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BACKGROUND & AIMS: Hepatic mitochondrial respiration is higher in steatosis, but lower in overt type 2 diabetes. We hypothesized that hepatic OXPHOS capacity increases with a greater degree of insulin resistance in obesity, independent of other metabolic diseases. METHODS: We analysed 65 humans without diabetes (BMI 50±7 kg/m2, HbA1c 5.5±0.4%) undergoing bariatric surgery. MASLD stages were assessed by histology, whole-body insulin sensitivity (PREDIcted-M index) by oral glucose tolerance tests, and maximal ADP-stimulated mitochondrial OXPHOS capacity by high-resolution respirometry of liver samples. RESULTS: Prediabetes was present in 30 participants, and MASLD in 46 participants. Thereof, 25 had metabolic dysfunction-associated steatohepatitis (MASH), and seven had F2-F3 fibrosis. While simple regression did not detect an association of insulin sensitivity with hepatic OXPHOS capacity, interaction analyses revealed that the regression coefficient of OXPHOS capacity depended on fasting plasma glucose (FPG) and liver lipid content. Interestingly, the respective slopes were negative for FPG ≤100 mg/dl, but positive for FPG >100 mg/dl. Liver lipid content displayed similar behavior, with a threshold value of 24%. Post-challenge glycemia affected the association between insulin sensitivity and OXPHOS capacity normalized for citrate synthase activity. Presence of prediabetes affected hepatic insulin signaling, mitochondrial dynamics and fibrosis prevalence, while the presence of MASLD related to higher biomarkers of hepatic inflammation, cell damage and lipid peroxidation in people with normal glucose tolerance. CONCLUSIONS: Rising liver lipid contents and plasma glucose concentrations, even in the non-diabetic range, are associated with a progressive decline of hepatic mitochondrial adaptation in people with obesity and insulin resistance. CLINTRIALS. GOV IDENTIFIER: NCT01477957.
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AIM: To investigate the associations of the Dietary Approaches to Stop Hypertension (DASH) score with subcutaneous (SAT) and visceral (VAT) adipose tissue volume and hepatic lipid content (HLC) in people with diabetes and to examine whether changes in the DASH diet were associated with changes in these outcomes. METHODS: In total, 335 participants with recent-onset type 1 diabetes (T1D) and type 2 diabetes (T2D) from the German Diabetes Study were included in the cross-sectional analysis, and 111 participants in the analysis of changes during the 5-year follow-up. Associations between the DASH score and VAT, SAT and HLC and their changes were investigated using multivariable linear regression models by diabetes type. The proportion mediated by changes in potential mediators was determined using mediation analysis. RESULTS: A higher baseline DASH score was associated with lower HLC, especially in people with T2D (per 5 points: -1.5% [-2.7%; -0.3%]). Over 5 years, a 5-point increase in the DASH score was associated with decreased VAT in people with T2D (-514 [-800; -228] cm3). Similar, but imprecise, associations were observed for VAT changes in people with T1D (-403 [-861; 55] cm3) and for HLC in people with T2D (-1.3% [-2.8%; 0.3%]). Body mass index and waist circumference changes explained 8%-48% of the associations between DASH and VAT changes in both groups. In people with T2D, adipose tissue insulin resistance index (Adipo-IR) changes explained 47% of the association between DASH and HLC changes. CONCLUSIONS: A shift to a DASH-like diet was associated with favourable VAT and HLC changes, which were partly explained by changes in anthropometric measures and Adipo-IR.
