Glycemic Variability and Acute Ischemic Stroke: The Missing Link?

Translational Stroke Research

Volumn 5, Issue 6, 2014, Pages 638-646

  González Moreno, Emmanuel I ^a   Cámara Lemarroy, Carlos R ^a   González González, José G ^a   Góngora Rivera, Fernando ^a  

^a HOSPITAL UNIVERSITARIO DR JOSÉ ELEUTERIO GONZÁLEZ   (Mexico)

Author keywords

Glycemic variability; Hyperglycemia; Intensive insulin therapy; Strict diabetes control; Stroke

Indexed keywords

GLUCOSE BLOOD LEVEL;

ANIMAL; BRAIN; BRAIN ISCHEMIA; CEREBROVASCULAR ACCIDENT; COMPLICATION; DIABETES MELLITUS; GLUCOSE BLOOD LEVEL; GLYCEMIC INDEX; HUMAN; HYPERGLYCEMIA; METABOLISM;

ANIMALS; BLOOD GLUCOSE; BRAIN; BRAIN ISCHEMIA; DIABETES COMPLICATIONS; GLYCEMIC INDEX; HUMANS; HYPERGLYCEMIA; STROKE;

EID: 84936140088     PISSN: 18684483     EISSN: 1868601X     Source Type: Journal    
DOI: 10.1007/s12975-014-0365-7     Document Type: Review

References (134)

1. Kruyt ND, Biessels GJ, Devries JH, Roos YB. Hyperglycemia in acute ischemic stroke: pathophysiology and clinical management. Nat Rev Neurol. 2010;6(3):145–55.
2. Piironen K, Putaala J, Rosso C, Samson Y. Glucose and acute stroke: evidence for an interlude. Stroke J Cereb Circ. 2012;43(3):898–902.
3. Monnier L, Colette C. Glycemic variability: should we and can we prevent it? Diabetes Care. 2008;31 Suppl 2:S150–4.
4. Ceriello A, Ihnat MA. ‘Glycaemic variability’: a new therapeutic challenge in diabetes and the critical care setting. Diabet Med J Br Diabet Assoc. 2010;27(8):862–7.
5. Jauch EC, Saver JL, Adams Jr HP, Bruno A, Connors JJ, Demaerschalk BM, et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke J Cereb Circ. 2013;44(3):870–947.
6. Kung HC, Hoyert DL, Xu J, Murphy SL. Deaths: final data for 2005. National vital statistics reports: from the Centers for Disease Control and Prevention, National Center for Health Statistics. Natl Vital Stat Syst. 2008;56(10):1–120.
7. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Borden WB, et al. Heart disease and stroke statistics—2013 update: a report from the American Heart Association. Circulation. 2013;127(1):e6–245.
8. Lloyd-Jones D, Adams R, Carnethon M, De Simone G, Ferguson TB, Flegal K, et al. Heart disease and stroke statistics—2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2009;119(3):e21–181.
9. Donnan GA, Fisher M, Macleod M, Davis SM. Stroke Lancet. 2008;371(9624):1612–23.
10. Dewey HM, Thrift AG, Mihalopoulos C, Carter R, Macdonell RA, McNeil JJ, et al. Cost of stroke in Australia from a societal perspective: results from the North East Melbourne Stroke Incidence Study (NEMESIS). Stroke J Cereb Circ. 2001;32(10):2409–16.
11. Taylor TN, Davis PH, Torner JC, Holmes J, Meyer JW, Jacobson MF. Lifetime cost of stroke in the United States. Stroke J Cereb Circ. 1996;27(9):1459–66.
12. Brown DL, Boden-Albala B, Langa KM, Lisabeth LD, Fair M, Smith MA, et al. Projected costs of ischemic stroke in the United States. Neurology. 2006;67(8):1390–5.
13. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. 2004;27(5):1047–53.
14. Luitse MJ, Biessels GJ, Rutten GE, Kappelle LJ. Diabetes, hyperglycaemia, and acute ischaemic stroke. Lancet Neurol. 2012;11(3):261–71.
