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Allele Symbol Allele Name Allele ID |
Tg(Ins2-cre)23Herr transgene insertion 23, Pedro Luis Herrera MGI:2387567 |
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| Summary |
40 genotypes
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
 N |
• beta cell do not transdifferentiate into alpha cells unlike in Nkx2-2tm2.1Suss homozygotes
|
|
|
• at E18.5
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|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• Cx36 channels are non functional as determined by "tracer" studies (beta cells are uncoupled)
|
|
• increased basal secretion of insulin
|
| N |
• normal in vivo tolerance for acute glucose load
• normal responsiveness to high glucose levels (16mM)
|
|
• increased basal secretion of insulin
|
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• do not respond to physiological concentrations of glucose
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
Abnormal glucose and insulin homeostasis in Ins2Akita/Ins2Akita and Ins2Akita/Ins2Akita Cebpbtm1.1Maka/Cebpbtm1.1Maka Tg(Ins2-cre)23Herr/0 but not Cebpbtm1.1Maka/Cebpbtm1.1Maka Tg(Ins2-cre)23Herr/0 mice.
|
• expression of apoptosis markers in the pancreas islet is decreased compared to in Ins2Akita homozygotes
|
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• mice exhibit improved beta cell mass compared to in Ins2Akita homozygotes
|
|
• pancreatic insulin levels are decreased compared to in wild-type mice
• however, pancreatic insulin content is 8-fold higher than in Ins2Akita homozygotes
|
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• pancreatic insulin levels are decreased compared to in wild-type mice
• however, pancreatic insulin content is 8-fold higher than in Ins2Akita homozygotes
|
|
• mice exhibit increased circulating glucose levels compared to in wild-type mice
• however, glucose serum level are increased compared to in Ins2Akita homozygotes
|
|
• mice exhibit decreased circulating glucose levels compared to in wild-type mice
• however, insulin serum level are increased compared to in Ins2Akita homozygotes
|
|
• expression of apoptosis markers in the pancreas islet is decreased compared to in Ins2Akita homozygotes
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
Increased beta cell mass in Leprdb/Leprdb mice and Leprdb/Leprdb Cebpbtm1.1Maka/Cebpbtm1.1Maka Tg(Ins2-cre)23Herr/0 mice
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• pancreatic islet cell apoptosis is decreased compared to in Leprdb homozygotes
|
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• compared to in Leprdb homozygotes
|
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• hyperglycemia develops more slowly and is ameliorated compared to in Leprdb homozygotes
|
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• at 12 weeks, plasma insulin levels are increased compared to in Leprdb homozygotes and wild-type mice
|
|
• pancreatic islet cell apoptosis is decreased compared to in Leprdb homozygotes
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice exhibit normal islet architecture, alpha cell number, total pancreas mass and beta cell cell death
• mice fed a high fat diet exhibit normal islet morphometry
|
|
• increased beta cell size and total number of granules
• however, the number of docked granules is normal
|
| N |
• mice fed a high fat diet exhibit normal glucose tolerance and energy expenditure
|
|
• at 10 weeks without altered insulin sensitivity
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|
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• random glucose compared with Lepob homozygotes
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• compared with Lepob homozygotes
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• after glucose challenge
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• after glucose challenge compared with Lepob homozygotes
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| N |
• mice exhibit normal numbers of glucagon expressing cells and pancreatic mass
|
|
• not as severe as in Lepob homozygotes
|
|
• not as severe as in Lepob homozygotes
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|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• 41.5% of mice developed insulinomas by 6 months of age and by 10 months, 100% of mutants have advanced insulinomas (carcinomas)
|
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• hyperplastic islets as early as 2 months of age, which progresses with aging
|
|
• 41.5% of mice developed insulinomas by 6 months of age and by 10 months, 100% of mutants have advanced insulinomas (carcinomas)
