Disrupted neurovascular-endocrine coupling in type 1 diabetes with impaired awareness of hypoglycemia

BACKGROUNDRecurrent hypoglycemia in type 1 diabetes (T1D) may culminate in impaired awareness of hypoglycemia (IAH). While neuroimaging studies identified affected brain regions, more complex perspectives integrating vascular dynamics with endocrine profile are needed.METHODSHere, 26 healthy adults, 30 T1D patients with normal hypoglycemia awareness (NAH), and 25 T1D patients with IAH underwent a hyperinsulinemic stepped clamp (euglycemia → hypoglycemia 50 mg/dL) combined with pseudo-continuous arterial spin-labeling MRI. Cerebral blood flow (CBF) and sympathetic vasomotor range (0.02-0.05 Hz) CBF oscillations were modeled against serially sampled plasma cortisol, epinephrine, norepinephrine, and glucagon.RESULTSIn healthy individuals treated as controls, hypoglycemia evoked robust thalamo-striatal and salience-interoceptive CBF increases (mean Cohen's d across significant clusters = 0.93) and suppression of vasomotor oscillations (d = 0.71). T1D retained CBF response but failed to attenuate oscillations (dT1D>controls = 0.43). IAH further blunted hypoglycemia-associated CBF increase, especially in thalamus, striatum, and insula (dNAH>IAH = 0.51). Hormone-CBF coupling differed quantitatively: cortisol/epinephrine-CBF correlations were positive in controls (r = 0.37/0.26), negative in NAH (-0.16/-0.40), and strongly positive in IAH (0.42/0.46).CONCLUSIONThus, our findings indicate that T1D disrupts dynamic, sympathetic modulation of CBF, whereas IAH additionally impairs perfusion reserve and shows maladaptive catecholamine-dependent CBF regulation, suggesting a qualitatively distinct neurovascular phenotype.TRIAL REGISTRATIONClinicalTrials.gov: NCT02747680 and NCT02866435.FUNDINGNIH (P41-EB-015894, P30-NS-076408, R01-DK-099137, R56-DK-099137, and DP1 AG093028); National Center for Advancing Translational Sciences of the NIH (KL2-TR-000113 and UL1-TR-000114); DP1 AG093028; Charles University, Czech Republic (Cooperatio Program, research area NEUR), Brain Dynamics (grant number CZ.02.01.01/00/22_008/0004643); General University Hospital in Prague (MH CZ-DRO-VFN64165).