Endocrinology 2000 141: 1917-1921, doi: 10.1210/en.141.6.1917  

Dominic J. Withers and Morris White  

Type 2 DiabetesPerspective: The Insulin Signaling System—A Common Link in the Pathogenesis of

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Perspective: The Insulin Signaling System—A CommonLink in the Pathogenesis of Type 2 Diabetes

The maintenance of normal carbohydrate metabolism re-quires an intricate interplay between insulin action and in-sulin secretion. Type 2 diabetes usually results from a com-bination of peripheral insulin resistance and defects in b-cellfunction. Analysis in humans has identified specific geneticdefects associated with early-onset forms of diabetes, but acommon molecular mechanism for the majority of cases oftype 2 diabetes has yet to be identified. Recent results froma number of murine knockout and transgenic models suggestthat disruption of insulin/insulin-like growth factor (IGF)-1signaling mechanisms, and in particular, alteration in thefunction of insulin-receptor substrate (IRS) proteins, mightcontribute to defects in both peripheral insulin action andb-cell function. These studies identify a potential commonfinal pathway to explain the cellular and physiological de-fects observed in type 2 diabetes. While the exact molecularnature of such defects in humans has yet to be identified,components of the insulin/IGF signaling network and itsdownstream effector molecules are attractive therapeutic tar-gets for the rationale treatment of this disease.

Genetic and physiological studies in diverse organismsfrom humans to C. elegans provide strong evidence that theinsulin/IGF-signaling system is an evolutionarily conservedmechanism integrating fuel metabolism with growth, devel-opment, reproduction, and longevity (1). At a cellular level,insulin/IGF-signaling regulates multiple processes, includ-ing carbohydrate and lipid metabolism, gene transcription,DNA synthesis, anti-apoptosis, and cell proliferation. Insulinand insulin-like growth factors (IGF-1 and IGF-2) bind tomembers of the insulin receptor tyrosine kinase family, in-cluding the type a and b insulin receptors (IRa and IRb) andthe IGF-1 receptor (IGF1r). Insulin and IGF-1 are relativelyspecific agonists for the insulin and IGF-1 receptors, respec-tively; however, IGF-2 provides cross-talk between thesereceptors as it binds with high affinity to the IGF1r, and toIRa that predominates during fetal development (Fig. 1). Inpostnatal life, insulin is an essential metabolic signal,whereas IGF-1 and IGF-2 promote cell proliferation, differ-entiation and survival; however, as IGF-1 receptor signalspromote pancreatic b-cell survival and expansion, theIGF1/2 might play important roles in the pathogenesis oftype 2 diabetes. Whereas the conventional view asserts thatdiabetic complications arise from the deleterious effects ofchronic hyperglycemia, type 2 diabetes might be best un-derstood as a global disorder of insulin/IGF1 signal trans-duction that ultimately dysregulates gene expression and cellfunction in a wide range of tissues. The use of transgenic mice

provides surprising new insights into the pivotal role ofinsulin/IGF signal transduction mechanisms in the patho-genesis of type 2 diabetes. Understanding the molecular ba-sis of insulin/IGF signaling might provide a common mo-lecular platform to rectify abnormal insulin action andinsulin secretion.

Multisystem insulin resistance, an essential elementin diabetes

Insulin resistance is a common element in type 2 dia-betes, which is thought to have its greatest impact incertain insulin “target tissues,” including muscle, adipo-cytes, and liver; insulin resistance in muscle is frequentlycited as the culprit in type 2 diabetes (2, 3). As expected,disruption of the insulin receptor in humans and mice islethal shortly after birth, owing to extreme hyperglycemia,and other poorly characterized developmental defects (4,5). By contrast, disruption of the insulin receptor gene inspecific target tissues using the Cre-loxP system yieldsviable mice that rarely develop diabetes. Mice withoutinsulin receptors in skeletal muscle never develop diabe-tes, suggesting that insulin sensitivity in skeletal musclemight not be a primary cause of diabetes (6). However,these mice display elevated fat mass, serum triglycerides,and FFA, suggesting that insulin resistance in muscle con-tributes to the altered fat metabolism associated with type2 diabetes. Overexpression of dominant negative dysfunc-tional insulin receptors in muscle also fails to cause dia-betes, although lipid metabolism is perturbed and glucoseintolerance ensues; this approach might be more severebecause it inhibits both insulin and IGF-1 receptor function(7). Mice lacking hepatic insulin receptors also fail to de-velop diabetes, as compensatory hyperinsulinemia appar-ently maintains fasting glucose within a normal range (8);however, these mice display a complex metabolic pheno-type, including glucose intolerance and reduced serumtriglycerides and FFA.

