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Journal of the American College of Nutrition, Vol. 22, No. 6, 487-493 (2003)
Published by the American College of Nutrition

Review

Insulin Clearance in Obesity

M. Elena Valera Mora, MD, Antonino Scarfone, MD, Menotti Calvani, MD, Aldo V. Greco, MD and Geltrude Mingrone, MD, PhD

Institute of Internal Medicine, Catholic University of Rome, Rome (M.E.V.M., A.S., A.V.G., G.M.), ITALY
Sigma Tau Pharmaceuticals, Pomezia (M.C.), ITALY

Address reprint requests to: M. Elena Valera Mora, M.D., Institute of Internal Medicine, Catholic University, Largo Agostino Gemelli, 8, 00168 Rome, ITALY. E-mail: valeramora{at}virgilio.it


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MOLECULAR STEPS OF CELLULAR...
 HEPATIC CLEARANCE
 KIDNEY CLEARANCE
 PERIPHERAL TISSUE CLEARANCE
 CONCLUSION
 REFERENCES
 
Insulin uptake and degradation is a complex and not yet completely understood process involving not only insulin sensitive tissues. The most important degradative system is insulin degrading enzyme which is a highly conserved metalloendopeptidase requiring Zn++ for its proteolytic action, although protein disulfide isomerase and cathepsin D are also involved in insulin metabolism. The liver and the kidney are the principal sites for insulin clearance. In obese subjects with hyperinsulinemia and high levels of free fatty acids, insulin hepatic clearance is impaired, while the glomerular filtration rate, renal plasma flow and albumin excretion are increased, suggesting a state of renal vasodilatation leading to an abnormally transmitted arterial pressure to the glomerular capillaries through a dilated afferent arteriole. Insulin can be cleared also by muscle, adipocytes, gastrointestinal cells, fibroblasts, monocytes and lymphocytes which contain insulin receptors and internalization and regulation mechanism for insulin metabolism.

Key words: insulin clearance, obesity, insulin resistance, diabetes mellitus, insulin degrading enzyme, liver clearance, kidney clearance

Key teaching points:

• Insulin controls glucose, lipid and protein metabolism with a determinant role also for cell growth and differentiation and its degradation mediates some aspects of its action.

• Insulin degrading enzyme is the most important degradative system for insulin degrading and glucagon, insulin-like growth factors I and II, ß-amyloid peptide, atrial natriuretic factor, growth hormone-releasing factor and ß-endorphin, and with regulatory functions for the activity of steroid receptors and proteasomes.

• During obesity, hyperinsulinemia, insulin resistance state, dyslipidemia and type 2 diabetes mellitus insulin clearance in the liver or in the kidney, the two most important organs for insulin degradation, decreases.

• Muscle and adipose tissues are also involved in insulin clearance as are non-insulin sensitive cells like lymphocytes, monocytes, fibroblasts and gastrointestinal cells.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MOLECULAR STEPS OF CELLULAR...
 HEPATIC CLEARANCE
 KIDNEY CLEARANCE
 PERIPHERAL TISSUE CLEARANCE
 CONCLUSION
 REFERENCES
 
After the discovery of insulin in 1921 by Banting and Best, an ever increasing number of studies have shed light on the role of this hormone in animal and human metabolism. Insulin controls not only glucose, but also lipid and protein metabolism, and exerts a determinant role for cell growth and differentiation. Insulin performs all these growth and metabolic actions by binding to its receptor, a heterotetramer consisting of two extracellular insulin-binding {alpha}-subunits linked by disulfide bonds to two transmembrane ß-subunits. The ß-subunits contain an intrinsic tyrosine kinase activity that is activated upon insulin binding to the {alpha}-subunits with phosphorylation of tyrosine residues of a variety of docking proteins, including insulin receptor substrate proteins (IRS) [1].

Insulin removal helps control the cellular response to the hormone by decreasing availability, and this degradation process may also be involved in mediating some aspects of insulin action [2].

A large body of literature has been focused on insulin secretion in different physiopathological conditions. In contrast, relatively little information is available on insulin clearance, being defined as the plasma volume which can be purified of insulin in a time unit. Insulin clearance is a complex mechanism involving multiple organs and cells, including liver, kidney, adipose and muscle tissues, fibroblasts, and gastrointestinal cells, and which is characterized by several steps, including binding to the insulin membrane receptor, its internalization and degradation by the insulin degrading enzyme or insulinase, or by lysosomal enzymatic processes.

