Increased Hepatic Levels of the Insulin Receptor Inhibitor, PC-1/NPP1, Induce Insulin Resistance and Glucose Intolerance
Hengjiang Dong1,
Betty A. Maddux2,
Jennifer Altomonte1,
Marcia Meseck1,
Domenico Accili3,
Robert Terkeltaub4,
Kristen Johnson4,
Jack F. Youngren2, and
Ira D. Goldfine2
1 Department of Gene Therapy and Molecular Medicine, Mount Sinai School of Medicine, New York, New York
2 Department of Medicine and Diabetes Center, University of California San Francisco, San Francisco, California
3 Russ Berrie Pavilion, Columbia University, New York, New York
4 Veterans Administration Medical Center, University of California San Diego, San Diego, California
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ABSTRACT
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The ectoenzyme, plasma cell membrane glycoprotein-1 (PC-1), is an insulin receptor (IR) inhibitor that is elevated in cells and tissues of insulin-resistant humans. However, the effects of PC-1 overexpression on insulin action have not been studied in animal models. To produce mice with overexpression of PC-1 in liver, a key glucose regulatory organ in this species, we injected them with a PC-1 adenovirus vector that expresses human PC-1. Compared with controls, these mice had two- to threefold elevations of PC-1 content in liver but no changes in other tissues such as skeletal muscle. In liver of PC-1 animals, insulin-stimulated IR tyrosine kinase and Akt/protein kinase B activation were both decreased. In this tissue, the IR-dependent nuclear factor Foxo1 was increased along with two key gluconeogenic enzymes, glucose-6-phosphatase and phosphenolpyruvate carboxykinase. The PC-1 animals had 3040 mg/dl higher glucose levels and twofold higher insulin levels. During glucose tolerance tests, these animals had peak glucose levels that were >100 mg/dl higher than those of controls. These in vivo data support the concept, therefore, that PC-1 plays a role in insulin resistance and suggest that animals with overexpression of human PC-1 in liver may be interesting models to investigate this pathological process.
Insulin resistance is a clinical abnormality that may affect >25% of the population of the U.S. and other countries (1,2). Insulin resistance is also a major contributor to both type 2 diabetes and the metabolic syndrome, which is a cluster of abnormalities that includes hypertension, dyslipidemia, and coronary artery disease (1,2). It has been proposed (3) that insulin resistance may result from multiple causes that include genetic and acquired influences. In most insulin-resistant individuals, however, the molecular cause(s) of insulin resistance are either unknown and/or unproven (3). Thus, specific therapy to treat this condition is not available.
One candidate molecule to cause insulin resistance is the ectoenzyme, plasma cell membrane glycoprotein-1 (PC-1/NPP1), a nucleotide pyrophosphatase-phosphodiesterase (NPP) that scavenges ATP under physiologic conditions (4). In insulin-resistant subjects, PC-1 is elevated in both tissues and fibroblasts (59). In addition, overexpression of PC-1 in cultured cells reduces both insulin-stimulated insulin receptor (IR) activation and downstream signaling (10). PC-1 binds to the IR but does not block insulin binding (5,11). Rather, PC-1 inhibits the insulin-induced conformational changes that lead to IR autophosphorylation and tyrosine kinase activation (11). Although these data suggest that PC-1 is involved in insulin resistance, a complete understanding of the role of PC-1 in this pathological process has been hampered by the lack of a convenient animal model of PC-1 overexpression.
In most mammals, the hormone insulin via the IR regulates fasting and postprandial glucose levels. In humans, during fasting, insulin and other hormones play a major role in regulating glucose levels by controlling hepatic gluconeogenesis (1,2). In humans, during the postprandial state, glucose levels are also regulated to a large extent by insulin-mediated glucose uptake into skeletal muscle (1,2). In rodents, however, hepatic regulation of glucose metabolism is important for both fasting and postprandial glucose regulation (12). In mice, for example, gene knockout of the IR in muscle is virtually without effect on insulin sensitivity (13,14), whereas IR gene knockout in liver leads to insulin resistance (15). Therefore, to investigate candidates for insulin resistance in this species, the liver must be targeted (1315).
