News & Research

Pittsburgh, Pennsylvania

Free fatty acids, p16, and pancreatic beta cell proliferation

General Research Subject: Both Type 1 And Type 2 Diabetes

Focus: Islet Biology\Beta Cell Growth and Differentiation, Islet Biology\Beta Cell Transcription Regulation, Islet Biology\Metabolic Regulation

Type of Grant: Basic Science

Project Start Date: July 1, 2011

Project End Date: June 30, 2014

Research Description

People with both type 1 and type 2 diabetes have reduced numbers of insulin-producing beta cells. The PI's goal is to find new therapeutic angles to increase beta cell mass. Most new beta cells come from replication of preexisting beta cells. Adult human beta cell replication is infrequent, suggesting that factors either intrinsic or extrinsic to the beta cell restrain beta cell replication. Such factors, however, remain unknown. Blood levels of free fatty acids (FFAs) are increased in both type 1 and type 2 diabetes. The PI has found that FFAs block beta cell replication in mice. In cell culture studies (both primary islet cells and INS-1 cells) FFAs act directly on the beta cell to slow replication. Intriguingly, FFAs induce the cell cycle inhibitor p16 (a protein that directly slows replication in many cell types) in islets in live mice, and in INS-1 cells. Furthermore, reducing p16 levels eliminated the anti-proliferative effects of FFA. This proposal will explore the mechanism and human relevance of these findings through the following specific aims: Aim 1: Establish whether p16 is required for FFA-inhibition of beta cell proliferation (using p16 knockout mice), Aim 2: Explore the mechanism by which FFA increase p16 levels in beta cells, and Aim 3: Determine whether FFA restrict human beta cell proliferation (using a mouse human islet transplant-infusion model). These studies have the potential to reveal targets for a new class of anti-diabetes drugs that enhance beta cell mass by blocking factors that restrict human beta cell proliferation.

Research Profile

What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?

People with diabetes, both type 1 and type 2, have insufficient numbers of the pancreatic beta cells that secrete insulin. In adult mice (and, we believe also in humans, although it’s not yet known for sure), the largest source of new beta cells is proliferation of existing beta cells. Recent experiments in my laboratory have shown that a form of fat called free fatty acids, that circulates in the bloodstream in all people, can prevent beta cell proliferation. Intriguingly, increasing free fatty acid levels in mice causes a protein called p16, which blocks proliferation by halting the cell cycle, to be more abundant in islets. When we studied this phenomenon in beta cells growing in a dish, we found that p16 was required for free fatty acids to block proliferation. The experiments we will perform as part of this grant application will determine whether p16 is important for this process in mice. We will also perform experiments to verify that our findings in mice also apply to human beta cells. If our hypothesis is correct, this work will uncover an important new therapeutic target to restore pancreatic insulin secretion to prevent or treat diabetes.

If a person with diabetes were to ask you how your project will help them in the future, how would you respond?

In my opinion, a true “cure” for diabetes means restoration of pancreatic beta cell mass and function. This project aims to understand one reason why beta cell mass fails to expand in people who become diabetic. If successful, our research will identify a new therapeutic pathway that may eventually allow restoration of pancreatic insulin secretory capacity in people with diabetes.

Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?

This award has enormous meaning for me. As a practicing Endocrinologist, I see patients every week who struggle with diabetes, both with the seemingly impossible recommendations to change fundamental aspects of how they live, and with the threat and, in some cases, reality of acute and chronic diabetes complications. This Association grant is my first independent research award. In today’s difficult funding climate, this award may mean the difference between success and failure as a diabetes researcher. The nature of this award, funded by small gifts from thousands of individuals with a personal stake in the future of diabetes research, gives me a strong sense of personal responsibility; I feel that a precious trust has been placed in me. I hope my efforts move the field of diabetes research forward in a meaningful way.

In what direction do you see the future of diabetes research going?

In the short term, I see improvements in therapy for diabetes, with closing the loop between glucose monitoring and insulin delivery. However, closed-loop insulin delivery will remain a highly specialized, labor intensive and expensive therapy that won’t be possible for all patients. My dream is to develop a true cure, meaning restoration of normal pancreatic glucose sensing and insulin secretion, which could be applied to all patients with prediabetes and diabetes.