The degradation process is not yet completely understood.

In this review we will focus our attention on the major insulin degradative system, the insulin degrading enzyme (IDE), and on the major sites for insulin clearance, the liver, the kidneys and other tissues. Moreover, we will analyze the variations of insulin clearance in obesity and type 2 diabetes mellitus, two diseases of great interest as their incidence is rapidly growing in the last few years.

The association of insulin resistance with central adiposity is considered a risk factor for type 2 diabetes and cardiovascular diseases; additional evidence is given by the net improvement of both conditions after weight loss [3–6].

Insulin resistance is a common feature in obese individuals, where the pancreatic ß-cell sensitivity to increments in plasma glucose concentration is largely reduced compared to subjects with normal insulin sensitivity. An increase in insulin clearance seems to occur after weight loss of about 10% of initial body weight, whereas decreases in insulin secretion seem to require a greater degree of weight loss and/or an improvement in insulin sensitivity. This difference in the observed effects of weight loss on insulin clearance and insulin secretion is due to the fact that weight loss in obese individuals will lead in a relatively uniform way to an increase in insulin clearance, but any change in pancreatic ß-cell sensitivity to glucose is dependent on an improvement in insulin sensitivity [7].

Insulin clearance includes both first-pass hepatic and peripheral insulin uptake and degradation and is a characteristic of all insulin-sensitive tissues [8–10]. Intravenous insulin has a short plasma half-life (4–6 minutes), as would be expected from the necessity to respond rapidly to changes in blood glucose [11,12]. At physiological concentrations, insulin uptake is mediated primarily by the insulin receptor with a smaller contribution from nonspecific processes, while at supraphysiological concentrations, non-receptor processes assume greater importance.

Insulin removal and degradation are regulated processes and abnormalities in insulin clearance are integral to diseases such as type 2 diabetes.


   MOLECULAR STEPS OF CELLULAR INSULIN UPTAKE AND DEGRADATION
TOP
 ABSTRACT
 INTRODUCTION
 MOLECULAR STEPS OF CELLULAR...
HEPATIC CLEARANCE
 KIDNEY CLEARANCE
 PERIPHERAL TISSUE CLEARANCE
 CONCLUSION
 REFERENCES
 
The first step in insulin catabolism is the binding to its receptor (Fig. 1). Receptor-bound insulin can return intact insulin to the circulation or deliver the hormone to an intracellular site. Internalized insulin can be found in cytosol, nucleus, Golgi or can be delivered to lysosomes, before degradation starts [13]. A part of cell-associated insulin returns to circulation intact or partially degraded although the biological significance of this partially degraded insulin is unknown [14]. Receptor-bound insulin is a substrate for insulin degrading enzyme, present in endosomes [15], which is considered an evolutionarily conserved protein degrading also glucagon, insulin-like growth factors I and II, ß-amyloid peptide, atrial natriuretic factor, growth-hormone-releasing factor and ß-endorphin.



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  		Fig. 1. The acidification of the endosomal lumen, due to the presence of proton pumps, results in dissociation of insulin from its receptor and the action of IDE leads to a production of multiple end-products.

 
The IDE also has regulatory functions for the activity of steroid receptors and proteasomes. Intracellular interactions of insulin with IDE may be involved in insulin control of cellular protein degradation and fat oxidation.

More than 50 years ago, Mirsky and Broh-Kahn described insulinase, or insulysin, a 110-kDa neutral thiol-metalloendopeptidase with a distinct Zn++ binding site [16] for the microelement necessary to activate its proteolytic activity. This active site consisted of the sequence -His-Xaa-Xaa-Glu-His-(HXXEH) in which the two histidines coordinate the binding of the essential zinc atom and the glutamate acts as a general base in catalysis. IDE can recognize free signal sequences suggesting that it belongs to the family of "signal peptide peptidases" [17]. Its general characteristics consists of a neutral pH optimum (6.0–8.5) with a Km for insulin of 20 nM.

IDE is considered the primary enzymatic mechanism for initiating cellular insulin processing and degradation. Thus, this proteolytic enzyme degrades insulin initially in endosomes with two or more cleavages in the ß chain. Subsequently, a reduction of the disulfide bonds by the protein disulfide isomerase (PDI), yielding an intact {alpha} chain and several ß chain fragments, which are further cleaved by multiple proteolytic systems, including lysosomes, takes place [18]. However, the internalized insulin is not entirely degraded into endosomes, this enzymatic process being dependent on insulin concentration, duration of exposure, and other factors [19].