Herein, to investigate the effect of increased levels of PC-1 on glucose metabolism in mice, we employed an adenoviral-mediated gene delivery system to transfer human PC-1 cDNA into the liver of adult mice (16). This approach results in the infection and transduction of the majority of hepatocytes in the liver. There is little infection of cells in extrahepatic tissues, including muscle, adipose, spleen, pancreas, and kidney (17). Compared with mice transfected with a control (empty viral vector), animals with increased PC-1 had hyperglycemia, hyperinsulinemia, impaired glucose tolerance, and the increased expression of key hepatic gluconeogenic enzymes. These results indicate, therefore, that PC-1 plays a role in the insulin resistance of type 2 diabetes.
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RESEARCH DESIGN AND METHODS
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Adenovirus PC-1.
The wild-type, full-length human PC-1 K allele was subcloned into pACCMVpLpA (which contains the genomic sequence of the replication-defective E1 mutant of adenovirus 5 and the SV 40 poly A tail) as previously described (16). Adenoviral vectors were produced in HEK293 cells and purified as described (18). The titer of the PC-1 vector is 2.5 x 1012 viral particles/ml (9.8 x 1010 pfu/ml). The control vector devoid of the PC-1 cDNA (empty vector) has a titer of 2.4 x 1012 viral particles/ml (8.8 x 1010 pfu/ml).
Hepatic PC-1 gene transfer.
Male C57 BL/6J mice were obtained from The Jackson Laboratory (Bar Harbor, ME) and fed with standard rodent diet and water ad libitum in a barrier animal facility with a 12-h light/dark cycle. Before treatment, animals were stratified by body weight and randomly assigned to two groups (n = 7 per group) to ensure a similar mean body weight (10 weeks old, 25.4 ± 1.7 g) among groups. The two groups of mice were treated with intravenous administration of 3 x 1012 viral particles/kg of the PC-1 vector or an equivalent dose of the control vector without PC-1 (empty vector), respectively. This vector dose has previously been defined to result in
70% transduction of hepatocytes in the liver by adenovirus following intravenous injection (17,18). Animals were killed following 1 week after PC-1 adenovirus treatment, and the liver tissue was collected for PC-1 analysis (see below) and preparation of total hepatic RNA.
Glucose tolerance test.
Mice were fasted for 5 h, followed by an intraperitoneal injection dose of glucose (3 g/kg body wt). Blood glucose levels were determined both before and at different times after the glucose.
Insulin tolerance test.
Fed mice were given an intraperitoneal injection of insulin (0.5 units/kg body wt). Blood glucose levels were determined both before and at different times after the injection.
PCR.
Real-time quantitative RT-PCR assay was employed to quantify the relative abundance of mRNA for the following enzymes: phosphenolpyruvate carboxykinase (Pck1), glucose-6-phosphatase (G6pc), glucokinase, and the forkhead transcription factor Foxo1. ß-Actin mRNA was used as an internal standard as described (18).
Tissue preparation.
Mouse tissue was pulverized under liquid nitrogen, and the resultant powder was homogenized in a polytron homogenizer (Kinematica, Lucerne, Switzerland) for 10 s. Homogenates were then centrifuged at 100,000g, solubilized for 1 h at 4 °C, then recentrifuged at 100,000g for 1 h (9).
Thymididne-5'-monophosphate-p-nitrophenyl ester assay.
Alkaline phosphodiesterase I activity was assayed by the hydrolysis of thymididne-5'-monophosphate-p-nitrophenyl ester (PNTP; Sigma) as previously described (9).
Western blot for PC-1.
Direct analysis of human and mouse PC-1 was as follows: 100 µg protein from each sample was treated with PAGEprep (Pierce Chemicals) and boiled in the presence of 5% ß-mercaptoethanol. Proteins were resolved on a 412% Tris-glycine gel (Cambrex) and transferred to nitrocellulose. Blots were blocked in SuperBlock (Pierce Chemicals) and then incubated with antiPC-1 antibody (gift from Dr. Scott Hickman) that recognizes both human and rodent PC-1. After washing, blots were incubated with anti-rabbit horseradish peroxidase. Signal was developed by using SuperSignal reagent (Pierce Chemicals).
