In patients with type 1 diabetes, significant deviations from normal dietary intake, unusual physical activity, infection, or any other forms of stress may worsen the metabolic imbalance, leading to diabetic ketoacidosis. The plasma glucose usually is in the range of 500 to 700 mg/dL as a result of absolute insulin deficiency and unopposed effects of counter-regulatory hormones (epinephrine, glucagon). The marked hyperglycemia causes an osmotic diuresis and dehydration characteristic of the ketoacidotic state. The second major effect is activation of the ketogenic machinery. Insulin deficiency leads to activation of hormone-sensitive lipase, with resultant excessive breakdown of adipose stores, giving rise to increased FFAs, which are oxidized by the liver to produce ketones. Ketogenesis is an adaptive phenomenon in times of starvation, generating ketones as a source of energy for consumption by vital organs (e.g., the brain). The rate at which ketones are formed may exceed the rate at which they can be used by peripheral tissues, leading to ketonemia and ketonuria. If the urinary excretion of ketones is compromised by dehydration, the accumulating ketones decrease blood pH, resulting in metabolic acidosis.
Type 2 diabetes also may manifest with polyuria and polydipsia. In some cases, medical attention is sought because of unexplained weakness or weight loss. Most frequently, however, the diagnosis is made after routine blood or urine testing in asymptomatic individuals. In the decompensated state, patients with type 2 diabetes may develop hyperosmolar nonketotic coma. This syndrome is engendered by severe dehydration resulting from sustained osmotic diuresis and urinary fluid loss due to chronic hyperglycemia. Typically, the affected individual is an older adult diabetic who is disabled by a stroke or an infection and is unable to maintain adequate water intake. The absence of ketoacidosis and its symptoms (nausea, vomiting, respiratory difficulties) delays recognition of the seriousness of the situation until the onset of severe dehydration and coma.
The morbidity associated with long-standing diabetes of any type results from the chronic complications of hyperglycemia, and the resulting damage induced in both largeand medium-sized muscular arteries (diabetic macro-vascular disease) and small-vessels (diabetic microvascular disease). Macrovascular disease causes accelerated atherosclerosis among diabetics, resulting in increased myocardial infarction, stroke, and lower-extremity ischemia. The effects of microvascular disease are most profound in the retina, kidneys, and peripheral nerves, resulting in diabetic retinopathy, nephropathy, and neuropathy, respectively (
Fig. 20.25 ). The pathologic findings in these tissues and their clinical consequences are described next. There is extreme variability among patients in the time of onset of these complications, their severity, and the particular organ or organs involved. In individuals with tight control of their diabetes, the onset may be delayed (hence the need for tight control of hyperglycemia).
Pathogenesis of Chronic Complications of Diabetes
The pathogenesis of the long-term complications of diabetes is multifactorial, although persistent hyperglycemia (glucotoxicity) seems to be a key mediator. At least three distinct metabolic pathways seem to be involved in the pathogenesis of long-term complications; it is likely that all of them play a role in a tissue-specific manner.