Endocrine Abstracts

GPR120 is a rhodopsin-like GPCR that has a high affinity for long-chain saturated fatty acids 14–18 carbons and unsaturated fatty acids 16–22 carbons. The beneficial effects of GPR120 on β-cell function and glucose homeostasis have recently been reported however its role in glucagon secretion is unknown. GPR120 and glucagon expression were examined by double immunohistochemical studies using a glucagon secreting cell line (α-TC1.9) and pancreatic tissue from normal and high-fat fed (HFF) NIH-Swiss mice. Mechanistic and molecular studies with GPR120 agonists were used to examine alterations in intracellular Ca²⁺ and GPR120 mRNA expression in α-TC1.9 cells. Cytotoxicity was assessed by LDH release. Acute in-vivo effects of lipid GPR120 agonists on plasma glucose and islet hormone levels were assessed in NIH-Swiss mice. Immunocytochemistry demonstrated GPR120 co-localisation with glucagon in mouse pancreatic islets; results were confirmed in α-TC1.9 cells. Histological studies revealed that insulin was reduced (P<0.001) whilst glucagon (P<0.01) and GPR120 (P<0.05) expression was increased in HFF model of diabetes compared to lean controls. In mechanistic studies, endogenous GPR120 agonist DHA increased intracellular Ca²⁺ by 4.2-fold (P<0.001) whilst synthetic agonist GW-9508 induced a threefold increase (P<0.05) in α-TC1.9 cells at 5.6 mM glucose. At 16.7 mM glucose, DHA and GW-9508 augmented intracellular Ca²⁺5.0-fold (P<0.01) and 2.6-fold (P<0.05), respectively. No cytotoxicity was observed. PCR studies revealed that DHA increased GPR120 mRNA expression in TC1.9 cells at 5.6 mM glucose. Administration of GPR120 agonists (0.1 μmol/kg per body weight) in glucose tolerance studies was tested in NIH-Swiss mice. DHA and ALA improved glucose tolerance (P<0.001), augmented insulin secretion (P<0.01) whilst DHA reduced glucagon secretion (P<0.001) by 94% after 30 min. GW-9508 augmented insulin secretion (P<0.01) by 48% after 15 min and glucagon secretion (P<0.001) by 67% after 30 min. GPR120 is expressed on pancreatic alpha cells, and agonists at this receptor modulate glucagon secretion, with therapeutic potential for type-2 diabetes.

Disclosure: This work was funded by DEL.