Effects of Mealtime Insulin Aspart and Bedtime NPH Insulin on Postprandial Inflammation and Endothelial Cell Function in Patients with Type 2 Diabetes

Abstract

Acute hyperglycaemia exerts deleterious effects on the arterial wall. We suggested that rapid-acting insulin has a beneficial postprandial effect on endothelial dysfunction and inflammation compared with intermediate-acting insulin because of its ability to lower postprandial hyperglycaemia. This was tested in a parallel, controlled study on well-controlled patients with type 2 diabetes randomly assigned to bedtime Neutral Protamine Hagedorn (NPH) insulin (n = 41) or mealtime insulin aspart (n = 37). They were served standard diabetic meals for breakfast (8.00) and lunch (12.00). Blood samples were collected at 7.40 (fasting), 9.30, 11.30, 13.30 and 15.30 and analysed for glucose, insulin, lipids, intercellular adhesion molecules (ICAM), C-reactive protein (CRP), von Willebrand factor (vWF) and fibrinogen. The postprandial glucose response differed significantly between insulin regimens with a postprandial increase on NPH insulin and a decrease on insulin aspart. There was a minor but significant postprandial decrease in ICAM, CRP and vWF on both insulin regimens and a decrease in fibrinogen on NPH insulin. No insulin group differences were observed in postprandial responses for ICAM, CRP, vWF and fibrinogen. The rapid-acting insulin analogue aspart and the intermediate-acting insulin NPH had different effects on postprandial glucose response but similar postprandial effects on markers of inflammation and endothelial dysfunction.Type 2 diabetes is associated with increased risk of cardiovascular disease [1]. There is a strong relationship between postprandial hyperglycaemia and the risk of cardiovascular disease in epidemiological studies where postprandial hyperglycaemia is more important than fasting blood glucose or HbA1c as predictors [2][3][4][5]. However, this concept has recently been challenged [6,7] and is still highly debated [8,9].Experimental data indicate that acute hyperglycaemia can exert deleterious effects on the arterial wall measured as flow-mediated vasodilatation [10][11][12]. In line with this, the link between acute hyperglycaemia and inflammation and endothelial cell dysfunction has been investigated, showing an acute increase in interleukin 6 (IL-6) and tumour necrosis factor alfa (TNFa) [ [21] or by the antioxidant glutathione [13,14]. In these studies, the hypoglycaemic agent was compared with placebo, and different treatment regimens have not been compared. It is assumed that pharmacological agents directed towards postprandial hyperglycaemia will be more effective in reducing postprandial inflammation and endothelial cell dysfunction than treatment directed towards fasting hyperglycaemia.The aim of this short-term study in well-controlled patients with type 2 diabetes was to compare the acute effect of two different insulin treatment regimens on postprandial inflammation and endothelial cell function evaluated by biochemical markers. We suggested that the rapid-acting insulin analogue insulin aspart, directed towards postprandial hyperglycaemia, has a beneficial postprandi...

Effects of mealtime insulin aspart and bedtime neutral protamine Hagedorn insulin on postprandial coagulation and fibrinolysis in patients with type 2 diabetes

“…Ceriello et al suggested that insulin dampens the effect of hyperglycaemia on FVII [14]. In our study, the postprandial total insulin levels (AUC and postprandial mean) were comparable in the two insulin groups [20] and might affect concentrations of FVII, D‐dimer and F1+2 to a similar extent. Equal insulin levels can also explain why the two insulin regimens had similar effects on fibrinolysis [18,19], and we observed highly significant correlations between the insulin response (AUC and postprandial mean) and the PAI response in both treatment groups (not shown).…”

“…The beneficial effect of reducing postprandial glucose on clinical endpoints was recently questioned in a randomised controlled trial (HEART2D) showing that the risk of future CVD is similar, when either mealtime insulin or bedtime insulin is used as secondary prevention in type 2 diabetes patients experiencing a recent acute myocardial infarction [29]. In line with this, the CVD risk markers vWF, fibrinogen, ICAM and CRP are affected equally in the postprandial state by insulin aspart and insulin NPH in spite of significantly different effects on postprandial glucose concentrations [20]. We suggest here that this is also the case for coagulation and fibrinolysis.…”

“…The optimal design for studying acute effects of meals in patients with insulin‐treated advanced type 2 diabetes is difficult to define and can be a major reason for the discrepancy between study results. We used well‐controlled patients, and we aimed at fairly equal HbA1c and total insulin dose despite difference in insulin treatment modality (Table 1) [20]. Unfortunately, the patients differed with respect to smoking (Table 1), which is known to influence some of the variables measured.…”

“…Patients with type 2 diabetes in the outpatient clinics at the Departments of Endocrinology, Hospital of South West Denmark, Esbjerg and Odense University Hospital, Odense, Denmark were invited to participate in the study, if they were at the same time participating in the South Danish Diabetes Study (SDDS) 1 year follow‐up period, in which diabetes patients 2–3 years previously were randomised to either insulin NPH at bedtime or mealtime insulin aspart thrice daily [21]. Seventy‐eight patients met the inclusion and exclusion criteria and were recruited for the present meal test study, which are described in detail elsewhere [20]. The population characteristics at study entry in the meal test study are described in Table 1.…”

“…It is assumed that pharmacologic agents directed towards postprandial hyperglycaemia will be more effective in reducing postprandial coagulation and fibrinolysis than treatment directed towards fasting hyperglycaemia. Recently, we showed that the rapid‐acting insulin analogue, insulin aspart and the intermediate‐acting insulin neutral protamine Hagedorn (NPH) have significantly different effects on postprandial glucose concentrations but similar effects on von Willebrand factor (vWF), fibrinogen, intercellular adhesion molecules (ICAM) and C‐reactive protein (CRP) indicating similar effects on inflammation and endothelial cell function [20]. These two insulin regimens have not previously been compared with respect to coagulation and fibrinolysis.…”