Insulin Resistance and the Metabolic Syndrome in Chronic Renal Disease

1

Introduction

Insulin resistance can broadly be defined as an impairment or defect in the ability of insulin to produce its normal biological, physiological, or clinical effects. Despite the simplicity of this concept and the relatively ease with which it can be demonstrated in vitro and in vivo, the true complexity and multiple clinical manifestations of insulin resistance have only recently been appreciated. Although the effects of insulin on carbohydrate, lipid, and protein metabolism are well recognized, insulin also has a multitude of actions involving cell growth and differentiation, regulation of vascular tone and blood pressure, ion transport, and inflammation.

Recently, there has been an increased appreciation of the role of the kidney in both the pathogenesis and consequences of insulin-resistant states. Diabetes and hypertension—two common diseases characterized by insulin resistance—are also the leading causes of chronic kidney disease. Conversely, almost all patients who develop end-stage renal disease, regardless of etiology, ultimately become insulin resistant. This chapter will provide an overview of the manifestations and implications of insulin resistance as they impact the kidney, with particular emphasis on the physiological and clinical aspects of the disorder.

2

Historical Perspective

The concept of insulin resistance was first introduced in the 1930s when Himsworth reported that the ability of injected insulin to lower the blood glucose level was greater in patients with diabetes who were young and lean compared with patients who were older and obese. He designated these two groups as “insulin-sensitive” and “insulin-insensitive” forms of diabetes, respectively–a distinction that we now recognize as type 1 and type 2 diabetes mellitus.

In 1960 Yalow and Berson developed the technique of radioimmunoassay that enabled the measurement of insulin concentrations in plasma. During the next decade, several studies revealed that, contrary to expectations, plasma levels of insulin were elevated in patients with obesity, mild to moderate type 2 diabetes, and other disorders characterized by hyperglycemia. This observation initially was considered paradoxical given the known ability of insulin to lower the plasma glucose concentration, and led to a revision of the prevailing wisdom that all forms of diabetes or other states of glucose intolerance were caused by insulin deficiency. It began to be appreciated that resistance to the biological effect of the hormone, and the body’s compensatory increase in insulin secretion to overcome this defect, were cardinal features of many glucose-intolerant states.

By the 1970s, investigators recognized that insulin, like other peptide hormones, induced its metabolic effects and other actions by binding to a receptor on the cell surface, which then transmitted the hormonal signal to the interior of the cell. Several studies reported that abnormalities in insulin receptor binding, either due to a reduction in receptor number or binding affinity, were observed in type 2 diabetes, obesity, and other hyperinsulinemic states. However, the impairment in insulin action could not be fully explained by receptor abnormalities, so attention turned to the post-receptor pathways involved in insulin signaling. The search for either genetic or acquired defects in the insulin signaling pathway remains one of the most active areas of investigation into the mechanisms underlying insulin-resistant states.

During the 1980s, a major conceptual advance occurred when investigators began to recognize that many diseases not classically associated with overt abnormalities in glucose tolerance were, in fact, characterized by insulin resistance. Although it had been recognized since the mid-1900s that diabetes, obesity, dyslipidemia, hypertension, and cardiovascular disease commonly coexisted in the same individual, Reaven is generally acknowledged to be the first to propose the hypothesis that the frequent concurrence of these diseases was due to a common underlying defect in insulin action that was manifest to varying degrees in different individuals. He called this association “syndrome X,” although now the terms “insulin resistance syndrome” or “metabolic syndrome” are more widely used. This concept forms the basis of our current physiological and clinical understanding of insulin resistance, which has been greatly expanded to include other abnormalities such as endothelial dysfunction, chronic inflammation, hypercoagulability, proteinuria, and increased sympathetic nervous system activity. We also now appreciate that while hyperinsulinemia is present in essentially all insulin-resistant states, unless there is a concurrent defect in insulin secretion, the varying manifestations of the syndrome often are due to tissue-specific differences in the relative sensitivity or resistance to insulin action.

