Disrupted neurovascular-endocrine coupling in type 1 diabetes with impaired awareness of hypoglycemia
Pavel Filip, Antonietta Canna, Heidi Grohn, Amir A. Moheet, Anjali F. Kumar, Xiufeng Li, Yuan Zhang, Lynn E. Eberly, Elizabeth R. Seaquist, Silvia Mangia
Pavel Filip, Antonietta Canna, Heidi Grohn, Amir A. Moheet, Anjali F. Kumar, Xiufeng Li, Yuan Zhang, Lynn E. Eberly, Elizabeth R. Seaquist, Silvia Mangia
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Clinical Research and Public Health Endocrinology Neuroscience

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

Abstract

BACKGROUND Recurrent 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.METHODS Here, 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.RESULTS In 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).CONCLUSION Thus, 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 REGISTRATION ClinicalTrials.gov: NCT02747680 and NCT02866435.FUNDING NIH (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).

Authors

Pavel Filip, Antonietta Canna, Heidi Grohn, Amir A. Moheet, Anjali F. Kumar, Xiufeng Li, Yuan Zhang, Lynn E. Eberly, Elizabeth R. Seaquist, Silvia Mangia

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Figure 1

Hormonal response to HG.

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Hormonal response to HG. Bar heights above 0 represent subgroup averages...
Bar heights above 0 represent subgroup averages, calculated as the average of the last 2 HG measurements minus the average of the 2 baseline measurements (5 samples in total; the initial hypoglycemic value was excluded to obtain a steadier estimate for this simplified visualization). Individual participant values are depicted as gray circles, with jitter along the x axis for better visibility. Significant intergroup differences between HCs and pooled T1D patients based on linear mixed-effect models (see Table 2) are marked with green bar and asterisk; significant differences between IAH and NAH T1D subgroups are marked with red bar and asterisk (*PFDR < 0.05). See Table 2 for formal statistical evaluation considering full time course of hormonal response.