Phenotypes Associated with This Genotype

Genotype
MGI:5707775

• Allelic Composition: Senp1^tm1Wami/Senp1^tm1Wami; Tg(Fabp4-cre)#Abel/0
• Genetic Background: B6.Cg-Senp1^tm1Wami Tg(Fabp4-cre)#Abel

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

adipose tissue

abnormal fat cell morphology ( J:228009 )

• peri-pancreatic adipocytes exhibit 1.8-fold smaller cell sizes with 2-3-fold more cell numbers than control adipocytes

• peri-pancreatic adipocytes express reduced differentiation markers

• gonadal and subcutaneous inguinal adipocytes show a smaller size at 14 weeks of age without increases in cell numbers

• mice fed a high-fat diet show an even more marked decrease in peri-pancreatic adipocyte cell size and increase in adipose cell numbers

decreased fat cell size ( J:228009 )

• peri-pancreatic adipocytes exhibit 1.8-fold smaller cell sizes

• gonadal and subcutaneous inguinal adipocytes show a smaller size at 14 weeks of age without increases in cell numbers

decreased total fat pad weight ( J:228009 )

• reduction in fat pad weight at 14 weeks of age

behavior/neurological

increased fluid intake ( J:228009 )

• increase in water consumption

• however, food consumption is similar to controls

cardiovascular system

myocarditis ( J:228009 )

• mice exhibit cardiac myocarditis at 14 weeks of age or older

endocrine/exocrine glands

abnormal pancreatic islet morphology ( J:228009 )

• structures of pancreatic islets are disrupted, with increased apoptosis of beta cells after onset of diabetes and more severe at later stages

decreased insulin secretion ( J:228009 )

• insulin secretion declines after 10 weeks of age

• glucose-stimulated insulin secretion from isolated islets is reduced

pancreas inflammation ( J:228009 )

• accumulation of white blood cells invading into islets

• CD8+ T and CD4+ T cells infiltrate into the islets by 12 weeks of age

• MCHII+CD11b+CD11c- macrophages, CD3e+ T cells and CD19+ B cells are increased in the pancreases of mutants

• macrophage infiltration into the pancreas by 14 weeks of age and these macrophages express high levels of proinflammatory cytokines

growth/size/body

decreased body weight ( J:228009 )

• lower body weight after onset of diabetes

homeostasis/metabolism

decreased insulin secretion ( J:228009 )

• insulin secretion declines after 10 weeks of age

• glucose-stimulated insulin secretion from isolated islets is reduced

hyperglycemia ( J:228009 )

• age-dependent increase in glucose levels

• high-fat diet accelerates hyperglycemia with onset at 8 weeks of age

decreased circulating insulin level ( J:228009 )

• basal and glucose-stimulated insulin levels are reduced

• high-fat diet causes further reduction of insulin levels

• however, insulin tolerance test shows similar insulin responses to controls

increased circulating ketone body level ( J:228009 )

• mice show increased beta-hydroxybutyrate levels in the blood

decreased circulating cholesterol level ( J:228009 )

• cholesterol levels, but not HDL or FFA, are slightly reduced after 18 weeks of age

• however, mice exhibit normal lipid profiles up to the age of 14 weeks, including total cholesterol, low-density lipoprotein, high-density lipoprotein, triglyceride and free fatty acid

decreased circulating triglyceride level ( J:228009 )

• triglyceride levels are slightly reduced after 18 weeks of age

increased circulating C-reactive protein level ( J:228009 )

• mice show increased C-reactive protein levels in the blood

impaired glucose tolerance ( J:228009 )

• mice develop glucose intolerance

insulin resistance ( J:228009 )

• liver insulin resistance is seen under basal conditions and is more pronounced under high-fat diet conditions

• high-fat diet induces insulin resistance to a greater extent than in controls

abnormal cytokine level ( J:228009 )

• peri-pancreatic adipose tissue expresses high levels of IL-6, TNF-alpha and IL-1 beta at 7 weeks of age

