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From bending DNA to diabetes: the curious case of HMGA1.

Semple RK - J. Biol. (2009)

Bottom Line: Although mice lacking the architectural DNA binding factor HMGA1 are diabetic and express very low levels of the insulin receptor, they have increased insulin sensitivity.A study in BMC Biology now suggests that changes in circulating retinol binding protein partly account for this paradox.

View Article: PubMed Central - HTML - PubMed

Affiliation: Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QR, UK. rks16@cam.ac.uk

ABSTRACT
Although mice lacking the architectural DNA binding factor HMGA1 are diabetic and express very low levels of the insulin receptor, they have increased insulin sensitivity. A study in BMC Biology now suggests that changes in circulating retinol binding protein partly account for this paradox.

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Related in: MedlinePlus

Model of the divergent consequences of HMGA1 deficiency. All actions that lower blood glucose are in green and influences that raise blood glucose are in red. Ins, insulin; GNG, gluconeogenesis. (a) In the normal physiological state, insulin action dominates, with RBP opposing insulin signaling in skeletal muscle. (b) In states of Hmga1 deficiency, both downregulation of insulin receptor expression, promoting insulin resistance, and RBP, promoting insulin sensitivity, are seen.
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Figure 1: Model of the divergent consequences of HMGA1 deficiency. All actions that lower blood glucose are in green and influences that raise blood glucose are in red. Ins, insulin; GNG, gluconeogenesis. (a) In the normal physiological state, insulin action dominates, with RBP opposing insulin signaling in skeletal muscle. (b) In states of Hmga1 deficiency, both downregulation of insulin receptor expression, promoting insulin resistance, and RBP, promoting insulin sensitivity, are seen.

Mentions: Chiefari et al. [1] hypothesized that altered Rbp4 expression might explain the discordance between reduced Insr expression and enhanced insulin sensitivity in Hmga1-/- mice. The first key evidence that this may be partly true comes from the demonstration that these mice do have severely reduced levels of Rbp4 mRNA and circulating RBP. Furthermore, the enhanced expression of Glut4 in muscle of the knockout mice is normalized by exogenous RBP, and the enhanced glucose-lowering effect of insulin in the knockout animals is markedly attenuated by the same treatment (Figure 1). In wild-type mice glucagon strongly stimulates expression of Hmga1 and then Rbp4, an effect absent in Hmga1-/- mice. This suggests that Hmga1 is at least permissive for glucagon-induced stimulation of Rbp4 via a direct effect of Hmga1 on the Rbp4 promoter. Glucagon exerts cellular effects largely through the second messenger cAMP, and together with previous in vitro studies, this implicates cAMP as a proximal cellular regulator of both genes. However, exactly how RBP impairs insulin signaling is unclear: insulin-stimulated phosphorylation of phosphatidylinositol 3-kinase (PI3K), a key proximal step in insulin's metabolic signaling, was said previously to be severely blunted in Hmga1-/- animals [6], whereas phosphorylation of Akt, the next step in the pathway, is increased in these mice according to Chiefari et al. [1] (Figure 1). Moreover, Rbp-/- mice show enhanced insulin-induced phosphorylation of insulin receptor substrate 1 and activation of PI3K, also seemingly at odds with the new findings [9]. These considerations should motivate further signaling studies.


From bending DNA to diabetes: the curious case of HMGA1.

Semple RK - J. Biol. (2009)

Model of the divergent consequences of HMGA1 deficiency. All actions that lower blood glucose are in green and influences that raise blood glucose are in red. Ins, insulin; GNG, gluconeogenesis. (a) In the normal physiological state, insulin action dominates, with RBP opposing insulin signaling in skeletal muscle. (b) In states of Hmga1 deficiency, both downregulation of insulin receptor expression, promoting insulin resistance, and RBP, promoting insulin sensitivity, are seen.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2736670&req=5

Figure 1: Model of the divergent consequences of HMGA1 deficiency. All actions that lower blood glucose are in green and influences that raise blood glucose are in red. Ins, insulin; GNG, gluconeogenesis. (a) In the normal physiological state, insulin action dominates, with RBP opposing insulin signaling in skeletal muscle. (b) In states of Hmga1 deficiency, both downregulation of insulin receptor expression, promoting insulin resistance, and RBP, promoting insulin sensitivity, are seen.
Mentions: Chiefari et al. [1] hypothesized that altered Rbp4 expression might explain the discordance between reduced Insr expression and enhanced insulin sensitivity in Hmga1-/- mice. The first key evidence that this may be partly true comes from the demonstration that these mice do have severely reduced levels of Rbp4 mRNA and circulating RBP. Furthermore, the enhanced expression of Glut4 in muscle of the knockout mice is normalized by exogenous RBP, and the enhanced glucose-lowering effect of insulin in the knockout animals is markedly attenuated by the same treatment (Figure 1). In wild-type mice glucagon strongly stimulates expression of Hmga1 and then Rbp4, an effect absent in Hmga1-/- mice. This suggests that Hmga1 is at least permissive for glucagon-induced stimulation of Rbp4 via a direct effect of Hmga1 on the Rbp4 promoter. Glucagon exerts cellular effects largely through the second messenger cAMP, and together with previous in vitro studies, this implicates cAMP as a proximal cellular regulator of both genes. However, exactly how RBP impairs insulin signaling is unclear: insulin-stimulated phosphorylation of phosphatidylinositol 3-kinase (PI3K), a key proximal step in insulin's metabolic signaling, was said previously to be severely blunted in Hmga1-/- animals [6], whereas phosphorylation of Akt, the next step in the pathway, is increased in these mice according to Chiefari et al. [1] (Figure 1). Moreover, Rbp-/- mice show enhanced insulin-induced phosphorylation of insulin receptor substrate 1 and activation of PI3K, also seemingly at odds with the new findings [9]. These considerations should motivate further signaling studies.

Bottom Line: Although mice lacking the architectural DNA binding factor HMGA1 are diabetic and express very low levels of the insulin receptor, they have increased insulin sensitivity.A study in BMC Biology now suggests that changes in circulating retinol binding protein partly account for this paradox.

View Article: PubMed Central - HTML - PubMed

Affiliation: Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QR, UK. rks16@cam.ac.uk

ABSTRACT
Although mice lacking the architectural DNA binding factor HMGA1 are diabetic and express very low levels of the insulin receptor, they have increased insulin sensitivity. A study in BMC Biology now suggests that changes in circulating retinol binding protein partly account for this paradox.

Show MeSH
Related in: MedlinePlus