Abstract
Newer classes of medications have been proven useful in glycemic control in type 2 diabetes (T2D), but many do not appear capable to slow down the progressive loss of ß-cell function, or to improve population-level glycemic control. Positive energy balance, e.g. surplus energy intake over expenditure, is at the core for developing metabolic syndrome and T2D. Currently available glycemic control drugs come to the market based on their 1-2 years risk-benefit profiles, but most of them do not correct positive energy balance and lose efficacy in the long-term. This denouement is destined by a positive energy balance of T2D. There is continuous endeavor/investment in new drugs for T2D. In this review, we compared the effects of commonly used oral hypoglycemic agents on energy balance and discussed several novel therapeutic targets/approaches for T2D that could potentially correct positive energy balance: changing the composition of intestinal host-microbiota to alleviate excess caloric consumption, controlling chylomicron uptake into intestinal lacteals to reduce excessive caloric intake, and activating pyruvate kinase M2 (PKM2) to ameliorate glucose metabolism and increase energy expenditure. We further reviewed how nicotine affects body weight and ameliorates positive energy balance, and ways to encourage people to adopt a more healthy lifestyle by exercising more and/or decreasing caloric intake. These potential targets/approaches may hopefully correct positive energy balance, delay disease progression, reverse some pathophysiological changes, and eventually prevent and/or cure the disease. Drug development strategies applying new insights into T2D process and therapeutic index to correct positive energy balance need to be seriously considered.
Keywords: Type 2 diabetes, positive energy balances, glycemic control, drug development strategy, intestinal microbiota, intestinal lacteal chylomicron, mitochondrial glycolytic flux.
Graphical Abstract
[1]
American Diabetes Association. 8. Pharmacologic approaches to glycemic treatment: Standards of medical care in diabetes - 2018. Diabetes Care 2018; 41(Suppl. 1): S73-85.
[2]
American Diabetes Association. Standards of medical care in diabetes-2017-pharmacologic approaches to glycemic treatment. Diabetes Care 2017; 40(Suppl. 1): S64-74.
[3]
New Drugs at FDA. Available at:. https://www.fda.gov/ Drugs/DevelopmentApprovalProcess/DrugInnovation/default.htm [accessed November 28, 2018].
[4]
Kahn SE. Haffner, Heise MA, Herman WH, Holman RR, Jones NP, Kravitz BG, Lachin JM, O’Neill MC, Zinman B, Viberti G, and ADOPT Study Group. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006; 355: 2427-43.
[5]
Lipska KJ, Yao X, Herrin J, et al. Trends in drug utilization, glycemic control, and rates of severe hypoglycemia, 2006–2013. Diabetes Care 2016; dc160985 Available at:
[http://dx.doi.org/10.2337/dc16-0985]
[http://dx.doi.org/10.2337/dc16-0985]
[6]
The Drug Development Process, Available at:. http://www.fda.gov/ ForPatients/Approvals/Drugs/default.htm [accessed November 28, 2018].
[7]
Bowes J, Brown AJ, Hamon J, et al. Reducing safety-related drug attrition: The use of in vitro pharmacological profiling. Nat Rev Drug Discov 2012; 11: 909-22.
[9]
Speakman JR. A nonadaptive scenario explaining the genetic predisposition to obesity: The ‘predation release’ hypothesis. Cell Metab 2007; 6: 5-12.
[10]
Cao W, Ning J, Yang X, Liu Z. Excess exposure to insulin is the primary cause of insulin resistance and its associated atherosclerosis. Curr Mol Pharmacol 2011; 4: 154-66.
[11]
Galgani J, Ravussin E. Energy metabolism, fuel selection and body weight regulation. Int J Obes (Lond) 2008; 32(Suppl. 7): S109-19.
[12]
What Is Metabolic Syndrome? Available at: https://www.nhlbi. nih.gov/health/health-topics/topics/ms [accessed November 28, 2018].
[13]
American Heart Association. Heart disease and stroke statistics - 2016 update. Circulation 133: e38-e360, 2016.
