100th anniversary of the discovery of insulin perspective: insulin and adipose tissue fatty acid metabolism.

Insulin inhibits systemic nonesterified fatty acid (NEFA) flux to a greater degree than glucose or any other metabolite. This remarkable effect is mainly due to insulin-mediated inhibition of intracellular triglyceride (TG) lipolysis in adipose tissues and is essential to prevent diabetic ketoacidosis, but also to limit the potential lipotoxic effects of NEFA in lean tissues that contribute to the development of diabetes complications. Insulin also regulates adipose tissue fatty acid esterification, glycerol and TG synthesis, lipogenesis, and possibly oxidation, contributing to the trapping of dietary fatty acids in the postprandial state. Excess NEFA flux at a given insulin level has been used to define in vivo adipose tissue insulin resistance. Adipose tissue insulin resistance defined in this fashion has been associated with several dysmetabolic features and complications of diabetes, but the mechanistic significance of this concept is not fully understood. This review focusses on the in vivo regulation of adipose tissue fatty acid metabolism by insulin and the mechanistic significance of the current definition of adipose tissue insulin resistance. One hundred years after the discovery of insulin and despite decades of investigations, much is still to be understood about the multifaceted in vivo actions of this hormone on adipose tissue fatty acid metabolism.

Serum glypican4 and glycosylphosphatidylinositol-specific phospholipase D levels are associated with adipose tissue insulin resistance in obese subjects with different glucose metabolism status.

OBJECTIVES: Glypican4 (GPC4) is a novel adipokine associated with obesity and insulin resistance. GPC4 was cleaved by the glycosylphosphatidylinositol-specific phospholipase D (GPLD1) in an anchored site of the glycosylphosphatidylinositol, and then was released into the extracellular environment. Herein, we investigated the changes of serum GPC4 and GPLD1 levels in obese subjects with different glucose metabolism status and their relationship with adipose tissue insulin resistance index (Adipo-IR) in Chinese north populations. METHODS: A total of 221 obese subjects and 37 normal controls (NC) were recruited in this study. Obese subjects were divided into normal insulin (NI) group, hyperinsulinemia (HI) group, impaired glucose tolerance (IGT) group, and type 2 diabetes mellitus (DM) group. Serum GPC4, GPLD1, and adiponectin were determined by commercially available ELISA kits. RESULTS: Serum GPC4 levels in the HI, IGT, and DM groups were significantly higher than those in the NC and NI groups (2.27 ± 0.58 ng/mL, 2.21 ± 0.60 ng/mL, 2.49 ± 0.67 ng/mL vs. 1.70 ± 0.33 ng/mL, 1.93 ± 0.34 ng/mL, P < 0.05). GPC4 was positively correlated with GPLD1, which was the most important influencing factor of GPC4. Adipo-IR was independently and positively associated with serum GPC4 and GPLD1. For GPC4, after adjustment for confounders, the risk of adipose tissue insulin resistance in subjects with the highest tertile was 2.974-fold that of those with the lowest tertile (OR = 2.974, P = 0.013). For GPLD1, before adjustment for lipids, the increased probability still existed (Model 2, OR = 3.568, P = 0.003). CONCLUSION: GPC4 is an adipokine associated with adipose tissue insulin resistance, and its activity may be regulated by GPLD1. GPC4 may be a marker for adipose tissue insulin resistance in Chinese north obese populations.

The risk of nonalcoholic fatty liver disease in gout patients with frequent flares: a retrospective cohort study.

