Diabetes is a syndrome – literally a “running together” of associated conditions. Type 1 diabetes associates with a number of autoimmune disorders, and these are considered in the section on type 1 diabetes. This section is mainly devoted to a number of disorders that occur in association with type 2 diabetes. Obesity, specifically central obesity, is prominent among these, and the combination of “diabesity” is associated with hypertension, dyslipidaemia and arterial disease – the so-called metabolic syndrome. More recently, it has been appreciated that certain types of cancer are more common in association with diabetes and obesity, and there has been controversy as to the extent to which treatments for diabetes can modulate the risk of cancer in one direction or the other. This section, accordingly, considers obesity, hypertension, dyslipidaemia, cancer and the metabolic syndrome in relation to type 2 diabetes.
Historical Background
Sir Harold Himsworth was possibly the first to describe diabetes as a syndrome, although earlier physicians had commented on the association between late-onset diabetes and obesity, hypertension and arterial disease. The earliest description of type 1 and type 2 diabetes specifically noted the association of these features with the type 2 diabetes phenotype.
Elliot Joslin is credited by Kelly West as being the first diabetologist to recognise the association between obesity and diabetes [West], and the association between diabetes, hypertension and arterial disease emerged in the 1930s. Hyperlipidaemia was added to this constellation in the 1950s, but the association between diabetes and cancer was not fully appreciated until the 21st century.
Gerald Reaven was the first investigator to propose a causal link and mechanism for the association between dysglycaemia, hyperlipidaemia, hypertension, and arterial disease, and to suggest insulin resistance as the common underlying mechanism. Obesity was not a major component of the syndrome (which he referred to as Syndrome X), as initially conceived. The syndrome eventually came to be termed the metabolic syndrome.
Obesity and Diabetes
The incidence of type 2 diabetes rises sharply in relation to obesity. The US Nurses’ Study showed a 100-fold increase in the rate of diabetes development between the leanest and most overweight recruits to the profession. The rising incidence of obesity in the general population has been associated with a progressive fall in the age of diagnosis, with the result that type 2 diabetes has manifested in overweight adolescents within the past 2-3 decades. As might be expected, earlier onset type 2 diabetes is associated with considerable overweight, and the differential in BMI between the diabetic and non-diabetic populations falls with increasing age.
The relationship between obesity, as measured by BMI, and diabetes varies between males and females; diabetes is triggered at a lower BMI in men than in women in any particular age group. The association with BMI also differs from one population to another. For example, diabetes develops at a lower BMI in Indians than in people of European extraction, although this difference might well be explained in terms of body fat distribution.
Obesity is associated with insulin resistance, although this is not invariable, and those who have obesity without marked insulin resistance appear to have a much better prognosis. The combination of obesity with insulin resistance or hyperinsulinaemia is however associated with all features of the metabolic syndrome, arterial disease and some types of cancer. Second only to smoking, obesity is considered the commonest avoidable environmental stimulus to cancer, associated with perhaps 40% of all cancers in affluent environments.
Hypertension and Diabetes
Hypertension may arise as a complication of diabetic nephropathy, or (more commonly) as a feature of the type 2 diabetes syndrome. The prevalence of hypertension is increased in those with abnormal glucose tolerance, and it is commonly present at the diagnosis of diabetes. The association is independent of potential confounders such as age, glucose control or proteinuria. Conversely, the incidence of diabetes is increased 2.5 fold in hypertensive vs normotensive individuals. Furthermore, effective treatment of hypertension has emerged as a key element in the prevention of both microvascular and macrovascular complications of diabetes.
Although various hypotheses have been put forward, the mechanism underlying the association, other than concomitant obesity, is not entirely clear.
Dyslipidaemia and Diabetes
The dyslipidaemia of diabetes is characterized by high triglycerides and low HDL cholesterol. This is considered due to overproduction (or reduced removal) of VLDL particles, which is itself a feature of insulin resistance. HDL cholesterol is reduced in type 2 (but not type 1) diabetes, but LDL and total cholesterol levels are relatively normal in most people with type 2 diabetes. The LDL particle itself does however show a shift towards a denser (type B) particle which is considered more atherogenic.
The Metabolic Syndrome
There is indeed an undoubted type 2 diabetes syndrome of central obesity, hypertension, hyperlipidaemia and arterial disease, and the presence of one element of the syndrome undoubtedly predisposes to the other components. Furthermore, the prognosis for cardiovascular disease or premature mortality undoubtedly rises in parallel with the number of syndromic features. There is however brisk controversy in this area. This has arisen both in relation to definition of the syndrome, and many different versions have been proposed. Proponents have seen the metabolic syndrome as a disease condition in its own right, with a shared pathogenesis, valuable both in the prediction and prevention of cardiovascular disease and diabetes.
Critics have pointed out the limitations of the proposed pathogenic mechanisms, and have questioned whether the whole is more than the sum of its parts; i.e. whether combined measurement of glucose, lipids and blood pressure adds anything to routine screening and treatment of these risk factors in isolation. There is a general view that the term metabolic syndrome is more useful as a shorthand clinical description than as a disease entity.
Cancer and Diabetes
Diabetes and obesity are associated with a similar range of cancers, including pancreatic, hepatic, endometrial, breast and colorectal cancers. All these are independently associated with insulin resistance and hyperinsulinaemia, and the contribution of hyperglycaemia itself to the risk or prognosis of cancer remains unclear.
Controversially, several of the treatments used for diabetes have been thought to modulate the risk of cancer. Thus, metformin has been claimed to reduce the risk of many types of cancer, the thiazolidinediones have been considered to reduce the risk of some cancers and increase the risk of others, notably bladder cancer with pioglitazone. Insulin glargine was suspected of increasing the risk of breast cancer, and the GLP-1 based therapies have been implicated in both pancreatic and thyroid cancer. All these associations remain somewhat conjectural.