15. Pulsinelli WA, Levy DE, Sigsbee B, Scherer P, Plum F. Increased damage after ischemic stroke in patients with hyperglycemia with or without established diabetes mellitus. Am J Med. 1983;74(4):540–4.
16. Capes SE, Hunt D, Malmberg K, Pathak P, Gerstein HC. Stress hyperglycemia and prognosis of stroke in nondiabetic and diabetic patients: a systematic overview. Stroke J Cereb Circ. 2001;32(10):2426–32.
17. Hewitt J, Castilla Guerra L, Fernandez-Moreno Mdel C, Sierra C. Diabetes and stroke prevention: a review. Stroke Res Treat. 2012;2012:673187.
18. Dave JA, Engel ME, Freercks R, Peter J, May W, Badri M, et al. Abnormal glucose metabolism in non-diabetic patients presenting with an acute stroke: prospective study and systematic review. QJM Mon J Assoc Phys. 2010;103(7):495–503.
19. Harris MI. Undiagnosed NIDDM: clinical and public health issues. Diabetes Care. 1993;16(4):642–52.
20. Ribo M, Molina C, Montaner J, Rubiera M, Delgado-Mederos R, Arenillas JF, et al. Acute hyperglycemia state is associated with lower tPA-induced recanalization rates in stroke patients. Stroke J Cereb Circ. 2005;36(8):1705–9.
21. Pandolfi A, Giaccari A, Cilli C, Alberta MM, Morviducci L, De Filippis EA, et al. Acute hyperglycemia and acute hyperinsulinemia decrease plasma fibrinolytic activity and increase plasminogen activator inhibitor type 1 in the rat. Acta Diabetol. 2001;38(2):71–6.
22. Gentile NT, Vaidyula VR, Kanamalla U, DeAngelis M, Gaughan J, Rao AK. Factor VIIa and tissue factor procoagulant activity in diabetes mellitus after acute ischemic stroke: impact of hyperglycemia. Thromb Haemost. 2007;98(5):1007–13.
23. Stegenga ME, van der Crabben SN, Levi M, de Vos AF, Tanck MW, Sauerwein HP, et al. Hyperglycemia stimulates coagulation, whereas hyperinsulinemia impairs fibrinolysis in healthy humans. Diabetes. 2006;55(6):1807–12.
24. Festa A, D’Agostino Jr R, Mykkanen L, Tracy RP, Zaccaro DJ, Hales CN, et al. Relative contribution of insulin and its precursors to fibrinogen and PAI-1 in a large population with different states of glucose tolerance. The Insulin Resistance Atherosclerosis Study (IRAS). Arterioscler Thromb Vasc Biol. 1999;19(3):562–8.
25. Meigs JB, Mittleman MA, Nathan DM, Tofler GH, Singer DE, Murphy-Sheehy PM, et al. Hyperinsulinemia, hyperglycemia, and impaired hemostasis: the Framingham Offspring Study. JAMA J Am Med Assoc. 2000;283(2):221–8.
26. Quast MJ, Wei J, Huang NC, Brunder DG, Sell SL, Gonzalez JM, et al. Perfusion deficit parallels exacerbation of cerebral ischemia/reperfusion injury in hyperglycemic rats. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metabol. 1997;17(5):553–9.
27. Venables GS, Miller SA, Gibson G, Hardy JA, Strong AJ. The effects of hyperglycaemia on changes during reperfusion following focal cerebral ischaemia in the cat. J Neurol Neurosurg Psychiatry. 1985;48(7):663–9.
28. Beckman JA, Goldfine AB, Gordon MB, Garrett LA, Creager MA. Inhibition of protein kinase Cbeta prevents impaired endothelium-dependent vasodilation caused by hyperglycemia in humans. Circ Res. 2002;90(1):107–11.
29. Williams SB, Goldfine AB, Timimi FK, Ting HH, Roddy MA, Simonson DC, et al. Acute hyperglycemia attenuates endothelium-dependent vasodilation in humans in vivo. Circulation. 1998;97(17):1695–701.