3

Cellular Mechanisms of Insulin Secretion and Action

Insulin is a 5808 Da peptide consisting of a 21 amino acid A chain and a 30 amino acid B chain linked by two disulfide bridges. It is synthesized in the beta cells of the pancreatic islets as a single chain precursor, proinsulin, from which a connecting peptide (C-peptide) is removed to yield the active insulin molecule. Insulin and C-peptide, along with small amounts of proinsulin and inactive insulin split products, are stored in secretory granules where they are released into the circulation in response to nutrient ingestion. Glucose, the primary stimulus to insulin secretion, enters the beta cell via the GLUT2 transporter and is metabolized by glucokinase to generate adenosine triphosphate (ATP). Glucokinase has a Km of 5.5 mmol/L, enabling it to provide a sensitive metabolic signal to changes in the plasma glucose concentration that are in the normal physiologic range (4.0–7.0 mmol/L). In response to the increased intracellular levels of ATP produced by glycolysis, an ATP-sensitive K ⁺ channel on the surface of the beta cell closes, leading to depolarization of the cell membrane. In response to this depolarization, voltage-sensitive Ca ⁺⁺ channels open, causing a rise in intracellular calcium levels and release of the insulin from the secretory vesicles ( Fig. 14.1 ). The release of insulin typically occurs in a biphasic pattern, with a first phase of secretion consisting primarily of rapid release of prestored insulin, and a more prolonged second phase that involves synthesis of new insulin in response to ongoing hyperglycemia.

Although glucose is considered to be the primary stimulus to the beta cell, insulin secretion also is induced by other nutrients including amino acids and fatty acids. Various other hormones may potentiate the insulin response to nutrients (including gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1)), directly stimulate insulin secretion [cholecystokinin (CCK)], or inhibit insulin secretion (somatostatin, epinephrine, norepinephrine). Several different classes of pharmacologic agents, including sulfonylureas, meglitinides, GLP-1 agonists, and dipeptidyl-peptidase-4 (DPP-4) inhibitors also stimulate or potentiate insulin secretion and are widely used in the treatment of type 2 diabetes.

After its release from the beta cells into the circulation, insulin binds to receptors on the cell surface to initiate its diverse effects on metabolism and cell growth. The insulin receptor is a heterodimeric protein consisting of two extracellular α-subunits attached to two transmembrane β-subunits ( Fig. 14.2 ). It belongs to the family of tyrosine kinase receptors and is closely related to the insulin-like growth factor-1 (IGF-1) receptor through which some of the growth-promoting effects of insulin are mediated. When insulin binds to the α-subunits, it induces a conformational change in the β-subunits, activating their tyrosine kinase activity. The β-subunits initially autophosphorylate, further increasing their kinase activity, and begin a cascade of phosphorylation of tyrosine residues on a series of intracellular proteins including insulin receptor substrates (IRS), SHC, and Grb-2. These phosphorylated proteins function as docking sites for other intracellular proteins, initiating a complex series of enzymatic effects that mediate the diverse effects of the hormone through two major pathways. The phosphatidylinositol 3-kinase (PI-3 kinase) pathway primarily mediates the metabolic effects of insulin, including stimulation of glucose transport and glycogen synthesis, inhibition of lipolysis, stimulation of protein synthesis, and, to a lesser extent, cell growth. The mitogen-activated protein kinase (MAP kinase) pathway (also known as the Ras-Raf-MEK-ERK pathway) is primarily involved in the effects of insulin on gene expression and cell growth and differentiation. Insulin receptors are extensively distributed in almost all tissues of the body—including muscle, liver, adipose tissue, kidney, brain, the vasculature, and many others—and the physiological effects of insulin vary widely depending upon the specific tissue type. The implications of these diverse effects and their role in the clinical manifestations of insulin-resistant states are discussed in greater detail below.

4

Clinical Physiology of Insulin Resistance

In healthy individuals, the plasma glucose concentration typically ranges between 70 and 100 mg/dL after an overnight fast, and usually does not exceed 120–140 mg/dL after ingestion of a meal. In the postabsorptive state, glucose is released into the circulation primarily from the liver, either by the breakdown of previously stored glycogen or by the process of gluconeogenesis involving the synthesis of new glucose from precursors such as lactate, pyruvate, glycerol, and the gluconeogenic amino acids, predominantly alanine and glutamine. Insulin is the primary hormone inhibiting the release of glucose from the liver and, after an overnight fast, circulates at concentrations ranging from about 4 to 8 μU/mL, depending on the age, weight and other demographic characteristics of the individual. Approximately half of all glucose produced in the fasting state is utilized by the brain, which does not require insulin for glucose uptake or metabolism.