OBJECTIVE: Nonalcoholic fatty liver disease (NAFLD) is a common chronic disease that is related to high serum uric acid; however, the association between the frequency of gout flares and NAFLD risk remains unclear. This study aimed to investigate whether frequent gout flares were associated with incident NAFLD and analyze the interaction of frequency of gout flares and Adipo-IR on NAFLD in the gout Chinese population. METHODS: A total of 350 cases of gout patients were enrolled in this retrospective cohort study. Cox proportional hazard regression analyses were performed to determine the association between frequent gout flares and NAFLD during follow-up and analyze the interaction of frequency of gout flares and Adipo-IR on NAFLD. Receiver operating curves (ROC) were plotted to explore the diagnostic value of frequent gout flares and Adipo-IR on the occurrence of NAFLD. RESULTS: NAFLD developed in 78 participants (22.3%) during follow-up. Logistic regression showed that Adipo-IR was an independent factor associated with frequent gout flares risk. The multivariate Cox regression analysis revealed that frequent gout flares and Adipo-IR were associated with NAFLD risk (HR: 7.88, 95% CI: 2.11-29.48, p < 0.01; HR: 1.058, 95% CI: 1.01-1.2, p < 0.05). And ROC showed that both of them had a great discriminant ability to diagnose NAFLD. CONCLUSIONS: Our data showed an independent association between the frequency of gout flares or Adipo-IR and incident NAFLD. Frequent gout flares and elevated Adipo-IR had a good predictive capability towards NAFLD development and played a synergistic role in the development of NAFLD. KEY POINTS: • Frequent gout flares and elevated Adipo-IR had a good diagnostic capability towards NAFLD development. • Frequent gout flares and Adipo-IR played a synergistic role in the development of NAFLD.

Adipose Tissue Insulin Resistance Predicts the Severity of Liver Fibrosis in Patients With Type 2 Diabetes and NAFLD.

CONTEXT: Although type 2 diabetes (T2D) is a risk factor for liver fibrosis in nonalcoholic fatty liver disease (NAFLD), the specific contribution of insulin resistance (IR) relative to other factors is unknown. OBJECTIVE: Assess the impact on liver fibrosis in NAFLD of adipose tissue (adipose tissue insulin resistance index [adipo-IR]) and liver (Homeostatic Model Assessment of Insulin Resistance [HOMA-IR]) IR in people with T2D and NAFLD. DESIGN: Participants were screened by elastography in the outpatient clinics for hepatic steatosis and fibrosis, including routine metabolites, cytokeratin-18 (a marker of hepatocyte apoptosis/steatohepatitis), and HOMA-IR/adipo-IR. SETTING: University ambulatory care practice. PARTICIPANTS: A total of 483 participants with T2D. INTERVENTION: Screening for steatosis and fibrosis with elastography. MAIN OUTCOME MEASURES: Liver steatosis (controlled attenuation parameter), fibrosis (liver stiffness measurement), and measurements of IR (adipo-IR, HOMA-IR) and fibrosis (cytokeratin-18). RESULTS: Clinically significant liver fibrosis (stage F ≥ 2 = liver stiffness measurement ≥8.0 kPa) was found in 11%, having more features of the metabolic syndrome, lower adiponectin, and higher aspartate aminotransferase (AST), alanine aminotransferase, liver fat, and cytokeratin-18 (P < 0.05-0.01). In multivariable analysis including just clinical variables (model 1), obesity (body mass index [BMI]) had the strongest association with fibrosis (odds ratio, 2.56; CI, 1.87-3.50; P < 0.01). When metabolic measurements and cytokeratin-18 were included (model 2), only BMI, AST, and liver fat remained significant. When fibrosis stage was adjusted for BMI, AST, and steatosis (model 3), only Adipo-IR remained strongly associated with fibrosis (OR, 1.51; CI, 1.05-2.16; P = 0.03), but not BMI, hepatic IR, or steatosis. CONCLUSIONS: These findings pinpoint to the central role of dysfunctional, insulin-resistant adipose tissue to advanced fibrosis in T2D, beyond simply BMI or steatosis. The clinical implication is that targeting adipose tissue should be the priority of treatment in NAFLD.

Adipose Tissue Insulin Resistance Is Positively Associated With Serum Uric Acid Levels and Hyperuricemia in Northern Chinese Adults.