30. Vallance P, Collier J, Moncada S. Effects of endothelium-derived nitric oxide on peripheral arteriolar tone in man. Lancet. 1989;2(8670):997–1000.
31. Fleming I, Busse R. Molecular mechanisms involved in the regulation of the endothelial nitric oxide synthase. Am J Physiol Regul Integr Comp Physiol. 2003;284(1):R1–12.
32. Ding Y, Vaziri ND, Coulson R, Kamanna VS, Roh DD. Effects of simulated hyperglycemia, insulin, and glucagon on endothelial nitric oxide synthase expression. Am J Physiol Endocrinol Metab. 2000;279(1):E11–7.
33. Du XL, Edelstein D, Dimmeler S, Ju Q, Sui C, Brownlee M. Hyperglycemia inhibits endothelial nitric oxide synthase activity by posttranslational modification at the Akt site. J Clin Invest. 2001;108(9):1341–8.
34. McCord JM. Oxygen-derived free radicals in postischemic tissue injury. N Engl J Med. 1985;312(3):159–63.
35. Kamada H, Yu F, Nito C, Chan PH. Influence of hyperglycemia on oxidative stress and matrix metalloproteinase-9 activation after focal cerebral ischemia/reperfusion in rats: relation to blood-brain barrier dysfunction. Stroke J Cereb Circ. 2007;38(3):1044–9.
36. Wei J, Huang NC, Quast MJ. Hydroxyl radical formation in hyperglycemic rats during middle cerebral artery occlusion/reperfusion. Free Radic Biol Med. 1997;23(7):986–95.
37. Suh SW, Shin BS, Ma H, Van Hoecke M, Brennan AM, Yenari MA, et al. Glucose and NADPH oxidase drive neuronal superoxide formation in stroke. Ann Neurol. 2008;64(6):654–63.
38. Martini SR, Kent TA. Hyperglycemia in acute ischemic stroke: a vascular perspective. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab. 2007;27(3):435–51.
39. Garg R, Chaudhuri A, Munschauer F, Dandona P. Hyperglycemia, insulin, and acute ischemic stroke: a mechanistic justification for a trial of insulin infusion therapy. Stroke J Cereb Circ. 2006;37(1):267–73.
40. Bemeur C, Ste-Marie L, Montgomery J. Increased oxidative stress during hyperglycemic cerebral ischemia. Neurochem Int. 2007;50(7–8):890–904.
41. Bemeur C, Ste-Marie L, Desjardins P, Vachon L, Butterworth RF, Hazell AS, et al. Dehydroascorbic acid normalizes several markers of oxidative stress and inflammation in acute hyperglycemic focal cerebral ischemia in the rat. Neurochem Int. 2005;46(5):399–407.
42. Anderson RE, Tan WK, Martin HS, Meyer FB. Effects of glucose and PaO2 modulation on cortical intracellular acidosis, NADH redox state, and infarction in the ischemic penumbra. Stroke J Cereb Circ. 1999;30(1):160–70.
43. Parsons MW, Barber PA, Desmond PM, Baird TA, Darby DG, Byrnes G, et al. Acute hyperglycemia adversely affects stroke outcome: a magnetic resonance imaging and spectroscopy study. Ann Neurol. 2002;52(1):20–8.
44. Lee WL, Klip A. Shuttling glucose across brain microvessels, with a little help from GLUT1 and AMP kinase. Focus on “AMP kinase regulation of sugar transport in brain capillary endothelial cells during acute metabolic stress”. Am J Physiol Cell Physiol. 2012;303(8):C803–5.
45. Amaral AI. Effects of hypoglycaemia on neuronal metabolism in the adult brain: role of alternative substrates to glucose. J Inherit Metab Dis. 2013;36(4):621–34.
46. Sprague JE, Arbelaez AM. Glucose counterregulatory responses to hypoglycemia. Pediatr Endocrinol Rev: PER. 2011;9(1):463–73. quiz 74-5.
47. Weimar C, Ziegler A, Konig IR, Diener HC. Predicting functional outcome and survival after acute ischemic stroke. J Neurol. 2002;249(7):888–95.
