Naomi Berrie Diabetes Center, Department of Medicine, College of Physicians & Surgeons of Columbia University, New York, New York 10032
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ABSTRACT |
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The hallmarks of type 2 diabetes are
impaired insulin action in peripheral tissues and decreased pancreatic
-cell function. Classically, the two defects have been viewed as
separate entities, with insulin resistance arising primarily from
impaired insulin-dependent glucose uptake in skeletal muscle, and
-cell dysfunction arising from impaired coupling of glucose sensing
to insulin secretion. Targeted mutagenesis and transgenesis involving
components of the insulin action pathway have changed our understanding
of these phenomena. It appears that the role of insulin signaling in
the pathogenesis of type 2 diabetes has been overestimated in classic insulin target tissues, such as skeletal muscle, whereas it has been
overlooked in liver, pancreatic
-cells, and brain, which had been
thought not to be primary insulin targets. We review recent progress
and try to reconcile areas of apparent controversy surrounding insulin
signaling in skeletal muscle and pancreatic
-cells.
knockout mice; genetics; -cells; hormone receptors
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INTRODUCTION |
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THE PATHOGENESIS OF TYPE 2 DIABETES involves defects in peripheral insulin signaling and
-cell function (1). Isolated genetic defects of one
branch of the fuel-sensing mechanism can cause diabetes in rare
patients with extreme insulin resistance due to insulin receptor
(Ir) gene mutations or with "Maturity-Onset Diabetes of
the Young" (15). However, most type 2 diabetics have
combined defects in insulin production and insulin action. Thus the
question is not whether insulin resistance precedes
-cell dysfunction or whether
-cell dysfunction exacerbates insulin resistance, but rather what signaling mechanisms regulate these complex events.
Type 2 diabetes is genetically heterogeneous and multigenic (33). Experimental crosses in mice and genome-wide scans in humans are consistent with an oligogenic model in which few susceptibility alleles account for the entire genetic load of the disease. For example, mice with double heterozygous mutations of Ir and Ir substrate 1 (Irs1) develop diabetes with greater frequency than mice with single heterozygous mutations (6, 20). Likewise, the susceptibility to diabetes in Mexican-Americans who have inherited a predisposing allele on chromosome 2 is increased by having a second susceptibility allele on chromosome 15 (12).
The definition of insulin resistance has undergone significant changes
in recent years (18). In subjects with overt diabetes, insulin resistance is found in all "classic" insulin target tissues such as muscle, adipose cells, and liver. However, this should be
considered a secondary result of chronic hyperinsulinemia and glucotoxicity (14). The site of the primary defect is
unclear, as is the relationship between insulin resistance and impaired -cell function.
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WHAT IS THE ROLE OF INSULIN SIGNALING IN SKELETAL MUSCLE? |
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In humans, skeletal muscle accounts for the largest fraction of insulin-dependent glucose disposal (14). Epidemiological data indicate that resistance of skeletal muscle to insulin-dependent glucose uptake and phosphorylation is an early step in the development of type 2 diabetes (11). Several studies have analyzed the role of insulin receptor (IR) signaling in skeletal muscle by use of transgenic and knockout mice. Early work by Moller and colleagues (Chang et al., Ref. 7) employed in mice a dominant-negative IR transgene to inhibit IR function in muscle. In these mice, metabolic control was unaffected despite decreased IR signaling. Likewise, conditional knockout of Ir in skeletal muscle using the Cre/loxp system leads to impaired insulin signaling without insulin resistance (5). A dominant-negative Ir transgene, bred onto an Ir heterozygous knockout background, impairs glucose tolerance but fails to cause diabetes (27). IR signaling in muscle appears to require IR substrate-1 (IRS-1), because ablation of IRS-2 has no effect on insulin-dependent glucose uptake (17). In view of the lack of insulin resistance in mice with a complete knockout of the main insulin-responsive glucose transporter GLUT4 (19), this body of work raised the question of whether skeletal muscle is indeed as pivotal a target of insulin action as it has been thought to be.
