OBJECTIVE -Chromium picolinate (CrPic) supplementation has been suggested to improve glycemia, but there are conflicting reports on efficacy. We sought to determine the effect of CrPic on insulin sensitivity, glycemic control, and body composition in subjects with type 2 diabetes.RESEARCH DESIGN AND METHODS -Thirty-seven subjects with type 2 diabetes were evaluated. After baseline, subjects were placed on a sulfonylurea (glipizide gastrointestinal therapeutic system 5 mg/day) with placebo for 3 months. Subjects were then randomized in a double-blind fashion to receive either the sulfonylurea plus placebo (n ϭ 12) or the sulfonylurea plus 1,000 g Cr as CrPic (n ϭ 17) for 6 months. Body composition, insulin sensitivity, and glycemic control were determined at baseline, end of the 3-month single-blind placebo phase, and end of study.RESULTS -Subjects randomized to sulfonylurea/placebo, as opposed to those randomized to sulfonylurea/CrPic, had a significant increase in body weight (2.2 kg, P Ͻ 0.001 vs. 0.9 kg, P ϭ 0.11), percent body fat (1.17%, P Ͻ 0.001 vs. 0.12%, P ϭ 0.7), and total abdominal fat (32.5 cm 2 , P Ͻ 0.05 vs. 12.2 cm 2 , P Ͻ 0.10) from baseline. Subjects randomized to sulfonylurea/CrPic had significant improvements in insulin sensitivity corrected for fat-free mass (28.8, P Ͻ 0.05 vs. 15.9, P ϭ 0.4), GHb (Ϫ1.16%, P Ͻ 0.005 vs. Ϫ0.4%, P ϭ 0.3), and free fatty acids (Ϫ0.2 mmol/l, P Ͻ 0.001 vs. Ϫ0.12 mmol/l, P Ͻ 0.03) as opposed to sulfonylurea/placebo.CONCLUSIONS -This study demonstrates that CrPic supplementation in subjects with type 2 diabetes who are taking sulfonylurea agents significantly improves insulin sensitivity and glucose control. Further, CrPic supplementation significantly attenuated body weight gain and visceral fat accumulation compared with the placebo group. Diabetes Care 29:1826 -1832, 2006T he primary strategy to improve metabolic control in patients with type 2 diabetes consists of lifestyle modification combined with pharmacologic intervention (1). However, alternative strategies, e.g., nutritional supplementation with over-the-counter agents, are extensively practiced by a large number of patients and are frequently undertaken without first informing the medical provider. According to the Food and Drug Administration, there are more than 29,000 different nutritional supplements available to consumers, and Americans spend over 12 billion dollars per year on these supplements (2,3). Unfortunately, considerable controversy exists regarding use of dietary supplements in subjects with diabetes because efficacy data for many of the supplements consist of only uncontrolled studies and anecdotal reports. As such, there is a paucity of data in humans in regard to the effect of most commercially available supplements to improve metabolic abnormalities.One supplement that has attracted considerable clinical interest is chromium (4). However, routine use of chromium in subjects with diabetes is not currently recommended, and the most recent 2006 Clinical Practice Recommendations from the A...

