Exaggerated glucagon responses to hypoglycemia in women with polycystic ovary syndrome

Susan Sam; Priyathama Vellanki; Sudha K. Yalamanchi; Richard N. Bergman; Andrea Dunaif

doi:10.1016/j.metabol.2017.03.008

Exaggerated glucagon responses to hypoglycemia in women with polycystic ovary syndrome

Susan Sam, Priyathama Vellanki, Sudha K. Yalamanchi, Richard N. Bergman, Andrea Dunaif^*

^*Corresponding author for this work

Medicine, Endocrinology Division

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

Abstract

Context Premenopausal women have blunted counter-regulatory hormone responses (CRR) to hypoglycemia compared to men. Postmenopausal women have CRR similar to men; the premenopausal pattern can be restored by estrogen. However, glucagon and pancreatic polypeptide (PP) responses remain lower in postmenopausal women than in men. Since hyperandrogenemia contributes to the metabolic phenotype of polycystic ovary syndrome (PCOS), we hypothesize that CRR to hypoglycemia especially of glucagon and PP is exaggerated in premenopausal women with PCOS compared to premenopausal control women. Study Subjects and Methods Ten obese women with PCOS and 9 control women of similar ethnicity, age and BMI underwent determination of CRR in response to hypoglycemia during 180-min 60 mU/m²/min insulin dose hypoglycemic clamp with isotopic assessment of endogenous glucose production (EGP). To assess CRR to hypoglycemia, glucagon, cortisol, growth hormone (GH), epinephrine, norepinephrine, PP, lactate, free fatty acid (FFA), β-hydroxybutyrate, and glycerol levels were sampled at 15-min intervals throughout the clamp. Main Findings Incremental glucagon levels were ~ 3-fold higher during hypoglycemia (P = 0.03) in PCOS. Postabsorptive, steady-state and incremental GH, cortisol, epinephrine, norepinephrine, PP, FFA, glycerol and β-hydroxybutyrate did not differ. At target glucose levels of ~ 52 mg/dL, insulin mediated glucose disposal (IMGD) was decreased by ~ 40% (P = 0.02) in PCOS, compared to control women, despite ~ 20% higher steady-state insulin levels (P = 0.03). Neither postabsorptive nor steady-state EGP differed. However, postabsorptive lactate levels were ~ 50% higher (P = 0.02). PCOS status (P = 0.04) and IMGD (P = 0.02) predicted the differential glucagon response to hypoglycemia in separate regression models, however, neither parameter remained an independent predictor in a combined model. Principal Conclusions Glucagon responses were increased in PCOS, whereas other CRR did not differ. Women with PCOS were insulin resistant under hypoglycemic conditions and higher postabsorptive lactate levels in PCOS were consistent with this finding. Insulin resistance may have contributed to exaggerated glucagon response to hypoglycemia in PCOS.

Original language	English (US)
Pages (from-to)	125-131
Number of pages	7
Journal	Metabolism: Clinical and Experimental
Volume	71
DOIs	https://doi.org/10.1016/j.metabol.2017.03.008
State	Published - Jun 1 2017

Funding

This research was supported by NIH grants R01 HD057223 (AD) and P50 HD044405 (AD). PV and SKY were supported in part by T32 DK007196. The clinical studies were supported in part by the Northwestern University Clinical and Translational Science Institute (NUCATS) UL1 RR025741. Some of the hormone analyses were supported in part by University of Virginia Center for Research in Reproduction Ligand Analysis and Assay Core U54 HD28934 and the Institute for Clinical and Translational Research Analytic Biomarker Research Core at Albert Einstein College of Medicine UT1 TR000086.

Keywords

Counter-regulatory hormones
Hypoglycemia
Polycystic ovary syndrome

ASJC Scopus subject areas

Endocrinology
Endocrinology, Diabetes and Metabolism

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10.1016/j.metabol.2017.03.008

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@article{6db5506e79504280a015858ca74b5522,

title = "Exaggerated glucagon responses to hypoglycemia in women with polycystic ovary syndrome",

