Diabetes:On the Endless Way of Finding a CureIntroductionDiabetes, though have long been documented, its impacton public health is getting greater. This situation, in which drugs ofunclarified molecular mechanisms are still beingused as primary methods oftreatment, seems so hard to understand considering modern advancement in biology and medicine. Luckily recentdevelopment of molecular biology and genetics have shed some light on uncoveringunderlying mechanism of diabetes and howdrugs work in coordination with body’s metabolic and signaling network tocorrect this condition. ALittle HistoryDescribed by an ancient Egyptian manuscript fromapproximately 1500 BCE, diabetes is now prevailing significantly throughout theworld. The Ancient Greek physician Aretaeus ofCappadocia (fl. 1st century CE)4 was believed to give the first completeclinical documentation, who also mentioned the excess amount of urine in thepatients.3 Since then, a series of milestones discoveries have provided ascientific framework for understanding the metabolic syndrome.
Major milestones include:45Development of Metformin in 1922 for treatment of type 2 Diabetes4Development of the long-acting insulin NPH in the 1940s by Novo-Nordisk2Reintroduction of the use of biguanides for Type 2 diabetes in the late1950s. The initial phenformin was withdrawn worldwide (in the U.S. in 1977) dueto its potential for sometimes fatal lactic acidosis, and metformin was firstmarketed in France in 1979, but not until 1994 in the US.4Invention of amino acid sequencing method and the sequencing of insulin’stwo peptides (by Sir Frederick Sanger’s Nobel Prize winning work).10The radioimmunoassay for insulin, as discovered by Rosalyn Yalow andSolomon Berson (gaining Yalow the 1977 Nobel Prize in Physiology orMedicine)12The three-dimensional structure of insulin (PDB: 2INS?)4Dr. Gerald Reaven’s identification of the constellation of symptoms nowcalled metabolic syndrome in 19884Identification of the first thiazolidinedione as an effective insulinsensitizer during the 1990s4Categories ofDiabetesToday’s medical science categorizediabetes into 3 major groups, type 1, type 2 and other specific types relatedto genetic defects of the glucose pathway components.101 Type 1 DiabetesType 1 diabetes resulted from cellularmediated ?-cell destruction,often by autoimmunity, while insulin receptor may remain fully functional.
101Some patients have permanent insulinopenia and are prone to ketoacidosis, buthave no evidence of autoimmunity.101 This condition called idiopathicdiabetes, are also categorized as type 1 diabetes. Though caused directly by apparenttissue damage, the precise origins of type 1 diabetes are largely unknown101,as it requires a deeper understanding of autoimmunity.
All patients eventuallybecome dependent on insulin for survival.101 In the end stage of type 1diabetes, very low or even no plasma C-peptide can be observed, resulting inlittle or no insulin secretion.101 Lifetime administration of insulinproducts can effectively suppress the symptom to an extent allowing patients tolive to their normal life expectancy.
102Type 2 DiabetesIn contrast, type 2 diabetes iscaused by deficient response of glucose-controlling system to insulin.101 Thepatients have relative rather than absolute insulin deficiency in this kind ofcases. From predominantly insulin resistance with relative insulin deficiencyto predominantly an insulin secretory defect with significant insulinresistance, are all within the range of the type 2 category.
101 Its frequency variesin different racial/ethnic subgroups. It is often associated with a stronggenetic predisposition, more so than is the autoimmune form of type 1diabetes.101 However, the genetics of this form of diabetes are complex andnot clearly defined.101,102Patients with this kind of diabetes develop their hyperglycemia slowly buthard to find and control101.
Astonishingly we are still relying on metformin,an ‘ancient’ drug, as one of a few drugs for this condition. According to AmericanDiabetes Association Standards of Medical Care in Diabetes106 and European Associationfor the Study of Diabetes, metformin is the only recommended first-line therapyfor type-2 diabetes. Our current knowledge about metformin molecular mechanismis limited but clear evidence of the molecule acting as a multi-pathwaymetabolic regulator.103,107,301 Other Than Type 1 and Type 2 DiabetesSeveral other forms of diabetes areassociated with genetic defects, or injuries to the pancreas. This categoryinclude genetic defect of the ?-cell, genetic defects in insulin action, diseases of the exocrinepancreas, endocrinopathies (excess hormones that antagonize insulin action),drug- or chemical-induced diabetes, infections, uncommon forms ofimmune-mediated diabetes (the stiff-man syndrome and the anti-insulin receptorautoimmunity, formerly termed type B insulin resistance).101New Advancements, New HopeRecent Developmentsin Type 1 DiabetesIt seems straightforward to treattype 1 diabetes simply with insulin. But recent studies show in some cases itis the gluten in foods has a close link to the autoimmune response that damages?-cell.