[14]
Catapano AL, Graham I, Backer GD, et al. 2016 ESC/EAS Guidelines for the management of dyslipidaemias. Eur Heart J 2011; 32: 1769-818.
[15]
Whelton PK, Carey RM, Aronow WS, et al. 2017 Guideline for the prevention, detection, evaluation, and management of high blood pressure in adults. Available at: https://www.acc.org/ ~/media/Non-Clinical/Files-PDFs-Excel-MS-Word-etc/Guidelines/ 2017/Guidelines_Made_Simple_2017_HBP.pdf [accessed November 28, 2018].
[16]
Mihaylova B, Emberson J, Blackwell L, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: Meta-analysis of individual data from 27 randomized trials. Lancet 2012; 380: 581-90.
[17]
Abramson JD, Rosenberg HG, Jewell N, Wright JM. Should people at low risk of cardiovascular disease take a statin? BMJ 347: f6123, 2013.
[18]
Ray KK, Seshasai SR, Erqou S, et al. Statins and all-cause mortality in high-risk primary prevention: A meta-analysis of 11 randomized controlled trials involving 65,229 participants. Arch Intern Med 2010; 170: 1024-31.
[19]
DuBroff R, de Lorgeril M. Cholesterol confusion and statin controversy. World J Cardiol 2015; 7: 404-9.
[20]
Seneff S. How statins really work explains why they don’t really work. Available at: https://people.csail.mit.edu/seneff/why_statins_ dont_really_work.html [accessed November 28, 2018].
[21]
Rojas LBA, Gomes MA. Metformin: An old but still the best treatment for type 2 diabetes. Diabetol Metab Syndr 2013; 5: 6.
[22]
Kirpichnikov M, McFarlane SI, Sowers JR. Metformin: An update. Ann Intern Med 2002; 137: 25-33.
[23]
Kim CH, Han KA, Oh HJ, et al. Safety, tolerability, and efficacy of metformin extended-release oral antidiabetic therapy in patients with type 2 diabetes: An observational trial in Asia. J Diabetes 2012; 4: 395-406.
[24]
Vallon V, and Thomas SC. Targeting renal glucose reabsorption to treat hyperglycemia: The pleiotropic effects of SGLT2 inhibition. Diabetologia 2017; 60: 215-25.
[25]
Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015; 373: 2117-28.
[26]
Fitchett D, Zinman B, Wanner C, et al. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: Results of the EMPA-REG OUTCOME® trial. Eur Heart J 2016; 37: 1526-34.
[27]
FDA approves Jardiance to reduce cardiovascular death in adults with type 2 diabetes. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm531517.htm [accessed November 28, 2018].
[29]
Ferrannini E, Mark M, Mayoux E. CV protection in the EMPA-REG outcome trial: A “Thrifty Substrate” hypothesis. Diabetes Care 2016; 39: 1108-14.
[30]
Neeland IJ, Natalia de Albuquerque R, McGuire DK. Cardiovascular effects of sodium glucose cotransporter 2 inhibitors: The search for the how and Why. Available at: http:// www.acc.org/latest-in-cardiology/articles/2016/06/29/13/48/cardio- vascular-effects-of-sodium-glucose-cotransporter-2-inhibitors? w_nav=TI [accessed November 28, 2018].
[31]
Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016; 375: 323-34.
[32]
Sodium-glucose Cotransporter-2 (SGLT2) Inhibitors. Available at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm446852.htm [accessed November 28, 2018].
[33]
FDA issues Boxed Warning for canagliflozin. Available at: http://www.healio.com/endocrinology/diabetes/news/online/%7B7a5e6431-49ac-4788-ba04-aa5b69aca34b%7D/fda-issues-boxed-warning-for-canagliflozin [accessed November 28, 2018].
[34]
Rieg T, Masuda T, Gerasimova M, et al. Increase in SGLT1-mediated transport explains renal glucose reabsorption during genetic and pharmacological SGLT2 inhibition in euglycemia. Am J Physiol Renal Physiol 2014; 306: F188-93.
