Galantamine alleviates inflammation and insulin resistance in patients with metabolic syndrome in a randomized trial

Fernanda M. Consolim-Colombo, Carine T. Sangaleti, Fernando O. Costa, Tercio L. Morais, Heno F. Lopes, Josiane M. Motta, Maria C. Irigoyen, Luiz A. Bortoloto, Carlos Eduardo Rochitte, Yael Tobi Harris, Sanjaya Satapathy, Peder S. Olofsson, Meredith Akerman, Sangeeta S. Chavan, Meggan MacKay, Douglas P. Barnaby, Martin L. Lesser, Jesse Roth, Kevin J. Tracey, Valentin A. Pavlov

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Abstract

BACKGROUND: Metabolic syndrome (MetS) is an obesity-driven condition of pandemic proportions that increases the risk of type 2 diabetes and cardiovascular disease. Pathophysiological mechanisms are poorly understood, though inflammation has been implicated in MetS pathogenesis. The aim of this study was to assess the effects of galantamine, a centrally acting acetylcholinesterase inhibitor with antiinflammatory properties, on markers of inflammation implicated in insulin resistance and cardiovascular risk, and other metabolic and cardiovascular indices in subjects with MetS. METHODS: In this randomized, double-blind, placebo-controlled trial, subjects with MetS (30 per group) received oral galantamine 8 mg daily for 4 weeks, followed by 16 mg daily for 8 weeks or placebo. The primary outcome was inflammation assessed through plasma levels of cytokines and adipokines associated with MetS. Secondary endpoints included body weight, fat tissue depots, plasma glucose, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), cholesterol (total, HDL, LDL), triglycerides, BP, heart rate, and heart rate variability (HRV). RESULTS: Galantamine resulted in lower plasma levels of proinflammatory molecules TNF (-2.57 pg/ml [95% CI -4.96 to -0.19]; P = 0.035) and leptin (-12.02 ng/ml [95% CI -17.71 to -6.33]; P < 0.0001), and higher levels of the antiinflammatory molecules adiponectin (2.71 μg/ml [95% CI 1.93 to 3.49]; P < 0.0001) and IL-10 (1.32 pg/ml, [95% CI 0.29 to 2.38]; P = 0.002) as compared with placebo. Galantamine also significantly lowered plasma insulin and HOMA-IR values, and altered HRV. CONCLUSION: Low-dose galantamine alleviates inflammation and insulin resistance in MetS subjects. These findings support further study of galantamine in MetS therapy. TRIAL REGISTRATION: ClinicalTrials.gov, number NCT02283242. FUNDING: Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brazil, and the NIH.

Original languageEnglish (US)
JournalJCI insight
Volume2
Issue number14
DOIs
StatePublished - Jul 20 2017

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Galantamine
Insulin Resistance
Inflammation
Heart Rate
Placebos
Homeostasis
Anti-Inflammatory Agents
Insulin
Adipokines
Adiponectin
Cholinesterase Inhibitors
Pandemics
Leptin
Interleukin-10
Type 2 Diabetes Mellitus
HDL Cholesterol
Brazil
Cardiovascular Diseases
Obesity
Fats

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Consolim-Colombo, F. M., Sangaleti, C. T., Costa, F. O., Morais, T. L., Lopes, H. F., Motta, J. M., ... Pavlov, V. A. (2017). Galantamine alleviates inflammation and insulin resistance in patients with metabolic syndrome in a randomized trial. JCI insight, 2(14). https://doi.org/10.1172/jci.insight.93340

Galantamine alleviates inflammation and insulin resistance in patients with metabolic syndrome in a randomized trial. / Consolim-Colombo, Fernanda M.; Sangaleti, Carine T.; Costa, Fernando O.; Morais, Tercio L.; Lopes, Heno F.; Motta, Josiane M.; Irigoyen, Maria C.; Bortoloto, Luiz A.; Rochitte, Carlos Eduardo; Harris, Yael Tobi; Satapathy, Sanjaya; Olofsson, Peder S.; Akerman, Meredith; Chavan, Sangeeta S.; MacKay, Meggan; Barnaby, Douglas P.; Lesser, Martin L.; Roth, Jesse; Tracey, Kevin J.; Pavlov, Valentin A.

In: JCI insight, Vol. 2, No. 14, 20.07.2017.