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AIM: Bariatric surgery is highly effective for the treatment of obesity in individuals without (OB1) and in those with type 2 diabetes (T2D2). However, whether bariatric surgery triggers similar or distinct molecular changes in OB and T2D remains unknown. Given that individuals with type 2 diabetes often exhibit more severe metabolic deterioration, we hypothesized that bariatric surgery induces distinct molecular adaptations in skeletal muscle, the major site of glucose uptake, of OB and T2D after surgery-induced weight loss. METHODS: All participants (OB, n = 13; T2D, n = 13) underwent detailed anthropometry before and one year after the surgery. Skeletal muscle biopsies were isolated at both time points and subjected to transcriptome and methylome analyses using a comprehensive bioinformatic pipeline. RESULTS: Before surgery, T2D had higher fasting glucose and insulin levels but lower whole-body insulin sensitivity, only glycemia remained higher in T2D than in OB after surgery. Surgery-mediated weight loss affected different subsets of genes with 2,013 differentially expressed in OB and 959 in T2D. In OB differentially expressed genes were involved in insulin, PPAR signaling and oxidative phosphorylation pathways, whereas ribosome and splicesome in T2D. LASSO regression analysis revealed distinct candidate genes correlated with improvement of phenotypic traits in OB and T2D. Compared to OB, DNA methylation was less affected in T2D in response to bariatric surgery. This may be due to increased global hydroxymethylation accompanied by decreased expression of one of the type 2 diabetes risk gene, TET2, encoding a demethylation enzyme in T2D. CONCLUSION: OB and T2D exhibit differential skeletal muscle transcriptome responses to bariatric surgery, presumably resulting from perturbed epigenetic flexibility.
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Metabolic dysfunction-associated steatotic liver disease (MASLD) closely associates with obesity and type 2 diabetes. Lifestyle intervention and bariatric surgery aiming at substantial weight loss are cornerstones of MASLD treatment by improving histological outcomes and reducing risks of comorbidities. Originally developed as antihyperglycemic drugs, incretin (co-)agonists and SGLT2 inhibitors also reduce steatosis and cardiorenovascular events. Certain incretin agonists effectively improve histological features of MASLD, but not fibrosis. Of note, beneficial effects on MASLD may not necessarily require weight loss. Despite moderate weight gain, one PPARγ agonist improved adipose tissue and MASLD with certain benefit on fibrosis in post-hoc analyses. Likewise, the first THRß-agonist was recently provisionally approved because of significant improvements of MASLD and fibrosis. We here discuss liver-related and metabolic effects induced by different MASLD treatments and their association with weight loss. Therefore, we compare results from clinical trials on drugs acting via weight loss (incretin (co)agonists, SGLT2 inhibitors) with those exerting no weight loss (pioglitazone; resmetirom). Furthermore, other drugs in development directly targeting hepatic lipid metabolism (lipogenesis inhibitors, FGF21 analogs) are addressed. Although THRß-agonism may effectively improve hepatic outcomes, MASLD treatment concepts should consider all cardiometabolic risk factors for effective reduction of morbidity and mortality in the affected people.
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Fígado Gorduroso , Obesidade , Redução de Peso , Humanos , Redução de Peso/fisiologia , Obesidade/metabolismo , Obesidade/complicações , Obesidade/terapia , Fígado Gorduroso/terapia , Fígado Gorduroso/metabolismo , Cirurgia Bariátrica , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/terapia , Hipoglicemiantes/uso terapêuticoRESUMO
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 1 H-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.
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Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica , Glândula Tireoide , Humanos , Masculino , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 2/complicações , Estudos Longitudinais , Hepatopatia Gordurosa não Alcoólica/complicações , Estudos Prospectivos , Glândula Tireoide/fisiologia , TireotropinaRESUMO
OBJECTIVE: The aim of this study was to discover novel markers underlying the improvement of skeletal muscle metabolism after bariatric surgery. METHODS: Skeletal muscle transcriptome data of lean people and people with obesity, before and 1 year after bariatric surgery, were subjected to weighted gene co-expression network analysis (WGCNA) and least absolute shrinkage and selection operator (LASSO) regression. Results of LASSO were confirmed in a replication cohort. RESULTS: The expression levels of 440 genes differing between individuals with and without obesity were no longer different 1 year after surgery, indicating restoration. WGCNA clustered 116 genes with normalized expression in one major module, particularly correlating to weight loss and decreased plasma free fatty acids (FFA), 44 of which showed an obesity-related phenotype upon deletion in mice. Among the genes of the major module, 105 represented prominent markers for reduced FFA concentration, including 55 marker genes for decreased BMI in both the discovery and replication cohorts. CONCLUSIONS: Previously unknown gene networks and marker genes underlined the important role of FFA in restoring muscle gene expression after bariatric surgery and further suggest novel therapeutic targets for obesity.
