Insulin-induced normoglycemia improves ischemic outcome in hyperglycemic rats.

Warner, David S.; Gionet, Thomas X.; Todd, Michael M.; McAllister, A.

doi:10.1161/01.str.23.12.1775

Cited by 68 publications

(23 citation statements)

References 39 publications

(24 reference statements)

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“…This result was unexpected because diabetes augmented intra ischemic acidosis to the same extent as acute hy perglycemia. In contrast, Warner et al (1992) re ported that 5-7 days of streptozotocin-induced dia-betes in rats without insulin treatment resulted in augmented ischemic damage. Differences in these studies might be attributed to one of several factors including the diabetic model, ischemia model, insu lin management, or duration of diabetes.…”

Section: Discussionmentioning

confidence: 88%

Poor Hemodynamic and Metabolic Recovery after Global Incomplete Cerebral Ischemia Associated with Short-Term Diabetes in Dogs

Palmon

Sieber

Brown

et al. 1995

J Cereb Blood Flow Metab

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Summary:We determined the effect of 4-5 weeks of di abetes on ATP recovery following global incomplete ce rebral ischemia. 31p magnetic resonance spectra of ATP, intracellular pH (pHj), and CBF (radiolabeled micro spheres) were measured in three groups of anesthetized dogs (n = 8/group): chronic hyperglycemic diabetes (pan createctomy followed by blood glucose of > to mM for 4-5 weeks); acute hyperglycemia (blood glucose of> to mM) during ischemia and reperfusion in nondiabetic dogs; and normoglycemic controls. Twenty minutes of incomplete ischemia was produced by ventricular fluid infusion to keep cerebral perfusion pressure (CPP) at to mm Hg during spontaneous variations in MABP. Intra cranial pressure was increased initially to similar levels, resulting in a similar Cushing response among the groups. However, during the final 8 min of ischemia, MABP de creased to a greater extent in diabetic (86 ± 42 mm Hg) than in hyperglycemic (162 ± 30 mm Hg) and normogly cemic (135 ± 54 mm Hg) groups and remained lower throughout 3 h of reperfusion. CPP was kept constant during ischemia, but was lower throughout reperfusion in diabetic dogs. During ischemia CBF was reduced simi larly among groups: 5 ± 3 ml . min -I • 100 g -1 in hyper glycemic and normoglycemic and 4 ± 3 ml . min -I . 100 g -I in diabetic dogs. During reperfusion early hyperemia During global cerebral ischemia, acute hypergly cemia is associated with increased neurologic dam age; however, the effects of chronic hyperglycemia secondary to diabetes on the cerebral ischemic re sponse are unclear. This is particularly true in aniReceived September 12, 1994; final revision received Novem ber 10, 1994; accepted November 11, 1994. Address correspondence and reprint requests to Dr. S. C. Palmon at Department of Anesthesiology and Critical Care Med icine, Johns Hopkins Hospital, 600 N. Wolfe St., Meyer 8-134, Baltimore, MD 21287-7834, U.S.A.Abbreviations used: CPP, cerebral perfusion pressure; ICP, intracranial pressure; MRS, magnetic resonance spectroscopy. 673was attenuated and delayed hypoperfusion was aug mented (7 ± 17 ml . min -I . 100 g-I by 180 min) as a result of low perfusion pressure in diabetics. However, medullary blood flow was similar among groups. End ischemic ATP was similar among groups (25 ± 34, 30 ± 25, and 4 ± 11% of baseline in normoglycemic, hypergly cemic and diabetic dogs, respectively). Following 180 min of reperfusion ATP was 87 ± 15,45 ± 38, and 7 ± 19% of control in normoglycemic, hyperglycemic and diabetic dogs, respectively. End-ischemic pHj was lower in hyper glycemic (5.94 ± 0.16) and diabetic (5.96 ± 0.08) than normoglycemic (6.32 ± 0.04) groups. By 45 min of reper fusion, pHi recovered in normoglycemic (7.02 ± 0.09) but not in diabetic (6.l3 ± 0.38) or hyperglycemic dogs (6.44 ± 0.28). This study shows that MABP, CBF, ATP, and pHi following global incomplete ischemia did not recover in diabetic dogs. In diabetics poor metabolic recovery was related to the MABP decreases during ischemia and reperfusion. These results contrast wi...

