Insulin Reduces Plasma Arginase Activity in Type 2 Diabetic Patients

Abstract

OBJECTIVE -We sought to determine whether dysregulation of arginine metabolism is related to insulin resistance and underlies impaired nitric oxide (NO) generation in type 2 diabetic patients.RESEARCH DESIGN AND METHODS -We measured plasma arginase activity, arginine metabolites, and skeletal muscle NO synthase (NOS) activity in 12 type 2 diabetic and 10 age-/BMI-matched nondiabetic subjects before and following a 4-h euglycemichyperinsulinemic clamp with muscle biopsies. Arginine metabolites were determined by tandem mass spectroscopy. Arginase activity was determined by conversion of [14 C] guanidoinoarginine to [14 C] urea.RESULTS -Glucose disposal (R d ) was reduced by 50% in diabetic versus control subjects. NOS activity was fourfold reduced in the diabetic group (107 Ϯ 45 vs. 459 Ϯ 100 pmol ⅐ min Ϫ1⅐ mg protein Ϫ1 ; P Ͻ 0.05) and failed to increase with insulin. Plasma arginase activity was increased by 50% in the diabetic versus control group (0.48 Ϯ 0.11 vs. 0.32 Ϯ 0.12 mol ⅐ ml Ϫ1 ⅐ h Ϫ1 ; P Ͻ 0.05) and markedly declined in diabetic subjects with 4-h insulin infusion (to 0.13 Ϯ 0.04 mol ⅐ ml Ϫ1 ⅐ h Ϫ1 vs. basal; P Ͻ 0.05). In both groups collectively, plasma arginase activity correlated positively with fasting plasma glucose (R ϭ 0.46, P Ͻ 0.05) and A1C levels (R ϭ 0.51, P Ͻ 0.02) but not with R d .CONCLUSIONS -Plasma arginase activity is increased in type 2 diabetic subjects with impaired NOS activity, correlates with the degree of hyperglycemia, and is reduced by physiologic hyperinsulinemia. Elevated arginase activity may contribute to impaired NO generation in type 2 diabetes, and insulin may ameliorate this defect via reducing arginase activity. Diabetes Care 31:134-139, 2008T ype 2 diabetes is an insulin-resistant state characterized by inflammation, oxidative stress, and accelerated atherosclerosis (1-3). Nitric oxide (NO) bioavailability, critical for normal vasomotor tone and function, is reduced in states of insulin resistance, including type 2 diabetes (4,5). In addition to enhancing endothelial function, NO has been shown to modulate insulin sensitivity and glucose disposal (6,7). Activation of NO synthase (NOS) augments blood flow to insulin-sensitive tissues (i.e., skeletal muscle, liver, adipose tissue), and its activity has been shown to be impaired by hyperglycemia and insulin resistance (8,9). Under conditions of low arginine levels, NOS is uncoupled, producing reactive oxygen species and oxidative stress in lieu of NO (10). Increased oxidative stress and concentrations of asymmetric dimethylarginine (ADMA), in turn, further reduce NO bioavailability and are predictive of cardiovascular risk (11).Previous reports have related increased ADMA, oxidative stress, and endothelial dysfunction in type 2 diabetes and obesity to the severity of insulin resistance (11,12). Our lab (13) and others (14,15) have previously demonstrated reduced NOS activity in patients with type 2 diabetes and an impaired ability of insulin to increase NOS activity compared with healthy nondiabetic subjects. However...

Role for high-glucose-induced protein O-GlcNAcylation in stimulating cardiac fibroblast collagen synthesis

“…Plasma arginase activity positively correlates with the severity of hyperglycemia in type 2 DM patients (20). In experimental DM animal models, aortic fibrosis is associated with increased arginase I and II protein levels and activity (29,30).…”

“…Arginase I is mainly cytoplasmic and II mitochondrial (29). Increases in arginase(s) activity correlate positively with the level of glycemic control and tissue fibrosis in DM patients (20,29,30). The role of arginases in regulating CF collagen synthesis in the setting of DM is yet to be explored.…”

“…Proline is a product of the arginine/arginase pathway (20), and a dysregulation of arginine metabolism has been implicated in the pathophysiology of DM (20). Arginase converts L-arginine to urea and ornithine.…”

Amino acid metabolism reflecting arginase activity is increased in patients with type 2 diabetes and associated with endothelial dysfunction

“…Furthermore, little is known regarding how changes in arginase activity are related to endothelial function among these patients. Kashyap et al 16 showed that patients with type 2 diabetes had increased plasma arginase activity in comparison with a control group. In addition, we recently demonstrated that arginase inhibition improves endothelial function in patients with type 2 diabetes and coronary artery disease.…”

Exercise and Oxidative Stress

“…Therefore, increased expression and/or activity of ARG have a deep impact on NOS efficiency. As an example, arginase activity is increased in type 2 diabetic subjects with impaired NOS activity, and such impairment correlates with the degree of hyperglycemia and is reduced by insulin (Kashyap et al, 2008). The problem is more interesting because results of experimental and clinical studies are quite controversial and can not definitely support relevant conclusions.…”