Nuclear SREBP-1a causes loss of pancreatic beta-cells and impaired insulin secretion.
Transgenic mice expressing nuclear sterol regulatory element-binding protein-1a under the control of the insulin promoter were generated to determine the role of SREBP-1a in pancreatic beta-cells. Only low expressors could be established, which exhibited mild hyperglycemia, impaired glucose tolerance, and reduced plasma insulin levels compared to C57BL/6 controls. The islets isolated from the transgenic mice were fewer and smaller, and had decreased insulin content and unaltered glucagon staining. Both glucose- and potassium-stimulated insulin secretions were decreased. The transgenic islets consistently expressed genes for fatty acids and cholesterol synthesis, resulting in accumulation of triglycerides but not cholesterol. PDX-1, BetaEpsilonTauAlpha2, MafA, and IRS-2 were suppressed, partially explaining the loss and dysfunction of beta-cell mass. The transgenic mice on a high fat/high sucrose diet still exhibited impaired insulin secretion and continuous beta-cell growth defect. Therefore, nuclear SREBP-1a, even at a low level, strongly disrupts beta-cell mass and function.
Iwasaki
Yuko
Y
Department of Internal Medicine (Endocrinology and Metabolism), Graduate School of Comprehensive Human Sciences, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
Iwasaki
Hitoshi
H
Yatoh
Shigeru
S
Ishikawa
Mayumi
M
Kato
Toyonori
T
Matsuzaka
Takashi
T
Nakagawa
Yoshimi
Y
Yahagi
Naoya
N
Kobayashi
Kazuto
K
Takahashi
Akimitsu
A
Suzuki
Hiroaki
H
Yamada
Nobuhiro
N
Shimano
Hitoshi
H
D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D005951:Glucose Tolerance Test; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology*; D051473:Maf Transcription Factors, Large / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000235:genetics / Q000378:metabolism
D018398:Homeodomain Proteins; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526298:Irs2 protein, mouse; D051473:Maf Transcription Factors, Large; C485160:Mafa protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D015534:Trans-Activators; D014280:Triglycerides; C084010:pancreatic and duodenal homeobox 1 protein; D002784:Cholesterol