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Section: Discussionmentioning

confidence: 88%

Poor Hemodynamic and Metabolic Recovery after Global Incomplete Cerebral Ischemia Associated with Short-Term Diabetes in Dogs

Palmon

Sieber

Brown

et al. 1995

J Cereb Blood Flow Metab

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“…In the rat forebrain ischemia model, preischemic treatment of DM hyperglycemia with insulin leads to a neurological outcome and histopathology similar to that in non-DM normoglycemic rats. 10 However, untreated hyperglycemia leads to a dismal neurological and histopathologic outcome. These results agree with studies using magnetic resonance spectroscopy, which suggest that the most hyperglycemic DM animals are at highest risk for poor neurological outcome.…”

Section: Discussionmentioning

confidence: 99%

Estrogen Decreases Infarct Size After Temporary Focal Ischemia in a Genetic Model of Type 1 Diabetes Mellitus

Toung

Hurn

Traystman

et al. 2000

Stroke

109

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Background and Purpose-It is unclear how genetic type 1 diabetes mellitus (DM) influences infarct size when blood glucose is tightly controlled. The aim of this study was to determine the effect of genetic type 1 DM, as occurs in BB rats, on infarct size after transient unilateral middle cerebral artery occlusion (MCAO) in male and female rats. In addition, studies suggest that male type 1 DM rats have a higher incidence of end-organ complications than do females. A second aim of this study was to determine the effect of chronic 17␤-estradiol (E 2 ) administration on infarct size in male BB rats. Methods-Diabetic male (MDiab, nϭ14) and female (FDiab, nϭ8) BB rats were studied and compared with background strain Wistar rats (MWist, nϭ16; FWist, nϭ14). Two additional male cohorts (MWistϩE 2 , nϭ15; MDiabϩE 2 , nϭ14) received subcutaneous 25 g E 2 implants 7 to 10 days before MCAO. Rats underwent 1 hour of MCAO followed by 22 hours of reperfusion. Physiological variables were controlled among groups, and the intraischemic laser Doppler flow signal was reduced similarly in all animals. Infarction volume was evaluated by 2,3,5-triphenyltetrazolium chloride staining and image analysis. Results-Preischemic blood glucose was 94Ϯ5, 127Ϯ13, 90Ϯ15, 63Ϯ18, 122Ϯ8, and 81Ϯ14 mg/dL in MWist, FWist, MDiab, FDiab, MWistϩE 2 , and MDiabϩE 2 rats, respectively (meanϮSE). Intraischemic laser Doppler flow was reduced to 20% to 25% of baseline in all groups. Striatal infarct size (percentage of ipsilateral caudate putamen) was increased in male diabetic rats relative to nondiabetic MWist rats (41Ϯ3% versus 28Ϯ3%). Striatal injury was not increased in FDiab rats, and infarction volume was smaller than that in FWist rats (23Ϯ4% in FWist versus 13Ϯ3% in FDiab). Chronic estrogen treatment reduced cortical and striatal infarction in MDiabϩE 2 rats compared with untreated MDiab rats. Conclusions-Type 1 DM is associated with increased infarct size after temporary MCAO, despite tight control of blood glucose. The deleterious effect of DM is evident only in males rats; female diabetic BB rats sustain small infarcts. Chronic E 2 treatment reduced injury in the male BB rat, providing neuroprotection even in the presence of DM. These data suggest that genetic diabetes even with mild glucose elevation plays a role in determining neuropathology in experimental stroke. However, factors such as reproductive steroids also determine outcome in DM stroke. (Stroke.