48. Woo D, Gebel J, Miller R, Kothari R, Brott T, Khoury J, et al. Incidence rates of first-ever ischemic stroke subtypes among blacks: a population-based study. Stroke J Cereb Circ. 1999;30(12):2517–22.
49. Gentile NT, Seftchick MW, Huynh T, Kruus LK, Gaughan J. Decreased mortality by normalizing blood glucose after acute ischemic stroke. Acad Emerg Med Off J Soc Acad Emerg Med. 2006;13(2):174–80.
50. Williams LS, Rotich J, Qi R, Fineberg N, Espay A, Bruno A, et al. Effects of admission hyperglycemia on mortality and costs in acute ischemic stroke. Neurology. 2002;59(1):67–71.
51. Gray CS, Hildreth AJ, Sandercock PA, O’Connell JE, Johnston DE, Cartlidge NE, et al. Glucose-potassium-insulin infusions in the management of post-stroke hyperglycaemia: the UK Glucose Insulin in Stroke Trial (GIST-UK). Lancet Neurol. 2007;6(5):397–406.
52. Yong M, Kaste M. Dynamic of hyperglycemia as a predictor of stroke outcome in the ECASS-II trial. Stroke J Cereb Circ. 2008;39(10):2749–55.
53. Allport L, Baird T, Butcher K, Macgregor L, Prosser J, Colman P, et al. Frequency and temporal profile of poststroke hyperglycemia using continuous glucose monitoring. Diabetes Care. 2006;29(8):1839–44.
54. Gray CS, Scott JF, French JM, Alberti KG, O’Connell JE. Prevalence and prediction of unrecognised diabetes mellitus and impaired glucose tolerance following acute stroke. Age Ageing. 2004;33(1):71–7.
55. Kernan WN, Viscoli CM, Inzucchi SE, Brass LM, Bravata DM, Shulman GI, et al. Prevalence of abnormal glucose tolerance following a transient ischemic attack or ischemic stroke. Arch Intern Med. 2005;165(2):227–33.
56. Matz K, Keresztes K, Tatschl C, Nowotny M, Dachenhausen A, Brainin M, et al. Disorders of glucose metabolism in acute stroke patients: an underrecognized problem. Diabetes Care. 2006;29(4):792–7.
57. Vancheri F, Curcio M, Burgio A, Salvaggio S, Gruttadauria G, Lunetta MC, et al. Impaired glucose metabolism in patients with acute stroke and no previous diagnosis of diabetes mellitus. QJM: Mon J Assoc Phys. 2005;98(12):871–8.
58. Gauna C, van den Berghe GH, van der Lely AJ. Pituitary function during severe and life-threatening illnesses. Pituitary. 2005;8(3–4):213–7.
59. Vanhorebeek I, Langouche L, Van den Berghe G. Endocrine aspects of acute and prolonged critical illness. Nat Clin Pract Endocrinol Metab. 2006;2(1):20–31.
60. Van den Berghe G. Novel insights into the neuroendocrinology of critical illness. Eur J Endocrinol Eur Fed Endocr Soc. 2000;143(1):1–13.
61. Barth E, Albuszies G, Baumgart K, Matejovic M, Wachter U, Vogt J, et al. Glucose metabolism and catecholamines. Crit Care Med. 2007;35(9 Suppl):S508–18.
62. Seematter G, Binnert C, Martin JL, Tappy L. Relationship between stress, inflammation and metabolism. Curr Opin Clin Nutr Metab Care. 2004;7(2):169–73.
63. Gearhart MM, Parbhoo SK. Hyperglycemia in the critically ill patient. AACN Clin Issues. 2006;17(1):50–5.
64. Hunt DG, Ivy JL. Epinephrine inhibits insulin-stimulated muscle glucose transport. J Appl Physiol. 2002;93(5):1638–43. Bethesda, Md: 1985.
65. O’Neill PA, Davies I, Fullerton KJ, Bennett D. Stress hormone and blood glucose response following acute stroke in the elderly. Stroke J Cereb Circ. 1991;22(7):842–7.