Immunoprecipitation and analysis of human PC-1.
A total of 100 µg protein was precleared with protein A Sepharose, and affinity-purified antiPC-1 (human specific) was added. The precipitates were analyzed by Western blot as above using human-specific PC-1 antibody.
PC-1 enzyme-linked immunosorbent assay.
Human PC-1 was measured as described (16). This PC-1 enzyme-linked immunosorbent assay (ELISA) is specific to human PC-1 with no significant cross-reactivity with mouse PC-1.
IR autophosphorylation and Akt/protein kinase B phosphorylation.
Western blots of IR autophosphorylation and Akt/protein kinase B (PKB) phosphorylation were measured in immunoprecipitates as described by Michael et al. (15). IR autophosphorylation in liver particles was measured by ELISA as described (11). Incubation conditions were as follows: 10 µmol/l ATP, 150 mmol/l NaCl, 2 mmol/l MnCl2, 10 mmol/l MgCl2, 50 mmol/l TRIS pH 7.4, and 50 µg/ml membrane protein. Insulin was measured using an insulin ELISA kit from Crystalchem.
Statistics.
Statistical analyses of data were performed by ANOVA using StatView software (Abacus Concepts, Piscataway, NJ). An unpaired ANOVA t test was conducted to study statistical significance between PC-1 and control vector treatment groups. Data were expressed as means ± SE. P values < 0.05 were considered significant.
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RESULTS
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Increased PC-1 expression in liver.
After PC-1 adenovirus administration, we employed several distinct approaches to document the expression and function of PC-1 in mouse liver (Fig. 1). Since PC-1 has phosphodiesterase activity, the protein is able to hydrolyze the substrate PNTP (9) (the enzyme activity of PC-1, however, is not necessary for its inhibition of the IR [10]). In PC-1 adenovirustreated mice, PNTP hydrolysis was over twofold greater than control animals treated with empty vector (Fig. 1A). To determine whether this activity was due to expression of human PC-1, we performed two types of experiments. First, we evaluated PC-1 content by human-specific PC-1 ELISA (Fig. 1B). Human PC-1 was detected in PC-1 adenovirustreated animals but not in controls. Second, we carried out two types of Western blots. Initially, we probed a solubilized, particulate fraction of liver with an antibody that recognizes both mouse and human PC-1 (Fig. 1C). Mouse PC-1 monomer has a molecular size of 120 kDa and was detected in livers from both PC-1 adenovirus animals and controls. In contrast, human PC-1 monomer, which has a molecular size of 130 kDa, was detected in the livers of only the PC-1 adenovirustreated animals. Next we employed a species-specific antibody that recognized only human PC-1. Human PC-1 was only detected in the PC-1 adenovirustreated animals (Fig. 1D).

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FIG. 1. Analysis of human PC-1 in liver. In these studies, seven PC-1 adenovirustreated animals and seven empty virus controls were studied 1 week after infection. Livers were removed, and a solubilized high-speed membrane fraction was prepared (9). A: PC-1 activity was measured using the substrate PNTP. Results are means ± SE (P < 0.01). B: Human PC-1specific ELISA. C: Western blot in liver fractions of human (h) and mouse (m) PC-1 using an antibody that recognizes both proteins. Standards were prepared from cultured cells transfected with either human or mouse PC-1. D: Western blot of human PC-1 expression in liver using an antibody specific to human PC-1.
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Reduced IR function and signaling in liver.
In view of the fact that PC-1 inhibits IR autophosphorylation (5), we studied insulin activation of this function and the downstream mediator of IR signaling, Akt/PKB, in liver from adenovirus PC-1 animals in the fed state (see below). Western blots revealed that the PC-1 mice had decreased tyrosine autophosphorylation of the IR and decreased serine phosphorylation of Akt/PKB (Fig. 2A). Next, we studied the activity of the IR in vitro by employing liver particles. Both basal and insulin-stimulated IR autophosphorylation were significantly decreased by 2535% in liver from the PC-1 mice (Fig. 2B).