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“…findings, treatment of hyperglycemia with insulin in these models, improves the outcome (10,29,45). Notwithstanding extensive clinical and experimental data indicating that hyperglycemia exacerbates poststroke brain damage and evidence from animal models that reversal of hyperglycemia with insulin attenuates injury (10,29,45), in clinical practice, this approach is controversial (8,23,25,31,35,37).…”

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confidence: 99%

“…Notwithstanding extensive clinical and experimental data indicating that hyperglycemia exacerbates poststroke brain damage and evidence from animal models that reversal of hyperglycemia with insulin attenuates injury (10,29,45), in clinical practice, this approach is controversial (8,23,25,31,35,37). This disconcerting lack of clinical success is not entirely surprising, since insulin has pleiotropic effects on cell metabolism that extend beyond the lowering of blood glucose.…”

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confidence: 99%

Insulin and glucagon share the same mechanism of neuroprotection in diabetic rats: role of glutamate

Fanne¹,

Nassar²,

Heyman

et al. 2011

American Journal of Physiology-Regulatory, Integrative and Comp

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Abu Fanne R, Nassar T, Heyman SN, Hijazi N, Higazi AA. Insulin and glucagon share the same mechanism of neuroprotection in diabetic rats: role of glutamate. Am J Physiol Regul Integr Comp Physiol 301: R668 -R673, 2011. First published June 15, 2011 doi:10.1152/ajpregu.00058.2011In patients with acute ischemic stroke, diabetes and hyperglycemia are associated with increased infarct size, more profound neurologic deficits and higher mortality. Notwithstanding extensive clinical and experimental data, treatment of stroke-associated hyperglycemia with insulin is controversial. In addition to hyperglycemia, diabetes and even early prediabetic insulin resistance are associated with increased levels of amino acids, including the neurotoxic glutamate, in the circulation. The pleiotropic metabolic effects of insulin include a reduction in the concentration of amino acids in the circulation. In this article, we show that in diabetic rats exposed to transient middle cerebral artery occlusion, a decrease of plasma glutamate by insulin or glucagon reduces CSF glutamate, improves brain histology, and preserves neurologic function. The neuroprotective effect of insulin and glucagon was similar, notwithstanding their opposite effects on blood glucose. The therapeutic window of both hormones overlapped with the short duration (ϳ30 min) of elevated brain glutamate following brain trauma in rodents. Similar neuroprotective effects were found after administration of the glutamate scavenger oxaloacetate, which does not affect glucose metabolism. These data indicate that insulin and glucagon exert a neuroprotective effect within a very brief therapeutic window that correlates with their capacity to reduce glutamate, rather than by modifying glucose levels. stroke; brain damage; glutamate IN ϳ30 -40% OF PATIENTS WITH acute ischemic stroke, diabetes is found at presentation (5, 24), ϳ70% have elevated blood glucose levels (27), and about 25% develop persistent hyperglycemia (21). Hyperglycemia is associated with increased infarct size (5,9,12,21,36,44), as well as with a ϳ3-fold higher risk of death (15), and survivors have more profound neurologic deficits and disability (26). Hyperglycemia is also associated with aggravated postischemic brain damage in animal models. In cats, acute hyperglycemia is associated with a ϳ3-fold increase in the volume of hemispheric infarcts induced by cerebrovascular occlusion (19), and in dogs, even moderate hyperglycemia has been shown to increase brain damage and mortality induced by ischemia (33). Consistent with these findings, treatment of hyperglycemia with insulin in these models, improves the outcome (10, 29, 45). Notwithstanding extensive clinical and experimental data indicating that hyperglycemia exacerbates poststroke brain damage and evidence from animal models that reversal of hyperglycemia with insulin attenuates injury (10, 29, 45), in clinical practice, this approach is controversial (8,23,25,31,35,37). This disconcerting lack of clinical success is not entirely surprising, since insu...

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Insulin-induced normoglycemia improves ischemic outcome in hyperglycemic rats.

Cited by 68 publications

References 39 publications

Poor Hemodynamic and Metabolic Recovery after Global Incomplete Cerebral Ischemia Associated with Short-Term Diabetes in Dogs

Poor Hemodynamic and Metabolic Recovery after Global Incomplete Cerebral Ischemia Associated with Short-Term Diabetes in Dogs

Estrogen Decreases Infarct Size After Temporary Focal Ischemia in a Genetic Model of Type 1 Diabetes Mellitus

Insulin and glucagon share the same mechanism of neuroprotection in diabetic rats: role of glutamate

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