The role of insulin resistance in type 2 diabetes
Insulin resistance has a fundamental role in the development of type 2 diabetes and is also an independent risk factor for cardiovascular disease – Dr Miles Fisher discusses the significance of this important predictor of disease in primary care
The idea that insulin resistance is a major pathophysiological contributor to diabetes is not a new one. As early as 1936 Himsworth recognised that a large number of patients with diabetes were insulin insensitive and he divided diabetes into 'insulin sensitive' and 'insulin insensitive' categories1. Insulin resistance (or reduced insulin sensitivity) is now established as a key part of type 2 diabetes, when combined with ß-cell dysfunction, and more than 90 per cent of patients are insulin resistant2.
Understanding insulin resistance
A key step forwards in the understanding of insulin resistance came with the seminal work of Reaven3. He made two key observations.
First, resistance to insulin-stimulated glucose uptake is present in the majority of patients with impaired glucose tolerance and type 2 diabetes, and 25 per cent of non-obese individuals with normal glucose tolerance.
He suggested deterioration of
glucose tolerance could only be prevented if the ß-cell is able to increase insulin secretion and maintain chronic hyperinsulinaemia. When this cannot be achieved gross decompensation of glucose homeostasis occurs and diabetes develops.
Second, he observed 'clustering' of risk factors for coronary heart disease in individual subjects, including:
lImpaired glucose tolerance or diabetes
lIncreased plasma triglyceride concentration
lDecreased HDL-cholesterol concentration
He suggested these might be causally linked by insulin resistance and hyperinsulinaemia and referred to the cluster as Syndrome X. Others have referred to this as Reaven's syndrome, insulin resistance syndrome or metabolic syndrome4.
Whether there is a causal link or not, it is clear that insulin resistance is associated with other cardiovascular risk factors such as hyperglycaemia, hypertension and dyslipidaemia.
Causes of insulin resistance
It is unclear why some individuals are insulin resistant and genetic and environmental factors have both been implicated. In particular physical inactivity and obesity are associated with insulin resistance, but not all obese persons are insulin resistant.
Simplistically, insulin resistance may develop in genetically susceptible individuals who are overweight
and/or who are physically inactive.
There are several methods of measuring insulin resistance for research purposes, but none is available in routine clinical practice.
The gold stand is the euglycaemic clamp where there is a fixed rate of insulin infusion and a variable rate of glucose infusion to maintain euglycaemia.
This is time-consuming and cannot be performed on large numbers of subjects.
The simplest for large population studies is the measurement of serum insulin concentrations.
The homeostasis assessment model (HOMA) combines the measurement of fasting insulin concentrations with glucose and C-peptide concentrations, and allows a reasonably accurate measurement of insulin resistance in people who are not on treatment with exogenous insulin.
Using these techniques it has been shown insulin resistance is a fundamental defect in type 2 diabetes5 and that it is also a strong predictor of subsequent diabetes in non-diabetic individuals6.
Interestingly, a recent study from Italy has shown that on follow-up of 960 patients with type 2 diabetes, a one-unit increase in HOMA insulin resistance was associated with a 56 per cent increase in cardiovascular risk7.
This was as strong as the increase in cardiovascular risk associated with smoking.
Treating to targets
Insulin resistance is not at present a separate target for treatment in patients with diabetes and current treatments are based on the use of agents for risk factors of hyperglycaemia, hypertension and hyperlipidaemia.
The glitazones or insulin sensitisers are a new class of drugs that are available for the treatment of diabetes.
They improve insulin resistance on HOMA assessment and reduce HbA1c when used to treat patients with diabetes. They have also been demonstrated to lower blood pressure and increase HDL cholesterol concentrations8, which are other components of the insulin resistance syndrome.
Whether this will translate into added cardiovascular benefit is presently being studied in large multi-centre studies with hard cardiovascular end-points.
Miles Fisher is a consultant physician at Glasgow Royal Infirmary