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Post by Max on Jun 13, 2005 18:25:10 GMT -5
Major alterations of insulin sensitivity, insulin release and secretion, insulin production and liver responses
Various studies are pointing out clear interactions between (Ro)accutane and insulin function. The insulin patway is a major pathway in how (Ro)accutane mediates its effects, thus it should be considered an effect, and not a side-effect.
Significantly altered insulin release/secretion in response to glucose, and antiproliferative, possibly apoptotic effects on beta cells
Whereas it remains completely clear that insulin secretion is affected during exposure, it is uncertain how insulin release and secretion is affected after a (Ro)accutane exposure. Experiments in rats show that insulin secretion could be expected to be efficiently reduced , due to decreased lessened promoter activity of Sp1 and disruptions in the GC-box [11]. Another study of an INS-1 cell line points out the clear relation between the retinoid receptors and insulin release and suggests a significantly higher insulin release during exposure, but found cells to reaggregate to a single clump in massive doses [1]. The most probable is that insulin secretion, in massive doses of retinoic acid as seen in acne-subjects, is significantly impaired during exposure.
Retinoic acid in was found to induce the pyruvate decarboxylating activity in modest doses [19]. In rats the pyruvate decarboxylase is found to be dependent on Sp1 and NF-Y promoter activity [11]. It is therefore possible that a massive dose of retinoic acid, as seen in acne-subjects, inhibits the pyruvate decarboxylase through decreased Sp1 and NF-Y binding. The pyruvate carboxylase (PC) plays a crucial role in various metabolic pathways, including gluconeogenesis, lipogenesis, and glucose-induced insulin secretion. The pyruvate carboxylase gene is transcriptionally regulated by peroxisome proliferator-activated receptor-gamma (PPARgamma) [20].
In rats, pyruvate carboxylase plays diverse roles in different biosynthetic pathways, including glucose-induced insulin secretion in pancreatic beta-cells. Transient transfections of these constructs into INS-1 cells identified a CCAAT box and a GC box that are located at -65/-61 and -48/-41, respectively, as the important determinants. Disruption of the GC box resulted in a 4-fold reduction of the reporter activity. Electrophoretic mobility shift assays (EMSAs) and supershift EMSAs using nuclear extract from INS-1 cells demonstrated that Sp1 and Sp3 bind a GC box while the nuclear factor Y was shown to bind the proximal but not the distal CCAAT box [11].
In INS-1 cells retinoid receptors RAR and RXR were found to mediate insulin release [1]. In rat islets and in response to glucose (Ro)accutane (10(-4) M) stimulated insulin secretion at 9.7, 12.5, 16.7, and 27.7 mM glucose. Maximal effects of 13 cis-RA (174% of control) were evident during second phase release at 9.7 mM glucose. Thirteen cis-RA (10(-7) and 10(-6) M) caused cells to adhere to each other, and at higher concentrations, 13 cis-RA caused dispersed cells to reaggregate into a single clump. These retinoid-induced clumps were perifused in a Bio-Gel P-2 gel column. Secretion from the clump was twofold greater than from an equal number of perifused dispersed cells [7]. Both 9cRA and ATRA inhibit INS-1 cell proliferation [1].
Significant inhibition of response to insulin by SREBP-1c in liver
Transcription of the gene encoding sterol regulatory element-binding protein 1c (SREBP-1c) is known to be activated by insulin in the liver [2]. Synthesis of fatty acids in the liver and adipose tissue in response to insulin is critically dependent on the transcription factor SREBP-1c [3]. The rat SREBP-1c promoter contains binding sites for: 1) LXR (liver X receptor), which binds to liver X response elements (LXREs) 2) transcription factor Sp1, that has a binding site on SREs 3) transcription factor NF-Y (nuclear factor-Y) that also has a binding site on SREs and 4) SREBP itself, which also binds to sterol response elements (SREs) [3].
Each of these sites is required for the full stimulatory response of the SREBP-1c promoter to insulin [3]. Complete insulin response (increase of 6- to 11-fold) requires two binding sites for liver X receptors (LXRs), which are nuclear receptors that are activated by oxygenated sterols. Disruption of these binding sites did not lower basal transcription but severely reduced the response to insulin. In contrast, disruption of the closely linked binding sites for SREBPs and nuclear factor Y lowered basal transcription drastically but still permitted a 4- to 7-fold increase in response to insulin. Arachidonic acid, an inhibitor of LXR activation, blocked the response to insulin [2].
