A defective stimulus-secretion coupling rather than glucotoxicity mediates the impaired insulin secretion in the mildly diabetic F1 hybrids of GK-Wistar rats.
Adult F1 hybrids of male GK and female Wistar control rats exhibit mild, spontaneous non-insulin-dependent diabetes mellitus characterized by impaired glucose-induced insulin secretion. Using isolated pancreatic islets of hybrid rats, we first studied whether impaired glucose-induced insulin response is present not only in adult but also in neonatal rats. Furthermore, we investigated whether the impaired glucose-induced insulin response can be restored by long-term normalization of glycemia. Both 1-week- and 2- to 3-month-old hybrid rats had similar body weights but increased fed blood glucose levels (P < 0.05) compared with age-matched control rats. At 5.5 mmol/l glucose, insulin release was two- to threefold lower in isolated islets of hybrid than in control rats of both age groups (P < 0.05). At 16.7 mmol/l glucose, insulin secretion from hybrid islets was approximately 25% of that from control islets of both 1-week- and 2- to 3-month-old rats. For the second objective, batches of 250 islets from hybrid or control rats were transplanted under the kidney capsule of athymic, normoglycemic nude mice and maintained there for 4 weeks. Perfusion of kidneys demonstrated that glucose-induced (16.7 mmol/l) insulin secretion was impaired markedly in hybrid grafts compared with that in control grafts (0.66 +/- 0.23 vs. 1.8 +/- 0.38 pmol/20 min; P < 0.01), whereas stimulation by 20 mmol/l arginine resulted in similar insulin responses in both groups. The volumes of the grafted islets were similar in kidneys bearing either control or hybrid islets.(ABSTRACT TRUNCATED AT 250 WORDS)
Abdel-Halim
S M
SM
Department of Molecular Medicine, Karolinska Institute, Stockholm, Sweden.
Ostenson
C G
CG
Andersson
A
A
Jansson
L
L
Efendić
S
S
D000375:Aging / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D003433:Crosses, Genetic; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000503:physiopathology*; D005260:Female; D005947:Glucose / Q000494:pharmacology; D005951:Glucose Tolerance Test; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D016381:Islets of Langerhans Transplantation / Q000473:pathology / Q000502:physiology*; D007668:Kidney; D008297:Male; D051379:Mice; D008819:Mice, Nude; D051381:Rats; D011919:Rats, Inbred Strains; D017208:Rats, Wistar; D012016:Reference Values; D014183:Transplantation, Heterologous; D016042:Transplantation, Heterotopic
D001786:Blood Glucose; D007328:Insulin; D005947:Glucose