Carbohydrate and insulin metabolism in chronic kidney disease

INTRODUCTION — Advanced chronic kidney disease (CKD) is typically associated with impaired glucose metabolism. Some patients with CKD have hyperglycemia in response to oral and intravenous glucose loads, while others are able to maintain normoglycemia by raising plasma insulin levels. Studies utilizing the euglycemic and hyperglycemic clamp techniques suggest that several disturbances in carbohydrate handling may be present. Tissue insensitivity to insulin is of primary importance, but alterations in insulin degradation and insulin secretion also may contribute [1-3]. The variable severity of these changes in individual patients explains the variable plasma levels of insulin and glucose that may be seen both fasting and following a glucose load.

This topic will review the changes in carbohydrate and insulin metabolism that occur in CKD and the clinical implications of these abnormalities in patients without diabetes. The impact of these changes on the management of hyperglycemia in patients with diabetes and end-stage kidney disease is discussed separately. (See "Management of hyperglycemia in patients with type 2 diabetes and advanced chronic kidney disease or end-stage kidney disease".)

NORMAL RENAL HANDLING OF INSULIN — The kidney plays a central role in the metabolism of insulin in normal subjects [1,2,4]. Insulin has a molecular weight of 6000 and is therefore freely filtered. Of the total renal insulin clearance, approximately 60 percent occurs by glomerular filtration and 40 percent by extraction from the peritubular vessels. Insulin in the tubular lumen enters proximal tubular cells by carrier-mediated endocytosis and is then transported into lysosomes, where it is metabolized to amino acids [5]. The net effect is that <1 percent of filtered insulin appears in the final urine.

The renal clearance of insulin is 200 mL/min, significantly exceeding the normal glomerular filtration rate (GFR) of 120 mL/min due to the contribution of tubular secretion. From this rate of renal clearance, it can be calculated that 6 to 8 units of insulin are degraded by the kidney each day, which accounts for approximately 25 percent of the daily production of insulin by the pancreas. The contribution of kidney metabolism is enhanced in diabetic subjects receiving exogenous insulin since injected insulin enters the systemic circulation directly, without first passing through the liver.

INSULIN RESISTANCE — Impaired tissue sensitivity to insulin occurs in almost all patients with advanced CKD and is largely responsible for the abnormal glucose metabolism seen in this setting [1-3]. Possible mechanisms that could account for the reduction in insulin-mediated glucose handling include: (1) increased hepatic gluconeogenesis that does not suppress normally following insulin; (2) reduced hepatic and/or skeletal muscle glucose uptake; and (3) impaired intracellular glucose metabolism due either to decreased oxidation to carbon dioxide and water or to diminished synthesis of glycogen. Many of these effects have been linked to acquired abnormalities in intracellular signaling pathways, normally initiated by insulin binding to its receptor [6].

Both experimental and clinical studies suggest that hepatic glucose production and uptake are normal in patients with CKD and that skeletal muscle is the primary site of insulin resistance [1,2]. How this occurs is not clear, but a postreceptor defect is of primary importance [7,8]. Furthermore, the abnormality appears to specifically involve glycogen synthesis as the rate of glucose oxidation is relatively normal [8]. It is of interest in this regard that other actions of insulin, such as promoting potassium uptake by the cells and inhibiting proteolysis, are also maintained in kidney failure [8-10]. (See "Treatment and prevention of hyperkalemia in adults".)

Accumulation of a uremic toxin or toxins and excess parathyroid hormone (PTH), resulting from abnormalities in phosphate and vitamin D metabolism (see "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)"), are thought to be responsible for the insulin resistance [11-13]. As an example, the observation that tissue sensitivity to insulin can be substantially improved by dialysis is consistent with a role for uremic toxins [2,11].

There is also increasing evidence for an important role of PTH and calcitriol (1,25-dihydroxyvitamin D). In one study, for example, acute intravenous administration of calcitriol to hemodialysis patients enhanced insulin release and improved glucose tolerance [12]. This effect was independent of changes in the plasma concentrations of calcium or PTH. Two longer trials demonstrated that intravenous calcitriol essentially normalized insulin sensitivity [13,14]. Plasma PTH levels also fell so that it was not possible to determine whether the improvement was due to calcitriol per se and/or to reversal of hyperparathyroidism.

