RGD Reference Report - The Rab-GTPase activating protein, TBC1D1, is critical for maintaining normal glucose homeostasis and β-cell mass. - Rat Genome Database

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The Rab-GTPase activating protein, TBC1D1, is critical for maintaining normal glucose homeostasis and β-cell mass.

Authors: Paglialunga, Sabina  Simnett, Genevieve  Robson, Holly  Hoang, Monica  Pillai, Renjitha  Arkell, Alicia M  Simpson, Jeremy A  Bonen, Arend  Huising, Mark  Joseph, Jamie W  Holloway, Graham P 
Citation: Paglialunga S, etal., Appl Physiol Nutr Metab. 2017 Jun;42(6):647-655. doi: 10.1139/apnm-2016-0585. Epub 2017 Jan 31.
RGD ID: 150521607
Pubmed: PMID:28177704   (View Abstract at PubMed)
DOI: DOI:10.1139/apnm-2016-0585   (Journal Full-text)

Tre-2/USP6, BUB2, cdc16 domain family, member 1 (TBC1D1), a Rab-GTPase activating protein, is a paralogue of AS160, and has been implicated in the canonical insulin-signaling cascade in peripheral tissues. More recently, TBC1D1 was identified in rat and human pancreatic islets; however, the islet function of TBC1D1 remains not fully understood. We examined the role of TBC1D1 in glucose homeostasis and insulin secretion utilizing a rat knockout (KO) model. Chow-fed TBC1D1 KO rats had improved insulin action but impaired glucose-tolerance tests (GTT) and a lower insulin response during an intraperitoneal GTT compared with wild-type (WT) rats. The in vivo data suggest there may be an islet defect. Glucose-stimulated insulin secretion was higher in isolated KO rat islets compared with WT animals, suggesting TBC1D1 is a negative regulator of insulin secretion. Moreover, KO rats displayed reduced β-cell mass, which likely accounts for the impaired whole-body glucose homeostasis. This β-cell mass reduction was associated with increased active caspase 3, and unaltered Ki67 or urocortin 3, suggesting the induction of apoptosis rather than decreased proliferation or dedifferentiation may account for the decline in islet mass. A similar phenotype was observed in TBC1D1 heterozygous animals, highlighting the sensitivity of the pancreas to subtle reductions in TBC1D1 protein. An 8-week pair-fed high-fat diet did not further alter β-cell mass or apoptosis in KO rats, suggesting that dietary lipids per se, do not lead to a further impairment in glucose homeostasis. The present study establishes a fundamental role for TBC1D1 in maintaining in vivo β-cell mass.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Tbc1d1Ratnegative regulation of insulin secretion involved in cellular response to glucose stimulus  IMP  RGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
SD-Tbc1d1Tn(sb)1FkhRatabnormal endocrine pancreas physiology inducesIMPcontrolled fat content dietcompared to Wild type RGD 
Tbc1d1Ratabnormal endocrine pancreas physiology inducesIMPcontrolled fat content dietcompared to Wild type RGD 
Tbc1d1Tn(sb)1FkhRatabnormal endocrine pancreas physiology inducesIMPcontrolled fat content dietcompared to Wild type RGD 
SD-Tbc1d1Tn(sb)1FkhRatdecreased circulating insulin level inducesIMPglucose and fasting and controlled fat content dietcompared to Wild typeRGD 
Tbc1d1Ratdecreased circulating insulin level inducesIMPglucose more ...compared to Wild typeRGD 
Tbc1d1Tn(sb)1FkhRatdecreased circulating insulin level inducesIMPglucose more ...compared to Wild typeRGD 
SD-Tbc1d1Tn(sb)1FkhRatdecreased fasting circulating glucose level inducesIMPinsulin and controlled fat content dietcompared to Wild type and heterozygousRGD 
Tbc1d1Ratdecreased fasting circulating glucose level inducesIMPinsulin and controlled fat content dietcompared to Wild type and heterozygousRGD 
Tbc1d1Tn(sb)1FkhRatdecreased fasting circulating glucose level inducesIMPinsulin and controlled fat content dietcompared to Wild type and heterozygousRGD 
SD-Tbc1d1Tn(sb)1FkhRatdecreased insulin secretion inducesIMPdiazoxide and glucose and potassium chloride solutioncompared to Wild type RGD 
Tbc1d1Ratdecreased insulin secretion inducesIMPdiazoxide more ...compared to Wild type RGD 
Tbc1d1Tn(sb)1FkhRatdecreased insulin secretion inducesIMPdiazoxide more ...compared to Wild type RGD 
SD-Tbc1d1Tn(sb)1FkhRatdecreased pancreatic beta cell mass inducesIMPcontrolled fat content dietcompared to Wild type RGD 
Tbc1d1Ratdecreased pancreatic beta cell mass inducesIMPcontrolled fat content dietcompared to Wild type RGD 
Tbc1d1Tn(sb)1FkhRatdecreased pancreatic beta cell mass inducesIMPcontrolled fat content dietcompared to Wild type RGD 
SD-Tbc1d1Tn(sb)1FkhRatincreased apoptosis  IMP  RGD 
Tbc1d1Ratincreased apoptosis  IMP  RGD 
Tbc1d1Tn(sb)1FkhRatincreased apoptosis  IMP  RGD 
Crl:CD(SD)Ratincreased circulating insulin level inducesIAGPglucose and fasting and controlled fat content diet RGD 
SD-Tbc1d1Tn(sb)1FkhRatincreased fasting circulating glucose level inducesIMPglucose and controlled fat content dietcompared to Wild typeRGD 
Tbc1d1Ratincreased fasting circulating glucose level inducesIMPglucose and controlled fat content dietcompared to Wild typeRGD 
Tbc1d1Tn(sb)1FkhRatincreased fasting circulating glucose level inducesIMPglucose and controlled fat content dietcompared to Wild typeRGD 
Objects Annotated

Genes (Rattus norvegicus)
Tbc1d1  (TBC1 domain family member 1)
Tbc1d1Tn(sb)1Fkh  (TBC1 domain family member 1; Sleeping Beauty induced mutant 1, Fkh)

Strains
Crl:CD(SD)  (NA)
SD-Tbc1d1Tn(sb)1Fkh  (NA)


Additional Information