Dissociation Between Insulin Resistance and Abnormalities in Lipoprotein Particle Concentrations and Sizes in Normal-Weight Chinese Adults.

Insulin resistance in obesity coincides with abnormalities in lipid profile and lipoprotein subclass distribution and size even before abnormalities in glucose homeostasis manifest. We aimed to assess this relationship in the absence of obesity. Insulin sensitivity (3-h intravenous glucose tolerance test and minimal modeling) and lipoprotein particle concentrations and sizes (proton nuclear magnetic resonance spectroscopy) were evaluated in 15 insulin-resistant and 15 insulin-sensitive lean Asians of Chinese descent with normal glucose tolerance, matched on age, sex, and body mass index. Despite a ~50% lower insulin sensitivity index (Si) in insulin-resistant than in insulin-sensitive subjects, which was accompanied by significantly greater acute insulin response to glucose (AIRg) and fasting insulin concentration but not different fasting glucose concentration, there were no significant differences between groups in the blood lipid profile (p ≥ 0.44) or the lipoprotein subclass concentrations (p ≥ 0.30) and particle sizes (p ≥ 0.43). We conclude that, contrary to observations in subjects with obesity, insulin resistance is not accompanied by unfavorable changes in the plasma lipid profile and lipoprotein particle concentrations and sizes in lean Asians with normal glucose tolerance. Therefore, insulin resistance at the level of glucose metabolism is mechanistically or temporally dissociated from lipid and lipoprotein metabolism. Trial Registration: clinicaltrials.gov, NCT03264001.

Association between Serum Vitamin D Metabolites and Metabolic Function in Healthy Asian Adults.

The association between low vitamin D status and the development of type 2 diabetes mellitus is well established; however, intervention trials that increased serum vitamin D (through ultraviolet B exposure or dietary supplementation) provide mixed outcomes. Recent evidence suggests that metabolites directly related to vitamin D receptor activation-1α,25-dihydroxyvitamin D3 and 24R,25-dihydroxyvitamin D3-may be better markers of vitamin D repletion status. We tested the hypothesis that a vitamin D metabolite (VDM) index, calculated as the sum of normalized fasting serum concentrations of 1α,25-dihydroxyvitamin D3 and 24R,25-dihydroxyvitamin D3, is associated with metabolic function. We measured subcutaneous and visceral adipose tissue volume, intrahepatic triglyceride content, maximum oxygen uptake, insulin sensitivity (4 h hyperinsulinemic-euglycemic clamp), and insulin secretion (3 h meal tolerance test with mathematical modeling) and calculated the VDM index in 65 healthy Asian adults. Subjects with a low VDM index had lower peripheral insulin sensitivity and beta-cell function compared to subjects with a high VDM index (both p < 0.05), matched for age, sex, BMI, and serum 25-hydroxyvitamin D3. Serum 25-hydroxyvitamin D3 was not associated with peripheral insulin sensitivity or beta-cell function. Our results suggest that, rather than enhancing vitamin D substrate availability, upregulation of vitamin D action is more likely to lead to improvements in glucose homeostasis.

Targeted Inhibition of Purine Metabolism Is Effective in Suppressing Hepatocellular Carcinoma Progression.

