Effects of insulin in relatives of patients with type 1 diabetes mellitus

J. S. Skyler, D. Brown, H. P. Chase, E. Collier, C. Cowie, G. S. Eisenbarth, J. Fradkin, G. Grave, C. Greenbaum, R. A. Jackson, F. R. Kaufman, J. P. Krischer, Jennifer B Marks, J. P. Palmer, A. Ricker, D. A. Schatz, D. Wilson, W. E. Winter, J. Wolfsdorf, A. ZeidlerH. Dickler, R. C. Eastman, N. K. Maclaren, J. I. Malone, P. R. Robertson, J. S. Skyler, J. P. Krischer, J. Wolfsdorf, C. Cowie, J. P. Palmer, C. Greenbaum, D. Cuthbertson, Lisa Rafkin, F. R. Kaufman, H. P. Chase, J. P. Palmer, H. P. Chase, C. Cowie, J. Fradkin, G. S. Eisenbarth, C. Greenbaum, K. Herold, F. R. Kaufman, J. P. Krischer, J. B. Marks, L. Rafkin-Mervis, D. A. Schatz, Jay S Skyler, B. Aneju, D. Conboy, R. Cook, M. A. Dennis, L. Finney, S. Harris, D. Matheson, M. McCulloch-Olsen, T. Smith, J. Valenzuela, N. Vega, O. B. Crofford, D. DeMets, J. M. Lachin, A. Rossini, A. Schiffrin, M. Steffes, A. Tsiatis, B. Zinman

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Abstract

Background It is unknown whether insulin therapy can delay or prevent diabetes in nondiabetic relatives of patients with diabetes. Methods In a randomized, controlled, nonblinded clinical trial, we screened 84,228 first-degree and second-degree relatives of patients with diabetes for islet-cell antibodies; 3152 tested positive; 2103 of the 3152 underwent genetic, immunologic, and metabolic staging to quantify their risk; 372 of the 2103 had a projected five-year risk of more than 50 percent; 339 of the 372 (median age, 11.2 years) were randomly assigned to undergo either close observation or an intervention that consisted of low-dose subcutaneous ultralente insulin, administered twice daily for a total dose of 0.25 unit per kilogram of body weight per day, plus annual four-day continuous intravenous infusions of insulin. Oral glucose-tolerance tests were performed every six months. Median follow-up was 3.7 years. The primary end point was a diagnosis of diabetes. Results Diabetes was diagnosed in 69 subjects in the intervention group and 70 subjects in the observation group. The annualized rate of progression to diabetes was 15.1 percent in the intervention group and 14.6 percent in the observation group. The cumulative incidence of diabetes was similar in the two groups (relative risk in the intervention group as compared with the observation group, 0.96). Most subjects in whom diabetes developed were asymptomatic. Progression to diabetes occurred at a faster rate among subjects with abnormal base-line glucose tolerance (22 percent per year) than among those with normal base-line glucose tolerance (10 percent per year, P<0.001). There were no episodes of severe hypoglycemia. The incidence of chemical hypoglycemia, assessed without ascertainment bias, was similar in the two groups. Conclusions In persons at high risk for diabetes, insulin at the dosage used in this study does not delay or prevent type 1 diabetes.

Original languageEnglish
Pages (from-to)1685-1691
Number of pages7
JournalNew England Journal of Medicine
Volume346
Issue number22
DOIs
StatePublished - May 30 2002

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Type 1 Diabetes Mellitus
Observation
Insulin
Hypoglycemia
Ultralente Insulin
Glucose
Incidence
Glucose Tolerance Test
Intravenous Infusions
Randomized Controlled Trials
Body Weight
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

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Skyler, J. S., Brown, D., Chase, H. P., Collier, E., Cowie, C., Eisenbarth, G. S., ... Zinman, B. (2002). Effects of insulin in relatives of patients with type 1 diabetes mellitus. New England Journal of Medicine, 346(22), 1685-1691. https://doi.org/10.1056/NEJMoa012350