|
|
• glucose levels decreased after 8 months of agae, as tumorigenesis progressed
|
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• insulin levels increased starting at 4 months of age and continued to increase with age
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| multiple endocrine neoplasia type 1 | DOID:10017 |
OMIM:131100 |
J:85133 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
Higher plasma insulin levels and increased pancreatic insulin content in Cebpbtm1.1Maka/Cebpbtm1.1Maka Tg(Ins2-cre)23Herr/0 mice
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• pancreas insulin levels are higher than in Cebpbtm1.1Maka homozygotes
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| N |
• mice exhibit normal circulating insulin and glucose levels
|
|
• pancreas insulin levels are higher than in Cebpbtm1.1Maka homozygotes
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|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
Glud1tm1.1Pma/Glud1tm1.1Pma Tg(Ins2-cre)23Herr/0 mice have impaired insulin secretion
|
• 67% of islets are disorganized compared to 30% in wild-type mice
• however, pancreas insulin content is normal
|
|
• glucose-stimulated insulin secretion in the pancreas is decreased 48% during the first phase and 37% in the second phase compared to in similarly treated wild-type mice
• isolated islets exhibit a 68% reduction in the first phase and 49% reduction in the second phase of glucose-stimulated insulin secretion compared to similarly treated wild-type islets
• insulin secretion is decreased 38% 15 minutes following intraperitoneal glucose injection at 2 months of age
• however, fasted insulin levels are normal and ectopic expression of Glud1 in islet cells restores normal glucose-stimulated insulin secretion
|
| N |
• despite disruptions in stimulated insulin secretion, mice exhibit normal growth
|
| N |
• despite disruptions in stimulated insulin secretion, mice exhibit normal glucose homeostasis and age-dependent insulin resistance
|
|
• glucose-stimulated insulin secretion in the pancreas is decreased 48% during the first phase and 37% in the second phase compared to in similarly treated wild-type mice
• isolated islets exhibit a 68% reduction in the first phase and 49% reduction in the second phase of glucose-stimulated insulin secretion compared to similarly treated wild-type islets
• insulin secretion is decreased 38% 15 minutes following intraperitoneal glucose injection at 2 months of age
• however, fasted insulin levels are normal and ectopic expression of Glud1 in islet cells restores normal glucose-stimulated insulin secretion
|
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• 55% when in a fed state
|
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• glutamate dehydrogenase activity is reduced by 60% in islets compared to in wild-type mice
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|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• beta-cells show elevated mitochondrial membrane potential (hyperpolarization) under basal conditions that collapses upon elevated glucose exposure; this loss of mitochondrial membrane potential indicates an inability to maintain the mitochondrial electron gradient under high glucose
• acute treatment with rapamycin mitigates the hyperpolarization seen in beta-cells and the loss of mitochondrial membrane potential with high glucose exposure is rescued
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|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• fed blood glucose concentration were significantly reduced relative to that in Irs2tm1Mfw homozygous mice, though remained slightly higher than normal control
|
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• both fasting and fed insulin levels were higher than in wild-type mice similar to the level found in Irs2tm1Mfw homozygous mice
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|
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• in 7 day and 1, but not 3, month old mice
|
|
• 2-fold increase in blood vessel density in insulin-positive areas
• however, beta cell organization is normal
|
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• at 3 months
• 2.5-fold at 3 to 4 months
|
|
• glucose-stimulated at 4, but not 1, months
|
|
• glucose-stimulated at 4, but not 1, months
|
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• at 3 to 4 months
|
|
• 2-fold increase in blood vessel density in insulin-positive areas
|
| N |
• mice exhibit normal body weight
|
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• in 7 day and 1, but not 3, month old mice
