Body composition and body fat distribution in tissue-specific insulin resistance and in response to a 12-week isocaloric dietary macronutrient intervention.

BACKGROUND: Body composition and body fat distribution are important predictors of cardiometabolic diseases. The etiology of cardiometabolic diseases is heterogenous, and partly driven by inter-individual differences in tissue-specific insulin sensitivity. OBJECTIVES: To investigate (1) the associations between body composition and whole-body, liver and muscle insulin sensitivity, and (2) changes in body composition and insulin sensitivity and their relationship after a 12-week isocaloric diet high in mono-unsaturated fatty acids (HMUFA) or a low-fat, high-protein, high-fiber (LFHP) diet. METHODS: This subcohort analysis of the PERSON study includes 93 individuals (53% women, BMI 25-40 kg/m2, 40-75 years) who participated in this randomized intervention study. At baseline and after 12 weeks of following the LFHP, or HMUFA diet, we performed a 7-point oral glucose tolerance test to assess whole-body, liver, and muscle insulin sensitivity, and whole-body magnetic resonance imaging to determine body composition and body fat distribution. Both diets are within the guidelines of healthy nutrition. RESULTS: At baseline, liver fat content was associated with worse liver insulin sensitivity (ß [95%CI]; 0.12 [0.01; 0.22]). Only in women, thigh muscle fat content was inversely related to muscle insulin sensitivity (-0.27 [-0.48; -0.05]). Visceral adipose tissue (VAT) was inversely associated with whole-body, liver, and muscle insulin sensitivity. Both diets decreased VAT, abdominal subcutaneous adipose tissue (aSAT), and liver fat, but not whole-body and tissue-specific insulin sensitivity with no differences between diets. Waist circumference, however, decreased more following the LFHP diet as compared to the HMUFA diet (-3.0 vs. -0.5 cm, respectively). After the LFHP but not HMUFA diet, improvements in body composition were positively associated with improvements in whole-body and liver insulin sensitivity. CONCLUSIONS: Liver and muscle insulin sensitivity are distinctly associated with liver and muscle fat accumulation. Although both LFHP and HMUFA diets improved in body fat, VAT, aSAT, and liver fat, only LFHP-induced improvements in body composition are associated with improved insulin sensitivity. TRIAL REGISTRATION: NCT03708419 (clinicaltrials.gov).

Immunometabolic Signatures of Circulating Monocytes in Humans With Obesity and Insulin Resistance.

Obesity is associated with chronic inflammation and metabolic complications, including insulin resistance (IR). Immune cells drive inflammation through the rewiring of intracellular metabolism. However, the impact of obesity-related IR on the metabolism and functionality of circulating immune cells, like monocytes, remains poorly understood. To increase insight into the interindividual variation of immunometabolic signatures among individuals and their role in the development of IR, we assessed systemic and tissue-specific IR and circulating immune markers, and we characterized metabolic signatures and cytokine secretion of circulating monocytes from 194 individuals with a BMI ≥25 kg/m2. Monocyte metabolic signatures were defined using extracellular acidification rates (ECARs) to estimate glycolysis and oxygen consumption rates (OCRs) for oxidative metabolism. Although monocyte metabolic signatures and function based on cytokine secretion varied greatly among study participants, they were strongly associated with each other. The ECAR-to-OCR ratio, representing the balance between glycolysis and oxidative metabolism, was negatively associated with fasting insulin levels, systemic IR, and liver-specific IR. These results indicate that monocytes from individuals with IR were relatively more dependent on oxidative metabolism, whereas monocytes from more insulin-sensitive individuals were more dependent on glycolysis. Additionally, circulating CXCL11 was negatively associated with the degree of systemic IR and positively with the ECAR-to-OCR ratio in monocytes, suggesting that individuals with high IR and a monocyte metabolic dependence on oxidative metabolism also have lower levels of circulating CXCL11. Our findings suggest that monocyte metabolism is related to obesity-associated IR progression and deepen insights into the interplay between innate immune cell metabolism and IR development in humans.

Interaction of Diet/Lifestyle Intervention and TCF7L2 Genotype on Glycemic Control and Adiposity among Overweight or Obese Adults: Big Data from Seven Randomized Controlled Trials Worldwide.

Objective. The strongest locus which associated with type 2 diabetes (T2D) by the common variant rs7903146 is the transcription factor 7-like 2 gene (TCF7L2). We aimed to quantify the interaction of diet/lifestyle interventions and the genetic effect of TCF7L2 rs7903146 on glycemic traits, body weight, or waist circumference in overweight or obese adults in several randomized controlled trials (RCTs).Methods. From October 2016 to May 2018, a large collaborative analysis was performed by pooling individual-participant data from 7 RCTs. These RCTs reported changes in glycemic control and adiposity of the variant rs7903146 after dietary/lifestyle-related interventions in overweight or obese adults. Gene treatment interaction models which used the genetic effect encoded by the allele dose and common covariates were applicable to individual participant data in all studies.Results. In the joint analysis, a total of 7 eligible RCTs were included (n=4,114). Importantly, we observed a significant effect modification of diet/lifestyle-related interventions on the TCF7L2 variant rs7903146 and changes in fasting glucose. Compared with the control group, diet/lifestyle interventions were related to lower fasting glucose by -3.06 (95% CI, -5.77 to -0.36) mg/dL (test for heterogeneity and overall effect: I2=45.1%, p<0.05; z=2.20, p=0.028) per one copy of the TCF7L2 T risk allele. Furthermore, regardless of genetic risk, diet/lifestyle interventions were associated with lower waist circumference. However, there was no significant change for diet/lifestyle interventions in other glycemic control and adiposity traits per one copy of TCF7L2 risk allele.Conclusions. Our findings suggest that carrying the TCF7L2 T risk allele may have a modestly greater benefit for specific diet/lifestyle interventions to improve the control of fasting glucose in overweight or obese adults.