Increased serum kallistatin levels in type 1 diabetes patients with vascular complications

Abstract

BackgroundKallistatin, a serpin widely produced throughout the body, has vasodilatory, anti-angiogenic, anti-oxidant, and anti-inflammatory effects. Effects of diabetes and its vascular complications on serum kallistatin levels are unknown.MethodsSerum kallistatin was quantified by ELISA in a cross-sectional study of 116 Type 1 diabetic patients (including 50 with and 66 without complications) and 29 non-diabetic controls, and related to clinical status and measures of oxidative stress and inflammation.ResultsKallistatin levels (mean(SD)) were increased in diabetic vs. control subjects (12.6(4.2) vs. 10.3(2.8) μg/ml, p = 0.007), and differed between diabetic patients with complications (13.4(4.9) μg/ml), complication-free patients (12.1(3.7) μg/ml), and controls; ANOVA, p = 0.007. Levels were higher in diabetic patients with complications vs. controls, p = 0.01, but did not differ between complication-free diabetic patients and controls, p > 0.05. On univariate analyses, in diabetes, kallistatin correlated with renal dysfunction (cystatin C, r = 0.28, p = 0.004; urinary albumin/creatinine, r = 0.34, p = 0.001; serum creatinine, r = 0.23, p = 0.01; serum urea, r = 0.33, p = 0.001; GFR, r = -0.25, p = 0.009), total cholesterol (r = 0.28, p = 0.004); LDL-cholesterol (r = 0.21, p = 0.03); gamma-glutamyltransferase (GGT) (r = 0.27, p = 0.04), and small artery elasticity, r = -0.23, p = 0.02, but not with HbA1c, other lipids, oxidative stress or inflammation. In diabetes, geometric mean (95%CI) kallistatin levels adjusted for covariates, including renal dysfunction, were higher in those with vs. without hypertension (13.6 (12.3-14.9) vs. 11.8 (10.5-13.0) μg/ml, p = 0.03). Statistically independent determinants of kallistatin levels in diabetes were age, serum urea, total cholesterol, SAE and GGT, adjusted r2 = 0.24, p < 0.00001.ConclusionsSerum kallistatin levels are increased in Type 1 diabetic patients with microvascular complications and with hypertension, and correlate with renal and vascular dysfunction.

Kallistatin as a marker of microvascular complications in children and adolescents with type 1 diabetes mellitus: Relation to carotid intima media thickness

“…6 In this study, the most common microvascular complication was microalbuminuria with an incidence of 31.7%. This was in agreement with Cohen-Bucay and Viswanathan 28 who reported that diabetic nephropathy affects approximately one-third of all people with diabetes.…”

“…In line with these results, McBride et al 30 found a positive correlation between kallistatin and HbA1c in type 2 diabetes. Jenkins et al 6 found that kallistatin levels were higher in type 1 diabetic patients with hypertension and were significantly correlated with total cholesterol and LDL as well as renal function. The correlation between kallistatin and inflammation among the studied population supports other studies.…”

“…Elevated kallistatin levels in patients with type 1 diabetes, even in those without complications including patients with normoalbuminuria, could imply the significant role of this marker as a potential predictor of diabetic vascular complications even before development of microalbuminuria. Jenkins et al 6 showed that kallistatin levels were higher in adults with type 1 diabetes and microvascular complications than in controls, but did not differ between complication-free diabetic patients and controls. Recently, McBride et al 30 reported that circulation levels of kallistatin were elevated in type 2 diabetic patients with diabetic vascular complications and may contribute to impaired wound healing through inhibition of Wnt/β-catenin signaling.…”

“…5 Hyperglycemia, hypertension, dyslipidemia, smoking, adiposity, inflammation and oxidative stress may promote vascular complications, 4 and some effects of these stresses may be mediated by disturbances in the levels of, or balance of pro-and anti-angiogenic factors, such as (anti-angiogenic) kallistatin. 6 Kallistatin, a serine proteinase inhibitor, was first identified as a tissue kallikrein-binding protein. 7 It has multiple biologic functions including blood pressure regulation, protection against inflammation, vasculature relaxation, and stimulation of neointima hyperplasia.…”

“…18 Only one study evaluated kallistatin in adult patients with type 1 diabetes and found elevated levels in microvascular complications, as a compensatory mechanism. 6 Therefore, we determined the circulating kallistatin levels in children and adolescents with type 1 diabetes and assessed its relation to inflammation, glycemic control and microvascular complications. In addition, CIMT was assessed as a surrogate marker of atherosclerosis and its relationship to microangiopathy and kallistatin levels.…”