Long-term exposure to hyperglycemia adversely affects numerous body systems although great variability exists between rates of these complications. Individual differences in disease control efforts, duration of disease, age at disease onset and presence/control of comorbidities (e.g. hypertension, dyslipidemia, depression and anxiety) all contribute to the development and severity of diabetes-related complications. These complications can be divided into microvascular and macrovascular conditions. Generally, T1D is more commonly associated with microvascular complications while macrovascular complications occur more frequently among those with T2D.
3.1.1 Microvascular Complications
Chronic hyperglycemia damages small blood vessels throughout the body. The most common diabetes-related microvascular complications are retinopathy, nephropathy and neuropathy. For individuals with T1D, these conditions are typically diagnosed many years after the onset of diabetes. For many with T2D, it is not uncommon for patients to show early signs of at least one of the three above-mentioned conditions at the time of their T2D diagnosis.
Diabetic retinopathy is the leading cause of blindness among adults ages 20-74 in the
United States.32 This is a progressive condition, characterized by growth of new blood vessels
along the retina and often associated with a build-up of fibrous tissue between the vessels and the retina. These new blood vessels are prone to hemorrhaging, leading to macular edema and increased risk of glaucoma, all of which can lead to partial or complete permanent blindness. Diabetes duration appears to be the strongest predictor of retinopathy.33 Within 15 years of
their diagnosis, 25-50% of patients with T1D develop some degree of retinopathy; the condition affects virtually 100% of T1D patients within 30 years of diagnosis.34 The prevalence of non-
proliferative retinopathy is somewhat lower in T2D than in T1D, affecting approximately 20- 30% of T2D patients within 15 years of diagnosis. According to Crawford et al. (2009), proliferative retinopathy was found in only 3% of T2D patients compared to 17% of T1D patients 11 years post-diagnosis.34
Diabetic nephropathy in the forms of intercapillary glomerulonephritis, nodular diabetic
glomerulosclerosis or Kimmelstiel-Wilson syndrome occurs in 20-30% of those with T1D or T2D.35 In its earliest stage, termed microalbuminuria, low but abnormal levels of albumin can
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be detected in urine samples. Glomerular filtration function continues to decline at a variable rate, ranging from a loss of 2-20 ml/min/yr., depending on individual factors.36 Confirmation of overt nephropathy (ON) occurs when urine protein levels surpass 300 mg/day.35
According to the 2004 American Diabetes Association (ADA) position statement, 80% of T1D patients with microalbuminuria will progress to ON within 10-15 years if they do not receive some type of intervention. Among T1D patients with ON, 50% will progress to end stage renal disease (ESRD) within 10 years, and in more than 75% within 20 years, unless they receive some type of targeted intervention.35 Microalbuminuria is present in 20-25% of T2D patients at
time of diagnosis, due to the long latency between the biological onset and diagnosis of T2D.36
Without specific intervention, roughly 20-40% of T2D patients will progress from micro- albuminuria to ON over a 20 year period. Unlike T1D patients, however, only 20% of T2D patients with ON will progress to ESRD within 20 years of the onset of nephropathy. This may be due to the high mortality rate related to cardiovascular disease (CVD) among T2D patients; as T2D-related CVD mortality rates fall, there may be a related increase in ESRD in this population.35
Diabetic neuropathy is a common microvascular complication affecting nerve function.
Several types exist, affecting different areas of the nervous system; these can be focal or diffuse. The most common types are distal symmetric polyneuropathy (DSP) and neuropathies involving the autonomic nervous system.37 Roughly half of those with DSP are asymptomatic; these individuals are at a greater risk of unrecognized injuries to the extremities, resulting in greater risk for amputations. Symptomatic individuals describe burning or “electrical” pain or numbness in the feet, legs and/or hands, with intensification of pain at night.32 Those with an
autonomic neuropathy are at an increased risk of morbidity and mortality, particularly those with cardiac autonomic neuropathy (CAN).37 Other organ systems can also be affected, leading to “gastroparesis, constipation, diarrhea, anhidrosis, bladder dysfunction, erectile dysfunction, exercise intolerance, resting tachycardia, silent ischemia, and even sudden cardiac death.”32 The exact etiology of diabetic neuropathy remains unclear, but exposure to chronic hyperglycemia, tissue ischemia, oxidative stress and accumulation of advanced glycation end- products (AGEs) all potentially contribute to the development of diabetic neuropathy.32
3.1.2 Macrovascular Complications
Exposure to chronic hyperglycemia and resultant AGEs, as well as chronic inflammation and oxidative stress, damage large blood vessels throughout the body, primarily via atherosclerosis. Plaques accumulate throughout the arteries, leading to reduced blood flow and increased pressure against the arterial walls. An acute vascular event will occur should one of these lesions rupture.32 Because people with T2D are more likely to also have metabolic syndrome
with high risk factors for cardiovascular disease, such as central adiposity, dyslipidemia and hypertension, they have a greater risk of suffering from diabetes-related macrovascular complications compared to those with T1D.38 Results from the United Kingdom Prospective Diabetes Study (UKPDS) show that tight control of cardiovascular risk factors decreased mortality from T2D-related conditions by 32%, two-thirds of which were related to cardiovascular disease.39
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Coronary artery disease (CAD) is the leading cause of death in people with T2D.40 In fact,
the risk of a first myocardial infarction (MI) in those with T2D is equivalent to the risk of a second MI in people without diabetes. Those with T2D are also more likely to die from a first MI compared to people without diabetes.41 Among T1D patients, CAD is highly associated with increased mortality, with evidence of an association between chronically elevated blood glucose and an increased risk of fatal CAD.42 This same study also found that lower insulin dose, in addition to many standard risk factors for cardiovascular disease, was associated with a greater prevalence of non-fatal CAD.42
Cerebrovascular disease (CVD) includes stroke and transient ischemic attack (TIA). Data
from the Baltimore-Washington Cooperative Young Stroke Study found more than a ten-fold higher risk for stroke among DM participants younger than age 44 compared to those without diabetes.43 Additionally, those with DM are more likely to die from a stroke compared to
individuals without diabetes. Furthermore, individuals with DM who survive a stroke are more likely to experience another stroke and have more than triple the risk of developing stroke- related dementia compared to individuals without diabetes.44
Peripheral artery disease (PAD) occurs due to reduced blood flow to the extremities. It is
particularly common in the legs and is highly associated with intermittent claudication (pain when standing or walking).45 Diabetes doubles to quadruples the risk of developing PAD and this reduced blood flow in the legs is associated with a 20-fold increased risk of lower extremity amputations among adults age 65-74 years.44 Controlling glycemic levels and treating dyslipidemia and hypertension significantly lower the risk of PAD and other macrovascular complications in patients with DM.44