The goal of this application is to provide Dr. Linnemann with a comprehensive 5-year training program that will allow her to emerge as an independent academic scientist. Through this program she will gain valuable research experience in the fields of islet cell biology, in vivo physiology, obesity, and metabolic pathways Dr. Dawn Belt Davis and Dr. Michael MacDonald will serve as the primary co- mentors for her career and scientific development. Dr. Davis is an emerging leader in the field of diabetes and obesity research. Dr. MacDonald is an established leader in diabetes and metabolism and has a proven track record of mentoring both basic and clinical scientists. Dr. Linnemann has also assembled a mentoring committee comprised of outstanding scientists to provide the full spectrum of career development and scientific guidance. Her mentoring committee includes Dr. Vincent Cryns, Dr. Molly Carnes, and Dr. Michelle Kimple. The research plan involves the study of pancreatic beta cell protection from apoptosis in an obese environment. Obesity is associated with generalized inflammation and an increase in circulating cytokines such as interleukin-6 (IL-6). However, there is conflicting evidence as to the specific role of IL-6 in an obese state. Preliminary data suggests that circulating IL-6 initiates a cascade of intra-islet production of classic gut hormones, namely GLP-1 and cholecystokinin (CCK), that modulate beta cell survival and thus islet mass. Taking this into account, the central hypothesis is that obesity driven IL-6 stimulates adaptive stress response that promotes beta cell function and mass regulation.
The specific aims of this application include 1) To determine how a multicomponent IL-6 driven pathway regulates beta cell survival; and 2) To define the in vivo role of IL-6 in obesity driven beta cell mass regulation. Together, these aims will allow the identification of a novel pathway in the protection of beta cells from apoptosis that may serve as a therapeutic target to aid in beta cell mass expansion.
More than 1 in 3 adults in the United States are obese and the prevalence of type 2 diabetes is rising rapidly. This project will increase our understanding o the fundamental mechanisms that underlie the development of diabetes in association with obesity. The ultimate goal of this work is to reveal new therapeutic targets to prevent or slow progression of this devastating disease.
|Marasco, Michelle R; Conteh, Abass M; Reissaus, Christopher A et al. (2018) Interleukin-6 Reduces ?-Cell Oxidative Stress by Linking Autophagy With the Antioxidant Response. Diabetes 67:1576-1588|
|Marasco, Michelle R; Linnemann, Amelia K (2018) ?-Cell Autophagy in Diabetes Pathogenesis. Endocrinology 159:2127-2141|
|Linnemann, Amelia K; Blumer, Joseph; Marasco, Michelle R et al. (2017) Interleukin 6 protects pancreatic ? cells from apoptosis by stimulation of autophagy. FASEB J 31:4140-4152|
|Linnemann, Amelia K; Davis, Dawn Belt (2016) Glucagon-like peptide-1 and cholecystokinin production and signaling in the pancreatic islet as an adaptive response to obesity. J Diabetes Investig 7 Suppl 1:44-9|
|Linnemann, Amelia K; Neuman, Joshua C; Battiola, Therese J et al. (2015) Glucagon-Like Peptide-1 Regulates Cholecystokinin Production in ?-Cells to Protect From Apoptosis. Mol Endocrinol 29:978-87|