Metabolic relationship between diabetes and Alzheimer's Disease affected by Cyclo(His-Pro) plus zinc treatment.

BACKGROUND: Association of Alzheimer's Disease (AD) with Type 2 Diabetes (T2D) has been well established. Cyclo(His-Pro) plus zinc (Cyclo-Z) treatment ameliorated diabetes in rats and similar improvements have been seen in human patients. Treatment of amyloid precursor protein (APP) transgenic mice with Cyclo-Z exhibited memory improvements and significantly reduced Aß-40 and Aß-42 protein levels in the brain tissues of the mice. SCOPE OF REVIEW: Metabolic relationship between AD and T2D will be described with particular attention to insulin sensitivity and Aß degradation in brain and plasma tissues. Mechanistic effect of insulin degrading enzyme (IDE) in decreasing blood glucose and brain Aß levels will be elucidated. Cyclo-Z effects on these biochemical parameters will be discussed. MAJOR CONCLUSION: Stimulation of IDE synthesis is effective for the clinical treatment of metabolic diseases including AD and T2D. GENERAL SIGNIFICANCE: Cyclo-Z might be the effective treatment of AD and T2D by stimulating IDE synthesis.

Different roles of zinc plus arachidonic acid on insulin sensitivity between high fructose- and high fat-fed rats.

AIMS: This study was to determine the effects of zinc plus arachidonic acid (ZA) treatment on the insulin action in the specific ZA target organs using hyperinsulinemic euglycemic clamp method. MAIN METHODS: 18 Sprague-Dawley rats weighing ~130 g were divided into 3 groups of 6 rats and treated them with 1) normal rat chow, 2) high fructose (60.0%) diet only, or 3) the same fructose diet plus drinking water containing 10mg zinc plus 50mg arachidonic acid (AA)/L. In a separate study, male Wistar rats weighing ~250 g were fed normal rat chow (n=4) or high fat (66.5%) diet with drinking water containing zero (n=9) or 10mg AA plus 20mg zinc /L (n=9). After 4 week treatment, insulin action was assessed using the hyperinsulinemic eguglycemic clamp technique. KEY FINDINGS: High fructose feeding impaired suppression of hepatic glucose output by insulin compared to controls during the clamp procedure (4.39 vs. 2.35 mg/kg/min; p<0.05). However, ZA treatment in high fructose-fed rats showed a significant improvement of hepatic insulin sensitivity compared to non-treatment controls (4.39 vs. 2.18 mg/kg/min; p<0.05). Glucose infusion rates in Wistar rats maintained on a high fat diet (HFD) were significantly lower compared to control rats (22.8 ± 1.3 vs. 31.9 ± 1.4 mg/kg/min; p<0.05). ZA treatment significantly improved (~43%) peripheral tissue insulin sensitivity in HFD fed animals (26.7 ± 1.3 [n=9] vs. 22.8 ± 1.3mg/kg/min; p<0.05). SIGNIFICANCE: These data demonstrate that ZA treatment is effective in improving glucose utilization in hyperglycemic rats receiving either a high-fructose or a high-fat diet.

Brainstem thyrotropin-releasing hormone regulates food intake through vagal-dependent cholinergic stimulation of ghrelin secretion.

The brainstem is essential for mediating energetic response to starvation. Brain stem TRH is synthesized in caudal raphe nuclei innervating brainstem and spinal vagal and sympathetic motor neurons. Intracisternal injection (ic) of a stable TRH analog RX77368 (7.5-25 ng) dose-dependently stimulated solid food intake by 2.4- to 3-fold in freely fed rats, an effect that lasted for 3 h. By contrast, RX77368 at 25 ng injected into the lateral ventricle induced a delayed and insignificant orexigenic effect only in the first hour. In pentobarbital-anesthetized rats, RX77368 (50 ng) ic induced a significant bipeak increase in serum total ghrelin levels from the basal of 8.7+/-1.7 ng/ml to 13.4+/-2.4 ng/ml at 30 min and 14.5+/-2.0 ng/ml at 90 min, which was prevented by either bilateral vagotomy (-60 min) or atropine pretreatment (2 mg/kg, -30 min) but magnified by bilateral adrenalectomy (-60 min). TRH analog ic-induced food intake in freely fed rats was abolished by either peripheral atropine or ghrelin receptor antagonist (D-Lys-3)-GHRP-6 (10 micromol/kg) or ic Y1 receptor antagonist 122PU91 (10 nmol/5 microl). Brain stem TRH mRNA and TRH receptor 1 mRNA increased by 57-58 and 33-35% in 24- and 48-h fasted rats and returned to the fed levels after a 3-h refeeding. Natural food intake in overnight fasted rats was significantly reduced by ic TRH antibody, ic Y1 antagonist, and peripheral atropine. These data establish a physiological role of brainstem TRH in vagal-ghrelin-mediated stimulation of food intake, which involves interaction with brainstem Y1 receptors.

