1: J Biol Chem. 2003 Jan 31;278(5):2997-3005. Epub 2002 Nov 15. 

Critical reduction in beta-cell mass results in two distinct outcomes over time.
Adaptation with impaired glucose tolerance or decompensated diabetes.

Laybutt DR, Glandt M, Xu G, Ahn YB, Trivedi N, Bonner-Weir S, Weir GC.

Section of Islet Transplantation and Cell Biology, Joslin Diabetes Center,
Boston, Massachusetts 02215, USA.

We have proposed that hyperglycemia-induced dedifferentiation of beta-cells is a
critical factor for the loss of insulin secretory function in diabetes. Here we
examined the effects of the duration of hyperglycemia on gene expression in
islets of partially pancreatectomized (Px) rats. Islets were isolated, and mRNA
was extracted from rats 4 and 14 weeks after Px or sham Px surgery. Px rats
developed different degrees of hyperglycemia; low hyperglycemia was assigned to
Px rats with fed blood glucose levels less than 150 mg/dl, and high
hyperglycemia was assigned above 150 mg/dl. beta-Cell hypertrophy was present at
both 4 and 14 weeks. At the same time points, high hyperglycemia rats showed a
global alteration in gene expression with decreased mRNA for insulin, IAPP,
islet-associated transcription factors (pancreatic and duodenal homeobox-1,
BETA2/NeuroD, Nkx6.1, and hepatocyte nuclear factor 1 alpha), beta-cell
metabolic enzymes (glucose transporter 2, glucokinase, mitochondrial glycerol
phosphate dehydrogenase, and pyruvate carboxylase), and ion channels/pumps
(Kir6.2, VDCC beta, and sarcoplasmic reticulum Ca(2+)-ATPase 3). Conversely,
genes normally suppressed in beta-cells, such as lactate dehydrogenase-A,
hexokinase I, glucose-6-phosphatase, stress genes (heme oxygenase-1, A20, and
Fas), and the transcription factor c-Myc, were markedly increased. In contrast,
gene expression in low hyperglycemia rats was only minimally changed at 4 weeks
but significantly changed at 14 weeks, indicating that even low levels of
hyperglycemia induce beta-cell dedifferentiation over time. In addition, whereas
2 weeks of correction of hyperglycemia completely reverses the changes in gene
expression of Px rats at 4 weeks, the changes at 14 weeks were only partially
reversed, indicating that the phenotype becomes resistant to reversal in the
long term. In conclusion, chronic hyperglycemia induces a progressive loss of
beta-cell phenotype with decreased expression of beta-cell-associated genes and
increased expression of normally suppressed genes, these changes being present
with even minimal levels of hyperglycemia. Thus, both the severity and duration
of hyperglycemia appear to contribute to the deterioration of the beta-cell
phenotype found in diabetes.

PMID: 12438314 [PubMed - indexed for MEDLINE]


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2: Diabetes. 2002 Jun;51(6):1793-804. 

Overexpression of c-Myc in beta-cells of transgenic mice causes proliferation
and apoptosis, downregulation of insulin gene expression, and diabetes.

Laybutt DR, Weir GC, Kaneto H, Lebet J, Palmiter RD, Sharma A, Bonner-Weir S.

Section of Islet Transplantation and Cell Biology, Joslin Diabetes Center,
Boston, Massachusetts, USA.

To test the hypothesis that c-Myc plays an important role in beta-cell growth
and differentiation, we generated transgenic mice overexpressing c-Myc in
beta-cells under control of the rat insulin II promoter. F(1) transgenic mice
from two founders developed neonatal diabetes (associated with reduced plasma
insulin levels) and died of hyperglycemia 3 days after birth. In pancreata of
transgenic mice, marked hyperplasia of cells with an altered phenotype and
amorphous islet organization was displayed: islet volume was increased threefold
versus wild-type littermates. Apoptotic nuclei were increased fourfold in
transgenic versus wild-type mice, suggesting an increased turnover of
beta-cells. Very few cells immunostained for insulin; pancreatic insulin mRNA
and content were markedly reduced. GLUT2 mRNA was decreased, but other
beta-cell-associated genes (IAPP [islet amyloid pancreatic polypeptide], PDX-1
[pancreatic and duodenal homeobox-1], and BETA2/NeuroD) were expressed at
near-normal levels. Immunostaining for both GLUT2 and Nkx6.1 was mainly
cytoplasmic. The defect in beta-cell phenotype in transgenic embryos (embryonic
days 17-18) and neonates (days 1-2) was similar and, therefore, was not
secondary to overt hyperglycemia. When pancreata were transplanted under the
kidney capsules of athymic mice to analyze the long-term effects of c-Myc
activation, beta-cell depletion was found, suggesting that, ultimately,
apoptosis predominates over proliferation. In conclusion, these studies
demonstrate that activation of c-Myc in beta-cells leads to 1) increased
proliferation and apoptosis, 2) initial hyperplasia with amorphous islet
organization, and 3) selective downregulation of insulin gene expression and the
development of overt diabetes.

PMID: 12031967 [PubMed - indexed for MEDLINE]


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