Effects of insulin in relatives of patients with type 1 diabetes mellitus. / Skyler, J. S.; Brown, D.; Chase, H. P.; Collier, E.; Cowie, C.; Eisenbarth, G. S.; Fradkin, J.; Grave, G.; Greenbaum, C.; Jackson, R. A.; Kaufman, F. R.; Krischer, J. P.; Marks, Jennifer B; Palmer, J. P.; Ricker, A.; Schatz, D. A.; Wilson, D.; Winter, W. E.; Wolfsdorf, J.; Zeidler, A.; Dickler, H.; Eastman, R. C.; Maclaren, N. K.; Malone, J. I.; Robertson, P. R.; Skyler, J. S.; Krischer, J. P.; Wolfsdorf, J.; Cowie, C.; Palmer, J. P.; Greenbaum, C.; Cuthbertson, D.; Rafkin, Lisa; Kaufman, F. R.; Chase, H. P.; Palmer, J. P.; Chase, H. P.; Cowie, C.; Fradkin, J.; Eisenbarth, G. S.; Greenbaum, C.; Herold, K.; Kaufman, F. R.; Krischer, J. P.; Marks, J. B.; Rafkin-Mervis, L.; Schatz, D. A.; Skyler, Jay S; Aneju, B.; Conboy, D.; Cook, R.; Dennis, M. A.; Finney, L.; Harris, S.; Matheson, D.; McCulloch-Olsen, M.; Smith, T.; Valenzuela, J.; Vega, N.; Crofford, O. B.; DeMets, D.; Lachin, J. M.; Rossini, A.; Schiffrin, A.; Steffes, M.; Tsiatis, A.; Zinman, B.

In: New England Journal of Medicine, Vol. 346, No. 22, 30.05.2002, p. 1685-1691.