[35]
Port A, Macha S, Seman L, et al. Safety, tolerability, pharmacokinetics and pharmacodynamics of BI 10773, a sodium glucose cotransporter-2 (SGLT2) inhibitor, in healthy volunteers. Presented at the 70th Annual Meeting of the American Diabetes Association. 25- 29 June 2010, Orlando.
[36]
Komoroski B, Vachharajani N, Boulton D, et al. Dapagliflozin, a novel SGLT2 inhibitor, induces dose-dependent glucosuria in healthy subjects. Clin Pharmacol Ther 2009; 85: 520-6.
[37]
Martinez-Martin FJ, Jimenez-Martin N, Sablon-Gonzalez N. SGLT1 does compensate for SGLT2 inhibition. Eur Heart J Cardiovasc Pharmacother 2016; 2: 256.
[38]
Neeland IJ, McGuire DK, Clinton R, et al. Empagliflozin reduces body weight and indices of adipose distribution in patients with type 2 diabetes mellitus. Diab Vasc Dis Res 2016; 13: 119-26.
[39]
Neeland IJ, Gupta S, Ayers CR, et al. Relation of regional fat distribution to left ventricular structure and function. Circ Cardiovasc Imaging 2013; 6: 800-7.
[40]
Neeland IJ, Turer AT, Ayers CR, et al. Body fat distribution and incident cardiovascular disease in obse adults. J Am Coll Cardiol 2015; 65: 2150-1.
[42]
Vidal-Puig AJ, Considine RV, Jimenez-Liñan M, et al. Peroxisome proliferator-activated receptor gene expression in human tissues. Effects of obesity, weight loss, and regulation by insulin and glucocorticoids. J Clin Invest 1997; 99: 2416.
[43]
Iwamoto Y, Kosaka K, Kuzuya T, et al. Effects of troglitazone: A new hypoglycemic agent in patients with NIDDM poorly controlled by diet therapy. Diabetes Care 1996; 19: 151.
[44]
Nolan JJ, Ludvik B, Beerdsen P, et al. Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone. N Engl J Med 1994; 331: 1188.
[45]
Ferwana M, Firwana B, Hasan R, et al. Pioglitazone and risk of bladder cancer: A meta-analysis of controlled studies. Diabetes medicine 2013. 30: 1026-32.
[46]
Dormandy JA, Charbonnel B, Eckland DJA, et al. PROactive Investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macrovascular Events): A randomised controlled trial. Lancet 2005; 366: 1279-89.
[47]
Singh S, Loke YK, Furberg CD. Long-term risk of cardiovascular events with rosiglitazone: A meta-analysis. JAMA 2007; 298: 1189-95.
[48]
Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: A meta-analysis of randomized trials. JAMA 2007; 298: 1180-8.
[49]
Liu H, Hong T, Wen G, et al. Increased basal level of Akt-dependent insulin signaling may be responsible for the development of insulin resistance. Am J Physiol Endocrinol Metab 2009; 297: E898-906.
[50]
Vella A. Mechanism of action of dpp-4 inhibitors-new insights. J Clin Endocrinol Metab 2012; 97: 2626-8.
[51]
Zhang Y, McCoy RG, Mason JE, et al. Second-line agents for glycemic control for type 2 diabetes: Are newer agents better? Diabetes Care 2014; 37: 1338-45.
[52]
van Raalte DH, Verchere CB. Glucagon-like peptide-1 receptor agonists: Beta-cell protection or exhaustion? Trends in Endocrinology & Metabolism 2016; 27: 442-5.
[53]
Abdulreda MH, Rodriguez-Diaz R, Caicedo A, Berggren PO. Liraglutide compromises pancreatic beta cell function in a humanized mouse model. Cell Metab 2016; 23: 541-6.
[54]
Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Microbial ecology: Human gut microbes associated with obesity. Nature 2006; 444: 1022-3.
