In Vivo Mutagenesis of the Insulin Receptor*
Haruka Okamoto
and
Domenico Accili
¶
From the
Department of Medicine and
Institute of Human Nutrition, College of
Physicians & Surgeons of Columbia University, New York, New York
10032
 |
ABSTRACT
|
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Mice bearing targeted gene mutations that affect insulin receptor (Insr)
function have contributed important new information on the pathogenesis of
type 2 diabetes. Whereas complete Insr ablation is lethal, conditional
mutagenesis in selected tissues has more limited consequences on metabolism.
Studies of mice with tissue-specific ablation of Insr have indicated that both
canonical (e.g. muscle and adipose tissue) and noncanonical
(e.g. liver, pancreatic
-cells, and brain) insulin target
tissues can contribute to insulin resistance, albeit in a pathogenically
distinct fashion. Furthermore, experimental crosses of Insr mutants with mice
carrying mutations that affect insulin action at more distal steps of the
insulin signaling cascade have begun to unravel the genetics of type 2
diabetes. These studies are consistent with an oligogenic inheritance, in
which synergistic interactions among few alleles may account for the genetic
susceptibility to diabetes. In addition to mutant alleles conferring an
increased risk of diabetes, these studies have uncovered mutations that
protect against insulin resistance, thus providing proof-of-principle for the
notion that certain alleles may confer resistance to diabetes.
 |
INTRODUCTION
|
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Diabetes is a growing threat to public health worldwide
(1). Type 1 diabetes is caused
by autoimmune destruction of pancreatic
-cells
(2), whereas type 2 diabetes
results from insulin resistance and impaired
-cell function
(3). Insulin resistance is
found in the main insulin target tissues (muscle, adipose cells, liver) of
patients with overt diabetes. However, this is a consequence of chronic
hyperinsulinemia and glucotoxicity
(4). The question of whether
insulin resistance represents a generalized impairment of insulin action or is
initially restricted to specific organs has remained unclear, as has its
relationship to impaired
-cell function. Although insulin receptor
(Insr)1 defects are
uncommon as a cause of diabetes
(5), this gene remains an
attractive target for in vivo studies of insulin resistance, as it
has been shown to be the master switch of the metabolic
(6,
7) and growth-promoting actions
(8,
9) of insulin.
 |
Insulin Receptor Gene Knock-out
|
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Mice homozygous for null Insr alleles are born at term with slight
growth retardation (9) but
rapidly develop metabolic abnormalities, followed by diabetic ketoacidosis and
death (6,
7). The marked difference
between this phenotype and that of humans lacking INSR
(5) has been reviewed elsewhere
(10).
 |
Conditional Insr Ablation
|
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The lethal phenotype of Insr knock-out mice precludes a detailed
analysis of Insr function in different tissues in adult mice. This problem has
been circumvented by generating conditional knockouts using the
Cre/loxP binary system
(11) or combined
haploinsufficient and dominant-negative mutations
(Table I).
 |
Insulin Action in Skeletal Muscle and Insulin Resistance
|
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The cornerstone of current theories on the pathogenesis of type 2 diabetes
is that skeletal muscle, the main site of insulin-dependent glucose disposal,
is intrinsically unable to respond to insulin, either as a result of genetic
predisposition or as a consequence of environmental factors
(4). Indeed, an impairment of
insulin-dependent glucose uptake and phosphorylation is an early step in the
development of type 2 diabetes
(12). Thus, several studies
have tried to replicate this abnormality using either dominant-negative
mutations (13,
14) or conditional
inactivation of Insr (15) to
abrogate insulin signaling. When Insr was inactivated by Cre-mediated
recombination, MIRKO mice developed a metabolic syndrome with increased fat
stores, hypertriglyceridemia
(15). Nevertheless, they
failed to develop hyperinsulinemia and diabetes, in part because they are able
to shunt glucose utilization from muscle to adipose tissue
(16)
(Fig. 1). Similarly, in crosses
of mice heterozygous for a systemic Insr knock-out with transgenics
bearing a dominant-negative Insr transgene in muscle, there was a
greater than 90% decrease in Insr kinase activity and a blunting of
insulin-dependent glucose uptake but no diabetes
(14). Results in transgenics
expressing the dominant-negative transgene were inconclusive
(13).

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FIG. 1. Synopsis of conditional mutagenesis of Insr. As complete
inactivation of Insr is lethal immediately after birth, methods have been
developed to ablate Insr function in selected tissues using
Cre/loxP-mediated recombination, as well as dominant-negative
transgenes. The results of these experiments are summarized in this figure.
