Review article: Biomedical intelligence
Vol. 150 No. 2526 (2020)
Insulin under the influence of light
Summary
The discovery and administration of exogenous insulin has revolutionised diabetes treatment and continues, almost 100 years on, to be the basis for the management of insulin deficiency. However, insulin therapy still has potentially life-threatening side effects such as hypoglycaemia and increased risk of cardiovascular disease. So far, improvements in insulin therapy have focused mainly on modulating its pharmacokinetic and pharmacodynamic properties and improving delivery methods, while variations in the insulin sensitivity of peripheral tissues has received relatively little attention. Notably, tissue insulin sensitivity has been shown to vary considerably around the clock, which could contribute greatly to the effect (and risk of side effects) of a given dose of insulin. Recent evidence suggests that photic inputs regulate diurnal variations in the insulin sensitivity of metabolically relevant tissues via a previously unrecognised mechanism involving the ventromedial hypothalamic nucleus. Therefore, understanding the mechanisms underlying photic control of insulin action is of paramount medical importance. In addition, considering “when” (i.e., the time of day) could assist in deciding “how much” insulin should be administered and hence could aid the fine-tuning of insulin dosage, lowering the risk of side effects, and improving the quality of life of patients with insulin deficiencs.
References
- Unger RH, Orci L. Paracrinology of islets and the paracrinopathy of diabetes. Proc Natl Acad Sci USA. 2010;107(37):16009–12. doi:.https://doi.org/10.1073/pnas.1006639107
- Mueckler M, Thorens B. The SLC2 (GLUT) family of membrane transporters. Mol Aspects Med. 2013;34(2-3):121–38. doi:.https://doi.org/10.1016/j.mam.2012.07.001
- Parton LE, Ye CP, Coppari R, Enriori PJ, Choi B, Zhang CY, et al. Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity. Nature. 2007;449(7159):228–32. doi:.https://doi.org/10.1038/nature06098
- Hoang Do O, Thorn P. Insulin secretion from beta cells within intact islets: location matters. Clin Exp Pharmacol Physiol. 2015;42(4):406–14. doi:.https://doi.org/10.1111/1440-1681.12368
- Orci L, Amherdt M, Henquin JC, Lambert AE, Unger RH, Renold AE. Pronase effect on pancreatic beta cell secretion and morphology. Science. 1973;180(4086):647–9. doi:.https://doi.org/10.1126/science.180.4086.647
- Meda P, Halban P, Perrelet A, Renold AE, Orci L. Gap junction development is correlated with insulin content in the pancreatic B cell. Science. 1980;209(4460):1026–8. doi:.https://doi.org/10.1126/science.6773144
- Pettus J, Santos Cavaiola T, Tamborlane WV, Edelman S. The past, present, and future of basal insulins. Diabetes Metab Res Rev. 2016;6(32):478–96. doi:. https://doi.org/10.1002/dmrr.2763
- Balland E, Chen W, Dodd GT, Conductier G, Coppari R, Tiganis T, et al. Leptin Signaling in the Arcuate Nucleus Reduces Insulin’s Capacity to Suppress Hepatic Glucose Production in Obese Mice. Cell Rep. 2019;26(2):346–355.e3. doi:.https://doi.org/10.1016/j.celrep.2018.12.061
- Coppari R. Hypothalamic neurones governing glucose homeostasis. J Neuroendocrinol. 2015;27(6):399–405. doi:.https://doi.org/10.1111/jne.12276
- Blüher M, Michael MD, Peroni OD, Ueki K, Carter N, Kahn BB, et al. Adipose tissue selective insulin receptor knockout protects against obesity and obesity-related glucose intolerance. Dev Cell. 2002;3(1):25–38. doi:.https://doi.org/10.1016/S1534-5807(02)00199-5
- Guerra C, Navarro P, Valverde AM, Arribas M, Brüning J, Kozak LP, et al. Brown adipose tissue-specific insulin receptor knockout shows diabetic phenotype without insulin resistance. J Clin Invest. 2001;108(8):1205–13. doi:.https://doi.org/10.1172/JCI13103
- Michael MD, Kulkarni RN, Postic C, Previs SF, Shulman GI, Magnuson MA, et al. Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction. Mol Cell. 2000;6(1):87–97. doi:.https://doi.org/10.1016/S1097-2765(05)00015-8
- Brüning JC, Michael MD, Winnay JN, Hayashi T, Hörsch D, Accili D, et al. A muscle-specific insulin receptor knockout exhibits features of the metabolic syndrome of NIDDM without altering glucose tolerance. Mol Cell. 1998;2(5):559–69. doi:.https://doi.org/10.1016/S1097-2765(00)80155-0
- Taniguchi CM, Emanuelli B, Kahn CR. Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol. 2006;7(2):85–96. doi:.https://doi.org/10.1038/nrm1837
- Brady MJ, Bourbonais FJ, Saltiel AR. The activation of glycogen synthase by insulin switches from kinase inhibition to phosphatase activation during adipogenesis in 3T3-L1 cells. J Biol Chem. 1998;273(23):14063–6. doi:.https://doi.org/10.1074/jbc.273.23.14063
- Depré C, Veitch K, Hue L. Role of fructose 2,6-bisphosphate in the control of glycolysis. Stimulation of glycogen synthesis by lactate in the isolated working rat heart. Acta Cardiol. 1993;48(1):147–64.
