How fat could help solve part of the diabetes problem
Sydney scientists now describe how a fat recycling system within pancreatic ‘beta cells’ determines the amount of insulin to secrete, and so may provide a target for future diabetes therapies.
The pancreas is a large organ that wraps around our gut, producing the exact amount of insulin our bodies need when we eat. But, diabetes slows insulin production down.
A small structure inside the beta cell, known as a ‘lysosome,’ behaves like an intracellular recycling unit that breaks down unwanted fats and proteins in such a way they can be re-used.
When PhD student Gemma Pearson and Professor Trevor Biden from Sydney’s Garvan Institute of Medical Research prevented lysosomes from breaking down fat, they found that beta cells secreted more insulin.
Their study is published in Diabetologia, now online.
While this is a very early stage cell biology story, it nonetheless holds promise, and encourages the scientific community to look at diabetes therapies through a fatty lens.
“There are many different ways fats can be used within the beta cell – so if you stop them being recycled, you force them to be used in a different way,” said Gemma Pearson, whose PhD examines the “lipid profile” of beta cells.
Pearson continues: “When you shift fats from the lysosome, you store them in other parts of the cell, and they become available to participate in various signaling pathways.
"Fat molecules are not the inert blobs you might think – they can bind to proteins and activate them, causing a range of downstream events to occur."
Gemma Pearson, PhD, Garvan Institute of Medical Research, Sydney Australia
"One of these pathways clearly increases insulin secretion. The good thing about this particular pathway is that it is only stimulated by glucose. That limits the beta cell to producing excess insulin only to deal with food, rather than around the clock. Too much insulin circulating in the blood, or hyperinsulinaemia, can be very detrimental to health in many respects.
“If in the future a drug were to be developed to block fat degradation in the lysosome, it would have to be tweaked to affect beta cells only,” added Pearson.
Lipolytic breakdown of endogenous lipid pools in pancreatic beta cells contributes to glucose-stimulated insulin secretion (GSIS) and is thought to be mediated by acute activation of neutral lipase's in the amplification pathway. Recently it has been shown in other cell types that endogenous lipid can be metabolized by autophagy, and this lipophagy is catalyzed by lysosomal acid lipase (LAL). This study aimed to eluciate a role for LAL and lipophagy in pancreatic beta cells.
We employed pharmacological and/or genetic inhibition of autophagy and LAL in MIN6 cells and primary islets. Insulin secretion following inhibition was measured using RIA. Lipid accumulation was assessed by MS and confocal microscopy (to visualize lipid droplets) and autophagic flux was analyzed by western blot.
Insulin secretin was increased following chronic (>8 h) inhibition of LAL. This was more pronounced with glucose than with non-nutrient stimuli and was accompanied by augmentation of neutral lipid species. Similarly, following inhibition of autophagy in MIN6 cells, the number of lipid droplets was increased and GSIS was potentted. Inhibition of LAL or autophagy in primary islets also increased insulin secretion. This augmentation of GSIS following LAL or autophagy inhibition was dependent on the acute activation of neutral lipases.
Our data suggest that lysosomal lipid degradation, using LAL and potentially lipophagy, contributes to neutral lipid turnover in beta cells. It also serves as a constitutive negative regulator of GSIS by depletion of substrate for the non-lysosomal neutral lipase's that are activated acutely by glucose.
The Garvan Institute of Medical Research was founded in 1963. Initially a research department of St Vincent's Hospital in Sydney, it is now one of Australia's largest medical research institutions with over 600 scientists, students and support staff. Garvan's main research areas are: Cancer, Diabetes & Obesity, Immunology and Inflammation, Osteoporosis and Bone Biology and Neuroscience. Garvan's mission is to make significant contributions to medical science that will change the directions of science and medicine and have major impacts on human health. The outcome of Garvan's discoveries is the development of better methods of diagnosis, treatment, and ultimately, prevention of disease.
Original press release:http://www.garvan.org.au/news-events/news/how-fat-could-help-solve-part-of-the-diabetes-problem.html