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.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

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 (

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).