- Vogt MC, Brüning JC. CNS insulin signaling in the control of energy homeostasis and glucose metabolism - from embryo to old age. Trends Endocrinol Metab. 2013;24(2):76–84. doi:.https://doi.org/10.1016/j.tem.2012.11.004
- Spanswick D, Smith MA, Mirshamsi S, Routh VH, Ashford ML. Insulin activates ATP-sensitive K+ channels in hypothalamic neurons of lean, but not obese rats. Nat Neurosci. 2000;3(8):757–8. doi:.https://doi.org/10.1038/77660
- Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature. 2001;414(6865):799–806. doi:.https://doi.org/10.1038/414799a
- Anderson JG, Ramadori G, Ioris RM, Galiè M, Berglund ED, Coate KC, et al. Enhanced insulin sensitivity in skeletal muscle and liver by physiological overexpression of SIRT6. Mol Metab. 2015;4(11):846–56. doi:.https://doi.org/10.1016/j.molmet.2015.09.003
- Abel ED, Peroni O, Kim JK, Kim YB, Boss O, Hadro E, et al. Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver. Nature. 2001;409(6821):729–33. doi:.https://doi.org/10.1038/35055575
- Rossetti L, Rothman DL, DeFronzo RA, Shulman GI. Effect of dietary protein on in vivo insulin action and liver glycogen repletion. Am J Physiol. 1989;257(2 Pt 1):E212–9.
- Foufelle F, Ferré P. New perspectives in the regulation of hepatic glycolytic and lipogenic genes by insulin and glucose: a role for the transcription factor sterol regulatory element binding protein-1c. Biochem J. 2002;366(2):377–91. doi:.https://doi.org/10.1042/bj20020430
- Foretz M, Guichard C, Ferré P, Foufelle F. Sterol regulatory element binding protein-1c is a major mediator of insulin action on the hepatic expression of glucokinase and lipogenesis-related genes. Proc Natl Acad Sci USA. 1999;96(22):12737–42. doi:.https://doi.org/10.1073/pnas.96.22.12737
- Weber G, Singhal RL. Insulin: inducer of phosphofructokinase. The integrative action of insulin at the enzyme biosynthetic level. Life Sci. 1965;4(20):1993–2002. doi:.https://doi.org/10.1016/0024-3205(65)90057-3
- Ahmadian M, Duncan RE, Jaworski K, Sarkadi-Nagy E, Sul HS. Triacylglycerol metabolism in adipose tissue. Future Lipidol. 2007;2(2):229–37. doi:.https://doi.org/10.2217/17460875.2.2.229
- Yechoor VK, Patti ME, Ueki K, Laustsen PG, Saccone R, Rauniyar R, et al. Distinct pathways of insulin-regulated versus diabetes-regulated gene expression: an in vivo analysis in MIRKO mice. Proc Natl Acad Sci USA. 2004;101(47):16525–30. doi:.https://doi.org/10.1073/pnas.0407574101
- Henquin JC. Triggering and amplifying pathways of regulation of insulin secretion by glucose. Diabetes. 2000;49(11):1751–60. doi:.https://doi.org/10.2337/diabetes.49.11.1751
- Fujikawa T, Berglund ED, Patel VR, Ramadori G, Vianna CR, Vong L, et al. Leptin engages a hypothalamic neurocircuitry to permit survival in the absence of insulin. Cell Metab. 2013;18(3):431–44. doi:.https://doi.org/10.1016/j.cmet.2013.08.004
- Ezaki O, Fukuda N, Itakura H. Role of two types of glucose transporters in enlarged adipocytes from aged obese rats. Diabetes. 1990;39(12):1543–9. doi:.https://doi.org/10.2337/diab.39.12.1543
- Matsumoto M, Ogawa W, Teshigawara K, Inoue H, Miyake K, Sakaue H, et al. Role of the insulin receptor substrate 1 and phosphatidylinositol 3-kinase signaling pathway in insulin-induced expression of sterol regulatory element binding protein 1c and glucokinase genes in rat hepatocytes. Diabetes. 2002;51(6):1672–80. doi:.https://doi.org/10.2337/diabetes.51.6.1672
- Shimomura I, Bashmakov Y, Ikemoto S, Horton JD, Brown MS, Goldstein JL. Insulin selectively increases SREBP-1c mRNA in the livers of rats with streptozotocin-induced diabetes. Proc Natl Acad Sci USA. 1999;96(24):13656–61. doi:.https://doi.org/10.1073/pnas.96.24.13656
- Meijssen S, Cabezas MC, Ballieux CG, Derksen RJ, Bilecen S, Erkelens DW. Insulin mediated inhibition of hormone sensitive lipase activity in vivo in relation to endogenous catecholamines in healthy subjects. J Clin Endocrinol Metab. 2001;86(9):4193–7. doi:.https://doi.org/10.1210/jcem.86.9.7794
- Spooner PM, Chernick SS, Garrison MM, Scow RO. Insulin regulation of lipoprotein lipase activity and release in 3T3-L1 adipocytes. Separation and dependence of hormonal effects on hexose metabolism and synthesis of RNA and protein. J Biol Chem. 1979;254(20):10021–9.