202,205,207,208,201 Gluten tendsto cause loss of a kind of proteins, Zonulin202,207, which constitutes tightjunctions between intestinal epithelium cells. This loss of Zonulin, in certainpeople, can cause severe damage to the intestinal lining, letting gluten toenter the bloodstream directly and then comes autoimmunity.206 Patientshaving pathologic pathway can be successfully treated by removing gluten fromtheir daily diet without using insulin.201 This discovery shows how little weknow about its original cause and further researches are needed to validate thedirect link between gluten and cell damage.
Metformin: One SimpleMolecule, Several New Discoveries, One Long Quest On the year of 1957, Jean Sternintroduced biguanides to diabetes treatment.301 The biguanides successfullyavoid toxicity and side-effects of other guanide species. Metformin was chosenfor further clinical development based on animal experiments data, followed bytwo more potent molecules from the same family-phenformin and buformin. However, phenformin and buformin weresoon found to have severe side-effects, especially lactic acidosis, thereforewere withdrawn from medical use.302 Worldwide use of metformin wassignificantly affected since it also belongs to biguanides family.301Metformin became available in the British National Formulary in 1958. It wassold in the UK by Rona, a subsidiary of Aron Laboratories.
Metformin wasapproved in Canada in 1972 but did not receive approval by the US FDA until1994301, partly due to the concern for its safety after the withdraw.Years later a research from theUnited Kingdom Prospective Diabetes Study (UKPDS) helped regain confidence inthe drug. Giving the strongest evidence of safety and effectiveness, theresearch revealed the benefits of metformin in reducing cardiovascularmortality and increasing the overall survival rate of obese diabeticpatients.
301,303 Along with other convincing data analysis corroborating metformin’smedical viability and incomparable benefits.304,305Now as research of metformin’smolecular mechanism accumulate, we are finally able to draw the framework ofthe drug’s unique interaction with cell metabolism pathways. Although the exacttarget of the drug on molecular level remains unidentified306, the primaryeffect of metformin is mostly by mild inhibition of mitochondrial respiratory-chaincomplex 1307. Metformin’s maximum inhibitory effect on complex 1 is about 40%compared to about 80% of the reference inhibitor rotenone.307 This causes AMP/ATPratio to rise. AMP is an allosteric activator of tumor suppressorserine/threonine kinase 11 (STK11/LKB1) and CaMKK?, and these two upstreamkinases phosphorylate Thr172 of AMP-activated protein kinase’s (AMPK) ? subunit, activating it.308 AMPK is a phylogeneticallyconserved serine/threonine protein kinase viewed as a fuel gauge monitoringsystemic and cellular energy status and which plays a crucial role inprotecting cellular functions under energy-restricted conditions.
306 Interestinglyrecent discoveries also find ADP. Therefore ADP/ATP ratio could directlyregulate AMPK’s ? subunit,too.309,310 The whole process in all switches cells from anabolic tocatabolic state. Fig. 1. Themitochondrial respiratory-chain complex 1 is the primary target of metformin.306Due to its high acid dissociation constant (pKa=12.
4) metformin exists in apositively charged protonated form under physiological conditions and, as aresult, can only marginally cross the plasma membrane by passive diffusion.Thus, its intracellular transport is mediated by different isoforms of theorganic cation transporters (OCT) depending on the tissue considered (e.g.,OCT1 in liver or OCT2 in kidney).306Maida et al. discoveredthat metformin acutely increases plasma levels of glucagon-like peptide 1(GLP-1) and induces islet incretin receptor geneexpression through a mechanism that is dependent on peroxisomeproliferator-activated receptor (PPAR)-?.
315However, a growing body of evidence from clinical studies andanimal models suggests that the primary function of metformin is to decreasehepatic glucose production312, mainly by inhibiting gluconeogenesis313,314.The improvement in insulinsensitivity by metformin could be ascribed to its positive effects on insulinreceptor expression and tyrosine kinase activity.311 Conclusion andSummaryJean Sterne noted in the firstpublication on metformin that “It metformin is well-tolerated in man, attherapeutic doses, but its mechanism of action and its ultimate place in themanagement of diabetes requires further study.”301 This miracle drug stillhas huge potential even by today’s standard. After 90 years and many newdiscoveries on its biological function, metformin never stops giving us surprisessince its first synthesis in 1927. Its exact mechanism is the core tounderstand diabetes and will yield unimaginable medical value once clarified bystructural biology.References3.4.
Trikkalinou A, Papazafiropoulou AK, Melidonis A.Type 2 diabetes and quality of life. World J Diabetes 2017; 8(4): 120-129.5. 101.
