The roles of insulin resistance and fl-cell dysfunction in glucocorticoid-induced diabetes were determined in Wistar and Zucker (fa/fa) rats. All Wistar rats treated with 5 mg/kg per d of dexamethasone for 24 d exhibited increased f-cell mass and basal and arginine-stimulated insulin secretion, indicating insulin resistance, but only 16% became diabetic. The insulin response to 20 mM glucose was normal in the perfused pancreas of all normoglycemic dexamethasone-treated rats but absent in every diabetic rat. Immunostainable high K. f-cell transporter, GLUT-2, was present in -100% of f-cells of normoglycemic rats, but in only 25% of f, cells of diabetic rats.GLUT-2 mRNA was not reduced. All Zucker (fia/fa) rats treated with 0.2-0.4 mg/kg per d of dexamethasone for 24 d became diabetic and glucose-stimulated insulin secretion was absent in all. High K. glucose transport in islets was 50% below nondiabetic controls. Only 25% of cells of diabetic rats were GLUT-2-positive compared with -100% in controls. Total pancreatic GLUT-2 mRNA was increased twofold suggesting a posttranscriptional abnormality. We conclude that dexamethasone induces insulin resistance, whether or not it induces hyperglycemia. Whenever hyperglycemia is present, GLUT-2-positive fi cells are reduced, high K. glucose transport into cells is attenuated and the insulin response to glucose is absent. (J. Clin. Invest. 1992. 90:497-504.)
The role of defective glucose transport in the pathogenesis of noninsulin-dependent diabetes (NIDDM) was examined in Zucker diabetic fatty rats, a model of NIDDM. As in human NIDDM, insulin secretion was unresponsive to 20 mM glucose. Uptake of 3-O-methylglucose by islet cells was less than 19% of controls. The beta cell glucose transporter (GLUT-2) immunoreactivity and amount of GLUT-2 messenger RNA were profoundly reduced. Whenever fewer than 60% of beta cells were GLUT-2-positive, the response to glucose was absent and hyperglycemia exceeded 11 mM plasma glucose. We conclude that in NIDDM underexpression of GLUT-2 messenger RNA lowers high Km glucose transport in beta cells, and thereby impairs glucose-stimulated insulin secretion and prevents correction of hyperglycemia.
Purpose. The present study is an attempt to develop a vitamin E loaded naringenin (NRG) Nanoemulsion (NE) for direct nose-to-brain delivery for better management of Parkinson's disease (PD). Methods. The optimized NE was evaluated for efficacy in PD using multiple behavioral studies (including narrow beam test, muscular coordination test, grip strength test, forced swimming test, and akinesia test) in a rat model. Optimized formulation was evaluated for droplet size, polydispersity index (PDI), refractive index, transmittance, zeta potential, and viscosity. Results. Optimized NE had a droplet size of 38.70 ± 3.11nm, PDI of 0.14 ± 0.0024, refractive index of 1.43 ± 0.01, transmittance of 98.12 ± 0.07 %, zeta potential of − 27.4 ± 0.14 mV, and viscosity of 19.67 ± 0.25 Pa s. Behavioral studies showed that 6-OHDA induced PD in rats were successfully reversed when administered with NRG NE intranasally along with the levodopa. While the levels of GSH and SOD were significantly higher, levels of MDA were significantly lower in the group treated with NRG NE via intranasal route along with levodopa. Conclusion. Encouraging results from current study provide evidence for possible efficacy of a novel noninvasive intranasal delivery system of NRG for management of PD related symptoms.
A cDNA termed reg was recently isolated by differential screening of a library prepared from regenerating islets isolated from pancreatic remnants of rats subjected to 90% pancreatectomy and nicotinamide treatment. This led to speculation that this gene may be involved in expansion of beta-cell mass. In the current study we have measured reg expression after implantation and resection of a solid insulinoma tumor into rats, maneuvers known, respectively, to reduce and reexpand the volume of beta-cells in the islet. Animals with an implanted insulinoma tumor became profoundly hypoglycemic. Islet beta-cells declined from the normal 75% of total islet volume to less than 30%, in concert with a marked reduction in the reg mRNA level. Removal of the tumor resulted in a sharp increase in beta-cell replication, as measured by [3H]thymidine incorporation and a return to normal beta-cell volume within 4 days of tumor resection. This was associated with a transient induction in reg expression compared to that in tumor-bearing animals, effectively returning the amount of reg mRNA to the levels found in normal animals within 48 h; at later time points after tumor removal (3-7 days) reg expression declined, but then rose toward normal. In situ hybridization analysis localized the initial induction in reg mRNA expression to the exocrine pancreas. Continuous infusion of insulin into normal rats for 4 days, a maneuver that does not significantly reduce beta-cell mass, resulted in dramatically reduced insulin mRNA in islets, but no change in the levels of reg mRNA. We conclude that the diminution in pancreatic beta-cell mass caused by subcutaneous implantation of an insulinoma is associated with reduced reg gene expression and that the increase in beta-cell replication after resection of the tumor is preceded by return of reg gene expression toward normal.
