Differential regulation of thyrotropin-releasing hormone receptor mRNA levels by thyroid hormone in vivo and in vitro (GH3 cells).

We studied the effect of thyroid status on thyrotropin-releasing hormone receptor (TRH-R) mRNA levels both in vivo and in vitro (GH3 cells) using a cloned rat TRH-R cDNA by RT-PCR. Experimental hypothyroid rats were produced by total thyroidectomy and were then killed 7 days after the operation. TRH receptor binding in the anterior pituitary and serum TSH level were elevated approximately 2-fold and 8-fold, respectively, in 7 day thyroidectomized rats. TRH-R mRNA levels in hypothyroid rats were also increased significantly compared with those of normal rats. In GH3 cells, however, no significant change of TRH-R mRNA level was observed between cultures treated with triiodothyronine (T3, 10(-9) and 10(-7) M) and the untreated group. The present data indicate that 1) the in vivo effects of thyroid status on TRH-R mRNA levels differ from the in vitro one, and that 2) the down regulation of TRH-R binding by thyroid hormone in GH3 cells may be mediated by translational or post-translational mechanisms.     

Efficacy of Ankaferd Blood Stopper on bone healing in diabetic rats: a stereological and histopathological study

We evaluated the effects of Ankaferd Blood Stopper (ABS) and routine antibiotic prophylaxis (AP) on early healing of bone defects in diabetic rats. We used 48 rats in the study. Diabetes was induced in 24 rats using streptozotocin; the remaining 24 healthy untreated rats served as controls. Twelve of the diabetic rats and 12 of the healthy rats were treated with AP for 3 days before surgery. Bilateral bone defects were created in the mandible of all animals. ABS was applied to the defects on the left sides of the mandibles, while nothing was applied to the right sides. Animals were sacrificed on days 7 and 14 after operation and examined for histopathology and by stereology. The volume of newly formed bone was significantly less in the diabetic rats on both days 7 and 14. Local administration of ABS significantly increased the mean volume of newly formed bone in both diabetic and nondiabetic rats at days 7 and 14. No significant difference in new bone formation was found between AP and ABS treatment in diabetic rats. Both AP and local administration of ABS have beneficial effects on bone healing in diabetic animals.     

Effects of diabetes on glucose oxidation in rat aorta after hypophysectomy and adrenalectomy

The influence of diabetes, hypophysectomy and adrenalectomy on glucose oxidation in rat aorta was studied. Diabetes was induced in normal, adrenalectomized and hypophysectomized-cortisone substituted rats by streptozotocin (65 mg/kg body weight). The oxidation of glucose to CO2 was determined during incubation of rat aorta in vitro for 2-3 hours. The aortic glucose oxidation was reduced after hypophysectomy but was unaffected by adrenalectomy. After streptozotocin treatment the rise in blood glucose concentration was similar in normal, adrenalectomized and hypophysectomized-cortisone substituted rats. In shamoperated diabetic rats the aortic glucose oxidation was reduced after a diabetes duration of 4 days. In adrenalectomized diabetic rats the aortic glucose oxidation was not significantly affected after 4 days but was reduced after a diabetes duration of 14 days. When adrenalectomized diabetic rats were treated with hydrocortisone the aortic glucose oxidation was reduced after diabetes for 4 days. After incubation of normal rat aorta in vitro for 6 hours with cortisol (1 microgram/ml) in the incubation medium a decrease in the aortic glucose oxidation was found. Incubation of aorta with only growth hormone had no effect. These results suggest that cortisol is of importance for the lowered glucose oxidation in diabetic rat aorta.     

