Ekspresi Protein FoxO1 dan Gen Glukosa 6 Fosfatase  pada Tikus dengan Diet Restriksi Vitamin B12

Imelda Rosalyn  Sianipar; Trinovita  Andraini; Dewi Irawati Soeria Santoso; Irena   Ujianti; Marcel Antoni

doi:10.36452/jkdoktmeditek.v28i2.2351

Authors

Imelda Rosalyn Sianipar Departemen Fisiologi Medik, Fakultas Kedokteran, Universitas Indonesia
Trinovita Andraini Departemen Fisiologi Medik, Fakultas Kedokteran, Universitas Indonesia
Dewi Irawati Soeria Santoso Departemen Fisiologi Medik, Fakultas Kedokteran, Universitas Indonesia
Irena Ujianti Departemen Fisiologi Medik, Fakultas Kedokteran, Universitas Prof.Dr.Hamka
Marcel Antoni Departemen Fisiologi, Fakultas Kedokteran dan Ilmu Kesehatan, Universitas Kristen Krida Wacana, Jakarta, Indonesia

DOI:

https://doi.org/10.36452/jkdoktmeditek.v28i2.2351

Keywords:

FoxO1, G6Pc, hiperhomosisteinemia, resistensi insulin, vitamin B12

Abstract

^{Pada penelitian awal didapatkan diet restriksi vitamin B12 menyebabkan hiperhomosisteinemia dan resistensi insulin, yang ditandai oleh hiperglikemia dan meningkatnya nilai Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). Dengan menggunakan sampel jaringan biologik tersimpan, hati tikus Spraque-Dawley dari penelitian tersebut, penelitian lanjutan ini bertujuan mengetahui penyebab hiperglikemia, dalam hubungannya dengan proses glukoneogenesis, dengan melihat ekspresi forkhead box protein-O1 (FoxO1) dan gen glukosa 6 fosfatase (G6Pc). Adapun sampel terdiri dari 4 kelompok: kelompok kontrol dan tiga kelompok dengan diet restriksi vitamin B12 masing-masing selama 4, 8, dan 12 minggu. Ekspresi FoxO1 diperiksa dengan metode kuantitatif Western-Blot, sedangkan gen G6Pc diperiksa dengan metode real-time Polymerase Chain Reaction (rt-PCR). Hasil yang diperoleh, tidak terdapat perbedaan bermakna ekspresi FoxO1 (P > 0,05) dan gen G6Pc (P > 0,05) antara kelompok tikus kontrol dan kelompok diet restriksi vitamin B12. Hal ini menunjukkan, hiperglikemia pada diet restriksi vitamin B12 tidak terkait dengan glukoneogenesis. Pada kondisi resistensi insulin, insulin masih dapat meneruskan efek metaboliknya melalui jalur lain, seperti melalui reseptor yang memiliki kemiripan struktur dan fungsi dengan reseptor insu}

^{lin. Penyebab-penyebab lain terjadinya hiperglikemia seperti gangguan utilisasi glukosa oleh sel dan gangguan proses glikogenesis perlu diteliti lebih lanjut.}

References

Green R, Allen LH, Bjorke-Monsen AL, Brito A, Gueant JL, Miller JW, et al. Vitamin B12 deficiency. Nature Reviews Disease Primers. 2017;3:17040.

Mahalle N, Kulkarni MV, Garg MK, Naik SS. Vitamin B12 deficiency and hyperhomocysteinemia as correlates of cardiovascular risk factors in Indian subjects with coronary artery disease. Journal of Cardiology. 2013;61(4):289–94.

Sianipar IR, Ujianti I, Yolanda S, Murthi AK, Amani P, Santoso DIS. Developing vitamin B12 deficient rat model based on duration of restriction diet: Assessment of plasma vitamin B12, homocysteine (Hcy), and blood glucose levels. AIP Conference Proccedings. 2019;2092(020004).

Sianipar IR, Ujianti I, Yolanda S, Jusuf AA, Kartinah NT, Amani P, et al. Low vitamin B12 diet increases liver homocysteine levels and leads to liver steatosis in rats. Universa Medicina. 2019;38(3):194–201.

Dubaj C, Czyż K, Furmaga-Jabłońska W. Vitamin B12 deficiency as a cause of severe neurological symptoms in breast fed infant – a case report. Italian Journal of Pediatrics. 2020;46(1):40.

Ankar, Kumar A. Vitamin B12 Deficiency. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2020.

Selhub J. Homocysteine metabolism. Annual Review of Nutrition. 1999;19:217-46.

Škovierová H, Vidomanová E, Mahmood S, Sopková J, Drgová A, Červeňová T, et al. The molecular and cellular effect of homocysteine metabolism imbalance on human health. International Journal of Molecular Sciences. 2016;17(10):1733.

Najib S, Sanchez-Margalet V. Homocysteine thiolactone inhibits insulin signaling, and glutathione has a protective effect. Journal of Molecular Endocrinology. 2001;27(1): 85-91.