66. Tarkowski E, Rosengren L, Blomstrand C, Wikkelso C, Jensen C, Ekholm S, et al. Early intrathecal production of interleukin-6 predicts the size of brain lesion in stroke. Stroke J Cereb Circ. 1995;26(8):1393–8.
67. Vila N, Castillo J, Davalos A, Chamorro A. Proinflammatory cytokines and early neurological worsening in ischemic stroke. Stroke J Cereb Circ. 2000;31(10):2325–9.
68. Chrousos GP. The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation. N Engl J Med. 1995;332(20):1351–62.
69. del Aguila LF, Claffey KP, Kirwan JP. TNF-alpha impairs insulin signaling and insulin stimulation of glucose uptake in C2C12 muscle cells. Am J Physiol. 1999;276(5 Pt 1):E849–55.
70. Rask-Madsen C, Dominguez H, Ihlemann N, Hermann T, Kober L, Torp-Pedersen C. Tumor necrosis factor-alpha inhibits insulin’s stimulating effect on glucose uptake and endothelium-dependent vasodilation in humans. Circulation. 2003;108(15):1815–21.
71. Plomgaard P, Bouzakri K, Krogh-Madsen R, Mittendorfer B, Zierath JR, Pedersen BK. Tumor necrosis factor-alpha induces skeletal muscle insulin resistance in healthy human subjects via inhibition of Akt substrate 160 phosphorylation. Diabetes. 2005;54(10):2939–45.
72. Bruno A, Williams LS, Kent TA. How important is hyperglycemia during acute brain infarction? Neurologist. 2004;10(4):195–200.
73. de Courten-Myers G, Myers RE, Schoolfield L. Hyperglycemia enlarges infarct size in cerebrovascular occlusion in cats. Stroke J Cereb Circ. 1988;19(5):623–30.
74. Kent TA, Soukup VM, Fabian RH. Heterogeneity affecting outcome from acute stroke therapy: making reperfusion worse. Stroke J Cereb Circ. 2001;32(10):2318–27.
75. Melamed E. Reactive hyperglycaemia in patients with acute stroke. J Neurol Sci. 1976;29(2–4):267–75.
76. McCormick MT, Muir KW, Gray CS, Walters MR. Management of hyperglycemia in acute stroke: how, when, and for whom? Stroke J Cereb Circ. 2008;39(7):2177–85.
77. Baird TA, Parsons MW, Phan T, Butcher KS, Desmond PM, Tress BM, et al. Persistent poststroke hyperglycemia is independently associated with infarct expansion and worse clinical outcome. Stroke J Cereb Circ. 2003;34(9):2208–14.
78. Allport LE, Butcher KS, Baird TA, MacGregor L, Desmond PM, Tress BM, et al. Insular cortical ischemia is independently associated with acute stress hyperglycemia. Stroke J Cereb Circ. 2004;35(8):1886–91.
79. Fuentes B, Castillo J, San Jose B, Leira R, Serena J, Vivancos J, et al. The prognostic value of capillary glucose levels in acute stroke: the GLycemia in Acute Stroke (GLIAS) study. Stroke J Cereb Circ. 2009;40(2):562–8.
80. Stollberger C, Exner I, Finsterer J, Slany J, Steger C. Stroke in diabetic and non-diabetic patients: course and prognostic value of admission serum glucose. Ann Med. 2005;37(5):357–64.
81. Stead LG, Gilmore RM, Bellolio MF, Mishra S, Bhagra A, Vaidyanathan L, et al. Hyperglycemia as an independent predictor of worse outcome in non-diabetic patients presenting with acute ischemic stroke. Neurocrit Care. 2009;10(2):181–6.
82. Egi M, Bellomo R, Stachowski E, French CJ, Hart GK, Hegarty C, et al. Blood glucose concentration and outcome of critical illness: the impact of diabetes. Crit Care Med. 2008;36(8):2249–55.
83. Umpierrez GE, Isaacs SD, Bazargan N, You X, Thaler LM, Kitabchi AE. Hyperglycemia: an independent marker of in-hospital mortality in patients with undiagnosed diabetes. J Clin Endocrinol Metab. 2002;87(3):978–82.
