Moon K. Song

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 μg/mL and 5.0 μg/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.

Effects of bovine prostate powder on zinc, glucose, and insulin metabolism in old patients with non-insulin-dependent diabetes mellitus

Since rabbit prostate extract strongly stimulated intestinal zinc absorption and improved the diabetic condition of streptozotocin-induced diabetic rats, we examined the effects of 200 mg bovine prostate powder supplemented with 20 mg zinc (Pro-Z) on the clinical manifestations of older male patients with type II diabetes. Twenty-two male patients who received Pro-Z capsules two to four times per day for 3 months showed reduced mean fasting blood glucose levels from 202 to 169 mg/dL, hemoglobin A1C-(HbA1C) concentrations from 12.2% to 9.5%, and mean values for the 3-hour area response above the fasting glucose concentration (TAFGC) from 141 to 102 mg glucose/dL/h. In eighteen patients who received placebo, mean values for fasting blood glucose decreased from 167 to 165 mg/dL and HbA1C from 10.4% to 10.2%, and for TAFGC increased from 121 to 126 mg glucose/dL/h. No detrimental changes occurred in the liver and kidney function of patients receiving either Pro-Z or placebo. However, blood cholesterol and low-density lipoprotein in patients receiving Pro-Z decreased slightly, whereas values in the placebo group tended to increase. The mean fasting plasma insulin decreased 15.5 to 13.8 microU/mL in subjects given Pro-Z, while the zinc concentration increased from 1.21 to 1.39 microg/mL. In contrast, the mean value for plasma insulin in the placebo group changed from 14.4 to 15.4 microU/mL (worsened), and for zinc, from 1.24 to 1.30 microg/ml. Interestingly, fasting urinary glucose concentrations in subjects given Pro-Z decreased from 1,249 to 378 mg/dL, whereas in those given placebo the values changed from 877 to 778 mg/dL. Since plasma zinc concentrations in both the placebo and the Pro-Z group were normal, these results suggest that biochemical constituents in the prostate including zinc may be involved in controlling glucose metabolism in patients with non-insulin-dependent diabetes mellitus.

Effects of arachidonic acid and cyclo (his-pro) on zinc transport across small intestine and muscle tissues.

Previously we have shown that arachidonic acid (AA) plus zinc or cyclo (his-pro) (CHP) plus zinc improve clinical signs of diabetes in streptozotocin-induced diabetic rats. Since streptozotocin destroys pancreatic beta-cells, we hypothesize that the effect of either AA or CHP, plus zinc on glucose metabolism is via mobilization of intracellular zinc which in turn stimulates glucose uptake by peripheral tissues. We now report the relationship between zinc and AA and between zinc and CHP in controlling zinc influx and efflux across hindlimb muscle cells isolated from three-month old rats. Although CHP increased muscle zinc influx in a dose-dependent manner, AA was not effective. However, AA was more effective in stimulating zinc efflux than CHP. We have previously demonstrated that AA stimulates intestinal zinc uptake and absorption, and now present evidence that CHP also influences intestinal zinc transport. These results suggest that both AA and CHP affect glucose uptake in muscle cells via stimulating intestinal zinc absorption and muscle cell zinc flux.

Body weight reduction in rats by oral treatment with zinc plus cyclo-(His-Pro).

Background and purpose:  We have previously shown that treatment with zinc plus cyclo‐(His‐Pro) (CHP) significantly stimulated synthesis of the insulin degrading enzyme and lowered plasma insulin and blood glucose levels, alongside improving oral glucose tolerance in genetically type 2 diabetic Goto‐Kakizaki (G‐K) rats and in aged obese Sprague‐Dawley (S‐D) rats. Thus, we postulated that zinc plus CHP (ZC) treatment might also improve body weight control in these rats. We therefore determined the effects of ZC treatment on body weights in both genetically diabetic, mature G‐K rats and non‐diabetic, obese S‐D rats.