The effect of treatment of rats with pituitary growth hormone on the activities of some enzymes involved in fatty acid degradation and synthesis

1. Measurements have been made of the activities of acyl-CoA dehydrogenase, enoyl-CoA hydratase, beta-hydroxyacyl-CoA dehydrogenase and ketothiolase in the livers of rats treated for either 12hr. or 3 days with pituitary growth hormone. 2. There was a significant increase in the activity of acyl-CoA dehydrogenase in rats treated with the hormone for 3 days. 3. Measurements were also made of the lipogenic enzymes acetyl-CoA carboxylase and palmitate synthase in the livers of similarly treated animals. 4. There was a depression of the activity of both enzymes after 12hr. treatment and a further decline after 3 days. 5. The results are discussed in relation to the known increase in the rate of fatty acid oxidation and inhibition of fatty acid synthesis in rats treated with growth hormone.     

Effects of glucagon on physiologic and compensatory renal growth in the rat

Glucagon has been implicated as a growth-promoting hormone in the kidneys of diabetic animals, but its role in the nondiabetic state is unknown. We evaluated the effect of subcutaneous glucagon administration on renal growth in intact rats with two kidneys and after 50% reduction in renal mass. The relative kidney weight was increased in intact rats treated with a glucagon infusion for 7 days (p less than 0.01), but decreased in uninephrectomized rats treated with glucagon (p less than 0.05). Absolute kidney weight gain and rates of renal DNA synthesis were also significantly blunted by glucagon infusion in uninephrectomized rats. These data suggest that 'physiologic' and 'compensatory' renal growth are governed by separate processes. Furthermore, the observation that glucagon promotes renal growth in intact nondiabetic animals supports its possible role as a growth factor in the early stages of diabetes.     

Growth hormone-induced alteration of morphology and tubulin expression in 3T3 preadipose cells

Effects of growth hormone on morphology and cytoskeletal protein expression were examined in 3T3-F442A preadipocytes in serum-free medium. Between 2 and 5 days of culture 2 nM methionyl human growth hormone converted 3T3-F442A cells from a flat fibroblastic morphology to a rounded form with numerous membrane convolutions. Growth hormone treated cultures manifested a 30-40% reduction in cell volume. Growth hormone induced changes in morphology and volume preceded and were independent of lipogenesis. In cells treated with growth hormone, expression of alpha and beta-tubulin as determined by Western blotting was found to increase approximately 50% within 72 h as compared to untreated cells. After 7 days, tubulin levels in growth hormone treated cells were approximately 40% of control levels. This indicated that morphological changes and alteration of tubulin expression were signatures of growth hormone action on 3T3-F442A cells.     

Altered release of growth hormone from dispersed adenohypophysial cells of streptozotocin diabetic rats. I. Effects of growth hormone releasing factor and somatostatin

As growth hormone has been implicated in the "dawn phenomenon," an early morning rise in serum glucose, we have studied the control of growth hormone release in diabetes using an acutely dispersed system of adenohypophysial cells from normal or diabetic rats (65 mg/kg streptozotocin, 8 days before sacrifice; serum glucose, 490 +/- 17 mg/dL). Growth hormone release is normally controlled by the two hypothalamic hormones, growth hormone releasing factor and somatostatin. We have found cells of the diabetic rats exhibit changes in sensitivity that result in increased growth hormone release in static incubation. In normal cells, rat growth hormone releasing factor increases growth hormone release three- to four-fold with an EC50 of 151 +/- 27 pM (n = 7). In contrast, in cells from diabetic rats, there was a significant (twofold) increase in sensitivity to growth hormone releasing factor (EC50 = 75 +/- 15 pM, n = 7) which resulted in increased growth hormone release with lower but not maximal (10 nM) growth hormone releasing factor. Basal nonstimulated release was unchanged. Somatostatin inhibition of stimulated growth hormone release was reduced (n = 7); half-maximal inhibition occurred with 0.21 +/- 0.03 nM (normal) and 0.76 +/- 0.17 nM somatostatin (diabetic). In perifusion the peak secretion rate was significantly lower for diabetic cells stimulated by a maximal dose of growth hormone releasing factor. These studies suggest somatotrophs of diabetic rats have altered sensitivity in vitro to the controlling hormones growth hormone releasing factor and somatostatin.     