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Post by Max on Jun 30, 2005 8:07:28 GMT -5
Significant inhibition of the insulin receptor, suggested inhibition of response to insulin due to inhibition of insulin receptor promoter
The human insulin receptor promoter region (HINSR) contains six GGGCGG sequences [4]. Sp1 binds to canonical GGGCGG or its atypical hexanucleotide sequence, called "GC box" motif, of several cellular and viral genes and activates transcription of these genes by RNA polymerase II. Retinoid receptors RARs/RXRs physically interact with Sp1, potentiate Sp1 binding to the GC box motifs [5]. However, in massive doses of retinoic acid as seen in acne-subjects, Sp1 binding affinity to the GC box may be decreased, thus resulting in downregulation of the insulin receptor.
Altered renal clearance of insulin
Renal clearance is a major pathway for regulating the levels of insulin and other low molecular weight polypeptide hormones in the systemic circulation.
Reabsorption of insulin from the glomerular filtrate occurs by binding to megalin on the luminal surface of proximal tubule cells followed by endocytosis and degradation in lysosomes. An insulin binding site, megalin, was identified in renal microvillar membranes. Megalin is a large multiligand binding endocytic receptor that is abundantly expressed in clathrin-coated pits on the apical surface of proximal tubule cells. Megalin is able to internalize insulin into endocytic vesicles. In ligand blotting assays, megalin also bound several other low molecular weight polypeptides, including beta2-microglobulin, epidermal growth factor, prolactin, lysozyme, and cytochrome c, suggesting that megalin may play a significant role as a renal reabsorption receptor for the uptake of insulin and other low molecular weight polypeptides from the glomerular filtrate [6].
Suggested alteration of insulin production
Well-orchestrated transcriptional regulation of pancreatic beta cells is essential for insulin production and glucose homeostasis. Pancreas duodenum homeobox-1 (PDX-1) is a key regulator of glucose-dependent insulin production and glucose metabolism. We find that PDX-1 interacts with the PDZ-domain coactivator Bridge-1 in yeast interaction trap assays. Rat Bridge-1 and PDX-1 interact directly in GST pull-down assays via Bridge-1 interactions with the amino-terminal transactivation domain of PDX-1. Bridge-1 also interacts with wild-type and mutant human PDX-1 (IPF-1) proteins and strongly interacts with the amino-terminal PDX-1 P63fsdelC (MODY4) mutant protein. Transcriptional activation by PDX-1 is increased by addition of Bridge-1 in multiple contexts, including synergistic activation of a Gal4 reporter by Gal4-Bridge-1 and Gal4-PDX-1 fusion proteins, activation of the somatostatin promoter TAAT1 enhancer, and synergistic activation of the rat insulin I promoter FarFlat enhancer by PDX-1, E12, and E47. We propose that the coactivator Bridge-1 modulates PDX-1 functions in the regulation of its target genes [8].
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Post by Max on Jun 30, 2005 8:08:12 GMT -5
Reduced resistin levels
In small doses, Retinoic acid (RA), the acid form of vitamin A, exerts funtions a signal that inhibits the expression of resistin, an adipocyte-secreted protein previously proposed to act as an inhibitor of adipocyte differentiation and as a systemic insulin resistance factor. Both 9-cis and all-trans RA reduced resistin mRNA levels in white and brown adipocyte cell model systems; the effect was time- and dose-dependent, was followed by a reduced secretion of resistin, and was reproduced by selective agonists of both RA receptors and retinoid receptors. Association of CCAAT/enhancer-binding protein alpha (a positive regulator of the resistin gene) and its coactivators p300, cAMP response element-binding protein binding protein, and retinoblastoma protein with the resistin gene promoter was reduced in RA-treated adipocytes. RA administration to normal mice resulted in reduced resistin mRNA levels in brown and white adipose tissues, reduced circulating resistin levels, reduced body weight, and improved glucose tolerance. Resistin expression was also downregulated after dietary vitamin A supplementation in mice. The results raise the possibility that vitamin A status may contribute to modulate systemic functions through effects on the production of adipocyte-derived protein signals [9].
