PAM Haploinsufficiency Does Not Accelerate the Development of Diet- and Human IAPP-Induced Diabetes in Mice
This week we profile a recent publication in Diabetologia from Dr. Yi-Chun Chen (pictured) in
the laboratory of Dr. Bruce Verchere at UBC and BC Children’s Hospital Research Institute.
Can you provide a brief overview of your lab’s current research focus?
Dr. Verchere’s lab is interested in understanding how insulin-producing beta cells in the pancreas normally function, and why they are dysfunctional or lost in both type 1 and type 2 diabetes. In particular, our lab studies how two peptide hormones in the beta cell, insulin and islet amyloid polypeptide (IAPP), are made from their precursor proteins, proinsulin and proIAPP, respectively, and how islet prohormones may be used as biomarkers of beta cell dysfunction in diabetes. We also aim to understand how inflammation occurs in the pancreatic islet in diabetes, and the role of islet macrophages in mediating both inflammation and repair of islets. Our research has found that aggregates of IAPP, the precursors to islet amyloid (a pathological characteristic of the pancreas in type 2 diabetes), trigger the recruitment and activation of macrophages in the islet. We aim to develop cell and molecular based therapeutics that can replace or protect beta cells in diabetes.
What is the significance of the findings in this publication?
Peptidyl-alpha amidating monooxgenase (PAM) is an enzyme that converts immature neuroendocrine peptides into amidated mature hormones. Recent genome and population studies suggest that PAM variant carriers have impaired insulin secretion and a higher risk of developing type 2 diabetes. This study was led by a JDRF-funded post-doctoral fellow in the lab, Dr. Yi-Chun Chen, who is studying how pathways involved in beta cell peptide hormone synthesis and processing may confer risk of diabetes. To understand why PAM variant carriers have impaired insulin secretion and increased diabetes risk, Dr. Chen and her collaborators examined the function of insulin-producing beta cells in a mouse model of diabetes and PAM insufficiency. Specifically, she studied heterozygous PAM knockout mice (mimicking the 50% loss of PAM activity in PAM variant carriers) during the development of obesity and islet amyloid-induced diabetes. Surprisingly, she found that PAM haploinsufficiency in mice does not accelerate the development of diabetes, even during the stress of diet-induced obesity or amyloid-induced diabetes. These findings in mice suggest that PAM haploinsufficiency alone cannot explain the impaired insulin secretion and increased risk of type 2 diabetes observed in PAM variant carriers, and that other mechanisms are likely involved.
What are the next steps for this research?
We plan to study the role of PAM specifically in pancreatic beta cells, using beta cell-specific PAM knockout mice. We will investigate how complete loss of PAM function in beta cells may impact insulin secretion and risk of diabetes in mice. We hope to identify substrates of PAM-mediated amidation in beta cells that may be important in conferring increased diabetes risk in PAM variant carriers.
This work was funded by:
Funded by CIHR and JDRF.