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FIG. 2. Insulin receptor signaling in liver. A: Effect of PC-1 expression on IR autophosphorylation in vivo. Liver fractions were obtained from four fed animals and immunoprecipitated with antibodies to either the IR or Akt/PKB, normalized to equal amounts of protein, and Western blotted against an antibody to phosphotyrosine. B: Effect of PC-1 expression on IR autophosphorylation in vitro. Liver fractions from the animals in Fig. 1 were incubated with insulin, ATP, and metals and IR autophosphorylation measured.
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Key gluconeogenic enzymes are elevated in liver.
In view of the decreased IR signaling in liver, we measured the expression of two key enzymes: Pck1 and G6pc by quantitative PCR. Both are negatively regulated by insulin at the transcriptional level (18). In mice with elevated hepatic levels of PC-1, the levels of Pck1 and G6pc were twofold higher than in controls (Fig. 3A and B). In contrast, the hepatic enzyme glucokinase, which is not regulated by insulin, was unchanged in the animals with elevated PC-1 (Fig. 3C). These observations indicate that the livers of these animals were resistant to suppression of G6pc and Pck1 expression by insulin and are in concert with the observation that insulin-induced IR autophosphorylation was decreased.

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FIG. 3. Analysis of liver enzymes by RT-PCR. mRNAs for four hepatic enzymes were measured in fed animals 7 days after infection. A: Pck1. B: G6pc. C: Glucokinase. D: Foxo1. Except for glucokinase, the differences between PC-1 adenovirus and empty adenovirus were significant (P < 0.01 for Pck1 and G6Pase and P < 0.05 for Foxo1). Data are expressed relative to ß-actin.
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It is now recognized that forkhead transcription factor, Foxo1, mediates the negative transcriptional effects on G6pc and Pck1 by the IR (18,19). The activation of the IR by insulin leads to activation of the serine kinase Akt/PKB. Akt/PKB reduces both Foxo1 content and its presence in the nucleus. Accordingly, Foxo1 expression was measured (Fig. 3D). In mice with elevated hepatic expression of PC-1, we observed that the expression of this nuclear regulatory factor was significantly increased, indicating that this tissue was resistant to the effect of insulin on function.
PC-1 mice have elevated glucose and insulin levels and abnormal glucose tolerance.
Next, we characterized the metabolic status of mice with elevated levels of PC-1 in liver. In the fed state, mice with increased hepatic PC-1 showed glucose levels that were 3040 mg/dl higher than those of controls (Fig. 4A). Moreover, they had an over twofold increase in insulin levels, indicating that they were resistant to the action of insulin (Fig. 4B). To study the mechanisms through which elevated PC-1 levels in liver induced insulin resistance, we performed glucose tolerance tests. Because the liver is the primary site of glucose regulation in rodents (12,15) and in view of elevated content of hepatic PC-1 with decreased IR autophosphorylation, we predicted that these mice would be glucose intolerant. Indeed, during glucose tolerance tests, glucose levels were significantly higher in mice with increased hepatic PC-1 at all time points (Fig. 4C). At 30 min after glucose administration, the glucose levels were >100 mg/dl higher in the animals with elevated PC-1; at 2 h, there was still an elevation in this function.


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FIG. 4. Metabolic effects of increased PC-1 levels. A and B: Serum was obtained from fed animals 7 days after infection, and glucose and insulin were measured. The differences in these parameters between PC-1 adenovirus and control animals were significant (insulin and glucose levels P < 0.01). C: In fasting mice, glucose tolerance tests were performed in groups of animals at 3 and 5 days after infection, and the same results were obtained on both days. Data from day 5 are shown. Differences in glucose levels were significant at 30, 60, 90, and 120 min (P < 0.05 or 0.01).
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Studies in skeletal muscle and heart.
