Metformin Improves Peripheral Insulin Sensitivity in Youth with Type 1 Diabetes

Melanie Cree-Green, Bryan C. Bergman, Eda Cengiz, Larry A. Fox, Tamara Hannon, Kellee Miller, Brandon Nathan, Laura Pyle, Darcy Kahn, Michael Tansey, Eileen Tichy, Eva Tsalikian, Ingrid Libman, Kristen J. Nadeau

Research output: Contribution to journalArticle

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Abstract

Context Type 1 diabetes in adolescence is characterized by insulin deficiency and insulin resistance (IR), both thought to increase cardiovascular disease risk. We previously demonstrated that adolescents with type 1 diabetes have adipose, hepatic, and muscle IR, and that metformin lowers daily insulin dose, suggesting improved IR. However, whether metformin improves IR in muscle, hepatic, or adipose tissues in type 1 diabetes was unknown. Objective Measure peripheral, hepatic, and adipose insulin sensitivity before and after metformin or placebo therapy in youth with obesity with type 1 diabetes. Design Double-blind, placebo-controlled clinical trial. Setting Multi-center at eight sites of the T1D Exchange Clinic Network. Participants A subset of 12- to 19-year-olds with type 1 diabetes (inclusion criteria: body mass index ≥85th percentile, HbA1c 7.5% to 9.9%, insulin dosing ≥0.8 U/kg/d) from a larger trial (NCT02045290) were enrolled. Intervention Participants were randomized to 3 months of metformin (N = 19) or placebo (N = 18) and underwent a three-phase hyperinsulinemic euglycemic clamp with glucose and glycerol isotope tracers to assess tissue-specific IR before and after treatment. Main Outcome Measures Peripheral insulin sensitivity, endogenous glucose release, rate of lipolysis. Results Between-group differences in change in insulin sensitivity favored metformin regarding whole-body IR [change in glucose infusion rate 1.3 (0.1, 2.4) mg/kg/min, P = 0.03] and peripheral IR [change in metabolic clearance rate 0.923 (-0.002, 1.867) dL/kg/min, P = 0.05]. Metformin did not impact insulin suppression of endogenous glucose release (P = 0.12). Adipose IR was not assessable with traditional methods in this highly IR population. Conclusions Metformin appears to improve whole-body and peripheral IR in youth who are overweight/obese with type 1 diabetes.

Original languageEnglish (US)
Pages (from-to)3265-3278
Number of pages14
JournalJournal of Clinical Endocrinology and Metabolism
Volume104
Issue number8
DOIs
StatePublished - Jun 19 2019

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Metformin
Medical problems
Type 1 Diabetes Mellitus
Insulin Resistance
Insulin
Glucose
Placebos
Vascular Resistance
Liver
Metabolic Clearance Rate
Muscle
Muscles
Glucose Clamp Technique
Lipolysis
Inclusion Bodies
Controlled Clinical Trials
Tissue
Isotopes
Glycerol
Adipose Tissue

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

Cite this

Metformin Improves Peripheral Insulin Sensitivity in Youth with Type 1 Diabetes. / Cree-Green, Melanie; Bergman, Bryan C.; Cengiz, Eda; Fox, Larry A.; Hannon, Tamara; Miller, Kellee; Nathan, Brandon; Pyle, Laura; Kahn, Darcy; Tansey, Michael; Tichy, Eileen; Tsalikian, Eva; Libman, Ingrid; Nadeau, Kristen J.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 104, No. 8, 19.06.2019, p. 3265-3278.

Research output: Contribution to journalArticle

Cree-Green, M, Bergman, BC, Cengiz, E, Fox, LA, Hannon, T, Miller, K, Nathan, B, Pyle, L, Kahn, D, Tansey, M, Tichy, E, Tsalikian, E, Libman, I & Nadeau, KJ 2019, 'Metformin Improves Peripheral Insulin Sensitivity in Youth with Type 1 Diabetes', Journal of Clinical Endocrinology and Metabolism, vol. 104, no. 8, pp. 3265-3278. https://doi.org/10.1210/jc.2019-00129
Cree-Green, Melanie ; Bergman, Bryan C. ; Cengiz, Eda ; Fox, Larry A. ; Hannon, Tamara ; Miller, Kellee ; Nathan, Brandon ; Pyle, Laura ; Kahn, Darcy ; Tansey, Michael ; Tichy, Eileen ; Tsalikian, Eva ; Libman, Ingrid ; Nadeau, Kristen J. / Metformin Improves Peripheral Insulin Sensitivity in Youth with Type 1 Diabetes. In: Journal of Clinical Endocrinology and Metabolism. 2019 ; Vol. 104, No. 8. pp. 3265-3278.
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abstract = "Context Type 1 diabetes in adolescence is characterized by insulin deficiency and insulin resistance (IR), both thought to increase cardiovascular disease risk. We previously demonstrated that adolescents with type 1 diabetes have adipose, hepatic, and muscle IR, and that metformin lowers daily insulin dose, suggesting improved IR. However, whether metformin improves IR in muscle, hepatic, or adipose tissues in type 1 diabetes was unknown. Objective Measure peripheral, hepatic, and adipose insulin sensitivity before and after metformin or placebo therapy in youth with obesity with type 1 diabetes. Design Double-blind, placebo-controlled clinical trial. Setting Multi-center at eight sites of the T1D Exchange Clinic Network. Participants A subset of 12- to 19-year-olds with type 1 diabetes (inclusion criteria: body mass index ≥85th percentile, HbA1c 7.5{\%} to 9.9{\%}, insulin dosing ≥0.8 U/kg/d) from a larger trial (NCT02045290) were enrolled. Intervention Participants were randomized to 3 months of metformin (N = 19) or placebo (N = 18) and underwent a three-phase hyperinsulinemic euglycemic clamp with glucose and glycerol isotope tracers to assess tissue-specific IR before and after treatment. Main Outcome Measures Peripheral insulin sensitivity, endogenous glucose release, rate of lipolysis. Results Between-group differences in change in insulin sensitivity favored metformin regarding whole-body IR [change in glucose infusion rate 1.3 (0.1, 2.4) mg/kg/min, P = 0.03] and peripheral IR [change in metabolic clearance rate 0.923 (-0.002, 1.867) dL/kg/min, P = 0.05]. Metformin did not impact insulin suppression of endogenous glucose release (P = 0.12). Adipose IR was not assessable with traditional methods in this highly IR population. Conclusions Metformin appears to improve whole-body and peripheral IR in youth who are overweight/obese with type 1 diabetes.",
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T1 - Metformin Improves Peripheral Insulin Sensitivity in Youth with Type 1 Diabetes

