Functional Connectivity of Insula, Basal Ganglia, and Prefrontal Executive Control Networks during Hypoglycemia in Type 1 Diabetes

Abstract

Human brain networks mediating interoceptive, behavioral, and cognitive aspects of glycemic control are not well studied. Using group independent component analysis with dual-regression approach of functional magnetic resonance imaging data, we examined the functional connectivity changes of large-scale resting state networks during sequential euglycemic-hypoglycemic clamp studies in patients with type 1 diabetes and nondiabetic controls and how these changes during hypoglycemia were related to symptoms of hypoglycemia awareness and to concurrent glycosylated hemoglobin (HbA1c) levels. During hypoglycemia, diabetic patients showed increased functional connectivity of the right anterior insula and the prefrontal cortex within the executive control network, which was associated with higher HbA1c. Controls showed decreased functional connectivity of the right anterior insula with the cerebellum/basal ganglia network and of temporal regions within the temporal pole network and increased functional connectivity in the default mode and sensorimotor networks. Functional connectivity reductions in the right basal ganglia were correlated with increases of self-reported hypoglycemic symptoms in controls but not in patients. Resting state networks that showed different group functional connectivity during hypoglycemia may be most sensitive to glycemic environment, and their connectivity patterns may have adapted to repeated glycemic excursions present in type 1 diabetes. Our results suggest that basal ganglia and insula mediation of interoceptive awareness during hypoglycemia is altered in type 1 diabetes. These changes could be neuroplastic adaptations to frequent hypoglycemic experiences. Functional connectivity changes in the insula and prefrontal cognitive networks could also reflect an adaptation to changes in brain metabolic pathways associated with chronic hyperglycemia.

Compensatory Hyperconnectivity in Developing Brains of Young Children With Type 1 Diabetes

“…As the brain is reliant on glucose for metabolism, the effect of dysglycemia on brain development and functioning is an area of physiological and clinical interest (1). Several previous studies have found that individuals diagnosed with T1D at a younger age (∼4 years) may be at a greater risk for developing neuropsychological deficits at later ages (2–4).…”

“…(1). Thus, different brain functional units must coordinate as networks to mediate the cognitive and behavioral aspects associated with dysglycemia (1).…”

“…(1). Thus, different brain functional units must coordinate as networks to mediate the cognitive and behavioral aspects associated with dysglycemia (1). However, very little is known about the deleterious effects of T1D on this network-level coordinated functioning across brain regions in young children.…”

“…Two studies have previously used resting-state functional MRI (rsfMRI) to examine differences in intrinsic (or at-rest) connectivity among brain regions in adults with T1D as compared with control subjects without diabetes (1,5). Bolo et al (1) used a sequential euglycemic-hypoglycemic clamp to examine changes in resting-state functional connectivity (RSFC) associated with experimentally induced hypoglycemia in adults with T1D and control subjects without diabetes.…”

“…Bolo et al (1) used a sequential euglycemic-hypoglycemic clamp to examine changes in resting-state functional connectivity (RSFC) associated with experimentally induced hypoglycemia in adults with T1D and control subjects without diabetes. The authors found that during hypoglycemia, adults with T1D showed increased within-group RSFC in the right prefrontal and insular brain regions.…”