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Title: Beta-cell function, incretin effect, and incretin hormones in obese youth along the span of glucose tolerance from normal to prediabetes to Type 2 diabetes

item MICHALISZYN, SARA - University Of Pittsburgh Medical Center
item MARI, ANDREA - Cnr Institute Of Biomedical Engineering
item LEE, SOJUNG - University Of Pittsburgh Medical Center
item BACHA, FIDA - Children'S Nutrition Research Center (CNRC)
item TFAYLI, HALA - American University Of Beirut
item FARCHOUKH, LAMA - University Of Pittsburgh Medical Center
item FERRANNINI, ELE - University Of Pisa
item ARSLANIAN, SILVA - University Of Pittsburgh Medical Center

Submitted to: Diabetes
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/30/2014
Publication Date: 6/19/2014
Citation: Michaliszyn, S.F., Mari, A., Lee, S., Bacha, F., Tfayli, H., Farchoukh, L., Ferrannini, E., Arslanian, S. 2014. Beta-cell function, incretin effect, and incretin hormones in obese youth along the span of glucose tolerance from normal to prediabetes to Type 2 diabetes. Diabetes. 63(11):3846-3855.

Interpretive Summary: It is not clear if impairment in the secretion or action of hormones produced in the gut called incretins, are involved in the pathogenesis of type 2 diabetes in children. We investigated the levels and effect of these hormones after an oral glucose tolerance test (OGTT) and after intravenous glucose load in youth with normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and type 2 diabetes (T2D). We found that the youth with IGT and T2D have decreased responsiveness of insulin secretion in response to blood glucose levels compared with NGT youth. They also had evidence of lower incretin hormone action without decrease in incretin hormone levels. We conclude that both of these mechanisms are involved in the progression from normal glucose tolerance to diabetes.

Technical Abstract: Using the hyperglycemic and euglycemic clamp, we demonstrated impaired Beta-cell function in obese youth with increasing dysglycemia. Herein we describe oral glucose tolerance test (OGTT)-modeled Beta-cell function and incretin effect in obese adolescents spanning the range of glucose tolerance. Beta-Cell function parameters were derived from established mathematical models yielding Beta-cell glucose sensitivity (BetaCGS), rate sensitivity, and insulin sensitivity in 255 obese adolescents (173 with normal glucose tolerance [NGT], 48 with impaired glucose tolerance [IGT], and 34 with type 2 diabetes [T2D]). The incretin effect was calculated as the ratio of the OGTT-BetaCGS to the 2-h hyperglycemic clamp-BetaCGS. Incretin and glucagon concentrations were measured during the OGTT. Compared with NGT, BetaCGS was 30 and 65% lower in youth with IGT and T2D, respectively; rate sensitivity was 40% lower in T2D. Youth with IGT or T2D had 32 and 38% reduced incretin effect compared with NGT in the face of similar changes in GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) in response to oral glucose. We conclude that glucose sensitivity deteriorates progressively in obese youth across the spectrum of glucose tolerance in association with impairment in incretin effect without reduction in GLP-1 or GIP, similar to that seen in adult dysglycemia.