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|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
Reduction in islet insulin content in Gt(ROSA)26Sortm1(Kcnj11*V59M)Fmas/Gt(ROSA)26Sor+ Tg(Ins2-cre)23Herr/0 mice
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• the percentage of islet area occupied by beta cells is somewhat decreased
|
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• alpha cells are not confined to the islet mantle
|
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• relative increase in the number of alpha cells
|
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• some of the beta cells are irregularly shaped
|
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• the percentage of beta cells is decreased
|
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• reduction in islet insulin content by 5 weeks of age but not at 5 days of age
• K(sub)ATP currents in beta cells are larger compared to control cells an inhibition of these currents by glucose is impaired
• glucose induced calcium responses of beta cells are impaired
|
|
• impairment in basal and both first and second-phase glucose induced insulin secretion
|
|
• impairment in basal and both first and second-phase glucose induced insulin secretion
|
|
• elevated glucose levels develop by P3
• overt diabetes develops by 5 weeks of age
|
|
• slightly elevated
|
|
• seen in males by 4 to 6 weeks of age
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| permanent neonatal diabetes mellitus | DOID:0060639 |
OMIM:606176 |
J:144715 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• in a fed state from 4 until 32 weeks of age
|
|
• after 36 week of age, mice exhibit increased plasma glucose levels compared to wild-type mice
• however, treatment of mice with rapamycin prevents the development of hyperglycemia
|
|
• after 40 weeks of age
• however, treatment of mice with rapamycin prevents the decrease in plasma insulin levels
|
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• at 12 weeks of age until 32 weeks
|
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• at 8 weeks of age
|
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• at 8 weeks of age
|
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• at 40 weeks of age, islet cell density is decreased compared to in wild-type mice
|
|
• at 6 weeks of age, beta cell mass and size is increased compared to in wild-type mice
• at 40 weeks of age, beta cell mass decreases to lower than normal
• however, the number of beta cells is normal
• beta cell size is not decreased after 40 weeks of age
|
|
• at 40 weeks of age, beta cell number is decreased due to apoptosis
• however, treatment of mice with rapamycin prevents the decrease in beta cell mass observed at 40 weeks of age
|
|
• at 6 weeks of age
|
|
• after 48 weeks of age
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|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• double mutants have improved blood glucose levels compared to Pdk1-deficient mice; glucose levels of 200-300 mg/dl are maintained in double mutants at 20-24 weeks
|
|
• plasma insulin level is significantly higher in double mutants compared to Pdk1-deficient mice
|
|
• Foxo-haploinsufficiency results in a significant increase in beta cell number in double mutants
|
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• insulin content of the pancreas in double mutant mice is 6-fold higher than in Pdk1-deficient mice; number of proliferating beta cells is much greater in double mutants compared to Pdk1-null mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• undetectable at P0
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• decreased perinatal beta cell proliferation without an increase in apoptosis
• however, adult beta cell proliferation is normal and mice exhibit S-961-induced proliferation
|
|
• without a change in pancreas size
|
|
• at 9 weeks of age when fed standard chow or when fed a high-fat diet
|
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• following tolbutamide treatment, P0 pancreas fails to exhibit an increase in serotonin secretion unlike control pancreas
|
|
• decreased perinatal beta cell proliferation without an increase in apoptosis
• however, adult beta cell proliferation is normal and mice exhibit S-961-induced proliferation
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• all male knockouts die between 12 and 24 weeks of age from uncontrolled diabetes
|
|
• after 8 weeks of age, mutant body weights increase at a lower rate compared to control
|