- Kharroubi AT, Darwish HM. Diabetes mellitus: The epidemic of the century. World J Diabetes. 2015;6(6):850–67. doi:.https://doi.org/10.4239/wjd.v6.i6.850
- Fujikawa T, Coppari R. Living without insulin: the role of leptin signaling in the hypothalamus. Front Neurosci. 2015;9:108. doi:.https://doi.org/10.3389/fnins.2015.00108
- Coppari R. Diabetes present and future. Int J Biochem Cell Biol. 2017;88:197. doi:.https://doi.org/10.1016/j.biocel.2017.05.012
- WHO. Diabetes. [cited 2019 August 30]; Available from: https://www.who.int/health-topics/diabetes.
- American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2014;37(Suppl 1):S81–90. doi:.https://doi.org/10.2337/dc14-S081
- Daneman D. Type 1 diabetes. Lancet. 2006;367(9513):847–58. doi:.https://doi.org/10.1016/S0140-6736(06)68341-4
- Vianna CR, Coppari R. A treasure trove of hypothalamic neurocircuitries governing body weight homeostasis. Endocrinology. 2011;152(1):11–8. doi:.https://doi.org/10.1210/en.2010-0778
- Coppari R, Ramadori G, Elmquist JK. The role of transcriptional regulators in central control of appetite and body weight. Nat Clin Pract Endocrinol Metab. 2009;5(3):160–6.
- Biessels GJ, van der Heide LP, Kamal A, Bleys RL, Gispen WH. Ageing and diabetes: implications for brain function. Eur J Pharmacol. 2002;441(1-2):1–14. doi:.https://doi.org/10.1016/S0014-2999(02)01486-3
- Ramadori G, Coppari R. Does hypothalamic SIRT1 regulate aging? Aging (Albany NY). 2011;3(3):325–8. doi:.https://doi.org/10.18632/aging.100311
- Taylor R. Insulin resistance and type 2 diabetes. Diabetes. 2012;61(4):778–9. doi:.https://doi.org/10.2337/db12-0073
- Brown MS, Goldstein JL. Selective versus total insulin resistance: a pathogenic paradox. Cell Metab. 2008;7(2):95–6. doi:.https://doi.org/10.1016/j.cmet.2007.12.009
- Cherrington AD. Banting Lecture 1997. Control of glucose uptake and release by the liver in vivo. Diabetes. 1999;48(5):1198–214. doi:.https://doi.org/10.2337/diabetes.48.5.1198
- Matsumoto M, Han S, Kitamura T, Accili D. Dual role of transcription factor FoxO1 in controlling hepatic insulin sensitivity and lipid metabolism. J Clin Invest. 2006;116(9):2464–72. doi:.https://doi.org/10.1172/JCI27047
- Schwarz JM, Linfoot P, Dare D, Aghajanian K. Hepatic de novo lipogenesis in normoinsulinemic and hyperinsulinemic subjects consuming high-fat, low-carbohydrate and low-fat, high-carbohydrate isoenergetic diets. Am J Clin Nutr. 2003;77(1):43–50. doi:.https://doi.org/10.1093/ajcn/77.1.43
- Iozzo P, Turpeinen AK, Takala T, Oikonen V, Bergman J, Grönroos T, et al. Defective liver disposal of free fatty acids in patients with impaired glucose tolerance. J Clin Endocrinol Metab. 2004;89(7):3496–502. doi:.https://doi.org/10.1210/jc.2003-031142
- Ginsberg HN, Zhang YL, Hernandez-Ono A. Regulation of plasma triglycerides in insulin resistance and diabetes. Arch Med Res. 2005;36(3):232–40. doi:.https://doi.org/10.1016/j.arcmed.2005.01.005
- Kraemer FB, Shen WJ. Hormone-sensitive lipase: control of intracellular tri-(di-)acylglycerol and cholesteryl ester hydrolysis. J Lipid Res. 2002;43(10):1585–94. doi:.https://doi.org/10.1194/jlr.R200009-JLR200
- Cho J-H, Kim JW, Shin JA, Shin J, Yoon KH. β-cell mass in people with type 2 diabetes. J Diabetes Investig. 2011;2(1):6–17. doi:.https://doi.org/10.1111/j.2040-1124.2010.00072.x
- Ramadori G, Ljubicic S, Ricci S, Mikropoulou D, Brenachot X, Veyrat-Durebex C, et al. S100A9 extends lifespan in insulin deficiency. Nat Commun. 2019;10(1):3545. doi:.https://doi.org/10.1038/s41467-019-11498-x
- Coppari R, Bjørbæk C. Leptin revisited: its mechanism of action and potential for treating diabetes. Nat Rev Drug Discov. 2012;11(9):692–708. doi:.https://doi.org/10.1038/nrd3757
- Agius L, Chowdhury MH, Davis SN, Alberti KG. Regulation of ketogenesis, gluconeogenesis, and glycogen synthesis by insulin and proinsulin in rat hepatocyte monolayer cultures. Diabetes. 1986;35(11):1286–93. doi:.https://doi.org/10.2337/diab.35.11.1286
- Turton JL, Raab R, Rooney KB. Low-carbohydrate diets for type 1 diabetes mellitus: A systematic review. PLoS One. 2018;13(3):e0194987. doi:.https://doi.org/10.1371/journal.pone.0194987
- Chawla A, Chawla R, Jaggi S. Microvasular and macrovascular complications in diabetes mellitus: Distinct or continuum? Indian J Endocrinol Metab. 2016;20(4):546–51. doi:.https://doi.org/10.4103/2230-8210.183480
- Mazur A. Why were “starvation diets” promoted for diabetes in the pre-insulin period? Nutr J. 2011;10(1):23. doi:.https://doi.org/10.1186/1475-2891-10-23
- Quianzon CC, Cheikh I. History of insulin. J Community Hosp Intern Med Perspect. 2012;2(2):18701. doi:.https://doi.org/10.3402/jchimp.v2i2.18701
- Bliss M. The history of insulin. Diabetes Care. 1993;16(Suppl 3):4–7. doi:.https://doi.org/10.2337/diacare.16.3.4
- Rosenfeld L. Insulin: discovery and controversy. Clin Chem. 2002;48(12):2270–88. doi:.https://doi.org/10.1093/clinchem/48.12.2270
- Banting FG, Best CH, Collip JB, Campbell WR, Fletcher AA. Pancreatic Extracts in the Treatment of Diabetes Mellitus. Can Med Assoc J. 1922;12(3):141–6.
