Puzzling About Partial Glucagon Responses to Hypoglycemia in Intrahepatic Islet Recipients: Missing Pieces

Fifteen years ago, Shapiro et al. (1), at the University of Alberta in Edmonton, Canada, published an article in the New England Journal of Medicine that caused great excitement. They reported that seven consecutive recipients with type 1 diabetes who had received intrahepatic infusions of human islet allografts maintained normal levels of HbA1c for more than 1 year after transplant (4.4–14.9 months) without insulin treatment (1). They attributed their success to the infusion of a large total number of islets and the avoidance of glucocorticoid use for immunosuppression. The number of islet infusions depended on whether or not success was achieved with the preceding infusion. The average total mass of islets used was 11,547 ± 1,604 islet equivalents/kg body weight (approximately 80% of that believed to be in a normal human pancreas). Glucocorticoids were avoided because of their known toxic effect on β-cells. Posttransplant C-peptide levels were stimulated twofold by mixed-meal tolerance tests. A subsequent publication by this group in 2002 reported that success appeared to be continuing as evidenced by sophisticated measures of β-cell function (2). However, by the fifth year of follow-up, these first blushes of prolonged success began to lose their glow. In 2005, Ryan et al. (3) reported that of 65 recipients, approximately 10% maintained insulin independence, 10% …