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• mutants exhibit hyperglycemia with blood glucose levels greater than 500 mg/dl by 12-16 weeks of age
|
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• at 12 weeks of age, plasma insulin in the fed state is lower in mutants; by 20 weeks of age, it is close to the lower detection limit
|
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• beta cells proliferate much less in islets of null mice; proliferation is ~50% lower at 4 weeks and ~75% lower at 8 weeks
|
|
• at 4 weeks of age, size of islets is smaller than in controls; islet density is lower than in controls and is only ~40% that of controls at 16 weeks
|
|
• insulin content of the pancreas in null mice is lower than in control mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• at age 8 weeks
|
|
• 70% reduction
|
|
• at age 8 weeks
|
|
• 70% reduction
|
|
• 50% reduction
|
| N |
• normal body weight
|
|
• increased proinsulin levels
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|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
 |
• reduced protein synthesis in pancreatic islets
|
|
N |
• normal glucose-induced insulin secretion (GSIS) from isolated pancreatic islets on regular chow and after 12 weeks on high-fat diet (HFD)
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|
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• at age 16 weeks on regular chow and after 12 weeks on high-fat diet (HFD)
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|
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• low pancreatic insulin level at age 16 weeks on regular chow and after 12 weeks on high-fat diet (HFD)
|
|
N |
• normal body weight on regular chow and after 12 weeks on high-fat diet (HFD)
|
|
N |
• normal blood glucose level on regular chow and after 12 weeks on high-fat diet (HFD)
• normal glucose-induced insulin secretion (GSIS) from isolated pancreatic islets on regular chow and after 12 weeks on high-fat diet (HFD)
|
|
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• reduced protein synthesis in pancreatic islets
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|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• beta cells are reprogrammed to alpha cells
|
|
• beta cells are reprogrammed to alpha cells
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• 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
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|
• 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
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|
• mice exhibit hyperglycemia in the fasted, refed, and random-fed states as early as 12 weeks of age
|
|
• mice exhibit lower plasma insulin levels in fasted, refed, and random-fed states, although not significant in the latter state
|
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• mice show impaired glucose tolerance that worsens progressively with age during intraperitoneal glucose tolerance tests, without changes to peripheral insulin sensitivity
|
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• as mice age to 12 months, beta cell dedifferentiation occurs
|
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• 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
|
|
• 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
|
|
• as mice age to 12 months, beta cell dedifferentiation occurs
|
|
• 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 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• median survival is 69 weeks
|
| N |
• islet proliferation is normal
|
|
• atypia in 2 of 16 mice at 8 months of age
|
|
• in 1 of 8 mice at 2 months of age
• in 3 of 16 mice at 8 months of age
|
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• in 2 of 21 mice at 10 months of age
|
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• in 2 of 21 mice at 10 months of age
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• median survival is 45 weeks
|
|
• in 5 of 10 mice at 2 months of age
• in 4 of 9 mice at 4 months of age
|
|
• in 5 of 10 mice at 2 months of age
• in 4 of 9 mice at 4 months of age
|
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• in 3 of 16 mice at 8 months of age
• in all mice at 10 months of age
|
|
• islet proliferation is increased compared to in control mice
|
|
• in 3 of 16 mice at 8 months of age
• in all mice at 10 months of age
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• undetectable at P0
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• mice exhibit beta to alpha cell transdifferentiation
|
|
• mice exhibit beta to alpha cell transdifferentiation
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• at 24 weeks of age, but not at 16, have lower weights