Research output: Contribution to journalArticle

Consolim-Colombo, FM, Sangaleti, CT, Costa, FO, Morais, TL, Lopes, HF, Motta, JM, Irigoyen, MC, Bortoloto, LA, Rochitte, CE, Harris, YT, Satapathy, S, Olofsson, PS, Akerman, M, Chavan, SS, MacKay, M, Barnaby, DP, Lesser, ML, Roth, J, Tracey, KJ & Pavlov, VA 2017, 'Galantamine alleviates inflammation and insulin resistance in patients with metabolic syndrome in a randomized trial', JCI insight, vol. 2, no. 14. https://doi.org/10.1172/jci.insight.93340
Consolim-Colombo, Fernanda M. ; Sangaleti, Carine T. ; Costa, Fernando O. ; Morais, Tercio L. ; Lopes, Heno F. ; Motta, Josiane M. ; Irigoyen, Maria C. ; Bortoloto, Luiz A. ; Rochitte, Carlos Eduardo ; Harris, Yael Tobi ; Satapathy, Sanjaya ; Olofsson, Peder S. ; Akerman, Meredith ; Chavan, Sangeeta S. ; MacKay, Meggan ; Barnaby, Douglas P. ; Lesser, Martin L. ; Roth, Jesse ; Tracey, Kevin J. ; Pavlov, Valentin A. / Galantamine alleviates inflammation and insulin resistance in patients with metabolic syndrome in a randomized trial. In: JCI insight. 2017 ; Vol. 2, No. 14.
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abstract = "BACKGROUND: Metabolic syndrome (MetS) is an obesity-driven condition of pandemic proportions that increases the risk of type 2 diabetes and cardiovascular disease. Pathophysiological mechanisms are poorly understood, though inflammation has been implicated in MetS pathogenesis. The aim of this study was to assess the effects of galantamine, a centrally acting acetylcholinesterase inhibitor with antiinflammatory properties, on markers of inflammation implicated in insulin resistance and cardiovascular risk, and other metabolic and cardiovascular indices in subjects with MetS. METHODS: In this randomized, double-blind, placebo-controlled trial, subjects with MetS (30 per group) received oral galantamine 8 mg daily for 4 weeks, followed by 16 mg daily for 8 weeks or placebo. The primary outcome was inflammation assessed through plasma levels of cytokines and adipokines associated with MetS. Secondary endpoints included body weight, fat tissue depots, plasma glucose, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), cholesterol (total, HDL, LDL), triglycerides, BP, heart rate, and heart rate variability (HRV). RESULTS: Galantamine resulted in lower plasma levels of proinflammatory molecules TNF (-2.57 pg/ml [95{\%} CI -4.96 to -0.19]; P = 0.035) and leptin (-12.02 ng/ml [95{\%} CI -17.71 to -6.33]; P < 0.0001), and higher levels of the antiinflammatory molecules adiponectin (2.71 μg/ml [95{\%} CI 1.93 to 3.49]; P < 0.0001) and IL-10 (1.32 pg/ml, [95{\%} CI 0.29 to 2.38]; P = 0.002) as compared with placebo. Galantamine also significantly lowered plasma insulin and HOMA-IR values, and altered HRV. CONCLUSION: Low-dose galantamine alleviates inflammation and insulin resistance in MetS subjects. These findings support further study of galantamine in MetS therapy. TRIAL REGISTRATION: ClinicalTrials.gov, number NCT02283242. FUNDING: Funda{\cc}{\~a}o de Amparo a Pesquisa do Estado de S{\~a}o Paulo (FAPESP) and Conselho Nacional de Desenvolvimento Cient{\'i}fico e Tecnol{\'o}gico (CNPq), Brazil, and the NIH.",
author = "Consolim-Colombo, {Fernanda M.} and Sangaleti, {Carine T.} and Costa, {Fernando O.} and Morais, {Tercio L.} and Lopes, {Heno F.} and Motta, {Josiane M.} and Irigoyen, {Maria C.} and Bortoloto, {Luiz A.} and Rochitte, {Carlos Eduardo} and Harris, {Yael Tobi} and Sanjaya Satapathy and Olofsson, {Peder S.} and Meredith Akerman and Chavan, {Sangeeta S.} and Meggan MacKay and Barnaby, {Douglas P.} and Lesser, {Martin L.} and Jesse Roth and Tracey, {Kevin J.} and Pavlov, {Valentin A.}",
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T1 - Galantamine alleviates inflammation and insulin resistance in patients with metabolic syndrome in a randomized trial

AU - Consolim-Colombo, Fernanda M.

AU - Sangaleti, Carine T.

AU - Costa, Fernando O.

AU - Morais, Tercio L.