It is unknown how the levels of resistin are affected during a severe retinoic acid exposure and how resisitin levels are affected in a chronical vitamin A deficient condition.
Significant interaction with the pancreatic secretin receptor
The human secretin receptor (hSR) is an important glycoprotein receptor for regulating the secretion of pancreatic bicarbonate, water, and electrolytes. The secretin receptor is in humans suggested to be regulated by Sp1 and Sp3 binding to GC-box in the promoter [10]. A significant downregulation of the secretin receptor in association with (Ro)accutane exposure is therefore here suggested.
Alterations of glucose transport
GLUT-1
In the development of diabetic nephropathy, angiotensin (Ang) II is thought to exert numerous actions on the glomerulus, and especially on the mesangium. However, the role(s) played by Ang II in the glucose metabolism per se in mesangial cells remains unclear. Ang II, at least via its type 1 receptor (AT1-R)-mediated effect, phosphorylates extracellular signal regulated kinase (ERK) by transactivation of epidermal growth factor receptors (EGF-Rs) via the Ca2+ or protein kinase C (PKC) pathways. Ang II upregulated GLUT1 mRNA accumulation in a time- and dose-dependent manner (peaking at 12 h; approximately 3.8-fold vs. control), and this upregulation was completely inhibited by the PKC inhibitor calphostin-C. The Ang Il-induced GLUT1 expression was significantly inhibited by the EGF-R inhibitor AG1478 (approximately 80% inhibition), by inactivation of ERK by PD98059, and by pretreatment with heparin and the metalloproteinase (MMP) inhibitor batimastat [13]. In Xenopus oocytes, all six native cysteine residues of GLUT1 were changed to either glycine or serine residues by site-directed mutagenesis, resulting in a functional Glut1 construct with Cys mutated to Gly/Ser (C-less). The GLUT1 reporter molecule was engineered from C-less GLUT1 by creating a unique cleavage site for factor Xa protease within the central cytoplasmic loop and by eliminating the site of N-linked glycosylation [14]. The data suggests that the clusering of GLUT-1 is of importance for function.
GLUT-2
ATRA ralsed the GLUT 2 mRNA in a bell-shaped concentration response curve after 48 h [1]. This bell shaped curve is here suggested to possibly result in inhibition of GLUT-2 in higher doses of retinoic acid. In mice, the expression of type 2 glucose transporter isoform (GLUT2) could be regulated by PPAR-gamma in the liver through binding of PPARgamma to the GLUT-2 promoter [21].
Gene 33 is found to be regulated by both insulin and glucocorticoids. It is suggested that that the MEK-ERK, but not the phosphatidylinositol 3-kinase (PI3-K), pathway plays a direct role in insulin regulation of Gene33 transcription and protein expression. Gene33 is found to be involved in proliferation and differentiation of cells [16]. Inhibition of insulin signaling via the ERK pathway is thus suggested to contribute to apoptosis, and and pathway of (Ro)accutane induced hypometabolism.
Significant downregulation of the farnesoid X receptor (FXR)
Dyslipidemia and gallbladder diseases are two current anomalies observed in patients suffering from the metabolic syndrome and type 2 diabetes. The bile acid-activated nuclear receptor farnesoid X receptor (FXR) controls bile acid as well as lipid metabolism. Recent observations indicate a role for FXR also in carbohydrate metabolism. Hepatic FXR expression is altered in diabetic animal models in vivo and regulated by hormones and nutrients in vitro. At the molecular level, FXR activation modifies the transcriptional activity of different transcription factors controlling gluconeogenesis and lipogenesis, thus affecting in concert bile acid, lipid and carbohydrate metabolism [12].
Calpain
Calpains have shown to be altered during the caspases, and modulate NF-kappB, both mechanisms that are involved in (Ro)accutane exposure.
The mRNA expression of type 2 diabetes-related genes in white blood cells (WBC) was examined before and after onset in Otsuka Long-Evans Tokushima Fatty (OLETF) rat. The level of the calpain 10 (CAPN10) transcript was significantly decreased compared to control animals in WBC before and after onset. Significant decreases in this gene expression were also found in the major insulin-target tissues as well as WBC before onset. These results suggest that gene expression in WBC could be a useful screening system for predicting the incidence of type 2 diabetes before onset in OLETF rats, and that CAPN10 represents a potential candidate gene for predicting type 2 diabetes in human [15].