After the ingestion of glucose or a mixed meal, nutrients are absorbed from the intestinal tract and stimulate the release of insulin from the pancreatic beta cells into the portal vein. Insulin initially reaches the liver where its major physiologic effects include stimulation of glycogen and triglyceride synthesis, inhibition of gluconeogenesis, and suppression of lipolysis and ketogenesis ( Fig. 14.3 ). Approximately 50%–60% of insulin secreted by the pancreas is removed by the liver, primarily by receptor-mediated clearance, before reaching the systemic circulation. Systemic levels of insulin vary widely after nutrient ingestion and may range from 20 to over 100 μU/mL, depending on the content and size of the meal as well as the metabolic characteristics of the individual. In response to the systemic hyperinsulinemia, (1) glucose is removed from the circulation, primarily by muscle, and either stored as glycogen or oxidized to meet ongoing energy requirements, (2) lipolysis is inhibited and fatty acids are re-esterified into triglycerides, and (3) amino acids are taken up by a wide variety of tissues for tissue growth and repair. After about 3–5 h, most of the nutrients have been cleared from the circulation and the basal state is restored.

In patients with insulin resistance, several defects in this process are evident. In the fasting or postabsorptive state, insulin is no longer able to fully restrain hepatic glucose production, resulting in a small rise in the fasting plasma glucose concentration. This induces a compensatory increase in insulin secretion so that a new steady state is achieved with mild fasting hyperglycemia and hyperinsulinemia—the classic finding in insulin-resistant states. In the postprandial state, insulin also is not able to fully stimulate glucose uptake into muscle so there is an excessive rise in the plasma glucose concentration leading to even greater hyperinsulinemia. Similar abnormalities in lipid metabolism also occur, with elevated fasting and postprandial levels of free fatty acids and triglycerides. Although the pancreas initially is able to compensate for the higher levels of glucose, the continued exposure to hyperglycemia eventually leads to beta-cell failure. The first phase of insulin secretion is particularly sensitive to this process and typically becomes impaired when the fasting plasma glucose concentration exceeds 100 mg/dL, leading to more prolonged postprandial hyperglycemia and even greater demand on the beta cell. Once the fasting plasma glucose concentration is consistently above 120 mg/dL, the second phase of insulin secretion also begins to fail, and the patient often progresses to overt type 2 diabetes shortly thereafter ( Fig. 14.4 ).

5

Measurement of Insulin Resistance

Several clinical research techniques have been developed to measure insulin resistance. They are generally divided into dynamic tests (which measure the response to administered glucose or insulin) or static tests (which are performed in the fasting state). The most widely used dynamic method is the euglycemic hyperinsulinemic clamp technique, which is generally considered to be the gold standard for measuring insulin sensitivity in vivo. With this technique a primed-continuous infusion of insulin is administered to raise the plasma insulin concentration to a predetermined physiological or pharmacological level. The plasma glucose concentration is then measured at 5 min intervals, and a variable infusion of exogenous glucose is administered to maintain the plasma glucose concentration constant at the fasting level. Since the plasma glucose concentration remains unchanged, the amount of exogenous glucose infused must equal the amount of glucose utilized in response to the hyperinsulinemia and, thus, provides a direct measure of whole-body sensitivity to insulin. The insulin clamp is frequently combined with infusions of small amounts of stable or radioisotopically labeled glucose to measure hepatic glucose production, or with labeled amino acids or fatty acids to measure protein or lipid metabolism. It also can be combined with indirect calorimetry to measure rates of glucose or lipid oxidation and nonoxidative glucose disposal, hemodynamic measures to assess the effects of insulin on vascular function, or with imaging techniques to measure rates of glucose metabolism in specific tissues or organs.

