Insulin resistance drives hepatic de novo lipogenesis in nonalcoholic fatty liver disease

BACKGROUNDAn increase in intrahepatic triglyceride (IHTG) is the hallmark feature of nonalcoholic fatty liver disease (NAFLD) and is decreased by weight loss. Hepatic de novo lipogenesis (DNL) contributes to steatosis in individuals with NAFLD. The physiological factors that stimulate hepatic DNL and the effect of weight loss on hepatic DNL are not clear.METHODSHepatic DNL, 24-hour integrated plasma insulin and glucose concentrations, and both liver and whole-body insulin sensitivity were determined in individuals who were lean (n = 14), obese with normal IHTG content (n = 26), or obese with NAFLD (n = 27). Hepatic DNL was assessed using the deuterated water method corrected for the potential confounding contribution of adipose tissue DNL. Liver and whole-body insulin sensitivity was assessed using the hyperinsulinemic-euglycemic clamp procedure in conjunction with glucose tracer infusion. Six subjects in the obese-NAFLD group were also evaluated before and after a diet-induced weight loss of 10%.RESULTSThe contribution of hepatic DNL to IHTG-palmitate was 11%, 19%, and 38% in the lean, obese, and obese-NAFLD groups, respectively. Hepatic DNL was inversely correlated with hepatic and whole-body insulin sensitivity, but directly correlated with 24-hour plasma glucose and insulin concentrations. Weight loss decreased IHTG content, in conjunction with a decrease in hepatic DNL and 24-hour plasma glucose and insulin concentrations.CONCLUSIONSThese data suggest hepatic DNL is an important regulator of IHTG content and that increases in circulating glucose and insulin stimulate hepatic DNL in individuals with NAFLD. Weight loss decreased IHTG content, at least in part, by decreasing hepatic DNL.TRIAL REGISTRATIONClinicalTrials.gov NCT02706262.FUNDINGThis study was supported by NIH grants DK56341 (Nutrition Obesity Research Center), DK20579 (Diabetes Research Center), DK52574 (Digestive Disease Research Center), and RR024992 (Clinical and Translational Science Award), and by grants from the Academy of Nutrition and Dietetics Foundation, the College of Natural Resources of UCB, and the Pershing Square Foundation

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Abstract Rationale: 3,4-Methylenedioxymethamphetamine (MDMA) produces a long-term depletion of serotonin (5-HT) in the rat brain; this depletion may have some functional consequences. Objective: The aim of the present study was to evaluate the acute effects of MDMA on the extracellular concentrations of dopamine and 5-HT, body temperature and the 5-HT behavioral syndrome in rats 7 days following a neurotoxic regimen of MDMA. Methods: One week after the rats were treated with a neurotoxic regimen of MDMA (10 mg/kg, IP, every 2 h for a total of four injections), the rats were injected with a subsequent injection of MDMA. In vivo microdialysis combined with HPLC was utilized to measure the extracellular concentration of 5-HT and dopamine in the striatum. The increase in body temperature was determined by rectal temperature measurements, and the 5-HT behavioral syndrome was scored using a rating scale following the administration of MDMA.Results: The neurotoxic regimen produced a 45% reduction in brain 5-HT concentrations. The magnitude of the MDMA-induced increase in the extracellular concentration of 5-HT, but not dopamine, in the striatum produced by an acute injection of MDMA (7.5 mg/kg, IP) was reduced in rats treated previously with the neurotoxic regimen of MDMA when compared with that in control animals. In addition, the magnitude of the 5-HT behavioral syndrome, as well as the hyperthermic response, produced by MDMA was markedly diminished in rats that had previously received the neurotoxic regimen of MDMA. Conclusions: It is concluded that the long-term depletion of brain 5-HT produced by MDMA is accompanied by impairments in 5-HT function, as evidenced by the deficits in the neurochemical, thermal and behavioral responses to subsequent MDMA administration

Association of muscle mass measured by D3-Creatine (D3Cr), sarcopenic obesity, and insulin-glucose homeostasis in postmenopausal women.

