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Title: B-cell impairment and clinically meaningful alterations in glycemia in obese youth across the glucose tolerance spectrum

Author
item KIM, JOON YOUNG - Syracuse University
item TFAYLI, HALA - American University Of Beirut
item BACHA, FIDA - Children'S Nutrition Research Center (CNRC)
item LEE, SOJUNG - Kyung Hee University
item GEBARA, NOUR - University Of Pittsburgh Medical Center
item ARSLANIAN, SILVA - University Of Pittsburgh Medical Center

Submitted to: Metabolism: Clinical and Experimental
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/17/2020
Publication Date: 11/1/2020
Citation: Kim, J., Tfayli, H., Bacha, F., Lee, S., Gebara, N., Arslanian, S. 2020. B-cell impairment and clinically meaningful alterations in glycemia in obese youth across the glucose tolerance spectrum. Metabolism: Clinical and Experimental. 112:154346. https://doi.org/10.1016/j.metabol.2020.154346.
DOI: https://doi.org/10.1016/j.metabol.2020.154346

Interpretive Summary: Some youth with obesity have increased risk for type 2 diabetes. The risk for diabetes is related to loss of beta cell function which refers to impairment in the function of the cells of the pancreas that make insulin. However, it is not clear what degree of impairment in beta cell function leads to impaired glucose tolerance (IGT) and eventually to diabetes characterized by very high blood sugars. In this study, we investigated 152 youth. They underwent glucose tolerance test (oral glucose challenge) and assessment of insulin sensitivity and secretion. We calculated the disposition index (DI) which is a measure of insulin secretion relative to insulin resistance. We found that as in youth with IGT or diabetes compared with those with normal glucose tolerance (NGT), the difference in disposition index (DI) corresponds to a certain degree of elevation of blood sugar levels after the glucose challenge. We conclude that at least ~35-50% recovery in beta cell function might be needed to have clinically meaningful improvement in glucose tolerance in individuals with IGT and diabetes. Therefore, future studies should test the degree of improvement in beta cell function to assess effect of interventions aiming at reversing diabetes.

Technical Abstract: In obese youth, it is not clear what degree of B-cell impairment translates to glucose dysregulation commensurate with shifts from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT) to type 2 diabetes. We aimed to investigate the quantitative relationship between B-cell (clamp-measured disposition index [DI]) and OGTT glucose area under the curve (G-AUC) in obese youth across the spectrum of glucose tolerance. Data from 152 youth (58 African-American [AA] and 94 American-White [AW]; 73 NGT, 48 IGT, and 31 type 2 diabetes) who completed a 3-h hyperinsulinemic (80 mu/m2/min)-euglycemic clamp, and a 2-h hyperglycemic (225 mg/dL) clamp synchronized with a 2-h OGTT were examined. In IGT vs. NGT, 36% lower DI corresponded to 27% higher G-AUC; in type 2 diabetes vs. IGT, 65% lower DI related to 25% higher G-AUC, and in type 2 diabetes vs. NGT, 78% lower DI paralleled 59% higher G-AUC. Although AA vs. AW youth had larger decrements in DI, from NGT to IGT and from NGT to type 2 diabetes, they displayed comparable increments in G-AUC. At least ~35-50% recovery in B-cell function might be needed to have clinically meaningful improvement in G-AUC commensurate with conversion to better glucose tolerance. Mechanism(s) protective against dysglycemia might be operative in AA vs. AW youth despite greater declines in DI. Treatments aiming to improve B-cell function should focus on degree of change in DI commensurate with clinically meaningful changes in glycemia, reflective of restoration of glucose tolerance.