Circadian and Age-dependent Expression Patterns of GLUT2 and Glucokinase in the Pancreatic β-Cell of Diabetic and Nondiabetic Rats

Abstract

Alterations in glucose sensing are well-known in both humans and animal models of non-insulin-dependent diabetes mellitus. However, the circadian- and age-dependent expression of glucose-sensing genes has not previously been investigated in vivo. In the present paper, we show a progressive loss of β-cell GLUT2-mRNA and, by immunocytochemistry, a gain of soluble, cytoplasmic GLUT2-protein in Goto-Kakizaki rat islets. We report that GLUT2-mRNA shows significant diurnal variation, which is stronger in metabolically healthy rats. We also demonstrate the significant diurnal variation of glucokinase-mRNA, with higher levels in the pancreas of 6-week-old Goto-Kakizaki rats than in Wistar rats. This leads to a maximum glucose phosphorylation capacity in-phase with food intake, enhanced glucose-stimulated insulin secretion, and prevents postprandial hyperglycemia. Perfusion experiments showed a reduction in glucose-stimulated insulin secretion in Goto-Kakizaki rat islets with an impaired first phase. Hyperglycemia and hypoinsulinemia in newborn and up to 3-week-old Goto-Kakizaki rats are thus probably due to reduced pancreatic β-cell content, reduced β-cell insulin content and impaired glucose sensing. The de-compensation of the metabolic situation in 42-week-old Goto-Kakizaki rats is likely to be caused by β-cell destruction accompanied by negligible accumulation of GLUT2 in the cell membrane and further reduction of glucokinase expression.

Key words

Glucose sensing - diabetes - GK rat - real-time RT-PCR - immunohistochemistry - perfusion

References

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