Dose response of protein turnover in rat skeletal muscle to triiodothyronine treatment

Skeletal muscle protein turnover has been examined in thyroidectomized rats treated with 0, 0.3, 0.75, 2, 20 and 100 micrograms triidothyronine/day for 7 days by implanted osmotic minipump. Protein synthesis in gastrocnemius, plantaris and soleus muscle were measured in vivo by the constant infusion method and protein degradation estimated as the difference between gross and net rates of synthesis. Serum levels of triidothyronine (T3) and insulin were also measured in addition to oxygen consumption rates in some cases. Compared with untreated intact rats muscle growth rates were unchanged at 0.3, 0.75 and 2 micrograms T3/day and, judging by plasma T3 levels, 0.75 microgram T3/day was a replacement dose. Slowing of growth was evident in the untreated thyroidectomized rats mid-way through the 7 day experimental period (6-7 days after throidectomy). High doses of T3 (20 and 100 micrograms/day) promptly supressed growth but there was subsequent recovery. Protein synthesis and degradation were generally lower in the hypothyroid state and normal or elevated in the hyperthyroid state. The changes in protein synthesis were mediated by changes in both RNA concentration and RNA activity (protein synthesis per unit RNA). Gastrocnemius and plantaris muscles were most responsive in the hypothyroid range. Since protein synthesis is particularly depressed in these muscles in malnutrition, the fall in protein degradation induced by the lowered thyroid status in this condition will be an important adaptive response to conserve protein. The increased protein turnover in the hyperthyroid rats was most marked in the soleus muscle and it is argued that this is necessary to allow the changes in protein composition and metabolic character which occur in response to hyperthyroidism in this muscle.     

Localization of Human Mesenchymal Stem Cells from Umbilical Cord Blood and Their Role in Repair of Diabetic Foot Ulcers in Rats

The aim of this study is to explore the localization of human mesenchymal stem cells from umbilical cord matrix (hMSCs-UC) and the role of these cells in the repair of foot ulcerate tissue in diabetic foot ulcers in rats. A diabetic rat model was established by administering Streptozotocin. Diabetic foot ulceration was defined as non-healing or delayed-healing of empyrosis on the dorsal hind foot after 14 weeks. hMSCs-UC were delivered through the left femoral artery. We evaluated the localization of hMSCs-UC and their role in tissue repair in diabetic foot ulcers by histological analysis, PCR, and immunohistochemical staining. A model for diabetes was established in 54 out of 60 rats (90% success rate) and 27 of these rats were treated with hMSCs-UC. The area of ulceration was significantly and progressively reduced at 7 and 14 days following treatment with hMSCs-UC. This gross observation was strongly supported by the histological changes, including newly developed blood vessels and proliferation of inflammatory cells at 3 days post-treatment, significant increase in granulation tissue at 7 days post-treatment and squamous epithelium or stratified squamous epithelium at 14 days post-treatment. Importantly, human leukocyte antigen type-I (HLA-1) was confirmed in ulcerated tissue by RT-PCR. The expression of cytokeratin 19 was significantly increased in diabetic model rats, with no detectable change in cytokeratin 10. Additionally, both collagens I and III increased in model rats treated with hMSCs-UC, but the ratio of collagen I/III was less significant in treated rats compared with control rats. These results suggest that hMSCs-UC specifically localize to the target ulcerated tissue and may promote the epithelialization of ulcerated tissue by stimulating the release of cytokeratin 19 from keratinocytes and extracellular matrix formation.     

