About 75% of patients with type 2 diabetes die from macrovascular complications; however, only 35% of patients with type 1 diabetes do so. This significant difference is linked to the underlying disorders of type 2 diabetes: insulin resistance and beta-cell dysfunction. Insulin action at the metabolically active cell level increases glucose uptake, but activation of insulin receptors at the inner layer of the arteries induces the production of nitric oxide (NO) and mediates a variety of vasoprotective and anti-inflammatory effects at the endothelial level (Figure 1). Therefore, insulin resistance leads to hyperglycemia but also to impairment of vasoprotection and substantial endothelial dysfunction, with increased secretion of adhesion molecules and increased monocyte activation and migration into the vascular wall.1
At the same time, beta-cell dysfunction is followed by increased secretion of the insulin precursor, proinsulin, which is considered to be an instigator of adipogenesis and a cardiovascular risk factor by stimulating plasminogen activator inhibitor (PAI)-1 expression and by blocking fibrinolysis.2,3 In fact, intact proinsulin secretion forced by increasing insulin resistance can be regarded as the independent contribution of beta-cell dysfunction to the overall increased cardiovascular risk in patients with type 2 diabetes.4 An increased level of fasting intact proinsulin is a specific indirect indicator of insulin resistance that is suitable for diagnosis of insulin resistance in daily practice.5,6 Based on this background, it is to be expected that drugs addressing the underlying pathophysiology of type 2 diabetes should also induce improvements in vascular function and the macrovascular risk profile.
Patients and methods
We performed the PIOglitazoNe: study for the Evaluation of the Efficacy in cardiovascular Risk reduction (PIONEER) study, a prospective, parallel, 6-month investigation of the effect of two oral antidiabetic treatment approaches—peroxisome proliferator-activated receptor-gamma (PPARg) activation with pioglitazone (Actos) and stimulation of beta-cell secretion with glimepiride (Amaryl)
—on glucose metabolism, cardiovascular risk, insulin resistance, and beta-cell dysfunction in orally treated patients with type 2 diabetes. Patients received either 45 mg of pioglitazone or 1 to 6 mg of glimepiride adjusted to optimize glucose control. The study was completed by 173 patients (66 women, 107 men), with a mean age (± SD) of 63 ± 8 years. The mean duration of disease was 7.2 ± 7.2 years, and the mean glycosylated hemoglobin (A1C) was 7.5 ± 0.9%. Observation parameters at baseline and the end point were A1C, glucose, insulin, intact proinsulin, lipids, adiponectin, high-sensitivity C-reactive protein (hsCRP), matrix metalloproteinase (MMP)-9, monocyte chemoattractant protein (MCP)-1 levels, and intima-media thickness (IMT). The latter measurement was performed by one single investigator and a blinded independent analyst to minimize the variability of the method.
A1C was equally improved in both treatment arms (—0.6 ± 0.8% in the glimepiride group and –0.8 ± 0.9% in the pioglitazone group; P < .001) compared with baseline. There was no significant difference between the two groups at baseline and end point. Marked improvements, however, were seen only in the pioglitazone group for the cardiovascular risk profile (a reduction in IMT, hsCRP, MMP-9, and MCP-1 levels and an increase in adiponectin and high-density lipoprotein levels), beta-cell dysfunction (reduction of fasting insulin and proinsulin), and insulin resistance (reduction of homeostasis model of insulin resistance [HOMA-IR] and intact proinsulin), as shown in Figure 2.7-9
Insulin receptors exist on multiple cell types in the human body. In the majority of the cells, insulin induces glucose uptake. This is not the case in the endothelial cell, however, where insulin receptor activation stimulates NO-synthetase. NO induces a variety of vasoprotective actions, including but not limited to reduction of adhesion molecule secretion, improvement of erythrocyte deformability, and reduction of monocyte/macrophage activation.10 The endothelial cell layer provides the barrier between the inner cells and the bloodstream. It is directly exposed to those molecules in the blood that produce oxidative stress and toxic effects (eg, glucose in concentrations above 180 mg/dL). As a result, deterioration of insulin action by development of insulin resistance leads to an impairment of endothelial function, and the organism is less protected against systemic arteriosclerosis.
PPARg activation by pioglitazone, for example, improves the intracellular insulin signal transduction process and decreases overall insulin resistance. This effect is, of course, not limited to metabolic insulin resistance, but is also effective at the vascular level in the endothelial cells. As shown in our study, the response to effective insulin resistance treatment by thiazolidinediones is an overall reduction of IMT and vascular inflammation. The additionally observed improvement in beta-cell dysfunction leads to a beneficial reduction of intact proinsulin secretion and an increase in adiponectin levels. These findings support our current understanding of the connection between beta-cell dysfunction insulin resistance and the metabolic syndrome, as shown in Figure 2. It is noteworthy that adipogenesis seems to be the driver for hypertension, dyslipidemia, and inflammatory activity. In contrast to drugs targeting blood glucose levels only, pioglitazone addresses insulin resistance, which breaks the lethal cycle of insulin resistance and adipogenesis and may consequently reduce further symptoms of the metabolic syndrome (Figure 3).
Our findings, however, also induce another critical thought that is linked to the current understanding of type 2 diabetes diagnosis and treatment. Di-agnosis of type 2 diabetes is solely based on deteriorated blood glucose levels, and the deleterious effects of insulin resistance at the vascular level are not considered. The exclusive definition of type 2 diabetes as a fasting blood glucose level above 127 mg/dL or 2-hour values above 200 mg/dL after a glucose challenge11 is the reason many patients with type 2 diabetes suffer from macrovascular disease at the time of “official” diabetes diagnosis. It is expected that different phenotypes of type 2 diabetes exist. They are associated with different degrees of vascular and metabolic insulin resistance, which finally defines the clinical picture. Although a myocardial infarction or arteriosclerosis may be the first symptom of the disease in some patients, other patients may predominantly manifest with major blood glucose deterioration.
Effective treatment of insulin resistance with appropriate methods (diet, exercise, and sensitizing drugs) may be a much more efficient treatment approach than solely performing “blood glucose cosmetics,” for example, using sulfonylurea drugs. Further substantial information regarding the effect of thiazolidinedione treatment on cardiovascular mortality can be expected from ongoing large outcome studies. The results of the most advanced trial, the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive),12 were published recently.13 As expected from our findings, it showed a significant decrease by 16% of the combined hard end points of all-cause mortality (—9%), myocardial infarction (–22%), and stroke (–18%) after just 3 years of observation in comparison to placebo treatment. Thus, it proved the beneficial effect of pioglitazone treatment on cardiovascular outcome in patients with type 2 diabetes.