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Key Event Title
Key Event Components
Key Event Overview
AOPs Including This Key Event
|All life stages||High|
Key Event Description
Hyperglycemia is the inability to effectively lower blood glucose post-prandially and maintain glucose homeostasis. Hyperglycemia is a characteristic symptom of metabolic disorders including metabolic syndrome and type 2 diabetes (T2D) (11).
Blood glucose is primarily modulated by two pancreatic endocrine hormones, insulin and glucagon (13). The former is an anabolic peptide hormone secreted post-prandially by β-cells that lowers blood glucose by increasing glycogen storage in muscle and hepatic tissue. The latter is a catabolic peptide hormone secreted during fasting by α-cells that increases blood glucose by metabolizing stored glycogen.
The inability to maintain blood glucose homeostasis can occur due to damage to pancreatic β-cells and subsequent inability to secrete insulin in response to nutrients (11), and/or tolerance to the anabolic effects of insulin at target tissues known as insulin resistance (14).
How It Is Measured or Detected
In humans, hyperglycemia is characterized as a random blood glucose of ≥ 200 mg/dL (11.1 mmol/L) (17).
In research animals, hyperglycemia is typically characterized as a significant difference in fasted blood glucose relative to a control group. To get a more dynamic understanding of blood glucose homeostasis, a glucose tolerance test can be performed. Briefly, following the administration of a bolus of glucose, blood glucose can be measured sequentially, typically in 15-minutes intervals for research animals (1) and 30-minutes in humans (6), for 120 minutes. Individual time points can be compared (i.e., 15-minutes post-glucose exposure) relative to controls as well as the overall area under the curve.
The most basic form of measuring blood glucose is applying a droplet of blood onto a glucometer. Most glucometers utilize the glucose oxidase method (10).
Glucose oxidase assay: The concentration of glucose in a sample, blood plasma or media, can be estimated using a commercially available glucose oxidase assay kit. Briefly, the sample is exposed to glucose oxidase that oxidizes glucose into gluconolactone and produces hydrogen peroxide as a by-product. The hydrogen peroxide reacts with a dye and the resulting colour change is measured using a colorimeter and used to estimate glucose concentration (16). A similar method utilizes a Beckman oxygen electrode to measure oxygen consumption to estimate glucose concentration (16).
Hexokinase assay: The concentration of glucose in a sample, blood plasma or media, can be estimated using a commercially available hexokinase assay kit. Briefly, the sample is exposed to hexokinase in the presence of adenosine triphosphate to produce glucose-6-phosphate (G6P) and adenosine diphosphate (3). The subsequent oxidation of G6P by G6P dehydrogenase to 6-phosphogluconate is coupled to the reduction of nicotinamide adenine dinucleotide (NAD+/NADH). The amount of reduction of NAD+ to NADH is used to estimate the concentration of glucose.
Ferricyanide oxidation assay: The concentration of glucose in a sample, blood plasma or media, can be estimated by oxidizing to gluconic acid with ferricyanide. Briefly, the sample is exposed to a ferricyanide salt and the amount of reduced ferricyanide can be determined by iodometric titration to estimate the concentration of glucose (5).
Glycated hemoglobin assay: The concentration of glycated hemoglobin in blood can be estimated using a variety of procedures that have been standardized (7).
Domain of Applicability
Taxonomy: Both vertebrates (15) and invertebrates (2, 12) use blood (or functional equivalents like hemolymph) that carry carbohydrates like glucose. Invertebrate models of hyperglycemia have been developed (for example, see 7, 8).
Life Stages: Glucose (or functional equivalents) is present in blood at all life stages and its concentration in serum can vary.
Sex Applicability: Both male and females have glucose in their blood (for example, see 4).
1. Ayala JE, Samuel VT, Morton GJ, Obici S, Croniger CM, Shulman GI, Wasserman DH, McGuinness OP, Consortium NIHMMPC. Standard operating procedures for describing and performing metabolic tests of glucose homeostasis in mice. Dis Model Mech 3: 525–534, 2010. doi: 10.1242/dmm.006239.
