Evolution of the diagnostic value of "the sugar of the blood": hitting the sweet spot to identify alterations in glucose dynamics

Abstract

In this paper, we provide an overview of the evolution of the definition of hyperglycemia during the past century and the alterations in glucose dynamics that cause fasting and postprandial hyperglycemia. We discuss how extensive mechanistic, physiological research into the factors and pathways that regulate the appearance of glucose in the circulation and its uptake and metabolism by tissues and organs has contributed knowledge that has advanced our understanding of different types of hyperglycemia, namely prediabetes and diabetes and their subtypes (impaired fasting plasma glucose, impaired glucose tolerance, combined impaired fasting plasma glucose, impaired glucose tolerance, type 1 diabetes, type 2 diabetes, gestational diabetes mellitus), their relationships with medical complications, and how to prevent and treat hyperglycemia.

Keywords: diabetes; hyperglycemia; obesity; prediabetes; β-cell.

Graphical abstract

FIGURE 1.

Definitions and prevalence of different types of hyperglycemia and related comorbidities. A: definitions of different types of hyperglycemia, proposed by the American Diabetes Association (ADA) (3) and the World Health Organization (WHO) (30), assessed by fasting plasma glucose concentration (FPG), glucose concentration at 2 h after a 75-g oral glucose tolerance test (OGTT) (no difference between ADA and WHO criteria), or glycated hemoglobin (HbA1c) as an index of the 3-mo-long average plasma glucose concentration (no difference between ADA and WHO criteria). IFG, impaired fasting glucose; IGT, impaired glucose tolerance. B: risk for developing type 2 diabetes (T2D) with different types of prediabetic hyperglycemia and future medical complications according to the type of hyperglycemia. C: proportion of population with different types of hyperglycemia, defined by the different ADA criteria described in A, with data from Refs , . Overall prevalence of normoglycemia, prediabetes, and T2D was 44%, 44%, and 12%, respectively. D: prevalence of IFG, IGT, or both in all individuals with prediabetes (left) or only individuals with obesity and prediabetes (right), based on data from Refs , , –, where prediabetes was defined as fasting hyperglycemia, glucose intolerance, or both according to fasting and 2 h OGTT plasma glucose criteria proposed by the ADA (see A). People with obesity account for ∼30% of all people with prediabetes (7, 8). CVD, cardiovascular diseases; NAFLD, nonalcoholic fatty liver disease; NFG, normal fasting glucose; NGT, normal glucose tolerance.

FIGURE 2.

Plasma glucose dynamics. Sources of glucose in the circulation, sites of removal from the portal and arterial circulation for storage or metabolism, and key glucose-responsive factors [insulin, glucagon, gastric inhibitory polypeptide (GIP), glucagon-like peptide 1 (GLP-1), neurotransmitters] that directly or indirectly (via secondary messengers) regulate the appearance of glucose into plasma and its disappearance from the circulation. Additional glucose-dependent and glucose-independent factors, including hormones, dietary components, metabolites, and muscle contraction, can also affect glucose appearance and disappearance. GI, gastrointestinal; GNG, gluconeogenesis; GU, glucose uptake.

FIGURE 3.

Effect of marked weight loss on basal and postprandial glucose dynamics. Plasma glucose concentration (A and B), ingested glucose appearance rate (C and D), endogenous glucose appearance rate (E and F) before and after mixed meal ingestion (starting at t = 0), plasma insulin concentration, assessed as the area under the curve (AUC) after ingestion of the meal (G and H, left), and whole body insulin sensitivity, assessed as the glucose infusion rate in relation to plasma insulin concentration during a hyperinsulinemic-euglycemic clamp procedure (GIR/I) (G and H, right) in people with obesity without (A, C, E, and G) and with (B, D, F, and H) type 2 diabetes before and after massive weight loss (17–20% of initial body weight) induced by consumption of a low-calorie diet alone or in conjunction with gastric banding. Drawn with data from Refs 168, 169, with permission from New England Journal of Medicine and Journal of Clinical Investigation, respectively. FFM, fat-free mass.