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Excess free fatty acids, an imbalance of adipocytokines and mitochondrial dysfunction all contribute to abnormalities in hepatocellular lipid content in diabetes and can lead to steatosis and insulin resistance. Thus liver fat is a novel target for therapies such as fat-reduced diets and thiazolidendiones. Hepatic steatosis is defined by an increased content of hepatocellular lipids (HCLs) and is frequently observed in insulin-resistant states including type 2 diabetes mellitus. A dietary excess of saturated fat contributes significantly to HCL accumulation. Elevated HCL levels mainly account for hepatic insulin resistance, which is probably mediated by partitioning of free fatty acids to the liver (fat overflow) and by an imbalance of adipocytokines (decreased adiponectin and/or increased proinflammatory cytokines). Both free fatty acids and adipocytokines activate inflammatory pathways that include protein kinase C, the transcription factor nuclear factor κB, and c-Jun N-terminal kinase 1 and can thereby accelerate the progression of hepatic steatosis to nonalcoholic steatohepatitis and cirrhosis. Proton magnetic resonance spectroscopy has made it possible to quantify HCL concentrations and to detect even small changes in these concentrations in clinical settings. Moderately hypocaloric, fat-reduced diets can decrease HCL levels by ∼40–80% in parallel with loss of up to 8% of body weight. Treatment with thiazolidinediones (e.g. pioglitazone and rosiglitazone) reduces HCL levels by 30–50% by modulating insulin sensitivity and endocrine function of adipose tissue in type 2 diabetes. Metformin improves hepatic insulin action without affecting HCL levels, whereas insulin infusion for 67 h increases HCL levels by ∼18%; furthermore, HCL levels positively correlate with the insulin dosage in insulin-treated type 2 diabetes. In conclusion, liver fat is a critical determinant of metabolic fluxes and inflammatory processes, thereby representing an important therapeutic target in insulin resistance and type 2 diabetes mellitus. Key Points Hepatic steatosis is diagnosed when more than 5% of the content of liver cells is lipid and is typical in insulin-resistant states, including type 2 diabetes mellitus Free fatty acids (fat overflow) and imbalance of adipocytokines contribute to elevated hepatocellular lipid (HCL) levels and hepatic insulin resistance Mitochondrial dysfunction and activation of inflammatory pathways seem to be the major intracellular mechanisms determining hepatic steatosis and its progression to nonalcoholic steatohepatitis Proton magnetic resonance spectroscopy allows quantification of HCL concentrations in clinical settings Fat-reduced diets and thiazolidinediones decrease HCL levels by ∼30–80%, whereas insulin infusion increases HCL levels by ∼18% Liver fat is a novel therapeutic target in insulin resistance and type 2 diabetes mellitus

Nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions worldwide. NAFLD and type 2 diabetes mellitus (T2DM) are known to frequently coexist and act synergistically to increase the risk of adverse (hepatic and extra-hepatic) clinical outcomes. T2DM is also one of the strongest risk factors for the faster progression of NAFLD to nonalcoholic steatohepatitis, advanced fibrosis or cirrhosis. However, the link between NAFLD and T2DM is more complex than previously believed. Strong evidence indicates that NAFLD is associated with an approximate twofold higher risk of developing T2DM, irrespective of obesity and other common metabolic risk factors. This risk parallels the severity of NAFLD, such that patients with more advanced stages of liver fibrosis are at increased risk of incident T2DM. In addition, the improvement or resolution of NAFLD (on ultrasonography) is associated with a reduction of T2DM risk, adding weight to causality and suggesting that liver-focused treatments might reduce the risk of developing T2DM. This Review describes the evidence of an association and causal link between NAFLD and T2DM, discusses the putative pathophysiological mechanisms linking NAFLD to T2DM and summarizes the current pharmacological treatments for NAFLD or T2DM that might benefit or adversely affect the risk of T2DM or NAFLD progression. This Review describes the evidence of an association and causal link between nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM), discusses their pathophysiological mechanisms and summarizes the pharmacological treatments that might benefit or adversely affect the risk of T2DM or NAFLD progression. Key points An updated meta-analysis of 33 observational studies showed that nonalcoholic fatty liver disease (NAFLD) is associated with an approximate doubled risk of type 2 diabetes mellitus (T2DM), irrespective of obesity and other metabolic risk factors. Patients with more advanced stages of liver fibrosis are at increased risk of T2DM; some observational studies have shown that improvement or resolution of NAFLD on ultrasonography is closely associated with a reduction of diabetes risk. NAFLD exacerbates hepatic and peripheral insulin resistance, predisposes to atherogenic dyslipidaemia and causes the systemic release of pro-inflammatory cytokines and hepatokines that can promote the development of T2DM. Treatment of NAFLD and T2DM is based on lifestyle modifications aiming at substantial weight loss in individuals with overweight or obesity. Although no pharmacotherapy is currently approved for NAFLD, some antihyperglycaemic drugs, such as pioglitazone, glucagon-like peptide 1 analogues and sodium–glucose cotransporter 2 inhibitors, have some efficacy. Multiple investigational compounds for NAFLD treatment, including modulators of bile acid and lipid metabolism, are in phase II and phase III randomized controlled trials.

