title: 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.
  
  
  CONCLUSIONS
  The major factor limiting improved glucose control in type 1 diabetes is the significant increase in hypoglycemia associated with insulin treatment. Repeated exposure to hypoglycemia alters patients' ability to recognize the autonomic and neuroglycopenic symptoms associated with low plasma glucose levels. We examined brain resting state networks during the induction of hypoglycemia in diabetic and control subjects and found differences in networks involved in sensorimotor function, cognition, and interoceptive awareness that were related to chronic levels of glycemic control. These findings identify brain regions that are sensitive to variations in plasma glucose levels and may also provide a basis for understanding the mechanisms underlying the increased incidence of cognitive impairment and affective disorders seen in patients with diabetes.
authors.affiliation: Brain Imaging Center, McLean Hospital, Belmont, Massachusetts 02478, Harvard Medical School, Boston, Massachusetts 02115, gail.musen@joslin.harvard.edu nbolo@bidmc.harvard.edu.
authors.forename: Nicolas R
authors.identifier: http://orcid.org/0000-0002-9941-622X
authors.initials: NR
authors.lastname: Bolo
authors.affiliation: Harvard Medical School, Boston, Massachusetts 02115, Research Division, Joslin Diabetes Center, Boston, Massachusetts 02215, gail.musen@joslin.harvard.edu nbolo@bidmc.harvard.edu.
authors.forename: Gail
authors.initials: G
authors.lastname: Musen
authors.affiliation: Harvard Medical School, Boston, Massachusetts 02115, Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Boston, Massachusetts 02115.
authors.forename: Donald C
authors.initials: DC
authors.lastname: Simonson
authors.affiliation: Brain Imaging Center, McLean Hospital, Belmont, Massachusetts 02478, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Nickerson
authors.affiliation: Research Division, Joslin Diabetes Center, Boston, Massachusetts 02215.
authors.forename: Veronica L
authors.initials: VL
authors.lastname: Flores
authors.affiliation: Brain Imaging Center, McLean Hospital, Belmont, Massachusetts 02478.
authors.forename: Tamar
authors.initials: T
authors.lastname: Siracusa
authors.affiliation: Department of Psychiatry, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215.
authors.forename: Brandon
authors.identifier: http://orcid.org/0000-0002-3659-3448
authors.initials: B
authors.lastname: Hager
authors.affiliation: Ewha Brain Institute and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, South Korea, and.
authors.forename: In Kyoon
authors.initials: IK
authors.lastname: Lyoo
authors.affiliation: Brain Imaging Center, McLean Hospital, Belmont, Massachusetts 02478, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Perry F
authors.initials: PF
authors.lastname: Renshaw
authors.affiliation: Harvard Medical School, Boston, Massachusetts 02115, Research Division, Joslin Diabetes Center, Boston, Massachusetts 02215, Research Institute, Winthrop University Hospital, Mineola, New York 11501.
authors.forename: Alan M
authors.initials: AM
authors.lastname: Jacobson
mesh_terms: D000328:Adult; D001479:Basal Ganglia / Q000503:physiopathology*; D001931:Brain Mapping; D002540:Cerebral Cortex / Q000503:physiopathology*; D003922:Diabetes Mellitus, Type 1 / Q000503:physiopathology* / Q000523:psychology; D056344:Executive Function / Q000502:physiology*; D005260:Female; D006801:Humans; D007003:Hypoglycemia / Q000503:physiopathology* / Q000523:psychology; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009415:Nerve Net / Q000503:physiopathology*; D017397:Prefrontal Cortex / Q000503:physiopathology*; D055815:Young Adult
keywords: executive control resting-state network; functional connectivity; functional magnetic resonance imaging; hypoglycemia; independent component analysis; type 1 diabetes