The D3-Creatine (D3Cr) dilution method is a direct and accurate measure of skeletal muscle mass. In this study, we examined the association of D3Cr muscle mass with measures of insulin-glucose homeostasis in community dwelling postmenopausal women. Additionally, we examined association of sarcopenic obesity, defined as low D3Cr muscle mass and high percent body fat, with fasting plasma glucose, insulin, hemoglobin A1c and insulin resistance. Insulin resistance was measured by the homeostatic measure of insulin resistance (HOMA-IR). This pilot study included 74 participants (mean age = 82.3 years) from the Women's Health Initiative-Buffalo site. The D3Cr method was initiated at a clinic visit and used to measure muscle mass via remote urine sample collection. Descriptive and graphical approaches and age-adjusted linear regression models were used to analyze study data. We examined muscle mass as an absolute value (kg) and scaled to body weight (D3Cr muscle mass/kg). There was an inverse relationship between skeletal muscle mass, and impaired insulin-glucose homeostasis. Women with low muscle mass had higher levels of insulin (uIU/mL; β = -0.40; 95% CI: -0.79, -0.01), fasting plasma glucose (mg/dL; β = -0.1; 95% CI: -0.2, 0.03), HbA1c (%; β = -2.30; 95% CI: -5.7, 1.1), and calculated homeostatic model of insulin resistance, HOMA-IR, (β = -1.49; 95% CI: -2.9, -0.1). Sarcopenic obesity was common in this population of women; 41% of participants were categorized as having low muscle mass and high percent body fat. Results demonstrate that D3Cr muscle mass is independently associated with measures of insulin-glucose homeostasis, but obesity is a stronger predictor of insulin resistance than muscle mass

Association of muscle mass measured by D3-Creatine (D3Cr), sarcopenic obesity, and insulin-glucose homeostasis in postmenopausal women

The D3-Creatine (D3Cr) dilution method is a direct and accurate measure of skeletal muscle mass. In this study, we examined the association of D3Cr muscle mass with measures of insulin-glucose homeostasis in community dwelling postmenopausal women. Additionally, we examined association of sarcopenic obesity, defined as low D3Cr muscle mass and high percent body fat, with fasting plasma glucose, insulin, hemoglobin A1c and insulin resistance. Insulin resistance was measured by the homeostatic measure of insulin resistance (HOMA-IR). This pilot study included 74 participants (mean age = 82.3 years) from the Women’s Health Initiative-Buffalo site. The D3Cr method was initiated at a clinic visit and used to measure muscle mass via remote urine sample collection. Descriptive and graphical approaches and age-adjusted linear regression models were used to analyze study data. We examined muscle mass as an absolute value (kg) and scaled to body weight (D3Cr muscle mass/kg). There was an inverse relationship between skeletal muscle mass, and impaired insulin-glucose homeostasis. Women with low muscle mass had higher levels of insulin (uIU/mL; β = -0.40; 95% CI: -0.79, -0.01), fasting plasma glucose (mg/dL; β = -0.1; 95% CI: -0.2, 0.03), HbA1c (%; β = -2.30; 95% CI: -5.7, 1.1), and calculated homeostatic model of insulin resistance, HOMA-IR, (β = -1.49; 95% CI: -2.9, -0.1). Sarcopenic obesity was common in this population of women; 41% of participants were categorized as having low muscle mass and high percent body fat. Results demonstrate that D3Cr muscle mass is independently associated with measures of insulin-glucose homeostasis, but obesity is a stronger predictor of insulin resistance than muscle mass

The Association of Muscle Mass Measured by D3-Creatine Dilution Method With Dual-Energy X-Ray Absorptiometry and Physical Function in Postmenopausal Women.

