α-Synuclein Suppression by Targeted Small Interfering RNA in the Primate Substantia Nigra

The protein α-synuclein is involved in the pathogenesis of Parkinson's disease and other neurodegenerative disorders. Its toxic potential appears to be enhanced by increased protein expression, providing a compelling rationale for therapeutic strategies aimed at reducing neuronal α-synuclein burden. Here, feasibility and safety of α-synuclein suppression were evaluated by treating monkeys with small interfering RNA (siRNA) directed against α-synuclein. The siRNA molecule was chemically modified to prevent degradation by exo- and endonucleases and directly infused into the left substantia nigra. Results compared levels of α-synuclein mRNA and protein in the infused (left) vs. untreated (right) hemisphere and revealed a significant 40–50% suppression of α-synuclein expression. These findings could not be attributable to non-specific effects of siRNA infusion since treatment of a separate set of animals with luciferase-targeting siRNA produced no changes in α-synuclein. Infusion with α-synuclein siRNA, while lowering α-synuclein expression, had no overt adverse consequences. In particular, it did not cause tissue inflammation and did not change (i) the number and phenotype of nigral dopaminergic neurons, and (ii) the concentrations of striatal dopamine and its metabolites. The data represent the first evidence of successful anti-α-synuclein intervention in the primate substantia nigra and support further development of RNA interference-based therapeutics

Differences in first-phase insulin release between normal blacks and whites

This study was designed to compare insulin release during the intravenous glucose tolerance test (GTT) in normal blacks and whites. The study included 14 normal blacks (9 males and 5 females) and 15 normal whites (10 males and 5 females). The index of first phase insulin release (sum of 1 + 3 min insulin levels and total area under the curve for the first 10 min of the GTT) was significantly higher in blacks. The difference is discussed in terms of genetic and acquired traits.This study was designed to compare insulin release during the intravenous glucose tolerance test (GTT) in normal blacks and whites. The study included 14 normal blacks (9 males and 5 females) and 15 normal whites (10 males and 5 females). The index of first phase insulin release (sum of 1 + 3 min insulin levels and total area under the curve for the first 10 min of the GTT) was significantly higher in blacks. The difference is discussed in terms of genetic and acquired traits23865565

Insulin Resistance In Psoriasis

The oral glucose tolerance test (OGTT) and intravenous insulin tolerance test (15-min ITT) were applied to ten patients with psoriasis and to 11 control subjects. No significant differences in mean plasma glucose levels were detected between psoriatic patients and normal individuals. In contrast, serum insulin levels were significantly higher for the psoriatic patients as compared to the controls at 30, 60 and 120 min during the OGTT (P < 0.05). The glucose disappearance rate during the 15-min ITT was lower in patients with psoriasis than in controls (5.1 ± 0.5%/min vs 7.5 ± 0.4%/min, P < 0.05), demonstrating a state of insulin resistance. Interestingly, the reduction in serum potassium levels during the ITT was also lower in the patients than in the controls (0.6 ± 0.06 mEq/l vs 1.06 ± 0.07 mEq/l, P < 0.05), suggesting that the insulin resistance observed in psoriasis is not only related to glucose metabolism, but also to another important action of insulin, namely extrarenal potassium homeostasis.28329730

Insulin Resistance In Psoriasis.

The oral glucose tolerance test (OGTT) and intravenous insulin tolerance test (15-min ITT) were applied to ten patients with psoriasis and to 11 control subjects. No significant differences in mean plasma glucose levels were detected between psoriatic patients and normal individuals. In contrast, serum insulin levels were significantly higher for the psoriatic patients as compared to the controls at 30, 60 and 120 min during the OGTT (P < 0.05). The glucose disappearance rate during the 15-min ITT was lower in patients with psoriasis than in controls (5.1 +/- 0.5%/min vs 7.5 +/- 0.4%/min, P < 0.05), demonstrating a state of insulin resistance. Interestingly, the reduction in serum potassium levels during the ITT was also lower in the patients than in the controls (0.6 +/- 0.06 mEq/l vs 1.06 +/- 0.07 mEq/l, P < 0.05), suggesting that the insulin resistance observed in psoriasis is not only related to glucose metabolism, but also to another important action of insulin, namely extrarenal potassium homeostasis.28297-30

