PEPCK activity in the liver of 16-hour fasted wild type (WT) and FynKO mice.

<p>PEPCK mRNA expression levels in wild type (WT, black bars) and FynKO (open bars) mice. *<i>p</i><0.05. n= 5 WT, n=5 FynKO, experiments were repeated 3 times. (B) PEPCK protein levels in wild type (WT) and FynKO mice (blots are representative of n=3 independent experiments). </p

Gluconeogenic capacity assessed by stable isotope assessment of hepatic glucose production (HGP) (A) and intraperitoneal (B) Pyruvate and (C) Lactate;Pyruvate (9:1) tolerance tests in fasted wild type (WT, black circles) and FynKO (open circles) mice.

<p>*p<0.05. n= 5 WT, n=5 FynKO, experiments were repeated 4 times for the intraperitoneal tests. *p<0.05. n= 5 WT, n=5 FynKO for the stable isotope experiment.</p

Aldolase and fructokinase expression levels in livers of 16-hour fasted wild type (WT) and FynKO mice.

<p>(A) Fructokinase mRNA expression levels and (B) Aldolase A, B and C isoform mRNA expression levels in fasted wild type (WT, black bars) and FynKO (open bars) mice. (C) Aldolase protein expression in the liver of wild type (WT) and FynKO mice. p115 was used as internal loading control. Blots are representative of n=3 independent experiments.</p

Fructose-driven glucose production in 16-hour fasted wild type (WT) and FynKO mice (A) Fructose tolerance test in fasted wild type (WT, black circles) and FynKO (open circles) mice.

<p>*p<0.05. n= 5 WT, n=5 FynKO, experiments were repeated 4 times. (B) Hexose phosphate levels in liver of wild type (WT) and FynKO mice: glucose-6-phosphate (G-6-P), fructose-6-phosphate (F-6-P) and fructose-1,6- bisphosphate (F-1,6-P). *<i>p</i><0.05, n=3 WT, n=3 FynKO. </p

Glycerol metabolites and triose phosphate levels in the liver of wild type (WT, black bars) and FynKO (open bars) mice.

<p>(A) alpha-Glycerol phosphate (α-Gly-P) in liver extracts. (B) Glycerol kinase protein expression in the liver of wild type (WT) and FynKO mice. p115 was used as internal loading control. Blot is representative of 3 independent experiments. (C) dihydroxyacetone phosphate (DHAP) and glyceraldehyde-3 phosphate (G-3P) levels in liver extracts. n=3 WT, n=3 FynKO.</p

Alterations in adipose tissue distribution, cell morphology and function mark primary insulin hypersecretion in youths with obesity

Excessive insulin secretion independent of insulin resistance, defined as primary hypersecretion, is associated with obesity and an unfavorable metabolic phenotype. We examined the characteristics of the adipose tissue in youths with primary insulin hypersecretion and the longitudinal metabolic alterations influenced by the complex adipo-insular interplay. In a multiethnic cohort of non-diabetic adolescents with obesity, primary insulin hypersecretors had enhanced model-derived β-cell glucose sensitivity and rate sensitivity, but worse glucose tolerance, despite similar demographics, adiposity, and insulin resistance measured by both OGTT and euglycemic-hyperinsulinemic clamp. Hypersecretors had greater intrahepatic and visceral fat depots at abdominal MRI, hypertrophic abdominal subcutaneous adipocytes, higher FFA and leptin serum levels per fat mass, and faster in vivo lipid turnover assessed by a long-term 2H2O labeling protocol. At 2-year follow up, hypersecretors had greater fat accrual and 3-fold higher risk for abnormal glucose tolerance, while individuals with hypertrophic adipocytes or higher leptin levels showed enhanced β-cell glucose sensitivity. Primary insulin hypersecretion is associated with marked alterations in adipose tissue distribution, cellularity, and lipid dynamics, independent of whole-body adiposity and insulin resistance. Pathogenetic insight into the metabolic crosstalk between β-cell and adipocyte may help identify individuals at risk for chronic hyperinsulinemia, body weight gain, and glucose intolerance. </p