2. Caldari-Torres C, Banta-Long W, Bruss A, Choi E, Fiegel H, Jollis MS, Ly S, Viswanathan S. Hemolymph Glucose Levels as a Measure of Crayfish Stress: A Methodology Using a Human Glucometer. FASEB J 32: lb224–lb224, 2018. doi: https://doi.org/10.1096/fasebj.2018.32.1_supplement.lb224.
3. Dickson LM, Buchmann EJ, Janse Van Rensburg C, Norris SA. The impact of differences in plasma glucose between glucose oxidase and hexokinase methods on estimated gestational diabetes mellitus prevalence. Sci Rep 9: 7238, 2019. doi: 10.1038/s41598-019-43665-x.
4. Faerch K, Borch-Johnsen K, Vaag A, Jørgensen T, Witte DR. Sex differences in glucose levels: a consequence of physiology or methodological convenience? The Inter99 study. Diabetologia 53: 858–865, 2010. doi: 10.1007/s00125-010-1673-4.
5. Hulme AC, Narain R. The ferricyanide method for the determination of reducing sugars: A modification of the Hagedorn-Jensen-Hanes technique. Biochem J 25: 1051–1061, 1931. doi: 10.1042/bj0251051.
6. Jagannathan R, Neves JS, Dorcely B, Chung ST, Tamura K, Rhee M, Bergman M. The Oral Glucose Tolerance Test: 100 Years Later. Diabetes Metab Syndr Obes 13: 3787–3805, 2020. doi: 10.2147/DMSO.S246062.
7. Little RR. Glycated Hemoglobin Standardization – National Glycohemoglobin Standardization Program (NGSP) Perspective. 41: 1191–1198, 2003. doi: doi:10.1515/CCLM.2003.183.
8. Matsumoto Y, Sumiya E, Sugita T, Sekimizu K. An invertebrate hyperglycemic model for the identification of anti-diabetic drugs. PLoS One 6: e18292–e18292, 2011. doi: 10.1371/journal.pone.0018292.
9. Musselman LP, Fink JL, Baranski TJ. Similar effects of high-fructose and high-glucose feeding in a Drosophila model of obesity and diabetes [Online]. PLoS One 14: e0217096, 2019. https://doi.org/10.1371/journal.pone.0217096.
10. Norouzi P, Faridbod F, Larijani B, Ganjali MR. Glucose biosensor based on MWCNTs-gold nanoparticles in a nafion film on the glassy carbon electrode using flow injection FFT continuous cyclic voltammetry. Int J Electrochem Sci 5: 1213–1224, 2010.
11. Porte Jr. D. Mechanisms for Hyperglycemia in the Metabolic Syndrome: The Key Role of β-Cell Dysfunction. Ann N Y Acad Sci 892: 73–83, 1999. doi: https://doi.org/10.1111/j.1749-6632.1999.tb07786.x.
12. Principe SC, Augusto A, Costa TM. Point-of-care testing for measuring haemolymph glucose in invertebrates is not a valid method. Conserv Physiol 7: coz079–coz079, 2019. doi: 10.1093/conphys/coz079.
13. Röder P V, Wu B, Liu Y, Han W. Pancreatic regulation of glucose homeostasis. Exp Mol Med 48: e219–e219, 2016. doi: 10.1038/emm.2016.6.
14. Tomas E, LIn Y-S, Dagher Z, Saha A, Luo Z, Ido Y, Ruderman NB. Hyperglycemia and Insulin Resistance: Possible Mechanisms. Ann N Y Acad Sci 967: 43–51, 2002. doi: https://doi.org/10.1111/j.1749-6632.2002.tb04262.x.
15. Umminger BL. Relation of whole blood sugar concentrations in vertebrates to standard metabolic rate. Comp Biochem Physiol Part A Physiol 56: 457–460, 1977. doi: https://doi.org/10.1016/0300-9629(77)90267-5.
16. Yuen VG, McNeill JH. Comparison of the glucose oxidase method for glucose determination by manual assay and automated analyzer. J Pharmacol Toxicol Methods 44: 543–546, 2000. doi: https://doi.org/10.1016/S1056-8719(01)00117-4.
17. Diagnosis and classification of diabetes mellitus. Diabetes Care 33, 2010. doi: 10.2337/dc10-S062.