|
|
• both fasting and fed glucose:insulin ratios are elevated
• develop diabetes
|
|
• impaired glucose-stimulated insulin secretion
|
|
• progressive development of hyperglycemia
• fed glucose concentrations are higher at 24 weeks of age, but mean fasted glucose concentrations are normal
|
|
• fasting insulin levels are significantly reduced at 12 weeks of age and fed insulin levels are reduced at 12 and 24 weeks of age
|
|
• progressive glucose intolerance, with mild glucose intolerance 60 min after glucose injection by 12 weeks of age and significant glucose intolerance 30, 60, and 120 min after glucose injection by 16 weeks of age
|
|
• 2.5-fold increase in caspase 3-positive nuclei in islets, indicating increased apoptosis
|
|
• reduction of beta cell mass is seen at 24 weeks of age
|
|
• reduction of the beta cell:pancreas ratio is seen at 24 weeks of age
|
|
• asymmetry and disruption of islet architecture is apparent at 12 weeks of age, with an alteration of the ratio of beta to non-beta cells within the islet
|
|
• secretory granules are reduced in beta cells and majority of cells exhibit abundant dilated ER, indicating increased ER stress in beta cells
|
|
• impaired glucose-stimulated insulin secretion
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| Wolfram syndrome 1 | DOID:0110629 |
OMIM:222300 |
J:104712 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• body weight of neonates is normal
• growth retardation after birth
• body weight is 50% of controls by three months
• pancreas weight/body weight ratio is normal
|
|
• by 6 weeks of age loss of response to injected glucose
|
|
• dramatic lowering of glucose levels after insulin injection
|
|
• blood glucose is over 200mg/dl within 2 weeks of birth
• progressively increases to over 600mg/dl by 2 months
|
|
• levels become undetectable as diabetes becomes more severe
|
|
• significantly elevated early in diabetes development
|
|
• plasma insulin levels decrease with time
|
|
• alpha cells infiltrate center of islets after the onset of diabetes
|
|
• are lost as diabetes becomes more severe
|
|
• beta cells are lost as diabetes develops
|
|
• number of islet is reduced by 50% early in diabetes and by more than 90% later
|
|
• islet mass decreases to about 10% of controls
|
|
• pancreas weight relative to controls becomes reduced over time
• pancreas weight/body weight ratio is normal
|
|
• insulin content of pancreas drops to about 10% of control levels
|
|
• by 6 weeks of age loss of response to injected glucose
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| permanent neonatal diabetes mellitus | DOID:0060639 |
OMIM:606176 |
J:146650 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• streptozotocin-treated mice develop hyperglycemia as in wild-type mice
|
|
• streptozotocin-treated mice exhibit increased glucose serum levels that is not as severe as in wild-type mice
|
|
• streptozotocin-treated mice exhibit reduced apoptosis and elevation of glucose serum levels compared with controls but not as much as in double null mice
|
|
• streptozotocin-treated mice exhibit reduced apoptosis compared with controls but not as much as in double null mice
|
|
• streptozotocin-treated mice exhibit reduced apoptosis compared with controls but not as much as in double null mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice exhibit normal glucose homeostasis with no differences in body weight, non-fasting and fasting glycemia, non-fasting plasma insulin, and glucose tolerance observed in males at 4, 8 and 14 weeks of age, or in glucose tolerance observed in females at 13-14 weeks of age relative to gender- and age-matched controls
• aged male mice show normal body weight and glucose tolerance at 44 weeks of age
• islets isolated from 7-month old male mice show normal glucose-stimulated insulin secretion with no differences in insulin content relative to control values
• glucose metabolism is relatively normal even after exposure to a high fat diet or a high branched chain amino acid (BCAA) diet for 8 weeks
|
|
• after long-term exposure (16 weeks) to a BCAA diet, mice exhibit slightly impaired glucose tolerance relative to controls; however, no significant differences in plasma insulin levels, non fasting glycemia, beta cell mass or islet morphology are observed
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• impaired mitophagy flux in pancreatic beta cells
|
|
• reduction in the number of LC3+ puncta co-stained with the lysosome-specific dye Lysotracker (reflecting the presence of autophagolysosomes) in pancreatic beta cells from 18-day old islets
