Hydrogen sulfide (H(2)S) is emerging as a physiological neuromodulator as well as a smooth muscle relaxant. We submit the first evidence that blood H(2)S levels are significantly lower in fasting blood obtained from type 2 diabetes patients compared with age-matched healthy subjects, and in streptozotocin-treated diabetic rats compared with control Sprague-Dawley rats. We further observed that supplementation with H(2)S or an endogenous precursor of H(2)S (l-cysteine) in culture medium prevents IL-8 and MCP-1 secretion in high-glucose-treated human U937 monocytes. These first observations led to the hypothesis that lower blood H(2)S levels may contribute to the vascular inflammation seen in diabetes.
This study examined the hypothesis that L-cysteine supplementation can lower insulin resistance, glycemia, oxidative stress and markers of vascular inflammation in type 2 diabetes using zucker diabetic rats (ZDF) rats as a model. Starting at age of 6 wks, ZDF rats were supplemented orally (daily gavage, 8 wks) with saline-placebo (D) or L-cysteine (LC, 1mg/KgBW) and fed a high calorie diet. 6 weeks age rats without any supplementation were considered baseline (BL) rats. D rats showed elevated fasting blood glucose, GHb, CRP, and MCP-1 when compared with BL in which there was no onset of diabetes. LC supplementation significantly lowered blood levels of glucose (18%, p=0.05), GHb (8%, p=0.02), CRP (23%, p=0.02), MCP-1 (32%, p=0.01) and insulin resistance (25%) compared with levels seen in saline-supplemented D. There was a decrease in plasma protein oxidation levels (p<0.01); however, GSH levels were similar in LC and D groups. While LC did not change blood hematocrit or levels of transaminases, it did lower alkaline phosphatase (29%, p=0.01) levels in comparison to D. Western blotting analyses of liver showed increased activation of NFkB and Akt (50% pNFkB and 20% pAkt) in D compared with BL. LC supplementation inhibited these effects (17% pAkt, 18% pNFkB). This is the first report showing L-cysteine supplementation can lower glycemia and markers of vascular inflammation in diabetes apparently mediated by preventing NFkB activation in a diabetic animal model.
Aim
Chromium and cysteine supplementation can improve glucose metabolism in animal studies. This study examined the hypothesis that a cysteinate complex of chromium is significantly beneficial than either of them in lowering blood glucose and vascular inflammation markers in ZDF rats.
Methods
Starting at the age of 6 wks, ZDF rats were supplemented orally (daily gavages for 8 more wks) with saline-placebo (D) or chromium (400µg Cr/KgBW) as chromium-dinicocysteinate (CDNC), chromium-dinicotinate (CDN), or chromium-picolinate (CP) or equimolar L-cysteine (LC, img/Kg BW), and fed Purina 5008 diet for 8 wks. ZDF rats of 6 wks age before any supplementations and onset of diabetes were considered as baseline (BL).
Results
D rats showed elevated levels of fasting blood glucose, HbA1, CRP, MCP-1, ICAM-1 and oxidative stress (LP) and lower adiponectin and vitamin C, when compared to BL rats. In comparison to D group, CDNC group had significantly lower blood glucose, HbA1, CRP, MCP-1, ICAM-1 and LP and increased vitamin C and adiponectin levels. CDN, CP or LC showed significantly less or no effect on these biomarkers. Only CDNC lowered blood creatinine levels in comparison to D. While CDN and CP had no effect, activation of NFkB, Akt and GLUT-2 levels were decreased, IRS-1 activation increased in livers of CDNC-rats. CDNC effect on glycemia, NFkB, Akt and IRS-1 in liver was significantly greater compared with LC. Blood chromium levels did not differ between Cr-groups. Exogenous vitamin C supplementation significantly inhibited MCP-1 secretion in U937 monocytes cultured in high-glucose-medium.
Conclusions
CDNC is a potent hypoglycemic compound with anti-inflammatory activity apparently mediated by elevated blood vitamin C and adiponectin and inhibition of NFkB, Akt, and Glut-2 and increased IRS-1 activation in livers of type 2 diabetic rats.
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