Li Y, Zhang H, Jiang C, Xu M, Pang Y, Feng J, et al. Hyperhomocysteinemia promotes insulin resistance by inducing endoplasmic reticulum stress in adipose tissue. Journal of Biological Chemistry. 2013;288(14):9583-92.

Rains JL, Jain SK. Oxidative stress, insulin signaling, and diabetes. Free Radical Biology and Medicine. 2011;50(5):567-75.

Hall JE. Guyton and hHall Textbook of medical physiology 12th ed. Singapore: Elsevier; 2016. p.892-909.

Sherwood L. Human physiology: from cells to systems 8th ed. Jakarta: EGC; 2013. p. 748-64.

Oh KJ, Han HS, Kim MJ. CREB and FoxO1: two transcription factors for the regulation of hepatic gluconeogenesis. BMB Reports. 2013;46(12):567–74.

Boucher J, Kleinridders A, Kahn CR. Insulin receptor signaling in normal and insulin-resistant states. Cold Spring Harbor Perspectives in Biology. 2014;6(1).

Puigserver P, Rhee J, Donovan J, Walkey CJ, Yoon JC, Oriente F, et al. Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1 alpha interaction. Nature. 2003;423(6939):550–5.

Poloz Y, Stambolic V. Obesity and cancer, a case for insulin signaling. Cell Death & Disease. 2015;6(12): 2037.

Peng S, Li W, Hou N, Huang N. A review of FoxO1-regulated metabolic diseases and related drug discoveries. Cells. 2020;9(1):184.

Wang Y, Zhou Y, Graves DT. FOXO transcription factors: their clinical significance and regulation. BioMed Research International. 2014; 925350.

Bender DA. Gluconeogenesis and the control of blood glucose. Dalam: Robert K, Murray DAB, Botam KM, et al, editor. Harper’s Biochemistry 28th ed. United States: McGraw Hill; 2009. p.165-73.

Hutton JC, O’Brien RM. Glucose-6-phosphatase catalytic subunit gene family. Journal Biological Chemistry. 2009;284(43):29241-5.

Cullen RW, Oace SM. Dietary pectin shortens the biologic half-life of vitamin B-12 in rats by increasing fecal and urinary losses. The Journal of Nutrition. 1989;119(8):1121–7.

Sangüesa G, Shaligram S, Akther F, Roglans N, Laguna JC, Rahimian R, et al. Type of supplemented simple sugar, not merely calorie intake, determines adverse effects on metabolism and aortic function in female rats. The American Journal of Physiology Heart and Circulatory Physiology. 2017;312(2): H289–304.

Zhang H, Li Y, Hu J, Shen W-J, Singh M, Hou X, et al. Effect of creosote bush-derived NDGA on expression of genes involved in lipid metabolism in liver of high-fructose fed rats: relevance to NDGA amelioration of hypertriglyceridemia and hepatic steatosis. PloS One. 2015;10(9):e0138203-e.

Valenti L, Rametta R, Dongiovanni P, Maggioni M, Fracanzani AL, Zappa M, et al. Increased expression and activity of the transcription factor FOXO1 in nonalcoholic steatohepatitis. Diabetes. 2008;57(5): 1355-62.

Yu X, Huang Y, Hu Q, Ma L. Hyperhomocysteinemia stimulates hepatic glucose output and PEPCK expression. Acta Biochim Biophys Sin (Shanghai). 2009;41(12):1027-32.

Hatting M, Tavares CDJ, Sharabi K, Rines AK, Puigserver P. Insulin regulation of gluconeogenesis. Annals of the New York Academy of Sciences. 2018;1411(1):21-35.

Titchenell PM, Chu Q, Monks BR, Birnbaum MJ. Hepatic insulin signalling is dispensable for suppression of glucose output by insulin in vivo. Nature Communications. 2015;6(1):1-9.

Petersen MC, Vatner DF, Shulman GI. Regulation of hepatic glucose metabolism in health and disease. Nature Reviews Endocrinology. 2017;13(10):572-87.

Samuel VT, Beddow SA, Iwasaki T, Zhang XM, Chu X, Still CD, et al. Fasting hyperglycemia is not associated with increased expression of PEPCK or G6Pc in patients with Type 2 Diabetes. Proc Natl Acad Sci U S A. 2009;106(29): 12121-6.

Janah L, Kjeldsen S, Galsgaard KD, Winther-Sørensen M, Stojanovska E, Pedersen J, et al. Glucagon receptor signaling and glucagon resistance. International Journal of Molecular Sciences. 2019;20(13): 3314.

Sherwin RS, Sacca L. Effect of epinephrine on glucose metabolism in humans: contribution of the live. The American Physiological Society. 1984;247(2 Pt 1):E157-65.

Kuo T, McQueen A, Chen T-C, Wang J-C. Regulation of glucose homeostasis by glucocorticoids. Advances in Experimental Medicine and Biology. 2015;872:99-126.