Perit Dial Int
29(Supplement_2):
145-148
2009
© 2009 International Society for Peritoneal Dialysis
Part 4: Metabolic Syndrome and Nutrition in PD |
INSULIN RESISTANCE AND GLUCOSE HOMEOSTASIS IN PERITONEAL DIALYSIS
Paulo Cezar Fortes,
Thyago Proença de Moraes,
Jamille Godoy Mendes,
Andrea E. Stinghen,
Silvia Carreira Ribeiro and
Roberto Pecoits-Filho
Center for Health and Biological Sciences, Pontifícia Universidade
Católica do Paraná, Curitiba, Brazil
Correspondence to: R. Pecoits–Filho, Center for Health and Biological
Sciences, Imaculada Conceição, 1155, Curitiba PR 80215-901
Brazil.
r.pecoits{at}pucpr.br
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ABSTRACT
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Cardiovascular disease (CVD) is the main cause of death in peritoneal
dialysis (PD) patients, a situation that can be explained by a combination of
traditional and nontraditional risk factors for CVD in these patients. Glucose
and insulin homeostasis are altered in chronic kidney disease (CKD) patients
even in the early stages of CKD, leading to insulin resistance by various
pathways. Several factors have been implicated in the pathogenesis of insulin
resistance, including anemia, dyslipidemia, uremia, malnutrition, excess of
parathyroid hormone, vitamin D deficiency, metabolic acidosis, and increase in
plasma free fatty acids and proinflammatory cytokines. Insulin resistance and
dyslipidemia are observed and increase with the progression of CKD, playing an
important role in the pathogenesis of hypertension and atherosclerosis.
Particularly in PD patients, exposure to glucose from dialysis fluid
accentuates the foregoing metabolic abnormalities. In conclusion, insulin
resistance and altered glucose metabolism are frequently observed in CKD, and
although dialysis partly corrects those disturbances, the use of glucose PD
solutions intensifies a series of harmful metabolic consequences. New
therapeutic measures aimed at reducing metabolic disorders are urgently needed
and perhaps will improve PD patient survival.
KEY WORDS: Chronic kidney disease; insulin resistance.
Cardiovascular (CV) disease is the main cause of death in peritoneal
dialysis (PD) patients, but the mechanisms mediating the increased CV risk
observed in this group of patients are still largely unknown, which limits the
perspective of effective therapeutic strategies. The leading hypothesis that
tries to explain this high CV risk observed in PD patients is that they are
already exposed to a number of traditional risk factors at initiation of
chronic kidney disease (CKD). As renal dysfunction progresses, CKD-related
risk factors are introduced, changing the profile both of the CV disease and
of the risk markers. In this phase, the list of risk factors is expanded with
mineral metabolism disturbances, anemia, fluid overload, uremic toxicity, and
increased signs of oxidative stress and inflammation. Also, increases in
insulin resistance and dyslipidemia are observed and rise with the progression
of CKD. Also, potential additional harm is introduced after the initiation of
PD, particularly because of the absorption of glucose. In this review, we
analyze the available published data concerning glucose homeostasis and
insulin resistance in PD patients.
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GLUCOSE AND INSULIN HOMEOSTASIS IN CKD
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Insulin regulates glucose homeostasis at many sites, reducing hepatic
glucose output (by decreased gluconeogenesis and glycogenolysis) and
increasing the rate of glucose uptake, primarily into muscle and adipose
tissue. Insulin affects cells through binding to its receptor on the surface
of insulin-responsive cells. The stimulated insulin receptor phosphorylates
itself, and several substrates—including members of the insulin receptor
substrate (IRS) family—initiate downstream signaling events. The
inhibition of signaling downstream of the insulin receptor is a primary
mechanism through which inflammatory signaling leads to insulin resistance
(Figure 1).
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Figure 1 — In patients on peritoneal dialysis (PD), uremic toxicity and
factors related to peritoneal dialysis fluid bioincompatibility trigger the
production of reactive oxygen species (ROS) and induce an inflammatory
response through endoplasmic reticulum (ER). Hyperlipidemia, hyperglycemia,
and obesity also induce production of ROS and amplify the inflammatory
response. As a consequence, inflammatory pathways [Jun N-terminal kinase (JNK)
and inhibitor of nuclear factor  B (NFKβ) kinase (IKK)] are
activated, blocking insulin action and normal lipoprotein metabolism. This
mechanism promotes a condition of insulin resistance and dyslipidemia. IRS =
insulin receptor substrate; PPAR = peroxisome proliferator–activated
receptor.
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Glucose metabolism is altered in CKD patients even in the earliest stages.
