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The cAMP-HMGA1-RBP4 system: a novel biochemical pathway for modulating glucose homeostasis.

Chiefari E, Paonessa F, Iiritano S, Le Pera I, Palmieri D, Brunetti G, Lupo A, Colantuoni V, Foti D, Gulletta E, De Sarro G, Fusco A, Brunetti A - BMC Biol. (2009)

Bottom Line: These results indicate that HMGA1 is an important modulator of RBP4 gene expression in vivo.Further, they provide evidence for the identification of a novel biochemical pathway involving the cAMP-HMGA1-RBP4 system, whose activation may play a role in glucose homeostasis in both rodents and humans.Elucidating these mechanisms has importance for both fundamental biology and therapeutic implications.

View Article: PubMed Central - HTML - PubMed

Affiliation: Dipartimento di Medicina Sperimentale e Clinica G. Salvatore, Catanzaro, Italy. echiefari@libero.it

ABSTRACT

Background: We previously showed that mice lacking the high mobility group A1 gene (Hmga1-knockout mice) developed a type 2-like diabetic phenotype, in which cell-surface insulin receptors were dramatically reduced (below 10% of those in the controls) in the major targets of insulin action, and glucose intolerance was associated with increased peripheral insulin sensitivity. This particular phenotype supports the existence of compensatory mechanisms of insulin resistance that promote glucose uptake and disposal in peripheral tissues by either insulin-dependent or insulin-independent mechanisms. We explored the role of these mechanisms in the regulation of glucose homeostasis by studying the Hmga1-knockout mouse model. Also, the hypothesis that increased insulin sensitivity in Hmga1-deficient mice could be related to the deficit of an insulin resistance factor is discussed.

Results: We first show that HMGA1 is needed for basal and cAMP-induced retinol-binding protein 4 (RBP4) gene and protein expression in living cells of both human and mouse origin. Then, by employing the Hmga1-knockout mouse model, we provide evidence for the identification of a novel biochemical pathway involving HMGA1 and the RBP4, whose activation by the cAMP-signaling pathway may play an essential role for maintaining glucose metabolism homeostasis in vivo, in certain adverse metabolic conditions in which insulin action is precluded. In comparative studies of normal and mutant mice, glucagon administration caused a considerable upregulation of HMGA1 and RBP4 expression both at the mRNA and protein level in wild-type animals. Conversely, in Hmga1-knockout mice, basal and glucagon-mediated expression of RBP4 was severely attenuated and correlated inversely with increased Glut4 mRNA and protein abundance in skeletal muscle and fat, in which the activation state of the protein kinase Akt, an important downstream mediator of the metabolic effects of insulin on Glut4 translocation and carbohydrate metabolism, was simultaneously increased.

Conclusion: These results indicate that HMGA1 is an important modulator of RBP4 gene expression in vivo. Further, they provide evidence for the identification of a novel biochemical pathway involving the cAMP-HMGA1-RBP4 system, whose activation may play a role in glucose homeostasis in both rodents and humans. Elucidating these mechanisms has importance for both fundamental biology and therapeutic implications.

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Effects of RBP4 on insulin sensitivity. Insulin-tolerance test (ITT) was assessed in Hmga1-deficient mice injected with saline alone (left), and in Hmga1 mutants injected chronically with purified RBP4 (right) (n = 6–8 per genotype in each condition). ITT was performed by measuring blood glucose levels in 12-h-fasted conscious mice injected intraperitoneally with human insulin (Human Actrapid, Novo Nordisk), 1 U/kg body weight. Open squares, Hmga1+/+; open circles, Hmga1+/-; open diamonds, Hmga1-/-. The degree of statistical significance was less in RBP4-injected Hmga1-deficient mice compared with the significance for saline-injected Hmga1 mutants. *P < 0.0001, saline-injected Hmga1-deficient mice versus Hmga1+/+; # P < 0.05, RBP4-injected Hmga1-/- mice versus Hmga1+/+.
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Figure 9: Effects of RBP4 on insulin sensitivity. Insulin-tolerance test (ITT) was assessed in Hmga1-deficient mice injected with saline alone (left), and in Hmga1 mutants injected chronically with purified RBP4 (right) (n = 6–8 per genotype in each condition). ITT was performed by measuring blood glucose levels in 12-h-fasted conscious mice injected intraperitoneally with human insulin (Human Actrapid, Novo Nordisk), 1 U/kg body weight. Open squares, Hmga1+/+; open circles, Hmga1+/-; open diamonds, Hmga1-/-. The degree of statistical significance was less in RBP4-injected Hmga1-deficient mice compared with the significance for saline-injected Hmga1 mutants. *P < 0.0001, saline-injected Hmga1-deficient mice versus Hmga1+/+; # P < 0.05, RBP4-injected Hmga1-/- mice versus Hmga1+/+.