Objective: Adipose tissue plays a crucial role in serum uric acid (UA) metabolism, but the relative contribution of adipose tissue insulin resistance (IR) to serum UA levels and hyperuricemia have not explicitly been illustrated. Herein, we aimed to investigate the association between the adipose tissue insulin resistance index (Adipo-IR) and hyperuricemia in this cross-sectional study. The homeostasis model assessment of insulin resistance (HOMA-IR) index, another widely applied marker to determine systemic IR, was also explored. Methods: A total of 5821 adults were included in this study. The relationship between Adipo-IR or HOMA-IR and serum UA levels was assessed by multivariate linear regression. Binary logistic regression analyses were applied to determine the sex-specific association of the Adipo-IR tertiles and HOMA-IR tertiles with hyperuricemia. Participants were then divided into normal BMI (18.5 ≤ BMI < 24) and elevated BMI (BMI ≥ 24) groups for further analysis. Results: Both Adipo-IR and HOMA-IR were positively correlated with serum UA (P < 0.001). Compared with the lowest tertile, the risks of hyperuricemia increased across Adipo-IR tertiles (middle tertile: OR 1.52, 95%CI 1.24-1.88; highest tertile: OR 2.10, 95%CI 1.67-2.63) in men after full adjustment (P for trend < 0.001). In women, only the highest tertile (OR 2.09, 95%CI 1.52-2.87) was significantly associated with hyperuricemia. Those associations remained significant in participants with normal BMI status. As for HOMA-IR, only the highest tertile showed positive relationships with hyperuricemia in both genders after full adjustment (P for trend < 0.001). The association between HOMA-IR and hyperuricemia disappeared in men with normal BMI status. Conclusions: Adipo-IR was strongly associated with serum UA and hyperuricemia regardless of BMI classification. In men with normal BMI, Adipo-IR, rather than HOMA-IR, was closely associated with hyperuricemia. Altogether, our finding highlights a critical role of adipose tissue IR on serum UA metabolism and hyperuricemia.

The Effect of Acute Intermittent and Continuous Hypoxia on Plasma Circulating ßOHB Levels Under Different Feeding Statuses in Humans.

Introduction: Acute hypoxia is known to increase circulating nonesterified fatty acid (NEFA) levels. Adipose tissue lipolysis is a major source of NEFA into circulation and insulin suppresses this process when the tissue is insulin sensitive. NEFA can be esterified to triglycerides and/or completely/partially oxidized, the latter leading to ketogenesis in the liver. To our knowledge, the effect of hypoxia on ketogenesis, more specifically ß-hydroxybutyrate (ßOHB) levels, remains unknown in humans. Therefore, the objective of this study was to determine the effect of acute intermittent and continuous hypoxia on circulating ßOHB levels under different feeding status. Methods: Plasma samples from three different randomized crossover studies were assessed for ßOHB concentrations. In the first study, 14 healthy men (23 ± 3.5 years) were exposed to 6 h of normoxia or intermittent hypoxia (IH-Fed) (15 hypoxic events/hour) following an isocaloric meal. In the second study, 10 healthy men (26 ± 5.6 years) were exposed to 6 h of continuous normobaric hypoxia (CH-Fasted) (FiO2 = 0.12) or normoxia in the fasting state. In the third study (CH-Fed), 9 healthy men (24 ± 4.5 years) were exposed to 6 h of normoxia or CH in a constant prandial state. ßOHB, NEFA and insulin levels were measured during all sessions. Results: In the IH-Fed study, ßOHB and NEFA levels tended to be greater over 6 h of IH (condition × time interaction, ßOHB p = 0.108 and NEFA p = 0.062) compared to normoxia. In the CH-Fasted study, ßOHB and NEFA levels increased over time in both experimental conditions, this effect being greater under CH (condition × time interaction, ßOHB p = 0.070; NEFA p = 0.046). In the CH-Fed study, ßOHB levels slightly increased up to 180 min before falling back to initial concentrations by the end of the protocol in both normoxia and CH (main effect of time, p = 0.062), while NEFA were significantly higher under CH (p = 0.006). Conclusion: Acute normobaric hypoxia exposure tends to increase plasma ßOHB concentrations over time in healthy men. The stimulating effect of hypoxia on plasma ßOHB levels is however attenuated during postprandial and prandial states.

Adipose Tissue Insulin Resistance is Closely Associated with Metabolic Syndrome in Northern Chinese Populations.