Poly(ADP-ribose) polymerase (PARP) activation, an important factor in the pathogenesis of diabetes complications, is considered a downstream effector of oxidativenitrosative stress. However, some recent findings suggest that it is not necessarily the case and that PARP activation may precede and contribute to free radical and oxidantinduced injury. This study evaluated the effect of PARP inhibition on oxidative-nitrosative stress in diabetic peripheral nerve, vasa nervorum, aorta, and high glucoseexposed human Schwann cells. In vivo experiments were performed in control rats and streptozocin (STZ)-induced diabetic rats treated with and without the PARP inhibitor 3-aminobenzamide (ABA) (30 mg ⅐ kg ؊1 ⅐ day ؊1 i.p. for 2 weeks after 2 weeks of untreated diabetes). Human Schwann cells (HSC) (passages 7-10; ScienCell Research Labs) were cultured in 5.5 or 30 mmol/l glucose with and without 5 mmol/l ABA. Diabetes-induced increase in peripheral nerve nitrotyrosine immunoreactivity, epineurial vessel superoxide and nitrotyrosine immunoreactivities, and aortic superoxide production was reduced by ABA. PARP-1 (Western blot analysis) was abundantly expressed in HSC, and its expression was not affected by high glucose or ABA treatment. High-glucose-induced superoxide production and overexpression of nitrosylated and poly(ADPribosyl)ated protein, chemically reduced amino acid-(4)-hydroxynonenal adducts, and inducible nitric oxide synthase were decreased by ABA. We concluded that PARP activation contributes to superoxide anion radical and peroxynitrite formation in peripheral nerve, vasa nervorum, and aorta of STZ-induced diabetic rats and highglucose-exposed HSC. The relations between oxidativenitrosative stress and PARP activation in diabetes are birather than unidirectional, and PARP activation cannot only result from but also lead to free radical and oxidant generation. Diabetes 54:3435-3441, 2005 O xidative-nitrosative stress produced by free radicals and oxidants contributes to nerve conduction deficits (1-3), metabolic changes (3,4), impaired neurotrophic support (5), neurovascular dysfunction (1,2), abnormal sensation, and pain (6,7), as well as morphological abnormalities (8) characteristic for peripheral diabetic neuropathy (PDN). Enhanced oxidative-nitrosative stress is manifest in peripheral nerve, dorsal root and sympathetic ganglia, and vasculature of the peripheral nervous system of animals with both type 1 and type 2 diabetes (1,3,9 -13). One of the important, currently considered as downstream, effectors of oxidative-nitrosative injury and associated DNA single-strand breakage is activation of the nuclear enzyme poly(ADPribose) polymerase (PARP). Once activated, PARP cleaves nicotinamide adenine dinucleotide (NAD ϩ ) with formation of nicotinamide and ADP-ribose residues, which are attached to nuclear proteins with formation of poly(ADPribosyl)ated protein polymers. The process leads to 1) NAD ϩ depletion and energy failure (16,17), 2) changes of transcriptional regulation and gene expression (18), and 3) po...

Gettys, T. "Quercetin transiently increases energy expenditure but persistently decreases circulating markers of inflammation in C57BL/6J mice fed a high-fat diet", Rutgers University Community Repository, . DOI: http://dx.doi.org/doi:10.7282/T3FJ2F6GTerms of Use: Copyright for scholarly resources published in RUcore is retained by the copyright holder. By virtue of its appearance in this open access medium, you are free to use this resource, with proper attribution, in educational and other non-commercial settings. Other uses, such as reproduction or republication, may require the permission of the copyright holder. Article begins on next pageSOAR is a service of RUcore, the Rutgers University Community Repository.RUcore is developed and maintained by Rutgers University Libraries. AbstractQuercetin, a polyphenolic compound and a major bioflavonoid in the human diet, has anti-inflammatory properties and has been postulated to enhance energy expenditure (EE). We sought to determine whether quercetin alters body weight, body composition, EE, and circulating markers of inflammation. At 6 weeks (W) of age, 2 cohorts of C57BL/6J mice (N = 80) were placed on one of 2 diets for 3W or 8W: (1) high fat (HF) (45% kcal fat) or (2) high fat + quercetin (HF + Q) (45% kcal fat + 0.8% quercetin). Quercetin concentrations in the diet and plasma were evaluated using mass spectrometry. Body weight, composition (nuclear magnetic resonance), and food consumption were measured weekly. Energy expenditure was measured by indirect calorimetry at 3 and 8W, and inflammatory markers were measured in plasma obtained at 8W. The presence of quercetin in the HF diet did not alter food consumption over time in the HF + Q group and did not differ from the HF group at any time point. However, circulating plasma quercetin concentrations declined between 3 and 8W. At 3W, EE was higher during both day and night phases (P b .0001) in the HF + Q group compared with the HF group; but this difference was not detected at 8W and did not translate into significant differences between the HF + Q and HF groups with respect to body weight or body composition. During the night phase, concentrations of the inflammatory markers (interferon-γ, interleukin-1α, and interleukin-4) were significantly lower when compared with HF treatment group (P b .05). Dietary supplementation with quercetin produces transient (3W) increases in EE that are not detected after 8W on the diet. A corresponding decrease in circulating quercetin between 3 and 8W suggests that metabolic adaptation may have diminished the impact of quercetin's early effect on EE and diminished its overall effect on nutrient partitioning and adiposity. However, quercetin at the levels provided was effective in reducing circulating markers of inflammation observed in animals on an HF diet at 8W.

