Objective: Preclinical research implicates hypothalamic glial cell
responses in the pathogenesis of obesity and type 2 diabetes. The current study
sought to translate such findings into humans by testing if radiologic markers
of gliosis in the mediobasal hypothalamus (MBH) were greater in persons with
obesity and impaired glucose homeostasis or type 2 diabetes.
<p>Research Design and Methods: Using cross-sectional and prospective cohort
study designs, we applied a validated, quantitative magnetic resonance imaging
(MRI) approach to assess gliosis in 67 adults with obesity and normal glucose
tolerance, impaired glucose tolerance, or type 2 diabetes. Assessments of
glucose homeostasis were conducted via oral glucose tolerance tests (OGTT) and
β-cell modeling. </p>
<p> Results: We found significantly
greater T2 relaxation times (a marker of gliosis by MRI), that were independent
of adiposity, in the impaired glucose tolerance and type 2 diabetes groups as
compared to the normal glucose tolerance group. Findings were present in the
MBH, but not control regions. Moreover, positive linear associations were
present in the MBH but not control regions between T2 relaxation time and
glucose area under the curve during an OGTT, fasting glucose concentrations,
hemoglobin A1c, and visceral adipose tissue mass, whereas negative linear
relationships were present in the MBH for markers of insulin sensitivity and
β-cell function. In a prospective cohort study, greater MBH T2 relaxation times
predicted declining insulin sensitivity over one year. </p>
Conclusions: Findings support a role for hypothalamic
gliosis in the progression of insulin resistance in obesity and, thus, type 2
diabetes pathogenesis in humans.