Tumor-specific metabolic rewiring, acquired to confer a proliferative and survival advantage over nontransformed cells, represents a renewed focus in cancer therapy development. Hepatocellular carcinoma (HCC), a malignancy that has hitherto been resistant to compounds targeting oncogenic signaling pathways, represents a candidate cancer to investigate the efficacy of selectively antagonizing such adaptive metabolic reprogramming. To this end, we sought to characterize metabolic changes in HCC necessary for tumorigenesis. We analyzed gene expression profiles in three independent large-scale patient cohorts who had HCC. We identified a commonly deregulated purine metabolic signature in tumors with the extent of purine biosynthetic enzyme up-regulation correlated with tumor grade and a predictor of clinical outcome. The functional significance of enhanced purine metabolism as a hallmark in human HCC was then validated using a combination of HCC cell lines, patient-derived xenograft (PDX) organoids, and mouse models. Targeted ablation of purine biosynthesis by knockdown of the rate-limiting enzyme inosine-5'-monophosphate dehydrogenase (IMPDH) or using the drug mycophenolate mofetil (MMF) reduced HCC proliferation in vitro and decreased the tumor burden in vivo. In comparing the sensitivities of PDX tumor organoids to MMF therapy, we found that HCC tumors defined by high levels of IMPDH and guanosine nucleosides were most susceptible to treatment. Mechanistically, a phosphoinositide 3-kinase (PI3K)-E2F transcription factor 1 (E2F1) axis coordinated purine biosynthetic enzyme expression, deregulation of which altered the activity of mitogen-activated protein kinase/RAS signaling. Simultaneously abolishing PI3K signaling and IMPDH activity with clinically approved inhibitors resulted in greatest efficacy in reducing tumor growth in a PDX mouse model. Conclusion: Enhanced purine metabolic activity regulated by PI3K pathway-dependent activation of E2F1 promotes HCC carcinogenesis, suggesting the potential for targeting purine metabolic reprogramming as a precision therapeutic strategy for patients with HCC.

Dose-Dependent Effects of Exercise and Diet on Insulin Sensitivity and Secretion.

PURPOSE: A single bout of aerobic exercise increases insulin sensitivity the next day. The effects of exercise on insulin secretion, the role of exercise-induced energy deficit, and possible dose-response relationships are not well understood. This study aimed to evaluate insulin sensitivity and insulin secretion after progressively greater negative energy balance induced by exercise or diet. METHODS: Acute energy deficits (20% or 40% of weight maintenance needs) were induced by a single day of aerobic exercise (cycling at moderate intensity, n = 13) or dietary restriction (n = 19) in healthy men and women (age, 26 ± 2 yr; body mass index, 21.8 ± 0.5 kg·m). Intravenous glucose tolerance tests in conjunction with minimal modeling were performed the next morning, and blood samples were collected for 3 h to measure glucose and insulin concentrations. RESULTS: Insulin sensitivity increased linearly after exercise-induced energy deficits (P = 0.007) but did not change after equivalent diet-induced energy deficits (P = 0.673). Acute insulin response decreased after both exercise (P < 0.001) and dietary restriction (P = 0.005). The disposition index and glucose effectiveness were not affected by exercise (P = 0.138 and 0.808, respectively), but both decreased after 40% dietary restriction (P = 0.048 and 0.002, respectively). CONCLUSIONS: These results indicate that insulin sensitivity and insulin secretion are related to exercise energy expenditure, albeit in a different fashion (insulin sensitivity increases linearly, whereas insulin secretion drops to a nadir with a low exercise dose and does not decrease further). These changes cannot be replicated by equivalent energy deficits induced by dietary restriction, suggesting that exercise and diet have different effects on the mechanisms regulating glucose homeostasis. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03264001.

Ectopic fat and aerobic fitness are key determinants of glucose homeostasis in nonobese Asians.

