Altered oxidant and antioxidant levels are associated with vascular stiffness and diabetic kidney disease in type 1 diabetes after exposure to acute and chronic hyperglycemia

Abstract

Background: Hyperglycemia-induced oxidative stress is a well-established pathological mediator of vascular complications in diabetes. We assessed plasma oxidant and antioxidant levels in response to acute and chronic hyperglycemia in relation to vascular stiffness and varying degrees of kidney disease in type 1 diabetes individuals.

Methods: The acute hyperglycemia study included 22 type 1 diabetic individuals with normal albumin excretion rate (AER) and 13 non-diabetic controls. These individuals received an acute glucose challenge during a 120-minute hyperglycemic clamp. The chronic hyperglycemia study included 118 type 1 diabetic individuals with chronically low (n = 60) or high (n = 58) HbA1c concentrations and varying degrees of diabetic kidney disease (DKD) classified as normal, moderate, or severe albuminuria (AER). Levels of malondialdehyde (MDA), reactive oxygen metabolites (ROMs), total antioxidant capacity (TAC), biological antioxidant potential (BAP) and superoxide dismutase (SOD) were measured from plasma or serum samples in the FinnDiane study.

Results: Levels of MDA (p < 0.01) and ROMs (p < 0.01) were elevated in type 1 diabetes individuals compared to non-diabetic controls at baseline. Acute hyperglycemia further increased MDA levels (p < 0.05) and sustained the elevation of ROMs in type 1 diabetes individuals. Acute hyperglycemic challenge impaired TAC in both non-diabetic (p < 0.05) and type 1 diabetes (p < 0.01) individuals compared to baseline whereas BAP was increased (p < 0.05) with no difference observed in non-diabetic controls. There was a positive association between high circulating MDA and AIx (r2 = 0.611, p = 0.05), and between delta ROMs and delta AIx (r2 = 0.955, p = 0.014) in combined analysis of individuals with type 1 diabetes and non-diabetic controls. Type 1 diabetes individuals with varying status of DKD, showed elevated levels of ROMs in those with high HbA1c compared to their counterpart with low HbA1c (p < 0.05). Individuals with severe albuminuria showed elevated ROM levels (p < 0.01) and depressed antioxidant capacity (p < 0.01) compared to those with normal AER of comparable HbA1c concentrations.

Conclusions: Biomarkers of oxidative stress are associated with vascular stiffness and DKD following acute and chronic hyperglycemic exposure and may provide added value to HbA1c in understanding disease pathology, predicting risk and assessing the status of secondary complications of type 1 diabetes.

Keywords: Antioxidant capacity; Arterial stiffness; Diabetes; Diabetic kidney disease; Hyperglycemia; Oxidative stress.

Fig. 1

Altered levels of oxidant and antioxidant markers in response to acute hyperglycemia. Plasma levels of MDA, a lipid peroxidation product (A), ROMs (B), total antioxidant capacity by Trolox test (C), and antioxidant levels by biological antioxidant potential test (D) were measured in type 1 diabetes (dotted line) and non-diabetes (solid line) individuals at baseline (normoglycemia) and 120 min after a hyperglycemic challenge. All values are presented as mean ± SEM. **p < 0.01 at baseline; *p < 0.05 compared with control group (120 min); and †p < 0.05 compared with the type 1 diabetes group at baseline. MDA, malondialdehyde; ROMs, reactive oxygen metabolites

Fig. 2

Association between arterial stiffness and oxidative stress markers in type 1 diabetes and non-diabetes individuals. Linear regression analyses were performed to assess the relationship between the arterial stiffness as measured by AIx with plasma levels of MDA, SOD and ROMs. High levels of MDA at baseline (A; diabetes and non-diabetic individuals combined) correlated with increased vascular stiffness (AIx). Following an acute hyperglycemic challenge, change in MDA levels (delta MAD) were positively associated with change in arterial stiffness (delta AIx, B) in individuals with type 1 diabetes. Hyperglycemia-increased ROM levels associated positively with increased AIx (C), whereas increased SOD levels correlated negatively with AIx (D) both in type 1 diabetes and non-diabetic subjects (combined). Delta changes were calculated by subtracting the baseline measurement from that obtained after 120 min of a hyperglycemic challenge. AIx, augmentation index; MDA, malondialdehyde; ROMs, reactive oxygen metabolites; and SOD, superoxide dismutase

Fig. 3

Elevated oxidant levels in type 1 diabetes individuals with varying status of diabetic kidney disease along with low or high HbA1c. Individuals with high HbA1c concentrations (empty bars) show increased plasma reactive oxygen metabolites (ROM) levels compared to individuals with low HbA1c concentrations (filled bars), irrespective of the presence or severity of diabetic kidney disease. Despite comparable HbA1c concentrations, type 1 diabetes individuals with moderate and severe albuminuria showed higher ROM levels when compared to their normal AER counterparts. ROM levels are expressed in mean Carratelli Units (U.CARR.) ± SEM. *p < 0.05 compared with low HbA1c group; **p < 0.01 compared with normal AER, low HbA1c group; and † p < 0.01 compared with normal AER, high HbA1c group

Fig. 4

Impaired antioxidant capacity in type 1 diabetes individuals with varying status of diabetic kidney disease along with low or high HbA1c. Type 1 diabetes individuals with high HbA1c (empty bars) and normal AER or moderate albuminuria exhibit elevated plasma antioxidant levels measured as the biological antioxidant potential (BAP) when compared to low HbA1c individuals (filled bars) of comparable diabetic kidney disease status. Conversely, the antioxidant capacity of those with severe albuminuria was no different between high and low HbA1c groups. However, individuals with severe albuminuria display significantly reduced BAP, when compared to individuals with normal AER, despite comparably high HbA1c concentrations. BAP is expressed as the mean [antioxidant] ± SEM. *p < 0.05 compared with low HbA1c group; **p < 0.01 compared with normal AER, low HbA1c group; and †p < 0.01 compared with normal AER, high HbA1c group