The prevalence of obesity is increasing worldwide, and this epidemic is accompanied by a high incidence of type 2 diabetes mellitus and cardiovascular disease.¹ Although overall obesity delineates an important risk factor for these diseases, it is recognized that body fat distribution additionally represents an independent determinant. For any given amount of total body fat, individuals with a selective excess of intra-abdominal (visceral) adipose tissue, estimated by an increased waist circumference, are at substantially higher risk of being insulin resistant and having a cardiovascular risk profile.^2-8 Excess visceral fat accumulation results from the inability of adipose tissue to appropriately store the excess energy. According to this hypothesis, energy is deposited as fat intra-abdominally and in ectopic depots such as the liver and the skeletal muscle, resulting in an increased risk of type 2 diabetes mellitus and cardiovascular disease. In contrast, when extra energy is directed toward the subcutaneous depots or is burned within the mitochondria in the liver and muscle, the individual, although having a positive energy balance, will be protected against the development of these diseases.⁹ Accordingly, it may be possible to identify a metabolically benign fat distribution phenotype even in the obese spectrum. Such individuals may be protected from type 2 diabetes mellitus and cardiovascular disease.

Type 2 diabetes and cardiovascular disease represent a serious threat to the health of the population worldwide. Although overall adiposity and particularly visceral adiposity are established risk factors for these diseases, in the recent years fatty liver emerged as an additional and independent factor. However, the pathophysiology of fat accumulation in the liver and the cross-talk of fatty liver with other tissues involved in metabolism in humans are not fully understood. Here we discuss the mechanisms involved in the pathogenesis of hepatic fat accumulation, particularly the roles of body fat distribution, nutrition, exercise, genetics, and gene-environment interaction. Furthermore, the effects of fatty liver on glucose and lipid metabolism, specifically via induction of subclinical inflammation and secretion of humoral factors, are highlighted. Finally, new aspects regarding the dissociation of fatty liver and insulin resistance are addressed.

OBJECTIVE: To evaluate whether the sodium–glucose cotransporter 2 inhibitor empagliflozin (EMPA) reduces liver fat content (LFC) in recent-onset and metabolically well-controlled type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: Patients with T2D (n = 84) (HbA1c 6.6 ± 0.5% [49 ± 10 mmol/mol], known disease duration 39 ± 27 months) were randomly assigned to 24 weeks of treatment with 25 mg daily EMPA or placebo. The primary end point was the difference of the change in LFC as measured with magnetic resonance methods from 0 (baseline) to 24 weeks between groups. Tissue-specific insulin sensitivity (secondary outcome) was assessed by two-step clamps using an isotope dilution technique. Exploratory analysis comprised circulating surrogate markers of insulin sensitivity and liver function. Statistical comparison was done by ANCOVA adjusted for respective baseline values, age, sex, and BMI. RESULTS: EMPA treatment resulted in a placebo-corrected absolute change of −1.8% (95% CI −3.4, −0.2; P = 0.02) and relative change in LFC of −22% (−36, −7; P = 0.009) from baseline to end of treatment, corresponding to a 2.3-fold greater reduction. Weight loss occurred only with EMPA (placebo-corrected change −2.5 kg [−3.7, −1.4]; P < 0.001), while no placebo-corrected change in tissue-specific insulin sensitivity was observed. EMPA treatment also led to placebo-corrected changes in uric acid (−74 mol/L [−108, −42]; P < 0.001) and high-molecular-weight adiponectin (36% [16, 60]; P < 0.001) levels from 0 to 24 weeks. CONCLUSIONS: EMPA effectively reduces hepatic fat in patients with T2D with excellent glycemic control and short known disease duration. Interestingly, EMPA also decreases circulating uric acid and raises adiponectin levels despite unchanged insulin sensitivity. EMPA could therefore contribute to the early treatment of nonalcoholic fatty liver disease in T2D.