BACKGROUND: The importance of ectopic fat deposition and physical fitness in the pathogenesis of insulin resistance and beta cell dysfunction in subjects from the nonobese Asians is not known. MATERIALS AND METHODS: We conducted a cross-sectional study and measured insulin sensitivity (M value; 4-hour hyperinsulinaemic-euglycaemic clamp), insulin secretion rate (3-hour mixed meal tolerance test with oral minimal modelling), percent body fat, visceral adipose tissue, intramyocellular and intrahepatic lipid contents (magnetic resonance imaging and spectroscopy), cardiorespiratory fitness (VO2 max; graded exercise test) and habitual physical activity (short International Physical Activity Questionnaire) in 60 healthy nonobese Asian subjects (BMI = 21.9 ± 1.7 kg/m2 , age = 41.8 ± 13.4 years). RESULTS: M was inversely associated with percent body fat (r = -0.460, P < 0.001), visceral fat (r = -0.623, P < 0.001) and liver fat (r = -0.601, P < 0.001), whereas insulin secretion correlated positively with these adiposity indices (percent body fat: r = 0.303, P = 0.018; visceral fat: r = 0.409, P = 0.010; hepatic fat: r = 0.393, P = 0.002). VO2 max correlated negatively with insulin secretion rate (r = -0.420, P < 0.001) and positively with M (r = 0.658, P < 0.001). The amount of vigorous physical activity was positively associated with VO2 max (r = 0.682, P < 0.001). Multiple stepwise linear regression analyses indicated that VO2 max, age, and IHTG or VAT were independent determinants of insulin sensitivity and secretion (adjusted R2  = 69% and 33%, respectively, P < 0.001). CONCLUSIONS: Increased ectopic fat deposition is associated with reduced insulin sensitivity and increased insulin secretion in healthy nonobese Asians. Poor cardiorespiratory fitness, likely due to inadequate participation in vigorous exercise, is strongly related to suboptimal metabolic function. Interventions to encourage engagement in physical activity may thus be important for improving metabolic health in nonobese Asians.

Sex Differences in Glucose and Fatty Acid Metabolism in Asians Who Are Nonobese.

Context: The prevalence of diabetes is increasing throughout Asia, even in the absence of obesity, and is lower in women than in men. The underlying mechanisms are not well understood. Objective: To evaluate the sex differences in glucose and fatty acid metabolism in Asians who are nonobese. Design: Cross-sectional study. Setting: Clinical Nutrition Research Centre, Singapore. Participants: Healthy Asian men (n = 32; body mass index, 21.8 ± 1.5 kg/m2; age, 42 ± 14 years) and women (n = 28; body mass index, 21.4 ± 2.0 kg/m2; age, 41 ± 13 years). Main Outcome Measures: Insulin sensitivity (insulin-mediated glucose uptake normalized for steady-state insulin; hyperinsulinemic-euglycemic clamp), postprandial glucose, insulin and fatty acid concentrations, insulin secretion (mixed meal tolerance test with mathematical modeling), insulin clearance, body composition and fat distribution (dual-energy X-ray absorptiometry, MRI, and spectroscopy), cardiorespiratory fitness (maximal oxygen uptake; graded exercise test), and handgrip strength (dynamometry). Results: Women had more total body fat but less visceral fat than men; liver and muscle lipid contents were not different. Maximal oxygen uptake and handgrip strength were lower in women than men. The postprandial glucose concentrations were ~8% lower, the insulin-mediated glucose uptake was ~16% greater, and the meal-induced suppression of fatty acid concentrations was significantly greater in women than in men (P < 0.05 for all). However, muscle insulin sensitivity was not different between the sexes. No differences were found in postprandial insulin secretion and clearance rates; however, the steady-state insulin clearance was ~17% lower in women. Conclusions: Asian women who are nonobese are more insulin-sensitive than men at the level of adipose tissue but not skeletal muscle. Therefore, sex differences in glucose tolerance are likely the result of sexual dimorphism in hepatic insulin action.

Lipoprotein Subclass Profile after Progressive Energy Deficits Induced by Calorie Restriction or Exercise.