The other most widely used dynamic method for assessing insulin sensitivity is the frequently sampled intravenous glucose tolerance test (FSIVGTT), also known as the minimal model technique. With this procedure a bolus of glucose, typically 300 mg/kg, is rapidly administered intravenously, and plasma glucose and insulin levels are measured frequently for the next 3 h. The resulting curves defined by the changes in plasma glucose and insulin are then fit using nonlinear modeling to derive indices reflecting the rate of change in plasma glucose level in response to the ambient insulin level (S _I , or insulin sensitivity), the rate of change in glucose independent of the level of insulin (S _G , or glucose effectiveness), and first and second phases of insulin secretion (Φ ₁ and Φ ₂ ). Although this technique is somewhat simpler to perform than the insulin clamp, it does not provide a steady state of glucose metabolism in response to a known level of insulin, and thus typically cannot be combined with the other techniques used to assess intermediary metabolism, substrate oxidation, hemodynamic measures, or imaging techniques. Dynamic tests may also be performed with oral administration of glucose, during which indices of insulin sensitivity are derived from the plasma glucose and insulin response to a 75 g oral glucose challenge. Other less commonly used techniques for measuring insulin sensitivity include the insulin suppression test, isolated organ or limb perfusion techniques, or intravenous insulin tolerance test.

Because the aforementioned techniques are labor intensive and not suited for large population-based studies or routine clinical use, static (fasting) measures of insulin resistance have been proposed. The most widely used is the homeostasis model assessment of insulin resistance (HOMA-IR), which is calculated as [fasting plasma insulin level (in μU/mL) × fasting plasma glucose level (in mmol/L)]/22.5. A value of 1.00 is considered normal, and higher values indicate progressively severe states of insulin resistance. A similar measure known as the quantitative insulin sensitivity check index (QUICKI) is also used and is calculated as 1/[log fasting plasma glucose (in mg/dL) + log fasting plasma insulin (in μU/mL)]. Both of these measures are much more variable than either the insulin clamp or FSIVGTT, primarily due to the wide range of “normal” values for fasting plasma insulin. Also, they cannot be used in patients with diabetes where the normal homeostatic relationship between plasma glucose and insulin levels no longer exists, and they have theoretical limitations based on the fact that they attempt to measure insulin sensitivity in the fasting state when the majority of glucose uptake is independent of insulin.

Measurement of insulin resistance in chronic kidney disease is complicated by the fact that the kidney is one of the major sites of insulin removal from the systemic circulation. Through the processes of glomerular filtration and endocytosis by peritubular capillaries, more than 30% of circulating insulin is removed by the kidney. As a result of this decrease in insulin clearance, static measurements such as HOMA or QUICKI, which rely on a normal feedback relationship between plasma glucose and insulin, may not be accurate. Dynamic measures are less likely to be affected in the setting of chronic renal disease.

6

Metabolic Syndrome

6.1

Overview

The metabolic syndrome is a collection of clinical and laboratory abnormalities that are associated with insulin resistance and an increased risk of several diseases, predominantly atherosclerotic cardiovascular disease (ASCVD) and type 2 diabetes. Although at different stages in its evolution it has been known as “syndrome X,” “Reaven’s syndrome” or the “deadly quartet,” the terms “metabolic syndrome” and “insulin resistance syndrome” are currently the most widely used in the medical literature. In clinical practice, the diagnosis is coded as either “dysmetabolic syndrome x” (ICD-9-CM diagnosis 277.7) or “metabolic syndrome” (ICD-10-CM diagnosis code E88.81).

The core factors that define the syndrome are obesity (particularly intraabdominal or visceral obesity), hyperglycemia, dyslipidemia, hypertension, and atherosclerosis. Other associated abnormalities include elevated levels of inflammatory markers, a procoagulant state, increased sympathetic nervous system activity, endothelial dysfunction, hyperuricemia, and proteinuria ( Fig. 14.5 ). Although chronic kidney disease traditionally had not been included as one of the primary components of the metabolic syndrome, it has become increasingly evident that renal disease plays a central role as both a cause and a consequence of the syndrome. Because all of these risk factors and their clinical consequences are associated with insulin resistance, many investigators believe that insulin resistance is the primary physiologic abnormality underlying the syndrome. While this may be correct, based on our current understanding it is preferable to consider this to be a true syndrome, i.e., the common association of pathological states that may have more than one etiology.