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Title: Increased lipolysis, diminished adipose tissue insulin sensitivity and impaired B-cell function relative to adipose tissue insulin sensitivity in obese youth with impaired glucose tolerance (IGT)

Author
item KIM, JOON - UNIVERSITY OF PITTSBURGH MEDICAL CENTER
item NASR, ALEXIS - UNIVERSITY OF PITTSBURGH MEDICAL CENTER
item TFAYLI, HALA - AMERICAN UNIVERSITY OF BEIRUT
item BACHA, FIDA - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC)
item MICHALISZYN, SARA - YOUNGSTOWN STATE UNIVERSITY
item ARSLANIAN, SILVA - UNIVERSITY OF PITTSBURGH MEDICAL CENTER

Submitted to: Diabetes
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/4/2017
Publication Date: 9/20/2017
Citation: Kim, J.Y., Nasr, A., Tfayli, H., Bacha, F., Michaliszyn, S.F., Arslanian, S. 2017. Increased lipolysis, diminished adipose tissue insulin sensitivity and impaired B-cell function relative to adipose tissue insulin sensitivity in obese youth with impaired glucose tolerance (IGT). Diabetes. https://doi.org/10.2337/db17-0551.

Interpretive Summary: Insulin resistance at the level of the skeletal muscle is a primary risk factor for type 2 diabetes in obese youth. The imbalance between insulin production and insulin resistance leads to the development of type 2 diabetes. The relationship of insulin resistance at the level of the fat (adipose) tissue and insulin production remains poorly understood in youth with impaired glucose tolerance (a state of increased risk for type 2 diabetes). Therefore, the purpose of this study was to measure fat breakdown and utilization in the fasting state and under the effect of insulin and to characterize the relationship between insulin sensitivity of the fat tissue and insulin production in obese youth with impaired glucose tolerance (IGT) compared to those with normal glucose tolerance (NGT). We found that obese youth with IGT vs. NGT demonstrate impaired insulin action in suppressing fat breakdown. This leads to lower adipose tissue insulin sensitivity. This is consistent with impaired insulin action at various tissues in the body in obese youth with IGT. In the presence of decreased insulin secretion in youth IGT vs. NGT, this increases the risk for progression to type 2 diabetes in these youth.

Technical Abstract: Despite evidence of insulin resistance and B-cell dysfunction in glucose metabolism in youth with prediabetes, the relationship between adipose tissue insulin sensitivity (ATIS) and B-cell function remains unknown. We investigated whole-body lipolysis, ATIS and B-cell function relative to ATIS [adipose disposition index (DI)] in obese youth with IGT vs. normal glucose tolerance (NGT). Whole-body lipolysis (glycerol appearance rate [GlyRa] ([2H5]glycerol at baseline and during a hyperinsulinemic-euglycemic clamp)), lipid oxidation (indirect calorimetry), insulin secretion (2-hr hyperglycemic clamp), and body composition (DEXA) were examined. Adipose DI was calculated as ATIS (1/GlyRa x fasting insulin) x 1st-phase insulin secretion. Despite similar percent body fat, IGT vs. NGT youth had higher GlyRa, lower ATIS at baseline and during hyperinsulinemia, and higher lipid oxidation. Adipose DI was ~43% lower in IGT youth and correlated positively with glucose DI. The lower ATIS and diminished adipose DI in IGT vs. NGT is in line with the compromised glucose metabolism reflected in impaired B-cell function relative to peripheral insulin resistance. We conclude that IGT youth manifest a global decline in insulin sensitivity, including impaired insulin action in suppressing lipolysis and lipid oxidation, accompanied by B-cell dysfunction in fat and glucose metabolism enhancing their risk of type 2 diabetes.