It has been postulated that a glucose transporter of (3 cells (GLUT-2) may be important In glucosestimulated insulin secretion. To determine whether this transporter is constitutively expressed or regulated, we subjected conscious unrestrained Wistar rats to perturbations in glucose homeostasis and qmntitated (-cell GLUT-2 mRNA by in situ hybridization. After 3 hr of hypoglycemia (glucose at 29 ± 5 mg/dl), GLUT-2 and proinsulin mRNA signal deities were reduced by 25% of the level in control rats. After 4 days (blood glucose at 57 ± 7 mg/dl vs. 120 ± 10 mg/dl in saline-infused control rats), GLUT-2 and proinsulin mRNA densities were reduced by 85% and 65%, respectively (P = 0.001). After 12 days (glucose at 54 ± 8 mg/dl), GLUT-2 mRNA signal density was undetectable whereas proinsulin mRNA was reduced by 51%. After 12 days of hypoglycemia, the K. for 3-0-methyl-D-glucose transport in isolated rat islets, normally 18-20 mM, was 2.5 mM. This provides functional evidence of a profound reduction of high K. glucose transporter in P cells. In contrast, GLUT-2 was only slightly reduced by hypoglycemia in liver. To determine the effect of prolonged hyperglycemia, we also infused animal with 50% (wt/vol) glucose for 5 days (glucose at 200 ± 50 mg/dl). Hyperglycemic clamping increased GLUT-2 mRNA by 46% (P = 0.001) whereas proinsulin mRNA doubled (P = 0.001). We conclude that GLUT.2 expression in (3 cells, but not liver, is subject to regulation by certain perturbations in blood glucose homeostasis.In recent years biochemical and molecular studies have revealed the existence of a family of glucose transporters with distinct functional properties but with related primary sequences (1, 2). Glucose uptake into hepatocytes (3) and pancreatic .8 cells (4) occurs with a Km of 17-20 mM and is likely mediated by the so-called glucose transporter 2 (GLUT-2) (5) or L type (6) glucose transporter that has identical primary sequence in the two tissues (4, 7). In most other tissues the Km for glucose uptake is in the 1-2 mM range (8) and is mediated by the low Km transporter that is termed glucose transporter 1 (GLUT-1) (5) or the E type (6). Normal 13cells express GLUT-2 but not GLUT-1 (1, 4, 7) whereas in clonal insulinoma cell lines such as RINm5F, GLUT-1 mRNA predominates (1). The lack of responsiveness to glucose exhibited by such insulinoma lines has been attributed to a reduction in glucose transport that in normal P cells is believed not to be rate-limiting (9). Replacement of GLUT-2 with GLUT-1 in insulinoma cells may render glucose transport rate-limiting, thereby contributing to their glucose insensitivity. Expression of the high Km GLUT-2 transporter may thus be required for the normal insulin response to glucose, which in turn is essential for normal blood glucose homeostasis. Indeed, loss of glucose-stimulated insulin secretion is the earliest known defect in both autoimmune and nonautoimmune forms of diabetes (10-12).It is not known at present if the GLUT-2 gene is constitutively expressed or if it is regulated b...
These studies demonstrate in vivo glucose-regulated insulin secretion from an autologous non-beta cell leading to fasting euglycemia and an improved glucose tolerance, thereby supporting the feasibility of hepatocyte-based insulin gene-therapy for treatment of type 1 diabetes mellitus.
Hence we can conclude that IN administration of LMT NLCs in rats is able to maintain higher brain concentration of LMT compared to IN and oral drug solution.
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