As mentioned above, in contrast to humans, most rodent models of muscle insulin resistance are not glucose intolerant, reflecting major species-specific differences (12). In contrast to liver, in skeletal muscle and heart, there was no evidence for increased PC-1 activity as evidenced by PNTP hydrolysis (Fig. 5), PC-1 ELISA (<1 ng/mg protein), and Western blot (data not shown). Moreover, IR autophosphorylation was not altered in these tissues (data not shown). Because muscle is the major tissue for glucose disposal in response to insulin, we predicted that insulin tolerance tests would be normal in these animals. Indeed, when these tests were performed, there was no difference between PC-1 and control mice (Fig. 6).

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FIG. 5. Analysis of human PC-1 activity in heart and skeletal muscle. In these studies, seven PC-1 adenovirustreated animals and seven empty virus controls were studied 1 week after infection. Skeletal muscle and heart were removed, and a solubilized high-speed membrane fraction was prepared (9). PNTP activity was measured. In both tissues, no significant changes were observed between PC-1 and control animals.
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FIG. 6. Insulin tolerance tests. Tests were performed 7 days after infection in fed animals. Data are expressed as the percent of the control glucose values shown in Fig. 4. Differences in glucose levels were not significant at any time point.
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DISCUSSION
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In humans, there is considerable evidence linking insulin resistance with PC-1. PC-1 is elevated two- to threefold in muscle and adipose tissue of insulin-resistant humans (7,9,20). These two key tissues for regulating insulin-mediated glucose metabolism are resistant to insulin action in humans with type 2 diabetes (2). Moreover, PC-1 is elevated in cultured fibroblasts from many insulin-resistant subjects (5,6,8). This observation indicates that there may be a genetic or intrinsic overexpression of this protein in certain insulin-resistant subjects. There are two alleles of PC-1, the common arginine-encoding (K) allele at amino acid 121 and the less-common glutamine-encoding (Q) allele at this site (21). The latter binds to the IR with higher affinity than the K allele and is more potent in inhibiting IR autophosphorylation. Moreover, in some ethnic populations, the Q allele is strongly associated with insulin resistance (21). The PC-1 gene is at locus 6q2223. Duggirala et al. (22), studying Hispanic families in San Antonio, Texas, have found linkage with the q2223 locus and insulin resistance. Also, in a genome-wide scan, Meyre et al. (23) have found linkage between 6q22.31-q23.2 and childhood obesity traits and insulin resistance.
The present study indicates that modest (two- to threefold) overexpression of human PC-1 in mouse liver by adenovirus infection leads to insulin resistance in this tissue. IR autophosphorylation and downstream signaling were impaired, as was glucose tolerance. There was no detectable human PC-1 expression in muscle, and IR signaling was not affected in this tissue. A comparison of these data and the IR knockout data in liver and muscle (24) are of interest. In the liver knockout mice, like the mice studied herein, the glucose tolerance test was impaired. Since the impairment of the IR in the adenovirus PC-1 mice was much less severe than in the knockout mice, these data suggest that this function is very sensitive to the status of the liver IR. In the liver knockout, but not in the animals studied herein, there was also impairment of the insulin tolerance test. There are several possible explanations for these seemingly discordant observations. In contrast to the PC-1 adenovirus animals, the knockout animals have the lesion from very early in development. Also, the impairment of the liver IR signaling pathway in the knockout animals is much greater than with the PC-1 adenovirus animals. Thus, in the liver knockout animals, it is likely that other unrecognized factors (i.e., developmental or compensatory) may be present leading to the loss of muscle function.
Although there is considerable evidence that PC-1 may contribute to insulin resistance, a major drawback in investigating the role of PC-1 has been the lack of convenient animal models for studying the effects of elevated PC-1 content on insulin and glucose economy. The obese, insulin-resistant rhesus monkey has elevated PC-1 levels in muscle that correlate with insulin resistance (25), but it is not an animal that can be easily investigated. For two reasons, therefore, the present studies with mice having elevated liver content of PC-1 are important. First, they support the concept that PC-1 plays a role in clinical insulin resistance. Second, they present an animal model in which agents that antagonize PC-1 can be tested. Thus, with these and similar types of engineered animals having PC-1 overexpression, it should be feasible to test the effects of antiPC-1 agents, such as small molecules (26) and antibodies (11), on impaired insulin action in vivo. Thus, an in vivo approach may have the potential to lead to the development of new agents for the treatment of clinical insulin resistance.