American Diabetes Association. (2010). Diagnosisand Classification of Diabetes Mellitus. Diabetes Care, 33(Suppl 1), S62–S69. http://doi.org/10.2337/dc10-S062102.
Nature Publishing Group. (2000). Targeteddisruption of the glucose transporter 4selectively in muscle causes insulin resistance and glucose intolerance. NatureMedicine 6, 924–928. doi:10.1038/78693103. Gunton JE, Delhanty PJ, Takahashi S, Baxter RC.
Metformin rapidly increases insulin receptor activation in human liver andsignals preferentially through insulin-receptor substrate-2. J Clin EndocrinolMetab. 2003;88:1323–1332.106. Inzucchi SE, Bergenstal RM, Buse JB, et al.Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American DiabetesAssociation (ADA) and the European Association for the Study of Diabetes(ESAD). Diabets Care 2012; 35: 1364-79.107.
Zhou, G., Myers, R., Li, Y., Chen, Y.
, Shen, X.,Fenyk-Melody, J., … Moller, D.
E. (2001). Roleof AMP-activated protein kinase in mechanism of metformin action. Journal ofClinical Investigation; 108(8), 1167–1174.
301. Patade GR,Marita AR. Metformin: A Journey from countrysideto the bedside. J Obes Metab Res 2014; 1: 127-30.302. Nattrass M, Alberti KG. Biguanides.
Diabetologia1978; 14: 71-4.303. Effect of intensive blood-glucose control withmetformin on complications in overweight patients with type 2 diabetes (UKPDS34). The Lancet; Volume 352, Issue 9131, 854 – 865.304. Hermann LS. Metformin: A review of itspharmacological properties and therapeutic use. DiabeteMetab 1979; 5: 233-45.
305. Campbell IW, Howlett HC. Worldwide experience ofmetformin as an effective glucose-lowering agent: A meta-analysis.
DiabetesMetab Rev 1995; 11 Suppl 1: S57-62.306. Viollet, B., Guigas, B., Sanz Garcia, N.,Leclerc, J., Foretz, M., & Andreelli, F.
(2012). Cellular and molecularmechanisms of metformin: an overview. Clinical Science (London, England: 1979);122(6): 253–270. http://doi.org/10.1042/CS20110386307. Stephenne X, Foretz M, Taleux N, van der Zon G,Sokal E, Hue L, Viollet B, Guigas B. Metformin activates AMP-activated proteinkinase in primary human hepatocytes by decreasing cellular energy status.
Diabetologia. 2011 in the press.308. Viollet B, Guigas B, Leclerc J, Hebrard S,Lantier L, Mounier R, Andreelli F, Foretz M. AMP-activated protein kinase inthe regulation of hepatic energy metabolism: from physiology to therapeuticperspectives. Acta Physiol (Oxf) 2009; 196: 81–98.
309. Oakhill JS, Steel R, Chen ZP, Scott JW, Ling N,Tam S, Kemp BE. AMPK is a direct adenylate charge-regulated protein kinase.Science. 2011; 332: 1433–1435.310.
Xiao B, Sanders MJ, Underwood E, Heath R, MayerFV, Carmena D, Jing C, Walker PA, Eccleston JF, Haire LF, Saiu P, Howell SA,Aasland R, Martin SR, Carling D, Gamblin SJ. Structure of mammalian AMPK andits regulation by ADP. Nature. 2011; 472: 230–233.
311. Gunton JE, Delhanty PJ, Takahashi S, Baxter RC.Metformin rapidly increases insulin receptor activation in human liver andsignals preferentially through insulin-receptor substrate-2. J Clin EndocrinolMetab. 2003; 88: 1323–1332.312. Cusi K, Consoli A, DeFronzo RA. Metabolic effectsof metformin on glucose and lactate metabolism in noninsulin-dependent diabetesmellitus.
J Clin Endocrinol Metab. 1996; 81: 4059–4067.313.
Hundal RS, Krssak M, Dufour S, Laurent D, LebonV, Chandramouli V, Inzucchi SE, Schumann WC, Petersen KF, Landau BR, ShulmanGI. Mechanism by which metformin reducesglucose production in type 2 diabetes. Diabetes. 2000; 49: 2063–2069.314.
Natali A, Ferrannini E. Effects of metformin andthiazolidinediones on suppression of hepatic glucose production and stimulationof glucose uptake in type 2 diabetes: a systematic review. Diabetologia. 2006;49: 434–441.315. Maida A, Lamont BJ, Cao X, Drucker DJ.
Metforminregulates the incretin receptor axis via a pathway dependent on peroxisomeproliferator-activated receptor-alpha in mice. Diabetologia. 2011; 54: 339–349