Multisystem insulin resistance might be an essential ele-ment in the pathogenesis of type 2 diabetes, either exacer-bating usual compensatory mechanisms or directly interfer-ing with insulin secretion. Although the later possibility isgenerally ignored, the disruption of insulin receptors in pan-creatic b-cells reveals an unexpected role for insulin signal-ing during insulin secretion. Without insulin receptors, glu-cose-stimulated insulin secretion is reduced in b-cells, andglucose intolerance develops with age, although diabetesdoes not occur (9, 10). Combined insulin resistance in b-cellsand hepatic/muscle might be an important component oftype 2 diabetes. Thus, tissue specific insulin receptor dis-ruption highlights the integrated nature of insulin-regulatedmetabolism.

Received April 6, 2000.Address all correspondence and requests for reprints to: Morris F.

White, Ph.D., Howard Hughes Medical Institute, Joslin Diabetes Center,1 Joslin Place, Boston, Massachusetts 02215. E-mail: morris.white@joslin.harvard.edu.

0013-7227/00/$03.00/0 Vol. 141, No. 6Endocrinology Printed in U.S.A.Copyright © 2000 by The Endocrine Society

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The IRS-proteins coordinate the insulin signaling cascade

Recent studies on the mechanisms of insulin/IGF actionreveal common signaling pathways that are coordinatedby the insulin receptor substrate family of proteins (IRS-proteins). Members of the IRS-protein family are tyrosinephosphorylated by the receptors for insulin and IGF-1, aswell as certain cytokines receptors coupled to Janus ki-nases (11). At least four IRS-proteins occur in mammals:IRS-1 and IRS-2 are widely expressed; IRS-3 is restrictedto adipose tissue, b-cells, and possibly liver; and IRS-4 isexpressed in the thymus, brain, and kidney. Disruption ofeach IRS-proteins in mice suggests that IRS-1 and IRS-2coordinate essential effects of insulin/IGF upon periph-eral metabolism, b-cell function, reproduction, and mu-rine growth and development (9, 12, 13). By contrast, IRS-3and IRS-4 might have redundant roles in insulin/IGF ac-tion; however, in combination with IRS-1 disruption, a roleof IRS-3 in adipose function is revealed.1

IRS-proteins have a conserved amino terminus composedof adjacent pleckstrin homology and phosphotyrosine-bind-ing domains that mediate coupling to activated receptortyrosine kinases. By contrast, the COOH-terminus of eachIRS-protein contains a set of tyrosine phosphorylation sites

that act as on/off switches to recruit and regulate variousdownstream signaling proteins. Each tyrosine phosphoryla-tion site is surrounded by a unique amino acid motif thatbinds and activates specific effector proteins, including en-zymes (PI 3-kinase; a phosphotyrosine phosphatase SHP2;and Src-like kinase, fyn) and adapter proteins (Grb-2, nck,crk, and others) (Fig. 1).

IRS-proteins are an important site of signal divergence.The activation of the Erk-kinase cascade through Grb-2 bind-ing promotes gene transcription; this pathway might inhibitinsulin signals by promoting serine phosphorylation of IRS-proteins or the insulin receptor. The association of SHP2 withIRS-1 during insulin stimulation promotes phosphotyrosinedephosphorylation, which attenuates insulin signals by re-ducing the association of Grb-2 and PI 3-kinase. By contrast,activation of the type 1a PI 3-kinase during association withIRS-proteins is implicated in many biological responses toinsulin/IGF, including glucose transport, DNA synthesis,and cell survival (Fig. 1). Interaction of a tyrosine phosphor-ylated IRS-protein with both SH2 domains of the regulatorysubunit activates the associated catalytic subunit, which gen-erates various 39-phospholipids, including phosphatidylino-sitol (3, 4)bisphosphate (PI-3,4-P2) and phosphatidylinositol(3, 4, 5)triphosphate (PI-3,4,5-P3); the levels of these phos-pholipids are attenuated by the action of specific phospha-1 Kahn, C. R., et al., personal communication.

