Porth's Essentials of Pathophysiology, 4e

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Endocrine System

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Protein Kinase C. Diacylglycerol (DAG) and pro- tein kinase C (PKC) are critical intracellular signaling molecules that can regulate many vascular functions, including permeability, vasodilator release, endothe- lial activation, and growth factor signaling. Levels of DAG and PKC are elevated in diabetes. Activation of PKC in blood vessels of the retina, kidney, and nerves can produce vascular damage. A PKC inhibitor was previously studied for the treatment of diabetic reti- nopathy and neuropathy, but showed variable results and is not marketed. 3 Diabetic Neuropathies Although the incidence of neuropathies is high among people with diabetes (approximately 50% compared with 2% in the general population and approximately 15% when age >40 years), it is difficult to document exactly how many people are affected by these disorders because of the diversity in clinical manifestations and because the condition often is far advanced before it is recognized. Results of the DCCT study showed that intensive diabetic therapy can reduce the incidence of clinical neuropathy by 60% compared with conventional therapy. 52 Several types of pathologic changes have been observed in connection with diabetic neuropathies. These include thickening of the walls of the nutrient vessels that supply the nerve, leading to the assumption that vessel ischemia plays a major role in the develop- ment of these neural changes. Another finding is a seg- mental demyelinization process that affects the Schwann cell. This demyelinization process is accompanied by a slowing of nerve conduction. Although there are several methods for classifying the diabetic peripheral neuropathies, a simplified system divides them into the somatic and autonomic nervous system neuropathies (Chart 33-2). Somatic Neuropathy. A distal symmetric polyneu- ropathy, in which loss of function typically occurs in a stocking–glove pattern, is the most common form of peripheral neuropathy. Somatic sensory involvement usually occurs first, often is bilateral and symmetric, and is associated with diminished perception of vibration, pain, and temperature, particularly in the lower extrem- ities. 53 In addition to the discomforts associated with the loss of sensory or motor function, lesions in the periph- eral nervous system predispose a person with diabetes to other complications. The loss of feeling, touch, and position sense increases the risk of falling. Impairment of temperature and pain sensation increases the risk of serious burns and injuries to the feet. Denervation of the small muscles of the foot result in clawing of the toes and displacement of the submetatarsal fat pad ante- riorly. These changes, together with joint and connec- tive tissue changes, alter the biomechanics of the foot, increasing plantar pressure and predisposing to develop- ment of foot trauma and ulcers. 53 Painful diabetic neuropathy involves the somato- sensory neurons that carry pain impulses. This disor- der, which causes hypersensitivity to light touch and

hyperglycemia is the best-established concomitant factor associated with diabetic complications. 48,49 The Diabetes Control and Complications Trial (DCCT) and its ongo- ing long-term observational study, the Epidemiology of Diabetes Interventions and Complications Study (EDIC) conducted in 1441 patients with type 1 diabetes, demon- strated that the incidence of retinopathy, nephropathy, and neuropathy can be reduced by intensive glycemic control. 49 Similar results have been demonstrated by the United Kingdom Prospective Diabetes Study (UKPDS) in 5000 patients with type 2 diabetes. 50 Theories of Pathogenesis The interest among researchers in explaining the causes and development of chronic lesions in a person with diabetes has led to a number of theories. At least three distinct metabolic pathways have been proposed in long- term complications of diabetes: intracellular hypergly- cemia and disturbance in polyol pathways, formation of advanced glycation end products, and activation of protein kinase C. 3,48,51 Polyol Pathway. A polyol is an organic compound that contains three or more hydroxyl (OH) groups. The polyol pathway refers to the intracellular mecha- nisms responsible for changing the number of hydroxyl units on a glucose molecule. In the sorbitol pathway, glucose is transformed first to sorbitol and then to fruc- tose. This process is activated by the enzyme aldose reductase. Although glucose is converted readily to sorbitol, the rate at which sorbitol can be converted to fructose and then metabolized is limited. Sorbitol is osmotically active, and it has been hypothesized that the presence of excess intracellular amounts may alter cell function in the tissues that use this pathway (e.g., lens, kidneys, nerves, blood vessels). In the lens, for example, the osmotic effects of sorbitol cause swelling and opacity. Increased sorbitol also is associated with a decrease in myoinositol and reduced ATP activity. The reduction of these compounds may contribute to the pathogenesis of neuropathies caused by Schwann cell damage. Aldose reductase inhibitors have been tested with the aim of reducing complications resulting from this pathway; however, to date none of them has been successful. Formation of Advanced Glycation End Products. Glycoproteins, or what could be called glucose proteins, are normal components of the basement membrane in smaller blood vessels and capillaries. These glycopro- teins are also termed advanced glycation end prod- ucts (AGEs). It has been suggested that the increased intracellular concentration of glucose associated with uncontrolled blood glucose levels in diabetes favors the formation of AGEs. These abnormal glycoproteins are thought to produce structural defects in the basement membrane of the microcirculation and to contribute to eye, kidney, and vascular complications. Some of the altered cellular functions resulting from AGEs are due to binding to specific receptors for AGEs (RAGEs).