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Cirurgia Bariátrica , Transcriptoma , Humanos , Animais , Camundongos , Obesidade/genética , Obesidade/cirurgia , Obesidade/metabolismo , Músculo Esquelético/metabolismo , Redução de Peso/genética , Ácidos Graxos não Esterificados/metabolismo , Redes Reguladoras de GenesRESUMO
BACKGROUND: Obesity and type 2 diabetes frequently have metabolic dysfunction-associated steatotic liver disease (MASLD) including steatohepatitis (MASH). In obesity, the liver may adapt its oxidative capacity, but the role of mitochondrial turnover in MASLD remains uncertain. METHODS: This cross-sectional study compared individuals with class III obesity (n = 8/group) without (control, OBE CON; NAFLD activity score: 0.4 ± 0.1) or with steatosis (OBE MASL, 2.3 ± 0.4), or MASH (OBE MASH, 5.3 ± 0.3, p < 0.05 vs. other groups). Hepatic mitochondrial ultrastructure was assessed by transmission electron microscopy, mitochondrial respiration by high-resolution respirometry, biomarkers of mitochondrial quality control and endoplasmic reticulum (ER) stress by Western Blot. RESULTS: Mitochondrial oxidative capacity was 31 % higher in OBE MASL, but 25 % lower in OBE MASH (p < 0.05 vs. OBE CON). OBE MASH showed ~1.5fold lower mitochondrial number, but ~1.2-1.5fold higher diameter and area (p < 0.001 vs. other groups). Biomarkers of autophagy (p62), mitophagy (PINK1, PARKIN), fission (DRP-1, FIS1) and fusion (MFN1/2, OPA1) were reduced in OBE MASH (p < 0.05 vs. OBE CON). OBE MASL showed lower p62, p-PARKIN/PARKIN, and p-DRP-1 (p < 0.05 vs. OBE CON). OBE MASL and MASH showed higher ER stress markers (PERK, ATF4, p-eIF2α-S51/eIF2α; p < 0.05 vs. OBE CON). Mitochondrial diameter associated inversely with fusion/fission biomarkers and with oxidative capacity, but positively with H2O2. CONCLUSION: Humans with hepatic steatosis already exhibit impaired mitochondrial turnover, despite upregulated oxidative capacity, and evidence for ER stress. In MASH, oxidative stress likely mediates progressive decline of mitochondrial turnover, ultrastructure and respiration indicating that mitochondrial quality control is key for energy metabolism and may have potential for targeting MASH. ClinGovTrial:NCT01477957.
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Diabetes Mellitus Tipo 2 , Fígado Gorduroso , Hepatopatia Gordurosa não Alcoólica , Humanos , Estudos Transversais , Peróxido de Hidrogênio , Mitofagia , Obesidade/complicações , Obesidade/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , BiomarcadoresRESUMO
AIMS: Body weight loss improves insulin resistance and growth hormone secretion in obesity, which may be regulated by leptin according to preclinical studies. How changes in leptin, lipids and insulin sensitivity after bariatric (metabolic) surgery affect the human growth hormone system is yet unclear. PARTICIPANTS AND METHODS: People with obesity (OBE, n = 79, BMI 50.8 ± 6.3 kg/m2) were studied before, 2, 12, 24 and 52 weeks after metabolic surgery and compared to lean healthy humans (control; CON, n = 24, BMI 24.3 ± 3.1 kg/m2). Tissue-specific insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamps with D-[6,6-2H2]glucose. Fasting leptin, growth hormone (GH), insulin-like growth factor 1 (IGF-1) and IGF-binding proteins (IGFBP1, IGFBP3) were measured using ELISA. RESULTS: At baseline, OBE exhibited higher glycemia and leptinemia as well as pronounced peripheral, adipose tissue and hepatic insulin resistance compared to CON. GH and IGFBP1 were lower, while IGF1 was comparable between groups. At 52 weeks, OBE had lost 33% body weight and doubled their peripheral insulin sensitivity, which was paralleled by continuous increases in GH, IGF-1 and IGFBP1 as well as decrease in leptin. The rise in GH correlated with reductions in free fatty acids, adipose tissue insulin resistance and insulinemia, but not with changes in body weight, peripheral insulin sensitivity, glycemia or leptinemia. The rise in IGF-1 correlated with reduction in high-sensitive C-reactive protein. CONCLUSION: Reversal of alterations of the GH-IGF-1 axis after surgically-induced weight loss is unlikely related to improved leptin secretion and/or insulin sensitivity, but is rather associated with restored adipose tissue function and reduced low-grade inflammation.