Weight loss, induced by chronic energy deficit, improves the blood lipid profile. However, the effects of an acute negative energy balance and the comparative efficacy of diet and exercise are not well-established. We determined the effects of progressive, acute energy deficits (20% or 40% of daily energy requirements) induced by a single day of calorie restriction (n = 19) or aerobic exercise (n = 13) in healthy subjects (age: 26 ± 9 years; body mass index (BMI): 21.8 ± 2.9 kg/m²). Fasting plasma concentrations of very low-, intermediate-, low-, and high-density lipoprotein (VLDL, LDL, IDL, and HDL, respectively) particles and their subclasses were determined using nuclear magnetic resonance. Total plasma triglyceride and VLDL-triglyceride concentrations decreased after calorie restriction and exercise (all p ≤ 0.025); the pattern of change was linear with an increasing energy deficit (all p < 0.03), with no evidence of plateauing. The number of circulating large and medium VLDL particles decreased after diet and exercise (all p < 0.015), with no change in small VLDL particles. The concentrations of IDL, LDL, and HDL particles, their relative distributions, and the particle sizes were not altered. Our data indicate that an acute negative energy balance induced by calorie restriction and aerobic exercise reduces triglyceride concentrations in a dose-dependent manner, by decreasing circulating large and medium VLDL particles.

Visceral adipose tissue tracks more closely with metabolic dysfunction than intrahepatic triglyceride in lean Asians without diabetes.

Increased visceral adipose tissue (VAT) and intrahepatic triglyceride (IHTG) are important risk factors for the development of type 2 diabetes in subjects with obesity. The relative contribution of these ectopic fat depots to cardiometabolic risk differs between populations, depends on the degree of obesity and the level of cardiorespiratory fitness, and is difficult to dissect because VAT and IHTG typically covary. The aim of this study was to evaluate the effect of an isolated increase in VAT or IHTG on insulin sensitivity and insulin secretion in apparently healthy normal-weight Asian subjects. Total body fat (dual X-ray absorptiometry), VAT and IHTG (magnetic resonance), insulin sensitivity (4-h hyperinsulinemic-euglycemic clamp), beta cell responsivity and insulin secretion rate (3-h mixed meal with mathematical modeling), and cardiorespiratory fitness (maximal oxygen consumption [V̇o2max]) were evaluated in groups of lean subjects with low or high VAT (687 ± 94 vs. 1,279 ± 197 ml, matched for IHTG; n = 13 each) and low or high IHTG (1.7 ± 0.3 vs. 6.7 ± 2.0%, matched for VAT; n = 15 each). All groups were matched for age, sex, total body fat, and V̇o2max. High-VAT subjects had ~25% lower insulin sensitivity, ~20%-40% greater beta cell responsivity and insulin secretion rate, ~35% greater fasting triglyceride concentration, and ~40% lower adiponectin concentration than low-VAT subjects (all P < 0.05). No differences were observed between low-IHTG and high-IHTG subjects. Accumulation of excess fat in the intra-abdominal area is more strongly associated with metabolic dysfunction than accumulation of liver fat in lean Asians without diabetes. NEW & NOTEWORTHY It is not known whether metabolic abnormalities in Asians without obesity track more closely with visceral or liver fat. We found an isolated increase in visceral fat was associated with reduced insulin sensitivity, greater insulin secretion, greater triglyceride, and lower adiponectin concentrations; no differences were observed with an isolated increase in liver fat. These results suggest that visceral fat is a better correlate of metabolic dysfunction than liver fat in Asians without obesity.

Moderate Weight Loss Improves Body Composition and Metabolic Function in Metabolically Unhealthy Lean Subjects.

OBJECTIVE: Individuals who have "metabolically obese normal weight" (MONW) have an increased risk for cardiometabolic disease. Moderate weight loss has multiple benefits in people with obesity, but its effects in lean people are unknown. Thus, the effects of diet-induced 5% weight loss on body composition and metabolic function in MONW subjects were evaluated. METHODS: Total body fat, visceral adipose tissue (VAT) and subcutaneous abdominal adipose tissue (SAT) volumes, intrahepatic and intramyocellular lipid contents, insulin sensitivity (hyperinsulinemic-euglycemic clamp), glucose tolerance, and postprandial insulin secretion and clearance rates (mixed meal with minimal modeling) were measured before and after 4.8% ± 0.5% weight loss in 11 MONW Asians (48 ± 3 years old, six men and five women, BMI 22.7 ± 0.4 kg/m2 ). RESULTS: Weight loss decreased total fat mass by ∼9%, VAT and SAT volumes by ∼11% and ∼17%, respectively, and intrahepatic fat by ∼50% (all P < 0.05). Fasting plasma insulin, triglyceride, and total low- and high-density lipoprotein cholesterol concentrations were also reduced (P < 0.05). Insulin sensitivity indexes (M-value and M/I ratio) increased by 21% to 26% (both P < 0.05); ß-cell responsivity and postprandial insulin secretion rate did not change, but insulin clearance rate increased by 16% (P < 0.05). CONCLUSIONS: Diet-induced moderate weight loss improves body composition, lipid profile, and insulin sensitivity and thereby reduces cardiometabolic risk in MONW Asians.