[55]
Ridaura VK, Faith JJ, Rey FE, et al. Cultured gut microbiota from twins discordant for obesity modulate adiposity and metabolic phenotypes in mice. Science 2013; 341: 1241214.
[56]
Kootte RS, Levin E, Salojarvi J, et al. Improvement of insulin sensitivity after lean donor feces in metabolic syndrome is driven by baseline intestinal microbiota composition. Cell Metab 2017; 26: 611-9.
[57]
Vijay-Kumar M, Aitken JD, Carvalho FA, et al. Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science 2010; 328: 228-31.
[58]
Lu P, Sodhi CP, Yamaguchi Y, et al. Intestinal epithelial Toll-like receptor 4 prevents metabolic syndrome by regulating interactions between microbes and intestinal epithelial cells in mice. Mucosal Immunol 2018; 11: 727-40.
[59]
Iqbal J, Hussain MM. Intestinal lipid absorption. Am J Physiol Endocrinol Metab 2009; 296: E1183-94.
[60]
Dixon JB. Mechanisms of chylomicron uptake into lacteals. Ann N Y Acad Sci 2010; 1207(Suppl. 1): E52-7.
[62]
Bae D, Lu S, Taglienti CA, Mercurio AM. Metabolic stress induces the lysosomal degradation of neuropilin-1 but not neuropilin-2. J Biol Chem 2008; 283: 28074-80.
[63]
Roth L, Prahst C, Ruckdeschel T, et al. Neuropilin-1 mediates vascular permeability independently of vascular endothelial growth factor receptor-2 activation. Sci Signal 2016; 9: ra42.
[64]
NRP1 neuropilin 1 [ Homo sapiens (human)]. Available at: https://www.ncbi.nlm.nih.gov/gene/8829 [accessed November 28, 2018].
[65]
Guo H, Vander Kooi CW. Neuropilin functions as an essential cell surface receptor. J Biol Chem 2015; 290: 29120-6.
[66]
Eichmann AC. Neurovascular cross-talk and passible pathological implications. Keystone Symposia Santa Fe NM 2018; p. 25.
[67]
Keenan HA, Costacou T, Sun JK, et al. Clinical factors associated with resistance to microvascular complications in diabetic patients of extreme disease duration - the 50-year medalist study. Diabetes Care 2007; 30: 1995-7.
[68]
Qi W, Keenan HA, Li Q, et al. Pyruvate kinase M2 activation may protect against the progression of diabetic glomerular pathology and mitochondrial dysfunction. Nat Med 2017; 23: 753-62.
[69]
Mazurek S. Pyruvate kinase type M2: A key regulator of the metabolic budget system in tumor cells. Int J Biochem Cell Biol 2011; 43: 969-80.
[70]
Dong G, Mao Q, Xia W, et al. PKM2 and cancer: The function of PKM2 beyond glycolysis. Oncol Lett 2016; 11: 1980-6.
[71]
Hsu M, Hung W. Pyruvate kinase M2 fuels multiple aspects of cancer cells: From cellular metabolism, transcriptional regulation to extracellular signaling. Mol Cancer 2018; 17: 35.
[72]
Christofk HR, Vander Heiden MG, Harris MH, et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumor growth. Nat 2008; 452: 230-3.
[73]
Israelsen WJ, Dayton TL, Davidson SM, et al. PKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells. Cell 2013; 155: 397-409.
[74]
Dayton TL, Gocheva V, Miller KM, et al. Germline loss of PKM2 promotes metabolic distress and hepatocellular carcinoma. Genes Dev 2016; 30: 1020-33.
[75]
Lin Y, Meng F, Lu Z, et al. Knockdown of PKM2 suppresses tumor progression in human cervical cancer by modulating epithelial - mesenchymal transition via Wnt/β-catenin signaling. Cancer Manag Res 2018; 10: 4191-202.
[76]
Spoden GA, Mazurek S, Morandell D, et al. Isotype‐specific inhibitors of the glycolytic key regulator pyruvate kinase subtype M2 moderately decelerate tumor cell proliferation. Carcinogenesis 2008; 123: 312-21.