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Cirurgia Bariátrica , Hormônio do Crescimento Humano , Resistência à Insulina , Humanos , Hormônio do Crescimento Humano/metabolismo , Hormônio do Crescimento , Leptina , Fator de Crescimento Insulin-Like I/análise , Obesidade , Tecido Adiposo/metabolismo , Peso Corporal , InsulinaRESUMO
AIMS/HYPOTHESIS: Hyperbaric oxygen (HBO) therapy may improve hyperglycaemia in humans with type 2 diabetes, but underlying mechanisms are unclear. Our objective was to examine the glucometabolic effects of HBO on whole-body glucose disposal in humans with type 2 diabetes. METHODS: In a randomised placebo-controlled crossover trial located at the German Diabetes Center, 12 male individuals with type 2 diabetes (age 18-75 years, BMI <35 kg/m2, HbA1c 42-75 mmol/mol [6-9%]), randomly allocated by one person, underwent 2-h HBO, once with 100% (240 kPa; HBO) and once with 21% oxygen (240 kPa; control, CON). Insulin sensitivity was assessed by hyperinsulinaemic-euglycaemic clamps with D-[6,6-2H2]glucose, hepatic and skeletal muscle energy metabolism were assessed by 1H/31P-magnetic resonance spectroscopy, while high-resolution respirometry measured skeletal muscle and white adipose tissue (WAT) mitochondrial capacity. All participants and people assessing the outcomes were blinded. RESULTS: HBO decreased fasting blood glucose by 19% and increased whole-body, hepatic and WAT insulin sensitivity about one-third (p<0.05 vs CON). Upon HBO, hepatic γ-ATP concentrations doubled, mitochondrial respiratory control doubled in skeletal muscle and tripled in WAT (p<0.05 vs CON). HBO increased myocellular insulin-stimulated serine-473/threonine-308 phosphorylation of Akt but decreased basal inhibitory serine-1101 phosphorylation of IRS-1 and endoplasmic reticulum stress (p<0.05 vs CON). CONCLUSIONS/INTERPRETATION: HBO-mediated improvement of insulin sensitivity likely results from decreased endoplasmic reticulum stress and increased mitochondrial capacity, possibly leading to low-dose reactive oxygen species-mediated mitohormesis in humans with type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT04219215 FUNDING: German Federal Ministry of Health, German Federal Ministry of Education and Research, North-Rhine Westfalia Ministry of Culture and Science, European-Regional-Development-Fund, German-Research-Foundation (DFG), Schmutzler Stiftung.
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Diabetes Mellitus Tipo 2 , Oxigenoterapia Hiperbárica , Resistência à Insulina , Humanos , Masculino , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Diabetes Mellitus Tipo 2/terapia , Oxigênio , Glucose , SerinaRESUMO
During mammalian energy homeostasis, the glucagon receptor (Gcgr) plays a key role in regulating both glucose and lipid metabolisms. However, the mechanisms by which these distinct signaling arms are differentially regulated remain poorly understood. Using a Cy5-glucagon agonist, we show that the endosomal protein Vps37a uncouples glucose production from lipid usage downstream of Gcgr signaling by altering intracellular receptor localization. Hepatocyte-specific knockdown of Vps37a causes an accumulation of Gcgr in endosomes, resulting in overactivation of the cAMP/PKA/p-Creb signaling pathway to gluconeogenesis without affecting ß-oxidation. Shifting the receptor back to the plasma membrane rescues the differential signaling and highlights the importance of the spatiotemporal localization of Gcgr for its metabolic effects. Importantly, since Vps37a knockdown in animals fed with a high-fat diet leads to hyperglycemia, although its overexpression reduces blood glucose levels, these data reveal a contribution of endosomal signaling to metabolic diseases that could be exploited for treatments of type 2 diabetes.
