Hyperglycemia is due to a dysregulation in the complex mechanisms implicated in glucose homeostasis. Chronic hyperglycemia, as measured by hemoglobin A1c (HbA1c), is a key risk factor for the development of microvascular and macrovascular complications, which in turn negatively influence the prognosis of patients with diabetes. Several studies have shown that acute hyperglycemia can add to the effect of chronic hyperglycemia in inducing tissue damage. Acute hyperglycemia can manifest as high fasting plasma glucose (FPG) or high postprandial plasma glucose (PPG) and can activate the same metabolic and hemodynamic pathways as chronic hyperglycemia. Glucose variability, as expressed by the intraday glucose fluctuations from peaks to nadirs, is another important parameter, which has emerged as an HbA1c-independent risk factor for the development of vascular complications, mainly in the context of type 2 diabetes. Treatments able to decrease HbA1c have been associated with positive effects in terms of reducing risk for the development and progression of complications. Further studies are required to clarify the impact of strategies more specifically targeting components of acute hyperglycemia, to improve outcomes in patients with diabetes.
Hyperglycemia, complications, vascular, acute, chronic
M Loredana Marcovecchio has nothing to disclose in relation to this article. No funding was received in the publication of this article. This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors.
Authorship: Thel named author meets the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, takes responsibility for the integrity of the work as a whole, and has given final approval to the version to be published.
February 27, 2017 Accepted
March 30, 2017
M Loredana Marcovecchio, University of Cambridge, Box 116, Level 8, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0QQ, UK. E: firstname.lastname@example.org
This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit.
From glucose homeostasis to hyperglycemia
Glucose homeostasis is maintained by a complex neurohormonal system, which modulates peripheral glucose uptake, hepatic glucose production, and exogenous glucose utilization following food ingestion.1,2 This allows the maintenance of plasma glucose concentrations within normal range, with average values of around 90 mg/dl throughout a 24-hour period, postmeal concentration below 140 mg/dl, and minimal values, such as those after moderate fasting or exercise, above 55 mg/dl.1,2
Hormones implicated in glucose regulation include insulin, glucagon, amylin, glucagon-like petide-1 (GLP-1), glucose-dependent insulinotropic peptide, epinephrine, cortisol, and growth hormone.3 These hormones act on several target tissues, including muscle, liver, adipocyte, and brain to regulate glucose levels.3
Insulin is a key glucoregulatory hormone, produced by pancreatic β-cells, whose levels are low during the fasting state, whereas they increase during the postprandial phase, when insulin stimulates utilization of dietary glucose by peripheral tissues, and in the meantime represses hepatic glucose production.4 Another important hormone regulating glucose metabolism is glucagon, produced by pancreatic α-cells during fasting conditions, when it induces hepatic glucose production through the activation of glycogenolysis and, with more prolonged fasting, also stimulation of gluconeogenesis.5
A dysregulation in the mechanisms implicated in glucose homeostasis can cause acute or chronic hyperglycemia.6 Decreased/assent insulin production and/or reduced insulin sensitivity are important contributing factors to the development of hyperglycemia and they represent the underlying abnormalities of diabetes.4 Along with a decreased/absent insulin secretion, diabetes is also characterized by impaired glucagon production, which can predispose to the risk of hypoglycemia in these patients.5 However, there is also extensive evidence that in patients with diabetes, hyperglycemia is often associated with hyperglucagonemia.5
The combined alterations in insulin and glucagon production/secretion in diabetes is the reason why recently there has been increasing interest in developing new therapeutic strategies to achieve normoglycemia based on a bihormonal approach, delivering insulin and glucagon simultaneously.5 In addition, the ongoing advances in the understanding of the complex hormonal regulation of glucose metabolism have also led to the development of new drugs to be implemented to treat hyperglycemia, such as GLP-1 or amylin analogs.3
The spectrum of hyperglycemia
Chronic hyperglycemia is the hallmark of diabetes mellitus, a chronic condition characterized not only by hyperglycemia but also by alterations in protein and lipid metabolism.7 The definition of diabetes is based on fasting glucose levels ≥126 mg/dl or random glucose levels ≥200 mg/dl.7