OBJECTIVE In a genome-wide association scan, the rs738409 C>G single nucleotide polymorphism (SNP) in the patatin-like phospholipase 3 gene (PNPLA3) was strongly associated with increased liver fat but not with insulin resistance estimated from fasting values. We investigated whether the SNP determines liver fat independently of visceral adiposity and whether it may even play a role in protecting from insulin resistance. RESEARCH DESIGN AND METHODS Liver fat was measured by ¹H magnetic resonance spectroscopy and total and visceral fat by magnetic resonance tomography in 330 subjects. Insulin sensitivity was estimated during an oral glucose tolerance test and the euglycemic-hyperinsulinemic clamp (n = 222). PNPLA3 and tumor necrosis factor-α mRNA and triglyceride content were measured in liver biopsies from 16 subjects. RESULTS Liver fat correlated strongly with insulin sensitivity (P < 0.0001) independently of age, sex, total fat, and visceral fat. G allele carriers of the SNP rs738409 had higher liver fat (P < 0.0001) and an odds ratio of 2.38 (95% CI 1.37–4.20) for having fatty liver compared to C allele homozygotes. Interestingly, insulin sensitivity (oral glucose tolerance test: P = 0.99; clamp: P = 0.32), serum C-reactive protein levels, lipids, or liver enzymes (all P > 0.14) were not different among the genotypes. Additional adjustment for liver fat actually revealed increased insulin sensitivity in more obese carriers of the G allele (P = 0.01). In liver biopsies triglyceride content correlated positively with expression of the proinflammatory gene tumor necrosis factor-α in C allele homozygotes (n = 6, P = 0.027) but not in G allele carriers (n = 10, P = 0.149). CONCLUSIONS PNPLA3 may be an important key to understand the mechanisms discriminating fatty liver with and without metabolic consequences.

Objective: Lifestyle intervention with diet modification and increase in physical activity is effective for reducing hepatic steatosis in patients with non-alcoholic fatty liver disease (NAFLD). However, for a similar weight loss, there is a large variability in the change in liver fat. We hypothesised that cardiorespiratory fitness may predict the response to the intervention. Design: Longitudinal study with increase in physical activity and diet modification. Setting: University teaching hospital. Patients: 50 adults with NAFLD and 120 controls at risk for metabolic diseases. Main outcome measures: Total-, subcutaneous abdominal- and visceral adipose tissue by magnetic resonance tomography, liver fat by 1HMR spectroscopy and cardiorespiratory fitness (VO_2,max) by a maximal cycle exercise test at baseline and after 9 months of follow-up. Results: In all subjects total-, subcutaneous abdominal- and visceral adipose tissue decreased and fitness increased (all p<0.0001) during the intervention. The most pronounced changes were found for liver fat (−31%, p<0.0001). Among the parameters predicting the change in liver fat, fitness at baseline emerged as the strongest factor, independently of total- and visceral adipose tissue as well as exercise intensity (p = 0.005). In the group of subjects with NAFLD at baseline, a resolution of NAFLD was found in 20 individuals. For 1 standard deviation increase in VO_2,max at baseline the odds ratio for resolution of NAFLD was 2.79 (95% confidence interval, 1.43–6.33). Conclusions: Cardiorespiratory fitness, independently of total adiposity, body fat distribution and exercise intensity, determines liver fat content in humans, suggesting that fitness and liver fat are causally related to each other. Moreover, measurement of fitness at baseline predicts the effectiveness of a lifestyle intervention in reducing hepatic steatosis in patients with NAFLD.

OBJECTIVE Recent data suggested that sex hormone–binding globulin (SHBG) levels decrease when fat accumulates in the liver and that circulating SHBG may be causally involved in the pathogenesis of type 2 diabetes in humans. In the present study, we investigated mechanisms by which high SHBG may prevent development to diabetes. RESEARCH DESIGN AND METHODS Before and during a 9-month lifestyle intervention, total body and visceral fat were precisely measured by magnetic resonance (MR) tomography and liver fat was measured by ¹H-MR spectroscopy in 225 subjects. Insulin sensitivity was estimated from a 75-g oral glucose tolerance test (IS_OGTT) and measured by a euglycemic hyperinsulinemic clamp (IS_clamp, n = 172). Insulin secretion was measured during the OGTT and an ivGTT (n = 172). RESULTS SHBG levels correlated positively with insulin sensitivity (IS_OGTT, P = 0.037; IS_clamp, P = 0.057), independently of age, sex, and total body fat. In a multivariate model, these relationships were also significant after additional adjustment for levels of the adipokine adiponectin and the hepatokine fetuin-A (IS_OGTT, P = 0.0096; IS_clamp, P = 0.029). Adjustment of circulating SHBG for liver fat abolished the relationships of SHBG with insulin sensitivity. In contrast, circulating SHBG correlated negatively with fasting glycemia, before (r = −0.17, P = 0.009) and after (r = −0.14, P = 0.04) adjustment for liver fat. No correlation of circulating SHBG with adjusted insulin secretion was observed (OGTT, P = 0.16; ivGTT, P = 0.35). The SNP rs1799941 in SHBG was associated with circulating SHBG (P ≤ 0.025) but not with metabolic characteristics (all P > 0.18). CONCLUSIONS Possible mechanisms by which high circulating SHBG prevents the development of type 2 diabetes involve regulation of fasting glycemia but not alteration of insulin secretory function.