The major part of insulin is internalized by receptor-mediated processes, although insulin can also be internalized by pinocytosis, which may represent the predominant mechanism at high insulin concentration [20]. IDE overexpression increases the rate of insulin degradation by cells [21].

The ubiquity of IDE supports the multifunctional role attributed to this protein. Kitabchi and Stentz [22], who studied the enzymatic activity of homogenates from various tissues, classified various organs in a decreasing order with their insulin degrading activity: liver, pancreas, kidney, testis, adrenal gland, spleen, ovary, lung, heart, muscle, brain and fat. In the rat, the highest levels of this enzyme were found in testis, tongue, brain, and brown adipose tissue; moderate levels were observed in kidney, prostate, heart, muscle, liver, intestine and skin and the lowest level in spleen, lung, thymus and uterus [23]. The highest levels of IDE gene expression was found in germinal epithelium suggesting an important role also in the regulation of cellular growth and differentiation.

Regarding the subcellular distribution of IDE, its major part (95%) is present in the cytosolic fraction, although a minor percentage (1% to 2%) is contained in peroxisomes, which show the highest relative concentration (i.e. enzyme per mg of protein) in the body, and in endosomes.

Ca++ plays a role in the activity of this enzyme in cells, as it has been demonstrated that Ca++-depleted muscle has decreased insulin degradation and reduced IDE activity, while Ca++ addition to muscle increases insulin degradation [24]. Insulin degradation by IDE can also be regulated by ATP [18]. A complete inhibition of insulin degradation with the addition of 5 mM of ATP to purified IDE was, in fact, demonstrated. However, the ATP inhibition does not preclude other regulatory mechanisms of insulin degradation, as protein-protein interactions or phosphorylation [25].

Several studies reported alterations of IDE activity in diabetes mellitus [11]. IDE activity was increased in type 2 diabetic patients, who were taking sulphonylureas, as well in a subgroup with well controlled diabetes mellitus, and in patients with secondary failure to oral therapy. Conversely, it was unmodified in type 1 diabetic patients in good control. In diabetic subjects the subcutaneous insulin administration is associated with alterations in insulin-degrading activity, while the intravenous insulin injection does not influence IDE activity [26]. Recently, the relationship between IDE activity and the onset and development of insulin resistance (IR) has also been investigated [27]. Increased IDE activity may be one of the mechanisms of insulin resistance in rat primary hepatocytes cultured with high concentrations of IDE.

Other enzymes involved in insulin degradation are protein disulfide isomerase (PDI), which acts after IDE cleavage of the ß chain of receptor-bound insulin, catalyzing a disulfide cleavage and leading to production of intracellular fragments of insulin with potential biological activity [28], and cathepsin D, an acidic proteinase located in lysosomes, which could be involved in the further acidic degradation of insulin [11], previously partially degraded by IDE and PDI.


   HEPATIC CLEARANCE
TOP
 ABSTRACT
 INTRODUCTION
 MOLECULAR STEPS OF CELLULAR...
 HEPATIC CLEARANCE
KIDNEY CLEARANCE
 PERIPHERAL TISSUE CLEARANCE
 CONCLUSION
 REFERENCES
 
The liver is the main site for insulin clearance, removing approximately 50% during the first portal passage [29,30], but this percentage varies widely under different conditions.

Hepatic uptake is not a static process as it is influenced by both physiological and pathophysiological factors. It is incompletely understood and involves several different systems and controls, including binding to a specific membrane receptor, internalization and intracellular compartmentalization of the insulin-receptor complex, and, finally, proteolytic degradation by a specific IDE [10].

Since most hepatic uptake is a receptor-mediated process, very high concentrations of insulin (500–2000 µU/mL) result in a decrease of its fractional uptake, although total uptake is increased [31,32]. Prolonged increases in portal insulin levels also result in reduced clearance due to receptor down regulation, as hepatic insulin extraction depends on insulin binding and degradation in proportion to a decreased receptor number [33,34]. Removal of insulin from the circulation does not imply immediate destruction of the hormone [35], because a significant amount of receptor-bound insulin is released from the cells and reenters the circulation.