Among the various forms of diabetes, type 1 diabetes (T1D) is characterized by an autoimmune destruction of pancreatic β-cells, and is the most frequent form in the pediatric population, representing more than 90% of all cases of diabetes diagnosed during childhood and adolescence.7 Over the last decades there has been a progressive increase in the incidence of T1D in children and adolescents.8 Based on recent data from the International Diabetes Federation, worldwide there are around 542,000 children younger than 14 years with T1D, with more than 86,000 newly diagnosed cases per year.9
Type 2 diabetes (T2D) is the most common form of diabetes in adults, and is characterized by the presence of a state of insulin resistance associated with a progressive loss of β-cell function.10 In recent years, concomitant with the growing epidemic of childhood obesity, there has also been the emergence of T2D among adolescents. Epidemiologic data indicate that in the US T2D now accounts for 8–87% of new cases of pediatric diabetes.11,12
Additional forms of diabetes include secondary diabetes, as a consequence of prolonged use of certain drugs, such as glucocorticoids, or occurring in the context of other diseases, such as cystic fibrosis, Cushing’s syndrome; monogenic forms of diabetes, such as neonatal diabetes or the maturity onset diabetes of the young (MODY), due to defects in genes regulating insulin secretion; and gestational diabetes.10
Prediabetes and other earlier forms of dysglycemia
Prediabetes is a condition characterized by abnormal glucose concentrations, which however, are still below the cutoff for the diagnosis of diabetes. Prediabetes includes two main conditions: impaired fasting glucose (IFG), characterized by fasting glucose levels between 100 and 125 mg/dl, and impaired glucose tolerance (IGT), defined by 2-hour postload glucose levels between 140 and 199 mg/dl.13,14 Based on epidemiologic data, about 60% of adults with T2D when assessed 5 years prior to diagnosis present either IGT or IGF.15
During more recent years there has been a lot of interest in identifying even earlier signs of dysglycemia, predictive of future risk of diabetes. Recent reports have shown that 1-hour postload glucose concentrations ≥155 mg/dl is a predictor of future risk of T2D in adults of different ethnic backgrounds, even in the presence of normal fasting or 2-hour postload glucose levels.15–19 In addition, this glucose cutoff is able to identify subjects with an impaired cardiometabolic profile, characterized by high blood pressure, dyslipidemia, liver steatosis, early signs of atherosclerosis, as well as an increased mortality.20–25
In children and adolescents, data on 1-hour postload glucose are not as extensive as in adults, but some preliminary studies have confirmed that a cutoff of 155 mg/dl, or even of 132 mg/dl, could predict future risk of T2D and identify young subjects with early cardiovascular abnormalities.26,27
1. Shrayyef MZ, Gerich JE, Normal Glucose Homeostasis. In Poretsky L (ed),Principles of Diabetes Mellitus, Boston, MA: Springer US, 2010;19–35.
2. Szablewski L, Glucose Homeostasis and Insulin Resistance, Bentham Science Publishers; 2011. doi: 10.2174/97816080518921110101.
3. Aronoff SL, Berkowitz K, Shreiner B, Want L, Glucose metabolism and regulation: beyond insulin and glucagon, Diabetes Spectr, 2004;17:183–90.
4. Rizza RA, Mandarino LJ, Gerich JE, Dose-response characteristics for effects of insulin on production and utilization of glucose in man, Am J Physiol, 1981;240:E630–9.
5. Campbell JE, Drucker DJ, Islet α cells and glucagon—critical regulators of energy homeostasis,Nat Rev Endocrinol, 2015;11:329–38.
6. Giugliano D, Ceriello A, Esposito K, Glucose metabolism and hyperglycemia, Am J Clin Nutr, 2008;87:217S–22S.
7. American Diabetes Association, 2. Classification and diagnosis of diabetes, Diabetes Care, 2017;40:S11–24.
8. Patterson CC, Dahlquist GG, Gyürüs E, et al., Incidence trends for childhood type 1 diabetes in Europe during 1989–2003 and predicted new cases 2005–20: a multicentre prospective registration study, Lancet, 2009;373:2027–33.
9. IDF diabetes atlas - Home [Internet], 2017. Available at: www.diabetesatlas.org/ (accessed February 26, 2017).
10. American Diabetes Association, 2. Classification and diagnosis of diabetes, Diabetes Care, 2017;40:S11–24.
11. D’Adamo E, Caprio S, Type 2 diabetes in youth: epidemiology and pathophysiology,Diabetes Care, 2011;34:S161–5.
12. Nadeau KJ, Anderson BJ, Berg EG, et al., Youth-onset type 2 diabetes consensus report: current status, challenges, and priorities, Diabetes Care, 2016;39:1635–42.
