Propposal of an Energy Dissipating Ptahway Regulated by the Extracellular Glucose Concentration That Precedes the Sustained Stimulation of Insulin Secretion

It is debated whether β-cells bioenergetic regulation is controlled by ATP supply or ATP demand. We proposed the hypothesis that an energy dissipating process precedes the stimulation of a continuous stimulation of insulin secretion by glucose. This process is mediated by connexin 36 hemichannels (Cx36H) or Cx36 connexons. Cx36H oligomers are expressed at the plasma membrane and their gating activity is activated by plasma membrane depolarization after the closure of K+ATP channels by glucose (<5 mM) metabolism. This initial depolarization might be responsible for the 1st phase of insulin secretion. Subsequent opening of CX36H increases β-cell plasma membrane permeability, allowing the efflux of metabolites (less than 1KD) (GABA, adenine nucleotides) and K+. This provokes a breakdown of oxidative glucose metabolism and repolarization of the plasma membrane. As extracellular glucose concentration increases (<< 5 mM), it exerts a progressive inhibition of Cx36H gating, allowing a continuous stimulation of insulin secretion (2nd phase). Glucose feature to regulate Cx36H closing with sigmoidal kinetics (8 mM IC50, and maximum around 20 mM) has been confirmed in mouse Cx36 connexin expression in Xenopus oocytes and in mouse islets stimulated by a range of glucose concentrations in the presence of 70 mM KCl. Its gating activity was also inhibited by some non-metabolized glucose analogues. Cx36H gating offers also the opportunity to use metabolic stimuli in vivo to potentiate the glucose secretory effect by, permeant or not, metabolic stimuli. It is concluded that β-cell bioenergetic regulation proceeds via ATP supply. This new proposal of a physiological function for Cx36Hs in β-cells place them as new susceptibility locus for type 1 and type 2 diabetes.