|
|
• impaired glucose-stimulated insulin secretion in pancreatic islets isolated from both 18-day and 35-day old mice
• impaired alpha-ketoisocaproic acid (alpha-KIC)-stimulated insulin secretion in pancreatic islets isolated from both 18-day and 35-day old mice
• normal potassium chloride (KCl)-stimulated insulin secretion in pancreatic islets isolated from both 18-day and 35-day old mice
• normal islet insulin content in 18-day old mice
|
|
• increased plasma glucose level in the freely-fed state as early as 18 days of age
|
|
• progressive hyperglycemia ultimately leading development of diabetes
• >2-fold elevation of plasma glucose level in the freely-fed state at 50 days of age
|
|
• 75% reduction of plasma insulin level in the freely-fed state at 50 days, but not at 18 days, of age
|
|
• increased protein abundance of cleaved-caspase 9, but not cleaved-caspase 3, in pancreatic islets
• however, the ratio of pro-apoptotic Bax to anti-apoptotic Bcl-2 (BAX:BCL-2) is reduced, suggesting that protective mechanisms may be activated in young mice
|
|
• increased surface density of docked large dense core vesicles (LDCV) in which insulin is packaged in pancreatic beta cells from 18-day old islets
• however, normal volume density of LDCV which reflects total number of insulin granules
|
|
• reduced beta cell mass in diabetic mice at 7 weeks of age
|
|
• reduced islet density in diabetic mice at 7 weeks of age
|
|
• impaired glucose-stimulated insulin secretion in pancreatic islets isolated from both 18-day and 35-day old mice
• impaired alpha-ketoisocaproic acid (alpha-KIC)-stimulated insulin secretion in pancreatic islets isolated from both 18-day and 35-day old mice
• normal potassium chloride (KCl)-stimulated insulin secretion in pancreatic islets isolated from both 18-day and 35-day old mice
• normal islet insulin content in 18-day old mice
|
|
• increased percentage of mitochondria with vesicular and swollen morphology in pancreatic beta cells isolated from 18-day old islets
|
|
• decreased expression of mitochondrial encoded genes and reduced mitochondrial DNA content in pancreatic islets
|
|
• increased percentage of swollen mitochondria in pancreatic beta cells isolated from 18-day old islets
|
|
• impaired mitophagy flux in pancreatic beta cells
|
|
• reduction in the number of LC3+ puncta co-stained with the lysosome-specific dye Lysotracker (reflecting the presence of autophagolysosomes) in pancreatic beta cells from 18-day old islets
|
|
• increased protein abundance of cleaved-caspase 9, but not cleaved-caspase 3, in pancreatic islets
• however, the ratio of pro-apoptotic Bax to anti-apoptotic Bcl-2 (BAX:BCL-2) is reduced, suggesting that protective mechanisms may be activated in young mice
|
|
• increased mRNA expression of ER stress markers (Ddit3 and Cebpb) in pancreatic islets isolated from both 18-day old mice
|
|
• after stimulation with 16.7 mM glucose, maximal decrease in TMRM fluorescence intensity is reduced by 40% in pancreatic islets isolated from 18-day old mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
|
• impaired glucose-stimulated as well as alpha-KIC- and KCl-stimulated insulin secretion in pancreatic islets isolated from 7-month old mice
• decreased pancreatic insulin content per weight of pancreas at 7 months of age
• however, islet insulin content is unchanged
|
|
|
• reduced plasma insulin level in non-fasted mice at 7 months of age
|
|
|
• increased total area under the curve (AUC) for plasma glucose (with a tendency toward impaired acute insulin response) during i.v. glucose tolerance testing in mice at 6 months of age
|
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• impaired glucose-stimulated as well as alpha-KIC- and KCl-stimulated insulin secretion in pancreatic islets isolated from 7-month old mice
• decreased pancreatic insulin content per weight of pancreas at 7 months of age
• however, islet insulin content is unchanged
|
|
|
• after stimulation with 16.7 mM glucose, maximal decrease in TMRM fluorescence intensity is reduced by 64% in pancreatic islets isolated from 7-month old mice
|
|
|
• increased basal levels of ATP in pancreatic islets isolated from 7-month old mice
• however, upon stimulation with 22 mM glucose, islet ATP content is lower than that in control islets
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice exhibit normal glucose tolerance when fed standard chow or a high-fat diet
|
|
• streptozotocin-treated mice exhibit increased glucose serum levels that is not as severe as in wild-type mice
• however, mice treated with STZ and fed a high-fat diet exhibit a normal hyperglycemic response