13. Unwin N, Shaw J, Zimmet P, Alberti KG, Impaired glucose tolerance and impaired fasting glycaemia: the current status on definition and intervention, Diabet Med, 2002;19:708–23.
14. Abdul-Ghani MA, Lyssenko V, Tuomi T, et al., The shape of plasma glucose concentration curve during OGTT predicts future risk of type 2 diabetes, Diabetes Metab Res Rev, 2010;26:280–6.
15. Abdul-Ghani MA, Williams K, DeFronzo RA, Stern M, What is the best predictor of future type 2 diabetes?,Diabetes Care, 2007;30:1544–8.
16. Abdul-Ghani MA, Abdul-Ghani T, Ali N, Defronzo RA, One-hour plasma glucose concentration and the metabolic syndrome identify subjects at high risk for future type 2 diabetes,Diabetes Care, 2008;31:1650–5.
17. Abdul-Ghani MA, Lyssenko V, Tuomi T, et al., Fasting versus postload plasma glucose concentration and the risk for future type 2 diabetes: results from the Botnia study, Diabetes Care, 2009;32:281–6.
18. Alyass A, Almgren P, Akerlund M, et al., Modelling of OGTT curve identifies 1 h plasma glucose level as a strong predictor of incident type 2 diabetes: results from two prospective cohorts, Diabetologia, 2014;58:87–97.
19. Jagannathan R, Sevick MA, Li H, et al., Elevated 1-hour plasma glucose levels are associated with dysglycemia, impaired beta-cell function, and insulin sensitivity: a pilot study from a real world health care setting, Endocrine, 2015;52:172–5.
20. Succurro E, Marini MA, Arturi F, et al., Elevated one-hour post-load plasma glucose levels identifies subjects with normal glucose tolerance but early carotid atherosclerosis, Atherosclerosis, 2009;207:245–9.
21. Bianchi C, Miccoli R, Trombetta M, et al., Elevated 1-hour postload plasma glucose levels identify subjects with normal glucose tolerance but impaired β-cell function, insulin resistance, and worse cardiovascular risk profile: the GENFIEV study, J Clin Endocrinol Metab, 2013;98:2100–5.
22. Sciacqua A, Miceli S, Carullo G, et al., One-hour postload plasma glucose levels and left ventricular mass in hypertensive patients, Diabetes Care, 2011;34:1406–11.
23. Sesti G, Hribal ML, Fiorentino TV, et al., Elevated 1 h postload plasma glucose levels identify adults with normal glucose tolerance but increased risk of non-alcoholic fatty liver disease, BMJ Open Diabetes Res Care, 2014;2:e000016.
24. Orencia AJ, Daviglus ML, Dyer AR, et al., One-hour postload plasma glucose and risks of fatal coronary heart disease and stroke among nondiabetic men and women: the Chicago Heart Association Detection Project in Industry (CHA) study, J Clin Epidemiol, 1997;50:1369–76.
25. Bergman M, Chetrit A, Roth J, et al., One-hour post-load plasma glucose level during the OGTT predicts dysglycemia, Diabetes Res Clin Pract, 2016;120:221–8.
26. Manco M, Miraglia Del Giudice E, Spreghini MR, et al., 1-Hour plasma glucose in obese youth, Acta Diabetol, 2012;49:435–43.
27. Tfayli H, Jung Lee S, Bacha F, Arslanian S, One-hour plasma glucose concentration during the OGTT: what does it tell about β-cell function relative to insulin sensitivity in overweight/obese children?, Pediatr Diabetes, 2011;12:572–9.
28. Brownlee M, The pathobiology of diabetic complications: a unifying mechanism, Diabetes, 2005;54:1615–25.
29. Orasanu G, Plutzky J, The pathologic continuum of diabetic vascular disease, J Am Coll Cardiol, 2009;53:S35–42.
30. Umpierrez G, Korytkowski M, Diabetic emergencies — ketoacidosis, hyperglycaemic hyperosmolar state and hypoglycaemia, Nat Rev Endocrinol, 2016;12:222–32.
31. Steenkamp DW, Alexanian SM, McDonnell ME, Adult hyperglycemic crisis: a review and perspective, Curr Diab Rep, 2013;13:130–7.
32. Wolfsdorf JI, Allgrove J, Craig ME, et al., Diabetic ketoacidosis and hyperglycemic hyperosmolar state, Pediatr Diabetes, 2014;15:154–79.
