Receptors In Diabetic Rats Research Articles

Chronic desensitization of the glucose-dependent insulinotropic polypeptide receptor in diabetic rats.

Rats were rendered diabetic by streptozotocin, after which serum glucose-dependent insulinotropic polypeptide (GIP) levels, duodenal mucosal GIP content, and GIP mRNA levels were nine times, 50% and 80%, respectively, greater than in control rats. To determine whether an increase in GIP gene expression might induce chronic desensitization of its receptor, normal rats were subjected to continuous intravenous GIP infusion. Serum GIP levels increased gradually in GIP-infused rats, and by 4 h a threefold increase was detected. In response to GIP infusion, the serum insulin concentration increased at 30 min, followed by a gradual decrease, and at 4 h, no increase in insulin levels was detected despite a sustained elevated serum GIP level. The response to glucagon-like peptide-1 (GLP-1) was preserved, a reporter cell line (LGIPR2) stably transfected with rat GIP receptor cDNA was studied. GIP stimulated adenosine 3', 5'-cyclic monophosphate (cAMP) production in LGIPR2 cells, which was first detected after 1 h of stimulation, reached maximum level at 4 h, and returned to basal concentrations by 16 h. Additional stimulation with GIP at 16 h did not affect cAMP generation, indicating desensitization of the GIP receptor by the ligand. In contrast, a response to prostaglandin E1 or forskolin in GIP-desensitization was a receptor-specific process. The results of these studies indicate that GIP gene expression is enhanced in diabetic animals and that elevated serum GIP level induces chronic desensitization of the GIP receptor in vivo and in a stably transfected cell line.

Receptors for atrial natriuretic peptide are decreased in the kidney of rats with streptozotocin-induced diabetes mellitus.

To determine whether decreased renal responsiveness to atrial natriuretic peptide (ANP) in diabetes is mediated by alterations in the renal ANP receptor, ANP receptor density and affinity were measured 17-20 d after streptozotocin injection and compared with values in vehicle-treated controls and streptozotocin-treated rats made euglycemic with insulin. Plasma ANP concentration was significantly greater in hyperglycemic diabetic rats than in control or euglycemic diabetic rats. Both in glomeruli and inner medulla, ANP receptor dissociation constant did not differ among the three study groups, whereas the maximum binding capacity was decreased significantly in hyperglycemic diabetics in comparison with controls and euglycemic diabetics. Glomerular clearance receptors were also decreased significantly in hyperglycemic diabetic rats in comparison with control and euglycemic diabetic rats. To determine whether the decreased number of renal ANP receptors in diabetic rats was associated with a decreased biological response, we measured ANP-dependent cyclic GMP (cGMP) accumulation by isolated glomeruli and inner medullary collecting duct cells in vitro. cGMP accumulation was significantly less in hyperglycemic diabetic rats than in controls or euglycemic diabetic rats both in the presence or absence of the phosphodiesterase inhibitor zaprinast. cGMP phosphodiesterase activity in inner medullary collecting duct cells obtained from control and hyperglycemic diabetic rats did not differ. Thus, the decreased number of biologically active ANP receptors in the kidneys of diabetic rats is accompanied by decreased biological responsiveness in vitro and provides a potential explanation for the reduction in renal sensitivity to ANP in this condition.

Expression of the glucose-dependent insulinotropic peptide (GIP) gene and chronic homologous desensitization of its receptor in diabetic rats: [formula omitted], M.O. Boylan, L.A. Jarboe, T.B. Usdin, and M.M. Wolfe. Gastroenterology Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; and Laboratory of Cell Biology, National Institute of Mental Health, Bethesda, MD

Expression of the glucose-dependent insulinotropic peptide (GIP) gene and chronic homologous desensitization of its receptor in diabetic rats: [formula omitted], M.O. Boylan, L.A. Jarboe, T.B. Usdin, and M.M. Wolfe. Gastroenterology Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; and Laboratory of Cell Biology, National Institute of Mental Health, Bethesda, MD

Autophosphorylation and kinase activity of insulin receptor in diabetic rats

Insulin resistance is observed in insulin-deficient diabetic states in spite of an increase in insulin binding to its target cells. To characterize this type of insulin resistance, autophosphorylation and kinase activity of the insulin receptor on liver was studied with streptozotocin (STZ)-induced and BB diabetic rats. Insulin binding capacity was increased in proportion to the severity of the diabetic state in the STZ rat. In the diabetic BB rat, the insulin binding capacity was also increased, and this was partially normalized by insulin treatment. By contrast, insulin-stimulated autophosphorylation of the beta-subunit of the insulin receptor was decreased in proportion to the severity of the diabetic state in the STZ rat. Peptide mapping by reverse-phase high-performance liquid chromatography revealed a decrease in labeling at all sites of autophosphorylation. Kinase activity of the insulin receptor to exogenous substrates was also decreased in proportion to the diabetic state. In the BB rat, autophosphorylation and kinase activity of the insulin receptor were both decreased in the diabetic state and partially normalized by insulin treatment. In addition to the beta-subunit of insulin receptor, a 170 kdalton phosphotyrosine-containing protein was also identified in the glycoprotein fraction of liver. Although the phosphorylation of this protein was not insulin dependent, it was decreased markedly in the diabetic state. This protein is immunologically distinct from the insulin receptor, but is rich in phosphotyrosine. Based on its size and phosphotyrosine content, this protein may be the epidermal growth factor receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin withdrawal impairs sexual receptivity and retention of brain cell nuclear estrogen receptors in diabetic rats.

Acute withdrawal of exogenous insulin significantly impairs estradiol and progesterone-induced sexual receptivity and retention of brain cell nuclear estrogen receptors in ovariectomized (OVX), streptozotocin-diabetic rats. Insulin withdrawal for 18--24 h of a 24 h estradiol benzoate (EB)-conditioning period resulted in significant reductions in mean lordosis ratings. Omission of insulin for any 12 h period during EB conditioning was without effect on sexual receptivity. 24 h insulin deprivation resulted in a signficant reduction of cell nuclear estrogen receptor levels in hypothalamus-preoptic area of rats sacrificed 26 h after EB administration. Withdrawal of insulin during the middle 12 h of conditioning had no significant effect on the quantities of brain cell nuclear estrogen receptors. These results are in agreement with the hypothesis that decreased cell nuclear binding of estradiol by neural target tissues may contribute to the reproductive dysfunctions of diabetics.