Autoimmune contribution to diabetic complications
An overproduction of cytokines are normally connected with a cell destruction in autoimmune diabetes. Indeed (Ro)accutane may trigger such an event, by for example a significant elevation of TGFbeta1. However, (Ro)accutane may exert an opposite effect, inhibit cytokine production, which also may affect several pathways that may severely affect the beta cells, production, release and response to insulin.
Cytokines are important humoral mediators of beta cell destruction in autoimmune diabetes. Exposure of RINm5F cells to IL-1beta or to a cytokine mixture (IL-1beta, TNF-alpha, IFN-gamma) for 6 h resulted in the differential expression of a functional gene cluster. Apart from the well-known up-regulation of the cytokine-responsive genes iNOS, NF-kappaB, MnSOD and Hsp70, several genes that belong to the functional cluster of the endocytotic pathway were identified. These endocytotic genes comprised: clathrin, megalin, synaptotagmin and calcineurin, which were up-regulated by IL-1beta or the cytokine mixture [18].
(Ro)accutane induced diabetes mellitus
The insulin patway is a major pathway in how (Ro)accutane mediates its effects. (Ro)accutane exposure in human subjects may result in diabetes mellitus. The (Ro)accutane induced general effects share quite well the picture with a diabetic diagnosis, and depending on severity, diabetes mellitus may be adequate in some subjects.
The clinical picture of type 2 diabetes mellitus (T2DM) is formed by impairment in insulin secretion and resistance to insulin action. Sequence differences in a few genes have been associated, so far, with complex, polygenic forms of T2DM, for example, calpain 10, PPARgamma, KCJN11, and insulin. In addition, some evidence exists that genes, such as adiponectin, IRS-1, and some others may also influence the susceptibility to T2DM. It is expected that in the nearest future more T2DM susceptibility genes will be identified [17].
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Post by Max on Jul 1, 2005 16:43:01 GMT -5
Conclusions
Insulin secretion and release are most definitely significantly affected during a (Ro)accutane exposure in human acne-subjects. The insulin receptors are found to be heavily affected by retinoid receptors, and their GC-boxes in the insulin receptor promoter area, show exact binding sites for Sp1 that are inhibited. The insulin receptors are with highest certainity significantly suppressed during a (Ro)accutane exposure, resulting in reduced insulin sensitivity. This is suggested not to be considered a side-effect, but an actual effect, which among other things is significantly antiproliferative. In the liver, the insulin response through SREBP-1 is suggested to be significantly inhibited.
Both renal clearance of insulin and angiotensin II are suggested to heavily affected, thus contibuting to inhibition of glutamate transporters. Glut-1 and Glut-2 via PPARgamma are found to be affected, but it is likely that more glutamate transporters are involved. Insulin production may be affected due to interaction with PDX promoters. A possible significant loss of insulin producing beta-cells can not be excluded.
Both resistin and secretin are heavily affected. (Ro)accutane induces, in the normal response profile, a significantly downregulated cytokine production, which may contribute to an atypical immune-dependent diabetes. The effects on the insulin-system are major, and may result in both type 1 and 2 diabetes, severe insulin resistance, or a combination.
