Acute untreated hyperglycaemia will ultimately result in death, either through hyperosmolar coma or through diabetic keto-acidosis. Thus, when insulin became available in 1921, two things about the life of those with diabetes drastically altered. The good news was that their life-expectancy dramatically increased. The bad news was that living with diabetes and chronic hyperglycaemia for a long time exposes a person to a burden of many complications. Thus, diabetes is now one of the leading causes of acquired blindness and renal failure. In addition, diabetes patients, particularly those with type 2 diabetes, are at an increased risk for myocardial infarction and stroke. Painful neuropathy, diabetic foot ulceration and lower extremity amputations are some of the other common complications, but diabetes complications come in many forms and guises. To aggravate all of this, many of the therapies used to treat diabetes come with side effects. The most common of these is hypoglycaemia, which can vary from mild (but annoying) to serious, with epileptic insults, coma or even death. Reducing the risk of all these complications and side effects has turned out to be the challenge of diabetes treatment in the last century.
Pathogenesis of diabetes complications
Despite an enormous amount of research, the exact pathogenetic mechanisms leading to the complications of diabetes are still far from clear. Initially, research was mainly focused on the harmful effects of glucose. In his pivotal 2005 Banting Lecture, Michael Brownlee suggested a unifying theory where the root cause of hyperglycaemic complications is the overproduction of reactive oxygen species, most notably superoxide, in the mitochondrial electron transport chain. This was supposed to be the initiating step that led to various other disturbances known to be implicated in diabetes complications, such as the formation of Advanced Glycation Endproducts (AGEs), Protein Kinase C (PKC) activation, an increased hexosamine pathway activity and an increased flux through the polyol pathway. While this concept is very helpful, it probably still represents a reductionist view of a very complex process.
Brownlee acknowledged that there are differences in individual susceptibilty to complications. Indeed, even though a higher HbA1c is clearly associated with an increased risk for complications, individual differences in HbA1c explain only about 11% of the difference in complication risk. Some individuals suffer from severe complications despite good glycaemic control, whereas others seem protected from complications despite persistently poor HbA1c values. The last few decades more and more research has focused on identifying these individual protection and susceptibility factors, both at the metabolic and genetic level.
Regardless of the underlying pathological processes, the metabolic alterations that result from hyperglycaemia ultimately lead to functional and/or structural changes in virtually all tissues. The most notable damage is to the endothelium, which plays an important part in the pathogenesis of the microvascular and macrovascular complications; but other tissues are important as well, as evidenced for instance by the contribution of structural changes in connective tissue to the occurrence of diabetic foot problems.
Hyperglycaemia has direct effects on the hydration state of the ocular lens, which explains why some patients complain of a blurry vision when acutely hyperglycaemic. And chronic hyperglycaemia can lead or contribute to cataract which gradually impairs vision. However, the true damage to the eye, diabetic retinopathy, starts with small retinal changes and only results in visual problems at the advanced proliferative stage when vitreous bleeding followed by retinal detachment can result in permanent visual loss. Fortunately, screening for diabetic retinopathy can detect the early changes, when preventive therapy (e.g. by laser coagulation) is still possible.
About 40% of patients have diabetic retinopathy, with a higher prevalence in those with longer duration of diabetes. The prevalence of of proliferative retinopathy is far lower. Moreover, there are some indications that the prevalence of retinopathy has dropped in the last decades.
Ppopulation prevalence of diabetic retinopathy by levels of glycemia. The sharp increase in retinopathy above a fasting plasma glucose (FPG) of 6.5 mmol/l (116mg/dl) was an important reason for setting the diagnostic thresholds for diabetes at glucose levels of 7 mmol/l.While hypertension and dyslipidaemia contribute markedly to macrovascular complications and to diabetic nephropathy and can indeed cause these complications without the presence of diabetes, diabetic retinopathy can result solely from hyperglycaemia and without hyperglycaemia it does not occur. Its relationship with diabetes is in fact so tight that the current diagnostic thresholds for making the diagnosis of diabetes are largely derived from the glycaemic levels in the population above which the prevalence of retinopathy starts to rise.
The first sign of diabetic nephropathy is micro-albuminuria, the presence of small quantities of albumin in the urine (30-300mg/24 hrs). At this stage of incipient nephropathy, kidney function as expressed by the glomerular filtration rate (GFR) is generally preserved. Moreover, the progression of albuminuria can be slowed or indeed reversed by appropriate treatment. Once macro-albuminuria (albumin excretion of over 300mg/24 hrs) develops, i.e. overt nephropathy, it is usually harder to stop the progression of the disease and a decline in kidney function (GFR) may ensue which can eventually necessitate renal replacement therapy (dialysis or kidney transplantation).