AU - Lopes, Heno F.

AU - Motta, Josiane M.

AU - Irigoyen, Maria C.

AU - Bortoloto, Luiz A.

AU - Rochitte, Carlos Eduardo

AU - Harris, Yael Tobi

AU - Satapathy, Sanjaya

AU - Olofsson, Peder S.

AU - Akerman, Meredith

AU - Chavan, Sangeeta S.

AU - MacKay, Meggan

AU - Barnaby, Douglas P.

AU - Lesser, Martin L.

AU - Roth, Jesse

AU - Tracey, Kevin J.

AU - Pavlov, Valentin A.

PY - 2017/7/20

Y1 - 2017/7/20

N2 - BACKGROUND: Metabolic syndrome (MetS) is an obesity-driven condition of pandemic proportions that increases the risk of type 2 diabetes and cardiovascular disease. Pathophysiological mechanisms are poorly understood, though inflammation has been implicated in MetS pathogenesis. The aim of this study was to assess the effects of galantamine, a centrally acting acetylcholinesterase inhibitor with antiinflammatory properties, on markers of inflammation implicated in insulin resistance and cardiovascular risk, and other metabolic and cardiovascular indices in subjects with MetS. METHODS: In this randomized, double-blind, placebo-controlled trial, subjects with MetS (30 per group) received oral galantamine 8 mg daily for 4 weeks, followed by 16 mg daily for 8 weeks or placebo. The primary outcome was inflammation assessed through plasma levels of cytokines and adipokines associated with MetS. Secondary endpoints included body weight, fat tissue depots, plasma glucose, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), cholesterol (total, HDL, LDL), triglycerides, BP, heart rate, and heart rate variability (HRV). RESULTS: Galantamine resulted in lower plasma levels of proinflammatory molecules TNF (-2.57 pg/ml [95% CI -4.96 to -0.19]; P = 0.035) and leptin (-12.02 ng/ml [95% CI -17.71 to -6.33]; P < 0.0001), and higher levels of the antiinflammatory molecules adiponectin (2.71 μg/ml [95% CI 1.93 to 3.49]; P < 0.0001) and IL-10 (1.32 pg/ml, [95% CI 0.29 to 2.38]; P = 0.002) as compared with placebo. Galantamine also significantly lowered plasma insulin and HOMA-IR values, and altered HRV. CONCLUSION: Low-dose galantamine alleviates inflammation and insulin resistance in MetS subjects. These findings support further study of galantamine in MetS therapy. TRIAL REGISTRATION: ClinicalTrials.gov, number NCT02283242. FUNDING: Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brazil, and the NIH.

AB - BACKGROUND: Metabolic syndrome (MetS) is an obesity-driven condition of pandemic proportions that increases the risk of type 2 diabetes and cardiovascular disease. Pathophysiological mechanisms are poorly understood, though inflammation has been implicated in MetS pathogenesis. The aim of this study was to assess the effects of galantamine, a centrally acting acetylcholinesterase inhibitor with antiinflammatory properties, on markers of inflammation implicated in insulin resistance and cardiovascular risk, and other metabolic and cardiovascular indices in subjects with MetS. METHODS: In this randomized, double-blind, placebo-controlled trial, subjects with MetS (30 per group) received oral galantamine 8 mg daily for 4 weeks, followed by 16 mg daily for 8 weeks or placebo. The primary outcome was inflammation assessed through plasma levels of cytokines and adipokines associated with MetS. Secondary endpoints included body weight, fat tissue depots, plasma glucose, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), cholesterol (total, HDL, LDL), triglycerides, BP, heart rate, and heart rate variability (HRV). RESULTS: Galantamine resulted in lower plasma levels of proinflammatory molecules TNF (-2.57 pg/ml [95% CI -4.96 to -0.19]; P = 0.035) and leptin (-12.02 ng/ml [95% CI -17.71 to -6.33]; P < 0.0001), and higher levels of the antiinflammatory molecules adiponectin (2.71 μg/ml [95% CI 1.93 to 3.49]; P < 0.0001) and IL-10 (1.32 pg/ml, [95% CI 0.29 to 2.38]; P = 0.002) as compared with placebo. Galantamine also significantly lowered plasma insulin and HOMA-IR values, and altered HRV. CONCLUSION: Low-dose galantamine alleviates inflammation and insulin resistance in MetS subjects. These findings support further study of galantamine in MetS therapy. TRIAL REGISTRATION: ClinicalTrials.gov, number NCT02283242. FUNDING: Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brazil, and the NIH.

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