Fulminant type 1 diabetes mellitus observed in insulin receptor substrate 2 deficient mice.
The objective of this study was to characterise the fulminant type 1 diabetes mellitus (DM) accompanying abrupt hyperglycaemia and ketonuria observed in insulin receptor substrate 2 (IRS2)-deficient mice. IRS2-deficient mice backcrossed onto the original C57BL/6J:Jc1 background (B6J-IRS2(-/-) mice) for more than 10 generations were used. Eight male IRS2-deficient mice with ketonuria and abrupt increase in plasma glucose concentrations over 25 mmol/l were used as the fulminant type 1 diabetic mice (diabetic mice) and 8 male IRS2-deficient mice (8 weeks old) without glycosuria were used as the control mice. Plasma metabolite, immunoreactive insulin (IRI) and C-peptide concentrations, hepatic energy metabolism related enzyme activities and histopathological change in pancreatic islets were investigated. The diabetic mice showed significantly higher plasma glucose and cholesterol concentrations and lower plasma IRI and C-peptide concentrations than the control mice. In livers of the diabetic mice, glycolytic and malate-aspartate shuttle enzyme activities decreased significantly and gluconeogenic, lipogenic and ketone body synthesis enzyme activities increased significantly compared to those in the control mice. The pancreatic islets of the diabetic mice decreased significantly in size and number of beta cells. The diabetic IRS2-deficient mice did not show the islet-related antibodies observed in the diabetic NOD mice in their sera. The characteristics of the diabetic IRS2-deficient mice resembled those of the human nonautoimmune fulminant type 1 DM. IRS2-deficient mice may be a useful animal model for studying the degradation mechanism of pancreatic beta cells in the process of development of fulminant type 1 DM.
Arai
T
T
Department of Veterinary Science, School of Veterinary Medicine, Nippon Veterinary and Life Science University, Musashino, Tokyo, 180-8602, Japan. tarai@nvlu.ac.jp
Hashimoto
H
H
Kawai
K
K
Mori
A
A
Ohnishi
Y
Y
Hioki
K
K
Ito
M
M
Saito
M
M
Ueyama
Y
Y
Ohsugi
M
M
Suzuki
R
R
Kubota
N
N
Yamauchi
T
T
Tobe
K
K
Kadowaki
T
T
Kosaka
K
K
D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000209:etiology*; D005230:Fatty Acids, Nonesterified / Q000097:blood; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D010750:Phosphoproteins / Q000502:physiology*; D014280:Triglycerides / Q000097:blood
D005230:Fatty Acids, Nonesterified; C526297:IRS2 protein, human; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526298:Irs2 protein, mouse; D010750:Phosphoproteins; D014280:Triglycerides