Mechanisms of chronic complications
Chronic elevation of blood glucose level leads to damage of blood vessels (angiopathy). The endothelial cells lining the blood vessels take in more glucose than normal, since they do not depend on insulin. They then form more surface glycoproteins than normal, and cause the basement membrane to grow thicker and weaker.
In diabetes, the resulting problems are grouped under "microvascular disease" (due to damage to small blood vessels) and "macrovascular disease" (due to damage to the arteries).However, some research challenges the theory of hyperglycemia as the cause of diabetic complications. The fact that 40% of diabetics who carefully control their blood sugar nevertheless develop neuropathy, requires explanation.
It has been discovered that the serum of diabetics with neuropathy is toxic to nerves even if its blood sugar content is normal. Recent research suggests that in type 1 diabetics, the continuing autoimmune disease which initially destroyed the beta cells of the pancreas may also cause retinopathy, neuropathy, and nephropathy. One researcher has even suggested that retinopathy may be better treated by drugs to suppress the abnormal immune system of diabetics than by blood sugar control.
The familial clustering of the degree and type of diabetic complications indicates that genetics may also play a role in causing complications such as diabetic retinopathy and nephropathy. Non-diabetic offspring of type 2 diabetics have been found to have increased arterial stiffness and neuropathy despite normal blood glucose levels, and elevated enzyme levels associated with diabetic renal disease have been found in non-diabetic first-degree relatives of diabetics.However, one study continued for 41 months found that the initial worsening of complications from improved glucose control was not followed by the expected improvement in the complications.
In a systematic review with meta-analysis including 6 randomized controlled trials involving 27,654 patients, tight blood glucose control reduces the risk for some macrovascular and microvascular events, without effect on all-cause mortality and cardiovascular mortality. In terms of pathophysiology, studies show that the two main types of DM (DM1 and DM2) cause a change in balancing of metabolites such as carbohydrates, lipids and blood coagulation factors, and subsequently bring about complications like microvascular and cardiovascular complications.
Examples of chronic complications
The damage to small blood vessels leads to a microangiopathy, which can cause one or more of the following:
- Diabetic cardiomyopathy, damage to the heart muscle, leading to impaired relaxation and filling of the heart with blood (diastolic dysfunction) and eventually heart failure; this condition can occur independent of damage done to the blood vessels over time from high levels of blood glucose.
- Diabetic nephropathy, damage to the kidney which can lead to chronic renal failure, eventually requiring dialysis. Diabetes mellitus is the most common cause of adult kidney failure in the developed world.
- Diabetic neuropathy, abnormal and decreased sensation, usually in a 'glove and stocking' distribution starting with the feet but potentially in other nerves, later often fingers and hands. When combined with damaged blood vessels this can lead to diabetic foot (see below). Other forms of diabetic neuropathy may present as mononeuritis or autonomic neuropathy. Diabetic amyotrophy is muscle weakness due to neuropathy.
- Diabetic retinopathy, growth of friable and poor-quality new blood vessels in the retina as well as macular edema (swelling of the macula), which can lead to severe vision loss or blindness. Retinal damage (from microangiopathy) makes it the most common cause of blindness among non-elderly adults in the US.
- Diabetic encephalopathy is the increased cognitive decline and risk of dementia, including (but not limited to) the Alzheimer's type, observed in diabetes. Various mechanisms are proposed, including alterations to the vascular supply of the brain and the interaction of insulin with the brain itself.
- Diabetic neuropathy, abnormal and decreased sensation, usually in a 'glove and stocking' distribution starting with the feet but potentially in other nerves, later often fingers and hands. When combined with damaged blood vessels this can lead to diabetic foot (see below). Other forms of diabetic neuropathy may present as mononeuritis or autonomic neuropathy. Diabetic amyotrophy is muscle weakness due to neuropathy.
- Diabetic retinopathy, growth of friable and poor-quality new blood vessels in the retina as well as macular edema (swelling of the macula), which can lead to severe vision loss or blindness. Retinal damage (from microangiopathy) makes it the most common cause of blindness among non-elderly adults in the US.
- Diabetic encephalopathy is the increased cognitive decline and risk of dementia, including (but not limited to) the Alzheimer's type, observed in diabetes. Various mechanisms are proposed, including alterations to the vascular supply of the brain and the interaction of insulin with the brain itself.
Macrovascular disease leads to cardiovascular disease, to which accelerated atherosclerosis is a contributor:
- Coronary artery disease, leading to angina or myocardial infarction ("heart attack")
- Coronary artery disease, leading to angina or myocardial infarction ("heart attack")
- Diabetic myonecrosis ('muscle wasting')
- Peripheral vascular disease, which contributes to intermittent claudication (exertion-related leg and foot pain) as well as diabetic foot.
- Stroke (mainly the ischemic type)
- Peripheral vascular disease, which contributes to intermittent claudication (exertion-related leg and foot pain) as well as diabetic foot.
- Stroke (mainly the ischemic type)
Diabetic foot, often due to a combination of sensory neuropathy (numbness or insensitivity) and vascular damage, increases rates of skin ulcers (diabetic foot ulcers) and infection and, in serious cases, necrosis and gangrene. It is why diabetics are prone to leg and foot infections and why it takes longer for them to heal from leg and foot wounds. It is the most common cause of non-traumatic adult amputation, usually of toes and or feet, in the developed world.
Carotid artery stenosis does not occur more often in diabetes, and there appears to be a lower prevalence of abdominal aortic aneurysm. However, diabetes does cause higher morbidity, mortality and operative risks with these conditions. In the developed world, diabetes is the most significant cause of adult blindness in the non-elderly and the leading cause of non-traumatic amputation in adults, and diabetic nephropathy is the main illness requiring renal dialysis in the United States.
A review of type 1 diabetes came to the result that, despite modern treatment, women with diabetes are at increased risk of female infertility, such as reflected by delayed puberty and menarche, menstrual irregularities (especially oligomenorrhoea), mild hyperandrogenism, polycystic ovarian syndrome, fewer live born children and possibly earlier menopause.
Animal models indicate that abnormalities on the molecular level caused by diabetes include defective leptin, insulin and kisspeptin signalling. Restrictive lung defect is known to be associated with diabetes. Lung restriction in diabetes could result from chronic low-grade tissue inflammation, microangiopathy, and/or accumulation of advanced glycation end products. In fact the presence restrictive lung defect in association with diabetes has been shown even in presence of obstructive lung diseases like asthma and copd in diabetic patients.
Animal models indicate that abnormalities on the molecular level caused by diabetes include defective leptin, insulin and kisspeptin signalling. Restrictive lung defect is known to be associated with diabetes. Lung restriction in diabetes could result from chronic low-grade tissue inflammation, microangiopathy, and/or accumulation of advanced glycation end products. In fact the presence restrictive lung defect in association with diabetes has been shown even in presence of obstructive lung diseases like asthma and copd in diabetic patients.
Lipohypertrophy may be caused by insulin therapy.Repeated insulin injections at the same site, or near to, causes an accumulation of extra subcutaneous fat and may present as a large lump under the skin. It may be unsightly, mildly painful, and may change the timing or completeness of insulin action.
Researchers have found an association of depression and diabetes in a 2010 study. A longitudinal study of 4,263 individuals diagnosed with type 2 diabetes were followed from 2005-2007 and were found to have a statistically significant association with depression and a high risk of micro and macro-vascular events.
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