PC-1 is a class II transmembrane protein that is expressed in most cell types and is a member of the NPP family (4,27). These members include PD-1
(autotaxin) and PD-1ß (gp103RB). PC-1 is the same protein as liver nucleotide pyrophosphatase-alkaline phosphodiesterase. PC-1 exists as a disulfide-linked homodimer of 230260 kDa; the reduced form of the protein has a molecular size of 114135 kDa, depending on the cell type and species. The physiological role of PC-1 is not completely defined, but there is evidence in bone and cartilage metabolism that PC-1 scavenges ATP and in doing so produces inorganic pyrophosphate (28). Pyrophosphate modulates pathologic calcification (28). Humans without PC-1 are severely ill, with abnormal bone deposition in the aorta and some periarticular tissues (29,30). Conversely, cartilage PC-1 expression and NPP activity become markedly upregulated in association with the aging-associated cartilage degenerative disorders osteoarthritis and chondrocalcinosis, where PC-1 overactivity appears to be part of an adaptive response to chondrocyte ATP depletion (31).
In conclusion, we have developed a mouse model of modest liver overexpression of the IR inhibitor PC-1. These animals are insulin resistant and glucose intolerant, mimicking early type 2 diabetes. Since PC-1 overexpression is common in humans with insulin resistance, our results suggest that PC-1 dysregulation is one cause of human insulin resistance. It should be pointed out, however, that given the major differences in the metabolism of glucose and insulin between mice and humans as stated above, further studies of PC-1 overexpression in muscle will be needed to support this hypothesis.
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ACKNOWLEDGMENTS
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This work is supported in part by National Institutes of Health Grants DK59892 (to H.D.) and DK56933 (to I.D.G.).
Address correspondence and reprint requests to Ira D. Goldfine, University of California San Francisco, Department of Medicine, Box 1616, MZ, San Francisco, CA 94143-1616. E-mail: idg43{at}itsa.ucsf.edu
Received for publication September 3, 2004
and accepted in revised form November 4, 2004
ELISA, enzyme-linked immunosorbent assay; IR, insulin receptor; NPP, nucleotide pyrophosphatase-phosphodiesterase; PC-1, plasma cell membrane glycoprotein-1; PNTP, thymididne-5'-monophosphate-p-nitrophenyl ester; Pck1, phosphenolpyruvate carboxykinase; PKB, protein kinase B; G6pc, glucose-6-phosphatase
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REFERENCES
|
---|
- Reaven GM: Banting lecture 1988: Role of insulin resistance in human disease.
Diabetes37
:1595
1607,1988[Abstract]
- DeFronzo RA: Lilly lecture 1987: The triumvirate: beta-cell, muscle, liver: a collusion responsible for NIDDM.
Diabetes37
:667
687,1988[Medline]
- Saltiel AR, Kahn CR: Insulin signalling and the regulation of glucose and lipid metabolism.
Nature414
:799
806,2001[Medline]
- Goding JW, Terkeltaub R, Maurice M, Deterre P, Sali A, Belli SI: Ecto-phosphodiesterase/pyrophosphatase of lymphocytes and non-lymphoid cells: structure and function of the PC-1 family.
Immunol Rev161
:11
26,1998[Medline]
- Maddux BA, Sbraccia P, Kumakura S, Sasson S, Youngren J, Fisher A, Spencer S, Grupe A, Henzel W, Stewart TA, et al.: Membrane glycoprotein PC-1 and insulin resistance in non-insulin-dependent diabetes mellitus.
Nature373
:448
451,1995[Medline]
- Frittitta L, Spampinato D, Solini A, Nosadini R, Goldfine ID, Vigneri R, Trischitta V: Elevated PC-1 content in cultured skin fibroblasts correlates with decreased in vivo and in vitro insulin action in nondiabetic subjects: evidence that PC-1 may be an intrinsic factor in impaired insulin receptor signaling.