AU - Cree-Green, Melanie

AU - Bergman, Bryan C.

AU - Cengiz, Eda

AU - Fox, Larry A.

AU - Hannon, Tamara

AU - Miller, Kellee

AU - Nathan, Brandon

AU - Pyle, Laura

AU - Kahn, Darcy

AU - Tansey, Michael

AU - Tichy, Eileen

AU - Tsalikian, Eva

AU - Libman, Ingrid

AU - Nadeau, Kristen J.

PY - 2019/6/19

Y1 - 2019/6/19

N2 - Context Type 1 diabetes in adolescence is characterized by insulin deficiency and insulin resistance (IR), both thought to increase cardiovascular disease risk. We previously demonstrated that adolescents with type 1 diabetes have adipose, hepatic, and muscle IR, and that metformin lowers daily insulin dose, suggesting improved IR. However, whether metformin improves IR in muscle, hepatic, or adipose tissues in type 1 diabetes was unknown. Objective Measure peripheral, hepatic, and adipose insulin sensitivity before and after metformin or placebo therapy in youth with obesity with type 1 diabetes. Design Double-blind, placebo-controlled clinical trial. Setting Multi-center at eight sites of the T1D Exchange Clinic Network. Participants A subset of 12- to 19-year-olds with type 1 diabetes (inclusion criteria: body mass index ≥85th percentile, HbA1c 7.5% to 9.9%, insulin dosing ≥0.8 U/kg/d) from a larger trial (NCT02045290) were enrolled. Intervention Participants were randomized to 3 months of metformin (N = 19) or placebo (N = 18) and underwent a three-phase hyperinsulinemic euglycemic clamp with glucose and glycerol isotope tracers to assess tissue-specific IR before and after treatment. Main Outcome Measures Peripheral insulin sensitivity, endogenous glucose release, rate of lipolysis. Results Between-group differences in change in insulin sensitivity favored metformin regarding whole-body IR [change in glucose infusion rate 1.3 (0.1, 2.4) mg/kg/min, P = 0.03] and peripheral IR [change in metabolic clearance rate 0.923 (-0.002, 1.867) dL/kg/min, P = 0.05]. Metformin did not impact insulin suppression of endogenous glucose release (P = 0.12). Adipose IR was not assessable with traditional methods in this highly IR population. Conclusions Metformin appears to improve whole-body and peripheral IR in youth who are overweight/obese with type 1 diabetes.

AB - Context Type 1 diabetes in adolescence is characterized by insulin deficiency and insulin resistance (IR), both thought to increase cardiovascular disease risk. We previously demonstrated that adolescents with type 1 diabetes have adipose, hepatic, and muscle IR, and that metformin lowers daily insulin dose, suggesting improved IR. However, whether metformin improves IR in muscle, hepatic, or adipose tissues in type 1 diabetes was unknown. Objective Measure peripheral, hepatic, and adipose insulin sensitivity before and after metformin or placebo therapy in youth with obesity with type 1 diabetes. Design Double-blind, placebo-controlled clinical trial. Setting Multi-center at eight sites of the T1D Exchange Clinic Network. Participants A subset of 12- to 19-year-olds with type 1 diabetes (inclusion criteria: body mass index ≥85th percentile, HbA1c 7.5% to 9.9%, insulin dosing ≥0.8 U/kg/d) from a larger trial (NCT02045290) were enrolled. Intervention Participants were randomized to 3 months of metformin (N = 19) or placebo (N = 18) and underwent a three-phase hyperinsulinemic euglycemic clamp with glucose and glycerol isotope tracers to assess tissue-specific IR before and after treatment. Main Outcome Measures Peripheral insulin sensitivity, endogenous glucose release, rate of lipolysis. Results Between-group differences in change in insulin sensitivity favored metformin regarding whole-body IR [change in glucose infusion rate 1.3 (0.1, 2.4) mg/kg/min, P = 0.03] and peripheral IR [change in metabolic clearance rate 0.923 (-0.002, 1.867) dL/kg/min, P = 0.05]. Metformin did not impact insulin suppression of endogenous glucose release (P = 0.12). Adipose IR was not assessable with traditional methods in this highly IR population. Conclusions Metformin appears to improve whole-body and peripheral IR in youth who are overweight/obese with type 1 diabetes.

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