β-cell metabolic alterations under chronic nutrient overload in rat and human islets

Area of Science:

• Endocrinology
• Cell Biology
• Metabolic Research

Background:

• Pancreatic beta cells are crucial for glucose homeostasis.
• Metabolic perturbations, including elevated glucose and free fatty acids (FFAs), can impair beta cell function.
• Understanding beta cell responses to nutrient overload is vital for diabetes research.

Purpose of the Study:

• To investigate multifactorial beta cell responses to metabolic stress in rat and human islets.
• To elucidate the role of mammalian target of rapamycin complex 1 (mTORC1) in nutrient-induced lipid accumulation.
• To compare the effects of nutrient overload on islet cell growth, insulin secretion, and biosynthesis between species.

Main Methods:

• Primary rat and human islets were exposed to elevated glucose and FFAs.
• Lipid droplet formation, cell size, DNA synthesis, insulin secretion, and biosynthesis were measured.
• The mTORC1 pathway was modulated using rapamycin, an mTORC1 inhibitor.
• Expression of adipose differentiation related protein (ADRP) was analyzed.

Main Results:

• Elevated glucose and FFAs increased lipid droplet size and number in rat beta cells in an mTORC1-dependent manner.
• Rapamycin treatment reduced triglyceride accumulation in rat islets.
• Lipid droplets accumulated specifically in beta cells, not alpha cells.
• Rat islets increased in size and DNA synthesis under nutrient overload.
• Insulin content and biosynthesis were reduced in nutrient-overloaded rat islets compared to glucose alone.
• Human islets also showed mTORC1-dependent lipid droplet formation but did not increase in size.
• Insulin secretion was normal in human islets despite nutrient overload.

Conclusions:

• mTORC1 signaling mediates lipid droplet accumulation in beta cells under metabolic stress.
• Nutrient overload differentially affects islet cell growth and insulin storage in rat versus human islets.
• These findings highlight species-specific adaptations in beta cell response to metabolic challenges.