We have previously shown that glycemic instability, as measured by the coefficient of variation for fasting plasma glucose (CV-FPG), is an independent predictor of cardiovascular mortality in type 2 diabetes (1,2). The mechanisms, if any, underlying the association between long-term plasma glucose instability and vascular diseases are difficult to explain.

In vitro studies with retinal capillary pericytes have shown that rapid glucose fluctuations in the culture medium induced cellular damage and death by apoptosis (3). Moreover, tubulointerstitial cells exposed to intermittent high glucose concentrations underwent changes in cellular growth, collagen synthesis, and cytokine secretion that were more severe than those observed in cells exposed to stable high-glucose concentrations (4). These data extrapolated in vivo are consistent with the notion that rapid excursions in glycemia may have relevant pathological effects. Recently, it has been demonstrated that some adhesion molecules (P-selectin in particular) and other markers of inflammation are important risk factors for cardiovascular diseases (5,6,7).

Therefore, the aim of the present study was to evaluate whether long-term glucose instability is associated with increased plasma concentrations of soluble adhesion molecules in type 2 diabetic patients. To test this hypothesis, type 2 diabetic patients attending the Verona Diabetes Center with at least three fasting plasma glucose (FPG) determinations per year over a 6-year period (1995–2000) were identified, and the CV-FPG was calculated. A total of 11 patients with unstable FPG (CV-FPG ≥25%) were selected (group A). To reduce the effects of confounders known to increase levels of adhesion molecules, participants had to be nonsmokers with no clinical evidence of cardiovascular diseases (assessed by physical examination, electrocardiogram, ankle-arm index, and intima-media thickness of the carotid artery). As the control, a group of 14 subjects with stable FPG (CV-FPG ≤10%), well-matched for sex, age, duration of diabetes, BMI, total cholesterol, HDL-cholesterol, triglycerides, and blood pressure, were selected (group B). The cutoff of CV-FPG was chosen based on the results of our previous study: a CV-FPG <15% was associated with the lowest cardiovascular mortality rate, whereas a CV-FPG >25% predicted the highest cardiovascular mortality rate (1,2).

Subjects with glucose instability had statistically significant higher mean FPG (183 ± 43 vs. 157 ± 17 mg/dl, P = 0.01) and were more frequently treated with insulin. Circulating levels of E-selectin, P-selectin, intracellular adhesion molecule (ICAM)-1, and vascular cell adhesion molecule (VCAM)-1 were measured in all patients between November 2000 and December 2000 by enzyme-linked immunoassay (Bender Medsystems), with intra- and interassay CVs <8%.

In the covariance analysis, after adjusting for mean FPG, P-selectin values were significantly higher in group A (371 ± 102 vs. 284 ± 66.7 ng/ml, P = 0.03). The other adhesion molecules tended to be higher in group A, but none of them reached statistical significance (ICAM-1 346 ± 102 vs. 299 ± 58.9 ng/ml, P = 0.07; VCAM-1 466 ± 175 vs. 381 ± 153 ng/ml, P = 0.12; E-selectin 62 ± 31 vs. 52 ± 30.3 ng/ml, P = 0.8). In conclusion, in this small selected sample of diabetic subjects, high FPG instability seems to be associated with an endothelial dysfunction that may increase the risk of cardiovascular morbidity and mortality. The present results must be confirmed in a large prospective study.

Muggeo M, Verlato G, Bonora E, Zoppini G, Corbellini M, de Marco R: Long-term instability of fasting plasma glucose, a novel predictor of cardiovascular mortality in elderly patients with non-insulin-dependent diabetes mellitus: the Verona Diabetes Study.
Muggeo M, Zoppini G, Bonora E, Brun E, Bonadonna RC, Moghetti P, Verlato G: Fasting plasma glucose variability predicts 10-year survival of type 2 diabetic patients: the Verona Diabetes Study.
Diabetes Care
Li W, Liu X, Yanoff M, Cohen S, Ye X: Cultured retinal capillary pericytes die by apoptosis after fluctuation from high to low glucose levels: a comparative study with retinal capillary endothelial cells.
Jones SC, Saunders HJ, Qi W, Pollock CA: Intermittent high glucose enhances cell growth and collagen synthesis in cultured human tubulointerstitial cells.
Frishman WH: Biologic markers as predictors of cardiovascular disease.
Am J Med
Oparil S, Oberman A: Nontraditional cardiovascular risk factors.
Am J Med Sci
Ridker PM, Buring JE, Rifai N: Soluble P-Selectin and the risk of future cardiovascular events.
103: 491–495, 2001

Address correspondence and reprint requests to Prof. Michele Muggeo, Divisione di Endocrinologia e Malattie del Metabolismo, Ospedale Civile Maggiore Borgo Trento, P.le Stefani 1, 37126 Verona, Italy. E-mail: michele.muggeo@mail.azosp.vr.it.