This Review discusses the association between mitochondrial function and insulin sensitivity in various tissues, such as skeletal muscle, liver and heart, with a main focus on studies in humans, and addresses the effects of therapeutic strategies that affect mitochondrial function and insulin sensitivity. Type 2 diabetes mellitus (T2DM) has been related to alterations of oxidative metabolism in insulin-responsive tissues. Overt T2DM can present with acquired or inherited reductions of mitochondrial oxidative phosphorylation capacity, submaximal ADP-stimulated oxidative phosphorylation and plasticity of mitochondria and/or lower mitochondrial content in skeletal muscle cells and potentially also in hepatocytes. Acquired insulin resistance is associated with reduced insulin-stimulated mitochondrial activity as the result of blunted mitochondrial plasticity. Hereditary insulin resistance is frequently associated with reduced mitochondrial activity at rest, probably due to diminished mitochondrial content. Lifestyle and pharmacological interventions can enhance the capacity for oxidative phosphorylation and mitochondrial content and improve insulin resistance in some (pre)diabetic cases. Various mitochondrial features can be abnormal but are not necessarily responsible for all forms of insulin resistance. Nevertheless, mitochondrial abnormalities might accelerate progression of insulin resistance and subsequent organ dysfunction via increased production of reactive oxygen species. This Review discusses the association between mitochondrial function and insulin sensitivity in various tissues, such as skeletal muscle, liver and heart, with a main focus on studies in humans, and addresses the effects of therapeutic strategies that affect mitochondrial function and insulin sensitivity. Key Points Overt type 2 diabetes mellitus is associated with reduced oxidative phosphorylation capacity, submaximal ADP-stimulated oxidative phosphorylation and mitochondrial plasticity in insulin-responsive tissues Acquired insulin resistance is associated with reduced insulin-stimulated mitochondrial plasticity that results in the inability of the organism to switch from fatty acid to glucose oxidation in skeletal muscle Hereditary insulin resistance can be linked to reduced resting mitochondrial activity at least partly due to a decreased mitochondrial content Lifestyle and pharmacological interventions can enhance oxidative phosphorylation capacity and mitochondrial content, and in most cases improve insulin resistance in (pre)diabetic states Reduced oxidative phosphorylation capacity is unlikely to be the general cause of all forms of insulin resistance but might accelerate its progression and subsequent organ dysfunction via increased production of reactive oxygen species

The increasing epidemic of obesity worldwide is linked to serious health effects, including increased prevalence of type 2 diabetes mellitus, cardiovascular disease and nonalcoholic fatty liver disease (NAFLD). NAFLD is the liver manifestation of the metabolic syndrome and includes the spectrum of liver steatosis (known as nonalcoholic fatty liver) and steatohepatitis (known as nonalcoholic steatohepatitis), which can evolve into progressive liver fibrosis and eventually cause cirrhosis. Although NAFLD is becoming the number one cause of chronic liver diseases, it is part of a systemic disease that affects many other parts of the body, including adipose tissue, pancreatic β-cells and the cardiovascular system. The pathomechanism of NAFLD is multifactorial across a spectrum of metabolic derangements and changes in the host microbiome that trigger low-grade inflammation in the liver and other organs. Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear regulatory factors that provide fine tuning for key elements of glucose and fat metabolism and regulate inflammatory cell activation and fibrotic processes. This Review summarizes and discusses the current literature on NAFLD as the liver manifestation of the systemic metabolic syndrome and focuses on the role of PPARs in the pathomechanisms as well as in the potential targeting of disease. This Review describes the pathophysiological roles of peroxisome proliferator-activated receptors (PPARs) in nonalcoholic steatohepatitis and related metabolic diseases, and summarizes the preclinical and clinical data on the use of PPAR agonists to treat nonalcoholic steatohepatitis as part of a systemic metabolic disease. Key points Nonalcoholic steatohepatitis (NASH) is the fastest growing liver disease worldwide; however, it is often not recognized until advanced disease stages. The management and treatment of NASH, the liver manifestation of the metabolic syndrome, require a holistic approach. Peroxisome proliferator-activated receptors (PPARs) regulate metabolism, inflammation and fibrosis, all of which determine NASH progression. There is an urgent need for medical therapy for patients with NASH. Both PPARα-β/δ dual agonism as well as PPARγ agonism have shown beneficial effects on liver histology in phase IIb clinical trials for NASH. Single, dual and pan-PPAR agonists are under development for the pharmacological treatment of NASH.

