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Diabetes compromises the bone marrow (BM) microenvironment and reduces the number of circulating [CD34.sup.+] cells. Diabetic autonomic neuropathy (DAN) may impact the BM, because the sympathetic nervous system is prominently involved in BM stem cell trafficking. We hypothesize that neuropathy of the BM affects stem cell mobilization and vascular recovery after ischemia in patients with diabetes. We report that, in patients, cardiovascular DAN was associated with fewer circulating [CD34.sup.+] cells. Experimental diabetes (streptozotocin-induced and ob/ob mice) or chemical sympathectomy in mice resulted in BM autonomic neuropathy, impaired [Lin.sup.-][cKit.sup.+][Sca1.sup.+] (LKS) cell and endothelial progenitor cell (EPC; [CD34.sup.+][Flk1.sup.+]) mobilization, and vascular recovery after ischemia. DAN increased the expression of the 66-kDa protein from the src homology and collagen homology domain (p66Shc) and reduced the expression of sirtuin 1 (Sirt1) in mice and humans. p66Shc knockout (KO) in diabetic mice prevented DAN in the BM, and rescued defective LKS cell and EPC mobilization. Hematopoietic Sirt1 KO mimicked the diabetic mobilization defect, whereas hematopoietic Sirt1 overexpression in diabetes rescued defective mobilization and vascular repair. Through p66Shc and Sirt1, diabetes and sympathectomy elevated the expression of various adhesion molecules, including CD62L. CD62L KO partially rescued the defective stem/progenitor cell mobilization. In conclusion, autonomic neuropathy in the BM impairs stem cell mobilization in diabetes with dysregulation of the life-span regulators p66Shc and Sirt1. Diabetes 2014;63:1353-1365 | DOI: 10.2337/db13-0894, Diabetes reduces the availability of bone marrow (BM)-derived circulating angiocompetent [CD34.sup.+] cells, especially in the presence of chronic vascular complications (1,2). This is believed to represent a risk factor for [...]

Defective endothelium is a key event in the development of atherosclerosis in diabetes: alteration of the L-arginine-nitric oxide (NO) pathway has been suggested. We propose a modeling approach of the L-arginine-NO pathway in vivo in both control and type 2 diabetic subjects based on the intravenous bolus injection of L-[[sup.15]N]arginine and subsequent noncompartmental and compartmental model analysis of L-[[sup.15]N] arginine in plasma and [[sup.15]N]nitrate in the urine. No differences in arginine kinetics were observed between normal subjects and diabetic patients. [[sup.15]N]nitrates were detectable up to 48 h from the L-[sup.15]ℕarginine administration; no differences were found in the tracer-to-tracee ratio in each urine collection. However, the NO synthesis in plasma from arginine was lower (P = 0.05 for the noncompartmental and 0.1208 for the compartmental analysis, by Mann-Whitney test) in diabetic patients than in control subjects when expressed both in absolute terms (50% decrease) and as percentage of NO turnover (30% decrease). This new modeling approach of L-arginine-NO pathway provides a detailed picture of arginine kinetics and nitrate metabolism. From our data, it appears that noncomplicated type 2 diabetic patients have a decreased conversion of arginine to NO., Endothelial dysfunction is a possible culprit of the accelerated atherosclerosis in diabetic patients. Several different mechanisms negatively act on endothelial function (1). The assessment of endothelial function in humans can [...]