Adolescents with T1D have adipose, hepatic and peripheral IR. This IR occurs regardless of obesity and metabolic syndrome features. Youth with T1D may benefit from interventions directed at improving IR in these tissues, and this area requires further research.
Adolescents with type 2 diabetes (T2D) have severe insulin resistance (IR) secondary to obesity, genetics, and puberty, and IR predicts metabolic comorbidities. Adults with T2D have multitissue IR, which has guided therapeutic developments, but this is not established in youth. We sought to assess adipose, hepatic, and peripheral insulin sensitivity in adolescents with and without T2D. Twenty-seven youth with T2D [age: 15.6 ± 0.4 yr; female: 78%; body mass index (BMI) percentile: 96.1 (52.6, 95.9), late puberty; hemoglobin A1c (HbA1c) 7.3% (6.2, 10.1)] and 21 controls of similar BMI, pubertal stage, and habitual activity were enrolled. Insulin action was measured with a four-phase hyperinsulinemic-euglycemic clamp (basal, 10, 16, and 80 mU·m−2·min−1 for studying adipose, hepatic, and peripheral IR, respectively) with glucose and glycerol isotope tracers. Total fat mass, fat-free mass, liver fat fraction, and visceral fat were measured with dual-energy x-ray absorptiometry (DXA) and MRI, respectively. Free fatty acids (FFAs), lipid profile, and inflammatory markers were also measured. Adolescents with T2D had higher lipolysis ( P = 0.012), endogenous glucose production ( P < 0.0001), and lower glucose clearance ( P = 0.002) during hyperinsulinemia than controls. In T2D, peripheral IR positively correlated to FFA ( P < 0.001), inflammatory markers, visceral ( P = 0.004) and hepatic fat ( P = 0.007); hepatic IR correlated with central obesity ( P = 0.004) and adipose IR ( P = 0.003). Youth with T2D have profound multitissue IR compared with BMI-equivalent youth without T2D. The development of multitissue interactions appears crucial to the pathogenesis of T2D. Therapeutic targets on multitissue IR may be of benefit, deserving of further research.
Objective This study aimed to phenotype and compare adipose, hepatic, and muscle insulin sensitivity (IS) in a diet‐ and physical activity–controlled cohort of normoglycemic youth with obesity with that of participants without obesity (controls) to distinguish early metabolic abnormalities in pediatric obesity. Methods Thirty‐eight participants (17 in the control group [BMI < 85th percentile] and 21 youth with obesity [BMI ≥ 95th percentile]; age: 12‐21 years; 76% female; Tanner stage 4‐5; sedentary) were enrolled. Tissue‐specific IS was measured using a four‐phase hyperinsulinemic‐euglycemic clamp with glucose and glycerol isotope tracers to assess suppression of endogenous glucose release and lipolysis by insulin. Intramyocellular lipid content was assessed by 1H–magnetic resonance spectroscopy, and hepatic fat fraction (HFF) and visceral fat were assessed by magnetic resonance imaging. Calf‐muscle mitochondrial activity was measured with exercise‐stimulated 31P–magnetic resonance spectroscopy. Results Youth with obesity had higher HFF (P < 0.001), visceral fat (P = 0.024), and intramyocellular lipid content (P = 0.017) and lower muscle (glucose clearance rate [P < 0.001]), adipose (P < 0.0001), and hepatic IS (P < 0.003). Mitochondria postexercise response was not different. In participants with obesity, muscle IS inversely correlated with HFF (r = 0.700, P = 0.002) and suppressed free fatty acid concentrations (r = −0.65, P = 0.003). Conclusions Inactive normoglycemic youth with obesity had decreased muscle, adipose, and hepatic IS. Free fatty acids and liver fat were inversely associated with muscle IS, which argues for lipid‐targeted interventions.
Background PCOS is common and associated with obesity and the metabolic syndrome. Adolescents with PCOS and obesity are more likely to have hepatic steatosis (HS) which portends worsening metabolic disease. Glucagon like peptide ‐1 receptor agonist (GLP1RA) therapy has been shown to reduce HS, but its influence on mechanisms such as decreasing of de novo lipogenesis (DNL) or free fatty acid (FFA) concentrations are unknown. Methods Adolescents with obesity and PCOS (N=22), half with HS, were enrolled. Participants underwent an overnight metabolic study followed by a morning oral sugar tolerance test (OSTT; 76‐78 g glucose +25 g fructose), with half treated with an evening and morning dose of GLP1RA. Serum for fasting and post‐OSTT hormones and metabolic markers was collected. DNL rates were measured fasting and during the OSTT using an overnight intravenous stable isotope 13C2 acetate infusion with measurements of incorporation of the tracer into VLDL‐triglyceride palmitate. Hepatic fat was measured with MRI utilizing the Dixon method. Groups were compared via t‐test or Mann‐Whitney U. Metabolic curves between groups were compared via linear mixed effects models. Results TheGLP1RA (N=10, age 15.3 ± 2.2 years, BMI 34.9 ± 7.7 kg/m2, 50% HS) and control groups (N=12, age 16.0 ± 2.2, BMI 36.3 ± 5.7, 50% HS) were similar at baseline in terms of hormonal and metabolic measures, although the fasting serum TG were significantly higher in GLP1RA (126 [95,169] vs 87 [75,106] mg/dL). In GLP1RA, OSTT glucose curveswere significantly lower (p<0.001 overall), as were time points 20, 60, 75, 90, 105, 120, 135, 150, 180, and 210 minutes. Although the OSTT response curves between the groups were not different for FFA, insulin, glycerol or glucagon, fasting glucagon was lower, and insulin at 60 min and glycerol at 300 min were higher in GLP1RA. No significant group differences were found between measures of fractional DNL, although the GLP1RA group was non‐significantly lower for every individual time point during fasting and post‐OSTT. The absolute DNL level was similar between groups. Conclusions Two doses of GLP1RA treatment impacted fasting and OSTT glucose, insulin and glucagon responses. Glycerol and FFA concentrations did not change and there was a trend for lower fractional DNL. Further study after a longer duration of GLP1RA treatment is needed to determine if decreased DNL is associated with decreases in hepatic steatosis following GLP1RA therapy.
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