Raw vegetable food containing high cyclo (his-pro) improved insulin sensitivity and body weight control.

Cyclo (his-pro), controlled-energy diet, soy protein hydrolysate (SPH), and raw vegetable food (RVF) are known to improve insulin sensitivity and body weight (BW) control. Enhancement of high cyclo (his-pro) content in SPH (HCS) was performed by refluxing SPH with 1 N KH(2)CO(3) dissolved in 70% ethanol for 2 weeks at room temperature. Using this material, we examined the effects of HCS plus RVF on glucose metabolism and BW control in genetically diabetic Goto-Kakizaki (G-K) and insulin-resistant aged overweight Sprague-Dawley (S-D) rats. Thirty 7-week-old G-K rats and 18 16- to 18-month-old S-D rats were divided into 3 groups and treated with normal chow (NC), RVF diet, or HCS diet for 8 weeks. Raw vegetable food diet was made of 1:3 RVF and 2:3 NC; HCS diet was made of 1:27 portion HCS, 8:27 RVF, and 2:3 NC. Oral glucose tolerance significantly improved in both RVF- (P<.01) and HCS-treated (P<.001) G-K rats and worsened in NC-fed rats compared with the baseline values. Similarly, oral glucose tolerance also improved in aged overweight S-D rats when treated with RVF (P<.05) and with HCS (P<.01), compared with the baseline values. Although HCS diet treatment very significantly lowered fed plasma insulin levels compared with NC diet treatment in G-K rats (P<.01), RVF diet treatment alone did not decrease plasma insulin levels. In contrast, there was no change of insulin levels in overweight aged S-D rats after either RVF or HCS diet treatment. Postfeeding glucose levels in G-K rats fed RVF or HCS significantly fell, compared with the rats fed NC (P<.05). Interestingly, fasting blood glucose levels in RVF- or HCS-fed rats were very significantly lower than in NC-fed rats (P<.001). There was no change of blood glucose levels in S-D rats due to treatments with different diet. In G-K rats, food intake did not decrease during the first 3 weeks but fell very significantly from the fifth to eighth weeks with RVF (P<.01) and HCS (P<.001) treatments in G-K rats. However, food intake reduction in aged S-D rats was shown only for the HCS-treated rat group (P<.05). Water intake slightly decreased in G-K rats with either RVF or HCS treatment (P<.05) but very significantly decreased in S-D rats with HCS treatment (P<.01). Body weight gain in young G-K rats and BW in aged S-D rats significantly decreased only when rats were treated with HCS diet (P<.05). These data suggest that regular consumption of HCS diet helps to control blood glucose metabolism in diabetic G-K rats and BW control in aged obese S-D rats.

Altered glucose and insulin responses to brain medullary thyrotropin-releasing hormone (TRH)-induced autonomic activation in type 2 diabetic Goto-Kakizaki rats.

Insulin secretion is impaired in type 2 diabetes (T2D). The insulin and glucose responses to central autonomic activation induced by excitation of brain medullary TRH receptors were studied in T2D Goto-Kakizaki (GK) rats. Blood glucose levels in normally fed, pentobarbital-anesthetized GK and nondiabetic Wistar rats were 193 and 119 mg/100 ml in males and 214 and 131 mg/100 ml in females. Intracisternal injection (ic) of the stable TRH analog RX 77368 (10 ng) induced significantly higher insulin response in both genders of overnight-fasted GK rats compared with Wistar rats and slightly increased blood glucose in female Wistar rats but significantly decreased it from 193 to 145 mg/100 ml in female GK rats. RX 77368 (50 ng) ic induced markedly greater glucose and relatively weaker insulin responses in male GK rats than Wistar rats. Bilateral vagotomy blocked ic RX 77368-induced insulin secretion, whereas adrenalectomy abolished its hyperglycemic effect. In adrenalectomized male GK but not Wistar rats, ic RX 77368 (50 ng) dramatically increased serum insulin levels by 6.5-fold and decreased blood glucose levels from 154 to 98 mg/100 ml; these changes were prevented by vagotomy. GK rats had higher basal pancreatic insulin II mRNA levels but a lower response to ic RX 77368 (50 ng) compared with Wistar rats. These results indicate that central-vagal activation-induced insulin secretion is susceptible in T2D GK rats. However, the dominant sympathetic-adrenal response to medullary TRH plays a suppressing role on vagal-mediated insulin secretion. This unbalanced vago-sympathetic activation by medullary TRH may contribute to the impaired insulin secretion in T2D.

Anti-hyperglycemic activity of zinc plus cyclo (his-pro) in genetically diabetic Goto-Kakizaki and aged rats.

