Nagesha Guthalu Kondegowda, Ph.D.

Our lab was one of the first to demonstrate that transgenic expression of a peptide factor in the beta cell can induce beta cell growth and increase beta cell mass in mice. Subsequently, after I joined the group, we have shown that this peptide, parathyroid hormone-related protein (PTHrP), as well as a small subpeptide of PTHrP are sufficient to enhance beta cell proliferation, survival and function not only in rodents but also in human beta cells. We have shown that the subpeptide of PTHrP has regenerative effects on rodent beta cells in vivo, when administered systemically and acutely under basal and conditions of increased demand such as partial pancreatectomy.

A first third-generation anti-breast cancer Food and Drug Administration (FDA)-approved drug, which is a selective inhibitor of CDK4/6, called palbociclib (Ibrance) was evaluated for its effect on beta cell homeostasis in young versus aged rats; and it did not affect glucose or beta cell homeostasis in aged rats.

i) Guthalu NK, Joshi-Gokhale S, Harb G, Williams K, Zhang XY, Takane KK, Zhang P, Scott D, Stewart AF, Garcia-Ocaña A, Vasavada RC. Parathyroid hormone-related protein (PTHrP) enhances human β-cell proliferation and function with simultaneous induction of cyclin-dependent-kinase 2 (cdk2) and Cyclin E expression. Diabetes 59: 3131-3138 (2010). PMID: 20876711

ii) Williams K, Abanquah D, Joshi-Gokhale S, Otero A, Lin H, Guthalu NK, Zhang XY, Mozar A, Bisello A, Stewart AF, Garcia-Ocaña A, Vasavada RC. Systemic and acute administration of parathyroid hormone-related peptide 1-36 stimulates endogenous beta cell proliferation while preserving function in adult mice. Diabetologia 54:2867-2877 (2011). PMID: 21800111

iii) Mozar A, Lin H, Williams K, Chin C, Guthalu NK, Stewart AF, Garcia-Ocana A, Vasavada RC. Parathyroid Hormone-Related peptide (1-36) enhances beta cell regeneration and increases beta cell mass in a mouse model of partial pancreatectomy. PLoS ONE 11(7): 1-15 (2016). PMID: 27391423

iv) Sacaan AI, Thibault S, Hong M, Guthalu NK, Nichols TC, Li R, Rosselot C, Evering W, Fenutria R, Vitsky A, Brown T, Finkelstein MB, Garcia-Ocaña A, Khan NK, Stewart AF, Vasavada RC. CDK4/6 Inhibition on Glucose and Pancreatic Beta Cell Homeostasis in Young and Aged Rats. Mol. Cancer Res.15:1531-1541 (2017). PMID: 28760782.

Effect of lactogens on beta cell survival:

Lactogenic hormones, such as prolactin and placental lactogen act by binding to a common receptor, the prolactin receptor, are indispensable in facilitating the normal growth and function of the beta cell during development and during pregnancy, as demonstrated by various studies. Though many studies have demonstrated that these hormones can induce proliferation and enhance function of beta cells, their effect on beta cell survival was not known. Based on the effects of these hormones in other cell types, we hypothesized that they would protect beta cells from cell death inducers. Indeed our work has demonstrated that these hormones protect rodent and human beta cells against varied cell death inducers relevant to the pathophysiology of type 1 and type 2 diabetes. We have also shown the importance of the downstream JAK2/STAT5 pathway and the anti-apoptotic molecule BclXL for mediating the prosurvival effects of these hormones in rodent and human beta cells. Our recent findings also demonstrated the protective effect of lactogens against endoplasmic reticulum stress (ER stress) induced rodent and human beta cell death and prevent diabetes incidence in Akita mice. Further, our yet unpublished research demonstrates that prolactin treatment in NOD-Ltj mice, a type 1 diabetic rodent model, not only prevents but also reverses recent-onset type 1 diabetes.

i) Guthalu NK, Zhang XY, Williams K, Mozar A, Vasavada RC. Growth factor-mediated regulation of beta cell survival. The Open Endocrine Journal 4:80-95 (2010).

ii) Guthalu NK, Mozar A, Otero A, Chin C, Garcia-Ocaña A, Vasavada RC. Lactogens protect rodent and human beta cells against glucolipotoxicity-induced cell death through Jak2/Stat5 signaling. Diabetologia 55:1721-1732 (2012). PMID: 22382519

iii) Li R, Guthalu NK, Filipowska J, Hampton RF, Leblanc S, Garcia-Ocana A, Vasavada RC. Lactogens reduce endoplasmic reticulum stress-induced rodent and human beta cell death and diabetes incidence in Akita mice. Diabetes 69:1463-1475 (2020). PMID: 32332156

Osteoprotegerin effect on beta cell homeostasis:

Our quest to find the downstream targets of lactogenic hormones led to a recent finding that the bone-related peptide, osteoprotegerin (OPG) is induced by lactogens in beta cells. We showed that OPG, besides mediating lactogen-induced beta cell proliferation, can also enhance rodent beta cell proliferation in vivo in young and aged mice. Furthermore, OPG has proliferative and pro-survival effects on human beta cells. Being a soluble decoy receptor, OPG acts by inhibiting the RANKL/RANK or the TRAIL/DR pathways. Our studies have found that the proliferative effect of OPG in rodent and human beta cells is mediated through inhibition of the RANKL/RANK pathway. We have used these findings to examine the potential of repurposing an FDA-approved osteoporosis drug, Denosumab, which is a RANKL antibody, on human beta cell proliferation and survival, for the treatment of diabetes. Currently we are studying the physiological, mechanistic, and therapeutic aspects of these molecules and pathways in the beta cell. We have two patents on the role of OPG in beta cell proliferation and survival.

i) Guthalu NK, Fenutria R, Pollack I, Orthofer M, Garcia-Ocaña A, Penninger J, Vasavada RC. Osteoprotegerin and Denosumab stimulate human beta cell proliferation through inhibition of the Receptor Activator of NF-κB Ligand (RANKL) pathway. Cell Metabolism 22:77-85 5.