The current classification of diabetes, based on hyperglycaemia, islet-directed antibodies and some insufficiently defined clinical features, does not reflect differences in aetiological mechanisms and in the clinical course of people with diabetes. This review discusses evidence from recent studies addressing the complexity of diabetes by proposing novel subgroups (subtypes) of diabetes. The most widely replicated and validated approach identified, in addition to severe autoimmune diabetes, four subgroups designated severe insulin-deficient diabetes, severe insulin-resistant diabetes, mild obesity-related diabetes and mild age-related diabetes subgroups. These subgroups display distinct patterns of clinical features, disease progression and onset of comorbidities and complications, with severe insulin-resistant diabetes showing the highest risk for cardiovascular, kidney and fatty liver diseases. While it has been suggested that people in these subgroups would benefit from stratified treatments, RCTs are required to assess the clinical utility of any reclassification effort. Several methodological and practical issues also need further study: the statistical approach used to define subgroups and derive recommendations for diabetes care; the stability of subgroups over time; the optimal dataset (e.g. phenotypic vs genotypic) for reclassification; the transethnic generalisability of findings; and the applicability in clinical routine care. Despite these open questions, the concept of a new classification of diabetes has already allowed researchers to gain more insight into the colourful picture of diabetes and has stimulated progress in this field so that precision diabetology may become reality in the future.

Increased dietary fat intake and lipolysis result in excessive lipid availability, which relates to impaired insulin sensitivity. Over the last years, several mechanisms possibly underlying lipid-mediated insulin resistance evolved. Lipid intermediates such as diacylglycerols (DAG) associate with changes in insulin sensitivity in many models. DAG activate novel protein kinase C (PKC) isoforms followed by inhibitory serine phosphorylation of insulin receptor substrate 1 (IRS1). Activation of Toll-like receptor 4 (TLR4) raises another lipid class, ceramides (CER), which induce pro-inflammatory pathways and lead to inhibition of Akt phosphorylation. Inhibition of glucosylceramide and ganglioside synthesis results in improved insulin sensitivity and increased activatory tyrosine phosphorylation of IRS1 in the muscle. Incomplete fat oxidation can increase acylcarnitines (ACC), which in turn stimulate pro-inflammatory pathways. This review analyzed the effects of lipid metabolites on insulin action in skeletal muscle of humans and rodents. Despite the evidence for the association of both DAG and CER with insulin resistance, its causal relevance may differ depending on the subcellular localization and the tested cohorts, e.g., athletes. Nevertheless, recent data indicate that individual lipid species and their degree of fatty acid saturation, particularly membrane and cytosolic C18:2 DAG, specifically activate PKCθ and induce both acute lipid-induced and chronic insulin resistance in humans.

Dietary intake of saturated fat is a likely contributor to nonalcoholic fatty liver disease (NAFLD) and insulin resistance, but the mechanisms that initiate these abnormalities in humans remain unclear. We examined the effects of a single oral saturated fat load on insulin sensitivity, hepatic glucose metabolism, and lipid metabolism in humans. Similarly, initiating mechanisms were examined after an equivalent challenge in mice. Fourteen lean, healthy individuals randomly received either palm oil (PO) or vehicle (VCL). Hepatic metabolism was analyzed using in vivo 13C/31P/1H and ex vivo 2H magnetic resonance spectroscopy before and during hyperinsulinemic-euglycemic clamps with isotope dilution. Mice underwent identical clamp procedures and hepatic transcriptome analyses. PO administration decreased whole-body, hepatic, and adipose tissue insulin sensitivity by 25%, 15%, and 34%, respectively. Hepatic triglyceride and ATP content rose by 35% and 16%, respectively. Hepatic gluconeogenesis increased by 70%, and net glycogenolysis declined by 20%. Mouse transcriptomics revealed that PO differentially regulates predicted upstream regulators and pathways, including LPS, members of the TLR and PPAR families, NF-κB, and TNF-related weak inducer of apoptosis (TWEAK). Saturated fat ingestion rapidly increases hepatic lipid storage, energy metabolism, and insulin resistance. This is accompanied by regulation of hepatic gene expression and signaling that may contribute to development of NAFLD.REGISTRATION. ClinicalTrials.gov NCT01736202. Germany: Ministry of Innovation, Science, and Research North Rhine-Westfalia, German Federal Ministry of Health, Federal Ministry of Education and Research, German Center for Diabetes Research, German Research Foundation, and German Diabetes Association. Portugal: Portuguese Foundation for Science and Technology, FEDER - European Regional Development Fund, Portuguese Foundation for Science and Technology, and Rede Nacional de Ressonância Magnética Nuclear.