Human studies suggest that chromium picolinate (CrPic) decreases insulin levels and improves glucose disposal in obese and type 2 diabetic populations. To evaluate whether CrPic may aid in treatment of the insulin resistance syndrome, we assessed its effects in JCR:LA-corpulent rats, a model of this syndrome. Male lean and obese hyperinsulinemic rats were randomly assigned to receive oral CrPic [80 microg/(kg. d); n = 5 or 6, respectively) in water or to control conditions (water, n = 5). After 3 mo, a 120-min intraperitoneal glucose tolerance test (IPGTT) and a 30-min insulin tolerance test were performed. Obese rats administered CrPic had significantly lower fasting insulin levels (1848 +/- 102 vs. 2688 +/- 234 pmol/L; P < 0.001; mean +/- SEM) and significantly improved glucose disappearance (P < 0.001) compared with obese controls. Glucose and insulin areas under the curve for IPGTT were significantly less for obese CrPic-treated rats than in obese controls (P < 0.001). Obese CrPic-treated rats had lower plasma total cholesterol (3.57 +/- 0.28 vs. 4.11 +/- 0.47 mmol/L, P < 0.05) and higher HDL cholesterol levels (1.92 +/- 0.09 vs. 1.37 +/- 0.36 mmol/L, P < 0.01) than obese controls. CrPic did not alter plasma glucose or cholesterol levels in lean rats. Total skeletal muscle glucose transporter (Glut)-4 did not differ among groups; however, CrPic significantly enhanced membrane-associated Glut-4 in obese rats after insulin stimulation. Thus, CrPic supplementation enhances insulin sensitivity and glucose disappearance, and improves lipids in male obese hyperinsulinemic JCR:LA-corpulent rats.

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Chromium is one of the few trace minerals for which a specific cellular mechanism of action has not been identified. Recent in vitro studies suggest that chromium supplementation may improve insulin sensitivity by enhancing insulin receptor signaling, but this has not been demonstrated in vivo. We investigated the effect of chromium supplementation on insulin receptor signaling in an insulin-resistant rat model, the JCR:LA-corpulent rat. Male JCR:LA-cp rats (4 mo of age) were randomly assigned to receive chromium picolinate (CrPic) (obese n=6, lean n=5) or vehicle (obese n=5, lean n=5) for 3 mo. The CrPic was provided in the water, and based on calculated water intake, rats randomized to CrPic received 80 microg/(kg.d). At the end of the study, skeletal muscle (vastus lateralis) biopsies were obtained at baseline and at 5, 15, and 30 min postinsulin stimulation to assess insulin signaling. Obese rats treated with CrPic had significantly improved glucose disposal rates and demonstrated a significant increase in insulin-stimulated phosphorylation of insulin receptor substrate (IRS)-1 and phosphatidylinositol (PI)-3 kinase activity in skeletal muscle compared with obese controls. The increase in cellular signaling was not associated with increased protein levels of the IRS proteins, PI-3 kinase or Akt. However, protein tyrosine phosphatase 1B (PTP1B) levels were significantly lower in obese rats administered CrPic than obese controls. When corrected for protein content, PTP1B activity was also significantly lower in obese rats administered CrPic than obese controls. Our data suggest that chromium supplementation of obese, insulin-resistant rats may improve insulin action by enhancing intracellular signaling.