For each tissue, we report the salient features of the relevant Insr
knock-out. References to each knockout are provided in
Table I and throughout the
text.
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These observations are unexpected because the prediction was that impaired
insulin signaling in muscle would lead to generalized insulin resistance. The
findings stand in sharp contrast to studies showing that ablation of the
insulin-dependent glucose transporter Glut4 in skeletal muscle can cause
diabetes (17). There are
several explanations for this apparent conundrum. In mice lacking muscle Insr,
two pathways can compensate for the ablation of insulin signaling: the Igf1r
pathway (18) and the
contraction-activated pathway
(19,
20).
The importance of Igf1r in muscle metabolism is highlighted by a mouse
model of combined ablation of insulin and Igf1 receptor function in skeletal
muscle, using a dominant-negative Igf1r transgene. The mutant Igf1r
impairs Insr function through trans-dominant inhibition of the kinase activity
of heterodimers composed of an Insr monomer and a mutant Igf1r monomer. Unlike
mice with isolated Insr ablation, these mice do develop diabetes with all the
characteristic changes of the insulin-resistant state
(21).
Collectively, these data indicate that there are branching pathways leading
to glucose uptake and Glut4 translocation in skeletal muscle and that these
compensatory mechanisms enable mice lacking Insr to overcome the impairment of
insulin signaling. In contrast, when Glut4 is mutated, the impairment of
glucose transport in muscle can result in severe metabolic derangement. It
should be emphasized, however, that not all Glut4 muscle-specific knock-out
mice develop diabetes. This may be due to genetic variability among different
mice on an outbred background. Whereas these models confirm the paramount role
of skeletal muscle as a site of insulin action, they also highlight the role
of genetic modifiers in determining muscle insulin sensitivity (see
below).
 |
Adipose Tissue
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Conditional ablation of Insr in adipocytes has been used to address how
insulin signaling affects the development of the common metabolic
complications arising from obesity. When Insr was ablated in white and brown
adipocytes using a Cre transgene driven by the adipose-specific aP2 promoter
(FIRKO) (22), mice showed an
50% decrease of gonadal fat mass and whole body triglyceride content.
Moreover, FIRKO mice are resistant to gaining weight during aging or following
administration of gold-thioglucose, a hypothalamic toxin that leads to
hyperphagia and obesity in normal mice. Similarly, FIRKO mice are protected
against hyperphagia-induced glucose intolerance. These findings indicate that
insulin signaling in adipose cells is not critical for the maintenance of
euglycemia in mice but is required for triglyceride storage in adipocytes. The
observation that insulin-dependent glucose uptake is nearly absent in FIRKO
mice, whereas triglycerides are only 50% lower than normal, raises the
question as to the source of 3-glycerol phosphate to carry out triglyceride
synthesis. One potential pathway is glycolysis from insulin-independent
glucose uptake through Glut1. Another pathway, reviewed elsewhere in this
series, is glyceroneogenesis, i.e. the generation of 3-glycerol
phosphate from pyruvate, lactate, and amino acids mediated by PEPCK
(23). It is conceivable that
the absence of Insr signaling increases PEPCK activity, leading to increased
intracellular re-esterification of triglycerides as a mechanism to preserve
scarce 3-glycerol phosphate derived from glycolysis.
As with muscle, knock-out of the insulin-dependent glucose transporter
Glut4 in fat has more profound effects on glucose homeostasis than Insr
knock-out, indicating that mutations at different steps in the insulin action
cascade can differ in their impact on whole body response to insulin
(24). The metabolic changes in
FIRKO are accompanied by a redistribution of adipocyte size, in which fat pads
have a decreased content of intermediate-sized adipose cells, with an increase
of large and small cells. These data will likely contribute to rekindling the
debate regarding the complex relationship between adipocyte size and insulin
sensitivity. In addition to its role in mature adipocytes, Insr
appears to play a pivotal developmental role in adipogenesis. Targeted
Insr inactivation in 3T3-L1 cells impairs their ability to fully
differentiate into adipocytes
(25).
Another interesting phenotype associated with impaired insulin receptor
signaling in adipocytes is the increase in longevity. FIRKO mice have an
20% increase in mean, median, and maximum lifespans. These data support
the notion that a decreased fat mass can affect lifespan independently of
caloric restriction (27) and
should be viewed in the context of the life-prolonging effects of mutations
affecting insulin/Igf signaling in Caenorhabditis elegans
(2832).
