New-Onset Post-Transplant Diabetes Mellitus after Allogeneic Hematopoietic Celltransplant Is Initiated By Insulin Resistance, Not Iatrogenesis

Abstract

The mortality rate triples for the 50% of allogeneic hematopoietic cell transplant (HCT) recipients diagnosed new-onset post-transplant diabetes mellitus (PTDM). Calcineurin inhibitors and corticosteroids are assumed the cause for hyperglycemia, however patients developing PTDM have elevated fasting C-peptide levels before HCT. We tested the hypotheses that an oral glucose tolerance test (OGTT) would predict new-onset PTDM and that PTDM progresses from established insulin resistance present before HCT. Glucose tolerance and insulin sensitivity were quantified with OGTTs and euglycemic hyperinsulinemic clamps before and 90 days after matched related donor peripheral blood HCT in 20 patients without diabetes. PTDM was diagnosed by a weekly fasting BG ≥126mg/dL or random BG ≥200mg/dL from day 0 to day+100. PTDM was diagnosed in 11 (55%) patients at a median of 22 days post-HCT (range, 0-88 days). Table 1 outlines patient characteristics and OGTT results. PTDM preceded grade 2-4 acute GVHD or corticosteroids in 9 (82%) and 11 (100%) patients, respectively. Pre-transplant 2-hour, post-prandial OGTT plasma glucose values did not discriminate between patients developing PTDM and those maintaining euglycemia after HCT. However, fasting pre-transplant glucose and C-peptide levels were elevated in patients developing PTDM. All 5 patients with impaired fasting glucose (100-125mg/dl) compared to 6 out of 15 individuals with normal fasting glucose levels ( PTDM risk is dependent on pre-transplant insulin resistance and independent of immunosuppression. Impaired fasting glucose levels identified PTDM susceptibility. Peripheral insulin resistance could be targeted for the prevention/treatment of PTDM.