Several observations in the past two years have clarified this apparent discrepancy. First, analysis of glucose uptake in cultures of IR-deficient myoblasts and primary muscle cultures indicated that two alternative signaling pathways compensate for the lack of IRs: insulin-like growth factor I (IGF-I) receptor (37) and contraction-activated signaling (40). The latter appears to be mediated through AMP-activated protein kinase (32). Moreover, shunting of glucose utilization from muscle to adipose tissue provides partial metabolic compensation in mice lacking IRs in muscle (22). The latter findings are consistent with data showing that simultaneous ablation of IRs in muscle and adipose tissue results in a more severe phenotype than muscle-restricted inactivation of IRs (27). In contrast, selective disruption of the insulin-sensitive glucose transporter GLUT4 in muscle results in a profound reduction of both insulin- and contraction-stimulated glucose transport, with early-onset insulin resistance and glucose intolerance (43). These studies indicate that, although the presence of compensatory mechanisms enables mice lacking muscle IRs to overcome the impairment of insulin signaling, a direct impediment to glucose uptake results in severe metabolic derangement. This explanation finds experimental support in a mouse model of combined ablation of insulin and IGF-I receptors in skeletal muscle. In this case, mice developed diabetes with metabolic changes typical of the insulin-resistant state (13).
In our attempt to reconcile these disparate data sets, we should be
mindful of two basic truths. First, some of the phenotypic variations
among these mouse models are due to the effects of genetic background
(21); second, the milder phenotype of genetic alterations
in muscle mirrors in part the different patterns of glycogen storage in
rodents and humans. Whereas hepatic glycogen content is comparable in
humans and mice, muscle glycogen content in mice is only ~10% of
human muscle glycogen content as a percentage of total body glycogen
(2). The phenotypes of mice with conditional knockouts of
Ir and Glut4 in skeletal muscle confirm that
muscle glucose disposal is central to fuel metabolism, but they
indicate that IR signaling is only one of the pathways leading to GLUT4 translocation and glucose uptake (Fig.
1).
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ROLE OF NONCANONICAL INSULIN TARGET TISSUES IN INSULIN RESISTANCE |
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It has been suggested that insulin has a direct effect on fuel metabolism in muscle and fat, whereas its effects on other organs are indirect and mediated in part by substrate fluxes (8). These findings have been challenged by the results of a combined ablation of IRs in muscle and adipose tissue (27), in which mice develop impaired glucose tolerance without diabetes, suggesting that hepatic insulin resistance is required for the onset of overt diabetes. Consistent with this prediction, mice lacking hepatic IRs develop insulin resistance and hyperglycemia, associated with increased hepatic glucose production (31). These data demonstrate that insulin exerts a direct effect on liver glucose metabolism. A broader implication of these findings is that noncanonical insulin target tissues play a central role in glucose homeostasis. Along these lines, the recent demonstration that neuronal IRs regulate food intake and reproductive function (4) represents an important paradigm shift.
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AKT AND GLUCOSE METABOLISM |
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Despite the large amount of information on mechanisms of insulin signaling, the sequence of molecular events leading to glucose transporter translocation and glucose uptake is still unknown (35). More specifically, the identity of the kinase(s) that couples activation of phosphatidylinositol (PI) 3-kinase to GLUT4 translocation remains controversial. The serine/threonine kinase Akt is a critical mediator of many insulin actions. Although biochemical evidence for the involvement of Akt in glucose metabolism is generally strong, a genetic dissection of its contribution to glucose uptake has proved hard to obtain, in part because there are three closely related isoforms. Cho et al. (9) have recently shown that mice lacking Akt2 have mild diabetes associated with defects in insulin action on liver and skeletal muscle. These data provide the first genetic evidence that Akt is indeed a physiological mediator of insulin action, although its specific role in GLUT4 translocation remains unclear.
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NEGATIVE REGULATORS OF INSULIN SENSITIVITY |
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In addition to mutations affecting insulin action, mutations in genes required to terminate or modulate insulin signaling have proved very informative in examining the pathophysiology of insulin resistance. The SH2 domain-containing inositol 5-phosphatase SHIP2 can dephosphorylate phosphoinositol, thus dampening insulin signaling. Mice lacking SHIP2 show increased insulin sensitivity, with severe neonatal hypoglycemia, decreased gluconeogenesis, and perinatal death. SHIP2 heterozygotes show improved glucose tolerance and insulin sensitivity (10). These data demonstrate both the involvement of phosphoinositides in insulin signaling and the specific role of this class of phosphatases in its negative control.
A similar, but milder, phenotype has been described in mice lacking protein-tyrosine-phosphatase-1B (PTP-1B). These mice show enhanced insulin sensitivity, increased IR phosphorylation, resistance to weight gain, and decreased insulin sensitivity when fed a high-fat diet. The evidence is consistent with a role of PTP-1B in insulin signaling through dephosphorylation of IR and IRSs (24).