Insr has been inactivated in brown adipose tissue using transgenic mice in
which the uncoupling protein-1 gene promoter was used to drive selective
ablation of the "floxed" Insr locus (BATIRKO). These mice
display an age-dependent loss of brown adipose tissue, accompanied by a
deterioration of
-cell function and a decrease of
-cell mass,
giving rise to hyperglycemia
(33). More studies are
required to examine the interaction between brown adipose tissue and
pancreatic
-cells.
 |
The Role of Non-canonical Insulin Target Tissues in Insulin
Resistance
|
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Conditional mutagenesis of Insr has been especially valuable in
addressing the controversial question of whether direct or indirect effects of
insulin are predominant in tissues other than muscle and fat. Simply put, the
question is whether insulin regulation of complex responses, such as glucose
production in the liver, appetite regulation in the brain, and gonadotropin
response in the ovary, is a direct result of the activation of Insr pathways
or is a secondary effect of insulin-induced substrate redistribution. Because
the current canon is that insulin resistance affects primarily tissues that
have the ability to respond to insulin by increasing glucose uptake, such as
muscle and adipose cells, we refer to the other target tissues of insulin as
"non-canonical."
Nowhere has this controversy been more keenly felt than in studies of
insulin regulation of hepatic glucose production. To simplify a large body of
rather complex evidence, the question is whether insulin suppression of
hepatic glucose production, the failure of which causes fasting hyperglycemia,
is mainly a result of Insr signaling in hepatocytes or of a reduced flux of
gluconeogenic precursors and free fatty acids from muscle and adipose tissue,
as well as inhibition of glucagon secretion
(34). Before we review the
work addressing the role of hepatic Insr signaling in this process, we should
emphasize that a wholesale application of these lessons to human metabolism
would be misleading, as patterns of tissue glycogen storage in rodents are
different from those found in other species. For example, in humans the amount
of glycogen per g of tissue protein in liver and muscle is comparable, whereas
in rodents hepatic glycogen is 10-fold or more abundant than muscle glycogen.
This important qualifier is all too often overlooked.
Initial evidence that the effect of insulin on hepatic glucose production
is largely a direct consequence of insulin binding to its receptor is derived
from mice in which Insr is ablated in muscle and adipose tissue, with
normal insulin signaling in the liver
(14). These mice develop
impaired glucose tolerance, do not progress to diabetes, and maintain normal
hepatic insulin sensitivity. The data provide indirect evidence that hepatic
insulin resistance is required for the onset of overt diabetes. However, they
also suggest that insulin resistance in the liver is not merely a by-product
of insulin resistance elsewhere but rather an intrinsic abnormality of insulin
signaling in hepatocytes.
This prediction found experimental support in mice with conditional,
liver-specific Insr knock-out (LIRKO). LIRKO mice exhibit marked insulin
resistance, glucose intolerance, and a failure of insulin to suppress hepatic
glucose production and to regulate hepatic gene expression
(35). In addition, the LIRKO
mouse exhibits marked hyperinsulinemia, with a 50% reduction in circulating
triglycerides and a trend toward lower free fatty acid levels. These data
indicate a critical role for hepatic Insr in regulating glucose
homeostasis, insulin clearance and hepatocyte lipid synthesis.
Although the interpretation of the LIRKO phenotype is complicated by the
onset of liver failure with age, these mice represent an important reagent for
addressing the role of hepatic insulin action in the pathogenesis of type 2
diabetes. Measurements of hepatic glucose fluxes using
hyperinsulinemic-euglycemic clamps reveal that insulin fails to suppress
gluconeogenesis in LIRKO mice, consistent with the view that Insr signaling is
required for both indirect and direct effects of insulin on the liver in mice
(36).
 |
Insr Ablation in Neurons
|
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Insr is widely expressed in several brain areas
(37). Brain Insr has been
implicated in the regulation of satiety, whereas glucose disposal occurs in an
insulin-independent manner
(38). This potential role of
Insr has been studied by generating a neuron-specific Insr knock-out
(NIRKO) using the nestin promoter. Ablation of Insr in
nestin-positive neurons results in increased food intake and moderate
diet-dependent obesity (39).