Research output: Contribution to journalArticle

Skyler, JS, Brown, D, Chase, HP, Collier, E, Cowie, C, Eisenbarth, GS, Fradkin, J, Grave, G, Greenbaum, C, Jackson, RA, Kaufman, FR, Krischer, JP, Marks, JB, Palmer, JP, Ricker, A, Schatz, DA, Wilson, D, Winter, WE, Wolfsdorf, J, Zeidler, A, Dickler, H, Eastman, RC, Maclaren, NK, Malone, JI, Robertson, PR, Skyler, JS, Krischer, JP, Wolfsdorf, J, Cowie, C, Palmer, JP, Greenbaum, C, Cuthbertson, D, Rafkin, L, Kaufman, FR, Chase, HP, Palmer, JP, Chase, HP, Cowie, C, Fradkin, J, Eisenbarth, GS, Greenbaum, C, Herold, K, Kaufman, FR, Krischer, JP, Marks, JB, Rafkin-Mervis, L, Schatz, DA, Skyler, JS, Aneju, B, Conboy, D, Cook, R, Dennis, MA, Finney, L, Harris, S, Matheson, D, McCulloch-Olsen, M, Smith, T, Valenzuela, J, Vega, N, Crofford, OB, DeMets, D, Lachin, JM, Rossini, A, Schiffrin, A, Steffes, M, Tsiatis, A & Zinman, B 2002, 'Effects of insulin in relatives of patients with type 1 diabetes mellitus', New England Journal of Medicine, vol. 346, no. 22, pp. 1685-1691. https://doi.org/10.1056/NEJMoa012350
Skyler JS, Brown D, Chase HP, Collier E, Cowie C, Eisenbarth GS et al. Effects of insulin in relatives of patients with type 1 diabetes mellitus. New England Journal of Medicine. 2002 May 30;346(22):1685-1691. https://doi.org/10.1056/NEJMoa012350
Skyler, J. S. ; Brown, D. ; Chase, H. P. ; Collier, E. ; Cowie, C. ; Eisenbarth, G. S. ; Fradkin, J. ; Grave, G. ; Greenbaum, C. ; Jackson, R. A. ; Kaufman, F. R. ; Krischer, J. P. ; Marks, Jennifer B ; Palmer, J. P. ; Ricker, A. ; Schatz, D. A. ; Wilson, D. ; Winter, W. E. ; Wolfsdorf, J. ; Zeidler, A. ; Dickler, H. ; Eastman, R. C. ; Maclaren, N. K. ; Malone, J. I. ; Robertson, P. R. ; Skyler, J. S. ; Krischer, J. P. ; Wolfsdorf, J. ; Cowie, C. ; Palmer, J. P. ; Greenbaum, C. ; Cuthbertson, D. ; Rafkin, Lisa ; Kaufman, F. R. ; Chase, H. P. ; Palmer, J. P. ; Chase, H. P. ; Cowie, C. ; Fradkin, J. ; Eisenbarth, G. S. ; Greenbaum, C. ; Herold, K. ; Kaufman, F. R. ; Krischer, J. P. ; Marks, J. B. ; Rafkin-Mervis, L. ; Schatz, D. A. ; Skyler, Jay S ; Aneju, B. ; Conboy, D. ; Cook, R. ; Dennis, M. A. ; Finney, L. ; Harris, S. ; Matheson, D. ; McCulloch-Olsen, M. ; Smith, T. ; Valenzuela, J. ; Vega, N. ; Crofford, O. B. ; DeMets, D. ; Lachin, J. M. ; Rossini, A. ; Schiffrin, A. ; Steffes, M. ; Tsiatis, A. ; Zinman, B. / Effects of insulin in relatives of patients with type 1 diabetes mellitus. In: New England Journal of Medicine. 2002 ; Vol. 346, No. 22. pp. 1685-1691.
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title = "Effects of insulin in relatives of patients with type 1 diabetes mellitus",
abstract = "Background It is unknown whether insulin therapy can delay or prevent diabetes in nondiabetic relatives of patients with diabetes. Methods In a randomized, controlled, nonblinded clinical trial, we screened 84,228 first-degree and second-degree relatives of patients with diabetes for islet-cell antibodies; 3152 tested positive; 2103 of the 3152 underwent genetic, immunologic, and metabolic staging to quantify their risk; 372 of the 2103 had a projected five-year risk of more than 50 percent; 339 of the 372 (median age, 11.2 years) were randomly assigned to undergo either close observation or an intervention that consisted of low-dose subcutaneous ultralente insulin, administered twice daily for a total dose of 0.25 unit per kilogram of body weight per day, plus annual four-day continuous intravenous infusions of insulin. Oral glucose-tolerance tests were performed every six months. Median follow-up was 3.7 years. The primary end point was a diagnosis of diabetes. Results Diabetes was diagnosed in 69 subjects in the intervention group and 70 subjects in the observation group. The annualized rate of progression to diabetes was 15.1 percent in the intervention group and 14.6 percent in the observation group. The cumulative incidence of diabetes was similar in the two groups (relative risk in the intervention group as compared with the observation group, 0.96). Most subjects in whom diabetes developed were asymptomatic. Progression to diabetes occurred at a faster rate among subjects with abnormal base-line glucose tolerance (22 percent per year) than among those with normal base-line glucose tolerance (10 percent per year, P<0.001). There were no episodes of severe hypoglycemia. The incidence of chemical hypoglycemia, assessed without ascertainment bias, was similar in the two groups. Conclusions In persons at high risk for diabetes, insulin at the dosage used in this study does not delay or prevent type 1 diabetes.",
author = "Skyler, {J. S.} and D. Brown and Chase, {H. P.} and E. Collier and C. Cowie and Eisenbarth, {G. S.} and J. Fradkin and G. Grave and C. Greenbaum and Jackson, {R. A.} and Kaufman, {F. R.} and Krischer, {J. P.} and Marks, {Jennifer B} and Palmer, {J. P.} and A. Ricker and Schatz, {D. A.} and D. Wilson and Winter, {W. E.} and J. Wolfsdorf and A. Zeidler and H. Dickler and Eastman, {R. C.} and Maclaren, {N. K.} and Malone, {J. I.} and Robertson, {P. R.} and Skyler, {J. S.} and Krischer, {J. P.} and J. Wolfsdorf and C. Cowie and Palmer, {J. P.} and C. Greenbaum and D. Cuthbertson and Lisa Rafkin and Kaufman, {F. R.} and Chase, {H. P.} and Palmer, {J. P.} and Chase, {H. P.} and C. Cowie and J. Fradkin and Eisenbarth, {G. S.} and C. Greenbaum and K. Herold and Kaufman, {F. R.} and Krischer, {J. P.} and Marks, {J. B.} and L. Rafkin-Mervis and Schatz, {D. A.} and Skyler, {Jay S} and B. Aneju and D. Conboy and R. Cook and Dennis, {M. A.} and L. Finney and S. Harris and D. Matheson and M. McCulloch-Olsen and T. Smith and J. Valenzuela and N. Vega and Crofford, {O. B.} and D. DeMets and Lachin, {J. M.} and A. Rossini and A. Schiffrin and M. Steffes and A. Tsiatis and B. Zinman",
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TY - JOUR

T1 - Effects of insulin in relatives of patients with type 1 diabetes mellitus

AU - Skyler, J. S.

AU - Brown, D.

AU - Chase, H. P.

AU - Collier, E.

AU - Cowie, C.

AU - Eisenbarth, G. S.

AU - Fradkin, J.

AU - Grave, G.

AU - Greenbaum, C.

AU - Jackson, R. A.

AU - Kaufman, F. R.

AU - Krischer, J. P.

AU - Marks, Jennifer B

AU - Palmer, J. P.

AU - Ricker, A.

AU - Schatz, D. A.

AU - Wilson, D.

AU - Winter, W. E.

AU - Wolfsdorf, J.

AU - Zeidler, A.

AU - Dickler, H.

AU - Eastman, R. C.

AU - Maclaren, N. K.

AU - Malone, J. I.

AU - Robertson, P. R.

AU - Skyler, J. S.

AU - Krischer, J. P.

AU - Wolfsdorf, J.