Nutrients, as free fatty acids (FFA), can also alter insulin uptake [36,37]. During the postabsorbtive state, the systemic FFA entry into the circulation and their rate of uptake, particularly by adipose tissue, can be considered also as a critical determinant of plasma FFA concentration.

Plasma FFA concentration reflects a balance between release (from the intravascular lipolysis of triglyceride-rich lipoproteins and lipolysis of adipose tissue triglyceride stores) and uptake (predominantly re-esterification in adipose tissue and liver and oxidation in muscle, heart, liver, and other tissues). Fatty acid oxidation may partly mediate the effect of FFA on insulin binding by increasing the rate of insulin receptor internalization and/or decreasing the rate of receptor recycling. In addition, FFA may activate protein kinase C, which can increase insulin receptor internalization [38]. This process has also been implicated in insulin resistance induced by FFA, which would explain the association between impaired insulin extraction and sensitivity. One of the factors that may account for the impaired hepatic insulin extraction in obesity is represented by elevated circulating FFA levels which have generally been found to be elevated when examined in large, well-characterized populations of individuals with obesity, insulin-resistance syndrome and type 2 diabetes [39, 40] and which can also alter hepatic and splanchnic insulin uptake and degradation being involved in the changes occurring in type 2 diabetes [41].

Several studies in humans did not show differences in peripheral insulin levels when hyperinsulinemic euglycemic clamps were carried out with or without intralipid plus heparin infusion, which allows supranormal plasma FFA levels [42]. Studies in rats have shown that the reduction in insulin clearance, that was observed during a hyperinsulinemic clamp, was greater after seven hours than two hours of the intralipid plus heparin infusion [43]. In further studies, the impairment in hepatic insulin extraction appeared to be greater when equimolar oleate infusion was given portally vs. peripherally, through the selective elevation of the hepatic FFA levels, a condition that mimics visceral obesity [44].

Since approximately 50% of insulin secreted by the pancreas is removed on first pass by the liver before reaching the peripheral circulation, a reduction in hepatic insulin extraction would lead, in insulin-resistant states, to a substantial peripheral hyperinsulinemia caused by both insulin hypersecretion and reduced hepatic extraction of insulin [45]. The FFA-mediated reduction in hepatic insulin extraction may be viewed as an adaptive mechanism to generate peripheral hyperinsulinemia and, thus, to partially overcome the peripheral insulin resistance induced by FFA, which could relieve the stress on pancreatic ß-cells imposed by insulin resistance [46].

Also glucose ingestion increases hepatic insulin uptake, presumably through signals from the gut—since intraportal glucose infusion does not show this effect—and decreases hepatic fractional extraction [20]. Increasing doses of glucose (10g, 25g and 100g) result in insulin secretion increase (1.8 U, 2.7 U and 7.2 U) with simultaneous decreased hepatic extraction (67%, 53%, 42%). [20].


   KIDNEY CLEARANCE
TOP
 ABSTRACT
 INTRODUCTION
 MOLECULAR STEPS OF CELLULAR...
 HEPATIC CLEARANCE
 KIDNEY CLEARANCE
PERIPHERAL TISSUE CLEARANCE
 CONCLUSION
 REFERENCES
 
The kidney is the major site for insulin clearance from the systemic circulation, removing 50% of peripheral insulin, 50% of circulating proinsulin and 70% of C-peptide by glomerular filtration [47]. Insulin clearance occurs in kidney by two mechanisms: glomerular filtration and proximal tubular reabsorption and degradation [48]. After entering the tubule lumen, more than 99% of the filtered insulin is reabsorbed by proximal tubule cells, primarily by endocytosis, and relatively little insulin is ultimately excreted in urine.

The kidney also clears insulin from the postglomerular, peritubular circulation via receptor-mediated processes [49].

In general, insulin degradation by kidney cells is accomplished by the same processes as by liver; insulin is internalized into endosomes where degradation is initiated [50] and some insulin is released from the cell by retroendocytosis.

Lysosomes play a greater and earlier role in kidney insulin degradation, with most of the endosomal insulin and partially degraded insulin fragments delivered directly to lysosomes where degradation is completed; intracellular and endosomal products of insulin degradation in kidney are identical to hepatic products and consistent with the action of IDE.

