Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04
  • 2024-05
  • 2024-06
  • 2024-07
  • 2024-08
  • 2024-09
  • 2024-10

    • br Introduction Maintaining blood glucose within an appropri

    2021-09-07


    Introduction Maintaining blood glucose within an appropriate range is crucial for survival. In diabetes, those who suffer episodes of severe hypoglycemia have an increased risk of death [1], [2]. The Bestatin hydrochloride is especially dependent on an adequate, continuous supply of circulating glucose to fuel metabolism and support function. To defend against falling blood glucose, a series of robust counter-regulatory responses normally prevent hypoglycemia from occurring [3]. These include the ability to switch off endogenous insulin secretion as blood glucose levels start to fall and release the key counter-regulatory hormones glucagon and epinephrine. In order to detect and respond to changes in blood glucose, a network of specialized glucose sensors in the periphery and brain forms an integrated network to trigger counter-regulation as hypoglycemia starts to develop [4]. The glucose-sensing apparatus in pancreatic β-cells includes the low affinity hexokinase glucokinase (GCK), which controls glycolytic flux into downstream metabolic sensing by ATP-gated potassium (KATP) channels. In the canonical β-cell pathway, a fall in glucose is detected as a fall in this metabolic flow, with opening of KATP channels leading to an early cessation of insulin release from β-cells [5]. If blood glucose falls further, glucagon release during hypoglycemia probably has a redundancy of controlling inputs. α-cells contain GCK and KATP channels and may sense hypoglycemia directly [6], [7]. α-cells also likely receive information from local paracrine signalling and/or direct contact from β and δ-cells within islets [7], [8], [9], [10]. Additionally, circulating catecholamines and pancreatic neural autonomic innervation may contribute to a coordinated homeostatic glucagon response [11], [12]. Epinephrine release as part of a sympatho-adrenal response to hypoglycemia is driven by increased outflow from the brain to the adrenal medulla [4]. Brain glucose sensors may be glucose-excited (GE) or inhibited (GI) [13]. Counter-regulatory responses may be triggered either by hypoglycemia-induced GI activation and/or GE silencing. Glucose sensing in brain sensors may employ mechanisms similar to those identified in the beta cell including GCK [14], [15], [16], [17], [18], [19], [20].
    Material and methods
    Results
    Discussion The ability to switch off endogenous insulin release during falling blood glucose is an important and sometimes under-appreciated defence against hypoglycemia. Consistent with an important role for GCK in beta cell glucose-sensing, humans with GCK-MODY showed greater suppression of C-peptide beginning at low normal blood glucose concentrations (from 3.8 mmolL−1) compared with T2D and healthy controls. While not unexpected that insulin secretion is influenced by the presence of a GCK mutation, to our knowledge, this is the first time that a different effect on endogenous insulin secretion between GCK-MODY and T2D has been demonstrated in vivo during acute hypoglycemia. Supporting a role for GCK in mediating glucagon release, we observed increased glucagon responses in GCK-MODY and I366F mice with whole body reduced GCK activity. A previous study of GCK-MODY also reported increased glucagon (but not epinephrine) responses during experimental hypoglycemia, although hypoglycemic challenges were not matched between groups [34]. Glucagon release from α-cells during hypoglycemia may be triggered both by direct α-cell sensing of glucose, local paracrine signalling from within islets and distal factors such as autonomic pancreatic innervation and circulating factors such as catecholamines [8]. This means that intra-islet GCK found in α- and β-cells and GCK at distal sensing sites such as brain could all potentially contribute to counter-regulatory glucagon responses. Here, we found that increased glucagon responses to hypoglycemia persisted in I366F mice following β-cell ablation, suggesting that local paracrine signalling from pancreatic β-cells was not necessary to mediate effects of mutant GCK. We saw no differences in glucagon responses in our brain GCKKO model suggesting that brain GCK was not predominantly involved in glucagon responses to hypoglycemia. Taken together, these data are consistent with direct GCK-mediated sensing of hypoglycemia by α-cells being an important part of the counter-regulatory glucagon response. In keeping with this, a recent paper described mice with α-cell GCK knockout displaying increased glucagon levels, although responses to hypoglycemia were not reported [35]. Our findings do not preclude other non-GCK brain glucose sensing, for example using GLUT-2, contributing to the central glucagon response [36], [37].