Understanding pancreatic endocrine and exocrine loss in pre-type 1 diabetes

For decades, type 1 diabetes (T1D) has been considered a disorder resulting from chronic autoimmune
destruction of insulin-producing pancreatic β-cells. While a broad number of intellectual advances have improved
our understanding of the natural history of T1D, significant gaps remain in the complex series of physiological
events, both immunologic and metabolic, that initiate β-cell autoimmunity, spur the loss of functional β-cell mass,
and culminate in clinical diabetes. People with a first-degree relative (FDR) with T1D have ~15-fold increased
lifetime risk of T1D. Importantly, natural history studies have informed the use of islet-associated autoantibodies
(AAb) as biomarkers to track progression to overt disease, and these biomarkers were transformative for the
field. Nevertheless, there remains significant heterogeneity in T1D progression, and additional biomarkers of
T1D risk are urgently needed. Studies by this group demonstrated that pancreas weights from organ donors with
T1D were significantly reduced, including at diabetes onset, and provided essential data using the ratio of
pancreas weight to body weight or BMI (relative pancreas volume, RPV) to normalize for subjects’ sex and age.
Yet more profound in terms of T1D pathogenesis, reductions in pancreas size were also observed in single AAb+
donors compared to autoantibody-negative (AAb-) control donors. Subsequently, a pilot cross-sectional DP3 trial
in NIH-NIDDK TrialNet (TN) subjects was completed using magnetic resonance imaging (MRI) to quantify RPV
in FDR in comparison to controls and patients with recent-onset T1D (< 1-year duration). Strikingly, a reduction
in RPV was observed in FDR without AAb (AAb-) with further reductions in RPV for FDR with single and multiple
AAb+. We hypothesize that a smaller pancreas size is predictive of T1D risk and a decline in pancreas
size over time is predictive for diabetes progression. This hypothesis will be tested at four TrialNet centers
in FDR subjects. To test our hypothesis, we will: Aim 1: Quantify pancreas volume (PV) and morphology in
FDR subjects by AAb status and test for longitudinal changes in PV. Aim 2: Correlate PV and morphology
with surrogate markers of β-cell function and mass. Aim 3: Correlate PV and morphology with surrogate
markers of acinar function. Aim 4: Perform SNP analyses for genetic determinants of pancreas size. The
successful completion of these studies will serve to expand the prognostic utility of pancreas MRI in
understanding T1D pathophysiology. Non-contrast pancreas MRI is safe and readily performed in children and
could add to biomarkers informing T1D risk predication, and potentially, progression. Endocrine-exocrine
interactions are novel and are expected to provide a new understanding of diabetes pathogenesis. Earlier
identification of subjects at highest risk for T1D progression is expected to significantly impact prevention
strategies and their successful application before the loss of functional β-cell mass is irreversible.

Grant Number: 5R01DK123329-04
NIH Institute/Center: NIH
Principal Investigator: MARTHA CAMPBELL-THOMPSON