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Review Diabetes Complications of Acute and Chronic Hyperglycemia M Loredana Marcovecchio University of Cambridge, Cambridge, UK H yperglycemia 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. Keywords From glucose homeostasis to hyperglycemia Hyperglycemia, complications, vascular, acute, chronic 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 Disclosure: 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: The 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. Open Access: 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. Received: February 27, 2017 Accepted: March 30, 2017 Citation: US Endocrinology, 2017;13(1):17–21 Corresponding Author: M Loredana Marcovecchio, University of Cambridge, Box 116, Level 8, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0QQ, UK. E: mlm45@medschl.cam.ac.uk 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 TOU CH MED ICA L MEDIA 17