Scientists from the University of Geneva (UNIGE), Switzerland, have discovered insulin-producing beta cells in pancreatic islets suffer less from excess sugar when they have previously been exposed to fat. The finding was published in the journal Diabetologia on January 12, in an article titled, “Glucolipotoxicity promotes the capacity of the glycerolipid/NEFA cycle supporting the secretory response of pancreatic beta cells.”
Through transcriptomic analyses of lipid pathways in human and rat pancreatic islets, the researchers revealed how a cycle of fat storage and mobilization (the glycerolipid/NEFA cycle) helps beta cells to adapt to excess sugar. This unexpected biological mechanism also explains how regular fasting could help obese patients maintain functional beta cells to stave off type2 diabetes and could be used to delay the onset of type 2 diabetes.
“The cycle of fat storage or mobilization emerges as a mechanism helping the beta cell to cope with glucotoxic conditions,” the authors noted.
Aberrant blood sugar regulation due to malfunctioning beta cells in type 2 diabetes is a major public health issue. In addition to secreting insulin, beta cells also store and mobilize neutral lipids—uncharged fatty acids or their derivatives that are soluble in organic solvents.
Prolonged exposure of pancreatic beta cells to sugar and fat is considered the culprit that damages beta cells (glucolipotoxicity). While the culpability of sugar is no longer in doubt, the mechanisms through which fat damages beta cells has remained unclear.
“To answer this key question, we studied how human and murine beta cells adapt to an excess of sugar and/or fat,” said Pierre Maechler, PhD, professor of cell physiology and metabolism at UNIGE faculty of medicine, and senior author of this study.
The researchers exposed beta cells to an excess of sugar, fat, or both, followed by RNA sequencing luminescence- and radioimmuno-assays to measure insulin secretion and electron microscopy to determine lipid mobilization rates. Their results confirm high levels of sugar reduce insulin secretion in beta cells.
“When cells are exposed to both too much sugar and too much fat, they store the fat in the form of droplets in anticipation of less prosperous times,” said Lucie Oberhauser, PhD, a postdoctoral researcher in the department of cell physiology and metabolism at UNIGE and first author of the study. “We have shown that this stock of fat, instead of worsening the situation, allows insulin secretion to be restored to near-normal levels. The adaptation of beta cells to certain fats would thus contribute to maintain normal blood sugar levels.”
The authors demonstrated the mobilization of fat molecules helps beta cells adapt to high sugar levels and maintain near-normal insulin secretion.
“This release of fat is not really a problem as long as the body uses it as a source of energy,” said Maechler. “To avoid developing diabetes, it is important to give this beneficial cycle a chance to be active, for example by maintaining regular physical activity.”
The authors also noted that the protective adaptation of the glycerolipid/NEFA cycle to glucolipotoxic conditions in beta cells suggests that periodic fasting could help obese patients maintain functional beta cells that secrete insulin and help maintain blood glucose levels.
The team is currently focused on determining the mechanism by which released fat stimulates insulin secretion. Targeting this mechanism may help delay the onset of diabetes.