Association Between Prehypertension, Metabolic And Inflammatory Markers, Decreased Adiponectin And Enhanced Insulinemia In Obese Subjects

Background: Obesity is associated with development of the cardiorenal metabolic syndrome, which is a constellation of risk factors, such as insulin resistance, inflammatory response, dyslipidemia, and high blood pressure that predispose affected individuals to well-characterized medical conditions such as diabetes, cardiovascular and kidney chronic disease. The study was designed to establish relationship between metabolic and inflammatory disorder, renal sodium retention and enhanced blood pressure in a group of obese subjects compared with age-matched, lean volunteers. Methods. The study was performed after 14 h overnight fast after and before OGTT in 13 lean (BMI 22.92 ± 2.03 kg/m2) and, 27 obese (BMI 36.15 ± 3.84 kg/m2) volunteers. Assessment of HOMA-IR and QUICKI index were calculated and circulating concentrations of TNF-α, IL-6 and C-reactive protein, measured by immunoassay. Results: The study shows that a hyperinsulinemic (HI: 10.85 ± 4.09 μg/ml) subgroup of well-characterized metabolic syndrome bearers-obese subjects show higher glycemic and elevated blood pressure levels when compared to lean and normoinsulinemic (NI: 5.51 ± 1.18 μg/ml, P &lt; 0.027) subjects. Here, the combination of hyperinsulinemia, higher HOMA-IR (HI: 2.19 ± 0.70 (n = 12) vs. LS: 0.83 ± 0.23 (n = 12) and NI: 0.98 ± 0.22 (n = 15), P &lt; 0.0001) associated with lower QUICKI in HI obese when compared with LS and NI volunteers (P &lt; 0.0001), suggests the occurrence of insulin resistance and a defect in insulin-stimulated peripheral action. Otherwise, the adiponectin measured in basal period was significantly enhanced in NI subjects when compared to HI groups (P &lt; 0.04). The report also showed a similar insulin-mediated reduction of post-proximal urinary sodium excretion in lean (LS: 9.41 ± 0.68% vs. 6.38 ± 0.92%, P = 0.086), and normoinsulinemic (NI: 8.41 ± 0.72% vs. 5.66 ± 0.53%, P = 0.0025) and hyperinsulinemic obese subjects (HI: 8.82 ± 0.98% vs. 6.32 ± 0.67%, P = 0.0264), after oral glucose load, despite elevated insulinemic levels in hyperinsulinemic obeses. Conclusion: In conclusion, this study highlights the importance of adiponectin levels and dysfunctional inflammatory modulation associated with hyperinsulinemia and peripheral insulin resistance, high blood pressure, and renal dysfunction in a particular subgroup of obeses. © 2014 de Almeida et al.; licensee BioMed Central Ltd.111Olshansky, S.J., Passaro, D.J., Hershow, R.C., Layden, J., Carnes, B.A., Brody, J., Hayflick, L., Ludwig, D.S., A potential decline in life expectancy in the United States in the 21st century (2005) New England Journal of Medicine, 352 (11), pp. 1138-1145. , DOI 10.1056/NEJMsr043743Pereira-Lancha, L.O., Campos-Ferraz, P.L., Lancha Jr., A.H., Obesity: Considerations about etiology, metabolism, and the use of experimental models (2012) Diabetes Metab Syndr Obes., 5, pp. 75-87. , 22570558Parker, D.R., Weiss, S.T., Troisi, R., Cassano, P.A., Vokonas, P.S., Landsberg, L., Relationship of dietary saturated fatty acids and body habitus to serum insulin concentrations: The normative