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Carbohydrate and insulin metabolism in chronic kidney disease

Authors: Biff F Palmer, MD, William L Henrich, MD, MACP

Section Editor: Jeffrey S Berns, MD
Deputy Editor: Alice M Sheridan, MD

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Mar 2018. | This topic last updated: Apr 05, 2017.

INTRODUCTION — Uremia is typically associated with impaired glucose metabolism. Some patients 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 chronic kidney disease
(CKD) and the clinical implications of these abnormalities in nondiabetics. The impact of these changes on the
management of hyperglycemia in diabetic patients with end-stage renal disease (ESRD) is discussed separately.
(See "Management of hyperglycemia in patients with type 2 diabetes and pre-dialysis chronic kidney disease or
end-stage renal 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 renal 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 uremic subjects 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.

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Both experimental and clinical studies suggest that hepatic glucose production and uptake are normal in uremia
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 [6,7]. Furthermore, the abnormality appears to specifically involve
glycogen synthesis as the rate of glucose oxidation is relatively normal [7]. 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 renal failure [7-9]. (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 [10-12]. As an example, the observation that
tissue sensitivity to insulin can be substantially improved by dialysis is consistent with a role for uremic toxins
[2,10].

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 [11]. 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 [12,13]. 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 renal function [14,15]. 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 renal 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 [16].

● 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 [17,18].

INSULIN DEGRADATION — There is little change in the metabolic clearance rate of insulin in renal 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 [19]. 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 [20]. 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 [21-23]. 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

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[24]. In experimental animals, these changes can be prevented by prior parathyroidectomy or by the
administration of the calcium channel blocker verapamil [22,23].

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 [11]. 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 [25].

As with the tissue sensitivity to insulin, hemodialysis has been shown to improve the insulin secretory response
to glucose [20]. 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 [26]. In another study, no change in
these parameters was seen after an oral glucose load [27].

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 [28].

Insulin requirements in diabetes mellitus — Insulin requirements show a biphasic course in diabetic patients
with renal disease. It is not uncommon for glucose control to deteriorate as renal function deteriorates, as
increasing insulin resistance can affect both type 1 and type 2 diabetics. 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 renal 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
[29,30]. 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 pre-dialysis chronic kidney disease or end-
stage renal disease".)

HYPOGLYCEMIA — An unusual manifestation of disturbed glucose metabolism in chronic kidney disease (CKD)
is the development of spontaneous hypoglycemia [2,31,32]. This complication can be seen in both diabetic and
nondiabetic subjects. 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

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[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) [33].

Multiple factors may play a contributory role. These include decreased caloric intake, reduced renal
gluconeogenesis due to the reduction in functioning renal mass, impaired release of the counterregulatory
hormone epinephrine due to the autonomic neuropathy of renal 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 [2,32].

SUMMARY AND RECOMMENDATIONS

● In patients with end-stage kidney disease, 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.)

● The kidney plays a central role in the metabolism of insulin in normal subjects. 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.)

● Impaired tissue sensitivity to insulin occurs in almost all subjects with end-stage kidney disease 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.)

● Despite abnormalities in insulin metabolism, most nondiabetic patients with impaired kidney function,
including end-stage kidney failure, do not develop persistent hyperglycemia, unless they have a genetic
predisposition to diabetes. (See 'Clinical implications' above.)

● Among patients with diabetes and kidney disease, insulin requirements show a biphasic course. Glucose
control commonly deteriorates as renal function deteriorates as increasing insulin resistance can affect both
type 1 and type 2 diabetics. In comparison, the marked fall in insulin clearance in advanced renal failure
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.)

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

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REFERENCES

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Topic 1974 Version 11.0

Contributor Disclosures
Biff F Palmer, MD Nothing to disclose William L Henrich, MD, MACP Nothing to disclose Jeffrey S Berns,
MD Consultant/Advisory Boards: Amgen [Clinical Trial EC (Darbepoetin)]. Alice M Sheridan, MD Nothing to
disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must conform to
UpToDate standards of evidence.

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