- Banting FG, Campbell WR, Fletcher AA. Further Clinical Experience with Insulin (Pancreatic Extracts) in the Treatment of Diabetes Mellitus. BMJ. 1923;1(3236):8–12. doi:.https://doi.org/10.1136/bmj.1.3236.8
- Vecchio I, Tornali C, Bragazzi NL, Martini M. The Discovery of Insulin: An Important Milestone in the History of Medicine. Front Endocrinol (Lausanne). 2018;9:613. doi:.https://doi.org/10.3389/fendo.2018.00613
- Zinman B. Newer insulin analogs: advances in basal insulin replacement. Diabetes Obes Metab. 2013;15(s1, Suppl 1):6–10. doi:.https://doi.org/10.1111/dom.12068
- Deckert T. Intermediate-acting insulin preparations: NPH and lente. Diabetes Care. 1980;3(5):623–6. doi:.https://doi.org/10.2337/diacare.3.5.623
- Cryer PE, Davis SN, Shamoon H. Hypoglycemia in diabetes. Diabetes Care. 2003;26(6):1902–12. doi:.https://doi.org/10.2337/diacare.26.6.1902
- Nathan DM, Genuth S, Lachin J, Cleary P, Crofford O, Davis M, et al., Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329(14):977–86. doi:.https://doi.org/10.1056/NEJM199309303291401
- Hirsch IB. Insulin analogues. N Engl J Med. 2005;352(2):174–83. doi:.https://doi.org/10.1056/NEJMra040832
- Levemir (Internet) Silver Spring. M.U.F.a.D.A. [cited 2019 September 3]; Available from: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails.
- Prescribing information: Insulin glargine injection for subcutaneous injection 2000 [cited 2019 September 3]; Available from: http://products.sanofi.us/lantus/lantus.html.
- Kurtzhals P. Pharmacology of insulin detemir. Endocrinol Metab Clin North Am. 2007;36(Suppl 1):14–20. doi:.https://doi.org/10.1016/S0889-8529(07)80004-1
- Evans M, Schumm-Draeger PM, Vora J, King AB. A review of modern insulin analogue pharmacokinetic and pharmacodynamic profiles in type 2 diabetes: improvements and limitations. Diabetes Obes Metab. 2011;13(8):677–84. doi:.https://doi.org/10.1111/j.1463-1326.2011.01395.x
- Kalra S, Gupta Y. Clinical use of Insulin Degludec: Practical Experience and Pragmatic Suggestions. N Am J Med Sci. 2015;7(3):81–5. doi:.https://doi.org/10.4103/1947-2714.153918
- Kalra S, Baruah MP, Niazi AK. Degludec: a novel basal insulin. Recent Pat Endocr Metab Immune Drug Discov. 2012;6(1):18–23. doi:.https://doi.org/10.2174/187221412799015326
- Kalra S. Insulin degludec: a significant advancement in ultralong-acting Basal insulin. Diabetes Ther. 2013;4(2):167–73. doi:.https://doi.org/10.1007/s13300-013-0047-6
- Kruger DF, Novak LM. Role of ultrafast-acting insulin analogues in the management of diabetes. J Am Assoc Nurse Pract. 2019;31(9):537–48. doi:.https://doi.org/10.1097/JXX.0000000000000261
- Senior P, Hramiak I. Fast-Acting Insulin Aspart and the Need for New Mealtime Insulin Analogues in Adults With Type 1 and Type 2 Diabetes: A Canadian Perspective. Can J Diabetes. 2019;43(7):515–23. doi:.https://doi.org/10.1016/j.jcjd.2019.01.004
- Brange J, Ribel U, Hansen JF, Dodson G, Hansen MT, Havelund S, et al. Monomeric insulins obtained by protein engineering and their medical implications. Nature. 1988;333(6174):679–82. doi:.https://doi.org/10.1038/333679a0
- van Bon AC, Bode BW, Sert-Langeron C, DeVries JH, Charpentier G. Insulin glulisine compared to insulin aspart and to insulin lispro administered by continuous subcutaneous insulin infusion in patients with type 1 diabetes: a randomized controlled trial. Diabetes Technol Ther. 2011;13(6):607–14. doi:.https://doi.org/10.1089/dia.2010.0224
- Shah RB, Patel M, Maahs DM, Shah VN. Insulin delivery methods: Past, present and future. Int J Pharm Investig. 2016;6(1):1–9. doi:.https://doi.org/10.4103/2230-973X.176456
- Selam JL. Evolution of diabetes insulin delivery devices. J Diabetes Sci Technol. 2010;4(3):505–13. doi:.https://doi.org/10.1177/193229681000400302