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WHAT IS THE ROLE OF INSULIN SIGNALING IN PANCREATIC
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Whether as a result of autoimmune destruction or impaired
function, diabetes is inevitably associated with -cell failure. Patients with type 2 diabetes tend to have increased
-cell mass. However, they do not have sufficient
-cells to compensate for insulin resistance. We do not know with certainty what the central defect in
-cells of type 2 diabetics is. However, they show an impairment of glucose-stimulated insulin secretion, which, at least in
part, is genetically determined (34).
Classically, insulin secretion is thought to be regulated by the
products of glucose metabolism in the -cell (30).
However, the possibility that signaling through receptor tyrosine
kinases participates in insulin synthesis and release has been raised on the basis of several observations. Conditional knockout of Ir in
-cells (25) or complete knockout of
Irs1 (26) leads to defective insulin secretion
in response to glucose and amino acids. On the other hand, inactivation
of Irs2 leads to impaired
-cell growth (39),
presumably for lack of neogenesis. These data are supported by evidence
that insulin promotes its own synthesis, as well as glucokinase mRNA
transcription, through its receptor (29). Overexpression
of Akt in
-cells increases neogenesis and results in increased
-cell mass and size, without affecting insulin secretion (3,
38), whereas ablation of its substrate protein p70 S6
kinase 1 (p70s6k1) results in decreased cell size and
hypoinsulinemia (32a). In contrast, mutations of the
eukaryotic translation initiation factor 2
(eIF2
)
(36) and its kinase Perk (16) impair the
metabolic stimulus/secretion coupling and result in frank diabetes.
From these data, it appears that signaling from receptor tyrosine
kinases through PI 3-kinase regulates both
-cell proliferation and
insulin secretion. However, the two signals appear to diverge
downstream of PI 3-kinase, possibly because of the activation of
different enzyme pools (29).
Other workers have reached opposite conclusions. Inhibition of PI
3-kinase signaling has been shown to increase insulin release (41), and IGF-I has been shown to inhibit insulin
secretion from -cells (42) and perfused rat pancreas
(28).
How does insulin control its own secretion? The pancreatic portal
system is designed to provide for insulin control of glucagon secretion, but it is less clear how insulin would control its own
secretion, given that IRs on -cells are presumably exposed to high
insulin concentrations and would thus be constantly downregulated. Thus, although the idea of IR signaling controlling insulin production is teleologically attractive, in that it would provide a unifying mechanism for insulin resistance and impaired
-cell function, mechanistically it remains to be shown how this is accomplished. Our
laboratory had set much stock by the hypothesis that an accessory receptor of the insulin family (insulin receptor-related receptor, Irr) played an important role in
-cell function. In fact,
because this receptor does not bind insulin but can form
heterotetrameric receptors with insulin and IGF-I receptors, it
could provide a signaling mechanism that would be resistant to
insulin-induced receptor downregulation. However, metabolic analyses
and insulin release studies from perifused islets of Irr
knockouts have failed thus far to demonstrate a role for this receptor
in
-cell function (23).
We are far from having reached a consensus on this contentious issue.
However, a tentative conclusion is outlined in Fig. 2, showing that receptor tyrosine kinases
modulate both -cell growth and insulin secretion. The patterns
appear to diverge downstream of PI 3-kinase, but the connection between
the latter and insulin synthesis is still tenuous.
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CONCLUSIONS |
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This rapid overview of insulin signaling in transgenic and knockout mice is intended to convey the daunting challenge of untangling this complex problem. Thanks in no small measure to technical advances in manipulating the mouse genome, our understanding of the different systems that determine insulin sensitivity has been broadened substantially. As our scientific challenge grows in scope, so do the possibilities of therapeutic intervention by identifying new targets among the vast array of molecular effectors.
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ACKNOWLEDGEMENTS |
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We thank members of the Accili laboratory for helpful discussions.
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FOOTNOTES |
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Work in the authors' laboratory is supported by National Institute of Diabetes and Digestive and Kidney Diseases (DK-57539 and DK-58282), the Juvenile Diabetes Research Foundation, and the American Diabetes Association. M. Letizia Hribal is the recipient of a Berrie Fellowship.
Address for reprint requests and other correspondence: D. Accili, Berrie Research Pavilion, 1150 St. Nicholas Ave., New York, NY 10032 (E-mail: da230{at}columbia.edu).
10.1152/ajpendo.00561.2001
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