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Beta Cell Generation

Workload-based tissue homeostasis in the pancreatic islet via the UPR



We were the first to describe the emerging concept that the unfolded protein response (UPR) can influence beta cell mass by increasing beta cell proliferation.  
The concept arose from a screen to find novel drivers of mouse beta cell proliferation. We now believe that in some stem-cell-independent tissues, such as the pancreatic beta cell and other secretory cell types, the UPR mechanism senses protein synthesis load and directs cells to replicate, thereby increasing cell number to offset the increased load by increasing tissue size. This concept identifies a novel role for the UPR, and is supported by a large volume of experimental data using different approaches in vitro and in vivo in our own hands, as well as through unexplained results in publications by other groups as summarized in the first reference below.

Sharma RB, O'Donnell AC, Stamateris RE, Ha B, McCloskey KM, Reynolds PR, Arvan P, Alonso LC.  
Insulin demand regulates β cell number via the unfolded protein response.  
J Clin Invest. 2015 Oct 1;125(10):3831-46. PMID: 26389675; PMCID: PMC4607122.

Stamateris RE, Sharma RB, Hollern DA, Alonso LC.
Adaptive β-cell proliferation increases early in high-fat feeding in mice, concurrent with metabolic changes, with induction of islet cyclin D2 expression.
Am J Physiol Endocrinol Metab. 2013 Jul 1;305(1):E149-59. PMID: 23673159; PMCID: PMC3725565.

 

Hyperglycemia increases mouse and human beta cell proliferation in vivo

My first work in islet biology was to develop an in vivo mouse model in which chronic (4 day) hyperglycemia is induced by direct intravenous glucose infusion. This is useful to the diabetes research community because hyperglycemia is not caused by damage to a glucose-regulatory tissue, and because it applies a stimulus for beta cell proliferation (glucose) that can be studied in vitro and in vivo. We used this model for proof of principal experiments showing that in vivo hyperglycemia increases human beta cell proliferation in islets engrafted in mice. At UMass we perform this procedure with the help of Jason Kim and the MMPC.

Stamateris RE, Sharma RB, Kong Y, Ebrahimpour P, Panday D, Ranganath P, Zou B, Levitt H, Parambil NA, O'Donnell CP, Garcia-Ocana A, Alonso LC.
Glucose induces mouse beta cell proliferation via IRS2, mTOR and cyclin D2 but not the insulin receptor.
Diabetes. 2016 Jan 6; PMID: 26740601; 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;19(4):667-81. PMID: 24703698; PMCID: PMC4058888.

Levitt HE, Cyphert TJ, Pascoe JL, Hollern DA, Abraham N, Lundell RJ, Rosa T, Romano LC, Zou B, O'Donnell CP, Stewart AF, Garcia-Ocaña A, Alonso LC.
Glucose stimulates human beta cell replication in vivo in islets transplanted into NOD-severe combined immunodeficiency (SCID) mice.
Diabetologia. 2011 Mar;54(3):572-82. PMID: 20936253; PMCID: PMC3034833.

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