FIG. 1. The IRS-protein-dependent insulin/IGF-1 signaling cascade. The insulin/IGF family consists of three hormones: insulin, IGF-1, andIGF-2. These hormones bind three receptors: insulin receptor, IGF-1 receptor, and mannose-6-phosphate receptor (M6Pr). The insulin receptoris the primary target for insulin during development and adult life. The IGF-1 receptor is the primary target for IGF-1. IGF-2 binds to the typeA insulin receptor during embryonic development and binds the IGF-1 receptor in adults. IGF-2 also binds to the mannose-6-phosphate receptor,which targets the IGF-2 for degradation instead of signaling. Activation of the insulin receptor or the IGF-1 receptor mediates signals primarilyvia the cytoplasmic proteins IRS-1 and IRS-2, which mediate somatic cell growth and metabolism. Activation of the receptors for insulin andIGF-1 stimulate tyrosine phosphorylation of the IRS-proteins, which bind PI 3-kinase, Grb2/SOS and SHP-2, and other SH2-proteins. TheGrb2/SOS complex binds p21ras to activate the MAPK cascade (Erk1/Erk2), which phosphorylates and activates transcription factors like elk1and c-fos. The activation of PI 3-kinase by IRS-protein produces phospholipids (PI 3,4P2 and PI 3,4,5P3) which activates a variety of downstreamkinase cascades, including mTOR 3 PHAS/p70s6k/eIF43protein synthesis; PKCs/PKB3GSK3, which might promote glucose uptake andglycogen synthesis; PKB3BAD/FKHRL1, which might promote cell survival. PI 3,4,5P3 is dephosphorylated by the action of PTEN, and SHIP2converts PI 3,4,5P3 to PI 3,4P2.

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tases, including pTEN, which hydrolyzes the 39-phosphateand SHIP2 which hydrolyzes the 59-phosphate from PI-3,4,5-P3 (Fig. 1). Products of the PI 3-kinase recruit serinekinases to the plasma membrane, including the phospholip-id-dependent kinases (PDK1/2) and protein kinase B (akt/PKB) (Fig. 1). During colocalization, the PDKs phosphorylateand activate akt/PKB, which might contribute directly to theregulation of various biological responses (Fig. 1). Togetherwith other PI 3-kinase-dependent serine kinases, akt/PKBpromotes glucose transport, protein synthesis, glycogen syn-thesis, cell proliferation, and cell survival in various cells andtissues (11, 14, 15).

The regulation of PI 3-kinase by IRS-proteins is an impor-tant site of signal redundancy and diversity. In cell-basedassays, IRS-1 and IRS-3 activate PI 3-kinase more stronglythan IRS-2, whereas IRS-4 barely activates PI 3-kinase (16,17). However, in murine liver, IRS-2 appears to play a majorrole in the regulation of PI 3-kinase (12). In addition to thediversity of the IRS-proteins, the PI 3-kinase itself exists asmultiple isoforms, owing to the differential expression anddimerization of multiple regulatory subunits (p85a, p85b,p55PIK, p55a, or p50a) and catalytic subunits (p110a, p110b,or p110d). (18). Disruption in mice of p85a reveals the re-dundancy and selectivity at this important signaling step.Unexpectedly, mice lacking p85a display increased insulinsensitivity and hypoglycemia due to increased glucose trans-port in skeletal muscle and adipocytes; insulin-stimulatedPI3K activity associated with IRS-proteins is mediatedthrough p50a, which augments the generation of PI-3,4,5-P3in adipocytes. Thus, IRS-proteins and PI 3-kinase provide animportant coordinate step in the regulation of insulin sig-naling cascade.

IRS-proteins integrate growth and development

IRS-1 plays a predominant role in somatic growth as de-letion of irs1 gene in mice reduces embryonic and neonatalgrowth 40%, whereas deletion of irs2 barely reduces prenataland postnatal growth by 10%. Additionally, the size of[irs11/2irs22/2] mice is reduced 40%, whereas the size of[irs12/2irs21/2] mice is reduced 70%, confirming that IRS-1is the principal element that mediating somatic growth. IRS-2also promotes growth, but it cannot fully replace IRS-1 in thisprocess, suggesting that the signaling pathways mediated byIRS-1 and IRS-2 overlap incompletely.