Rapid pacing-induced preconditioning is recaptured by farnesol treatment in hearts of cholesterol-fed rats: Role of polyprenyl derivatives and nitric oxide

Sodium selenate, administered intraperitoneally (i.p.), resulted in an improvement in glucose tolerance in treated diabetic rats. Fed rat plasma glucose levels were reduced by selenate treatment in streptozotocin diabetic rats. The lowest values of blood glucose were reached within 3 weeks of beginning the treatment. Food and fluid consumption was reduced in treated compared to untreated diabetic rats. Diabetic treated rats did not release insulin in response to a glucose challenge and insulin release in response to a challenge was markedly reduced in control treated rats. Assessment of heart function using a working heart apparatus showed that treated diabetic rats with improved blood glucose levels had normal heart function at 8 weeks of diabetes in contrast to hearts from non-treated diabetics. This study extends previous observations on the in vivo insulin-like effects of sodium selenate.     

Effect of subcutaneous pancreatic tissue transplants on streptozotocin-induced diabetes in rats. II. Endocrine and metabolic functions.

The present study examines the effect of subcutaneous pancreatic tissue grafts (SPTG) on endocrine and metabolic functions in streptozotocin (STZ)-induced diabetic rats using radioimmunoassay and biochemical techniques. SPTG survived even after 15 weeks of transplantation and significantly improved the weight of STZ-diabetic rats over a 15-week period. Although blood glucose-, cholesterol-, and glycosylated-haemoglobin (GHb) levels were not significantly lower in STZ-diabetic rats treated with SPTG, the values of these biochemical parameters were lower than those in untreated diabetic rats. Plasma and pancreatic immunoreactive C-peptide (IRCP) levels did not improve after SPTG (IRCP expressed as mean +/- standard deviation were 0.22 +/- 0.07, 0.072 +/- 0.02 and 0.08 +/- 0.03 pg ml-1 in the plasma non-diabetic diabetic and treated rats respectively, while IRCP levels in the pancreas of the non-diabetic, diabetic and treated rats were 433.8 +/- 0.1, 22.9 +/- 0.01 and 10.4 +/- 0.01 pg mg tissue-1 respectively). SPTG, however, improved plasma immunoreactive insulin (IRI) levels in both plasma and pancreas. IRI values in plasma were 54.7 +/- 13.6, 18.0 +/- 5.0 and 22.1 +/- 4.3 microUI ml-1 in non-diabetic, diabetic and treated rats respectively and were 277.3 +/- 37.1, 14.7 +/- 1.8 and 30.3 +/- 15.9 microIU micrograms tissue-1 in the pancreas of non-diabetic, diabetic and treated rats respectively. There was improvement in immunoreactive glucagon (IRG) levels after SPTG. IRG values in the plasma of non-diabetic, diabetic and treated rats were 147.0 +/- 10.7, 408.0 +/- 76.5 and 247.7 +/- 3 pg ml-1 respectively whereas, IRG measured in the pancreas was 1642.25 +/- 424.23, 1899.0 +/- 290.4 and 1714.1 +/- 301.98 pg micrograms tissue-1 in non-diabetic, diabetic and treated rats, respectively. The pancreas:plasma ratio of pancreatic hormones was deranged in untreated diabetes but improved after SPTG. In conclusion, SPTG significantly improved the weight gain, pancreatic insulin content, plasma IRG and pancreas: plasma ratio of IRCP, IRI and IRG. It also reduced blood glucose-, cholesterol-, and glycosylated-hemoglobin levels in STZ-diabetic rats.     

Immunoneutralization of endogenous glucagon-like peptide-2 reduces adaptive intestinal growth in diabetic rats