BACKGROUND: The D3-creatine (D3Cr) dilution method provides a direct measure of skeletal muscle. The aim of this study was to compare the association of D3Cr muscle mass with lean body mass (LBM) measured by dual-energy x-ray absorptiometry (DXA) and examine its relation with physical function in postmenopausal women. METHODS: Seventy-four community-dwelling women (mean age 82.3 ± 5.4) participated in this pilot study from the Buffalo, New York clinical site of the Womens Health Initiative (WHI). Participants attended a clinic visit which included anthropometric measures, blood draw, DXA scan, measures of physical function, and initiated the D3Cr protocol. Physical function was evaluated using hand grip strength, short physical performance battery (SPPB), and RAND-36 physical function scale. Descriptive statistics and logistic regression models were used to examine the associations of D3Cr muscle mass with functional outcomes. RESULTS: D3-creatine muscle mass was moderately correlated with DXA LBM (r = 0.50) and DXA appendicular lean mass (ALM) (r = 0.50). Individuals with high D3Cr muscle mass (%) had higher physical function compared to individuals with low muscle mass (%), indicated by high scores on SPPB (odds ratio [OR] = 5.24; 95% confidence interval [CI]: 1.40, 19.58). We observed stronger relationships between high D3Cr and physical function than either DXA LBM (OR = 3.40; 95% CI: 0.88, 13.11) or DXA ALM (OR = 4.15; 95% CI: 1.10, 15.68) and physical function. CONCLUSIONS: Our findings provide strong preliminary data for the associations of D3Cr muscle mass with measures of physical function in older women. These findings support and extend prior work on D3Cr muscle mass in older men

Dilution of oral D3‐Creatine to measure creatine pool size and estimate skeletal muscle mass: development of a correction algorithm

Abstract Background Muscle mass can be measured directly in vivo by isotope dilution, using Creatine‐(methyl‐d3) monohydrate (D3‐Cr) by mouth followed by measurement of the steady‐state enrichment of D3‐creatinine (D3‐Crn) in urine. Isotope dilution methods require knowledge of the amount of tracer delivered to the pool of interest. In a subset of human subjects, a small amount of orally administered D3‐Cr ‘spills’ into urine after absorption and prior to transport into skeletal muscle cells. The objectives were to develop a method to correct for spillage to compare the estimate of muscle mass by D3‐Cr dilution to other assessments of fat‐free mass. Methods Subjects (19 males, 23–81 years old; 20 females, 20–77 years old) ingested a single dose of 60 mg D3‐Cr and urine was collected prior to and daily for 4 days following the dose. Fasting morning urine samples was assessed for D3‐Cr, total Cr, D3‐Crn, and total Crn concentrations, as well as isotopic enrichments of D3‐Crn, by LC/MS. The 24‐h urine collections over 3 days after the dose of D3‐Cr were also performed to determine D3‐Cr spillage. Total body water, fat mass, and fat‐free mass were assessed by bioelectrical impedance spectroscopy (BIS). Results Spillage of D3‐Cr in the urine was greater in women than men. D3‐Crn enrichment and the ratio of Cr/Crn were used in an algorithm to calculate Cr pool size and muscle mass. Specifically, an algorithm was developed for the estimation of spillage based on the relationship between the fasting Cr/Crn ratio and the cumulative proportion of the D3‐Cr dose excreted over 3 days based on 24‐h urine collections. Muscle mass corrected using the algorithm based on fasting urine levels correlated (r = 0.9967, P < 0.0001) with that corrected by measuring D3‐Cr dose excreted. Muscle mass measured by D3‐Crn enrichment also correlated (r = 0.8579, P < 0.0001, algorithm corrected) with that measured by 24‐h Crn excretion. Muscle mass measured by D3‐Cr dilution method correlated with intracellular water by BIS, whether using spillage corrected by the algorithm (r = 0.9041, P < 0.0001) or measured by 3 day D3‐Cr losses (r = 0.91, P < 0.0001) and similarly correlated with fat‐free mass by BIA (r = 0.8857 and 0.8929, P < 0.0001, respectively). Conclusions The D3‐Cr dilution method is further validated here as a non‐invasive, easy‐to‐use test for measuring muscle mass. The technical issue of D3‐Cr spillage can be corrected for with a simple algorithm based on fasting spot urine samples. Muscle mass by Cr dilution potentially has broad applications in clinical and research settings

Comparison of self-report exercise and physical activity patterns among women with high and low muscle mass.

Comparison of self-report exercise and physical activity patterns among women with high and low muscle mass.</p