OBJECTIVE-Human adenovirus type 36 (Ad-36) increases adiposity but improves insulin sensitivity in experimentally infected animals. We determined the ability of Ad-36 to increase glucose uptake by human primary skeletal muscle (HSKM) cells. RESEARCH DESIGN AND METHODS-The effect of Ad-36 on glucose uptake and cell signaling was determined in HSKM cells obtained from type 2 diabetic and healthy lean subjects. Ad-2, another human adenovirus, was used as a negative control. Gene expression and proteins of GLUT1 and GLUT4 were measured by real-time PCR and Western blotting. Role of insulin and Ras signaling pathways was determined in Ad-36 -infected HSKM cells. RESULTS-Ad-36and Ad-2 infections were confirmed by the presence of respective viral mRNA and protein expressions. In a dose-dependent manner, Ad-36 significantly increased glucose uptake in diabetic and nondiabetic HSKM cells. Ad-36 increased gene expression and protein abundance of GLUT1 and GLUT4, GLUT4 translocation to plasma membrane, and phosphatidylinositol 3-kinase (PI 3-kinase) activity in an insulin-independent manner. In fact, Ad-36 decreased insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation and IRS-1-and IRS-2-associated PI 3-kinase activities. On the other hand, Ad-36 increased Ras gene expression and protein abundance, and Ras siRNA abrogated Ad-36 -induced PI 3-kinase activation, GLUT4 protein abundance, and glucose uptake. These effects were not observed with Ad-2 infection.CONCLUSIONS-Ad-36 infection increases glucose uptake in HSKM cells via Ras-activated PI 3-kinase pathway in an insulinindependent manner. These findings may provide impetus to exploit the role of Ad-36 proteins as novel therapeutic targets for improving glucose handling.

of Artemisia dracunculus L enhance cellular insulin signaling in primary human skeletal muscle culture", Rutgers University Community Repository, . DOI: http://dx.doi.org/doi:10.7282/T3N29VBXTerms of Use: Copyright for scholarly resources published in RUcore is retained by the copyright holder. By virtue of its appearance in this open access medium, you are free to use this resource, with proper attribution, in educational and other non-commercial settings. Other uses, such as reproduction or republication, may require the permission of the copyright holder. Article begins on next pageSOAR is a service of RUcore, the Rutgers University Community Repository.RUcore is developed and maintained by Rutgers University Libraries. Bioactives of AbstractAn alcoholic extract of Artemisia dracunculus L (PMI 5011) has been shown to decrease glucose and improve insulin levels in animal models, suggesting an ability to enhance insulin sensitivity. We sought to assess the cellular mechanism by which this botanical affects carbohydrate metabolism in primary human skeletal muscle culture. We measured basal and insulin-stimulated glucose uptake, glycogen accumulation, phosphoinositide 3 (PI-3) kinase activity, and Akt phosphorylation in primary skeletal muscle culture from subjects with type 2 diabetes mellitus incubated with or without various concentrations of PMI 5011. We also analyzed the abundance of insulin receptor signaling proteins, for example, IRS-1, IRS-2, and PI-3 kinase. Glucose uptake was significantly increased in the presence of increasing concentrations of PMI 5011. In addition, glycogen accumulation, observed to be decreased with increasing free fatty acid levels, was partially restored with PMI 5011. PMI 5011 treatment did not appear to significantly affect protein abundance for IRS-1, IRS-2, PI-3 kinase, Akt, insulin receptor, or Glut-4. However, PMI 5011 significantly decreased levels of a specific protein tyrosine phosphatase, that is, PTP1B. Time course studies confirmed that protein abundance of PTP1B decreases in the presence of PMI 5011. The cellular mechanism of action to explain the effects by which an alcoholic extract of A dracunculus L improves carbohydrate metabolism on a clinical level may be secondary to enhancing insulin receptor signaling and modulating levels of a specific protein tyrosine phosphatase, that is, PTP1B.