It is an apparently simple question, and one that clinicians face daily. Like many important clinical issues, this one is easy to ask but hard to answer. Even including the recently released U.K. Prospective Diabetes Study (UKPDS), no large randomized controlled clinical trial has been designed specifically to test the effect of insulin treatment on cardiovascular events. Such a study would be costly and would have to take into account many hard-to-control variables associated with type 2 diabetes. Also, the known adverse effects of poor diabetic control—from symptoms of hyperglycemia to worsening microvascular disease—weigh against initiating a study that intentionally withholds insulin therapy from those who need it to control glycemia.

Without definitive proof of how insulin therapy affects cardiovascular disease (CVD), as many as 30–40% of people with type 2 diabetes now receive insulin . Based on average glycemic control , it could well be that even more people would benefit from its use. The persistent reluctance among many practitioners to start insulin can be attributed in part to the increased risk of hypoglycemia and insulin's unpopularity with patients. But the rationale often given is that insulin is atherogenic. Insulin, used therapeutically, is alleged to cause, rather than prevent, macrovascular disease.

The reason for this concern is clear and is reviewed in this article. Some in vitro evidence suggests that insulin can promote lipid entry into atheromatous plaques and cause intimal hyperplasia. More impressively, a large body of evidence, though not entirely consistent, suggests that in the nondiabetic or prediabetic state, increased serum insulin (hyperinsulinism, or insulin resistance) is associated with increased incidence of CVD.

There is also counterbalancing evidence that poor glycemic control causes increased risk of macrovascular disease. Hyperglycemia itself may be a risk factor, not only for small-vessel disease.

The most important pathophysiological events, however, may be neither hyperinsulinemia nor hyperglycemia as such. The metabolic effects of poor diabetic control go well beyond hyperglycemia. It could well be that the effect of uncontrolled diabetes on macrovascular disease results from the associated lipid dysmetabolism, abnormalities of clotting factors, blood pressure, or other ill-defined derangements that accompany under-insulinization. Some of these factors are discussed, in support of the conclusion that when clinically indicated to control diabetes, insulin therapy reduces, rather than increases, the risk of macrovascular disease.

This is a very difficult question to answer. Theoretically in order to detect an effect (harmfull or protective) of insulin on CVD morbidity a randomized controlled prospective study should be undertaken in which paticipants would be randomly allocated to glucose control therapy with and without insulin and followed for a considerable period.

For obvious reasons no such study was evr done nor will ever be done. Insulin traated patients are'by definition, a high-risk group for CVD because they are older' have diabetes of longer duration and had been less well controlled than tose remaining on oral drugs.

The theories about the gowth promoting features of insulin and some evidence from experimental -animal studies are barely applicable to humans.

The bottom line is that we don't know whether insulin is atherogenisc in real life situation and we will probably never know.

Interesting question indeed.

DCCT trial, and especially its longer term follow-up demonstrated a decrease in mortality in type 1 diabetic patients with near normal HbA1c compared to patients with higher levels of HbA1c. Similar findings with the UKPDS trial in type 2 patients.

The issue is that these 2 studies are more epidemiological trails: the lower is HbA1c, the lower is the risk of micro- or macro-vascular complications. However interventional studies, versus placebo have been negative (in terms of decreasing the CV risk) or not done for other reasons (see below) so far. Interestingly HbA1c appears to be a good surrogate marker for micro-vascular complications, but is probably not the right one for macro-vascular complications.

If insulin cause some damage on cardiovascular cells, for sure that it is much less than that cause by constant hyperglycemia (high levels of HbA1c). As you can't perform a model of insulin treatment where you could isolate glycemia (hypo or hyper) related damages, you can just analyze toxic substances or elements presents in insulin like heavy metals and propose some prospective analyses bioaccumulation of those things. Despite in an study performed in Korea they didn't find correlation. I guess that it couldn't happens because the amount administrated isn't sufficient to make a big difference, and to access this information you need a nutritional profile analysis to ensure that those data isn't a feed bias. I can't get access to the full paper at home, fell free to read the it: http://www.ncbi.nlm.nih.gov/pubmed/23278294

Thanks all for putting valuable points.

