Correlation between beta cell mass and glycemic control in type 1 diabetic recipients of islet cell graft

Abstract

Islet grafts can induce insulin independence in type 1 diabetic patients, but their function is variable with only 10% insulin independence after 5 years. We investigated whether cultured grafts with defined beta cell number help standardize metabolic outcome. Nonuremic C-peptide-negative patients received an intraportal graft with 0.5-5.0 x 10(6) beta cells per kilogram of body weight (kg BW) under antithymocyte globulin and mycophenolate mofetil plus tacrolimus. Metabolic outcome at posttransplant (PT) month 2 was used to decide on a second graft under maintenance mycophenolate mofetil/tacrolimus. Graft function was defined by C-peptide >0.5 ng/ml and reduced insulin needs, metabolic control by reductions in HbA(1c), glycemia coefficient of variation, and hypoglycemia. At PT month 2, graft function was present in 16 of 17 recipients of >2 x 10(6) beta cells per kg BW versus 0 of 5 with lower number. The nine patients with C-peptide >1 ng/ml and glycemia coefficient of variation of <25% did not receive a second graft; five of them were insulin-independent until PT month 12. The 12 others received a second implant; it achieved insulin-independence at PT month 12 when the first and second graft contained >2 x 10(6) beta cells per kg BW. Of the 20 recipients of at least one graft with >2 x 10(6) beta cells per kg BW, 17 maintained graft function and metabolic control up to PT month 12. At PT month 12, beta cell function in insulin-independent patients ranged around 25% of age-matched control values. Thus, 1-year metabolic control can be reproducibly achieved and standardized by cultured islet cell grafts with defined beta cell number.

Fig. 1.

Flow diagram of islet β cell transplants in 22 nonuremic type 1 diabetic patients. Survival of a β cell implant in C-peptide-negative (<0.09 ng/ml) recipients was defined by PT plasma C-peptide ≥0.5 ng/ml.

Fig. 2.

Correlation between β cell number in the first graft and metabolic outcome at PT month 2 as measured by plasma C-peptide (Top), CV (Middle), and mean (Bottom) prebreakfast glycemia. A positive correlation was found between β cell number and plasma C-peptide (R = 0.69, P < 0.001) and CVgl (R = −0.69, P < 0.001) but not with mean glycemia (R = −0.14, P = 0.52).

Fig. 3.

Longitudinal follow-up of mean and CVgl, HbA1c, and daily insulin dose in the 18 type 1 diabetic patients with 1 year surviving grafts. Patients are divided in two groups according to their state of insulin (in)dependence at PT month 12: n = 10 insulin-independent (solid line) and n = 8 insulin-dependent (dashed line) patients. Data are means ± SEM. Statistical difference versus pretransplantation: ∗, P < 0.01; ∗∗, P < 0.001. Statistical difference between groups: †, P < 0.01; ††, P < 0.001.

Fig. 4.

Glucose-clamp induced C-peptide release in the absence and presence of glucagon. Data represent individual values of area under the curve (AUC) (ng/ml per min) measured in 10 insulin-independent graft recipients at PT month 12 (solid lines) and in 12 age- and BW-matched nondiabetic controls (dashed lines).