Phenotypes Associated with This Genotype

Genotype
MGI:5638417

• Allelic Composition: Foxo1^tm1Rdp/Foxo1^tm1Rdp; Foxo3^tm1Rdp/Foxo3^tm1Rdp; Foxo4^tm1Rdp/Foxo4^tm1Rdp; Tg(Ins2-cre)23Herr/0
• Genetic Background: involves: 129S6/SvEvTac * C57BL/6 * C57BL/6J * CBA/J

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

homeostasis/metabolism

abnormal glucose homeostasis ( J:215526 )

• mice show a defect in glucose-dependent insulin secretion that leads to early-onset, mild and moderately progressive diabetes

• mice subjected to hyperglycemic clamps require an approximate 50% lower rate of glucose infusion to maintain steady-state hyperglycemia

decreased insulin secretion ( J:215526 )

• mice are impaired in secreting insulin in response to the ATP-dependent K-channel blocker, glibenclamide, and to the depolarizing agent, I-arginine

• beta cells exhibit reduced calcium-dependent insulin secretion

• purified islets show lower insulin secretion in response to the sulfonylurea glibenclamide, the PKC activator PMA, and the L-type Ca channel activator Bay-K8644

hyperglycemia ( J:215526 )

• mice exhibit hyperglycemia in the fasted, refed, and random-fed states as early as 12 weeks of age

decreased circulating insulin level ( J:215526 )

• mice exhibit lower plasma insulin levels in fasted, refed, and random-fed states, although not significant in the latter state

impaired glucose tolerance ( J:215526 )

• mice show impaired glucose tolerance that worsens progressively with age during intraperitoneal glucose tolerance tests, without changes to peripheral insulin sensitivity

endocrine/exocrine glands

abnormal pancreatic beta cell differentiation ( J:215526 )

• as mice age to 12 months, beta cell dedifferentiation occurs

abnormal pancreatic beta cell physiology ( J:215526 )

• beta cells are metabolically inflexible such that they preferentially utilize lipids rather than carbohydrates as an energy source resulting in impaired ATP generation and reduced calcium-dependent insulin secretion

• glucose oxidation to carbon dioxide is impaired by about 50% in islets at most glucose concentrations

• palmitate oxidation by islets in the presence of basal glucose is 2-fold higher and nearly 2.5-fold higher in high glucose

• glycerolipid synthesis of islets is normal at low glucose concentrations but fails to increase at elevated glucose concentrations, resulting in lower conversion of palmitate into diacylglycerides and triglycerides indicating that beta cells appear to be locked in a lipid oxidative state

• membrane depolarization-induced calcium influx in response to rising glucose concentrations is lower in beta cells

decreased insulin secretion ( J:215526 )

• mice are impaired in secreting insulin in response to the ATP-dependent K-channel blocker, glibenclamide, and to the depolarizing agent, I-arginine

• beta cells exhibit reduced calcium-dependent insulin secretion

• purified islets show lower insulin secretion in response to the sulfonylurea glibenclamide, the PKC activator PMA, and the L-type Ca channel activator Bay-K8644

cellular

abnormal pancreatic beta cell differentiation ( J:215526 )

• as mice age to 12 months, beta cell dedifferentiation occurs

abnormal mitochondrial physiology ( J:215526 )

• islets show a decrease in glucose-induced oxygen consumption

• raising glucose levels does not increase ATP turnover in purified islets as in control islets

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
maturity-onset diabetes of the young		DOID:0050524	OMIM:606391	J:215526