Good thoughts from Thais and Moti Ravid....

Hypoglycemia is the main harmful effect on cardiovascular outcomes. Hypoglycemia causes cardiac arrhythmias, especially in those with preexisting cardiovascular disease. Further, hypoglycemia is more common in those with reduced renal function. Therefore insulin dosage will be proportionately reduced in those with reduced renal function.

Clinical Evidence has shown significant benefits of insulin therapy in diabetes treatment, which out weighs most possible side effects, with it's downstream effect on HBA1c, an important indicator in cardiovascular co-morbidity associated with diabetes. However analysis of insulin from a biochemical effect is an interesting view point. And the only thing that comes to mind is the effect of insulin on transporters of potassium( insulin has been shown to affect influx and infux of potassium) in cells. of course this can, and probably is routinely monitored in clinical practice to a avoid (hyperkalemia / hypoKalemia). And hyperkalemia is well noted for it effects on the RAAS and Anion Gap , as well as the arrhythmia associated with hyper/hypokalemic situation. this can often compound the illness in the diabetic. Moreover the effect of insulin-induced (hyperkalemia seems to be doseage-dependent.

In would be an interesting prospective study.

I am not a physician, but try to look for information about the GIK solution. The DIGAMI trial used it in diabetics

Insulin has direct effects on the cardiovascular system. It has effects on the autonomic control of heart. Insulin is said to reduce vagal influence on the heart and induces a relative hypersympathetic tone (Bellavere F et al). Insulin has vascular effects and causes expression of nitric oxide from the endothelium. Distinct MAPK-dependent insulin-signaling pathways regulate the secretion of endothelin-1, a potent vasoconstrictor, that might result in increased high blood pressure or coronary vasoconstriction can cause heart attacks.

In a multicentric trial, it has been shown that patients who develop insulin resistance have a higher incidence of congestive heart failure. Insulin resistance is an independent causative factor for CHF. Because of the complex interactions between various hormone levels and the response of ogans to clinically high levels of insulin, it is very difficult to define the adverse effects on cardiovascular system.

Associated with insulin resistance are low HDL levels that can result in heart attacks and high HDL levels which can result in clogged arteries and plaques formation. Insulin resistance is also known to cause inflammation. Inflammatory reaction together with high HDL levels can result in plaque formation and heart attacks or strokes.

Insulin is necessary to get the extracellular glucose within the cells. Since diabetic patients have excess glucose in the circulation, insulin therapy is necessary to get the excess sugar in the cells. Similarly the presence of insulin is necessary to get the extracellular potassium within the cells. Lack of insulin therapy in diabetic patients may result in hyperkalemia.

Diabetes can result in atherosclerotic changes in the vessels. Insulin helps in reducing the plaque build up. Thus insulin therapy as such does good for the diabetic patients and minimizes cardiovascular complications. However, the general effects of insulin are given above which could be seen in either diabetic or non-diabetic patients. As such cardiovascular complications of insulin therapy in diabetic patients have to be evaluated in large multicentric clinical trials.

It is an apparently simple question, and one that clinicians face daily. Like many important clinical issues, this one is easy to ask but hard to answer. Even including the recently released U.K. Prospective Diabetes Study (UKPDS), no large randomized controlled clinical trial has been designed specifically to test the effect of insulin treatment on cardiovascular events. Such a study would be costly and would have to take into account many hard-to-control variables associated with type 2 diabetes. Also, the known adverse effects of poor diabetic control—from symptoms of hyperglycemia to worsening microvascular disease—weigh against initiating a study that intentionally withholds insulin therapy from those who need it to control glycemia.

Without definitive proof of how insulin therapy affects cardiovascular disease (CVD), as many as 30–40% of people with type 2 diabetes now receive insulin . Based on average glycemic control , it could well be that even more people would benefit from its use. The persistent reluctance among many practitioners to start insulin can be attributed in part to the increased risk of hypoglycemia and insulin's unpopularity with patients. But the rationale often given is that insulin is atherogenic. Insulin, used therapeutically, is alleged to cause, rather than prevent, macrovascular disease.

