Sirtuin 3 (Sirt3) impairs glucose stimulated insulin secretion (GSIS) in pancreatic beta cells
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AbstractBackground and aims
Impairment of glucose induced insulin secretion (GSIS), a hallmark of type 2 diabetes, can be induced by a series of pathological conditions such as hyperglycemia and hyperlipidemia. Normal mitochondrial function of pancreatic beta cells is essential for GSIS. SIRT3 is a mitochondrial protein deacetylase which regulates several metabolic pathways including glucose metabolism and fatty acid oxidation. We aimed to investigate the protective role of Sirt3 in regulating GSIS in pancreatic beta cells.

Materials and methods
We generated pancreatic beta cell specific Sirt3 knockout (Sirt3βKO; Sirt3flox/flox; Ins1Cre/+) mice to compare with wild type (WT; Sirt3flox/flox) on the glycemic responses using beta cell specific Ins1 (insulin)-promoter driven Cre-mediated deletion of floxed Sirt3 allele. Both Sirt3βKO and WT mice were fed with high fat diet (HFD, 60Êl fat) and standard diet (STD) for 32 weeks. Fasting blood glucose (FBG) and body weight were measured every 4 weeks. Oral glucose tolerance test (OGTT) and insulin level were measured after the mice became diabetic (FBG of HFD mice above 7 mmol/l). Islets were isolated from these four groups for RNA sequencing (RNA-Seq) to explore the underlying mechanisms linking Sirt3 and beta cells function.

We first confirmed specific deletion by showing suppression of Sirt3 protein expression in β cells without any alternation in other tissues including liver, lung and heart in Sirt3βKO mice. Both Sirt3βKO and WT littermates were fed with HFD for 32 weeks to generate diabetic mice with impaired insulin secretion. The FBG and body weight of HFD mice, increased steadily between two genotypes compared with STD mice. After 16th week, FBG in Sirt3βKO+HFD group started to increase faster than WT+HFD group while FBG levels were similar in STD fed mice. More importantly, glucose tolerance was further impaired in HFD fed Sirt3βKO mice than HFD fed WT mice. Insulin levels measured during OGTT showed that impairment of GSIS was exacerbated in HFD fed Sirt3βKO mice than HFD fed WT mice. In addition, the insulin peak of Sirt3βKO+HFD mice appeared to be delayed than WT+HFD mice. RNA-Seq data from islets of these mice revealed that the 5-HT (serotonin) synthesis pathway might be activated in Sirt3βKO mice islets, which was characterized by elevated tryptophan hydroxylase 1 (Tph1) and tryptophan hydroxylase 2 (Tph2) expression. Since serotonin synthesis might be related to insulin secretion, further mechanistic studies are in progress to examine how Sirt3 inhibition influence Tph1 and Tph2, causing impairment of insulin secretion/production in beta cells.

Our current results suggest that Sirt3 plays a protective role in pancreatic beta cell GSIS in the context of type 2 diabetes as inhibition of Sirt3 renders beta cell more vulnerable to high fat diet induced dysfunction in insulin secretion.
All Author(s) ListMing X, Tian XY, Chung CK, Lee HM, Cao HY, Chan CN, Kong PS
Name of ConferenceThe 55th Annual Meeting of the European Association for the Study of Diabetes (EASD)
Start Date of Conference16/09/2019
End Date of Conference20/09/2019
Place of ConferenceBarcelona
Country/Region of ConferenceSpain
LanguagesEnglish-United States

Last updated on 2020-14-05 at 15:47