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Post by Max on Jul 1, 2005 17:17:49 GMT -5
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Central role for liver X receptor in insulin-mediated activation of Srebp-1c transcription and stimulation of fatty acid synthesis in liver. (2004) Proc Natl Acad Sci U S A. Aug 3;101(31):11245-50. [3] Cagen LM, Deng X, Wilcox HG, Park EA, Raghow R, Elam MB. Insulin activates the rat sterol-regulatory-element-binding protein 1c (SREBP-1c) promoter through the combinatorial actions of SREBP, LXR, Sp-1 and NF-Y cis-acting elements. (2005) Biochem J. Jan 1;385(Pt 1):207-16. [4] Mamula PW, Wong KY, Maddux BA, McDonald AR, Goldfine ID. Sequence and analysis of promoter region of human insulin-receptor gene. (1988) Diabetes. Sep;37(9):1241-6. [5] Jun Shimada, Yasuhiro Suzuki, Seong-Jin Kim, Pi-Chao Wang, Masatoshi Matsumura and Soichi Kojima Transactivation via RAR/RXR-Sp1 Interaction: Characterization of Binding Between Sp1 and GC Box Motif (2001) Molecular Endocrinology 15 (10): 1677-1692 [6] Orlando RA, Rader K, Authier F, Yamazaki H, Posner BI, Bergeron JJ, Farquhar MG. Megalin is an endocytic receptor for insulin. (1998) J Am Soc Nephrol. Oct;9(10):1759-66. [7] Chertow BS, Baranetsky NG, Sivitz WI, Meda P, Webb MD, Shih JC. Cellular mechanisms of insulin release. Effects of retinoids on rat islet cell-to-cell adhesion, reaggregation, and insulin release. (1983) Diabetes. Jun;32(6):568-74. [8] Stanojevic V, Yao KM, Thomas MK.
The coactivator Bridge-1 increases transcriptional activation by pancreas duodenum homeobox-1 (PDX-1). (2005) Mol Cell Endocrinol. Jun 15;237(1-2):67-74. [9] Felipe F, Bonet ML, Ribot J, Palou A. Modulation of resistin expression by retinoic acid and vitamin A status. (2004) Diabetes. Apr;53(4):882-9. [10] Pang RT, Lee LT, Ng SS, Yung WH, Chow BK.
CpG methylation and transcription factors Sp1 and Sp3 regulate the expression of the human secretin receptor gene. (2004) Mol Endocrinol. Feb;18(2):471-83. [11] Sunyakumthorn P, Boonsaen T, Boonsaeng V, Wallace JC, Jitrapakdee S. Involvement of specific proteins (Sp1/Sp3) and nuclear factor Y in basal transcription of the distal promoter of the rat pyruvate carboxylase gene in beta-cells. (2005) Biochem Biophys Res Commun. Apr 1;329(1):188-96. [12] Duran-Sandoval D, Cariou B, Fruchart JC, Staels B. Potential regulatory role of the farnesoid X receptor in the metabolic syndrome.
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(2003) Hypertens Res. Jan;26(1):67-73. [14] Alisio A, Mueckler M. Relative proximity and orientation of helices 4 and 8 of the GLUT1 glucose transporter. (2004) J Biol Chem. Jun 18;279(25):26540-5. [15] Sato Y, Kuwajima M, Kamiya H, Harashima H. Calpain 10 as a predictive gene for type 2 diabetes: evidence from a novel screening system using white blood cells of Otsuka Long-Evans Tokushima Fatty (OLETF) rats. (2003) Biol Pharm Bull. Dec;26(12):1765-8. [16] Keeton AB, Xu J, Franklin JL, Messina JL.
Regulation of Gene33 expression by insulin requires MEK-ERK activation. (2004) Biochim Biophys Acta. Sep 17;1679(3):248-55. [17] Malecki MT. Genetics of type 2 diabetes mellitus. (2005) Diabetes Res Clin Pract. Jun;68 Suppl 1:S10-21. [18] Souza KL, Elsner M, Mathias PC, Lenzen S, Tiedge M. Cytokines activate genes of the endocytotic pathway in insulin-producing RINm5F cells.
(2004) Diabetologia. Jul;47(7):1292-302. [19] Constantopoulos G, Barranger JA.
Nonenzymatic decarboxylation of pyruvate. (1984) Anal Biochem. Jun;139(2):353-8. [20] Jitrapakdee S, Slawik M, Medina-Gomez G, Campbell M, Wallace JC, Sethi JK, O'rahilly S, Vidal-Puig AJ. The Peroxisome Proliferator-activated Receptor-{gamma} Regulates Murine Pyruvate Carboxylase Gene Expression in Vivo and in Vitro.
(2005) J Biol Chem. Jul 22;280(29):27466-76. [21] Im SS, Kim JW, Kim TH, Song XL, Kim SY, Kim HI, Ahn YH. Identification and characterization of peroxisome proliferator response element in the mouse GLUT2 promoter. (2005) Exp Mol Med. Apr 30;37(2):101-10.
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Post by jdjhjgf on Sept 7, 2018 19:45:57 GMT -5
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