33. Marcovecchio ML, Tossavainen PH, Dunger DB, Prevention and treatment of microvascular disease in childhood type 1 diabetes, Br Med Bull, 2010;94:145–64.
34. Orasanu G, Plutzky J, The pathologic continuum of diabetic vascular disease, J Am Coll Cardiol, 2009;53:S35–42.
35. Gross JL, de Azevedo MJ, Silveiro SP, et al., Diabetic nephropathy: diagnosis, prevention, and treatment, Diabetes Care, 2005;28:164–76.
36. Solomon SD, Chew E, Duh EJ, et al., Diabetic retinopathy: a position statement by the American Diabetes Association, Diabetes Care, 2017;40:412–8.
37. Pop-Busui R, Boulton AJM, Feldman EL, et al., Diabetic neuropathy: a position statement by the American Diabetes Association, Diabetes Care, 2017;40:136–54.
38. Duca L, Sippl R, Snell-Bergeon JK, Is the risk and nature of CVD the same in Type 1 and Type 2 diabetes?, Curr Diab Rep, 2013;13:350–61.
39. Forbes JM, Cooper ME, Mechanisms of diabetic complications, Physiol Rev, 2013;93:137–88.
40. Pirola L, Nathan D, Zinman B, et al., The DCCT/EDIC study: epigenetic clues after three decades, Diabetes, 2014;63:1460–2.
41. Nathan DM, McGee P, Steffes MW, Lachin JM, DCCT/EDIC Research Group, Relationship of glycated albumin to blood glucose and HbA1c values and to retinopathy, nephropathy, and cardiovascular outcomes in the DCCT/EDIC study, Diabetes, 2014;63:282–90.
42. Group TDC and CTR, 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;329:977–86.
43. Kilpatrick ES, Rigby AS, Atkin SL, The diabetes control and complications trial: the gift that keeps giving, Nat Rev Endocrinol, 2009;5:537–45.
44. White NH, Sun W, Cleary PA, et al., Effect of prior intensive therapy in type 1 diabetes on 10-year progression of retinopathy in the DCCT/EDIC: comparison of adults and adolescents, Diabetes, 2010;59:1244–53.
45. Pirola L, The DCCT/EDIC study: epigenetic clues after three decades, Diabetes, 2014;63:1460–2.
46. Chen Z, Miao F, Paterson AD, et al., Epigenomic profiling reveals an association between persistence of DNA methylation and metabolic memory in the DCCT/EDIC type 1 diabetes cohort, Proc Natl Acad Sci, 2016;201603712.
47. Zhong X, Liao Y, Chen L, et al., The microRNAs in the pathogenesis of metabolic memory, Endocrinology, 2015;156:3157–68.
48. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group, Lancet, 1998;352:837–53.
49. Nathan DM, Singer DE, Hurxthal K, Goodson JD, The clinical information value of the glycosylated hemoglobin assay, N Engl J Med, 1984;310:341–6.
50. Tahara Y, Shima K, The response of GHb to stepwise plasma glucose change over time in diabetic patients, Diabetes Care, 1993;16:1313–4.
51. Marcovecchio ML, Dalton RN, Chiarelli F, Dunger DB, A1C variability as an independent risk factor for microalbuminuria in young people with type 1 diabetes, Diabetes Care, 2011;34:1011–3.
52. Gorst C, Kwok CS, Aslam S, et al., Long-term glycemic variability and risk of adverse outcomes: a systematic review and meta-analysis, Diabetes Care, 2015;38:2354–69.
53. Monnier L, Lapinski H, Colette C, Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA(1c), Diabetes Care, 2003;26:881–5.
54. Suh S, Kim JH, Glycemic variability: how do we measure it and why is it important?, Diabetes Metab J, 2015;39:273.
55. Nalysnyk L, Hernandez-Medina M, Krishnarajah G, Glycaemic variability and complications in patients with diabetes mellitus: evidence from a systematic review of the literature, Diabetes Obes Metab, 2010;12:288–98.
56. Smith-Palmer J, Brändle M, Trevisan R, et al., Assessment of the association between glycemic variability and diabetes-related complications in type 1 and type 2 diabetes, Diabetes Res Clin Pract, 2014;105:273–84.
57. Kilpatrick ES, Rigby AS, Atkin SL, The effect of glucose variability on the risk of microvascular complications in Type 1 diabetes, Diabetes Care, 2006;29:1486–90.
Hyperglycemia, complications, vascular, acute, chronic