- Hirsch IB. Does size matter? Thoughts about insulin pen needles. Diabetes Technol Ther. 2012;14(12):1081. doi:.https://doi.org/10.1089/dia.2012.0274
- Aronson R, Gibney MA, Oza K, Bérubé J, Kassler-Taub K, Hirsch L. Insulin pen needles: effects of extra-thin wall needle technology on preference, confidence, and other patient ratings. Clin Ther. 2013;35(7):923–933.e4. doi:.https://doi.org/10.1016/j.clinthera.2013.05.020
- Moser EG, Morris AA, Garg SK. Emerging diabetes therapies and technologies. Diabetes Res Clin Pract. 2012;97(1):16–26. doi:.https://doi.org/10.1016/j.diabres.2012.01.027
- Steineck I, Ranjan A, Nørgaard K, Schmidt S. Sensor-Augmented Insulin Pumps and Hypoglycemia Prevention in Type 1 Diabetes. J Diabetes Sci Technol. 2017;11(1):50–8. doi:.https://doi.org/10.1177/1932296816672689
- Peyser T, Dassau E, Breton M, Skyler JS. The artificial pancreas: current status and future prospects in the management of diabetes. Ann N Y Acad Sci. 2014;1311(1):102–23. doi:.https://doi.org/10.1111/nyas.12431
- Mibu K, Yatabe T, Hanazaki K. Blood glucose control using an artificial pancreas reduces the workload of ICU nurses. J Artif Organs. 2012;15(1):71–6. doi:.https://doi.org/10.1007/s10047-011-0611-7
- Umpierrez GE, Klonoff DC. Diabetes Technology Update: Use of Insulin Pumps and Continuous Glucose Monitoring in the Hospital. Diabetes Care. 2018;41(8):1579–89. doi:.https://doi.org/10.2337/dci18-0002
- Tosur M, Redondo MJ, Lyons SK. Adjuvant Pharmacotherapies to Insulin for the Treatment of Type 1 Diabetes. Curr Diab Rep. 2018;18(10):79. doi:.https://doi.org/10.1007/s11892-018-1041-1
- Sotagliflozin Approved in EU for Adults With Type 1 Diabetes. 2019 [cited 2019 September 5]; Available from: https://www.ajmc.com/newsroom/sotagliflozin-approved-in-eu-for-adults-with-type-1-diabetes.
- Ang KH, Sherr JL. Moving beyond subcutaneous insulin: the application of adjunctive therapies to the treatment of type 1 diabetes. Expert Opin Drug Deliv. 2017;14(9):1113–31. doi:.https://doi.org/10.1080/17425247.2017.1360862
- Chaudhury A, Duvoor C, Reddy Dendi VS, Kraleti S, Chada A, Ravilla R, et al. Clinical Review of Antidiabetic Drugs: Implications for Type 2 Diabetes Mellitus Management. Front Endocrinol (Lausanne). 2017;8:6. doi:.https://doi.org/10.3389/fendo.2017.00006
- Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al.; EMPA-REG OUTCOME Investigators. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015;373(22):2117–28. doi:.https://doi.org/10.1056/NEJMoa1504720
- Hernandez AF, Green JB, Janmohamed S, D’Agostino RB, Sr, Granger CB, Jones NP, et al.; Harmony Outcomes committees and investigators. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial. Lancet. 2018;392(10157):1519–29. doi:.https://doi.org/10.1016/S0140-6736(18)32261-X
- Beran D, Laing RO, Kaplan W, Knox R, Sharma A, Wirtz VJ, et al. A perspective on global access to insulin: a descriptive study of the market, trade flows and prices. Diabet Med. 2019;36(6):726–33. doi:.https://doi.org/10.1111/dme.13947
- Globally, Top 10 Insulin Manufacturers Are Dominated By Europe and North America. 2017 [cited 2019 September 2]; Available from: https://www.envisioninteligence.com/blog/globally-top-10-insulin-manufacturers/.
- Global Human Insulin Market to Worth $48 billion by 2020 – Leading Players are Pfizer, Inc., Novo Nordisk, Eli Lily and Company, Sanofi, GlaxoSmithKline and Merck & Co. 2018 [cited 2019 September 2]; Available from: https://www.medgadget.com/2018/05/global-human-insulin-market-to-worth-48-billion-by-2020-leading-players-are-pfizer-inc-novo-nordisk-eli-lily-and-company-sanofi-glaxosmithkline-and-merck-co.html.
