Disruption of GPR39 Impairs Insulin Secretion In Vivo

Abstract

GPR39 is a G protein-coupled receptor expressed in liver, gastrointestinal tract, adipose tissue and pancreas. We have recently shown that young GPR39 mice have normal body weight, food intake, and fasting glucose and insulin levels. In this study, we examined the role of GPR39 in aging and diet-induced obese mice. Body weight and food intake were similar in wild-type (WT) and GPR39 / mice as they aged from 12 to 52 weeks or when fed a low-fat/high-sucrose (LFHS) or high-fat/high-sucrose (HFHS) diet. 52-week-old GPR39 / mice showed a trend toward decreased insulin levels after oral glucose challenge. When fed either a LFHS or HFHS diet, GPR39 / mice had increased fed glucose levels and showed decreased serum insulin levels during an oral glucose tolerance test in the face of unchanged insulin tolerance. Pancreas morphology and glucose-stimulated insulin secretion in isolated islets from WT and GPR39 / mice were comparable, suggesting that GPR39 is not required for pancreas development or ex vivo insulin secretion. Small interfering RNA-mediated knockdown of GPR39 in clonal NIT-1 -cells revealed that GPR39 regulates the expression of IRS-2 and PDX-1 in a cell-autonomous manner; IRS-2 mRNA was also significantly decreased in the pancreas of GPR39 / mice. Taken together, our data indicate that GPR39 is required for the increased insulin secretion in vivo under conditions of increased demand, i.e. upon development of age-dependent and diet-induced insulin resistance. Thus, GPR39 agonists may have potential for the treatment of type 2 diabetes. Minireview: Thyrotropin-Releasing Hormone and the Thyroid Hormone Feedback Mechanism Maria Izabel Chiamolera and Fredric E. Wondisford (Endocrinology, published January 29, 2009, 10.1210/en.2008-1795) ABSTRACT Thyroid hormone (TH) plays a critical role in development, growth, and cellular metabolism. TH production is controlled by a complex mechanism of positive and negative regulation. Hypothalamic TRH stimulates TSH secretion from the anterior pituitary. TSH then initiates TH synthesis and release from the thyroid gland. The synthesis of TRH and TSH subunit genes is inhibited at the transcriptional level by TH, which also inhibits posttranslational modification and release of TSH. Although opposing TRH and TH inputs regulate the hypothalamic-pituitary-thyroid axis, TH negative feedback at the pituitary was thought to be the primary regulator of serum TSH levels. However, study of transgenic animals showed an unexpected, dominant role for TRH in regulating the hypothalamic-pituitary-thyroid axis and an unanticipated involvement of the thyroid hormone receptor ligand-dependent activation function (AF-2) domain in TH negative regulation. These results are summarized in the review. T R A N S L A T I O N A L H I G H L I G H T S F R O M E N D O C R I N O L O G YThyroid hormone (TH) plays a critical role in development, growth, and cellular metabolism. TH production is controlled by a complex mechanism of positive and negative regulation. Hypothalamic TRH stimulates TSH secretion from the anterior pituitary. TSH then initiates TH synthesis and release from the thyroid gland. The synthesis of TRH and TSH subunit genes is inhibited at the transcriptional level by TH, which also inhibits posttranslational modification and release of TSH. Although opposing TRH and TH inputs regulate the hypothalamic-pituitary-thyroid axis, TH negative feedback at the pituitary was thought to be the primary regulator of serum TSH levels. However, study of transgenic animals showed an unexpected, dominant role for TRH in regulating the hypothalamic-pituitary-thyroid axis and an unanticipated involvement of the thyroid hormone receptor ligand-dependent activation function (AF-2) domain in TH negative regulation. These results are summarized in the review. T R A N S L A T I O N A L H I G H L I G H T S F R O M E N D O C R I N O L O G Y