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Islet Studies

Residual Insulin Production and Pancreatic β-Cell Turnover After 50 Years of Diabetes: Joslin Medalist Study

  1. Hillary A. Keenan1,2,
  2. Jennifer K. Sun1,3,4,
  3. Jared Levine1,2,
  4. Alessandro Doria1,2,
  5. Lloyd P. Aiello1,3,4,
  6. George Eisenbarth5,
  7. Susan Bonner-Weir1,2 and
  8. George L. King1,2
  1. 1Research Division, Joslin Diabetes Center, Boston, Massachusetts;
  2. 2Department of Medicine, Harvard Medical School, Boston, Massachusetts;
  3. 3Beetham Eye Institute, Joslin Diabetes Center, Boston, Massachusetts;
  4. 4Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts;
  5. 5Barbara Davis Center for Childhood Diabetes, Denver, Colorado.
  1. Corresponding author: George L. King, George.King{at}joslin.harvard.edu.
Diabetes 2010 Nov; 59(11): 2846-2853. https://doi.org/10.2337/db10-0676
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  • FIG. 1.
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    FIG. 1.

    Distribution of the first 97% of C-peptide levels among 50-year Medalists. Inset shows C-peptide values from all values. These pictures demonstrate the outlying 3% in excess of 0.17 nmol/l. (A high-quality color representation of this figure is available in the online issue.)

  • FIG. 2.
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    FIG. 2.

    MMTT average response curves for responders and nonresponders. (A high-quality color representation of this figure is available in the online issue.)

  • FIG. 3.
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    FIG. 3.

    Mean C-peptide levels from MMTT at baseline and peak value of control subjects, responders, and nonresponders. *P value is from a paired t-test. Error bars represent standard deviation.

  • FIG. 4.
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    FIG. 4.

    Histologic findings in pancreases from nine Medalists. In seven of nine pancreases, there were mainly atrophic islets (A) in which all or almost all cells were immunostained for glucagon, with occasional small islets that had peripheral glucagon+ cells with unstained central cells (asterisks), and rare small clusters or scattered single insulin+ cells (B); all nine pancreases had these scattered insulin+ cells. In one antibody-positive Medalist, some insulin+ cells were TUNEL-positive (B). In another pancreas (from Medalist 8) (C–F), about half of the pancreas had only atrophic islets (C), although there were lobes within the body and tail of the pancreas, with most islets with significant proportion of insulin+ cells (D and E, adjacent sections) and some with amyloid deposits (F) (thioflavin S+). In another late-onset diabetes pancreas (Medalist 9; age 30 at onset) (G–I), every islet had at least one insulin+ cell, and most had 10–20% of normal (G). In this last Medalist pancreas, rare Ki67+insulin+ cells (arrows indicate Ki67+ nuclei, both within the islet and nearby) (H) were found. I: In three pancreases, CD3 cells were rarely found in insulin+ islets, whereas no other CD3 cells were found in the microscopic field. (A high-quality digital representation of this figure is available in the online issue.)

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  • TABLE 1

    Characteristics of Medalist study participants

    Male (%)47.0 (192)
    A1C (%)7.3 ± 1.1
    Age (years)67.2 ± 7.4
    Age at diagnosis (years)11.0 ± 6.5
    Duration (years)56.2 ± 5.8
    BMI (kg/m2)26.0 ± 5.1
    C-peptide (nmol/l)0.07 ± 0.12
    Cholesterol (mmol/l)4.2 ± 0.9
    Calculated HDL (mmol/l)1.6 ± 0.5
    LDL (mmol/l)2.2 ± 0.6
    Triglycerides (mmol/l)0.9 ± 0.5
    Insulin dose (u/kg)0.46 ± 0.2
    Family history of diabetes
        Any diabetes29.7 (122)
        Type 1 diabetes12.9 (53)
    DR3*38.8 (116)
    DR4*52.0 (156)
    DR3 or DR4*93.7 (295)
    DR3/4*39.1 (118)
    IA2 or GAD*29.7 (111)
    IA2*14.9 (56)
    GAD*18.4 (69)
    Proliferative diabetic retinopathy*55 (163)
    Microalbuminuria (ACR <7.91)*13.1 (45)
    Neuropathy (MNSI >2)*60.6 (183)
    Cardiovascular disease*48.3 (160)
    • Data are means ± SD or % (n).

    • *Percentages reflect calculations done on data available. ACR, albumin-to-creatinine ratio; MNSI, Michigan Neuropathy Screening Instrument.

