C57BL/6J Diet-Induced Obesity (380050)

NONcNZO10/LtJ (004456)

TALLYHO/JngJ (005314)

B6 DIO

RCS-10

TH

·Diet-induced obesity when fed a 60 kcal% high fat diet

·Pre-diabetic fed blood glucose levels with glucose intolerance by 8 weeks of age

·Improved glucose tolerance and insulin resistance when treated with Rosiglitazone

·Pancreatic beta cell hypertrophy without islet atrophy

·Hyperinsulinemia, hyperleptinemia, leptin resistance, and hypertension

·Moderate diet-induced obesity without hyperphagia when fed a 27 kcal% (10-11% wt/wt) fat diet

·Males transition from impared glucose tolerance to stable non-fasting hyperglycemia by 10 weeks of age

·Moderately elevated plasma insulin, islets transition from hypertrophy and hyperplasia to atrophy by 24 weeks

·Elevated leptin and triglycerides

·Moderate obesity in both males and females

·Males are normoglycemic at weaning, become glucose intolerant by 4 weeks, and begin developing hyperglycemia by 10-14 weeks of age

·Males are hyperinsulinemic, exhibiting plasma insulin levels between 8-12 ng/ml by 8 weeks of age

·Both sexes develop pancreatic islet hypertrophy and hyperplasia

·Males have severe dyslipidemia, with elevated triglycerides, total cholesterol, HDL cholesterol, and free fatty acids

DIO tips

DIO appearance and care

·Mild glomerulosclerotic changes

· Males respond to high-dose Rosiglitazone with lower blood glucose and improved glucose  tolerance (The Jackson Laboratory, unpublished)

Phenotyping and  effects of rosiglitazone on DIO Mice 

Phenotype information for 004456

Phenotyping information and  effects of rosiglitazone for 005314

Collins et al. 2004;  Petro et al. 2004;  Rossmeisl  et al. 2003;  Van  Heek  et al. 1997;  Surwit  et al. 1995

Leiter  and  Reifsnyder  2004; 

Reifsnyder  and  Leiter  2002

Kim et al. 2001, 2005, 2006

KK.Cg-A^y/J (002468)

BTBR.V(B6)-Lep^ob/WiscJ (004824)

BKS.Cg-Lepr^db Nos3^tm1Unc/RhrsJ (008340)

KK-Ay, KKAy

BTBR obese

eNOS^-/- C57BLKS/J ^db

· Hyperphagia with moderate obesity

·Early, severe hyperglycemia and glucose intolerance

·Hyperinsulinemia and insulin resistance, with islet hypertrophy and hyperplasia

·Elevated HbA1c and microalbuminuria

· Hyperphagic, leading to significant obesity by 6 weeks of age

· Male and female homozygotes become diabetic by 6 and 8 weeks of age, respectively

· Severe hyperglycemia, with fasting plasma glucose levels of 400 mg/dl by 10 weeks of age

· Progressive hypertriglyceridemia, with higher blood triglycerides in males

· Early hypersecretion of insulin, then islets atrophy and mice become hypoinsulinemic

· Moderate systemic hypertension and rapidly progressive diabetic nephropathy

· Hyperphagic , becoming obese by four weeks of age

· Glucose intolerance with severe hyperglycemia by 8 weeks of age and transient hyperinsulinemia

· Severe islet atrophy causing hypoinsulinemia and death by 10 months of age

· Polydipsic, polyuric, increased gluconeogenic enzyme activity and increased metabolic efficiency

·Males develop diabetic glomerular nephritis and arteriosclerosis

·Early glomerular nephropathy by 8 weeks and histological characteristics of advanced diabetic nephropathy by 20-22 weeks

· Peripheral neuropathy, nephropathy, myocardial disease, and delayed wound healing

· Infertility (homozygous females); subfertility (homozygous males)

Phenotype information for 002468

Phenotype information for 004824

Phenotype information for 008340

Okazaki et al. 2002;  Asano et al. 2004;  Iwatsuka  et al. 1970; (Chang AY et al. 1986. The Upjohn colony of KKAy mice: a model of obese type II diabetes. In: Diabetes 1985. Serrano-Rios M, Lefebvre PJ (eds), Elsevier. Pp.466-70)

Lan et al. 2003;  Clee  et al. 2005;  Hudkins  et al. 2010

Zhao et al. 2006;  Hummel et al. 1966;  Like et al. 1970;  Norido  et al. 1984,  Wendt et al. 2003,  Giacomelli  et al. 1979,  Werner et al. 1994

MSNASH/PcoJ (030888)

MS-NASH

·Has an intact leptin pathway (similar to the human disease )

·Exhibits spontaneous obesity, dyslipidemia, rapid insulin resistance, high level of insulin secretion as hypersulinemia

·Develops liver steatosis leading to NAFLD/NASH

·Responds to anti-diabetic standard of care treatments e.g. Semaglutide (Ozempic^®) that results in a reduction of body weight, food intake, and blood glucose levels

Females do not exhibit the diabetic phenotype

Asgharpour et al., 2016, Peterson et al., 2017