Supraphysiological doses of glucagon-like peptide-2 (GLP-2) have been shown to induce intestinal growth by increasing villus height and crypt depth and by decreasing apoptosis, but a physiological effect of GLP-2 has not yet been demonstrated. Earlier, we found elevated levels of endogenous GLP-2 in untreated streptozotocin diabetic rats associated with marked intestinal growth. In the present study, we investigated the role of endogenous GLP-2 for this adaptive response. We included four groups of six rats: (1) diabetic rats treated with saline, (2) diabetic rats treated with non-specific antibodies, (3) diabetic rats treated with polyclonal GLP-2 antibodies and (4) non-diabetic control rats treated with saline. All animals were treated with once daily intraperitoneal injections for 13 days and killed on day 14. Diabetic rats treated with saline or non-specific antibodies had a significantly (P<0.01) increased area of mucosa (13.00+/-0.64 and 13.37+/-0.60 mm(2), respectively) in the proximal part of the small intestine compared with non-diabetic controls (7.97+/-0.70 mm(2)). In contrast, diabetic rats treated with GLP-2 antibodies had a significantly (P<0.01) smaller increase in area of mucosa in the proximal part of the small intestine (10.84+/-0.44 mm(2)). Antibody treatment had no effect on body weight, blood glucose concentrations and food intake. Thus, blocking of endogenous GLP-2 in a model of adaptive intestinal growth reduces the growth response, providing strong evidence for a physiological growth factor function of GLP-2.     

Systemic natural killer activity following cardiac engraftment in the rat: lack of correlation with graft survival

The systemic NK activity was studied both in untreated rats which acutely reject allogeneic heterotopic heart grafts and in cyclosporine-treated rats which tolerate their transplants. The trend and magnitude of changes in NK activity were similar at all time points for the two animal groups. Compared to naive rats, peak NK activity was noted 7-8 days after engraftment in untreated rats and 7-12 days after engraftment in cyclosporine-treated hosts. In both groups, NK activity returned to normal levels by 3 weeks. No evidence could be found for inactivation of NK cells or their precursors in vivo in ungrafted rats undergoing cyclosporine treatment alone. These data are consistent with prior studies and suggest that non-specific cytotoxic activity does not represent a crucial force contributing to acute rejection of vascularized organ grafts.     

The influence of biosynthetic human growth hormone on biomechanical properties and collagen formation in granulation tissue

Biomechanical properties and collagen formation in the granulation tissue of cellulose sponges, implanted subcutaneously in male rats for 7, 10 and 16 days, were tested after treatment with biosynthetic human growth hormone given subcutaneously in a dose of 0.5 mg/kg body weight/day. At each implantation period, one group started hormone treatment at the day of implantation and another group started hormone treatment 7 days prior to implantation. After 7 days of implantation, increases in maximum stress (36 per cent), relative failure energy (48 per cent) and strain at maximum stress (25 per cent) were found when treatment was started 7 days prior to implantation. After 10 days of implantation an increase in relative failure energy (60 per cent) was found when treatment was started 7 days prior to implantation. No differences were found after 7 and 10 days of implantation when treatment was started at the day of implantation. After 16 days of implantation, no influence on mechanical strength was found in any of the hormone treated groups. The collagen deposition after 7, 10 and 16 days did not differ in any of the hormone treated groups compared to controls.     

Precocious induction of tryptophan dioxygenase by glucocorticoid in suckling rats and correlation with change in glucocorticoid receptor

When young rats (less than 14 days old) were treated once a day for 2 days with 100 micrograms/100 g body weight of dexamethasone, their liver cytosol showed a sharp new peak of glucocorticoid binding protein (peak C) eluted with 0.14 M NaCl on DEAE-cellulose chromatography. When the young rats were given a single injection of the hormone, the chromatogram showed a dominant peak of binding protein (peak B), eluted with 0.07 M NaCl, which was similar to that in untreated rats. The appearance of peak C on two treatments of young rats with hormone was confirmed by both in vivo and in vitro labeling and also studies on the nuclear fraction. Peaks B and C were specific hormone-binding proteins as shown with excess unlabeled hormone. The appearance of peak C was concomitant with the precocious induction of tryptophan dioxygenase in the liver of the young rats, and pretreatment with two injections of dexamethasone were necessary for maximal enzyme induction. On the other hand, in adult rats a single injection of dexamethasone (of 20 micrograms/100 g body weight or more) was enough to cause the appearance of peak C and induce tryptophan dioxygenase activity maximally; an additional injection of the hormone did not change the chromatographic pattern of the specific binding or the enzyme activity. For this effect in young rats, dexamethasone could not be replaced by other hormones such as glucagon, growth hormone, thyroid hormones, insulin, sex steroids or short-acting glucocorticoid.     