Studies even in the 1980s showed that, although insulin secretion in CKD is
normal, a decreased tissue sensitivity to insulin is responsible for the
abnormal glucose uptake (1). In
advanced CKD, particularly in stages 4 and 5, significant metabolic
derangements in insulin metabolism occur. Interestingly, endogenous insulin is
substantially degraded by the liver, but exogenous insulin is eliminated
mainly by the kidney. Insulin is freely filtered at the glomerulus and
extensively reabsorbed in the proximal tubule after enzyme degradation into
smaller peptides. With the progression of kidney dysfunction, peritubular
insulin uptake increases, compensating for the decline in the breakdown of
filtered insulin. When the glomerular filtration rate reaches approximately 20
mL/min, insulin clearance decreases, and the half-life of insulin increases.
Moreover, renal gluconeogenesis is markedly reduced in advanced CKD; weight
loss as a result of wasting or appetite reduction is a common feature of this
condition. Taken together, these metabolic disturbances lead to a decline in
the requirement for exogenous insulin in advanced CKD.
Recent evidence showed that insulin is a anti-inflammatory hormone that
suppress several proinflammatory transcription factors such as nuclear factor
B (NF-B), early growth response protein 1, and activating
protein 1, which all mediate inflammation. An impairment of the action of
insulin because of insulin resistance would therefore result in the activation
of these proinflammatory transcription factors and in an increase of the
expression of the corresponding genes
(Figure 1). Derangements in
other biologic effects of insulin could be associated with certain pathologic
states in CKD such as hypertension and insulin resistance
(2,3).
Numerous factors have been implicated in the pathogenesis of insulin
resistance occurring before the initiation of dialysis therapy; examples
include anemia, dyslipidemia, uremia, malnutrition, excess of parathyroid
hormone, vitamin D deficiency, and metabolic acidosis. In this context,
initiation of dialysis therapy should not be delayed, because evidence
indicates that insulin resistance plays an important role in the pathogenesis
of hypertension and atherosclerosis, important risk factors in patients with
CKD. After the initiation of dialytic therapy, this situation is partially
corrected.
However, particularly in PD patients, the development of insulin resistance
after a initial improvement is generally attributed to a high glucose load
absorbed from dialysis fluid, contributing to a wide spectrum of metabolic
abnormalities including hypertriglyceridemia, poor glycemic control, new-onset
diabetes, hypertension, and central obesity. An amplifying loop in the process
of glucose absorption appears to be a consequence of the modifications in the
peritoneum associated with a loss of ultrafiltration capacity.
Taken together, these abnormalities stimulate a cascade effect of
inflammatory response, leading to a rise in mitochondrial production of
reactive oxygen species (ROS). Production of ROS is enhanced, which causes
further activation of inflammatory pathways. Several serine–threonine
kinases, including Jun N-terminal kinase (JNK) and inhibitor of NF-B
kinase, are activated by inflammatory or stressful stimuli and contribute to
the inhibition of insulin signaling. In response to stimuli such as
endoplasmic reticulum stress, cytokines, and fatty acids, JNK is activated.
Upon activation, JNK associates with and phosphorylates IRS-1, impairing
insulin action (4). This
sequence of events associating inflammation with insulin resistance, and vice
versa, has known metabolic consequences as shown in
Figure 1.
An increase in plasma free fatty acid (FFA) concentrations plays a key role
in the pathogenesis of insulin resistance through specific actions that block
insulin signal transduction. An increase in plasma FFA concentrations in
normal-weight subjects to levels comparable to those seen in obese subjects
also results in the induction of oxidative stress, inflammation, and subnormal
vascular reactivity, and causes insulin resistance. The FFAs are released in
abundance from an expanded adipose tissue mass. In the liver, FFAs produce
glucose, triglycerides, and very-low-density lipoprotein (VLDL). Associated
lipid and lipoprotein abnormalities include a reduction in high-density
lipoprotein (HDL) cholesterol and an increase in low-density lipoproteins. The
FFAs also reduce insulin sensitivity in muscle by inhibiting insulin-mediated
glucose uptake. Associated defects include a reduction in glucose partitioning
to glycogen and increased lipid accumulation in triglycerides. Increases in
circulating glucose (and, to some extent, FFAs) raise pancreatic insulin
secretion, resulting in hyperinsulinemia. Hyperinsulinemia may result in
enhanced sodium reabsorption and increased sympathetic nervous system (SNS)
activity. It may also contribute to hypertension— as might increased
levels of circulating FFAs.