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Diabetes Mellitus Tipo 2 , Receptores de Glucagon , Animais , Camundongos , Diabetes Mellitus Tipo 2/metabolismo , Endossomos/metabolismo , Glucagon/metabolismo , Glucose/metabolismo , Lipídeos , Fígado/metabolismo , Mamíferos/metabolismo , Camundongos Endogâmicos C57BL , Receptores de Glucagon/metabolismo , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismoRESUMO
BACKGROUND & AIMS: Adipose tissue dysfunction is involved in the development of insulin resistance and is responsible for excessive lipid delivery to other organs such as the liver. We tested the hypothesis that impaired mitochondrial function is a common feature of subcutaneous (SAT) and visceral adipose tissue (VAT), but may differently contribute to adipose tissue insulin resistance (IR) in obesity, non-alcoholic fatty liver (NAFL) and steatohepatitis (NASH). METHODS: In this cross-sectional study, we analyzed tissue-specific insulin sensitivity using stable isotope dilution and hyperinsulinemic-normoglycemic clamp tests. We also assessed mitochondrial respiration, mRNA and protein expression, and tissue morphology in biopsies of SAT and VAT from obese humans without NAFL, with NAFL or with NASH (n = 22/group). RESULTS: Compared to individuals without liver disease, persons with NAFL and NASH had about 30% (p = 0.010) and 33% (p = 0.002) lower maximal mitochondrial respiration, respectively, in VAT, but not in SAT. The lower maximal mitochondrial respiration of VAT was associated with lower adipose tissue insulin sensitivity (ß = 0.985, p = 0.041) and with increased VAT protein expression of tumor necrosis factor A across all groups (ß = -0.085, p = 0.040). VAT from individuals with NASH was characterized by lower expression of oxidative phosphorylation complex IV (p = 0.042) and higher mRNA expression of the macrophage marker CD68 (p = 0.002) than VAT from participants without NAFL. CONCLUSIONS: Humans with non-alcoholic fatty liver disease have distinct abnormalities of VAT energy metabolism, which correlate with adipose tissue dysfunction and may favor progression of NAFL to NASH. LAY SUMMARY: Adipose tissue (commonly called body fat) can be found under the skin (subcutaneous) or around internal organs (visceral). Dysfunction of adipose tissue can cause insulin resistance and lead to excess delivery of fat to other organs such as the liver. Herein, we show that dysfunction specifically in visceral adipose tissue was associated with fatty liver disease. CLINICAL TRIAL NUMBER: NCT01477957.
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Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica , Humanos , Estudos Transversais , Obesidade/complicações , Respiração , Tecido Adiposo , Mitocôndrias , RNA MensageiroRESUMO
OBJECTIVE: 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.
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Diabetes Mellitus Tipo 2 , Hepatopatia Gordurosa não Alcoólica , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Peróxido de Hidrogênio/metabolismo , Fígado/metabolismo , Cirrose Hepática/complicações , Mitocôndrias/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/complicaçõesRESUMO
AIMS: Empagliflozin treatment reduced liver fat in small type 2 diabetes cohorts. This post-hoc study evaluated effects of empagliflozin on risk for non-alcoholic fatty liver disease-related steatosis and fibrosis, as well as the relationship between risk categories and cardiorenal outcomes in the randomized, placebo-controlled EMPA-REG OUTCOME trial. MATERIALS AND METHODS: EMPA-REG OUTCOME treated 7020 people with type 2 diabetes and cardiovascular disease with 10/25 mg/day empagliflozin or placebo. For this analysis, the Dallas steatosis index, hepatic steatosis index, non-alcoholic fatty liver disease fibrosis score and Fibrosis-4 score were calculated to assess steatosis and fibrosis risk. Changes from baseline in scores were examined by mixed model repeated measures and their associations with cardiorenal outcomes and mortality by Cox regression. RESULTS: At baseline, 73% and 84% of participants had high steatosis risk by Dallas steatosis index and hepatic steatosis index, whereas 23% and 4% had a high risk of advanced fibrosis by non-alcoholic fatty liver disease fibrosis score and Fibrosis-4 score. Percentages of people at high steatosis risk slightly decreased with empagliflozin only, whereas empagliflozin did not improve percentages of individuals at high fibrosis risk over time compared with placebo. The high risk of advanced fibrosis at baseline related to higher risk for cardiovascular events. Effects of empagliflozin on cardiorenal and all-cause mortality outcomes were consistent across all risk groups. CONCLUSIONS: Empagliflozin may reduce steatosis but not fibrosis risk in individuals with type 2 diabetes and cardiovascular disease. The improvements in cardiorenal outcomes and mortality associated with empagliflozin therapy appear to be independent of steatosis and fibrosis risk.