84. Kruyt ND, Nys GM, van der Worp HB, van Zandvoort MJ, Kappelle LJ, Biessels GJ. Hyperglycemia and cognitive outcome after ischemic stroke. J Neurol Sci. 2008;270(1–2):141–7.
85. Bruno A, Levine SR, Frankel MR, Brott TG, Lin Y, Tilley BC, et al. Admission glucose level and clinical outcomes in the NINDS rt-PA Stroke Trial. Neurology. 2002;59(5):669–74.
86. Uyttenboogaart M, Koch MW, Stewart RE, Vroomen PC, Luijckx GJ, De Keyser J. Moderate hyperglycaemia is associated with favourable outcome in acute lacunar stroke. Brain J Neurol. 2007;130(Pt 6):1626–30.
87. Alvarez-Sabin J, Molina CA, Ribo M, Arenillas JF, Montaner J, Huertas R, et al. Impact of admission hyperglycemia on stroke outcome after thrombolysis: risk stratification in relation to time to reperfusion. Stroke J Cereb Circ. 2004;35(11):2493–8.
88. Leigh R, Zaidat OO, Suri MF, Lynch G, Sundararajan S, Sunshine JL, et al. Predictors of hyperacute clinical worsening in ischemic stroke patients receiving thrombolytic therapy. Stroke J Cereb Circ. 2004;35(8):1903–7.
89. Alvarez-Sabin J, Molina CA, Montaner J, Arenillas JF, Huertas R, Ribo M, et al. Effects of admission hyperglycemia on stroke outcome in reperfused tissue plasminogen activator–treated patients. Stroke J Cereb Circ. 2003;34(5):1235–41.
90. Saposnik G, Young B, Silver B, Di Legge S, Webster F, Beletsky V, et al. Lack of improvement in patients with acute stroke after treatment with thrombolytic therapy: predictors and association with outcome. JAMA J Am Med Assoc. 2004;292(15):1839–44.
91. van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, et al. Intensive insulin therapy in critically ill patients. N Engl J Med. 2001;345(19):1359–67.
92. Van den Berghe G, Wilmer A, Hermans G, Meersseman W, Wouters PJ, Milants I, et al. Intensive insulin therapy in the medical ICU. N Engl J Med. 2006;354(5):449–61.
93. Walters MR, Weir CJ, Lees KR. A randomised, controlled pilot study to investigate the potential benefit of intervention with insulin in hyperglycaemic acute ischaemic stroke patients. Cerebrovasc Dis. 2006;22(2-3):116–22. Basel, Switzerland.
94. Bruno A, Kent TA, Coull BM, Shankar RR, Saha C, Becker KJ, et al. Treatment of hyperglycemia in ischemic stroke (THIS): a randomized pilot trial. Stroke J Cereb Circ. 2008;39(2):384–9.
95. Kreisel SH, Berschin UM, Hammes HP, Leweling H, Bertsch T, Hennerici MG, et al. Pragmatic management of hyperglycaemia in acute ischaemic stroke: safety and feasibility of intensive intravenous insulin treatment. Cerebrovasc Dis. 2009;27(2):167–75. Basel, Switzerland.
96. Johnston KC, Hall CE, Kissela BM, Bleck TP, Conaway MR. Glucose Regulation in Acute Stroke Patients (GRASP) trial: a randomized pilot trial. Stroke J Cereb Circ. 2009;40(12):3804–9.
97. Staszewski J, Brodacki B, Kotowicz J, Stepien A. Intravenous insulin therapy in the maintenance of strict glycemic control in nondiabetic acute stroke patients with mild hyperglycemia. J Stroke Cerebrovasc Dis Off J Natl Stroke Assoc. 2011;20(2):150–4.
98. McCormick M, Hadley D, McLean JR, Macfarlane JA, Condon B, Muir KW. Randomized, controlled trial of insulin for acute poststroke hyperglycemia. Ann Neurol. 2010;67(5):570–8.