Mentions: Consistent with the condition of insulin hypersensitivity, we previously reported that the glucose-lowering effect of exogenous insulin was enhanced in Hmga1-deficient mice during insulin-tolerance test (ITT) [13]. To support further the role of RBP4 in insulin hypersensitivity in Hmga1 mutants, we have determined the effect of RBP4 administration on the glucose fall induced by insulin in these genotypes during ITT. As shown in Figure 9, injection of human RBP4 in heterozygous and homozygous Hmga1 mutants caused a less dramatic fall in blood glucose levels, lessening the hypoglycemic response to intraperitoneal insulin observed in the saline-injected animals. Thus, taken together, our findings consistently support the role of HMGA1 as a key element in the transcriptional regulation of genes involved in glucose metabolism and add new insights into the compensatory mechanisms that may contribute to counteract insulin resistance in vivo. By directly regulating RBP4 gene transcription, HMGA1 enhances peripheral insulin sensitivity, ensuring glucose uptake in skeletal muscle. This, if on one hand might represent an adaptive mechanism to ameliorate insulin resistance in animals with a disadvantageous metabolic risk profile, on the other might indicate that the cAMP/HMGA1-mediated RBP4 expression during fasting (when glucagon peaks) may act physiologically to reduce insulin sensitivity in peripheral tissues, thereby contributing to the maintenance of euglycemia under this condition. This was supported by the observation that after an overnight fasting period (12–16 h) plasma glucose concentration in wild-type mice was higher than that of Hmga1-deficient mice (89 ± 5 in Hmga1+/+ mice, versus 72 ± 6 and 62 ± 5 mg/dl in Hmga1+/- and Hmga1-/- mice, respectively; P < 0.05).


The cAMP-HMGA1-RBP4 system: a novel biochemical pathway for modulating glucose homeostasis.

Chiefari E, Paonessa F, Iiritano S, Le Pera I, Palmieri D, Brunetti G, Lupo A, Colantuoni V, Foti D, Gulletta E, De Sarro G, Fusco A, Brunetti A - BMC Biol. (2009)

Effects of RBP4 on insulin sensitivity. Insulin-tolerance test (ITT) was assessed in Hmga1-deficient mice injected with saline alone (left), and in Hmga1 mutants injected chronically with purified RBP4 (right) (n = 6–8 per genotype in each condition). ITT was performed by measuring blood glucose levels in 12-h-fasted conscious mice injected intraperitoneally with human insulin (Human Actrapid, Novo Nordisk), 1 U/kg body weight. Open squares, Hmga1+/+; open circles, Hmga1+/-; open diamonds, Hmga1-/-. The degree of statistical significance was less in RBP4-injected Hmga1-deficient mice compared with the significance for saline-injected Hmga1 mutants. *P < 0.0001, saline-injected Hmga1-deficient mice versus Hmga1+/+; # P < 0.05, RBP4-injected Hmga1-/- mice versus Hmga1+/+.
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Figure 9: Effects of RBP4 on insulin sensitivity. Insulin-tolerance test (ITT) was assessed in Hmga1-deficient mice injected with saline alone (left), and in Hmga1 mutants injected chronically with purified RBP4 (right) (n = 6–8 per genotype in each condition). ITT was performed by measuring blood glucose levels in 12-h-fasted conscious mice injected intraperitoneally with human insulin (Human Actrapid, Novo Nordisk), 1 U/kg body weight. Open squares, Hmga1+/+; open circles, Hmga1+/-; open diamonds, Hmga1-/-. The degree of statistical significance was less in RBP4-injected Hmga1-deficient mice compared with the significance for saline-injected Hmga1 mutants. *P < 0.0001, saline-injected Hmga1-deficient mice versus Hmga1+/+; # P < 0.05, RBP4-injected Hmga1-/- mice versus Hmga1+/+.
Mentions: Consistent with the condition of insulin hypersensitivity, we previously reported that the glucose-lowering effect of exogenous insulin was enhanced in Hmga1-deficient mice during insulin-tolerance test (ITT) [13]. To support further the role of RBP4 in insulin hypersensitivity in Hmga1 mutants, we have determined the effect of RBP4 administration on the glucose fall induced by insulin in these genotypes during ITT. As shown in Figure 9, injection of human RBP4 in heterozygous and homozygous Hmga1 mutants caused a less dramatic fall in blood glucose levels, lessening the hypoglycemic response to intraperitoneal insulin observed in the saline-injected animals. Thus, taken together, our findings consistently support the role of HMGA1 as a key element in the transcriptional regulation of genes involved in glucose metabolism and add new insights into the compensatory mechanisms that may contribute to counteract insulin resistance in vivo. By directly regulating RBP4 gene transcription, HMGA1 enhances peripheral insulin sensitivity, ensuring glucose uptake in skeletal muscle. This, if on one hand might represent an adaptive mechanism to ameliorate insulin resistance in animals with a disadvantageous metabolic risk profile, on the other might indicate that the cAMP/HMGA1-mediated RBP4 expression during fasting (when glucagon peaks) may act physiologically to reduce insulin sensitivity in peripheral tissues, thereby contributing to the maintenance of euglycemia under this condition. This was supported by the observation that after an overnight fasting period (12–16 h) plasma glucose concentration in wild-type mice was higher than that of Hmga1-deficient mice (89 ± 5 in Hmga1+/+ mice, versus 72 ± 6 and 62 ± 5 mg/dl in Hmga1+/- and Hmga1-/- mice, respectively; P < 0.05).