aging study (1993) American Journal of Clinical Nutrition, 58 (2), pp. 129-136Haslam, D.W., James, W.P.T., Obesity (2005) Lancet, 366 (9492), pp. 1197-1209. , DOI 10.1016/S0140-6736(05)67483-1, PII S0140673605674831Pinhal, C.S., Lopes, A., Torres, D.B., Felisbino, S.L., Rocha Gontijo, J.A., Boer, P.A., Time-course morphological and functional disorders of the kidney induced by long-term high-fat diet intake in female rats (2013) Nephrol Dial Transplant, 28 (10), pp. 2464-2476. , 10.1093/ndt/gft304 24078639Grassi, G., Sympathetic overdrive and cardiovascular risk in the metabolic syndrome (2006) Hypertension Research, 29 (11), pp. 839-847. , DOI 10.1291/hypres.29.839Aroor, A.R., McKarns, S., Demarco, F.G., Jia, G., Sowers, J.R., Maladaptive immune and inflammatory pathways lead to cardiovascular insulin resistance (2013) Metabolism, , http://dx.doi.org/10.1016/j.metabol.2013.07.001Faselis, C., Doumas, M., Kokkinos, J.P., Panagiotakos, D., Kheirbek, R., Sheriff, H.M., Hare, K., Kokkinos, P., Exercise capacity and progression from prehypertension to hypertension (2012) Hypertension, 60, pp. 333-338. , 10.1161/HYPERTENSIONAHA.112.196493 22753224Demarco, V.G., Johnson, M.S., Ma, L., Pulakat, L., Mugerfeld, I., Hayden, M.R., Garro, M., Sowers, J.R., Overweight female rats selectively breed for low aerobic capacity exhibit increased myocardial fibrosis and diastolic dysfunction (2012) Am J Physiol Heart Circ Physiol, 302, pp. 81667-H1682. , 10.1152/ajpheart.01027.2011 22345570Demarco, V.G., Ford, D.A., Henriksen, E.J., Aroor, A.R., Johnson, M.S., Habibi, J., Ma, L., Sowers, J.R., Obesity-related alterations in cardiac lipid profile and nondipping blood pressure pattern during transition to diastolic dysfunction in male db/db mice (2013) Endocrinology, 154, pp. 159-171. , 10.1210/en.2012-1835 23142808Hall, J.E., The kidney, hypertension, and obesity (2003) Hypertension, 41 (II3), pp. 625-633. , DOI 10.1161/01.HYP.0000052314.95497.78Abel, E.D., O'Shea, K.M., Ramasamy, R., Insulin resistance: Metabolic mechanisms and consequences in the heart (2012) Arterioscler Thromb Vasc Biol, 32, pp. 2068-2076. , 10.1161/ATVBAHA.111.241984 22895668Wong, C., Marwick, T.H., Obesity cardiomyopathy: Pathogenesis and pathophysiology (2007) Nature Clinical Practice Cardiovascular Medicine, 4 (8), pp. 436-443. , DOI 10.1038/ncpcardio0943, PII NCPCARDIO0943Wang, Z.V., Scherer, P.E., Adiponectin, cardiovascular function, and hypertension (2008) Hypertension, 51 (1), pp. 8-14. , DOI 10.1161/HYPERTENSIONAHA.107.099424Gontijo, J.A.R., Muscelli, E.O.A., Reduced renal sodium excretion in primary hypertensive patients after an oral glucose load (1996) Brazilian Journal of Medical and Biological Research, 29 (10), pp. 1291-1299Souza, M.L., Berardi, E.O., Gontijo, J.A., Leme Júnior, C.A., Cavicchio, J.R., Saad, M.J., Insulin resistance and myocardial hypertrophy in the attenuated reduction in mean arterial pressure after a glucose load in hypertensive patients (1995) Braz J Med Biol Res, 28 (9), pp. 967-972. , 8580884Tanaka, R.C.T., Gontijo, J.A.R., Urinary acidification and renal sodium handling in a case of renal Fanconi syndrome [5] (1998) Nephron, 78 (3), pp. 339-340. , DOI 10.1159/000044949Matthews, D.R., Hosker, J.P., Rudenski, A.S., Homeostasis