Impaired tissue sensitivity to insulin has also been demonstrated in patients with only mild to moderate reductions in kidney function [15,16]. Two observations suggest that decreased tissue oxygen delivery contributes to this abnormality:

●The degree of tissue insensitivity to insulin directly correlates with maximal aerobic work capacity, indicating that physical training may ameliorate insulin resistance in patients with kidney failure. Support for this hypothesis was provided by a study that noted that long-term exercise training in a group of patients on maintenance hemodialysis was associated with significantly reduced blood glucose levels, improved glucose disappearance rates, and reduced fasting serum insulin levels [17].

●Anemia also may be an important factor underlying insulin resistance in uremia as evidenced by an approximate 50 percent increase in insulin-induced glucose utilization following correction of anemia with erythropoietin [18,19].

INSULIN DEGRADATION — There is little change in the metabolic clearance rate of insulin in kidney disease until there has been a substantial reduction in the glomerular filtration rate (GFR) [1]. Increased peritubular insulin uptake is able to compensate for reduced filtration until the GFR has fallen to less than 15 to 20 mL/min [20]. At this point, there is a dramatic reduction in insulin clearance that is also mediated by a concomitant decline in hepatic insulin metabolism [1]. The hepatic defect may be induced by a uremic toxin since it is largely reversed with adequate dialysis [21]. As will be discussed below, these findings may become important clinically in diabetic patients treated with insulin.

INSULIN SECRETION — The expected response to impaired tissue sensitivity would be an augmentation in insulin secretion in an attempt to normalize glucose metabolism. In many cases, however, insulin secretion tends to be blunted; these patients tend to have the greatest impairment in glucose tolerance.

One factor that can suppress insulin release in chronic kidney disease (CKD) is the associated metabolic acidosis [2]. In addition, excess parathyroid hormone (PTH) may interfere with the ability of the beta cells to augment insulin secretion in response to hyperglycemia or amino acids [22-24]. A PTH-induced elevation in the intracellular calcium concentration may be responsible for the impairment in insulin release by decreasing both the cellular content of adenosine triphosphate (ATP) and Na-K-ATPase pump activity in the pancreatic beta cells [25]. In experimental animals, these changes can be prevented by prior parathyroidectomy or by the administration of the calcium channel blocker verapamil [23,24].

The common deficiency of calcitriol (1,25-dihydroxyvitamin D) in CKD also may contribute to the impairment in insulin secretion. As an example, acute administration of calcitriol to hemodialysis patients has been shown to enhance insulin release and improve glucose tolerance [12]. This effect was independent of changes in the plasma concentrations of calcium or PTH. The importance of the inhibiting effect of PTH and the stimulating effect of calcitriol was also suggested in a case report of a patient who developed hypoglycemia with high insulin levels after the combination of parathyroidectomy and large doses of calcitriol [26].

As with the tissue sensitivity to insulin, hemodialysis has been shown to improve the insulin secretory response to glucose [21]. The mechanism by which this occurs has yet to be determined, but partial correction of the acidemia may contribute.

Studies evaluating the effect of erythropoietin on insulin and carbohydrate metabolism in CKD have produced conflicting results. In one report, for example, the administration of erythropoietin was associated with increased insulin secretion and decreased blood glucose levels following a test meal [27]. In another study, no change in these parameters was seen after an oral glucose load [28].

CLINICAL IMPLICATIONS — While sophisticated tests disclose resistance to the hypoglycemic activity of insulin in virtually all uremic subjects, most nondiabetic patients do not develop persistent hyperglycemia, unless they have a genetic predisposition to diabetes [1,2]. In this setting, inadequate insulin secretion may combine with uremic insulin resistance to produce overt diabetes.

The hyperinsulinemia normally induced by insulin resistance may also contribute to the common development of hypertriglyceridemia in chronic kidney disease (CKD) (see "Lipid abnormalities in nephrotic syndrome"). Insulin enhances hepatic very low density lipoprotein (VLDL) triglyceride synthesis and may indirectly (via decreased sensitivity of lipoprotein lipase to insulin) reduce the rate of metabolism of VLDL.

