Berberine is an insulin secretagogue targeting the KCNH6 potassium channel
Miao-Miao Zhao, Jing Lu, Sen Li, Hao Wang, Xi Cao, Qi Li, Ting-Ting Shi, Kohichi Matsunaga, Chen Chen, Haixia Huang, Tetsuro Izumi, Jin-Kui Yang, Miao-Miao Zhao, Jing Lu, Sen Li, Hao Wang, Xi Cao, Qi Li, Ting-Ting Shi, Kohichi Matsunaga, Chen Chen, Haixia Huang, Tetsuro Izumi, Jin-Kui Yang
Abstract
Coptis chinensis is an ancient Chinese herb treating diabetes in China for thousands of years. However, its underlying mechanism remains poorly understood. Here, we report the effects of its main active component, berberine (BBR), on stimulating insulin secretion. In mice with hyperglycemia induced by a high-fat diet, BBR significantly increases insulin secretion and reduced blood glucose levels. However, in mice with hyperglycemia induced by global or pancreatic islet β-cell-specific Kcnh6 knockout, BBR does not exert beneficial effects. BBR directly binds KCNH6 potassium channels, significantly accelerates channel closure, and subsequently reduces KCNH6 currents. Consequently, blocking KCNH6 currents prolongs high glucose-dependent cell membrane depolarization and increases insulin secretion. Finally, to assess the effect of BBR on insulin secretion in humans, a randomized, double-blind, placebo-controlled, two-period crossover, single-dose, phase 1 clinical trial (NCT03972215) including 15 healthy men receiving a 160-min hyperglycemic clamp experiment is performed. The pre-specified primary outcomes are assessment of the differences of serum insulin and C-peptide levels between BBR and placebo treatment groups during the hyperglycemic clamp study. BBR significantly promotes insulin secretion under hyperglycemic state comparing with placebo treatment, while does not affect basal insulin secretion in humans. All subjects tolerate BBR well, and we observe no side effects in the 14-day follow up period. In this study, we identify BBR as a glucose-dependent insulin secretagogue for treating diabetes without causing hypoglycemia that targets KCNH6 channels.
Conflict of interest statement
The authors declare no competing interests.
© 2021. The Author(s).
Figures
References
- Newman DJ, Cragg GM. Natural products as sources of new drugs from 1981 to 2014. J. Nat. Products. 2016;79:629.
- Tu Y. The discovery of artemisinin (qinghaosu) and gifts from Chinese medicine. Nat. Med. 2011;17:1217–1220.
- Zhou, J. et al. Xiaokeyinshui extract combination, a berberine-containing agent, exerts anti-diabetic and renal protective effects on rats in multi-target mechanisms. J. Ethnopharmacol. 10.1016/j.jep.2020.113098 (2020).
- Liang Y, et al. Effects of berberine on blood glucose in patients with type 2 diabetes mellitus: a systematic literature review and a meta-analysis. Endocr. J. 2019;66:51–63.
- International Hypoglycaemia Study, G. Hypoglycaemia, cardiovascular disease, and mortality in diabetes: epidemiology, pathogenesis, and management. Lancet Diabetes Endocrinol. 2019;7:385–396.
- Hugill A, Shimomura K, Ashcroft FM, Cox RD. A mutation in KCNJ11 causing human hyperinsulinism (Y12X) results in a glucose-intolerant phenotype in the mouse. Diabetologia. 2010;53:2352–2356.
- Huopio H, et al. A new subtype of autosomal dominant diabetes attributable to a mutation in the gene for sulfonylurea receptor 1. Lancet. 2003;361:301–307.
- Yang JK, et al. From hyper- to hypoinsulinemia and diabetes: effect of KCNH6 on insulin secretion. Cell Rep. 2018;25:3800–3810.
- Herrington J, et al. Blockers of the delayed-rectifier potassium current in pancreatic beta-cells enhance glucose-dependent insulin secretion. Diabetes. 2006;55:1034–1042.
- Yang SN, et al. Glucose recruits K(ATP) channels via non-insulin-containing dense-core granules. Cell Metab. 2007;6:217–228.