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Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Hepatopatia Gordurosa não Alcoólica , Compostos Benzidrílicos/uso terapêutico , Biomarcadores , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Fibrose , Glucosídeos , Humanos , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Resultado do TratamentoRESUMO
Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide with high prevalence, especially in individuals with obesity and type 2 diabetes. Among individuals with type 2 diabetes, the severe insulin resistant subgroup has the greatest risk of NAFLD, likely due to dysfunctional adipose tissue mass but also genetic factors, and may progress earlier to inflammatory and profibrotic nonalcoholic steatohepatitis (NASH). NASH has been associated with increased liver-related as well as cardiovascular morbidity and mortality. International diabetes associations recommend certain screening and treatment strategies for NASH in type 2 diabetes, which, however, bear several limitations such as lack of accurate noninvasive diagnostic tools and targeted treatments. Currently, antihyperglycemic drug concepts based on glucagon-like peptide-1 receptor agonists and sodium glucose cotransporter 2 inhibitors offer metabolic as well as cardiorenal benefits and provide treatment options for both hyperglycemia and NASH in type 2 diabetes.
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Diabetes Mellitus Tipo 2 , Hepatopatia Gordurosa não Alcoólica , Inibidores do Transportador 2 de Sódio-Glicose , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Hipoglicemiantes/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/complicações , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêuticoRESUMO
BACKGROUND: The findings of observational studies can be distorted by a number of factors. So-called confounders are well known, but distortion by collider bias (CB) has received little attention in medical research to date. The goal of this article is to present the principle of CB, and measures that can be taken to avoid it, by way of a few illustrative examples. METHODS: The findings of a selective review of the literature on CB are explained with illustrative examples. RESULTS: The simplest case of a collider variable is one that is caused by at least two other variables. An example of CB is the observation that, among persons with diabetes, obesity is associated with lower mortality, even though it is associated with higher mortality in the general population. The false protective association between obesity and mortality arises from the restriction of the study population to persons with diabetes. CONCLUSION: CB is a distortion that arises through restriction on or stratification by a collider variable, or through statistical adjustment for a collider variable in a regression model. CB can arise in many ways. The graphic representation of causal structures helps to identify potential sources of CB. It is important to distinguish confounders from colliders, as methods that serve to correct for confounding can themselves cause bias when applied to colliders. There is no generally applicable method for correcting CB.
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Obesidade , Viés , Causalidade , Humanos , Obesidade/epidemiologia , Estudos Observacionais como AssuntoRESUMO
AIMS/HYPOTHESIS: Energy-dense nutrition generally induces insulin resistance, but dietary composition may differently affect glucose metabolism. This study investigated initial effects of monounsaturated vs saturated lipid meals on basal and insulin-stimulated myocellular glucose metabolism and insulin signalling. METHODS: In a randomised crossover study, 16 lean metabolically healthy volunteers received single meals containing safflower oil (SAF), palm oil (PAL) or vehicle (VCL). Whole-body glucose metabolism was assessed from glucose disposal (Rd) before and during hyperinsulinaemic-euglycaemic clamps with D-[6,6-2H2]glucose. In serial skeletal muscle biopsies, subcellular lipid metabolites and insulin signalling were measured before and after meals. RESULTS: SAF and PAL raised plasma oleate, but only PAL significantly increased plasma palmitate concentrations. SAF and PAL increased myocellular diacylglycerol and activated protein kinase C (PKC) isoform θ (p < 0.05) but only PAL activated PKCÉ. Moreover, PAL led to increased myocellular ceramides along with stimulated PKCζ translocation (p < 0.05 vs SAF). During clamp, SAF and PAL both decreased insulin-stimulated Rd (p < 0.05 vs VCL), but non-oxidative glucose disposal was lower after PAL compared with SAF (p < 0.05). Muscle serine1101-phosphorylation of IRS-1 was increased upon SAF and PAL consumption (p < 0.05), whereas PAL decreased serine473-phosphorylation of Akt more than SAF (p < 0.05). CONCLUSIONS/INTERPRETATION: Lipid-induced myocellular insulin resistance is likely more pronounced with palmitate than with oleate and is associated with PKC isoforms activation and inhibitory insulin signalling. TRIAL REGISTRATION: ClinicalTrials.gov .NCT01736202. 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 Regional Development Fund, German Research Foundation, German Center for Diabetes Research.