Effects of streptozotocin-diabetes and l-thyroxine treatment on plasma amino acid levels in thyroidectomized rats

1) Thirty days after surgical thyroidectomy, one group of rats were made diabetic by treatment with streptozotocin and were studied for the next 14 days. These diabetic thyroidectomized animals were similar in body weight to their thyroidectomized controls but had higher plasma concentrations of most amino acids. 2) Treatment with 0.5, 1.0 or 2.0 micrograms of L-thyroxine/100 g body wt for 7 days prior to sacrifice produced no changes in either parameter in the diabetic thyroidectomized animals. On the contrary, in thyroidectomized controls, the L-thyroxine treatment was followed by a dose-dependent increment in body weight. In these animals, the administration of 0.5 microgram of L-thyroxine per day was associated with a marked rise in the plasma level of most amino acids, while only basic amino acid levels increased with 1.0 microgram, and levels decreased with 2.0 micrograms. 3) In the diabetic thyroidectomized rats treated with insulin for the last 7 days before sacrifice, body weight gain and the biphasic change of plasma amino acid levels were restored. 4) It is proposed that treatment of thyroidectomized controls with small doses of L-thyroxine accelerate protein breakdown accompanied by minor changes in amino acid utilization, while this latter effect increases with higher doses of the hormone. 5) Present results demonstrate that a certain amount of circulating insulin is required to obtain the response to exogenous thyroxine in diabetic thyroidectomized animals. Results are discussed in terms of the role of interhormone synergism as it affects normal sensitivity of the different hormones.     

Effective control of glycemic status and toxicity in Zucker diabetic fatty rats with an orally administered vanadate compound

A novel black tea decoction containing vanadate has successfully replaced insulin in a rat model of insulin-dependent diabetes but is untested in non-insulin-dependent diabetic animals. A tea-vanadate decoction (TV) containing 30 or 40 mg sodium orthovanadate was administered by oral gavage to two groups of Zucker diabetic fatty rats and a conventional water vehicle containing 30 or 40 mg of sodium orthovanadate to two others. In the latter group receiving the 30-mg dose, vanadate induced diarrhea in 50% of the rats and death in 10%. In contrast, TV-treated rats had no incidence of diarrhea and no deaths. Symptoms were more severe in both groups with higher vanadate doses, so these were discontinued. After approximately 16 weeks, the level of vanadium in plasma and tissue extracts was negligible in a further group of untreated rats but highly elevated after vanadate treatment. Vanadium levels were not significantly different between the TV-treated diabetic rats and the diabetic rats given vanadate in a water vehicle. Over the 115 days of the study, blood glucose levels increased from approximately 17 to 25 mmol/L in untreated diabetic rats. This was effectively lowered (to <10 mmol/L) by TV treatment. Fasting blood glucose levels were 5, 7, and 20 mmol/L in control (nondiabetic, untreated), TV-treated and untreated diabetic rats, respectively. Rats required treatment with TV for only approximately 50% of the days in the study. Increase in body mass during the study was significantly lower in untreated diabetic rats (despite higher food intake) than the other groups. Body mass gain and food intake were normal in TV-treated rats. Water intake was 28 mL/rat daily in control rats, 130 mL/rat daily in untreated diabetic rats, and 52 mL/rat daily in TV-treated diabetic rats. Plasma creatinine and aspartate aminotransferase levels were significantly depressed in untreated diabetic rats, and TV treatment normalized this. Our results demonstrate that a novel oral therapy containing black tea and vanadate possesses a striking capacity to regulate glucose and attenuates complications in a rat model of type II diabetes.     