Diabetes47
:1095
1100,1998[Abstract]
- Frittitta L, Youngren J, Vigneri R, Maddux BA, Trischitta V, Goldfine ID: PC-1 content in skeletal muscle of non-obese, non-diabetic subjects: relationship to insulin receptor tyrosine kinase and whole body insulin sensitivity.
Diabetologia39
:1190
1195,1996[Medline]
- Teno S, Kanno H, Oga S, Kumakura S, Kanamuro R, Iwamoto Y: Increased activity of membrane glycoprotein PC-1 in the fibroblasts from non-insulin-dependent diabetes mellitus patients with insulin resistance.
Diabetes Res Clin Pract45
:25
30,1999[Medline]
- Youngren JF, Maddux BA, Sasson S, Sbraccia P, Tapscott EB, Swanson MS, Dohm GL, Goldfine ID: Skeletal muscle content of membrane glycoprotein PC-1 in obesity: relationship to muscle glucose transport.
Diabetes45
:1324
1328,1996[Abstract]
- Grupe A, Alleman J, Goldfine ID, Sadick M, Stewart TA: Inhibition of insulin receptor phosphorylation by PC-1 is not mediated by the hydrolysis of adenosine triphosphate or the generation of adenosine.
J Biol Chem270
:22085
22088,1995[Abstract/Free Full Text]
- Maddux BA, Goldfine ID: Membrane glycoprotein PC-1 inhibition of insulin receptor function occurs via direct interaction with the receptor
-subunit.
Diabetes49
:13
19,2000[Abstract]
- Hribal ML, Oriente F, Accili D: Mouse models of insulin resistance (Review).
Am J Physiol Endocrinol Metab282
:E977
E981,2002[Abstract/Free Full Text]
- Bruning JC, Michael MD, Winnay JN, Hayashi T, Horsch D, Accili D, Goodyear LJ, Kahn CR: A muscle-specific insulin receptor knockout exhibits features of the metabolic syndrome of NIDDM without altering glucose tolerance.
Mol Cell2
:559
569,1998[Medline]
- Lauro D, Kido Y, Castle AL, Zarnowski MJ, Hayashi H, Ebina Y, Accili D: Impaired glucose tolerance in mice with a targeted impairment of insulin action in muscle and adipose tissue.
Nat Genet20
:294
298,1998[Medline]
- Michael MD, Kulkarni RN, Postic C, Previs SF, Shulman GI, Magnuson MA, Kahn CR: Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction.
Mol Cell6
:87
97,2000[Medline]
- Johnson K, Vaingankar S, Chen Y, Moffa A, Goldring MB, Sano K, Jin-Hua P, Sali A, Goding J, Terkeltaub R: Differential mechanisms of inorganic pyrophosphate production by plasma cell membrane glycoprotein-1 and B10 in chondrocytes.
Arthritis Rheum42
:1986
1997,1999[Medline]
- Huard J, Lochmuller H, Acsadi G, Jani A, Massie B, Karpati G: The route of administration is a major determinant of the transduction efficiency of rat tissues by adenoviral recombinants.
Gene Ther2
:107
115,1995[Medline]
- Altomonte J, Richter A, Harbaran S, Suriawinata J, Nakae J, Thung SN, Meseck M, Accili D, Dong H: Inhibition of Foxo1 function is associated with improved fasting glycemia in diabetic mice.
Am J Physiol Endocrinol Metab285
:E718
E728,2003[Abstract/Free Full Text]
- Nakae J, Biggs WH 3rd, Kitamura T, Cavenee WK, Wright CV, Arden KC, Accili D: Regulation of insulin action and pancreatic beta-cell function by mutated alleles of the gene encoding forkhead transcription factor Foxo1.
Nat Genet32
:245
253,2002[Medline]
- Frittitta L, Youngren JF, Sbraccia P, DAdamo M, Buongiorno A, Vigneri R, Goldfine ID, Trischitta V: Increased adipose tissue PC-1 protein content, but not tumour necrosis factor-alpha gene expression, is associated with a reduction of both whole body insulin sensitivity and insulin receptor tyrosine-kinase activity.