Background To develop more efficient programmes for promoting dietary and/or physical activity change (in order to prevent type 2 diabetes) it is critical to ensure that the intervention components and characteristics most strongly associated with effectiveness are included. The aim of this systematic review of reviews was to identify intervention components that are associated with increased change in diet and/or physical activity in individuals at risk of type 2 diabetes. Methods MEDLINE, EMBASE, CINAHL, PsycInfo, and the Cochrane Library were searched for systematic reviews of interventions targeting diet and/or physical activity in adults at risk of developing type 2 diabetes from 1998 to 2008. Two reviewers independently selected reviews and rated methodological quality. Individual analyses from reviews relating effectiveness to intervention components were extracted, graded for evidence quality and summarised. Results Of 3856 identified articles, 30 met the inclusion criteria and 129 analyses related intervention components to effectiveness. These included causal analyses (based on randomisation of participants to different intervention conditions) and associative analyses (e.g. meta-regression). Overall, interventions produced clinically meaningful weight loss (3-5 kg at 12 months; 2-3 kg at 36 months) and increased physical activity (30-60 mins/week of moderate activity at 12-18 months). Based on causal analyses, intervention effectiveness was increased by engaging social support, targeting both diet and physical activity, and using well-defined/established behaviour change techniques. Increased effectiveness was also associated with increased contact frequency and using a specific cluster of \"self-regulatory\" behaviour change techniques (e.g. goal-setting, self-monitoring). No clear relationships were found between effectiveness and intervention setting, delivery mode, study population or delivery provider. Evidence on long-term effectiveness suggested the need for greater consideration of behaviour maintenance strategies. Conclusions This comprehensive review of reviews identifies specific components which are associated with increased effectiveness in interventions to promote change in diet and/or physical activity. To maximise the efficiency of programmes for diabetes prevention, practitioners and commissioning organisations should consider including these components.

Aims/hypothesis Cardiac autonomic nervous dysfunction (CAND) raises the risk of mortality, but the glycaemic threshold at which it develops is unclear. We aimed to determine the prevalence of, risk factors for and impact of CAND in glucose intolerance and diabetes. Methods Among 1,332 eligible participants aged 55–74 years in the population-based cross-sectional KORA S4 study, 130 had known diabetes mellitus (k-DM), and the remaining 1,202 underwent an OGTT. Heart rate variability (HRV) and QT variability were computed from supine 5 min ECGs. Results In all, 565 individuals had normal glucose tolerance (NGT), 336 had isolated impaired fasting glucose (i-IFG), 72 had isolated impaired glucose tolerance (i-IGT), 151 had combined IFG–IGT (IFG–IGT) and 78 had newly detected diabetes mellitus (n-DM). Adjusted normal HRV limits were defined in the NGT population (5th and 95th percentiles). Three HRV measures were more frequently abnormal in those with k-DM, n-DM, IFG–IGT and i-IFG than in those with NGT ( p <  0.05). The rates of CAND (≥2 of 4 HRV indices abnormal) were: NGT, 4.5%; i-IFG, 8.1%; i-IGT, 5.9%; IFG–IGT, 11.4%; n-DM, 11.7%; and k-DM, 17.5% ( p <  0.05 vs NGT, except for i-IGT). Reduced HRV was associated with cardiovascular risk factors used to construct a simple screening score for CAND. Mortality was higher in participants with reduced HRV ( p <  0.05 vs normal HRV). Conclusions/interpretation In the general population aged 55–74 years, the prevalence of CAND is increased not only in individuals with diabetes, but also in those with IFG–IGT and, to a lesser degree, in those with i-IFG. It is associated with mortality and modifiable cardiovascular risk factors which may be used to screen for diminished HRV in clinical practice.