- Cuddihy RM, Philis-Tsimikas A, Nazeri A. Type 2 diabetes care and insulin intensification: is a more multidisciplinary approach needed? Results from the MODIFY survey. Diabetes Educ. 2011;37(1):111–23. doi:.https://doi.org/10.1177/0145721710388426
- Standl E, Owen DR. New Long-Acting Basal Insulins: Does Benefit Outweigh Cost? Diabetes Care. 2016;39(Suppl 2):S172–9. doi:.https://doi.org/10.2337/dcS15-3011
- Sorli C, Heile MK. Identifying and meeting the challenges of insulin therapy in type 2 diabetes. J Multidiscip Healthc. 2014;7:267–82. doi:.https://doi.org/10.2147/JMDH.S64084
- Kalra S, Bajaj S, Sharma SK, Priya G, Baruah MP, Sanyal D, et al. A Practitioner’s Toolkit for Insulin Motivation in Adults with Type 1 and Type 2 Diabetes Mellitus: Evidence-Based Recommendations from an International Expert Panel. Diabetes Ther. 2020;11(3):585–606. doi:.https://doi.org/10.1007/s13300-020-00764-7
- Polonsky WH, Fisher L, Guzman S, Villa-Caballero L, Edelman SV. Psychological insulin resistance in patients with type 2 diabetes: the scope of the problem. Diabetes Care. 2005;28(10):2543–5. doi:.https://doi.org/10.2337/diacare.28.10.2543
- Mathew EM, Rajiah K. Assessment of medication adherence in type-2 diabetes patients on poly pharmacy and the effect of patient counseling given to them in a multispecialty hospital. J Basic Clin Pharm. 2013;5(1):15–8. doi:.https://doi.org/10.4103/0976-0105.128251
- Hoerger TJ, Segel JE, Gregg EW, Saaddine JB. Is glycemic control improving in U.S. adults? Diabetes Care. 2008;31(1):81–6. doi:.https://doi.org/10.2337/dc07-1572
- Brož J, Janíčková Žďárská D, Urbanová J, Brabec M, Doničová V, Štěpánová R, et al. Current Level of Glycemic Control and Clinical Inertia in Subjects Using Insulin for the Treatment of Type 1 and Type 2 Diabetes in the Czech Republic and the Slovak Republic: Results of a Multinational, Multicenter, Observational Survey (DIAINFORM). Diabetes Ther. 2018;9(5):1897–906. doi:.https://doi.org/10.1007/s13300-018-0485-2
- Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321(7258):405–12. doi:.https://doi.org/10.1136/bmj.321.7258.405
- Zhong VW, Juhaeri J, Cole SR, Kontopantelis E, Shay CM, Gordon-Larsen P, et al. Incidence and Trends in Hypoglycemia Hospitalization in Adults With Type 1 and Type 2 Diabetes in England, 1998-2013: A Retrospective Cohort Study. Diabetes Care. 2017;40(12):1651–60. doi:.https://doi.org/10.2337/dc16-2680
- Gregg EW, Li Y, Wang J, Rios Burrows N, Ali MK, Rolka D, et al. Changes in diabetes-related complications in the United States, 1990-2010. N Engl J Med. 2014;370(16):1514–23. doi:.https://doi.org/10.1056/NEJMoa1310799
- Mahoney GK, Henk HJ, McCoy RG. Severe Hypoglycemia Attributable to Intensive Glucose-Lowering Therapy Among US Adults With Diabetes: Population-Based Modeling Study, 2011-2014. Mayo Clin Proc. 2019;94(9):1731–42. doi:.https://doi.org/10.1016/j.mayocp.2019.02.028
- Kana Kadayakkara D, Balasubramanian P, Araque KA, Davis K, Javed F, Niaki P, et al. Multidisciplinary strategies to treat severe hypoglycemia in hospitalized patients with diabetes mellitus reduce inpatient mortality rate: Experience from an academic community hospital. PLoS One. 2019;14(8):e0220956. doi:.https://doi.org/10.1371/journal.pone.0220956
- Gagnum V, Stene LC, Jenssen TG, Berteussen LM, Sandvik L, Joner G, et al. Causes of death in childhood-onset Type 1 diabetes: long-term follow-up. Diabet Med. 2017;34(1):56–63. doi:.https://doi.org/10.1111/dme.13114
- Perlmuter LC, Flanagan BP, Shah PH, Singh SP. Glycemic control and hypoglycemia: is the loser the winner? Diabetes Care. 2008;31(10):2072–6. doi:.https://doi.org/10.2337/dc08-1441
- Cryer PE. The barrier of hypoglycemia in diabetes. Diabetes. 2008;57(12):3169–76. doi:.https://doi.org/10.2337/db08-1084
- Cryer PE. Mechanisms of hypoglycemia-associated autonomic failure and its component syndromes in diabetes. Diabetes. 2005;54(12):3592–601. doi:.https://doi.org/10.2337/diabetes.54.12.3592
- Horton JD, Goldstein JL, Brown MS. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest. 2002;109(9):1125–31. doi:.https://doi.org/10.1172/JCI0215593
