Abstract
Intensive diabetes control has been associated with increased mortality in type 2 diabetes (T2DM); this has been suggested to be due to increased hypoglycemia. We measured hypoglycemia-induced changes in endothelial parameters, oxidative stress markers and inflammation at baseline and after a 24-hour period in type 2 diabetic (T2DM) subjects versus age-matched controls. Case-control study: 10 T2DM and 8 control subjects. Blood glucose was reduced from 5 (90 mg/dl) to hypoglycemic levels of 2.8 mmol/L (50 mg/dl) for 1 hour by incremental hyperinsulinemic clamps using baseline and 24 hour samples. Measures of endothelial parameters, oxidative stress and inflammation at baseline and at 24-hours post hypoglycemia were performed: proteomic (Somalogic) analysis for inflammatory markers complemented by C-reactive protein (hsCRP) measurement, and proteomic markers and urinary isoprostanes for oxidative measures, together with endothelial function. Between baseline and 24 -hours after hypoglycemia, 15 of 140 inflammatory proteins differed in T2DM whilst only 1 of 140 differed in controls; all returned to baseline at 24-hours. However, elevated hsCRP levels were seen at 24-hours in T2DM (2.4 mg/L (1.2–5.4) vs. 3.9 mg/L (1.8–6.1), Baseline vs 24-hours, P < 0.05). In patients with T2DM, between baseline and 24-hour after hypoglycemia, only one of 15 oxidative stress proteins differed and this was not seen in controls. An increase (P = 0.016) from baseline (73.4 ng/mL) to 24 hours after hypoglycemia (91.7 ng/mL) was seen for urinary isoprostanes. Hypoglycemia resulted in inflammatory and oxidative stress markers being elevated in T2DM subjects but not controls 24-hours after the event.
Highlights
While type 2 diabetes (T2DM) is associated with an increased risk of cardiovascular disease[1], strict glycemic control does not result in obvious cardiovascular benefit in people with T2DM2–4
For the inflammatory marker panel, comparison of baseline to hypoglycemia in T2DM subjects showed 15 proteins of 140 that were significantly different (Table 2) after multiple comparison testing: C-X-C motif chemokine 10 (CXCL10), Interleukin-5 (IL5), Azurocidin (AZU1), C-type lectin domain family 7 member A (CLEC7A), Serine/threonine-protein kinase (TBK1), Protein kinase C zeta type (PRKCZ), Ribosomal protein S6 kinase alpha-5 (RPS6KA5), cluster of differentiation 40 (CD40) ligand (CD40LG), Interleukin-34 (IL34), High mobility group protein B1 (HMGB1), Protein S100-A9 (S100A9), Interleukin-1 beta (IL1B), C-C motif chemokine 19 (CCL19), Sialoadhesin (SIGLEC1) and Interleukin 10 receptor beta subunit (IL10RB)
Comparison of T2DM and controls revealed that 4 proteins remained significantly different (Table 2) after multiple comparison testing: Prostaglandin G/H synthase 2 (PTGS2), HMGB1, IL5 and CXCL10
Summary
While type 2 diabetes (T2DM) is associated with an increased risk of cardiovascular disease[1], strict glycemic control does not result in obvious cardiovascular benefit in people with T2DM2–4. It is well recognized that oxidative stress leads to damage of proteins and deoxyribonucleic acid (DNA)[9] and contributes to the diabetic complications of retinopathy, nephropathy, neuropathy and cardiovascular disorders[10,11,12,13], and is directly linked to vascular inflammation, precipitating both endothelial cell dysfunction and vascular damage[14]. Moderate hypoglycemia has been shown to increase activation of prothrombotic and proinflammatory effects in type 1 diabetes[23]; in this study, we examined inflammatory markers, oxidative stress and endothelial function following iatrogenic hypoglycemia in subjects with and without T2DM24
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