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 2

Cerebral hemodynamic response to HG in HCs.

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Cerebral hemodynamic response to HG in HCs. (A) HG > EU contrast for ...
(A) HG > EU contrast for CBF and spontaneous CBF oscillations. (B) Interaction between HG and composite hormonal response (cortisol, epinephrine, norepinephrine, and glucagon) by omnibus F test. Maps are provided as z statistics with threshold-free cluster enhancement, displayed at P < 0.05 (FDR corrected jointly across parcellation units, modalities, and contrasts). Warm colors (yellow–red) indicate significant increase; cool colors (blue) denote the reverse effect. Subcortical structures illustrated on 6 axial slices (MNI z = 15, 6, –3, –12, –21, and –30). Images follow neurological convention (right = right). (C) Scatterplots depicting HG-induced responses in absolute units of cortical CBF (x axis) versus individual hormones (y axis) for each hormone separately, with superimposed linear trend lines for visualization. For detailed cluster statistics and anatomical labels, see Supplemental Tables 1 and 2. For comparison of CBF versus hormonal response relationship in IAH, see Figure 4.