Heterogeneity in prediabetes: can phenotypes be identified?

Abstract

Prediabetes is a heterogeneous condition characterized by varying degrees of insulin resistance and beta cell dysfunction, which may precede the onset of diabetes (DM). Abnormalities in fasting glucose (FG), oral glucose tolerance test (OGTT), and the combination of both (FG+OGTT) represent distinct pathways that may evolve into DM. These states are characterized by different degrees of insulin sensitivity, absolute insulin secretion, hepatic glucose production, insulin secretion relative to insulin resistance, as well as secretion of other hormones, such as glucagon and incretins. These alterations may be present up to five years before the diagnosis of prediabetes¹.  The glucose metabolism profiles in different prediabetic phenotypes, classified by FG, OGTT, HbA1c, and 1-hour OGTT, were studied in the IMI-DIRECT study, with a longitudinal follow-up of 48 months.

The findings confirmed known notions about fasting insulin resistance in OGTT (which partly reflects hepatic insulin resistance). In the OGTT abnormalities there was decreased potentiation and sensitivity of insulin secretion with lower basal and total secretion, which is related to the potentiating effect of incretins on its secretion, so this could be the worst phenotype among the three with an isolated defect. The association of two or three abnormalities significantly increases the chances of progressing to DM, so people with a known risk should be tested to reveal the possible presence of the three defects possibly observed during prediabetes, as this seems relevant to determine the real risk of developing the disease².

In the Tübingen Family Study and Tübingen Lifestyle Program (TUEF/TULIP) cohorts, patients at high risk of developing DM were selected and given precise measurements of insulin sensitivity and secretion based on OGTT-derived variables, including HDL-c, magnetic resonance imaging (MRI)-derived measures of metabolically unfavorable and favorable fat compartments, hepatic fat content measured with 1H-MRI spectroscopy, and a polygenic risk score for DM2 assessing genetic propensity. Six subphenotypes were identified, three of which have higher blood glucose levels (groups 3, 5, and 6), but only those in groups 5 and 3 have imminent risks of DM. In contrast, those in group 6 have a moderate risk, but higher risk of kidney disease and all-cause mortality³.