- Lee YS, et al. Berberine, a natural plant product, activates AMP-activated protein kinase with beneficial metabolic effects in diabetic and insulin-resistant states. Diabetes. 2006;55:2256–2264.
- Yu YL, et al. Huang-lian-jie-du-decoction modulates glucagon-like peptide-1 secretion in diabetic rats. J. Ethnopharmacol. 2009;124:444–449.
- Zhou Z, Gong Q, Epstein ML, January CT. HERG channel dysfunction in human long QT syndrome. Intracellular transport and functional defects. J. Biol. Chem. 1998;273:21061–21066.
- El-Brolosy MA, et al. Genetic compensation triggered by mutant mRNA degradation. Nature. 2019;568:193–197.
- Ma Z, et al. PTC-bearing mRNA elicits a genetic compensation response via Upf3a and COMPASS components. Nature. 2019;568:259–263.
- Ito T, et al. Identification of a primary target of thalidomide teratogenicity. Science. 2010;327:1345–1350.
- Yoshida M, et al. Regulation of voltage-gated K+ channels by glucose metabolism in pancreatic beta-cells. FEBS Lett. 2009;583:2225–2230.
- MacDonald PE, et al. Inhibition of Kv2.1 voltage-dependent K+ channels in pancreatic beta-cells enhances glucose-dependent insulin secretion. J. Biol. Chem. 2002;277:44938–44945.
- Guo, J. H. et al. Glucose-induced electrical activities and insulin secretion in pancreatic islet β-cells are modulated by CFTR. Nat. Commun.10.1038/ncomms5420 (2014).
- Elahi D. In praise of the hyperglycemic clamp. A method for assessment of beta-cell sensitivity and insulin resistance. Diabetes Care. 1996;19:278–286.
- Hannon TS, et al. Review of methods for measuring beta-cell function: design considerations from the Restoring Insulin Secretion (RISE) Consortium. Diabetes Obes. Metab. 2018;20:14–24.
- Ye M, Fu S, Pi R, He F. Neuropharmacological and pharmacokinetic properties of berberine: a review of recent research. J. Pharm. Pharmacol. 2009;61:831–837.
- Li G, Zhao M, Qiu F, Sun Y, Zhao L. Pharmacokinetic interactions and tolerability of berberine chloride with simvastatin and fenofibrate: an open-label, randomized, parallel study in healthy Chinese subjects. Drug Des. Dev. Ther. 2019;13:129–139.
- Alolga RN, et al. Significant pharmacokinetic differences of berberine are attributable to variations in gut microbiota between Africans and Chinese. Sci. Rep. 2016;6:27671.
- Zhang Y, et al. Treatment of type 2 diabetes and dyslipidemia with the natural plant alkaloid berberine. J. Clin. Endocrinol. Metab. 2008;93:2559–2565.
- Dong H, Wang N, Zhao L, Lu F. Berberine in the treatment of type 2 diabetes mellitus: a systemic review and meta-analysis. Evid. Based Complement. Alternat. Med. 2012;2012:591654.
- Yin J, Xing H, Ye J. Efficacy of berberine in patients with type 2 diabetes mellitus. Metab. Clin. Exp. 2008;57:712–717.
- Lan J, et al. Meta-analysis of the effect and safety of berberine in the treatment of type 2 diabetes mellitus, hyperlipemia and hypertension. J. Ethnopharmacol. 2015;161:69–81.
- Ligtenberg JJ, Venker CE, Sluiter WJ, Reitsma WD, Van Haeften TW. Effect of glibenclamide on insulin release at moderate and high blood glucose levels in normal man. Eur. J. Clin. Invest. 1997;27:685–689.
- Eldor R, et al. Discordance between central (Brain) and pancreatic action of exenatide in lean and obese subjects. Diabetes Care. 2016;39:1804–1810.
- Gjesing AP, et al. High heritability and genetic correlation of intravenous glucose- and tolbutamide-induced insulin secretion among non-diabetic family members of type 2 diabetic patients. Diabetologia. 2014;57:1173–1181.
- Hameed A, et al. Coixol amplifies glucose-stimulated insulin secretion via cAMP mediated signaling pathway. Eur. J. Pharmacol. 2019;858:172514.
- DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am. J. Physiol. 1979;237:E214–E223.
- Finol-Urdaneta RK, et al. Block of Kv1.7 potassium currents increases glucose-stimulated insulin secretion. EMBO Mol. Med. 2012;4:424–434.
- International Hypoglycaemia Study, G. Minimizing hypoglycemia in diabetes. Diabetes Care. 2015;38:1583–1591.
- Shankar SS, et al. Insulin secretory effect of sitagliptin: assessment with a hyperglycemic clamp combined with a meal challenge. Am. J. Physiol. Endocrinol. Metab. 2018;314:E406–E412.
- Hu H, et al. A potent antiarrhythmic drug N-methyl berbamine extends the action potential through inhibiting both calcium and potassium currents. J. Pharmacol. Sci. 2020;142:131–139.
- Chen H, et al. Berberine attenuates spontaneous action potentials in sinoatrial node cells and the currents of human HCN4 channels expressed in Xenopus laevis oocytes. Mol. Med. Rep. 2014;10:1576–1582.
- Kim HJ, Kim H, Jung MH, Kwon YK, Kim BJ. Berberine induces pacemaker potential inhibition via cGMP-dependent ATP-sensitive K+ channels by stimulating mu/delta opioid receptors in cultured interstitial cells of Cajal from mouse small intestine. Mol. Med. Rep. 2016;14:3985–3991.
- Yu D, et al. Inhibitory effects and mechanism of dihydroberberine on hERG channels expressed in HEK293 cells. PLoS ONE. 2017;12:e0181823.
- Li J, et al. Amorphous solid dispersion of Berberine mitigates apoptosis via iPLA2beta/Cardiolipin/Opa1 pathway in db/db mice and in Palmitate-treated MIN6 beta-cells. Int. J. Biol. Sci. 2019;15:1533–1545.
- Jiang YY, et al. Protective role of berberine and Coptischinensis extract on T2MD rats and associated islet Rin5f cells. Mol. Med. Rep. 2017;16:6981–6991.
- Dong Y, et al. Metabolomics study of type 2 diabetes mellitus and the antidiabetic effect of Berberine in zucker diabetic fatty rats using Uplc-ESI-Hdms. Phytother. Res. 2016;30:823–828.
- Liu L, et al. Uncoupling protein-2 mediates the protective action of berberine against oxidative stress in rat insulinoma INS-1E cells and in diabetic mouse islets. Br. J. Pharmacol. 2014;171:3246–3254.
- Rayasam GV, et al. Identification of berberine as a novel agonist of fatty acid receptor GPR40. Phytother. Res. 2010;24:1260–1263.
- Gao N, Zhao TY, Li XJ. The protective effect of berberine on beta-cell lipoapoptosis. J. Endocrinol. Invest. 2011;34:124–130.
- Yu Y, et al. Modulation of glucagon-like peptide-1 release by berberine: in vivo and in vitro studies. Biochem. Pharmacol. 2010;79:1000–1006.
- Lu SS, et al. Berberine promotes glucagon-like peptide-1 (7-36) amide secretion in streptozotocin-induced diabetic rats. J. Endocrinol. 2009;200:159–165.
- Wang ZQ, et al. Facilitating effects of berberine on rat pancreatic islets through modulating hepatic nuclear factor 4 alpha expression and glucokinase activity. World J. Gastroenterol. 2008;14:6004–6011.
- Ko BS, et al. Insulin sensitizing and insulinotropic action of berberine from Cortidis rhizoma. Biol. Pharm. Bull. 2005;28:1431–1437.
- Leng SH, Lu FE, Xu LJ. Therapeutic effects of berberine in impaired glucose tolerance rats and its influence on insulin secretion. Acta Pharmacol. Sin. 2004;25:496–502.
- Bai M, et al. Berberine inhibits glucose oxidation and insulin secretion in rat islets. Endocr. J. 2018;65:469–477.
- Lamontagne J, et al. Pioglitazone acutely reduces insulin secretion and causes metabolic deceleration of the pancreatic beta-cell at submaximal glucose concentrations. Endocrinology. 2009;150:3465–3474.