99. Krinsley JS, Grover A. Severe hypoglycemia in critically ill patients: risk factors and outcomes. Crit Care Med. 2007;35(10):2262–7.
100. Egi M, Bellomo R, Stachowski E, French CJ, Hart GK, Taori G, et al. Hypoglycemia and outcome in critically ill patients. Mayo Clin Proc. 2010;85(3):217–24.
101. Casson RJ, Wood JP, Osborne NN. Hypoglycaemia exacerbates ischaemic retinal injury in rats. Br J Ophthalmol. 2004;88(6):816–20.
102. Dave KR, Tamariz J, Desai KM, Brand FJ, Liu A, Saul I, et al. Recurrent hypoglycemia exacerbates cerebral ischemic damage in streptozotocin-induced diabetic rats. Stroke J Cereb Circ. 2011;42(5):1404–11.
103. Dave KR, Pileggi A, Raval AP. Recurrent hypoglycemia increases oxygen glucose deprivation-induced damage in hippocampal organotypic slices. Neurosci Lett. 2011;496(1):25–9.
104. Chang YS, Park WS, Ko SY, Kang MJ, Han JM, Lee M, et al. Effects of fasting and insulin-induced hypoglycemia on brain cell membrane function and energy metabolism during hypoxia-ischemia in newborn piglets. Brain Res. 1999;844(1–2):135–42.
105. Rehni AK, Nautiyal N, Perez-Pinzon MA, Dave KR. Hyperglycemia/hypoglycemia-induced mitochondrial dysfunction and cerebral ischemic damage in diabetics. Metab Brain Dis. 2014.
106. Bagshaw SM, Bellomo R, Jacka MJ, Egi M, Hart GK, George C. The impact of early hypoglycemia and blood glucose variability on outcome in critical illness. Crit Care. 2009;13(3):R91. London, England.
107. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001;414(6865):813–20.
108. Ceriello A, Esposito K, Piconi L, Ihnat MA, Thorpe JE, Testa R, et al. Oscillating glucose is more deleterious to endothelial function and oxidative stress than mean glucose in normal and type 2 diabetic patients. Diabetes. 2008;57(5):1349–54.
109. Monnier L, Colette C, Mas E, Michel F, Cristol JP, Boegner C, et al. Regulation of oxidative stress by glycaemic control: evidence for an independent inhibitory effect of insulin therapy. Diabetologia. 2010;53(3):562–71.
110. Monnier L, Mas E, Ginet C, Michel F, Villon L, Cristol JP, et al. Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes. JAMA J Am Med Assoc. 2006;295(14):1681–7.
111. The 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.
112. Hirsch IB. Glycemic variability: it’s not just about A1C anymore! Diabetes Technol Ther. 2005;7(5):780–3.
113. Siegelaar SE, Holleman F, Hoekstra JB, DeVries JH. Glucose variability; does it matter? Endocr Rev. 2010;31(2):171–82.
114. Bragd J, Adamson U, Backlund LB, Lins PE, Moberg E, Oskarsson P. Can glycaemic variability, as calculated from blood glucose self-monitoring, predict the development of complications in type 1 diabetes over a decade? Diabetes Metab. 2008;34(6 Pt 1):612–6.
115. Dossett LA, Cao H, Mowery NT, Dortch MJ, Morris Jr JM, May AK. Blood glucose variability is associated with mortality in the surgical intensive care unit. Am Surg. 2008;74(8):679–85. discussion 85.
116. Egi M, Bellomo R, Stachowski E, French CJ, Hart G. Variability of blood glucose concentration and short-term mortality in critically ill patients. Anesthesiology. 2006;105(2):244–52.
117. Krinsley JS. Glycemic variability: a strong independent predictor of mortality in critically ill patients. Crit Care Med. 2008;36(11):3008–13.
118. Mendez CE, Mok KT, Ata A, Tanenberg RJ, Calles-Escandon J, Umpierrez GE. Increased glycemic variability is independently associated with length of stay and mortality in noncritically ill hospitalized patients. Diabetes Care. 2013;36(12):4091–7.
