Increasing β-cell mass requires additional stimulation for adaptation to secretory demand.
Type 2 diabetes mellitus (T2DM) is caused by relative insulin deficiency, subsequent to both reduced β-cell mass and insufficient insulin secretion, and both augmenting β-cell mass and β-cell function are therapeutic strategies for treating T2DM. However, the relative significance of increasing β-cell mass vs improving β-cell stimulus secretion coupling remains unclear. We have developed a mouse model that allows proliferation of β-cells in adult mice without affecting β-cell function by inducible expression of the positive cell cycle regulator cyclin A2 specifically in β-cells. In these mice, when kept on a standard diet, doubling of β-cell mass does not result in altered glucose tolerance or glucose-stimulated circulating insulin levels. Notably, a doubling of β-cell mass also does not confer improved glycemic control and ability of β-cells to respond to diabetogenic high-fat diet-induced glucose intolerance. However, in high-fat diet-exposed mice, an increase in endogenous β-cell mass confers increased potentiation of in vivo glucose-stimulated rise in circulating insulin in response to acute pharmacologic treatment with the incretin glucagon-like peptide-1 receptor agonist exendin-4. These observations indicate that increasing endogenous β-cell mass may not be sufficient to improve glycemic control in T2DM without additional strategies to increase β-cell stimulus secretion coupling.
Departments of Medicine (M.A.H.), Pediatrics (P.M., W.-J.S., Y.L., K.S.Y., M.A.H.), and Biological Chemistry (M.A.H.), Johns Hopkins University, Baltimore, Maryland 21287.
Prosenjit
P
Mondal
Woo-Jin
WJ
Song
Yuanyuan
Y
Li
Kil S
KS
Yang
Mehboob A
MA
Hussain
D000818:Animals; D002452:Cell Count; D049109:Cell Proliferation; D056751:Cyclin A2 / Q000096:biosynthesis / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D059305:Diet, High-Fat; D000067757:Glucagon-Like Peptide-1 Receptor / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D018149:Glucose Intolerance / Q000378:metabolism; D005951:Glucose Tolerance Test; D007328:Insulin / Q000172:deficiency*; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010179:Pancreas / Q000166:cytology / Q000378:metabolism
C508184:CCNA2 protein, mouse; D056751:Cyclin A2; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D005947:Glucose