Effect of Insulin Glulisine on Microvascular Blood Flow and Endothelial Function in the Postprandial State

Abstract

OBJECTIVE -To investigate the effect of insulin glulisine on postprandial microvascular blood flow in type 2 diabetes.RESEARCH DESIGN AND METHODS -A total of 15 patients with type 2 diabetes received insulin glulisine or human insulin before a liquid meal test. Thereafter, skin microvascular blood flow was measured by laser Doppler fluxmetry and blood samples were taken for measurement of plasma levels of glucose, insulin, intact proinsulin, asymmetric dimethylarginine, nitrotyrosine, interleukin-18, matrix metalloproteinase-9, oxidized LDL, and free fatty acids.RESULTS -Insulin glulisine injections resulted in higher postprandial insulin levels (means Ϯ SEM area under the curve [AUC] 0 -120 51.0 Ϯ 6.8 vs. 38.2 Ϯ 5.4 mU/l; P ϭ 0.004), while plasma glucose (AUC 0 -240 158 Ϯ 9 vs. 180 Ϯ 9 mg/dl; P Ͻ 0.05) and intact proinsulin (AUC 0 -240 26.2 Ϯ 3.5 vs. 31.2 Ϯ 4.3 pmol/l; P ϭ 0.002) were lower. Microvascular blood flow increased after insulin glulisine injection (27.9 Ϯ 3.1 to 51.7 Ϯ 9.9 arbitrary units [AU]; P Ͻ 0.05), while only a minor increase was found during human insulin (27.9 Ϯ 3.1 to 34.4 Ϯ 7.8 AU; not significant). Asymmetric dimethylarginine and nitrotyrosine levels were reduced after insulin glulisine (P Ͻ 0.05).CONCLUSIONS -Insulin glulisine is superior to human insulin in restoring postprandial metabolic and microvascular physiology. Diabetes Care 31:1021-1025, 2008S everal epidemiological studies have demonstrated an association between glucose spikes and the development of vascular complications in patients with type 2 diabetes. Postprandial generation of oxidative stress and impaired endothelial function are major contributors in the development of early vascular damage and atherosclerosis. Recent studies have shown that microvascular blood flow increases after a meal in gut, skin, heart, and adipose tissues (1-5). Postprandial regulation of microvascular blood flow is a complex process inversely affected by postprandial glucose and insulin excursions (2,6,7).Diminished prandial insulin secretion and an increase in postprandial plasma glucose excursions with increased postprandial oxidative stress and impaired endothelial function are early features of type 2 diabetes. Insulin glulisine attenuates the postprandial increase in plasma levels of intact proinsulin compared with regular human insulin, which may lead to a corresponding reduction in cardiovascular risk and ␤-cell protection. Therefore, the pharmacokinetics of prandial insulin formulations may be important not only in controlling postprandial glucose excursions, but also in the maintenance of normal endothelial function and microvascular blood flow. The aim of this study was to compare the effect of insulin glulisine with regular human insulin in terms of postprandial microvascular blood flow and several laboratory markers of endothelial function and oxidative stress in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS -This investigation wasa single-center, open-label, randomized, two-way crossover study of patients with type 2 ...

Standardized modulation of the injection site allows for insulin dose reduction without deterioration of metabolic control

“…In later stage diabetes, high-dose insulin treatment in an insulin-resistant state results in activation of mitogen-activated protein kinase with consecutive endothelin I secretion and development of atherosclerosis by binding to the same receptor 22,23 . We have been able to demonstrate that the kinetics of exogenously administered insulin has a major influence on the vascular action of this hormone and that a faster onset of action is associated with improvement of microcirculation and associated time courses of nitrotyrosine and other biomarkers of oxidative stress and atherosclerosis risk 8,24,25 . In consequence, insulin can be regarded as a bipotential hormone having positive or negative impact on vascular function, dependent on the time-action profile of the administered insulin and the stage of insulin resistance of the individual patient.…”

Postprandial Vascular Effects of VIAject Compared With Insulin Lispro and Regular Human Insulin in Patients With Type 2 Diabetes

“…Besides its role in the regulation of glucose metabolism, insulin has been shown to mediate important vascular effects by stimulating the endothelial secretion of nitric oxide (5,16). Recent studies suggest that the pharmacokinetic profile of subcutaneous insulin absorption might have an impact on the generation of postprandial oxidative stress and the development of endothelial dysfunction (9–11,17). Insulin may directly affect the generation or degradation of ADMA, and insulin resistance is associated with increased ADMA levels (18,19).…”

“…ADMA was chosen as the primary end point because a previous study had demonstrated a significant impact of fast-acting analogs on the generation of postprandial ADMA levels in patients with type 2 diabetes (10). A sample size of 14 patients was calculated to provide 80% power, assuming a comparable effect on the postprandial excursion of plasma ADMA levels and considering a two-sided test with a significance level of 5%.…”

“…These findings suggest that a physiological timing of prandial insulin release fulfills an important role not only in controlling postprandial blood glucose levels but also in maintaining normal tissue perfusion and nutrition. In addition, recent studies have shown that in insulin-treated patients with type 1 and type 2 diabetes, the pharmacokinetic profile of insulin formulations affects postprandial microvascular blood flow and that treatment with fast-acting insulin analogs reduces postprandial oxidative stress and restores endothelial function more effectively than treatment with human regular insulin (9–11). …”

Assessment of microvascular and metabolic responses in the skin

“…The vascular endothelium has been shown to play an important role in capillary recruitment by the release of NO. It has been shown that capillary recruitment by insulin also may occur in the skin (Hohberg et al, 2008) and that this process is impaired in hypertension, obesity and insulin resistance (de Jongh et al, 2004a;de Jongh et al, 2004b).…”