IRS-proteins mediate the effects of insulin on peripheralcarbohydrate metabolism

The complete disruption of the irs-1 gene in mice causesperipheral insulin resistance with nearly normal glucosehomeostasis, owing largely to lifelong compensatory hy-perinsulinemia (13, 19, 20). By contrast, mice lacking irs-2gene develop progressive diabetes during the first 10weeks of life (12). Hepatic insulin resistance is a majorcomponent of this process, but the development of overtdiabetes results from a concomitant failure of b-celldevelopment and compensation.

IRS-1 appears to exert its greatest effect on metabolism byregulating insulin signals in muscle and adipose tissue asdemonstrated by both in vivo clamp experiments and in vitro

tissue culture studies, whereas it plays a lesser role in me-diating insulin’s effects on the liver metabolism (6, 10, 12,20–22). To compare the impact of irs1 or irs2 gene disruptionson basal and insulin-stimulated carbohydrate and lipidmetabolism in vivo, we studied 18-h fasted chronically cath-eterized mice during basal and euglycemic (;5 mm), hyper-insulinemic (5 mUzkg21zmin21) clamp (90–210 min) condi-tions. Both IRS12/2 and IRS22/2 mice are markedly insulinresistant compared with wild-type mice as reflected by theabsence of insulin on the rate of glucose appearance. Most ofthe decreased insulin responsiveness in the IRS12/2 mice isrelated to decreased insulin-stimulated peripheral glucoseuptake, whereas insulin resistance in IRS22/2 mice is attrib-uted to both decreased peripheral glucose uptake and un-suppressed hepatic gluconeogenesis (Previs, S. F., J. Ren, D.Withers, M. F. White, and G. I. Shulman, in preparation).Moreover, insulin poorly suppresses lipolysis in IRS22/2

mice. These data suggest important tissue specific roles forIRS1 and IRS2 in mediating insulin’s effects on carbohydrateand lipid metabolism in vivo, with IRS-2 being important inliver and muscle, and IRS-1 having a major role in muscle.

To further refine these observations upon the interactionsof IRS-1 and IRS-2 with insulin receptor in the regulation ofmetabolism, we created combined heterozygous mutationsfor the insulin receptor, IRS-1 and IRS-2 (23). Insulin sensi-tivity was estimated by the relative activity of PI 3-kinase inmuscle and liver extracts, and compared against the fedserum insulin levels (Fig. 2). Mice lacking one allele of eachprotein [ir/irs1/irs2]1/2 display significant hepatic andskeletal muscle insulin resistance with marked hyperinsu-linemia; serum glucose levels are only slightly elevated (Fig.2). Less drastic disruption of these signaling elements, as inir1/2, [ir/irs1]1/2 or [ir/irs2]1/2 mice, attains better insulin-stimulated activation of PI 3-kinase and normal serum glu-

FIG. 2. The relation between insulin-stimulated PI 3-kinase activityin p85 immunoprecipitates from liver or muscle or wild-type (wt)mice, or mice lacking a single allele or the insulin receptor (ir1/2), orlacking single alleles of the insulin receptor and irs-1 [ir/irs1]1/2,insulin receptor and irs-2 [ir/irs2]1/2, or all three proteins [ir/irs1/irs2]1/2. PI 3-kinase activity is measured in p85a immunoprecipitatesand reported relative to the activity in wild-type mice. Insulin levelsare determined in blood taken from ad lib fed mice between 0900 hand 1100 h; serum glucose (mg/ml) is measured in these samples andreported in parenthesis on the graph. Mice used in this experimentare 6 months old. These data were previously reported but are re-potted for purposes of this discussion (23).

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cose levels with lower insulin levels (Fig. 2). These geneticexperiments might reflect the balance between insulin se-cretion and insulin action ordinarily encountered duringcompensation for peripheral insulin resistance.

