Figure 3.

Involvement of CFTR protein in hypoglycemia-sensing neurons. When circulating G levels drop (lower left), fewer molecules are transported by GLUT4 G-conducting channels into hypothalamic neurons specialized to respond to hypoglycemia.^{60, 62, 65} These neurons are located in a portion of the brain that has exposure to circulating G levels.⁶⁶ The decreased G levels trigger an increase in synthesis of NPY and AgRP. AMP levels rise while ATP levels drop, triggering an increase in AMPK activity.^{64, 65} AMPK activity is amplified by a positive feedback cycle involving phosphorylation of nNOS, an increase in NO that binds SGC, which causes an increase in cyclic guanosine monophosphate that positively feeds back on AMPK.⁶⁴ Increased AMPK blocks the action of CFTR protein, resulting in depolarization of the neuron which releases NPY and AgRP. Both peptides counter hypoglycemia by increasing appetite. CFTR protein dysfunction prevents normal depolarization and the release of NPY and AgRP, a mechanism consistent with the clinical observation that children with cystic fibrosis do not respond appropriately to hypoglycemia.⁵³ AgRP = agouti-related peptide; AMP = adenosine monophosphate; AMPK = adenosine monophosphate-kinase; ATP = adenosine triphosphate; G = glucose; GLUT4 = glucose transporter type 4; nNOS = neuronal nitric oxide synthase; NO = nitric oxide; NPY = neuropeptide Y; SGC = soluble guanylyl cyclase. See Figure 2 legend for expansion of other abbreviation.