OBJECTIVE: Adipose tissue insulin resistance is a common feature of obesity-related metabolic diseases. However, the relationship between adipose tissue insulin resistance and metabolic syndrome (MS) has not been fully elucidated. Here, we explored the relationship between the adipose tissue insulin resistance index (Adipo-IR) (fasting insulin × free fatty acids) and MS and the predictive power of Adipo-IR for MS in northern Chinese populations. METHODS: A total of 312 subjects, 186 subjects with MS, 80 nonmetabolic syndrome (NMS) subjects with central obesity, and 46 normal controls were recruited. The general clinical information, biochemical measurements, and oral glucose tolerance tests were evaluated. Serum adiponectin levels were determined using enzyme linked immunosorbent assay (ELISA). RESULTS: Adipo-IR was 2.32-fold higher in NMS subjects and 2.62-fold higher in MS subjects than in normal controls in male subjects; in female subjects, it was 1.75-fold and 3.58-fold higher, respectively (P < 0.05). Female subjects with MS had higher Adipo-IR than male subjects (P < 0.001). Adipo-IR was independently positively correlated with waist circumference, triglyceride, aspartate aminotransferase, and fasting blood glucose and negatively correlated with adiponectin (P < 0.05). Subjects with the highest Adipo-IR tertile had a 2.758-fold higher risk of MS than subjects with the lowest tertile after adjusting for potential confounders (95% confidence interval: 1.552-9.096; P = 0.003). Receiver operating characteristic curve analysis showed that the predictive power of Adipo-IR for MS was 73.1% and 79.2% in male and female subjects, respectively, with optimal cutoff values of 3.84 and 5.92 mU/L×mmol/L. CONCLUSION: Adipo-IR provides a simple method to study adipose tissue insulin sensitivity. Adipo-IR is associated with MS and is an important predictor of MS.

Beta cell functionality and hepatic insulin resistance are major contributors to type 2 diabetes remission and starting pharmacological therapy: from CORDIOPREV randomized controlled trial.

In order to assess whether previous hepatic IR (Hepatic-IRfasting) and beta-cell functionality could modulate type 2 diabetes remission and the need for starting glucose-lowering treatment, newly-diagnosed type 2 diabetes participants who had never received glucose-lowering treatment (190 out of 1002) from the CORonary Diet Intervention with Olive oil and cardiovascular PREVention study (a prospective, randomized and controlled clinical trial), were randomized to consume a Mediterranean or a low-fat diet. Type 2 diabetes remission was defined according to the American Diabetes Association recommendation for levels of HbA1c, fasting plasma glucose and 2h plasma glucose after oral glucose tolerance test, and having maintained them for at least 2 consecutive years. Patients were classified according to the median of Hepatic-IRfasting and beta-cell functionality, measured as the disposition index (DI) at baseline. Cox proportional hazards regression determined the potential for Hepatic-IRfasting and DI indexes as predictors of diabetes remission and the probability of starting pharmacological treatment after a 5-year follow-up. Low-Hepatic-IRfasting or high-DI patients had a higher probability of diabetes remission than high-Hepatic-IRfasting or low-DI subjects (HR:1.79; 95% CI 1.06-3.05; and HR:2.66; 95% CI 1.60-4.43, respectively) after a dietary intervention with no pharmacological treatment and no weight loss. The combination of low-Hepatic-IRfasting and high-DI presented the highest probability of remission (HR:4.63; 95% CI 2.00-10.70). Among patients maintaining diabetes, those with high- Hepatic-IRfasting and low-DI showed the highest risk of starting glucose-lowering therapy (HR:3.24;95% CI 1.50-7.02). Newly-diagnosed type 2 diabetes patients with better beta-cell functionality and lower Hepatic-IRfasting had a higher probability of type 2 diabetes remission in a dietary intervention without pharmacological treatment or weight loss, whereas among patients not achieving remission, those with worse beta-cell functionality and higher Hepatic-IRfasting index had the highest risk of starting glucose-lowering treatment after 5 years of follow-up.