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.
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.
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: email@example.com
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
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Hyperglycemia, complications, vascular, acute, chronic