GPR39, which may function as a Zn(2+) sensor, is a member of the
G protein-coupled receptor family that also includes the receptor for the hunger
hormone ghrelin. The down-regulation of GPR39
mRNA in adipose tissue of obese type 2 diabetic patients suggests that GPR39 may contribute to the pathogenesis of the disease. The present study aimed to investigate the role of GPR39 in the regulation of energy balance and
glucose homeostasis in wild-type (GPR39(+/+) ) and GPR39 knockout mice (GPR39(-/-) ) with
obesity-related
type 2 diabetes. GPR39
mRNA levels in adipose tissue of fasted GPR39(+/+) mice fed a high-fat diet (HFD) for 30 weeks were reduced and correlated positively with
blood glucose levels.
Body weight, fat percentage and energy intake were increased in the HFD group but did not differ between both genotypes. Within the HFD
group, blood glucose levels were lower in GPR39(-/-) than in GPR39(+/+) mice, despite significant reductions in prandial plasma
insulin levels. The latter may not be a result of changes in β-cell
hyperplasia because immunohistochemical staining of pancreata of mice on a HFD showed no differences between genotypes. The lower
blood glucose levels may involve alterations in
insulin sensitivity as revealed by
glucose tolerance tests and respiratory quotient measurements that showed a preference of obese GPR39(-/-) mice for the use of
carbohydrates as metabolic fuel. The increase in plasma
ghrelin levels in GPR39(-/-) mice fed a HFD may contribute to the alterations in
glucose homeostasis, whereas changes in gastric emptying or intestinal Zn(2+) absorption are not involved. The results obtained in the present study suggest that GPR39 plays a role in the pathogenesis of
obesity-related
type 2 diabetes by affecting the regulation of
glucose homeostasis.