• peri-pancreatic adipose tissue adipocytes show increased levels of IL-6, TNF-alpha and IL-1 beta

• however, pancreatic T cells and pancreatic macrophages exhibit cytokine levels similar to controls

abnormal circulating cytokine level ( J:228009 )

• circulating proinflammatory cytokines IL-6, TNF-alpha and IL-1 beta, but not IFN-gamma, are elevated before the onset of diabetes at 7 weeks of age

• mice exhibit increased systemic cytokines at 14 weeks of age or older

• high-fat diet augments cytokine production in peri-pancreatic adipose tissue and disruption of islets

increased circulating interleukin-1 beta level ( J:228009 )

increased circulating interleukin-6 level ( J:228009 )

increased circulating tumor necrosis factor level ( J:228009 )

abnormal chemokine level ( J:228009 )

• the chemokine CCL5 is upregulated in pancreatic islets at 7 weeks of age before diabetes onset, while other chemokines such as CCL2, CCL21, CXCL19, and CXCL10, are weakly upregulated

immune system

myocarditis ( J:228009 )

• mice exhibit cardiac myocarditis at 14 weeks of age or older

pancreas inflammation ( J:228009 )

• accumulation of white blood cells invading into islets

• CD8+ T and CD4+ T cells infiltrate into the islets by 12 weeks of age

• MCHII+CD11b+CD11c- macrophages, CD3e+ T cells and CD19+ B cells are increased in the pancreases of mutants

• macrophage infiltration into the pancreas by 14 weeks of age and these macrophages express high levels of proinflammatory cytokines

increased circulating C-reactive protein level ( J:228009 )

• mice show increased C-reactive protein levels in the blood

abnormal cytokine level ( J:228009 )

• peri-pancreatic adipose tissue expresses high levels of IL-6, TNF-alpha and IL-1 beta at 7 weeks of age

• peri-pancreatic adipose tissue adipocytes show increased levels of IL-6, TNF-alpha and IL-1 beta

• however, pancreatic T cells and pancreatic macrophages exhibit cytokine levels similar to controls

abnormal circulating cytokine level ( J:228009 )

• circulating proinflammatory cytokines IL-6, TNF-alpha and IL-1 beta, but not IFN-gamma, are elevated before the onset of diabetes at 7 weeks of age

• mice exhibit increased systemic cytokines at 14 weeks of age or older

• high-fat diet augments cytokine production in peri-pancreatic adipose tissue and disruption of islets

increased circulating interleukin-1 beta level ( J:228009 )

increased circulating interleukin-6 level ( J:228009 )

increased circulating tumor necrosis factor level ( J:228009 )

abnormal chemokine level ( J:228009 )

• the chemokine CCL5 is upregulated in pancreatic islets at 7 weeks of age before diabetes onset, while other chemokines such as CCL2, CCL21, CXCL19, and CXCL10, are weakly upregulated

increased susceptibility to autoimmune diabetes ( J:228009 )

• Th1 (IFN-gamma+CD4+) and Th17 (IL-17+CD4+) effecter T-cell subsets are expanded while the regulatory T-cell subset (CD4+CD25+Foxp3+) is reduced in the pancreatic lymph nodes

• increase in activated dendritic cells in the lymph node of pancreases

• autoantigen NRP-V7-positive CD8+ T cells, targeting a peptide from islet-specific glucose-6-phosphatase catalytic subunit-related protein, are detected in the pancreatic lymph nodes and the spleen at 12 weeks of age

• prophylactic insulin therapy at the age of 5 weeks for 9 weeks partially ameliorates development of diabetes phenotypes including immune cells infiltration, beta-cell apoptosis and islet disruptions

• mice treated with intraperitoneal injection of NF-kappaB activation inhibitor II JSH-23 at 5 weeks of age ameliorates diabetes progression

increased anti-insulin autoantibody level ( J:228009 )

• mice have increased levels of insulin autoantibody in the blood

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
type 1 diabetes mellitus		DOID:9744	OMIM:222100	J:228009