AU - Cowie, C.

AU - Palmer, J. P.

AU - Greenbaum, C.

AU - Cuthbertson, D.

AU - Rafkin, Lisa

AU - Kaufman, F. R.

AU - Chase, H. P.

AU - Palmer, J. P.

AU - Chase, H. P.

AU - Cowie, C.

AU - Fradkin, J.

AU - Eisenbarth, G. S.

AU - Greenbaum, C.

AU - Herold, K.

AU - Kaufman, F. R.

AU - Krischer, J. P.

AU - Marks, J. B.

AU - Rafkin-Mervis, L.

AU - Schatz, D. A.

AU - Skyler, Jay S

AU - Aneju, B.

AU - Conboy, D.

AU - Cook, R.

AU - Dennis, M. A.

AU - Finney, L.

AU - Harris, S.

AU - Matheson, D.

AU - McCulloch-Olsen, M.

AU - Smith, T.

AU - Valenzuela, J.

AU - Vega, N.

AU - Crofford, O. B.

AU - DeMets, D.

AU - Lachin, J. M.

AU - Rossini, A.

AU - Schiffrin, A.

AU - Steffes, M.

AU - Tsiatis, A.

AU - Zinman, B.

PY - 2002/5/30

Y1 - 2002/5/30

N2 - Background It is unknown whether insulin therapy can delay or prevent diabetes in nondiabetic relatives of patients with diabetes. Methods In a randomized, controlled, nonblinded clinical trial, we screened 84,228 first-degree and second-degree relatives of patients with diabetes for islet-cell antibodies; 3152 tested positive; 2103 of the 3152 underwent genetic, immunologic, and metabolic staging to quantify their risk; 372 of the 2103 had a projected five-year risk of more than 50 percent; 339 of the 372 (median age, 11.2 years) were randomly assigned to undergo either close observation or an intervention that consisted of low-dose subcutaneous ultralente insulin, administered twice daily for a total dose of 0.25 unit per kilogram of body weight per day, plus annual four-day continuous intravenous infusions of insulin. Oral glucose-tolerance tests were performed every six months. Median follow-up was 3.7 years. The primary end point was a diagnosis of diabetes. Results Diabetes was diagnosed in 69 subjects in the intervention group and 70 subjects in the observation group. The annualized rate of progression to diabetes was 15.1 percent in the intervention group and 14.6 percent in the observation group. The cumulative incidence of diabetes was similar in the two groups (relative risk in the intervention group as compared with the observation group, 0.96). Most subjects in whom diabetes developed were asymptomatic. Progression to diabetes occurred at a faster rate among subjects with abnormal base-line glucose tolerance (22 percent per year) than among those with normal base-line glucose tolerance (10 percent per year, P<0.001). There were no episodes of severe hypoglycemia. The incidence of chemical hypoglycemia, assessed without ascertainment bias, was similar in the two groups. Conclusions In persons at high risk for diabetes, insulin at the dosage used in this study does not delay or prevent type 1 diabetes.

AB - Background It is unknown whether insulin therapy can delay or prevent diabetes in nondiabetic relatives of patients with diabetes. Methods In a randomized, controlled, nonblinded clinical trial, we screened 84,228 first-degree and second-degree relatives of patients with diabetes for islet-cell antibodies; 3152 tested positive; 2103 of the 3152 underwent genetic, immunologic, and metabolic staging to quantify their risk; 372 of the 2103 had a projected five-year risk of more than 50 percent; 339 of the 372 (median age, 11.2 years) were randomly assigned to undergo either close observation or an intervention that consisted of low-dose subcutaneous ultralente insulin, administered twice daily for a total dose of 0.25 unit per kilogram of body weight per day, plus annual four-day continuous intravenous infusions of insulin. Oral glucose-tolerance tests were performed every six months. Median follow-up was 3.7 years. The primary end point was a diagnosis of diabetes. Results Diabetes was diagnosed in 69 subjects in the intervention group and 70 subjects in the observation group. The annualized rate of progression to diabetes was 15.1 percent in the intervention group and 14.6 percent in the observation group. The cumulative incidence of diabetes was similar in the two groups (relative risk in the intervention group as compared with the observation group, 0.96). Most subjects in whom diabetes developed were asymptomatic. Progression to diabetes occurred at a faster rate among subjects with abnormal base-line glucose tolerance (22 percent per year) than among those with normal base-line glucose tolerance (10 percent per year, P<0.001). There were no episodes of severe hypoglycemia. The incidence of chemical hypoglycemia, assessed without ascertainment bias, was similar in the two groups. Conclusions In persons at high risk for diabetes, insulin at the dosage used in this study does not delay or prevent type 1 diabetes.

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