model assessment: Insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man (1985) Diabetologia, 28 (7), pp. 412-419. , DOI 10.1007/BF00280883Katz, A., Nambi, S.S., Mather, K., Baron, A.D., Follmann, D.A., Sullivan, G., Quon, M.J., Quantitative insulin sensitivity check index: A simple, accurate method for assessing insulin sensitivity in humans (2000) Journal of Clinical Endocrinology and Metabolism, 85 (7), pp. 2402-2410. , DOI 10.1210/jc.85.7.2402Furlan, F.C., Marshall, P.S., Macedo, R.F., Carvalheira, J.B., Michelotto, J.B., Gontijo, J.A.R., Acute intracerebroventricular insulin microinjection after nitric oxide synthase inhibition of renal sodium handling in rats (2003) Life Sciences, 72 (23), pp. 2561-2569. , DOI 10.1016/S0024-3205(03)00170-XMesquita, F.F., Gontijo, J.A., Boer, P.A., Maternal undernutrition and the offspring kidney: From fetal to adult life (2010) Braz J Med Biol Res, 43 (11), pp. 1010-1018. , 10.1590/S0100-879X2010007500113 21049242Reaven, G.M., Insulin resistance: The link between obesity and cardiovascular disease (2011) Med Clin North Am, 95, pp. 875-892. , 10.1016/j.mcna.2011.06.002 21855697McCullough, A.J., Epidemiology of the metabolic syndrome in the USA (2011) J Dig Dis, 12, pp. 333-340. , 10.1111/j.1751-2980.2010.00469.x 21091931Aroor, A.R., Mandavia, C.H., Sowers, J.R., Insulin resistance and heart failure: Molecular mechanisms (2012) Heart Fail Clin, 8, pp. 609-617. , 10.1016/j.hfc.2012.06.005 22999243Stanhope, K.L., Role of fructose-containing sugars in the epidemics of obesity and metabolic syndrome (2012) Annu Rev Med, 63, pp. 329-343. , 10.1146/annurev-med-042010-113026 22034869Garver, W.S., Newman, S.B., Gonzales-Pacheco, D.M., Castillo, J.J., Jelinek, D., Heidenreich, R.A., Orlando, R.A., The genetics of childhood obesity and interaction with dietary macronutrients (2013) Genes Nutr, 8, pp. 271-287. , 10.1007/s12263-013-0339-5 23471855Drong, A.W., Lindgren, C.M., McCarthy, M.I., The genetic and epigenetic basis of type 2 diabetes and obesity (2012) Clin Pharmacol Ther., 92, pp. 707-715. , 10.1038/clpt.2012.149 23047653Ferrannini, E., Buzzigoli, G., Bonadonna, R., Insulin resistance in essential hypertension (1987) New England Journal of Medicine, 317 (6), pp. 350-357Florey, C.V., Uppal, S., Lowy, C., Relation between blood pressure, weight, and plasma sugar serum insulin levels in schoolchildren age 9-12 years in Westland (1976) Holland. Br Med J., 1, pp. 1368-1371. , 10.1136/bmj.1.6022.1368Manicardi, V., Camellini, L., Bellodi, G., Evidence for an association of high blood pressure and hyperinsulinemia in obese man (1986) Journal of Clinical Endocrinology and Metabolism, 62 (6), pp. 1302-1304Sowers, J.R., Diabetes mellitus and vascular disease (2013) Hypertension, 61, pp. 943-947. , 10.1161/HYPERTENSIONAHA.111.00612 23595139Witteles, R.M., Fowler, M.B., Insulin-resistant cardiomyopathy clinical evidence, mechanisms, and treatment options (2008) J Am Coll Cardiol., 51, pp. 93-102. , 10.1016/j.jacc.2007.10.021 18191731Whaley-Connell, A., Sowers, J.R., Oxidative stress in the cardiorenal metabolic syndrome (2012) Curr Hypertens Rep., 14, pp. 360-365. , 10.1007/s11906-012-0279-2 22581415Scherer, P.E., Adipose