• Diabetes Mellitus

GPR40 is a G-protein-coupled receptor that is highly expressed in pancreatic β-cells and is involved in free fatty acid-induced insulin secretion. TAK-875 is a GPR40-selective agonist that improves glucose control in type 2 diabetic animal models by stimulating glucose-dependent insulin secretion. In a study that was presented by Hiroaki Yahiro, Takeda Pharmaceuticals, Osaka, Japan, researchers examined the effects of the compound on insulin and glucagon secretion and on intracellular calcium (Ca²⁺) in pancreatic β- and α-cells from human and rat islets.

The islets were isolated through collagenase digestion. Radioimmunoassay was used to measure secreted insulin and glucagon. The human islets were derived from normal subjects aged 33 to 57 years.

In static incubation, TAK-875 augmented insulin secretion from rat and human islets at high (16 mmol/L) but not low (1 mmol/L) glucose.

An islet perfusion experiment was conducted to determine the glucose-dependent insulinotropic action of TAK-875. The compound enhanced both first- and second-phase insulin secretion at high glucose but had no effect at low glucose. It demonstrated comparable expression with a GLP-1 agonist and a sulfonylurea, enhancing glucose-dependent insulin secretion as much as GLP-1 in the static incubation experiment.

In both rat and human islets, TAK-875 had no effect on glucagon secretion, regardless of glucose dosing. Calcium measurements in intact rat and human islets showed that TAK-875 enhanced glucose-induced calcium in β-cells, while α-cells demonstrated an oscillatory [Ca²⁺]i response at low glucose that was suppressed by high glucose concentration. The addition of TAK-875 at high glucose did not affect α-cell oscillatory [Ca²⁺]i in rat islets, while it augmented the inhibitory effect of glucose in human islets.

These results demonstrate that TAK-875 potentiates glucose-dependent insulin secretion via direct stimulation of [Ca²⁺]_i in β-cells of both rat and human islets but has no effect on glucagon secretion or [Ca²⁺]_i in rat or human α-cells. This ability to affect insulin secretion without simultaneously increasing glucagon secretion may inhibit any hypoglycemic effects during use.

• © 2010 MD Conference Express