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. 2015 Mar;156(3):813-23.
doi: 10.1210/en.2014-1757. Epub 2015 Jan 5.

Peripheral insulin resistance and impaired insulin signaling contribute to abnormal glucose metabolism in preterm baboons

Cynthia L Blanco  1 , Lisa L McGill-Vargas, Amalia Gastaldelli, Steven R Seidner, Donald C McCurnin, Michelle M Leland, Diana G Anzueto, Marney C Johnson, Hanyu Liang, Ralph A DeFronzo, Nicolas Musi
Affiliations

Peripheral insulin resistance and impaired insulin signaling contribute to abnormal glucose metabolism in preterm baboons

Cynthia L Blanco et al. Endocrinology. 2015 Mar.

Abstract

Premature infants develop hyperglycemia shortly after birth, increasing their morbidity and death. Surviving infants have increased incidence of diabetes as young adults. Our understanding of the biological basis for the insulin resistance of prematurity and developmental regulation of glucose production remains fragmentary. The objective of this study was to examine maturational differences in insulin sensitivity and the insulin-signaling pathway in skeletal muscle and adipose tissue of 30 neonatal baboons using the euglycemic hyperinsulinemic clamp. Preterm baboons (67% gestation) had reduced peripheral insulin sensitivity shortly after birth (M value 12.5 ± 1.5 vs 21.8 ± 4.4 mg/kg · min in term baboons) and at 2 weeks of age (M value 12.8 ± 2.6 vs 16.3 ± 4.2, respectively). Insulin increased Akt phosphorylation, but these responses were significantly lower in preterm baboons during the first week of life (3.2-fold vs 9.8-fold). Preterm baboons had lower glucose transporter-1 protein content throughout the first 2 weeks of life (8%-12% of term). In preterm baboons, serum free fatty acids (FFAs) did not decrease in response to insulin, whereas FFAs decreased by greater than 80% in term baboons; the impaired suppression of FFAs in the preterm animals was paired with a decreased glucose transporter-4 protein content in adipose tissue. In conclusion, peripheral insulin resistance and impaired non-insulin-dependent glucose uptake play an important role in hyperglycemia of prematurity. Impaired insulin signaling (reduced Akt) contributes to the defect in insulin-stimulated glucose disposal. Counterregulatory hormones are not major contributors.

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Figures

Figure 1.
Figure 1.
Daily serum glucose concentrations and GIRs in preterm baboons. Serum glucose measurements are represented as medians with interquartile ranges shown as black lines (A). Daily median glucose infusion rates are expressed as milligrams per kilogram per minute and compared each day of life with interquartile ranges shown as black lines (B).
Figure 2.
Figure 2.
Plasma insulin concentrations and peripheral insulin sensitivity during euglycemic hyperinsulinemic clamp. (A) Serum insulin levels at baseline are shown in white boxes, whereas insulin levels are shown in dark boxes in both preterm and term baboons. Dotted line is depicted to mark where the graph was superimposed to decrease the height of the bar. **, P < .01. (B) Serum insulin levels are shown at 30-minute intervals during the 120-minute insulin clamp. Preterm baboons are shown with a dotted line and square markers, whereas term animals are shown with a solid line and circle markers. Error bars show mean ± 1.0 SE. (C) Insulin sensitivity (M value) is shown in preterm and term animals at 5DOL and 14DOL.
Figure 3.
Figure 3.
Developmental differences in adipose tissue. Serum concentrations of FFAs of preterm and term animals at baseline are shown in white boxes, whereas response of FFAs to insulin are shown in dark boxes at DOL5 and DOL14 (A). Protein content and gene expression of Akt (B) and GLUT4 (C) were measured by Western blotting and in preterm and term baboons at necropsy. Representative blots from each group are also shown. Data are means ± SE. *, P < .05. d, day.
Figure 4.
Figure 4.
Counterregulatory hormones. Plasma concentrations of glucagon (A), epinephrine (B), and norepinephrine (C) in fetal control, preterm, and term baboons are depicted. Fetal controls are shown in boxes with diagonal lines, basal concentrations are shown in white boxes, and concentrations during the insulin clamp are shown in dark boxes. Data are means ± SE. *, P < .05; **, P < .01.
Figure 5.
Figure 5.
Developmental differences in pAkt (normalized to Akt) and AKt-1 in skeletal muscle. Fold change (from basal) in protein content of pAKt (A) in preterm and term animals at DOL5 and DOL14 were measured by Western blotting and quantitative RT-PCR, respectively. Akt-1 gene expression is shown at DOL5 and DOL14 (B). Representative blots are also shown only a portion of ponceau S is shown, but the whole gel image confirmed equal loading. D, day. Data are means ± SE. *, P < .05.
Figure 6.
Figure 6.
Protein content and gene expression of key glucose transporters in skeletal muscle. Protein content and gene expression of GLUT1 and GLUT4 were measured by Western blotting (A and B) and quantitative RT-PCR (C and D) in preterm and term baboons at DOL5 and DOL14. Data from muscle samples taken at baseline are shown in white boxes, whereas those samples taken under insulin stimulation are shown in dark boxes in both preterm and term baboons. Representative blots from each group are also shown. GAPDH served as a loading control. d, day; GAPDH, glyceraldehyde-3-phosphate dehydrogenase. Data are means ± SE. *, P < .05; **, P < .01.
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