  • TABLE 2

    Characteristics of Medalist study participants by DCCT categories of residual insulin production

    Undetectable <0.03 nmol/lMinimal 0.03–0.2 nmol/lSustained ≥0.2 nmol/lP*
    N (%)33.0 (126)64.4 (246)2.6 (10)
    Male42.6 (55)50.2 (123)52.9 (7)0.4
    A1C (%)7.5 ± 1.07.1 ± 1.17.32 ± 0.70.005
    Age (years)67.5 ± 8.167.0 ± 7.271.7 ± 8.30.09
    Age at diagnosis (years)10.9 ± 6.810.9 ± 6.116.2 ± 8.60.02
    Duration (years)56.4 ± 6.056.1 ± 5.755.5 ± 4.10.7
    BMI (kg/m2)26.7 ± 2.826.0 ± 4.323.8 ± 3.60.5
    Insulin dose (u/kg)0.47 ± 0.20.5 ± 0.20.4 ± 0.20.5
    Cholesterol (mmol/l)4.2 ± 0.94.2 ± 0.94.2 ± 1.10.8
    Calculated HDL (mmol/l)1.6 ± 0.91.6 ± 0.51.7 ± 0.60.7
    LDL (mmol/l)2.2 ± 0.62.2 ± 0.62.2 ± 0.90.5
    Triglycerides (mmol/l)0.92 ± 0.50.89 ± 0.510.98 ± 0.650.9
    Family history of diabetes†
        Any diabetes27.8 (35)31.7 (78)20.0 (2)0.6
        Type 1 diabetes11.9 (15)14.2 (35)10.0 (1)0.8
    DR3†33.6 (39)43.8 (84)57.1 (4)0.03
    DR4†42.2 (49)57.7 (112)42.9 (3)0.03
    DR3/4†44.8 (52)36.6 (71)14.3 (1)0.14
    DR3 or DR495.7 (116)92.2 (177)100.0 (7)0.4
    IA2 or GAD†32.8 (40)27.2 (64)40.0 (4)0.7
    IA2†16.3 (20)13.9 (33)00.3
    GAD†21.1 (26)16.0 (38)36.4 (4)0.1
    Proliferative DR†53.9 (56)52.7 (97)36.4 (4)0.5
    Microalbuminuria (ACR <7.91)†15.1 (18)10.8 (19)23.1 (3)0.3
    Neuropathy (MNSI >2)†60.4 (67)60.7 (99)60.0 (6)0.9
    Cardiovascular disease†46.4 (52)50.0 (96)50.0 (5)0.8
    MMTT response0 (0/3)14.2 (3/21)57.1 (4/7)<0.0001
    • Data are means ± SD or % (n).

    • †Percentages reflect calculations done on data available.

    • *P values resulted from ANOVA.

  • TABLE 3

    Summary of findings in nine Medalist's pancreases, including insulin, Ki67, and TUNEL staining in cells

    IDSexAge (years)Age dx (years)HbA1C (%)ABHLAC-peptide (nmol/l)Insulin+Ki67+TUNEL+CD3+
    M1F6018.8GAD+DR3/DR40.01Very few, scattered singletsNDInsulin + clustersIn a few islets
    M2M5975.6NegDR30.02Scattered in separate lobes, + in ductsNegAutolysisIn a few islets
    M3M8959NegDR40.04Scattered in separate lobes, + in ductsIn ductsAutolysisND
    M4M7846.6IA2+DR30.06Scattered, clusters up to 8 cellsIn islets; no insulin+ cells+Cells, but not insulin+ND
    M5F7185.7NegDR3/DR40.06Scattered, clusters and some within isletsNDAutolysisND
    M6F7377.3NegDR3/DR40.09Scattered, within islets, rare clusterNDNegND
    M7F7259.8GAD+DR3/DR40.1Few scattered in small islets, rare glucagon+ in ductsNegAutolysisND
    M8F79236.7NegDR3/DR40.1650% islets none; 25% normal; 25% with amyloidNDCouple insulin+In a few islets
    M9M88307.1NegDR31.66All islets insulin+, Some small islets all insulin+; + in ductsInsulin+NDIn a few islets
    • dx, duration; ND, not determined; Neg, negative; Age dx, age of diagnosis; AB, antibody.

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Residual Insulin Production and Pancreatic β-Cell Turnover After 50 Years of Diabetes: Joslin Medalist Study
Hillary A. Keenan, Jennifer K. Sun, Jared Levine, Alessandro Doria, Lloyd P. Aiello, George Eisenbarth, Susan Bonner-Weir, George L. King
Diabetes Nov 2010, 59 (11) 2846-2853; DOI: 10.2337/db10-0676

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Residual Insulin Production and Pancreatic β-Cell Turnover After 50 Years of Diabetes: Joslin Medalist Study
Hillary A. Keenan, Jennifer K. Sun, Jared Levine, Alessandro Doria, Lloyd P. Aiello, George Eisenbarth, Susan Bonner-Weir, George L. King
Diabetes Nov 2010, 59 (11) 2846-2853; DOI: 10.2337/db10-0676
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