Experimental Models of Impaired Hypoglycaemia-Associated Counter-Regulation

Abstract

Impaired awareness of hypoglycaemia (IAH) affects around a quarter of patients with diabetes who receive insulin treatment. This condition is characterised by a progressive reduction in symptomatic and behavioural responses to hypoglycaemia, increasing risk of deeper drops in blood glucose, unconsciousness, and collapse. Thus, patients with IAH experience severe hypoglycaemic episodes more frequently, resulting in significant morbidity and mortality. IAH is thought to develop as a consequence of whole-body adaptations to repeated insulin-induced hypoglycaemia (RH), with widespread deficits in the hypoglycaemia counterregulatory response (CRR). Despite this important insight, the precise pathophysiology by which RH leads to an attenuated CRR is unknown. Studies into the underlying mechanisms of IAH have employed a variety of protocols in humans and experimental species. The use of animal models has many investigational benefits, including the unprecedented increase in the availability of transgenic strains. However, modelling impaired hypoglycaemia-associated counterregulation remains challenging and appropriate interpretation of findings across species and protocols even more so. Here, we review the experimental modelling of IAH and impaired hypoglycaemia-associated counter-regulation, with a focus on understanding species-specific variation in glucose homeostasis. This review will aid investigators in interpreting outputs from different studies in IAH and aid progress in the field. HighlightsImpaired awareness of hypoglycaemia (IAH) is a common and poorly understood complication of insulin-treated diabetes and evolves following repeated episodes of hypoglycaemia.An improved mechanistic understanding of IAH is required and necessitates a robust disease model with which to interrogate changes within the glucoseregulatory network.A large variety of experimental models have been outlined, leading to a lack of consensus among investigators in this field. Appreciating the influence of experimental parameters and physiological differences on findings can aid progress in the field.

Atherosclerosis Risk Factors in Patients with Reactive Hypoglycemia

“…37 Secondly, both hyperinsulinemia and the hypoglycemic episodes that precede it diminish the effectiveness of counter-regulatory mechanisms during the subsequent hypoglycemic episodes. 14,37 However, the comparison of patients with and without RH did not reveal the predominance of the former group in terms of insulin concentration. Moreover, insulin levels at hours 4 and 5 of the prolonged OGTT were significantly higher in the non-RH group than in the RH group (Table 3).…”

“…[10][11][12] Research has shown that patients with diabetic neuropathy may have a higher cardiovascular risk due to compromised counter-regulatory mechanisms following a hypoglycemic episode. 13,14 On the other hand, even an adequate response to hypoglycemia, including an increased catecholamine release or corticosteroid production, can be detrimental to the cardiovascular system, promote atherogenesis, and induce hypokalemia. 8,13 Furthermore, elevated levels of C-reactive protein, interleukin-6, interleukin-8, tumor necrosis factor alpha, endothelins, or growth factors can be found in diabetic patients during hypoglycemic episodes.…”

Brain-Body Control of Glucose Homeostasis—Insights From Model Organisms

“…This latter aspect of hypoglycemia "awareness" can be studied using a conditioned place preference test, which has so far been validated in rats but not in mice (57), largely because of the more rapid induction of defective counter-regulation in rats and their tractability for behavioral tests. The species differences between rats and mice in the adaptation to recurrent hypoglycemia are important considerations when designing a study and have been previously discussed in detail elsewhere (58). Seminal studies in rats revealed the presence of glucosensors in the hindbrain that can mount responses to restore blood glucose in the face of a glucoprivic challenge independent of forebrain structures or when the cerebral aqueduct is blocked (59,60).…”

“…The effectiveness of these protocols varies between mice and rats (and within strains of these species) with C57BLJ/6 mice being especially prone to dietinduced obesity (DIO) while inbred rat strains show both resistance or susceptibility to DIO (133,134). Similarly, rats more readily develop impaired awareness of hypoglycemia with fewer hypoglycemic bouts required for induction than mice (58). Nonmammalian species including zebrafish and drosophila also have transgenic strains that can model some facets of human disease, however, their distinct physiology from humans means that these models do not recapitulate human disease as faithfully as rodent models (135,136).…”

Mecanismos da sensibilidade à baixa glicose dos neurônios do núcleo do trato solitário de ratos

“…Além da relevância do tema para compreensão de patologias, a regulação da glicemia está ligada, desde a década de 1960, à compreensão dos mecanismos fisiológicos do comportamento alimentar (Anand et al, 1964;Ritter et al, 1981;Ritter & Strang, 1982;Aklan et al, 2020). Nesse contexto, pesquisadores vêm mostrando o papel fundamental da resposta contrarreguladora (CRR) para proteger nosso organismo contra condições hipoglicêmicas graves (Cryer, 1993;Sankar et al, 2020).…”