Diabetologia40
:282
289,1997[Medline]
- Pizzuti A, Frittitta L, Argiolas A, Baratta R, Goldfine ID, Bozzali M, Ercolino T, Scarlato G, Iacoviello L, Vigneri R, Tassi V, Trischitta V: A polymorphism (K121Q) of the human glycoprotein PC-1 gene coding region is strongly associated with insulin resistance.
Diabetes48
:1881
1884,1999[Abstract]
- Duggirala R, Blangero J, Almasy L, Arya R, Dyer TD, Williams KL, Leach RJ, OConnell P, Stern MP: A major locus for fasting insulin concentrations and insulin resistance on chromosome 6q with strong pleiotropic effects on obesity-related phenotypes in nondiabetic Mexican Americans.
Am J Hum Genet68
:1149
1164,2001[Medline]
- Meyre D, Lecoeur C, Delplanque J, Francke S, Vatin V, Durand E, Weill J, Dina C, Froguel P: A genome-wide scan for childhood obesity-associated traits in French families shows significant linkage on chromosome 6q22.31-q23.2.
Diabetes53
:803
811,2004[Abstract/Free Full Text]
- Nandi A, Kitamura Y, Kahn CR, Accili D: Mouse models of insulin resistance.
Physiol Rev84
:623
647,2004[Abstract/Free Full Text]
- Pender C, Ortmeyer HK, Hansen BC, Goldfine ID, Youngren JF: Elevated plasma cell membrane glycoprotein levels and diminished insulin receptor autophosphorylation in obese, insulin-resistant rhesus monkeys.
Metabolism51
:465
470,2002[Medline]
- Li M, Youngren JF, Manchem VP, Kozlowski M, Zhang BB, Maddux BA, Goldfine ID: Small molecule insulin receptor activators potentiate insulin action in insulin resistant cells.
Diabetes50
:2323
2328,2001[Abstract/Free Full Text]
- Buckley MF, Loveland KA, McKinstry WJ, Garson OM, Goding JW: Plasma cell membrane glycoprotein PC-1: cDNA cloning of the human molecule, amino acid sequence, and chromosomal location.
J Biol Chem265
:17506
17511,1990[Abstract/Free Full Text]
- Hessle L, Johnson KA, Anderson HC, Narisawa S, Sali A, Goding JW, Terkeltaub R, Millan JL: Tissue-nonspecific alkaline phosphatase and plasma cell membrane glycoprotein-1 are central antagonistic regulators of bone mineralization.
Proc Natl Acad Sci U S A99
:9445
9449,2002[Abstract/Free Full Text]
- Rutsch F, Vaingankar S, Johnson K, Goldfine I, Maddux B, Schauerte P, Kalhoff H, Sano K, Boisvert WA, Superti-Furga A, Terkeltaub R: PC-1 nucleoside triphosphate pyrophosphohydrolase deficiency in idiopathic infantile arterial calcification.
Am J Pathol158
:543
554,2001[Abstract/Free Full Text]
- Rutsch F, Ruf N, Vaingankar S, Toliat MR, Suk A, Hohne W, Schauer G, Lehmann M, Roscioli T, Schnabel D, Epplen JT, Knisely A, Superti-Furga A, McGill J, Filippone M, Sinaiko AR, Vallance H, Hinrichs B, Smith W, Ferre M, Terkeltaub R, Nurnberg P: Mutations in ENPP1 are associated with "idiopathic " infantile arterial calcification.
Nat Genet34
:379
381,2003[Medline]
- Johnson KA, Hessle L, Vaingankar S, Wennberg C, Mauro S, Narisawa S, Goding JW, Sano K, Millan JL, Terkeltaub R: Osteoblast tissue-nonspecific alkaline phosphatase antagonizes and regulates PC-1.
Am J Physiol Regul Integr Comp Physiol279
:R1365
R1377,2000[Abstract/Free Full Text]