Excess body weight is associated with functional and structural renal changes, such as increased glomerular filtration rate (GFR), renal plasma flow (RPF) and albumin excretion. A recent study shows that both GFR and RPF of extremely obese subjects are increased, the GFR being relatively more elevated than the RPF, resulting in an increased filtration fraction. The augmented RPF suggests a state of renal vasodilatation involving, mainly or solely, the afferent arteriole. The combination of increased arterial pressure abnormally transmitted to the glomerular capillaries through a dilated afferent arteriole is expected to cause an elevated glomerular capillary pressure, resulting in an increased transcapillary pressure gradient and an elevated GFR [51]. Insulin resistance in obese subjects is correlated with the increase of RPF, GFR, and filtration fraction.

A negative correlation between glucose disposal rate during hyperinsulinemic euglycemic clamp and filtration, i.e. a positive correlation between insulin resistance and filtration fraction, was also demonstrated in obese non-diabetic subjects with mild renal insufficiency [52]. This link could be an epiphenomenon indicative of an undetermined process occurring in the kidney of obese insulin resistant patients and not directly caused by insulin resistance.

Experimental studies have suggested a direct effect of insulin on microcirculation. In insulin-treated diabetic obese patients, kidney plays a greater role in insulin clearance than in normal subjects. Renal failure may reduce insulin requirements dramatically and increase the potential hypoglycemia in insulin treated subjects. In patients with residual ß-cell function, no exogenous insulin may be required for glucose control. Renal failure may result in hypoglycemia in insulin-secreting patients, at least partially due to reduced clearance.

Renal failure and uremia suppress cellular insulin metabolism by mechanisms not well established [53]. Muscle and hepatic insulin clearance and degradation are decreased in uremic subjects and in several studies the presence of circulating inhibitors of insulin degradation has been advocated as a possible cause. In fact, their effects persist in isolated muscle and liver preparations [54]. The presence of an altered insulin metabolism in kidney and muscle was also demonstrated in hypertension [55].


   PERIPHERAL TISSUE CLEARANCE
TOP
 ABSTRACT
 INTRODUCTION
 MOLECULAR STEPS OF CELLULAR...
 HEPATIC CLEARANCE
 KIDNEY CLEARANCE
 PERIPHERAL TISSUE CLEARANCE
CONCLUSION
 REFERENCES
 
All insulin-sensitive cells are involved in clearance and degradation of the insulin not cleared by kidney and liver. Muscle plays the major role in insulin removal with a mechanism that involves binding to its receptor, internalization, and degradation as in other tissues.

At high insulin concentration, as the hyperinsulinemic state present in obesity, the efficiency of insulin internalization was found to be impaired although the rate of insulin efflux was unaffected, with preferential processing of insulin through the non-degradative pathway [56]. It has been shown that insulin binds to its receptor with a low and high affinity with two different metabolic fates. The majority of low affinity surface binding leaves the cell surface by dissociation, while the high affinity surface binding should be largely deactivated through internalization, leading to an efficient uncoupling of insulin from its effector systems, like the adipocytes, allowing a rapid response to fluctuating levels of insulin.

Other cells involved in insulin uptake and degradation are fibroblasts, monocytes, lymphocytes and gastrointestinal cells, which contain insulin receptors and internalization and regulatory mechanisms for insulin metabolism.

A recent study suggests that insulin may be cleared and degraded extracellularly in wounds, and this degradation appears to be primarily due to IDE and may play a role in the wound-healing activity of insulin [57].


   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 MOLECULAR STEPS OF CELLULAR...
 HEPATIC CLEARANCE
 KIDNEY CLEARANCE
 PERIPHERAL TISSUE CLEARANCE
 CONCLUSION
REFERENCES
 
Insulin clearance is a process involving all tissues, not only insulin sensitive ones. Insulin degrading enzyme is an evolutionarily conserved ubiquitous protein that has been found in all tissues and with many actions including the regulation of cell growth and differentiation, and of steroid receptor and proteasomes actions. It is considered the major degradative insulin system, although other systems, like protein disulfide isomerase and lysosomal cathepsin D, are involved in insulin metabolism, which is a finely regulated process. Our attention has been focused on the liver and the kidney, as the most important organs for insulin clearance, in physiological conditions and in two major metabolic diseases, as obesity and type 2 diabetes mellitus.

Received January 22, 2003. Accepted June 6, 2003.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MOLECULAR STEPS OF CELLULAR...
 HEPATIC CLEARANCE
 KIDNEY CLEARANCE
 PERIPHERAL TISSUE CLEARANCE
 CONCLUSION
 REFERENCES
 

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