Hyperinsulinemia can also affect fibrinolysis by stimulating the production of plasminogen activator inhibitor-1. It may therefore play a role in the decreased systemic fibrinolytic activity characteristic of CKD [29].

Insulin requirements in diabetes mellitus — Insulin requirements show a biphasic course in diabetic patients with kidney disease. It is not uncommon for glucose control to deteriorate as kidney function deteriorates, as increasing insulin resistance can affect patients with both type 1 and type 2 diabetes. Thus, insulin requirements may increase in the former, while the institution of insulin therapy may be necessary in the latter.

In comparison, the marked fall in insulin clearance in advanced kidney failure often leads to an improvement in glucose tolerance. This may allow a lower dose of insulin to be given or even the cessation of insulin therapy [30,31]. Decreased caloric intake due to uremia-induced anorexia also may contribute to the decrease in insulin requirements [2].

With the institution of hemodialysis, the insulin requirement in any given patient will depend upon the net balance between improving tissue sensitivity and restoring normal hepatic insulin metabolism. As a result, one cannot readily predict insulin requirements in this setting, and careful observation of the patient in essential. (See "Management of hyperglycemia in patients with type 2 diabetes and advanced chronic kidney disease or end-stage kidney disease".)

HYPOGLYCEMIA — An unusual manifestation of disturbed glucose metabolism in CKD is the development of spontaneous hypoglycemia [2,32-34]. This complication can be seen in patients with and without diabetes. As an example, in a retrospective analysis of 243,222 patients, the incidence of hypoglycemia was significantly higher among patients with CKD (defined as estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m²) compared with patients without CKD both among those with diabetes (10.72 versus 5.33 per 100 patient-months, respectively) and without diabetes (3.46 versus 2.23 per 100 patient-months, respectively) [35].

Multiple factors may play a contributory role. These include decreased caloric intake, reduced renal gluconeogenesis due to the reduction in functioning kidney mass, impaired release of the counterregulatory hormone epinephrine due to the autonomic neuropathy of kidney failure, concurrent hepatic disease, and decreased metabolism of drugs that might promote a reduction in the plasma glucose concentration, such as alcohol, propranolol and other nonselective blockers, and disopyramide [2,33].

SUMMARY AND RECOMMENDATIONS

●Impaired glucose metabolism – In patients with advanced chronic kidney disease (CKD), several disturbances in carbohydrate handling may be present. Tissue insensitivity to insulin is of primary importance, but alterations in insulin degradation and insulin secretion also may contribute. (See 'Introduction' above.)

●Normal renal handling of insulin – The kidney plays a central role in the metabolism of insulin in normal individuals. Insulin is freely filtered in the kidney. Of the total renal insulin clearance, approximately 60 percent occurs by glomerular filtration and 40 percent by extraction from the peritubular vessels. (See 'Normal renal handling of insulin' above.)

●Insulin resistance, clearance/degradation, and secretion – Impaired tissue sensitivity to insulin occurs in almost all subjects with advanced CKD and is largely responsible for the abnormal glucose metabolism seen in this setting. There is also a dramatic reduction in insulin clearance that is also mediated by a concomitant decline in hepatic insulin metabolism. Further, insulin secretion tends to be blunted. (See 'Insulin resistance' above and 'Insulin degradation' above and 'insulin secretion' above.)

●Clinical implications

•Patients without diabetes – Despite abnormalities in insulin metabolism, most patients without diabetes who have impaired kidney function do not develop persistent hyperglycemia unless they have a genetic predisposition to diabetes. (See 'Clinical implications' above.)

•Patients with diabetes – Among patients with diabetes and kidney disease, insulin requirements show a biphasic course. Glucose control in patients with type 1 and type 2 diabetes commonly worsens as kidney function deteriorates, due to increasing insulin resistance. In comparison, the marked fall in insulin clearance in advanced CKD often leads to an improvement in glucose tolerance. This may allow a lower dose of insulin, conversion to oral therapy, or even the cessation of insulin therapy. (See 'Insulin requirements in diabetes mellitus' above.)

●Spontaneous hypoglycemia – An unusual manifestation of disturbed glucose metabolism in CKD is the development of spontaneous hypoglycemia. Multiple factors may play a contributory role. (See 'Hypoglycemia' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge William L Henrich, MD, MACP, who contributed to earlier versions of this topic review.