We previously reported that treatment of streptozotocin-induced diabetic rats with zinc plus cyclo (his-pro) (CHP) decreased fed blood glucose levels and water intake. The present study was conducted to examine the dose-dependent, acute, and chronic treatment effects of CHP on oral glucose tolerance (OGT), fed blood glucose levels, water intake, and plasma insulin levels in young and aged Sprague-Dawley (S-D) rats, nondiabetic Wistar rats, and genetically diabetic Goto-Kakizaki (G-K) rats. Acute gastric gavage of 10 mg zinc plus 1.0 mg CHP/kg body weight significantly improved OGT in 4- and 13-month-old nondiabetic S-D rats and in 2-month-old diabetic G-K rats. Young S-D and G-K rats returned to pretreatment OGT values 1 week after acute gavage of zinc plus CHP (ZC), but improved OGT values persisted for at least 1 week after gavage in aged S-D rats. OGT values and fed blood glucose decreased to the greatest extent among other treatments when G-K rats were given free access to drinking water containing 1.0 to 1.5 mg CHP/L plus 10 mg zinc/L for 2 weeks. Although food and water intake showed a tendency to decrease, no statistically significant differences were observed in young G-K rats. Plasma insulin levels and blood glucose levels in both normal and diabetic G-K rats decreased with 2-week treatment with ZC. To test the direct effects of ZC on muscle tissue, we observed the effect of various doses of ZC on normal and G-K rat muscle slices. The optimal level of CHP alone for maximal muscle glucose uptake in muscle slices from normal rats was 10 microg/mL and 5.0 microg/mL in G-K rats, and ZC stimulated glucose uptake. However, no statistically significant difference was demonstrated between normal and G-K rat tissues in this study. These results indicate that oral intake of an optimal dose of ZC stimulates blood glucose metabolism, probably by stimulating muscle glucose utilization.

Antidiabetic actions of arachidonic acid and zinc in genetically diabetic Goto-Kakizaki rats.

In previous studies, we showed that feeding arachidonic acid (AA) supplemented with a fixed amount of zinc lowered blood glucose concentrations in the fed state and water intake in rats with streptozotocin-induced diabetes. The present study was designed to determine dose-dependent effects of AA supplemented with a fixed amount of zinc on fed blood glucose levels, water intake, and glucose tolerance in genetically type 2 diabetic Goto-Kakizaki (G-K) Wistar rats. In an acute study, 20 mg/kg AA plus 10 mg/kg zinc administered via gastric gavage significantly improved oral glucose tolerance in G-K rats when compared to rats given distilled water (DW) only. When rats were treated chronically (2 weeks) with increasing doses of AA in drinking water, fed blood glucose concentrations and water intake were maximally decreased with diets containing 20 or 30 mg/L AA plus 10 mg/L zinc. Three-hour average area-above-fasting glucose concentrations (TAFGC; index of oral glucose tolerance) in diabetic G-K rats treated with 10, 20, or 30 mg/L AA plus 10 mg/L zinc for 2 weeks were significantly decreased relative to DW-treated rats. The effect on TAFGC values was maintained for an additional 2 weeks after cessation of treatment. Plasma insulin levels significantly increased in rats treated with 20 mg/L AA only or 10 mg/L AA plus 10 mg/L zinc, but not in rats treated with 20 or 30 mg/L AA plus 10 mg/L zinc, which are the most effective doses for the improvement of clinical signs of diabetes in G-K rats. In in vitro assays, 0.2 mg/mL AA in the incubation media was optimal for glucose uptake in isolated soleus muscle slices. These results suggest that treatment of genetically diabetic G-K rats with AA plus zinc lowers blood glucose levels via improvement of insulin sensitivity.

Metabolism of glucose by rat pancreatic islets and kidney: comparison of membrane preparations with intact tissue.

INTRODUCTION: Insulin secretion in the pancreatic islet of Langerhans is closely related to glucose oxidation. Our previous membrane preparations from the islet of Langerhans and kidney contained Na+/K+ ATPase. Although ATP is a modulator of insulin release, we have not demonstrated that membranes contain glycolytic enzymes. AIMS: To compare glucose oxidation in intact islets of Langerhans with that seen in islet membranes, and to examine renal tissue because of easy access to this tissue and because our previous work contrasted islets and kidney Na+/K+ ATPase activity. METHODOLOGY: To examine whether membrane preparations of both islets and kidney contain glycolytic activity, we designed an apparatus that determines tissue glucose oxidation rates by measuring 14CO2 production from 14C-1-D-glucose. In contrast to previous methods, O2 was supplied and pH was maintained in physiologic ranges throughout the incubations. RESULTS: At 5.5 mM glucose, oxidation was linear over 2 hours in intact islets and kidney. Islets produced approximately twice the 14CO2 as kidney, or 1000 nmol CO2/mg protein/hour. Membranes oxidized glucose at less than 10% of the rates observed with intact tissue. Concentration dependency was linear from 0-11.0 mM glucose; however, at 16.5 mM, oxidation decreased to less than half of that seen at 11.0 mM. CONCLUSION: Our "membrane" preparations contain some glycolytic activity but are unlikely to contribute significant amounts of ATP in most studies of ATP hydrolysis, such as that seen in experiments that measure ATPase activity.