The role of brain Insr on metabolism has also been studied using
intra-cerebroventricular injections of antisense oligonucleotides and blocking
antibodies to Insr (40). This
manipulation impaired hypothalamic Insr function in rats, causing a rapid
onset of hyperphagia and an increased fat mass, similar to the NIRKO mouse. In
addition, using an insulin-clamp, the authors showed that the ability of
insulin to blunt hepatic glucose output was decreased by
50%, extending
the role of hypothalamic Insr to control of peripheral glucose disposal
(41).
In addition to its metabolic functions, brain Insr appears to regulate
gonadotropin production. In fact, NIRKO mice also develop hypogonadotropic
hypogonadism, associated with impaired maturation of ovarian follicles in
females and reduced spermatogenesis in males, leading to reduced fertility
(39).
 |
Insr Signaling and Pancreatic -Cell Function
|
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There is an ample body of literature on the role of receptor tyrosine
kinase signaling in pancreatic
-cell proliferation and insulin secretion
(42). For example, ablations
of different Irs proteins have selective effects on insulin secretion (Irs1)
(43) or
-cell
proliferation (Irs2) (44).
The effects of targeted disruption of the three receptors of the Insr
subfamily have been examined in
-cells from mice bearing either
conditional or ubiquitous mutations of the relevant genes. The Insr-related
receptor (Irr) is an orphan receptor belonging to this subfamily and is
expressed at higher levels in
-cells than either insulin or Igf1
receptors (45). Metabolic
analyses and insulin release studies from islets of Irr knock-outs
have thus far failed to demonstrate a role for this receptor in
-cell
function (46).
Insr has been inactivated in
-cells using an insulin 2
promoter-driven Cre transgene to obtain conditional recombination
(
IRKO). Lack of Insr in
-cells results in a selective impairment
of glucose-dependent insulin release and, in some mice, overt diabetes
(47). This surprising
observation raises the intriguing possibility that the two fundamental defects
in type 2 diabetes, insulin resistance and
-cell failure, share a common
pathogenesis.
Similarly, Igf1r ablation in
-cells results in impaired insulin
secretion and altered glucose tolerance, without overt diabetes
(48,
49). Interestingly, the
ultrastructure of
-cells lacking Insr or Igf1r is quite different.
Whereas Insr-deficient
-cells do not display structural abnormalities
(47), Igf1r-deficient
-cells are depleted of insulin secretory granules and enriched in Golgi
stacks (49). These data could
be construed to indicate that lack of Igf1r results in unregulated,
constitutive insulin release, consistent with the known role of IGF1 in
inhibiting insulin secretion in vivo
(50).
The role of Insr and Igf1r in the pancreas is not limited
to the endocrine function of the organ. Genetic epistasis experiments have
recently revealed a novel function for the two receptors during pancreas
development. Combined inactivation of Insr and Igf1r, but
not of either receptor alone, resulted in a severe impairment of exocrine
pancreatic development with preserved endocrine cell development
(51). Because of the known
ability of IGF2 to bind both Insr and Igf1r with equal affinity
(52), the inhibition of
pancreatic development in embryos lacking both receptors, but not either
receptor alone, indicates that exocrine pancreatic growth is dependent on
IGF2.
Notably absent from this array of phenotypes due to Insr and Igf1r ablation
in
-cells are defects in cell proliferation, which have been shown to
arise from ablation of Irs2. A simple explanation is that the two receptors
can substitute for one another in promoting
-cell growth. This
possibility will be addressed when double conditional mutants lacking both
Insr and Igf1r are studied. Alternatively, it is possible that Irs2 mediates
the actions of additional receptors in promoting
-cell proliferation. We
have proposed that insulin/IGF signaling is important for proliferation and/or
terminal differentiation of the elusive
-cell progenitor, presumably
arising from cells embedded within pancreatic ducts
(53).
 |
Modeling the Genetics of Type 2 Diabetes in Insr Mutant Mice
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We have also used the Insr heterozygous mutants to mimic genetic
interactions leading to type 2 diabetes
(54). A first step in this
direction was the development of a polygenic model of insulin-resistant
diabetes by generating mice with combined heterozygous Insr and
Irs1 mutations. Whereas Irs1 heterozygotes are normal,
double heterozygous mice for both Insr- and Irs1-null
alleles develop severe hyperinsulinemia and hyperplasia of pancreatic
-cells, and by 46 months of age, nearly one-half of these mice
become frankly hyperglycemic. This process closely resembles the pathogenesis
of human diabetes (55,
56). Thus, even a major
predisposing allele, such as the null Insr mutation, has a modest
effect by itself but plays a major role in the context of a predisposing
background. This is confirmed by the observation that, when the double
heterozygous knock-out mice are bred onto different genetic backgrounds, the
prevalence of diabetes can vary from <2% to 85%
(57).2
The risk of the recurrence of diabetes in double heterozygous offspring
(Insr/Irs1+/) of
single heterozygous Insr parents increases 4-fold, similar to the
excess risk of diabetes in first degree relatives of humans with diabetes
(58,
59). The findings in the
Insr/Irs-1+/ mouse
are consistent with an oligogenic mode of inheritance of type 2 diabetes, in
which two subclinical defects of gene function can account for virtually the
entire genetic susceptibility to the disease.