|
|
• mice treated with streptozotocin exhibit a mild increase in beta cell apoptosis and glucose serum levels compared with similarly treated wild-type mice
• however, mice treated with STZ and fed a high-fat diet exhibit a normal hyperglycemic response
|
|
• streptozotocin-treated mice exhibit reduced apoptosis compared with controls but not as much as in double null mice
|
| N |
• mice exhibit normal weight when fed standard chow or a high-fat diet
|
|
• streptozotocin-treated mice exhibit reduced apoptosis compared with controls but not as much as in double null mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• young mice exhibit reduced insulin release following glucose administration
• islets fail to secrete insulin in response to leucine in 5-week-old mice
• islets show reduced glucose-stimulated first- and second-phase insulin secretion in 5-week-old mice
• exendin-4-augmented insulin secretion is slightly impaired in islets, while potassium chloride-induced insulin secretion is not altered, indicating an intact insulin secretion mechanism downstream of mitochondrial metabolism
• rapamycin treatment enhances insulin secretion under high glucose with no changes at resting glucose level
|
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• mice show increased fasting glucose levels at 20 weeks of age
|
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• mice show a progressive rise in fed glucose levels; while young mice are normoglycemic and normoinsulinemic until 6 weeks, hyperglycemia is evident by 10 weeks
|
|
• mice develop insulinopenic diabetes at pubertal age
• mice show low fasting serum insulin levels at 20 weeks of age
|
|
• young mice are mildly glucose intolerant with unchanged insulin sensitivity when challenged by intraperitoneal glucose tolerance test
• acute treatment with rapamycin marginally improves glucose intolerance
|
|
• by 20 weeks, but not at 5 weeks, islets exhibit large membraned vacuoles containing engulfed organelles, including insulin granules and damaged mitochondria
|
|
• mice show a progressive reduction in beta-cell mass without alterations in alpha-cell mass
|
|
• islets show nearly undetectable mitochondrial electron transport chain complex CII activity, elevated succinate levels, increase in protein lysine succinylation and increase in expression of the dessucinylation enzyme SIRT5
• islets show reduced basal and glucose-stimulated respiration and reduced maximal respiration and spare reserve capacity
• islets show a more than 50% reduction in ATP synthase-related oxygen consumption rate following oligomycin injection
• glucose-exposed islets fail to increase the ATP to ADP ratio
• islets show accumulation of succinate, with no change in fumarate levels, fatty acid intermediates, nucleic acid building blocks and precursors of protein synthesis despite a deficit of free amino acid pool
|
|
• homeostatic model assessment of beta-cell function as a percentage is reduced
• glucose-stimulated beta-cell replication is impaired in islets of prediabetic 5-week-old mice
|
|
• young mice exhibit reduced insulin release following glucose administration
• islets fail to secrete insulin in response to leucine in 5-week-old mice
• islets show reduced glucose-stimulated first- and second-phase insulin secretion in 5-week-old mice
• exendin-4-augmented insulin secretion is slightly impaired in islets, while potassium chloride-induced insulin secretion is not altered, indicating an intact insulin secretion mechanism downstream of mitochondrial metabolism
• rapamycin treatment enhances insulin secretion under high glucose with no changes at resting glucose level
|
|
• islets show reduced basal and glucose-stimulated respiration and reduced maximal respiration and spare reserve capacity
|
|
• islets show nearly undetectable mitochondrial electron transport chain complex CII activity, elevated succinate levels, increase in protein lysine succinylation and increase in expression of the dessucinylation enzyme SIRT5
|
Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| type 2 diabetes mellitus | DOID:9352 |
OMIM:125853 OMIM:601283 OMIM:601407 OMIM:603694 OMIM:608036 |
J:326592 | |
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• plasma insulin levels are increased at 2 min and 5 min of glucose challenge, but not at later 15 and 30 min time points
• mice fed a high-fat diet exhibit increased insulin secretion
• however, insulin sensitivity and insulin content remain unchanged and high-fat diet fed mice show unchanged intraperitoneal insulin tolerance test
|
|