Modification by bovine growth hormone of liver plasma membrane enzymes, phospholipids, and circular dichroism

Liver plasma membrane phospholipid distribution, protein conformation, and 5′-nucleotidase, Mg²⁺-adenosine triphosphatase and (Na⁺ + K⁺)-adenosine triphosphatase specific activities, were shown to depend on pituitary status and treatment with bovine growth hormone.In whole liver homogenates, hypophysectomy produced a decrease in the proportion of phosphatidyl serine, lysophosphatidyl choline, and phosphatidic acid and diphosphatidyl glycerol and an increased proportion of phosphatidyl ethanolamine. The phospholipid distribution in liver plasma membranes was the same for normal and hypophysectomized rats. Plasma membranes obtained from bovine growth hormone-treated hypophysectomized rats had approximately 50%, more phosphatidyl serine than membranes obtained from untreated hypophysectomized or normal rats.Plasma membranes from hypophysectomized rats had 75% of the 5′-nucleotidase, the same level of (Na⁺ + K⁺)-adenosine triphosphatase, and twice the Mg²⁺-adenosine triphosphatase of membranes from normal rats. Twelve hours after administration of bovine growth hormone to hypophysectomized rats, (Na⁺ + K⁺)-adenosine triphosphatase had almost doubled and Mg²⁺-adenosine triphosphatase decreased by 50%. 5′-Nucleotidase remained unchanged. Twenty-four hours after bovine growth hormone administration, both (Na⁺ + K⁺)-adenosine triphosphatase and 5′-nucleotidase had increased. Mg²⁺-adenosine triphosphatase was 23% of the baseline level of untreated hypophysectomized rats. Treatment for 3 days or 5 days increased the 5′-nucleotidase 2-fold.Circular dichroism spectra of liver plasma membranes isolated from hypophysectomized rats consistently showed greater negative ellipticity in the far ultraviolet range (250-190 nm) than those from normal rats or rats treated with bovine growth hormone.     

Miglitol (BAY m 1099) Treatment of Diabetic Hypothalamic-Dietary Obese Rats Improves Islet Response to Glucose

AXEN, KATHLEEN V., XUE LI, AND ANTHONY SCLAFANI. Miglitol (BAY m 1099) treatment of diabetic hypothalamic-dietary obese rats improves islet response to glucose. Obes Res. 1999;7:83–89. Objective : The well-absorbed α-glucosidase inhibitor, miglitol (BAY m 1099), was included in the diets of hypothalamic-dietary obese diabetic rats to investigate its ability to improve glycemia and thereby reverse glucotoxic effects on islet secretory response. Research Methods and Procedures : Female rats received bilateral electrolytic lesions of the ventromedial hypothalamus and were fed high-fat, sucrosesupplemented diets until hyperinsulinemia and hyperglycemia were observed after 3 hours of food deprivation (nonfed). Diabetic animals were assigned to miglitol-treated (40 mg/17 g of diet) or untreated groups for 3 weeks; pancreatic islets were isolated for incubation experiments. Results : No differences in food intake, body weights, or nonfed plasma glucose or insulin levels were seen between treated and untreated diabetic rats. Islets isolated from untreated diabetic rats showed elevated basal insulin release and no insulin secretory response to an elevation in glucose concentration. In contrast, islets obtained from miglitol-treated rats showed more normal basal release and a significant insulin secretory response to glucose. Incubation of islets, obtained from normal control rats or untreated diabetic rats, in media containing miglitol at levels estimated to exist in plasma of treated rats had no effect on islet insulin secretory responses to glucose. Discussion : Islet secretory response was improved despite continued hyperglycemia and severe insulin resistance. Miglitol treatment may improve islet sensitivity to glucose either through effects on islet metabolism requiring prolonged exposure or by improvement in postmeal glycemia, despite persistent hyperglycemia.