Whereas combined mutations of Insr and Irs1 have provided
insight into the polygenic nature of type 2 diabetes, comparisons of double
mutant mice with Insr/Irs1- or
Insr/Irs2-null alleles provide an illustration of genetic
heterogeneity, i.e. of the ability of different mutant loci to give
rise to similar phenotypes. Insr/Irs1 and
Insr/Irs2 double mutant mice develop diabetes with similar
frequencies. However, Insr/Irs1 mice are primarily
insulin-resistant in skeletal muscle, whereas the Insr/Irs2
are primarily insulin-resistant in liver
(55). These data indicate that
different insulin receptor substrates play tissue-specific roles, with Irs1
being the primary mediator of insulin action in muscle and Irs2 in liver
(60).
Not every mutation in the insulin signaling pathway is detrimental. For
example, mutations of the regulatory p85 subunit of PI 3-kinase increase
insulin sensitivity (61,
62), and heterozygous
p85 mutations protect from insulin resistance and diabetes caused by
either Insr or Irs1 mutations by improving the efficiency of
insulin signaling (63).
Increased insulin sensitivity and resistance to diet-induced metabolic
abnormalities is also observed in mice lacking the tyrosine phosphatase Ptp1b
(64).
Likewise, haploinsufficiency for the forkhead transcription factor
Foxo1 restores insulin sensitivity and prevents diabetes in
Insr+/ mice by decreasing
expression of glucogenetic genes in liver, improving
-cell compensation,
and decreasing adipocyte size
(65). Foxo1 was identified as
a potential negative regulator of insulin signaling based on studies in C.
elegans (66). Indeed,
transgenic mice expressing gain-of-function Foxo1 mutants are
diabetic and insulin-resistant
(65). Foxo1 appears to play a
widespread role in the transcriptional response to insulin. Its targets
include glucose-6-phosphatase, Pepck
(67), Pdx1
(53), and the cell cycle
control gene p21 during adipocyte differentiation
(68).
 |
Conclusions
|
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As we have pointed out in a recent publication
(69), the contribution of Insr
signaling to metabolic control appears to have been overestimated in canonical
insulin target tissues, such as muscle and fat, and underestimated in
non-canonical target tissues, such as liver, brain, and pancreatic
-cells. The findings in Insr mutant mice provide a better understanding
of the protean manifestations of insulin resistance, expand the repertoire of
potential targets for drug development, and suggest that treatments to improve
insulin resistance should selectively modulate specific insulin responses in
different tissues.
 |
FOOTNOTES
|
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* This minireview will be reprinted in the 2003 Minireview Compendium, which
will be available in January, 2004. This work was supported by National
Institutes of Health Grants DK57539 and DK58282, Juvenile Diabetes Research
Foundation Grant 893, and the American Diabetes Association. This is the first
article of six in the "New Animal Models for Study of Metabolism"
Minireview Series. 
¶
To whom correspondence should be addressed: Berrie Research Pavilion, 1150 St.
Nicholas Ave., New York, NY 10032. Tel.: 212-851-5332; Fax: 212-851-5331;
E-mail:
da230{at}columbia.edu.
1 The abbreviations used are: Insr, insulin receptor; Igf1r, type 1 IGF
receptor; IGF, insulin-like growth factor; Irr, insulin receptor-related
receptor; Irs, insulin receptor substrate; PI 3-kinase, phosphatidylinositol
3-kinase; PEPCK, phosphoenolpyruvate carboxykinase; MIRKO, muscle-specific
insulin receptor knock-out; FIRKO, fat-specific insulin receptor knock-out;
IRKO,
cell-specific insulin receptor knock-out; BATIRKO, brown
adipose tissue-specific insulin receptor knock-out. 
2 C. R. Kahn, personal communication. 
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ACKNOWLEDGMENTS
|
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We thank members of the Accili laboratory for critical reading of the
manuscript.
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