In spite of intensive research, the role of glucose excursions as an essential component in the pathophysiology of vascular complications in diabetes mellitus remains controversial. In this context, it must be emphasized that the definition of glucose excursions is blurred and often not used consistently. First, the distinction between glucose variability (fluctuations in blood glucose) and postprandial (pp) glucose excursions is crucial, even if the latter contribute to overall glucose variability.
Since the DCCT study revealed a reduced risk for the development of diabetic retinopathy in intensively vs. conventional treated patients, despite comparable HbA1c levels (1), the role of postprandial glucose control has received increasing attention. Consecutively, numerous observational trials underline a potential role of postprandial glucose excursions in the development of myocardial infarction, stroke, or an increased mortality (2-7). In a meta-analysis on 20 studies with 95783 subjects without diabetes, the blood glucose level two hours after an oral glucose load were found to be highly predictive for cardiovascular events (8). A recent investigation, including 2138 subjects without diabetes, which had undergone an oral glucose tolerance test at baseline, were followed up for a duration of 33 years (4). In this investigation, the one hour post load glucose level ≥ 155 mg/dl was associated with an increased mortality, even when the two hour post load glucose level indicated a normal glucose tolerance. Elevated pp glucose levels were found to be associated with carotid atherosclerosis (9-11), increased arterial stiffness (12), coronary artery disease (6,13), and an increased left ventricular mass (14). In contrast, a study by the Emerging Risk Factors Correlation did not find any additional predictive value of post load glucose levels over conventional risk factors in a 10-year survey on the risk of cardiovascular events in adults with known diabetes or a history of cardiovascular disease (15). There are very limited data from interventional trials to speculate on the role of pp glucose levels in the development of vascular complications. In the HEART2D study, prandial insulin treatment was not superior to basal insulin treatment with regard to the development of cardiovascular complications (16). A major issue of this trial was that the difference in pp glucose levels between the two treatments arms was much lower than expected, and the overall cardiac event rate was very low for both groups. The Heart2D study reflects the challenge that any glucose lowering treatment wills more or less effect fasting and pp glucose levels, making the interpretation of isolated postprandial effects in interventional trials difficult. Nevertheless, a post-hoc analysis of data from the HEART2D study surmised a lower risk of cardiovascular events with prandial versus basal insulin therapy in a subgroup of older patients of more than 64 years (17). In the NAVIGATOR trial, treatment with the short acting insulin secretagogue nateglinide compared to placebo had no effect on cardiovascular out comes (18). In the FLAT-SUGAR trial, treatment with the GLP-1 receptor agonist exenatide, in addition to basal insulin, was found to better control pp glucose levels compared with a basal bolus insulin treatment (19). In this study, treatment with the GLP-1 receptor agonist was found to lower cardiovascular risk as indicated by a reduction in body weight and serum amyloid A.
The atherogenic pathways linking elevated pp blood glucose concentrations with vascular complications are not fully elucidated. As shown in figure 1, several components (i.e. oxidative stress, lipid accumulation, PKC-β activation, increased inflammation, altered haemorheology, autonomic imbalance, endothelial dysfunction) most probably accumulate to the highly pro-atherogenic environment as observed in individuals with disturbed pp glucose regulation. Glucose spikes, such as occurring in the pp period, may underlie the development of complications due to oxidative stress, endothelial dysfunction, and a dysbalance between vasoconstricting and vasodilating vectors.
Figure 1: Potential mechanistic pathways linking elevated pp glucose excursions with vascular complications
In addition to other atherogenic mechanisms, impaired pp microvascular blood flow might contribute to the development of tissue damage in patients with diabetes mellitus. In subjects without diabetes, microvascular blood flow in retina, skin, or myocardium was found to increase after the ingestion of a meal (20,21). In contrast, in patients with impaired glucose control, the increase in microvascular blood after a meal was found to be blunted or even reversed (22). Especially in tissues prone for the development of ischaemic injury, reduced pp blood flow might accelerate to end-organ damage like myocardial infarction or stroke.
Figure 2: The endothelial cell as a regulator of vascular tone. Role of activators and inactivators of the endothelial nitric oxide synthetase (eNOS = endothelial nitric oxide synthetase; GC = guanylate cyclase; cGMP = cyclic guanosine-monophosphate; GTP = guanosine-triphosphate;)
As shown in figure 2, pp regulation of vascular blood flow is a dynamic process, regulated by a complex interaction of several balancing and counterbalancing forces. The production and release of nitric oxide from the endothelial cell plays a crucial role in the regulation of the vascular tone. Nitric oxide (NO) within the endothelial cell is synthesized from arginine by the enzyme endothelial nitric oxide synthetase (eNOS). After approaching the vascular smooth muscle cells, NO stimulates the guanylate-cyclase (GC), thereby increasing the intra-myocellular content of cyclic guanosine-monophosphate (cGMP), with subsequent relaxation of the vascular wall. In patients with diabetes mellitus, insulin resistance and a protracted insulin release from the beta cell does not only worse pp blood glucose levels, but also affect vascular function by disturbing the balance between activators (insulin, acetylcholine, C-peptide, bradykinin) and de-activators (elevated glucose concentration, asymmetric di-methyl arginine) of the eNOS system.
Beside reducing pp blood glucose concentrations, the use of fast acting insulin analogues (lispro, glulisine, aspart) were shown to reduce oxidative stress, to improve endothelial function, and to normalize pp microvascular blood flow in several tissues (22-25). Newer, even faster insulin analogues in clinical development will further smooth pp blood glucose excursions. In addition, numerous new anti-diabetic pharmacological interventions, like di-peptidyl-peptidase (DPP-IV) inhibitors, glucagon-1- receptor (GLP-1) receptor agonists, or sodium-glucose-transporter 2 (SGLT-2) antagonists reduce pp glucose concentrations without increasing the risk of hypoglycemia. There is increasing evidence that these treatments not only improve fasting and pp blood glucose concentrations but also have beneficial vascular effects in patients with diabetes mellitus (26). Together this will reinforce our discussion about the role of pp metabolic control in the prevention of vascular complications in patients with diabetes mellitus. In any way, the therapeutic goal must be to adapt blood glucose levels in patients with diabetes mellitus to normal physiology as close as possible, which includes the control of fasting as well as pp glucose values, and HbA1c without increasing the risk of hypoglycemia.