tissue: From lipid storage compartment to endocrine organ (2006) Diabetes, 55 (6), pp. 1537-1545. , http://diabetes.diabetesjournals.org/cgi/content/full/55/6/1537, DOI 10.2337/db06-0263Kalupahana, N.S., Moustaid-Moussa, N., Claycombe, K.J., Immunity as a link between obesity and insulin resistance (2012) Mol Aspects Med., 33, pp. 26-34. , 10.1016/j.mam.2011.10.011 22040698Gregor, M.F., Hotamisligil, G.S., Inflammatory mechanisms in obesity (2011) Annu Rev Immunol., 29, pp. 415-445. , 10.1146/annurev-immunol-031210-101322 21219177Shen, J., Obin, M.S., Zhao, L., The gut microbiota, obesity and insulin resistance (2013) Mol Aspects Med, 34, pp. 39-58. , 10.1016/j.mam.2012.11.001 23159341Brown, K., Decoffe, D., Molcan, E., Diet-induced dysbiosis of the intestinal microbiota and the effects on immunity and disease (2012) Nutrients., 4, pp. 1095-1119. , 10.3390/nu4081095 23016134Ohashi, K., Kihara, S., Ouchi, N., Kumada, M., Fujita, K., Hiuge, A., Hibuse, T., Shimomura, I., Adiponectin replenishment ameliorates obesity-related hypertension (2006) Hypertension, 47 (6), pp. 1108-1116. , DOI 10.1161/01.HYP.0000222368.43759.a1, PII 0000426820060600000015Iwashima, Y., Katsuya, T., Ishikawa, K., Ouchi, N., Ohishi, M., Sugimoto, K., Fu, Y., Ogihara, T., Hypoadiponectinemia is an independent risk factor for hypertension (2004) Hypertension, 43 (6), pp. 1318-1323. , DOI 10.1161/01.HYP.0000129281.03801.4bChow, W.-S., Cheung, B.M.Y., Tso, A.W.K., Xu, A., Wat, N.M.S., Fong, C.H.Y., Ong, L.H.Y., Lam, K.S.L., Hypoadiponectinemia as a predictor for the development of hypertension: A 5-year prospective study (2007) Hypertension, 49 (6), pp. 1455-1461. , DOI 10.1161/HYPERTENSIONAHA.107.086835Gontijo, J.A., Garcia, W.E., Figueiredo, J.F., Silva-Netto, C.R., Furtado, M.R., Renal sodium handling after noradrenergic stimulation of the lateral hypothalamic area in rats (1992) Braz J Med Biol Res., 25, pp. 937-942. , 1342841Mancia, G., Bousquet, P., Elghozi, J.L., Esler, M., Grassi, G., Julius, S., Reid, J., Van Zwieten, P.A., The sympathetic nervous system and the metabolic syndrome (2007) Journal of Hypertension, 25 (5), pp. 909-920. , DOI 10.1097/HJH.0b013e328048d004, PII 0000487220070500000002Tanida, M., Shen, J., Horii, Y., Matsuda, M., Kihara, S., Funahashi, T., Shimomura, I., Nagai, K., Effects of adiponectin on the renal sympathetic nerve activity and blood pressure in rats (2007) Experimental Biology and Medicine, 232 (3), pp. 390-397. , http://www.ebmonline.org/cgi/reprint/232/3/390Kirchner, K.A., Insulin increases loop segment chloride reabsorption in the euglycemic rat (1988) Am J Physiol., 255, pp. 61206-F1213. , 3059825Anderson, E.A., Hoffman, R.P., Balon, T.W., Sinkey, C.A., Mark, A.L., Hyperinsulinemia produces both sympathetic neural activation and vasodilation in normal human (1991) JCI., 87, pp. 2246-2252. , 10.1172/JCI115260 2040704Abboud, F.M., Harwani, S.C., Chapleau, M.W., Autonomic neural regulation of the immune system: Implications for hypertension and cardiovascular disease (2012) Hypertension., 59, pp. 755-762. , 10.1161/HYPERTENSIONAHA.111.186833 22331383Harrison, D.G., Marvar, P.J., Titze, J.M., Vascular inflammatory cells in hypertension (2012) Front Physiol., 3, p. 128. , 2258640