Bottom Line: These results indicate that HMGA1 is an important modulator of RBP4 gene expression in vivo.Further, they provide evidence for the identification of a novel biochemical pathway involving the cAMP-HMGA1-RBP4 system, whose activation may play a role in glucose homeostasis in both rodents and humans.Elucidating these mechanisms has importance for both fundamental biology and therapeutic implications.

View Article: PubMed Central - HTML - PubMed

Affiliation: Dipartimento di Medicina Sperimentale e Clinica G. Salvatore, Catanzaro, Italy. echiefari@libero.it

ABSTRACT

Background: We previously showed that mice lacking the high mobility group A1 gene (Hmga1-knockout mice) developed a type 2-like diabetic phenotype, in which cell-surface insulin receptors were dramatically reduced (below 10% of those in the controls) in the major targets of insulin action, and glucose intolerance was associated with increased peripheral insulin sensitivity. This particular phenotype supports the existence of compensatory mechanisms of insulin resistance that promote glucose uptake and disposal in peripheral tissues by either insulin-dependent or insulin-independent mechanisms. We explored the role of these mechanisms in the regulation of glucose homeostasis by studying the Hmga1-knockout mouse model. Also, the hypothesis that increased insulin sensitivity in Hmga1-deficient mice could be related to the deficit of an insulin resistance factor is discussed.

Results: We first show that HMGA1 is needed for basal and cAMP-induced retinol-binding protein 4 (RBP4) gene and protein expression in living cells of both human and mouse origin. Then, by employing the Hmga1-knockout mouse model, we provide evidence for the identification of a novel biochemical pathway involving HMGA1 and the RBP4, whose activation by the cAMP-signaling pathway may play an essential role for maintaining glucose metabolism homeostasis in vivo, in certain adverse metabolic conditions in which insulin action is precluded. In comparative studies of normal and mutant mice, glucagon administration caused a considerable upregulation of HMGA1 and RBP4 expression both at the mRNA and protein level in wild-type animals. Conversely, in Hmga1-knockout mice, basal and glucagon-mediated expression of RBP4 was severely attenuated and correlated inversely with increased Glut4 mRNA and protein abundance in skeletal muscle and fat, in which the activation state of the protein kinase Akt, an important downstream mediator of the metabolic effects of insulin on Glut4 translocation and carbohydrate metabolism, was simultaneously increased.

Conclusion: These results indicate that HMGA1 is an important modulator of RBP4 gene expression in vivo. Further, they provide evidence for the identification of a novel biochemical pathway involving the cAMP-HMGA1-RBP4 system, whose activation may play a role in glucose homeostasis in both rodents and humans. Elucidating these mechanisms has importance for both fundamental biology and therapeutic implications.

Show MeSH
Related in: MedlinePlus