- Hodish I. Insulin therapy, weight gain and prognosis. Diabetes Obes Metab. 2018;20(9):2085–92. doi:.https://doi.org/10.1111/dom.13367
- Herman ME, O’Keefe JH, Bell DSH, Schwartz SS. Insulin Therapy Increases Cardiovascular Risk in Type 2 Diabetes. Prog Cardiovasc Dis. 2017;60(3):422–34. doi:.https://doi.org/10.1016/j.pcad.2017.09.001
- Orchard TJ, Costacou T, Kretowski A, Nesto RW. Type 1 diabetes and coronary artery disease. Diabetes Care. 2006;29(11):2528–38. doi:.https://doi.org/10.2337/dc06-1161
- Larsen J, Brekke M, Sandvik L, Arnesen H, Hanssen KF, Dahl-Jorgensen K. Silent coronary atheromatosis in type 1 diabetic patients and its relation to long-term glycemic control. Diabetes. 2002;51(8):2637–41. doi:.https://doi.org/10.2337/diabetes.51.8.2637
- Coppari R, Bjørbæk C. Leptin revisited: its mechanism of action and potential for treating diabetes. Nat Rev Drug Discov. 2012;11(9):692–708. doi:.https://doi.org/10.1038/nrd3757
- Dongerkery SP, Schroeder PR, Shomali ME. Insulin and Its Cardiovascular Effects: What Is the Current Evidence? Curr Diab Rep. 2017;17(12):120. doi:.https://doi.org/10.1007/s11892-017-0955-3
- Orchard TJ, Olson JC, Erbey JR, Williams K, Forrest KY, Smithline Kinder L, et al. Insulin resistance-related factors, but not glycemia, predict coronary artery disease in type 1 diabetes: 10-year follow-up data from the Pittsburgh Epidemiology of Diabetes Complications Study. Diabetes Care. 2003;26(5):1374–9. doi:.https://doi.org/10.2337/diacare.26.5.1374
- Wu G, Meininger CJ. Nitric oxide and vascular insulin resistance. Biofactors. 2009;35(1):21–7. doi:.https://doi.org/10.1002/biof.3
- Boucher J, Kleinridders A, Kahn CR. Insulin receptor signaling in normal and insulin-resistant states. Cold Spring Harb Perspect Biol. 2014;6(1):a009191. doi:.https://doi.org/10.1101/cshperspect.a009191
- Stoekenbroek RM, Rensing KL, Bernelot Moens SJ, Nieuwdorp M, DeVries JH, Zwinderman AH, et al. High daily insulin exposure in patients with type 2 diabetes is associated with increased risk of cardiovascular events. Atherosclerosis. 2015;240(2):318–23. doi:.https://doi.org/10.1016/j.atherosclerosis.2015.03.040
- Wilcox G. Insulin and insulin resistance. Clin Biochem Rev. 2005;26(2):19–39.
- Vitaterna MH, Takahashi JS, Turek FW. Overview of circadian rhythms. Alcohol Res Health. 2001;25(2):85–93.
- Orozco-Solis R, Aguilar-Arnal L, Murakami M, Peruquetti R, Ramadori G, Coppari R, et al. The Circadian Clock in the Ventromedial Hypothalamus Controls Cyclic Energy Expenditure. Cell Metab. 2016;23(3):467–78. doi:.https://doi.org/10.1016/j.cmet.2016.02.003
- Orozco-Solis R, Ramadori G, Coppari R, Sassone-Corsi P. SIRT1 Relays Nutritional Inputs to the Circadian Clock Through the Sf1 Neurons of the Ventromedial Hypothalamus. Endocrinology. 2015;156(6):2174–84. doi:.https://doi.org/10.1210/en.2014-1805
- King DP, Takahashi JS. Molecular genetics of circadian rhythms in mammals. Annu Rev Neurosci. 2000;23(1):713–42. doi:.https://doi.org/10.1146/annurev.neuro.23.1.713
- Carroll KF, Nestel PJ. Diurnal variation in glucose tolerance and in insulin secretion in man. Diabetes. 1973;22(5):333–48. doi:.https://doi.org/10.2337/diab.22.5.333
- Gibson T, Jarrett RJ. Diurnal variation in insulin sensitivity. Lancet. 1972;300(7784):947–8. doi:.https://doi.org/10.1016/S0140-6736(72)92472-5
- Dyar KA, Ciciliot S, Wright LE, Biensø RS, Tagliazucchi GM, Patel VR, et al. Muscle insulin sensitivity and glucose metabolism are controlled by the intrinsic muscle clock. Mol Metab. 2014;3(1):29–41. doi:.https://doi.org/10.1016/j.molmet.2013.10.005
- Liu J, Zhou B, Yan M, Huang R, Wang Y, He Z, et al. CLOCK and BMAL1 Regulate Muscle Insulin Sensitivity via SIRT1 in Male Mice. Endocrinology. 2016;157(6):2259–69. doi:.https://doi.org/10.1210/en.2015-2027
- Carrasco-Benso MP, Rivero-Gutierrez B, Lopez-Minguez J, Anzola A, Diez-Noguera A, Madrid JA, et al. Human adipose tissue expresses intrinsic circadian rhythm in insulin sensitivity. FASEB J. 2016;30(9):3117–23. doi:.https://doi.org/10.1096/fj.201600269RR