- Zhou L, et al. Berberine acutely inhibits insulin secretion from beta-cells through 3’,5’-cyclic adenosine 5’-monophosphate signaling pathway. Endocrinology. 2008;149:4510–4518.
- Yin J, et al. Effects of berberine on glucose metabolism in vitro. Metab. Clin. Exp. 2002;51:1439–1443.
- Turner N, et al. Berberine and its more biologically available derivative, dihydroberberine, inhibit mitochondrial respiratory complex I: a mechanism for the action of berberine to activate AMP-activated protein kinase and improve insulin action. Diabetes. 2008;57:1414–1418.
- Li Y, et al. Activation of AMPK by berberine promotes adiponectin multimerization in 3T3-L1 adipocytes. FEBS Lett. 2011;585:1735–1740.
- Mandarino LJ, Gerich JE. Prolonged sulfonylurea administration decreases insulin resistance and increases insulin secretion in non-insulin-dependent diabetes mellitus: evidence for improved insulin action at a postreceptor site in hepatic as well as extrahepatic tissues. Diabetes Care. 1984;7:89–99.
- Shiba T. Improvement of insulin resistance by a new insulin secretagogue, nateglinide–analysis based on the homeostasis model. Diabetes Res. Clin. Pract. 2003;62:87–94.
- Foretz M, Guigas B, Viollet B. Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus. Nat. Rev. Endocrinol. 2019;15:569–589.
- Beiroa D, et al. GLP-1 agonism stimulates brown adipose tissue thermogenesis and browning through hypothalamic AMPK. Diabetes. 2014;63:3346–3358.
- Lee KY, Kim JR, Choi HC. Gliclazide, a KATP channel blocker, inhibits vascular smooth muscle cell proliferation through the CaMKKbeta-AMPK pathway. Vasc. Pharmacol. 2018;102:21–28.
- Wang Q, Heimberg H, Pipeleers D, Ling Z. Glibenclamide activates translation in rat pancreatic beta cells through calcium-dependent mTOR, PKA and MEK signalling pathways. Diabetologia. 2008;51:1202–1212.
- Le Y, et al. Liraglutide ameliorates palmitate-induced oxidative injury in islet microvascular endothelial cells through GLP-1 receptor/PKA and GTPCH1/eNOS signaling pathways. Peptides. 2020;124:170212.
- Kapoor RR, et al. Hyperinsulinaemic hypoglycaemia and diabetes mellitus due to dominant ABCC8/KCNJ11 mutations. Diabetologia. 2011;54:2575–2583.
- Vieira TC, Bergamin CS, Gurgel LC, Moises RS. Hyperinsulinemic hypoglycemia evolving to gestational diabetes and diabetes mellitus in a family carrying the inactivating ABCC8 E1506K mutation. Pediatr. Diabetes. 2010;11:505–508.
- Wang H, et al. Loss of granuphilin and loss of syntaxin-1A cause differential effects on insulin granule docking and fusion. J. Biol. Chem. 2011;286:32244–32250.
- Kasai K, et al. Rab27a mediates the tight docking of insulin granules onto the plasma membrane during glucose stimulation. J. Clin. Invest. 2005;115:388–396.
- Gao J, et al. Inhibition of voltage-gated potassium channels mediates uncarboxylated osteocalcin-regulated insulin secretion in rat pancreatic beta cells. Eur. J. Pharmacol. 2016;777:41–48.
- MacDonald PE, Salapatek AM, Wheeler MB. Glucagon-like peptide-1 receptor activation antagonizes voltage-dependent repolarizing K(+) currents in beta-cells: a possible glucose-dependent insulinotropic mechanism. Diabetes. 2002;51:S443–S447.
- Wang H, et al. Melanophilinaccelerates insulin granule fusion without predocking to the plasma membrane. Diabetes. 2020;69:2655–2666.
- Korytkowski M, et al. Glimepiride improves both first and second phases of insulin secretion in type 2 diabetes. Diabetes Care. 2002;25:1607–1611.
- Liu D, et al. Arterial, arterialized venous, venous and capillary blood glucose measurements in normal man during hyperinsulinaemic euglycaemia and hypoglycaemia. Diabetologia. 1992;35:287–290.
Source: PubMed