Effects of cyclo (his–pro) plus zinc on glucose metabolism in genetically diabetic obese mice

Aims:  The specific objective of this study was to determine acute and long‐term effects of cyclo (his–pro) (CHP) plus zinc and l‐histidine (CZH) treatment on glucose metabolism in genetically obese (ob/ob), type 2 diabetic mice.

The intestinal zinc transport in aged rats

To determine if there are any age-related alterations in the intestinal zinc absorption that may contribute to zinc deficiency, we studied the zinc transport across the jejunal segments of 3-, 12- and 24-month-old Fisher 344 male rats using the Ussing chamber technique. We also evaluated the effect of 5 microM arachidonic acid in tissue bathing media. The zinc transport from mucosa to serosa in 24-month-old rats (55.0 +/- 3.5 nmol/h/cm2) was significantly greater than the transport in 12-month-old (30.1 +/- 6.3 nmol/h/cm2) and 3-month-old rats (41.0 +/- 5.2 nmol/h/cm2). There was no age-dependent differences in the zinc transport from the serosa to the mucosa. The addition of 5 microM arachidonic acid to the serosal side only resulted in a significant decrease in zinc transport rate from serosa to mucosa. The magnitude of change in the 24-month-old rats (36.0 +/- 3.9 vs. 26.5 +/- 3.2 nmol/h/cm2) was similar to the change seen in 12-month-old rats (34.5 +/- 4.6 vs. 20.1 +/- 3.5 nmol/h/cm2) and 3-month-old rats (34.5 +/- 4.6 vs. 26.1 +/- 3.9 nmol/h/cm2). The results indicate that intestinal zinc transport is increased in the aged rats, and that arachidonic acid or one of its metabolites may be important regulators of net zinc absorption through their effect on intestinal zinc secretion rates.

FOCAL ENDOTHELIAL CELL DEGENERATION AND PROLIFERATIVE ENDARTERITIS IN TRAUMA-INDUCED EARLY LESIONS OF NECROBIOSIS LIPOIDICA DIABETICORUM

Microangiopalhy is an essential component in diabetic vascular pathology. We report ultrastructural observations of ballooning degeneration involving isolated endo-thelial cells of cutaneous capillaries, while leaving adjacent cndothclial cells relatively intact in six diabetic patients with early lesions of necrobiosis lipoidica induced by trauma. Focal proliferation of cndothclial cells encroaching upon the vascular lumina (obliterative endar-tcritis) was also observed. Lectin studies on biopsy specimens of older lesíons of neerobiosis lipoidica revealed paucity of dermal blood vessels. These observations enable us to gain further insight into the pathophysiological mechanisms that underlie diabetic microvascular disease.

Effects of arachidonic acid plus zinc on glucose disposal in genetically diabetic (ob/ob) mice.

Aim: The present study is designed to determine whether arachidonic acid (AA) plus zinc improves clinical signs of diabetes in genetically diabetic ob/ob mice.

Prostaglandin interacts with steroid sex hormones in the regulation of intestinal zinc transport.

1. The effects of prostaglandins (PGs) E1 and E2, testosterone, 17 beta-estradiol and indomethacin on the intestinal zinc transport rates of male and female rats were compared. 2. PGE1 stimulated Jms (the zinc flux rate from mucosa-to-serosa) of jejunal segments from male rats but inhibited Jms of those from female rats in Ussing chamber experiments. 3. 17 beta-Estradiol inhibited Jms of jejunal segments from male rats, while testosterone stimulated it in those from female rats. However, testosterone inhibited Jms of segments isolated from male rats and 17 beta-estradiol that of those from female rats, while in segments from ovariectomized rats, both of these steroid hormones stimulated Jms. 4. When PGE2 was added to an indomethacin containing medium, Jms significantly increased whereas Jsm (the zinc flux rate from serosa-to-mucosa) decreased further.

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

Background Association of Alzheimers 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 Aβ-40 and Aβ-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 Aβ degradation in brain and plasma tissues. Mechanistic effect of insulin degrading enzyme (IDE) in decreasing blood glucose and brain Aβ 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.