[77]
Goldberg MS, Sharp PA. Pyruvate kinase M2-specific siRNA induces apoptosis and tumor regression. J Exp Med 2012; 209: 217-24.
[78]
Anastasiou D, Yu Y, Israelsen WJ, et al. Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis. Nat Chem Biol 2012; 8: 839-47.
[79]
What Are the Risks of Smoking? Available at: https:// www.nhlbi.nih.gov/health/health-topics/topics/smo/risks [accessed November 28, 2018].
[80]
A Report of the Surgeon General, 2014, The Health Consequences of Smoking - 50 Years of Progress. Available at: https://www.surgeongeneral.gov/library/reports/50-years-of-progress/full-report.pdf [accessed November 28, 2018].
[81]
Fewer Americans smoke. More are obese. Is there a connection? Available at: https://www.statnews.com/2016/02/05/are-fewer-smokers-obesity-rate-linked/ [accessed November 28, 2018].
[82]
Williamson DF, Madans J, Anda RF, et al. Smoking cessation and severity of weight gain in a national cohort. N Engl J Med 1991; 324: 739-45.
[83]
Froom P, Melamed S, Benbassat J. Smoking cessation and weight gain. J Fam Pract 1998; 46: 460-4.
[84]
Aubin H, Farley A, Lycett D, Lahmek P, Aveyard P. Weight gain in smokers after quitting cigarettes: Meta-analysis. BMJ 2012; 345.
[85]
Courtemanche C, Tchernis R, Ukert B. The effect of smoking on obesity: Evidence from a randomized trial. National bureau of economic research working paper No. 21937, issued in January 2016. Available at: http://www.nber.org/papers/w21937 [accessed November 28, 2018].
[86]
Adult Obesity Facts. Available at: https://www.cdc.gov/obesity/ data/adult.html [accessed November 28, 2018].
[87]
Health Effects of Cigarette Smoking. Available at: https://www.cdc.gov/tobacco/data_statistics/fact_sheets/health_effects/effects_cig_smoking/ [accessed November 28, 2018].
[88]
Audrain-McGovern J, Benowitz NL. Cigarette smoking, nicotine, and body weight. Clin Pharmacol Ther 2011; 90: 164-8.
[89]
Nguyen-Huynh MN, Young JD, Alexeeff S, et al. Shake, rattle & roll trial - improving blood pressure control among african americans. International Stroke Conference, Houston, TX, February 23, 2017. Available at: http://www.abstractsonline.com/ pp8/#!/4172/ presentation/12313 [accessed November 28, 2018].
[90]
Description of the DASH Eating Plan. Available at: https://www.nhlbi.nih.gov/health/health-topics/topics/dash [accessed November 28, 2018].
[91]
Torgerson JS, Hauptman J, Boldrin MN, Sjöström L. XENical in the prevention of diabetes in obese subjects (XENDOS) study: A randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care 2004; 27: 155-61.
[92]
NIDDK. Prescription Medications to Treat Overweight and Obesity. Available at: https://www.niddk.nih.gov/health-information/ weight-management/prescription-medications-treat-overweight-obesity [accessed November 28, 2018].
[93]
Muller PY, Milton MN. The determination and interpretation of the therapeutic index in drug development. Nat Rev Drug Discov 2012; 11: 751-61.
[94]
Ahmadieh H, Ghazal N, Azar S. Role of sodium glucose co-transporter-2 inhibitors in pre-diabetes and their extra-glycemic effects. Int Arch Med 2016; 9(258)
[95]
SGLT2 inhibitors in prediabetes trials. Available at: https://clinicaltrials.gov/ct2/results?term=prediabetes+and+SGLT2+inhibitor&type=&rslt=&recr=&age_v=&gndr=&cond=&intr=&tit les=&outc=&spons=&lead=&id=&state1=&cntry1=&state2=&cntr y2=&state3=&cntry3=&locn=&rcv_s=&rcv_e=&lup_s=&lup_e= [accessed November 28, 2018].
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