- Shostak A, Meyer-Kovac J, Oster H. Circadian regulation of lipid mobilization in white adipose tissues. Diabetes. 2013;62(7):2195–203. doi:.https://doi.org/10.2337/db12-1449
- Aras E, Ramadori G, Kinouchi K, Liu Y, Ioris RM, Brenachot X, et al. Light Entrains Diurnal Changes in Insulin Sensitivity of Skeletal Muscle via Ventromedial Hypothalamic Neurons. Cell Rep. 2019;27(8):2385–2398.e3. doi:.https://doi.org/10.1016/j.celrep.2019.04.093
- Coppari R. Metabolic actions of hypothalamic SIRT1. Trends Endocrinol Metab. 2012;23(4):179–85. doi:.https://doi.org/10.1016/j.tem.2012.01.002
- Ramadori G, Fujikawa T, Anderson J, Berglund ED, Frazao R, Michán S, et al. SIRT1 deacetylase in SF1 neurons protects against metabolic imbalance. Cell Metab. 2011;14(3):301–12. doi:.https://doi.org/10.1016/j.cmet.2011.06.014
- Cheung IN, Zee PC, Shalman D, Malkani RG, Kang J, Reid KJ. Morning and Evening Blue-Enriched Light Exposure Alters Metabolic Function in Normal Weight Adults. PLoS One. 2016;11(5):e0155601. doi:.https://doi.org/10.1371/journal.pone.0155601
- Opperhuizen A-L, Stenvers DJ, Jansen RD, Foppen E, Fliers E, Kalsbeek A. Light at night acutely impairs glucose tolerance in a time-, intensity- and wavelength-dependent manner in rats. Diabetologia. 2017;60(7):1333–43. doi:.https://doi.org/10.1007/s00125-017-4262-y
- Versteeg RI, Stenvers DJ, Visintainer D, Linnenbank A, Tanck MW, Zwanenburg G, et al. Acute Effects of Morning Light on Plasma Glucose and Triglycerides in Healthy Men and Men with Type 2 Diabetes. J Biol Rhythms. 2017;32(2):130–42. doi:.https://doi.org/10.1177/0748730417693480
- Carrasco-Benso MP, Rivero-Gutierrez B, Lopez-Minguez J, Anzola A, Diez-Noguera A, Madrid JA, et al. Human adipose tissue expresses intrinsic circadian rhythm in insulin sensitivity. FASEB J. 2016;30(9):3117–23. doi:.https://doi.org/10.1096/fj.201600269RR
- Marcheva B, Ramsey KM, Buhr ED, Kobayashi Y, Su H, Ko CH, et al. Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes. Nature. 2010;466(7306):627–31. doi:.https://doi.org/10.1038/nature09253
- Masri S, Sassone-Corsi P. The circadian clock: a framework linking metabolism, epigenetics and neuronal function. Nat Rev Neurosci. 2013;14(1):69–75. doi:.https://doi.org/10.1038/nrn3393
- Petznick A. Insulin management of type 2 diabetes mellitus. Am Fam Physician. 2011;84(2):183–90.
- Coomans CP, van den Berg SA, Lucassen EA, Houben T, Pronk AC, van der Spek RD, et al. The suprachiasmatic nucleus controls circadian energy metabolism and hepatic insulin sensitivity. Diabetes. 2013;62(4):1102–8. doi:.https://doi.org/10.2337/db12-0507
- Zhou B, Zhang Y, Zhang F, Xia Y, Liu J, Huang R, et al. CLOCK/BMAL1 regulates circadian change of mouse hepatic insulin sensitivity by SIRT1. Hepatology. 2014;59(6):2196–206. doi:.https://doi.org/10.1002/hep.26992
- Fujikawa T, Coppari R. Hypothalamic-mediated control of glucose balance in the presence and absence of insulin. Aging (Albany NY). 2014;6(2):92–7. doi:.https://doi.org/10.18632/aging.100641
- Brenachot X, Ramadori G, Ioris RM, Veyrat-Durebex C, Altirriba J, Aras E, et al. Hepatic protein tyrosine phosphatase receptor gamma links obesity-induced inflammation to insulin resistance. Nat Commun. 2017;8(1):1820. doi:.https://doi.org/10.1038/s41467-017-02074-2
- LaForgia S, Morse B, Levy J, Barnea G, Cannizzaro LA, Li F, et al. Receptor protein-tyrosine phosphatase gamma is a candidate tumor suppressor gene at human chromosome region 3p21. Proc Natl Acad Sci USA. 1991;88(11):5036–40. doi:.https://doi.org/10.1073/pnas.88.11.5036
- Wu Y, Tang D, Liu N, Xiong W, Huang H, Li Y, et al. Reciprocal Regulation between the Circadian Clock and Hypoxia Signaling at the Genome Level in Mammals. Cell Metab. 2017;25(1):73–85. doi:.https://doi.org/10.1016/j.cmet.2016.09.009
- Halberg N, Khan T, Trujillo ME, Wernstedt-Asterholm I, Attie AD, Sherwani S, et al. Hypoxia-inducible factor 1α induces fibrosis and insulin resistance in white adipose tissue. Mol Cell Biol. 2009;29(16):4467–83. doi:.https://doi.org/10.1128/MCB.00192-09