Diabetic nephropathy is a leading cause of end-stage renal disease (ESRD) in the United States. The relationship between kidney function and insulin activity has important implications to the pharmacist providing pharmaceutical care to the diabetic patient with renal disease. Approximately one third of the body’s insulin is removed by the kidneys. Insulin is filtered at the glomerulus and largely resorbed in the proximal tubules. Additionally, the extraction of insulin by the kidneys is greater than the glomerular filtration rate, suggesting that much of the insulin is degraded in the renal cells. As a result, the patient in renal failure may require less insulin secondary to a decreased metabolism of insulin by the kidney. Additionally, in a state of uremia, the patient may exhibit insulin resistance. Hypoglycemia and hyperglycemia have also been observed in previously non-diabetic patients. This pathophysiology, as well as patient-specific considerations, make the management of the diabetic patient with renal disease complicated. Such patients often require intense pharmacologic management, as well as routine monitoring and follow-up.
Pathophysiology of Uremia and Insulin
As a patient’s renal function deteriorates, it is often clinically observed that blood glucose control becomes more challenging. Once a patient’s creatinine clearance declines to less than 15 mL/min, the clearance of insulin diminishes and the half-life is prolonged. As a result, the insulin requirements for the patient may decrease.
The uremic patient may exhibit insulin resistance. This is partially the result of an impaired glucose uptake by the muscle. The diminished insulin sensitivity and glucose metabolism appear to be associated with uremic toxins and have been shown to be reversible with dialysis. These abnormalities also appear to be improved with a low-protein diet. Gin et al. studied the impact of a low-protein diet on insulin sensitivity of tissue in insulin-dependent diabetes mellitus (IDDM) patients with chronic renal failure. The results of this study indicate that when uremic toxin production is decreased with a low-protein diet, tissue sensitivity to insulin improves. Interestingly, the number of insulin receptors and the affinity of insulin to the receptors do not appear to change as a result of uremia.
There appear to be two types of alterations in insulin secretion that are observed in the uremic patient. The first type of patient presents elevated insulin levels and normal glucose levels. The second type of patient presents normal or low insulin levels and elevated glucose levels. It is thought that the patient with normal glucose levels has beta cells in the pancreas that are able to secrete enough insulin to overcome the insulin resistance. The second type of patient does not have this capability. This may explain why some uremic patients become glucose intolerant and some remain normal.
Hyperparathyroidism and vitamin D deficiency have been postulated to affect insulin secretion. Hyperparathyroidism is a common complication observed in patients with renal failure. Mak reviewed the management of hyperparathyroidism in the ESRD patient by studying the results of animal and human studies that evaluated the effects of parathyroid hormone and vitamin D deficiency on insulin secretion. In his review, Mak wrote that elevated parathyroid hormone causes an inhibition of the beta cells of the pancreas to secrete insulin. This results in the clinical observation of glucose intolerance. Additionally, vitamin D deficiency may alter insulin secretion in the ESRD patient. Mak noted that the results of human studies have shown that when active vitamin D is administered, glucose intolerance is normalized. Allegra et al. studied the effect of active vitamin D, calcitriol, in 17 uremic patients. The results of their study showed that when calcitriol was given, the early phase of insulin secretion was improved. Their results also showed that glucose-induced insulin secretion may be inhibited by calcitriol deficiency. The beta cells of the pancreas appeared to be directly affected by the calcitrol. Clinical conditions influenced by an altered insulin metabolism are described in Table 1.
| Table 1.Clinical Conditions Influenced by Altered Insulin Activity |
| Hyperglycemia contributes to atherosclerotic disease |
| Hyperglycemia contributes to kidney disease |
| Hypertriglyceridemia can be aggravated by insulin resistance |
| Abnormal insulin activity can contribute to altered muscle production |
| Abnormal insulin activity can contribute to growth problems in the pediatric patient with ESRD |