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Gorduras na Dieta/administração & dosagem , Resistência à Insulina/fisiologia , Músculo Esquelético/metabolismo , Ácido Oleico/administração & dosagem , Palmitatos/administração & dosagem , Adulto , Glicemia/metabolismo , Calorimetria , Estudos Cross-Over , Diglicerídeos/sangue , Ácidos Graxos/sangue , Feminino , Técnica Clamp de Glucose , Voluntários Saudáveis , Humanos , Masculino , Óleo de Palmeira/administração & dosagem , Proteína Quinase C/sangue , Óleo de Cártamo/administração & dosagem , Adulto JovemRESUMO
Individuals with obesity or type 2 diabetes (T2D) have an increased risk of developing non-alcoholic fatty liver disease (NAFLD). In insulin-resistant states, altered adipose tissue function may be the initial abnormality underlying NAFLD. Hepatic lipid oversupply interferes with insulin signalling and mitochondrial function. In obese individuals, adaptation of hepatic mitochondrial respiration fails with the progression of NAFLD and can activate pro-inflammatory pathways. T2D as well as type 1 diabetes are associated with altered hepatic mitochondrial function. Screening for NAFLD remains challenging especially in those with diabetes because liver enzymes are often in the normal range and the performance of NAFLD scores is limited. Patients with T2D and severe insulin-resistant diabetes (SIRD) have the highest prevalence of NAFLD at diagnosis and the greatest risk of progression. In this subgroup, the single-nucleotide-polymorphism (SNP) rs738409(G) of the patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene is associated with high liver fat content and adipose tissue insulin resistance. This frequent SNP is also known to be associated with lean NAFLD so that genetic testing for this and other SNPs could improve future screening strategies to identify high-risk individuals. Although lifestyle modifications are effective, this approach is limited owing to difficulties with compliance and several classes of drugs are being tested to treat NAFLD. Antihyperglycaemic drugs such as glucagon-like peptide 1 receptor agonists (GLP-1 RA), sodium-glucose cotransporter 2 inhibitors (SGLT2i) and pioglitazone are promising and halt the progression of NAFLD. In conclusion, although NAFLD in diabetes may not be a separate entity, there are specific features to its pathogenesis and clinical management.
Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Humanos , Hipoglicemiantes/uso terapêutico , Fígado , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/terapia , PioglitazonaRESUMO
AIMS/HYPOTHESIS: People with diabetes have an increased cardiovascular risk with an accelerated development of atherosclerosis and an elevated mortality rate after myocardial infarction. Therefore, cardioprotective effects of glucose-lowering therapies are of major importance for the pharmacotherapy of individuals with type 2 diabetes. For sodium-glucose cotransporter 2 inhibitors (SGLT2is), in addition to a reduction in blood glucose, beneficial effects on atherosclerosis, obesity, renal function and blood pressure have been observed. Recent results showed a reduced risk of worsening heart failure and cardiovascular deaths under dapagliflozin treatment irrespective of the diabetic state. However, the underlying mechanisms are yet unknown. Platelets are known drivers of atherosclerosis and atherothrombosis and disturbed platelet activation has also been suggested to occur in type 2 diabetes. Therefore, the present study investigates the impact of the SGLT2i dapagliflozin on the interplay between platelets and inflammation in atherogenesis. METHODS: Male, 8-week-old LDL-receptor-deficient (Ldlr-/-) mice received a high-fat, high-sucrose diabetogenic diet supplemented without (control) or with dapagliflozin (5 mg/kg body weight per day) for two time periods: 8 and 25 weeks. In a first translational approach, eight healthy volunteers received 10 mg dapagliflozin/day for 4 weeks. RESULTS: Dapagliflozin treatment ameliorated atherosclerotic lesion development, reduced circulating platelet-leucocyte aggregates (glycoprotein [GP]Ib+CD45+: 29.40 ± 5.94 vs 17.00 ± 5.69 cells, p < 0.01; GPIb+lymphocyte antigen 6 complex, locus G+ (Ly6G): 8.00 ± 2.45 vs 4.33 ± 1.75 cells, p < 0.05) and decreased aortic macrophage infiltration (1.31 ± 0.62 vs 0.70 ± 0.58 ×103 cells/aorta, p < 0.01). Deeper analysis revealed that dapagliflozin decreased activated CD62P-positive platelets in Ldlr-/- mice fed a diabetogenic diet (3.78 ± 1.20% vs 2.83 ± 1.06%, p < 0.01) without affecting bleeding time (85.29 ± 37.27 vs 89.25 ± 16.26 s, p = 0.78). While blood glucose was only moderately affected, dapagliflozin further reduced endogenous thrombin generation (581.4 ± 194.6 nmol/l × min) × 10-9 thrombin vs 254.1 ± 106.4 (nmol/l × min) × 10-9 thrombin), thereby decreasing one of the most important platelet activators. We observed a direct inhibitory effect of dapagliflozin on isolated platelets. In addition, dapagliflozin increased HDL-cholesterol levels. Importantly, higher HDL-cholesterol levels (1.70 ± 0.58 vs 3.15 ± 1.67 mmol/l, p < 0.01) likely contribute to dapagliflozin-mediated inhibition of platelet activation and thrombin generation. Accordingly, in line with the results in mice, treatment with dapagliflozin lowered CD62P-positive platelet counts in humans after stimulation by collagen-related peptide (CRP; 88.13 ± 5.37% of platelets vs 77.59 ± 10.70%, p < 0.05) or thrombin receptor activator peptide-6 (TRAP-6; 44.23 ± 15.54% vs 28.96 ± 11.41%, p < 0.01) without affecting haemostasis. CONCLUSIONS/INTERPRETATION: We demonstrate that dapagliflozin-mediated atheroprotection in mice is driven by elevated HDL-cholesterol and ameliorated thrombin-platelet-mediated inflammation without interfering with haemostasis. This glucose-independent mechanism likely contributes to dapagliflozin's beneficial cardiovascular risk profile.
Assuntos
Compostos Benzidrílicos/uso terapêutico , Doença da Artéria Coronariana/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/uso terapêutico , Ativação Plaquetária/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Trombina/metabolismo , Adulto , Animais , Glicemia/metabolismo , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/prevenção & controle , HDL-Colesterol/sangue , Doença da Artéria Coronariana/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Citometria de Fluxo , Voluntários Saudáveis , Humanos , Imuno-Histoquímica , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Selectina-P/metabolismo , Contagem de Plaquetas , Reação em Cadeia da Polimerase em Tempo Real , Comportamento de Redução do RiscoRESUMO
Non-alcoholic fatty liver disease (NAFLD) comprises fatty liver (steatosis), non-alcoholic steatohepatitis (NASH) and fibrosis/cirrhosis and may lead to end-stage liver failure or hepatocellular carcinoma. NAFLD is tightly associated with the most frequent metabolic disorders, such as obesity, metabolic syndrome, and type 2 diabetes mellitus (T2DM). Both multisystem diseases share several common mechanisms. Alterations of tissue communications include excessive lipid and later cytokine release by dysfunctional adipose tissue, intestinal dysbiosis and ectopic fat deposition in skeletal muscle. On the hepatocellular level, this leads to insulin resistance due to abnormal lipid handling and mitochondrial function. Over time, cellular oxidative stress and activation of inflammatory pathways, again supported by multiorgan crosstalk, determine NAFLD progression. Recent studies show that particularly the severe insulin resistant diabetes (SIRD) subgroup (cluster) associates with NAFLD and its accelerated progression and increases the risk of diabetes-related cardiovascular and kidney diseases, underpinning the critical role of insulin resistance. Consequently, lifestyle modification and certain drug classes used to treat T2DM have demonstrated effectiveness for treating NAFLD, but also some novel therapeutic concepts may be beneficial for both NAFLD and T2DM. This review addresses the bidirectional relationship between mechanisms underlying T2DM and NAFLD, the relevance of novel biomarkers for improving the diagnostic modalities and the identification of subgroups at specific risk of disease progression. Also, the role of metabolism-related drugs in NAFLD is discussed in light of the recent clinical trials. Finally, this review highlights some challenges to be addressed by future studies on NAFLD in the context of T2DM.