Hyperglycemia: Type I Diabetes Mellitus

Transcription

1 296 PHYSIOLOGY CASES AND PROBLEMS Case 53 Hyperglycemia: Type I Diabetes Mellitus David Mandel was diagnosed with type I (insulin-dependent) diabetes mellitus when he was 12 years old (see Cases 30 and 34). At the time of his diagnosis, David was in middle school. He was an excellent student and had many friends. At a sleepover party, the unimaginable happened: David wet his sleeping bag! He might not have told his parents except that he was worried about other symptoms he was having. He was constantly thirsty and was urinating every minutes. Furthermore, despite a voracious appetite, he seemed to be losing weight; all of his pants had become loose in the waist. David's parents panicked because they knew that these were classic symptoms of diabetes mellitus. They took David to see his pediatrician immediately. The pediatrician performed a physical examination and ordered laboratory tests (Table 6-9). TABLE 6-9 David's Physical Examination and Laboratory Results Height 5 ft, 3 in Weight 100 lb (decreased 5 lb from his annual checkup 2 months earlier) Blood pressure 90/55 (lying down), 75/45 (standing up) Fasting plasma glucose 320 mg/(11. (normal, mg/dl) Plasma ketones 1+ (normal, none) Urinary glucose 4+ (normal, none) Urinary ketones 2+ (normal, none) All of the findings were consistent with a diagnosis of type I (insulin-dependent) diabetes mellitus. David immediately started taking injectable insulin and learned how to monitor his blood glucose level with a fingerstick. He excelled in high school and won a scholarship to the state university, where he is currently a premedical student and is planning a career in pediatric endocrinology. He has periodic checkups with his endocrinologist, who closely monitors his renal function. w QUESTIONS 1. How did insulin deficiency lead to an increase in David's blood glucose concentration? 2. How did insulin deficiency lead to the finding of ketones in David's blood and urine? 3. Why did David have glucose in his urine (glucosuria)? 4. Why did David have increased urine production (polyuria)? Why was he drinking so much (polydipsia)? 5. Why was David's blood pressure lower than normal? Why did it decrease further when he stood up? 6. David takes his insulin parenterally (by subcutaneous injection). Why can't he take insulin orally? 7. The endocrinologist closely monitors David's renal function. What is the major nephrologic complication of type I diabetes mellitus?

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3 298 PHYSIOLOGY CASES AND PROBLEMS ANSWERS AND EXPLANATIONS 1. David has type I diabetes mellitus his pancreatic J3 cells do not make sufficient insulin. Two consequences of insulin deficiency made David hyperglycemic: decreased uptake of glucose by cells and increased gluconeogenesis. These consequences are best understood by reviewing the normal actions of insulin and then considering what happens with insulin deficiency. (1) One important action of insulin is to direct insertion of a facilitated transporter for glucose (GLUT4) into cell membranes of muscle and adipose tissue. This transporter causes the uptake of glucose from blood into the cells. When insulin is deficient, GLUT4 transporters are not inserted into cell membranes, glucose is not transported into the cells, and the blood glucose concentration increases. (2) Insulin increases the storage of nutrients, including carbohydrates, proteins, and fats. Thus, insulin promotes glycogen formation (and inhibits gluconeogenesis), protein synthesis, and fat deposition (and inhibits lipolysis). When insulin is deficient, both protein catabolism (which generates amino acids) and lipolysis (which generates glycerol and fatty acids) are increased. Thus, insulin deficiency provides more amino acid and glycerol substrates for glucose synthesis (i.e., increased gluconeogenesis) (Figure 6-7). Insulin deficiency 4, Glucose uptake into cells + Protein catabolism Lipolysis 1 Hyperg ycemia + Amino acids + Glycerol Gluconeogenesis + Fatty acids 1 Ketoacids Figure 6-7 Metabolic effects of insulin deficiency. 2. David's blood and urine contained ketones because insulin deficiency increased the blood levels of fatty acids, which are the biosynthetic precursors of ketoacids. Insulin deficiency promotes catabolism of all nutrients, including fats (see Figure 6-7). Increased lipolysis leads to increased blood levels of fatty acids that are converted in the liver to the ketoacids fl-hydroxybutyric acid and acetoacetic acid. As the concentration of ketoacids increases in the blood, they are filtered across the glomerular capillaries and appear in the urine. 3. David had glucosuria (glucose in his urine) because he was hyperglycemic. His blood glucose concentration became so high that the amount of glucose filtered across the glomerular capillaries exceeded the reabsorptive capacity of the renal proximal tubule. Any glucose that was not reabsorbed was excreted in the urine. (For a more complete discussion of renal glucose reabsorption, see Case 30.) 4. David had polyuria (increased urine production) because his urine contained glucose. As discussed in the previous question, the filtered load of glucose was greater than the reabsorptive capacity of the proximal tubule and, as a result, glucose was excreted in the urine. The