Nevertheless, less than half of the [ir/irs1/irs21/2] micedevelop diabetes at 6 months of age in spite of hyperinsu-linemia, which suggests that other genetic or environmentalfactors influence successful compensation. Diabetes is 2-foldless frequent in double heterozygous mice, either [ir/irs1]1/2

or [ir/irs2]1/2; however, the pathophysiology in each case isdifferent: [ir/irs1]1/2 mice develop severe insulin resistancein skeletal muscle and liver with b-cell hyperplasia, whereas[ir/irs2]1/2 mice display hepatic insulin resistance and mod-est b-cell hyperplasia; moreover, diabetic [ir/irs2]1/2 micegenerally display lower insulin levels than measured in [ir/irs1]1/2 mice. These studies reveal that defects in commonsignaling elements in different tissues may underlie the met-abolic phenotype in type 2 diabetes and that oligogenic in-teractions might cause this disease.

The insulin/IGF signaling system regulates b-cell function

IRS-2 plays a special role in carbohydrate metabolism asit mediates both peripheral insulin action and pancreaticb-cell function. This relation is dramatically revealed in[irs12/2/irs21/2] mice. Although very small at birth, these

lean mice are insulin-resistant and become glucose intolerantwith age, but b-cell compensation is robust and diabetesnever develops (13). By contrast, the larger [irs11/2/irs22/2]littermates fail to compensate for peripheral insulin resis-tance and die by 30 days of age with few b-cells and extremehyperglycemia. Apparently the presence of a single allele ofirs-2 promotes sufficient b-cell expansion to compensate forsevere peripheral insulin resistance, whereas IRS-1 fails. Thisstriking distinction reveals IRS-2 signaling as a rational targetin the treatments for diabetes.

To delineate the signals that activate IRS-2 pathways inb-cells, we analyzed fetal igf1r2/2 mice, or postnataligf1r1/2 and [igf1r1/2/irs22/2] mice. Islets are reduced insize in igf1r1/2 mice, and develop poorly in igf1r2/2 miceas a reduced number of a-cells and b-cell fail to form typicalislet structures. The igf1r2/2 mice die at birth, whereasigf1r6 mice survive with reduced b-cell mass, and neverdevelop diabetes; however, combined with an irs2 disrup-tion, [igf1r1/2irs22/2] mice die at 30 days of age with severehyperglycemia, owing to small islets containing a reducednumber of a-cell and nearly no b-cells. These results suggestprovisionally that IGF13 IRS2 signaling pathway might becritical for both the embryonic development and postnatalgrowth of b-cells and reveal an important interface betweenthe insulin and IGF signaling pathways.

Conclusions

In summary, the murine models described here haveproved highly informative about the role of insulin signalingmechanisms and have given new insights into the patho-genesis of the diabetic phenotype. They reveal the importantrole of insulin/IGF signaling through the IRS-proteins inboth peripheral tissues and b-cells (Fig. 3). Insulin receptorand the IRS-proteins promote both peripheral insulin actionand promote b-cell survival and glucose-sensitive insulinsecretion. Thus, failure of the IRS-protein signaling systemmight cause both insulin resistance and impaired compen-satory b-cell insulin secretion. So far, significant mutations inthese core signaling elements have not been found in type 2diabetes; however, dysregulation of diverse signaling path-ways that regulate the function of the IRS-proteins mightplay significant roles in the development of diabetes. For themoment, the interaction of the insulin and IGF-1 receptorswith the IRS-proteins provides common ground in oursearches for the causes and treatments of diabetes.

Dominic J. Withers and Morris White

Department of Metabolic Medicine (D.J.W.),Imperial College School of Medicine,Hammersmith Campus, London,W12 0NN, United KingdomandHoward Hughes Medical Institute (M.W.)Joslin Diabetes CenterHarvard Medical SchoolBoston, Massachusetts 02215

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FIG. 3. Model: The relative importance of IRS-1/IRS-2 and insulin/IGF signaling in mammalian physiology. Insulin released by theb-cells of the islets mediates metabolic signaling in peripheral targettissues such as muscle, adipose, and liver. IRS-1 is relatively moreimportant in mediating the insulin signal in muscle and adiposetissue, while IRS-2 signaling dominates in the liver. However, thesesignals are also important for b-cell function. IGF-1 receptors in thepancreatic islets might promote islet and b-cell growth and survival,especially to compensate for peripheral insulin resistance. By con-trast, insulin receptors and IRS-1 might enhance glucose stimulatedinsulin secretion.

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