Islet amyloid polypeptide (amylin)-deficient mice develop a more severe form of alloxan-induced diabetes.
To examine whether islet amyloid polypeptide (IAPP), other than through amyloid formation, may be of importance in diabetes pathogenesis, IAPP-deficient mice (IAPP(-/-)) were challenged with alloxan (day 0). Diabetes in IAPP(-/-) mice was more severe at day 35, indicated by greater weight loss; glucose levels were higher in alloxan-treated IAPP(-/-) mice, whereas insulin levels were lower, indicating a greater impairment of islet function. Accordingly, glucose levels upon intravenous glucose challenges at days 7 and 35 were consistently higher in alloxan-treated IAPP(-/-) mice. At day 35, insulin mRNA expression, but not beta-cell mass, was lower in untreated IAPP(-/-) mice. Yet, upon alloxan administration, beta-cell mass and numbers of beta-cell-containing islets were significantly more reduced in IAPP(-/-) mice. Furthermore, they displayed exaggerated beta-cell dysfunction, because in their remaining beta-cells, insulin mRNA expression was significantly more impaired and the localization of glucose transporter-2 was perturbed. Thus the lack of IAPP has allowed exaggerated beta-cell cytotoxic actions of alloxan, suggesting that there may be beneficial features of IAPP actions in situations of beta-cell damage.
Mulder
H
H
Section for Molecular Signaling, Department of Cell and Molecular Biology, Lund University, SE-221 00 Lund, Sweden. mulder@utsw.swmed.edu
Gebre-Medhin
S
S
Betsholtz
C
C
Sundler
F
F
Ahrén
B
B
D000682:Amyloid / Q000172:deficiency*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000235:genetics* / Q000473:pathology*; D015870:Gene Expression / Q000235:genetics / Q000502:physiology; D005951:Glucose Tolerance Test; D051273:Glucose Transporter Type 2; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007328:Insulin / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D058228:Islet Amyloid Polypeptide; D007515:Islets of Langerhans / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D058287:Receptors, Islet Amyloid Polypeptide; D018000:Receptors, Peptide / Q000378:metabolism
D000682:Amyloid; D001786:Blood Glucose; D051273:Glucose Transporter Type 2; D007328:Insulin; D058228:Islet Amyloid Polypeptide; D009004:Monosaccharide Transport Proteins; D012333:RNA, Messenger; D058287:Receptors, Islet Amyloid Polypeptide; D018000:Receptors, Peptide