Role of Inflammation, Oxidative Stress and Adipokines in the Development of Insulin Resistance and Altered Glucose Homeostasis in Obese Youth.

Huerta, Milagros; Jaques, Cory; Mendosa, Pamela; Wasserfall, Clive; Silverstein, Janet; Atkinson, Mark; Nadler, Jerry

The prevalence of pediatric type 2 diabetes (T2D) has increased over the past decade. However, the pathophysiologic mechanisms leading to the development of T2D in youth have not been fully elucidated. To investigate the role of inflammation, oxidative stress (OS) and adipokines in this process, we studied 54 obese (O) (BMI: 32 ± 1 kg/m², age: 13.1 ± 0.3y) and 33 non-obese (NO) children (BMI: 19 ± 1, age: 13.7 ± 0.4y). Blood was drawn for adiponectin (AdipoQ), leptin, HghA1C (A1C) and hs-C reactive protein (CRP). Insulin and glucose (Glu) data from a frequently sampled IVGTT were analyzed using the Minimal Model program to determine insulin sensitivity (Si), Disposition Index (DI) and Acute Insulin Response to Glucose (AIRg). A 2-hour OGTT was used to determine 0' and 120' Glu and Glu area under the curve (AUCg) in O children. Peripheral blood monocytes were incubated with DHR[sup 123] to determine intracellular OS using flow cytomelry. Obese children had higher A1C (O: 5.3 ± 0.1 vs. NO: 5.1 ± 0.1% §), fasting Glu (O: 96.9 4 ± 0.8 vs. NO: 92.6 ± 1.2 mg/dL(‡)) and AIRg (O: 1040 ± 104 vs. NO: 338 ± 73 mu.l[sup -1].min(†)) and lower Si (O: 2.7 ± 0.6 vs. NO: 6.5 ± 0.8 [mU/1] [sup -1].min[sup -1](†)) than NO children. In O youth, DI was inversely correlated with 120' Glu (r=-0.35(§)) and AUCg (r= -0.38(§)) but not with fasting Glu or A1C. O subjects had higher intracellular OS (O: 20.2 ± 2.0 vs. NO: 14.3 ± 0.6 Arbitrary Fluorescence Units(§)), leptin (O: 34 ± 3 vs. NO: 4 ± 1 ng/mL(†)) and CRP (O: 3.1 ± 0.4 vs. NO: 0.8 ± 0.2 mg/L(†)), and lower AdipoQ (O: 13 ± 1 vs. NO: 31 ± 3 µg/mL(†)) than NO subjects. Si was directly correlated with AdipoQ (r=0.58(†)) and inversely correlated with leptin (r=-0.47(†)), CRP (r=-0.41(†)) and OS (r=-0.27(§)). AIRg correlated with leptin (r=0.54(†)), CRP (r=0.35(‡)) and OS (r=0.29(§)) and was inversely associated with AdipoQ (r=0.31(§)). In O subjects, leptin correlated with AIRg (r=0.38(§)) and was inversely correlated with Si (r=-0.39(§)). A1C correlated with CRP (r=0.26(§))and leptin (r=0.24(§)) and was inversely correlated with AdipoQ (r=0.24(§)). In O subjects, AUCg correlated with CRP (r=0.36(‡)). In obese youth, increased inflammation, oxidative stress and changes in adipokines may play a role in the development of insulin resistance and altered glucose metabolism. Because of its association with markers of glucose homeostasis, CRP may serve as marker of increased risk for T2D in youth. (†) p<0.001 (‡) p<0.01 (§) p<0.05

INFLAMMATION; OXIDATIVE stress; INSULIN resistance; DIABETES in children; TYPE 2 diabetes; DIABETES in youth; INSULIN; GLUCOSE

Diabetes, 2007, Vol 56, pA487

0012-1797

Academic Journal