different degrees of insulin resistance and histologically proven NAFLD. Obese people without NAFL (OBE-CON, n=20, 38±8 years, body mass index 53±6 kg/m2, 10% T2D), with NAFL (OBE-NAFL, n=20, 40±8 years, 51±5 kg/m2, 25% T2D) or NASH (OBE-NASH, n=20, 42±10 years, 51±6 kg/m2, 40% T2D) underwent metabolic phenotyping and tissue biopsies. O2 flux rates from different substrates were measured with high resolution respirometry in SAT and VAT. In VAT, maximal uncoupled respiration was lower in OBE-NAFL (least square means (LSM): 0.46 pmol*mg wet weight–1*s–1 [95% confidence interval 0.21;0.71], p & lt;0.05) and OBE-NASH (LSM: 0.51 [0.26;0.76], p & lt;0.001) compared to OBE-CON. Similar differences were seen for state 3 respiration related to complex I (glutamate) or combined complex I and II activity (succinate). In Pearson correlation analysis, combined complex I and II activity in VAT positively correlated with whole-body insulin sensitivity (M value; r= 0.29, p & lt;0.05). VAT mitochondrial content, as assessed from mitochondrial DNA copy number, was not different between the groups. Protein expression of electron transport chain complexes was similar in VAT and SAT of all groups, except for complex IV that tended to be lower in VAT in OBE-NASH than in OBE-CON (p=0.065). Of note, in SAT, oxidative capacity was comparable between groups despite a higher mitochondrial mass in OBE-NASH than in OBE-CON (p=0.045). In conclusion, oxidative capacity is downregulated in VAT, but not in SAT of obese humans with NAFLD, which may be related to the degree of insulin resistance. Disclosure K. Pafili: None. M. Schlensak: 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. S. Kahl: None. D. Pesta: None. K. Strassburger: None. L. Mastrototaro: None. J. Puetzer-furmanczak: None. B. Dewidar: None. T. Sarabhai: None. I. Esposito: None.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db21-1212-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2021
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  • 7
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    1165-P: Alterations of Hepatic Mitochondrial Respiration in Murine Models of Diabetes and Nonalcoholic Fatty Liver Disease (NAFLD)
    American Diabetes Association ; 2021
    In:  Diabetes Vol. 70, No. Supplement_1 ( 2021-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 70, No. Supplement_1 ( 2021-06-01)
    Abstract: Diabetes mellitus (DM) accelerates progression of fatty liver to nonalcoholic steatohepatitis (NASH) and fibrosis. Mitochondrial function is also frequently impaired in DM, but maybe differently regulated in NAFLD. Thus, we examined hepatic mitochondrial respiration during DM and NAFLD development. Two-days old male C57BL/6j mice received streptozotocin (STZ) or vehicle (placebo, PLC) and then high-fat diet (HFD) or continued regular chow diet (RCD) from week 4 to 12, yielding 4 models (n=8 each): obesity [PLC+HFD], DM [STZ+RCD] , NASH [STZ+HFD] and control [PLC+RCD] . Histology and immunohistochemistry were performed to describe NAFLD, including the NAFLD activity score (NAS) derived from steatosis, lobular inflammation and hepatocellular ballooning. High-resolution respirometry and hyperinsulinemic-euglycemic clamps were used to measure mitochondrial respiration and insulin sensitivity. DM and NASH showed & gt;200% higher blood glucose levels (p & lt;0.0001 vs. control). The NAS (mean±SEM) was not different in obese (1.38±0.32; p & gt;0.99), gradually higher in DM (2.50±0.42; p=0.063) and markedly increased in NASH (3.25±0.45; p & lt;0.01) compared to control (1.00±0.27). Main contributors to NAS were steatosis and hepatocellular ballooning in NASH (p & lt;0.001 and p & lt;0.05 vs. control) and hepatocellular ballooning in DM (p & lt;0.01 vs. control). Maximal uncoupled β-oxidation-associated respiration was 1.6-, 1.7-, and 1.9-fold higher in obesity, DM and NASH compared to control (all p & lt;0.01). Mitochondrial density was decreased in both DM and NASH (p & lt;0.05 vs. control), whereas β-oxidation-dependent mitochondrial leak control ratio was not different between all groups. Insulin-stimulated glucose disposal was 44% and 66% lower in obesity and NASH (both p & lt;0.001 vs. control). In conclusion, hyperglycemia and high-fat diet feeding associate with higher respiration but lower content of hepatic mitochondria, which may both contribute to progression of NAFLD. Disclosure B. Dewidar: None. M. Reinadofundo: None. C. Englisch: None. L. Mastrototaro: None. D. Pesta: None. C. Ress: None. I. Esposito: 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.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db21-1165-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2021
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  • 8
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    434-P: Diabetes in Patients with Pancreatic Cancer: Relationship of Tumor Grade with Glycemic Control
    American Diabetes Association ; 2019
    In:  Diabetes Vol. 68, No. Supplement_1 ( 2019-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 68, No. Supplement_1 ( 2019-06-01)
    Abstract: Diseases of the exocrine pancreas can result in impaired function of the endocrine pancreas with disturbed glucose homeostasis and ultimately overt diabetes mellitus. In diabetes which develops secondary to pancreatic carcinoma (type 3c diabetes or diabetes of the exocrine pancreas, DEP), the relationship between disturbed glycemic control and carcinoma is not fully understood. We hypothesized that the severity of pancreatic carcinoma positively associates with the degree of impairment of glycemic control. In 92 patients with potentially resectable pancreas neoplasm without diabetes (NOD, n=53, age 67±2 years, BMI 24.8±0.5 kg/m2), DEP (n=20, 71±3 years, 25.3±1.0 kg/m2) or preexisting type 2 diabetes (T2D, n=19, 71±3 years, 27.1±0.8 kg/m2), preoperative fasting glucose, insulin and HbA1c were measured. Pancreatic carcinoma was assessed by TNM classification and tumor grading. Patients with DEP or T2D had higher fasting glycemia (135±9 vs. 142±11 mg/dl), HbA1c (55±3 vs. 58±3 mmol/mol) and insulin resistance, as assessed by homeostatic model assessment for insulin resistance (HOMA-IR) (4.1±1.0 vs. 3.7±0.5), than NOD patients (88±2 mg/dl, 38±1 mmol/mol, 2.0 ± 0.3; all p & lt;0.01). Tumor grading revealed that patients with tumor grade G3 had higher levels of fasting glucose (124±36 mg/dl) and HbA1c (53±2 mmol/mol) compared to patients with non-malignant neoplastic lesions (103±38 mg/dl, 42±2 mmol/mol; all p & lt;0.01). Distribution patterns of tumor grades differed between DEP and T2D (p & lt;0.05) and NOD (p & lt;0.001), respectively. Particularly, the prevalence of G3 tumors was higher in DEP (79%) than in T2D (33%) or NOD patients (16%). Tumor stages did not relate to glycemic control. In conclusion, patients with pancreas carcinoma exhibit a higher diabetes prevalence, which relates to higher tumor grades but not stages. Disclosure J. Boeddeker: None. V. Burkart: None. K. Strassburger: None. P.E. Goretzki: None. W. Knoefel: None. C. Moebius: None. N. Hinsch: None. I. Esposito: 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. K. Muessig: None. 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; German Center for Diabetes Research
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db19-434-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2019
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