Regulation of glucose metabolism in nondiabetic, metabolically obese normal-weight Asians.

Type 2 diabetes in Asia occurs largely in the absence of obesity. The metabolically obese normal-weight (MONW) phenotype refers to lean subjects with metabolic dysfunction that is typically observed in people with obesity and is associated with increased risk for diabetes. Previous studies evaluated MONW subjects who had greater body mass index (BMI) or total body fat than respective control groups, making interpretation of the results difficult. We evaluated insulin sensitivity (hyperinsulinemic-euglycemic clamp); insulin secretion (mixed meal with oral minimal modeling); intra-abdominal, muscle, and liver fat contents (magnetic resonance); and fasting and postprandial glucose and insulin concentrations in 18 MONW subjects and 18 metabolically healthy controls matched for age (43 ± 3 and 40 ± 3 yr; P = 0.52), BMI (both 22 ± 1 kg/m2; P = 0.69), total body fat (17 ± 1 and 16 ± 1 kg; P = 0.33), and sex (9 men and 9 women in each group). Compared with controls, MONW subjects had an approximately twofold greater visceral adipose tissue volume and an approximately fourfold greater intrahepatic fat content (but similar muscle fat), 20-30% lower glucose disposal rates and insulin sensitivity, and 30-40% greater insulin secretion rates (all P < 0.05). The disposition index, fasting glucose, and HbA1c concentrations were not different between groups, whereas postprandial glucose and insulin concentrations were ~15% and ~65% greater, respectively, in MONW than control subjects (both P < 0.05). We conclude that the MONW phenotype is associated with accumulation of fat in the intra-abdominal area and the liver, profound insulin resistance, but also a robust ß-cell insulin secretion response that compensates for insulin resistance and helps maintain glucose homeostasis.

Lean, but not healthy: the 'metabolically obese, normal-weight' phenotype.

PURPOSE OF REVIEW: Obesity is commonly associated with metabolic dysfunction but there are obese persons who are metabolically healthy. On the opposite side of the coin, there are lean persons who carry multiple cardiometabolic risk factors, typically referred to as metabolically obese, normal-weight (MONW). This has called into question our understanding of obesity and metabolic dysfunction, as an appearance of normal weight may mask significant comorbidities and delay health interventions. RECENT FINDINGS: High heterogeneity in MONW prevalence rates has been observed, with estimates ranging from as low as 5% to as high as 45%. Reasons for this include sample size effects, differences in MONW definition, social and demographic factors, as well as assumptions made in establishing normal weight. MONW study participants are often characterized by excess visceral adipose tissue and ectopic fat deposition, adipose tissue inflammation, altered inflammatory and adipokine profiles, reduced skeletal muscle mass and low cardiorespiratory fitness. However, more often than not, groups of MONW study participants have been somewhat 'fatter' than the control groups of metabolically healthy lean study participants, which in itself could be responsible for some of the observed differences. Very limited data are available regarding interventions to improve metabolic function in MONW study participants. SUMMARY: There is a need for more research to better understand the characteristics of the MONW phenotype, the cause of metabolic dysfunction in the absence of obesity, and evaluate potential therapies so as to facilitate the establishment of clinical guidelines.