Superimposed and contributory to the insulin resistance produced by
excessive FFAs is the paracrine and endocrine effect of the proinflammatory
state. Enhanced secretion of interleukin-6 (IL-6) and tumor necrosis factor
, among other cytokines, by a variety of cells in adipose tissue
including adipocytes and monocyte-derived macrophages results in more insulin
resistance and lipolysis of adipose tissue triglyceride stores to circulating
FFAs. The IL-6 and other cytokines also are increased in the circulation and
may enhance hepatic glucose production, production of VLDL by the liver, and
insulin resistance in muscle. Cytokines and FFAs also increase the production
of fibrinogen and plasminogen activator inhibitor 1 (PAI-1) by the liver,
complementing the overproduction of PAI-1 by adipose tissue and resulting in a
prothrombotic state. Reductions in the production of the anti-inflammatory and
insulin-sensitizing cytokine adiponectin are also associated with metabolic
syndrome and may contribute to the pathophysiology of the syndrome.
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INSULIN RESISTANCE AND DIALYSIS MODALITY
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Although efficacious as a chronic renal replacement therapy, PD exposes
patients to a glucose load that could worsen the state of insulin resistance
observed in patients with CKD. Disturbances of carbohydrate metabolism seem to
be even more intense in nondiabetic PD patients than in hemodialysis patients.
We recently observed that patients on PD had significantly higher fasting
glucose, glycated hemoglobin (HbA1C), and homeostasis model assessment (HOMA)
index values than did patients on hemodialysis
(5). In addition, a recent
study showed that, after PD initiation, a large number of patients developed
new-onset hyperglycemia because of their exposure to hypertonic glucose
solutions
(6,7).
In fact, glucose absorption through the peritoneum results in significantly
higher serum glucose levels than are produced by an equivalent dose of oral
dextrose. Insulin resistance can be safely assessed by HOMA index in CKD
patients, and a study showed that a high HOMA index predicts mortality in CKD
patients (8).
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EFFECT OF HIGH PERITONEAL SOLUTE TRANSPORT RATE ON METABOLIC COMPLICATIONS OF PD
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Prolonged exposure of the peritoneum to hypertonic glucose solutions can
damage the peritoneal tissue, inducing histologic and functional changes in
the membrane. The peritoneal membrane of fast transporters present a large
effective peritoneal surface area or higher intrinsic membrane permeability,
and these patients are therefore prone to lose the osmotic gradient required
for sustained ultrafiltration capacity. In addition, fast transporters absorb
large quantities of glucose to the circulation. Longevity in PD (in terms of
both technique and patient survival) is directly affected by transport
characteristics, and patient and technique survival are both lower in patients
with a high peritoneal solute transport rate. The metabolic alterations
induced by fast transport potentially play a role in the development of CV
disease in PD patients with a high peritoneal transport status
(Table 1). Indeed, the
association between metabolic syndrome and peritoneal solute clearance and
transport rate has been recently reported
(9).
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TABLE 1 Impact of High Peritoneal Transport Status on Metabolic and Cardiovascular
Status in Peritoneal Dialysis Patients
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THE IMPORTANCE OF GLYCEMIC CONTROL AND THE ROLE OF GLUCOSE SPARING
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Improved glycemic control has the potential to reduce complications and
improve outcomes. These benefits are observed in pre-dialysis patients and in
patients under renal replacement therapy. Disturbances in glucose metabolism
are also associated with poor prognosis in nondiabetic populations. Indeed, a
recent study suggested that glycated hemoglobin is a predictor of all-cause
mortality in nondiabetic CKD patients, independent of other well-established
risk factors (10).
As therapeutic options, peroxisome proliferator–activated receptor
agonists (rosiglitazone, for instance) improve insulin resistance in diabetic
and nondiabetic PD patients and also reduce levels of C-reactive protein,
although an improvement in outcome has yet to be shown
(11). Glucose-sparing
solutions, such as those with amino acids or icodextrin, could potentially
benefit both diabetic and nondiabetic PD patients by improving disturbances in
carbohydrate metabolism (12).
Ongoing and future studies will clarify whether glucose-sparing solutions are
the best therapeutic approach to this important clinical problem.
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CONCLUSIONS
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Insulin resistance and altered glucose metabolism are frequently observed
in CKD, and dialysis only partly corrects the disturbances. The use of
glucose, the most common osmotic agent in PD solutions, intensifies a series
of metabolic consequences that range from acute hyperglycemia and
hyperinsulinemia to dyslipidemia and weight gain. New therapeutic measures are
urgently needed to provide reductions in metabolic disturbances and perhaps to
improve survival in PD patients.
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ABSTRACT
GLUCOSE AND INSULIN HOMEOSTASIS...
