Insulin and atherosclerosis: How are they related?

Monnier L, Hanefeld M, Schnell O et al.
Diabetes Metab. 2013 Mar 15.. doi: 10.1016/j.diabet.2013.02.001

Background

Three glycaemic conditions are at play in people with type 2 diabetes, to wit chronic hyperglycaemia, glycaemic variability and iatrogenic hypoglycaemia, each of which contributes to the increased risk of adverse cardiovascular (CV) outcomes. Progression of disease is often accompanied with high-dose insulin treatment. This raises the question whether therapeutic induction of hyperinsulinaemia could negatively affect the risk factors contributing to the pathogenesis of atherosclerosis in individuals with type 2 diabetes.
We here summarise how insulin metabolism and atherosclerosis pathogenesis may be intertwined, as described in this review article by Monnier et al.

The pathogenesis of atherosclerosis in diabetes

All states of insulin resistance in type 2 diabetes and/or obesity are associated with dyslipidaemia and chronic low-grade inflammation. Insulin normally stimulates glucose uptake in multiple peripheral tissues and regulates the body’s glucose homeostasis. In insulin-resistant type 2 diabetes the normal metabolic cascade leading to glucose transport is impaired. An alternative signalling pathway (involving mitogen-activated protein (MAP) kinase) remains responsive to insulin despite insulin-resistance. The MAP-kinase pathway is involved in inflammation, cell growth and proliferation, as well as progression of atherosclerosis. Overstimulation of this pathway through compensational mechanisms or exogenous high-dose insulin can thereby contribute to diabetic CV complications.

Moreover, type 2 diabetes is considered a chronic inflammatory condition, characterised by elevated levels of multiple inflammatory markers and cytokines. This is also seen in non-diabetic, obese individuals. These inflammatory markers can contribute to insulin resistance, increase platelet aggregation and can cause endothelial cell dysfunction and damage the vascular system.  
The causal role of persistent hyperglycaemia  in the development of vascular disease in type 1 and 2 diabetes has been concluded from landmark studies. In addition, increased glucose exposure leads to excess protein glycation, which has been shown to induce both oxidative stress and a prothrombotic state.

Acute hyperglycaemic surges can worsen the expression of CV risk factors, for instance vasculotoxic oxidant products. Intermittent glucose peaks were shown to increase apoptosis in endothelial cells. Also in patients urinary oxidative stress markers correlated well with glucose fluctuation. Also downward variations in glucose concentration have been associated with fluctuations of markers of oxidative stress.

Is insulin an anti- or proatherogenic hormone?

Results from a clinical study that compared the levels of a marker for oxidative stress in diabetic patients treated with either oral hypoglycaemic agents (OHA) or oral antidiabetic drugs (OAD) combined with insulin suggested that insulin per se exerts an inhibitory effect on the activation of oxidative stress. Insulin may normally be able to overcome the pro-oxidant effect of glycaemic variability.

 Various lines of evidence also point to an anti-inflammatory, antithrombotic and antiatherogenic effect of insulin. Some of these effects have been described to be independent of any improvement in plasma glucose concentration.
Some studies have suggested that the quality of diabetic control is an important factor in reducing long-term mortality after myocardial infarction. Thus, both the appropriate delivery of insulin and the intensified control of glycaemic disorders are of vital importance to improve survival rates.
Clinical trials have however failed to show a benefit of limiting glycaemic variability on CV risk, in type 2 diabetic patients treated with long-term insulin therapy.  Thus, the question remained how glycaemic variability can be a potent activator of oxidative stress in non-insulin-treated type 2 diabetic patients, while failing to show a significant effect on CV risk.

A model that explains the bifaceted effects of insulin on atherogenesis

The authors propose a model that may explain this controversy. It suggests that patients treated with insulin are mostly at risk of increased HbA1c levels indicating ambient hyperglycaemia and an excess of glycation, while the deleterious effects of acute glucose fluctuations can be neutralized by exogenous insulin, provided that iatrogenic hypoglycaemic episodes are avoided. This model may explain why glycaemic variability appears to play only a minor role in patients treated with insulin even when marked glucose surges are observed.    

Clinical consequences

Current evidence suggests that insulin may be a bifaceted hormone with beneficial antiatherogenic effects at doses that result in near-physiological circulating insulin levels, but with proatherogenic effects at high insulin doses that yield supraphysiological levels.
This underscores that the relationship between insulin and oxidative stress in type 2 diabetes is complex, and confirms that many questions remain on the effect of insulin on atherosclerose. It suggests that it could be better to initiate insulin therapy early in the course of disease, with smaller doses, rather than higher doses at a later stage.

The ORIGIN trial was designed to determine whether early basal insulin treatment by insulin glargine in high-risk individuals with newly diagnosed type 2 diabetes or prediabetes is a crucial CV risk determinant. No differences in the rates of CV events between basal insulin glargine and standard-care treatment was seen in the median 6.2 years of follow-up, despite the lower glucose exposure observed in the glargine group. The lack of difference found may have been a consequence of the near-physiological HbA1c levels, at which it is difficult to achieve or detect any improvement on CV outcome. Or it could be that any small positive effect from limiting hyperglycaemia in the glargine arm might have been counteracted by the potentially harmful effects of increased glucose variability.

The question of whether earlier implementation of basal insulin regimens are a better strategy than maintenance with an oral antidiabetic regimen cannot be answered as yet. Although many diabetologists prefer to give low-dose insulin treatment as early as possible to preserve beta-cell function and reduce the risk of long-term diabetic complications, the complexity of the relationships between insulin and macrovascular disease in type 2 diabetes patients should not be forgotten. The model proposed here may help to choose the best treatment strategy in patients with insulin-requiring type 2 diabetes.


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