4 ENDOCRINE AND REPRODUCTIVE PHYSIOLOGY 299 unreabsorbed glucose acted as an osmotic diuretic, causing a "back-flux" of NV and water into the proximal tubule. Thus, along with glucose, increased quantities of M. + and water were excreted. David had polydipsia because the hyperglycemia caused an increase in his serum osmolarity, which stimulated osmoreceptors in the anterior hypothalamus that increase thirst and promote drinking behavior. 5. David's arterial pressure was decreased secondary to the osmotic diuresis that was caused by glucose in his urine. Increased excretion of Na' and water decreased his extracellular fluid volume and his blood volume. Decreased blood volume led to a decrease in venous return to the heart, decreased cardiac output (by the Frank-Starling mechanism), and decreased arterial pressure. David's arterial pressure decreased further when he stood up (orthostatic hypotension) because, as blood pooled in the veins of the legs, venous return and cardiac output were compromised further. 6. Insulin is a protein; therefore, it must be administered parenterally (i.e., by routes other than the gastrointestinal tract). If given orally, it would be digested by intestinal peptidases to amino acids and di- and tripeptides. Once digested, it would no longer be insulin! Subcutaneous injection of insulin bypasses these degradative steps in the gastrointestinal tract. 7. A serious complication of type I diabetes mellitus is diabetic nephropathy. This condition can progress to end-stage renal failure that requires dialysis or renal transplantation. Therefore, David's renal function must be monitored for the rest of his life. The earliest phase of diabetic nephropathy is characterized by an increase in the glomerular filtration rate (GFR) that roughly correlates with the adequacy of glycemic control. In this hyperfiltration phase, the better the control of blood glucose concentration with insulin injections, the smaller the increase in GFR. In the next phase of diabetic nephropathy (and a consequence of hyperfiltration), histologic changes occur in the glomerular capillary barrier. The mesangial cells expand, and the basement membrane thickens. Eventually, these changes lead to diffuse glomerular scarring. During this phase, which occurs 5-15 years from the onset of type I diabetes mellitus, progressive glomerular changes occur. However, the GFR remains elevated, and no frank protein is found in the urine. Although this phase is clinically silent, microalbuminuria can be detected. Finally, in the later phases of diabetic nephropathy, there is gross proteinuria, decreased GFR, hypertension, and renal failure. David will be monitored closely for the presence of the microalbuminuria that signals the beginning of glomerular damage. If microalbuminuria is detected, David will be treated with an angiotensin-converting enzyme (ACE) inhibitor, which selectively dilates renal efferent arterioles and reduces glomerular filtration (preventing the damaging hyperfiltration).

5 300 PHYSIOLOGY CASES AND PROBLEMS Key topics Angiotensin-converting enzyme (ACE) inhibitor Diabetes mellitus type I Diabetic nephropathy Gluconeogenesis Glucosuria GLUT4 transporter Hyper-filtration Insulin deficiency Ketoacids Microalbuminuria Orthostatic hypotension Osmotic diuresis Polydipsia Polyuria