119. Matsushima K, Peng M, Velasco C, Schaefer E, Diaz-Arrastia R, Frankel H. Glucose variability negatively impacts long-term functional outcome in patients with traumatic brain injury. J Crit Care. 2012;27(2):125–31.
120. McCall AL, Cox DJ, Brodows R, Crean J, Johns D, Kovatchev B. Reduced daily risk of glycemic variability: comparison of exenatide with insulin glargine. Diabetes Technol Ther. 2009;11(6):339–44.
121. Irace C, Fiorentino R, Carallo C, Scavelli F, Gnasso A. Exenatide improves glycemic variability assessed by continuous glucose monitoring in subjects with type 2 diabetes. Diabetes Technol Ther. 2011;13(12):1261–3.
122. Lee CH, Yan B, Yoo KY, Choi JH, Kwon SH, Her S, et al. Ischemia-induced changes in glucagon-like peptide-1 receptor and neuroprotective effect of its agonist, exendin-4, in experimental transient cerebral ischemia. J Neurosci Res. 2011;89(7):1103–13.
123. Teramoto S, Miyamoto N, Yatomi K, Tanaka Y, Oishi H, Arai H, et al. Exendin-4, a glucagon-like peptide-1 receptor agonist, provides neuroprotection in mice transient focal cerebral ischemia. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab. 2011;31(8):1696–705.
124. Briyal S, Gulati K, Gulati A. Repeated administration of exendin-4 reduces focal cerebral ischemia-induced infarction in rats. Brain Res. 2012;1427:23–34.
125. Darsalia V, Mansouri S, Ortsater H, Olverling A, Nozadze N, Kappe C, et al. Glucagon-like peptide-1 receptor activation reduces ischaemic brain damage following stroke in type 2 diabetic rats. Clin Sci. 2012;122(10):473–83. London, England: 1979.
126. Guerci B, Monnier L, Serusclat P, Petit C, Valensi P, Huet D, et al. Continuous glucose profiles with vildagliptin versus sitagliptin in add-on to metformin: results from the randomized Optima study. Diabetes Metab. 2012;38(4):359–66.
127. Darsalia V, Ortsater H, Olverling A, Darlof E, Wolbert P, Nystrom T, et al. The DPP-4 inhibitor linagliptin counteracts stroke in the normal and diabetic mouse brain: a comparison with glimepiride. Diabetes. 2013;62(4):1289–96.
128. Yang D, Nakajo Y, Iihara K, Kataoka H, Yanamoto H. Alogliptin, a dipeptidylpeptidase-4 inhibitor, for patients with diabetes mellitus type 2, induces tolerance to focal cerebral ischemia in non-diabetic, normal mice. Brain Res. 2013;1517:104–13.
129. Jonassen I, Havelund S, Hoeg-Jensen T, Steensgaard DB, Wahlund PO, Ribel U. Design of the novel protraction mechanism of insulin degludec, an ultra-long-acting basal insulin. Pharm Res. 2012;29(8):2104–14.
130. Bergenstal RM, Rosenstock J, Bastyr 3rd EJ, Prince MJ, Qu Y, Jacober SJ. Lower glucose variability and hypoglycemia measured by continuous glucose monitoring with novel long-acting insulin LY2605541 versus insulin glargine. Diabetes Care. 2014;37(3):659–65.
131. Steinstraesser A, Schmidt R, Bergmann K, Dahmen R, Becker RH. Investigational new insulin glargine 300 U/ml has the same metabolism as insulin glargine 100 U/ml. Diabetes Obes Metab. 2014.
132. Maiorino MI, Petrizzo M, Capuano A, Giugliano D, Esposito K. The development of new basal insulins: is there any clinical advantage with their use in type 2 diabetes? Expert Opin Biol Ther. 2014;14(6):799–808.
133. Garber AJ. Will the next generation of basal insulins offer clinical advantages? Diabetes Obes Metab. 2014;16(6):483–91.
134. Owens DR, Matfin G, Monnier L. Basal insulin analogues in the management of diabetes mellitus: what progress have we made? Diabetes Metab Res Rev. 2014;30(2):104–19.