• mice stressed with low-dose streptozotocin (STZ) injections display a greater increase in blood glucose levels than treated controls
• mice fed a high-fat diet and treated with a single dose of STZ exhibit higher blood glucose levels
• however, random-fed blood glucose levels in high-fat diet fed mice are similar to controls
|
|
• STZ-injected mice show a reduction in plasma insulin levels by about 40% after 18 days compared to controls
|
|
• mice fed a normal diet show augmented glucose tolerance
• mice fed a high-fat diet for 12 weeks exhibit improved intraperitoneal glucose tolerance
|
|
• mice treated with S961 for 3 days exhibit lower BrdU incorporation in beta cells, indicating a reduced proliferative capacity under oxidative/metabolic stress conditions
• mice show an approximate 2-fold increase in apoptosis in beta cells 3 days after the last STZ injection
|
|
• mice show an approximate 2-fold increase in apoptosis in beta cells 3 days after the last STZ injection
• islets ex vivo treated with cytokines and interferon gamma show increased apoptosis of beta cells
|
|
• STZ-injected mice show an approximate 2-fold lower beta cell mass after 18 days compared to controls
• mice fed a high-fat diet and treated with a single dose of STZ exhibit lower beta cell mass
• mice treated with the insulin receptor antagonist S961 for 3 days exhibit a lower pancreatic beta cell mass than controls
• however, beta cell mass and islet morphology are normal under basal conditions
|
|
• STZ-injected mice show a reduction in total pancreatic insulin content by about 70% after 18 days compared to controls
• mice fed a high-fat diet and treated with a single dose of STZ exhibit lower total insulin content
• mice treated with S961 for 3 days exhibit lower BrdU incorporation in beta cells, indicating less proliferation under oxidative/metabolic stress conditions
|
|
• mice show an approximate 2-fold increase in apoptosis in beta cells 3 days after the last STZ injection
• islets ex vivo treated with cytokines and interferon gamma show increased apoptosis of beta cells
|
|
• plasma insulin levels are increased at 2 min and 5 min of glucose challenge, but not at later 15 and 30 min time points
• mice fed a high-fat diet exhibit increased insulin secretion
• however, insulin sensitivity and insulin content remain unchanged and high-fat diet fed mice show unchanged intraperitoneal insulin tolerance test
|
|
• STZ-injected mice show a decrease in body weight by about 20% after 18 days compared to controls
• however, body weight of high-fat diet fed mice is similar to controls
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
• at P0 without an increase in apoptosis
• however, adult beta cell proliferation is normal
|
|
• at P0 and in adults without a change in pancreas weight
|
|
• in fasting mice and after glucose stimulation
|
|
• at P0 without an increase in apoptosis
• however, adult beta cell proliferation is normal
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mice exhibit normal P0 beta cell proliferation and beta cell mass
|
| N |
• mice produce normal serotonin (5-HT) levels at P0
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
|
N |
• mice survive longer than Huwe1tm1Wgu/Y Tg(Ins2-cre)23Herr mice
|
|
N |
• diabetic symptoms (serum glucose and insulin levels and glucose intolerance) observed in Huwe1tm1Wgu/Y Tg(Ins2-cre)23Herr mice are improved
|
|
|
• in fasting mice at 9 months but not as severe as in Huwe1tm1Wgu/Y Tg(Ins2-cre)23Herr mice
• in fed mice at 3, 6 and 9 months but not as severe as in Huwe1tm1Wgu/Y Tg(Ins2-cre)23Herr mice
|
|
N |
• islet organization is improved compared to in Huwe1tm1Wgu/Y Tg(Ins2-cre)23Herr mice
|
|
|
| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
Loss of pancreatic beta-cells in aged Huwe1tm1Wgu/Y Tg(Ins2-cre)23Herr/0 mice
|
|
• more than half mice died at less than 1 year of age due to severe diabetic symptoms
|
|
|
• in fasting and fed mice at 6 and 9 months of age
|
|
|
• progressive
|
|
|
• in fasting mice at 9 months
• in fed mice at 6 and 9 months
|
|
|
• at 3 and 6 months
|
|
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• at 6 months and worsening at 9 months
|
|
|
• at 6 months and worsening at 9 months, mice exhibit infiltration of alpha cells into the middle of islets unlike in wild-type mice
|
|
|
• enlarged bladder
|
|
|
• at 9 months
|
Mouse Genome Database (MGD), Gene Expression Database (GXD), Mouse Models of Human Cancer database (MMHCdb) (formerly Mouse Tumor Biology (MTB)), Gene Ontology (GO) |
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last database update 04/23/2024 MGI 6.23 |
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