Fuel stimulated hormone release (HR) and the oxygen consumption rates (OCR) of isolated normal pancreatic islets are positively correlated illustrating that cellular energy state is a critical determinant of stimulus-secretion coupling. We investigated the relationship between hormone release and OCR in islets from donors with T1DM and T2DM, using unique oxygen measurement technology and optimized perifusion protocols. HR and OCR were quantified in 20 human donor islet preparations obtained from the Human Islet Resource Center at the University of Pennsylvania within 3-4 days after isolation (5 each of nondiabetic, T1DM, T2DM and anti-islet AutoAntiBody positive (AAB+). A physiological amino acid mixture (4mM) was used to stimulate glucagon release, then 3 and 16.7mM glucose were added to stimulate insulin release and inhibit glucagon release. Respiration was then uncoupled with FCCP and finally blocked by NaN3. Basal OCR was increased in islets from AAB+, T1DM and T2DM donors compared to controls. Low glucose failed to increase OCR in T1DM and T2DM islets while high glucose-stimulated OCR was both decreased and delayed. Glucose stimulated insulin release much less effectively and failed to suppress glucagon release in both T1DM and T2DM islets. AAB+ islets showed normal insulin release but lacked glucose suppression of glucagon release. The observation of increased basal-OCR of islets in all diabetes related conditions and reduced glucose-stimulated-OCR in T1DM and T2DM islets unrelated to hormone release rates is striking and indicates a profound alteration of bioenergetics regulation in these conditions hitherto unrecognized. Common to this pathophysiology are an increase in relative alpha-cell mass (T1DM and T2DM) or a functional defect of these cells (AAB+) providing a plausible explanation for this phenomenology and implying impaired alpha-cell energy metabolism.
N.M. Doliba: None. A.V. Rozo: None. W. Qin: None. J. Roman: None. C. Liu: None. A. Naji: None. K.H. Kaestner: None. D.A. Stoffers: None. F. Matschinsky: None.
National Institutes of Health (UC4DK112217)