Circadian and age-dependent expression patterns of GLUT2 and glucokinase in the pancreatic beta-cell of diabetic and nondiabetic rats.
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 beta-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 beta-cell content, reduced beta-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 beta-cell destruction accompanied by negligible accumulation of GLUT2 in the cell membrane and further reduction of glucokinase expression.
Frese
T
T
Institute of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Halle/Saale, Germany.
Bazwinsky
I
I
Mühlbauer
E
E
Peschke
E
E
D000367:Age Factors; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight; D002940:Circadian Rhythm / Q000235:genetics / Q000502:physiology*; D003921:Diabetes Mellitus, Experimental / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005941:Glucokinase / Q000235:genetics* / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D051273:Glucose Transporter Type 2 / Q000235:genetics* / Q000378:metabolism; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D051381:Rats; D017208:Rats, Wistar
D001786:Blood Glucose; D051273:Glucose Transporter Type 2; D007328:Insulin; C495683:Slc2a2 protein, rat; D005941:Glucokinase; D005947:Glucose