The decreasing prevalence (and possibly later onset) of diabetic nephropathy in subsequent year-cohorts. (Hovind, Diabetes Care 2003)Historically, about 40% of type 1 diabetes patients would develop diabetic nephropathy. However, improved glycaemic control and, more importantly, improved anti-hypertensive treatment using blockers of the renin-angiotensin system have reduced this risk and nowadays less than 10% of type 1 diabetes patients develop overt nephropathy. In patients with type 2 diabetes, where the presence of other risk factors such as hypertension and dyslipidemia aggravates the situation, the risk of nephropathy is still in the order of 20-50% depending on the genetic background of the population. And given the huge increase in the prevalence of type 2 diabetes, the need for renal replacement therapy in advanced diabetic nephropathy will continue to be a societal burden.
While a role for damage to the small vessels feeding the nerves is thought to play a part, the pathogenesis of diabetic neuropathy is still poorly understood. Two main forms can be distinguished. Peripheral (usually distal symmetrical) neuropathy affects the sensory system and leads to either loss of sensibility or to painful sensations in the feet or hands. Autonomic neuropathy can affect the normal functioning of many organs. Common manifestations of autonomic neuropathy are disordered motility of the gastro-intestinal system (gastroparesis, obstipation or diarrhea), disordered cardiovascular function (tachycardia, orthostasis) and disordered urogenital dysfunction (erectile dysfunction). Apart from improving glycaemic control there is no causal treatment for diabetic neuropathy and symptomatic treatments are often inadequate. Since these complications often interfere with normal social functioning, neuropathy contributes significantly to the burden of diabetes.
Heart and Vessels
The majority of diabetes patients will die of cardiovascular causes. While other risk factors, particularly smoking, probably contribute more to the global prevalence of cardiovascular diseases, the independent contribution of hyperglycaemia has been clearly established.
In the EPIC-Norfolk study (Khaw, BMJ 2001) there was a relation between higher glycaemia within the normal range of HbA1c and cardiovascular and all cause mortality.There is an almost continuous relation between glycaemic levels and macrovascular disease which extends into the normal range (figure 3), which is in contrast to the microvascular diseases where there seems to be some sort of glycaemic threshold for complications to occur.
Multifactorial risk management strategies can help substantially in reducing the risk of cardiovascular disease. Smoking cessation is of the utmost importance. Intensive lipid lowering and intensive blood pressure regulation are probably more important and easier to achieve than good glycaemic control, but both in type 1 (in the DCCT-EDIC study) and in type 2 (in the UKPDS-PTM study) diabetes glucose-lowering has an independent risk reducing effect.
It is the combination of many underlying pathologies that makes the diabetic foot one of the most feared and most difficult to treat complications of diabetes. Diabetic neuropathy and connective tissue damage will deform the foot, sometimes in subtle ways such as limited joint mobility and sometimes in destructive ways such as in Charcot’s foot; the deformed foot is more prone to pressure ulcers, which are often not noted by the patient because of the sensory neuropathy; ulcers occur more readily because underlying vascular pahology will impede oxygen supply to the tissues; and ulcers become rapidly infected and are subsequently difficult to treat since antibiotics poorly reach the tissues. All together this leads to a high risk of amputation and multidisciplinary frequent intervention is necessary to try and avoid this, leading to a tremendous cost and burden to patients and society.
Diabetes is associated with an increased risk of connective tissue disorders and an increased risk of infections. But diabetes can affect almost any tissue and treatment will sometimes have adverse consequences as well (e.g. lipohypertrophy or lipoatrophy following insulin treatment).
While mild hyperglycaemia is mainly detrimental in the long-run, acute severe hyperglycaemia as in the hyperglycemic hyperosmolar state and diabetic keto-acidosis are both immediately life-threatening disorders. For both, adequate therapy exists, but poor or delayed recognition of these disorders will still claim lives.
Similarly, mild hypoglycaemia, while annoying, is mostly harmless; but frequent hypoglycaemia begets more, and more severe hypoglycaemia, which is associated with an increased risk of accidents and mortality. Particularly in patients who are in tight control to avoid long-term complications, the increasing risk of severe hypoglycaemia must be weighed against the small incremental benefits of further reductions in average glycaemia.