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Type 2 Diabetes Genetics

 

Hyperlipidemia restricts beta cell proliferation, via the CDKN2A/B T2D risk locus

It was previously known that free fatty acids (FFAs) impair insulin secretion and increase beta cell death. Using our in vivo mouse intravenous chronic infusion system, we found that raising lipid levels prevented glucose-induced proliferation. We traced the anti-proliferative effect of lipids to a cell cycle inhibitor called p16, which is located at one of the human genome regions associated with risk for T2D (CDKN2A/B). The full impact of this discovery has not yet been realized. Work we are doing now may lead to understanding how the CDKN2A/B T2D risk locus contributes to disease, and, eventually, to genetics-informed “personalized” diabetes therapy. We are also working to determine why oral administration of lipids, in the form of high fat feeding, results in beta cell proliferation when intravenous administration of lipids blocks proliferation.

Kong Y, Sharma RB, Nwosu BU, Alonso LC. Islet biology, the CDKN2A/B locus and type 2 diabetes risk. Diabetologia. 2016 May 7; PMID: 27155872; PMCID: PMC4930689.

Sharma RB, Alonso LC. Lipotoxicity in the pancreatic beta cell: not just survival and function, but proliferation as well?  Curr Diab Rep. 2014 Jun;14(6):492. PMID: 24740729; PMCID: PMC4063119.

Pascoe J, Hollern D, Stamateris R, Abbasi M, Romano LC, Zou B, O'Donnell CP, Garcia-Ocana A, Alonso LC. Free fatty acids block glucose-induced β-cell proliferation in mice by inducing cell cycle inhibitors p16 and p18. Diabetes. 2012 Mar;61(3):632-41. PMID: 22338094; PMCID: PMC3282818.

Collaborations using our Infusion Model

Our intravenous glucose and lipid infusion models are useful methods to alter circulating nutrient levels without relying on damaging or interfering with the function of a metabolic tissue. However, these models are not easy to implement, so weI provide collaborative access to these samples and techniques. My group has successfully collaborated with groups at multiple universities, including Stanford, Northwestern, Michigan, Indiana, Johns Hopkins, Pittsburgh, the Jackson Labs, and Mount Sinai, and the University of British Columbia. This track record demonstrates my ability to work productively with colleagues.

Lakshmipathi J, Alvarez-Perez JC, Rosselot C, Casinelli GP, Stamateris RE, Rausell-Palamos F, O'Donnell CP, Vasavada RC, Scott DK, Alonso LC, Garcia-Ocaña A. PKC-ζ is essential for pancreatic beta cell replication during insulin resistance by regulating mTOR and cyclin-D2. Diabetes. 2016 Feb 11;PubMed PMID: 26868297; PubMed Central PMCID: PMC4839210.

Song WJ, Mondal P, Wolfe A, Alonso LC, Stamateris R, Ong BW, Lim OC, Yang KS, Radovick S, Novaira HJ, Farber EA, Farber CR, Turner SD, Hussain MA. Glucagon regulates hepatic kisspeptin to impair insulin secretion. Cell Metab. 2014 Apr 1;19(4):667-81. PubMed PMID: 24703698; PubMed Central PMCID: PMC4058888.

Kilic G, Alvarez-Mercado AI, Zarrouki B, Opland D, Liew CW, Alonso LC, Myers MG Jr, Jonas JC, Poitout V, Kulkarni RN, Mauvais-Jarvis F. The islet estrogen receptor-α is induced by hyperglycemia and protects against oxidative stress-induced insulin-deficient diabetes. PLoS One. 2014;9(2):e87941. PubMed PMID: 24498408; PubMed Central PMCID: PMC3912162.

Metukuri MR, Zhang P, Basantani MK, Chin C, Stamateris RE, Alonso LC, Takane KK, Gramignoli R, Strom SC, O'Doherty RM, Stewart AF, Vasavada RC, Garcia-Ocaña A, Scott DK. ChREBP mediates glucose-stimulated pancreatic β-cell proliferation. Diabetes. 2012 Aug;61(8):2004-15. PubMed PMID: 22586588; PubMed Central PMCID: PMC3402328.

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