The reason for this concern is clear and is reviewed in this article. Some in vitro evidence suggests that insulin can promote lipid entry into atheromatous plaques and cause intimal hyperplasia. More impressively, a large body of evidence, though not entirely consistent, suggests that in the nondiabetic or prediabetic state, increased serum insulin (hyperinsulinism, or insulin resistance) is associated with increased incidence of CVD.

There is also counterbalancing evidence that poor glycemic control causes increased risk of macrovascular disease. Hyperglycemia itself may be a risk factor, not only for small-vessel disease.

The most important pathophysiological events, however, may be neither hyperinsulinemia nor hyperglycemia as such. The metabolic effects of poor diabetic control go well beyond hyperglycemia. It could well be that the effect of uncontrolled diabetes on macrovascular disease results from the associated lipid dysmetabolism, abnormalities of clotting factors, blood pressure, or other ill-defined derangements that accompany under-insulinization. Some of these factors are discussed, in support of the conclusion that when clinically indicated to control diabetes, insulin therapy reduces, rather than increases, the risk of macrovascular disease.

this is connected more with the improper diabetic control that leads to hyper- and hypoglycemia. In this cases it is obvious that cardiovascular complications can be expected.

Thanks all for your interest as well as for writing valuable thoughts. "Simple question, dificult to find answer" as Sarah Dahmardeh stated above. Obviously, hypoglycemic shock is the most acut result during uncontrolled balance between insulin therapy and diet intake. Insulin is good hormone and most be replaced to sustain glucose homeostasis. Still question is that whether replacement therapy has any chronic adverse effects in cellular level? Question arises here based on few of reports showing insulin induced Cellular ROS production and also increases cell adhision molecules. However, I am trying to find any information that can show strong in vitro or invivo evedence.

Weight gain (and all obesity related cardiovascular risk factors) is a potential adverse effect of insulin therapy.

The main role of insulin in the heart under physiological conditions is regulation of substrate utilization, promotes glucose uptake and its utilization via glycolysis .Under normal conditions, heart -ATP production comes from the mitochondrial oxidation of different substrates, like long chain fatty acid being predominant over glucose and lactate.

In diabetic condition the level of circulating Ketone bodies , which are low under control conditions, rise upon starvation, in the presence of high blood concentrations of LCFAs, in chronic heart failure or in poorly controlled diabetes.

ketone bodies become a major substrate for the heart by inhibiting the oxidation of other substrates.

Altered mitochondrial biogenesis function in the hearts of diabetic patient, in one hand and other, impairment of vascular tone, because insulin regulate NO generation, pose further detrimental effect.

Moreover, Intensive insulin therapy has been recommended to prevent diabetese-induced secondary complication like Diabetic cardiomyopathy in type 1 DM or to some extent in the later stages of type 2 DM.

May I ask, What are the consequences of hyperinsulinemia on the cardiovascular system?

Dear all, nobody mentioned the recent study ORIGIN which demonstrated no any adverse effect of early insulin therapy on cardiovascular morbidity and mortality in T2DM and in prediabetic patients during 6 years of follow up. It seems to me to be a good evidence of insulin safety for cardiovascular system.

Bert Suys has made a study on cardiologic problemen in diabetic children. In some of them conduction problems were observed. (see anser by Omer Iqbal: effect on the autonomic control of the heart). I don't know the exact results, so you should search in pubmed under the names Bert Suys and/or Raoul Rooman.

Please see below for some of the beneficial effects of insulin:

Latest Report of Effects of Insulin on Cardiovascular System.

Recent findings from the Glucose Reduction and Atherosclerosis Continuing Evaluation (GRACE) Study, a substudy of the Outcome Reduction with an initial Glargine Interventions (ORIGIN) trial revealed that patients with early type 2 diabetes who were at high risk for cardiovascular events and those who received daily insulin-glargine (Lantus, Sanofi) injections had modestly improved measures of atherosclerosis progression, based on the examination of carotid artery intimal medial thickness, a surrogate for atherosclerosis progression. Dr. Eva Lonn reported that Insulin glargine "was safe [and] well tolerated; it reduced fasting glucose, glycated hemoglobine and also slightly reduced triglycerides, as expected; [it had] no effect on blood pressure or cholesterol; [and] there was a modest benefit on carotid intima media thickness".