abstract = "Context Premenopausal women have blunted counter-regulatory hormone responses (CRR) to hypoglycemia compared to men. Postmenopausal women have CRR similar to men; the premenopausal pattern can be restored by estrogen. However, glucagon and pancreatic polypeptide (PP) responses remain lower in postmenopausal women than in men. Since hyperandrogenemia contributes to the metabolic phenotype of polycystic ovary syndrome (PCOS), we hypothesize that CRR to hypoglycemia especially of glucagon and PP is exaggerated in premenopausal women with PCOS compared to premenopausal control women. Study Subjects and Methods Ten obese women with PCOS and 9 control women of similar ethnicity, age and BMI underwent determination of CRR in response to hypoglycemia during 180-min 60 mU/m2/min insulin dose hypoglycemic clamp with isotopic assessment of endogenous glucose production (EGP). To assess CRR to hypoglycemia, glucagon, cortisol, growth hormone (GH), epinephrine, norepinephrine, PP, lactate, free fatty acid (FFA), β-hydroxybutyrate, and glycerol levels were sampled at 15-min intervals throughout the clamp. Main Findings Incremental glucagon levels were ~ 3-fold higher during hypoglycemia (P = 0.03) in PCOS. Postabsorptive, steady-state and incremental GH, cortisol, epinephrine, norepinephrine, PP, FFA, glycerol and β-hydroxybutyrate did not differ. At target glucose levels of ~ 52 mg/dL, insulin mediated glucose disposal (IMGD) was decreased by ~ 40% (P = 0.02) in PCOS, compared to control women, despite ~ 20% higher steady-state insulin levels (P = 0.03). Neither postabsorptive nor steady-state EGP differed. However, postabsorptive lactate levels were ~ 50% higher (P = 0.02). PCOS status (P = 0.04) and IMGD (P = 0.02) predicted the differential glucagon response to hypoglycemia in separate regression models, however, neither parameter remained an independent predictor in a combined model. Principal Conclusions Glucagon responses were increased in PCOS, whereas other CRR did not differ. Women with PCOS were insulin resistant under hypoglycemic conditions and higher postabsorptive lactate levels in PCOS were consistent with this finding. Insulin resistance may have contributed to exaggerated glucagon response to hypoglycemia in PCOS.",

keywords = "Counter-regulatory hormones, Hypoglycemia, Polycystic ovary syndrome",

author = "Susan Sam and Priyathama Vellanki and Yalamanchi, {Sudha K.} and Bergman, {Richard N.} and Andrea Dunaif",

note = "Funding Information: This research was supported by NIH grants R01 HD057223 (AD) and P50 HD044405 (AD). PV and SKY were supported in part by T32 DK007196. The clinical studies were supported in part by the Northwestern University Clinical and Translational Science Institute (NUCATS) UL1 RR025741. Some of the hormone analyses were supported in part by University of Virginia Center for Research in Reproduction Ligand Analysis and Assay Core U54 HD28934 and the Institute for Clinical and Translational Research Analytic Biomarker Research Core at Albert Einstein College of Medicine UT1 TR000086. Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",

year = "2017",

month = jun,

day = "1",

doi = "10.1016/j.metabol.2017.03.008",

language = "English (US)",

volume = "71",

pages = "125--131",

journal = "Metabolism: Clinical and Experimental",

issn = "0026-0495",

publisher = "W.B. Saunders",

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TY - JOUR

T1 - Exaggerated glucagon responses to hypoglycemia in women with polycystic ovary syndrome

AU - Sam, Susan

AU - Vellanki, Priyathama

AU - Yalamanchi, Sudha K.

AU - Bergman, Richard N.

AU - Dunaif, Andrea

N1 - Funding Information: This research was supported by NIH grants R01 HD057223 (AD) and P50 HD044405 (AD). PV and SKY were supported in part by T32 DK007196. The clinical studies were supported in part by the Northwestern University Clinical and Translational Science Institute (NUCATS) UL1 RR025741. Some of the hormone analyses were supported in part by University of Virginia Center for Research in Reproduction Ligand Analysis and Assay Core U54 HD28934 and the Institute for Clinical and Translational Research Analytic Biomarker Research Core at Albert Einstein College of Medicine UT1 TR000086. Publisher Copyright: © 2017 Elsevier Inc.

PY - 2017/6/1

Y1 - 2017/6/1

N2 - Context Premenopausal women have blunted counter-regulatory hormone responses (CRR) to hypoglycemia compared to men. Postmenopausal women have CRR similar to men; the premenopausal pattern can be restored by estrogen. However, glucagon and pancreatic polypeptide (PP) responses remain lower in postmenopausal women than in men. Since hyperandrogenemia contributes to the metabolic phenotype of polycystic ovary syndrome (PCOS), we hypothesize that CRR to hypoglycemia especially of glucagon and PP is exaggerated in premenopausal women with PCOS compared to premenopausal control women. Study Subjects and Methods Ten obese women with PCOS and 9 control women of similar ethnicity, age and BMI underwent determination of CRR in response to hypoglycemia during 180-min 60 mU/m2/min insulin dose hypoglycemic clamp with isotopic assessment of endogenous glucose production (EGP). To assess CRR to hypoglycemia, glucagon, cortisol, growth hormone (GH), epinephrine, norepinephrine, PP, lactate, free fatty acid (FFA), β-hydroxybutyrate, and glycerol levels were sampled at 15-min intervals throughout the clamp. Main Findings Incremental glucagon levels were ~ 3-fold higher during hypoglycemia (P = 0.03) in PCOS. Postabsorptive, steady-state and incremental GH, cortisol, epinephrine, norepinephrine, PP, FFA, glycerol and β-hydroxybutyrate did not differ. At target glucose levels of ~ 52 mg/dL, insulin mediated glucose disposal (IMGD) was decreased by ~ 40% (P = 0.02) in PCOS, compared to control women, despite ~ 20% higher steady-state insulin levels (P = 0.03). Neither postabsorptive nor steady-state EGP differed. However, postabsorptive lactate levels were ~ 50% higher (P = 0.02). PCOS status (P = 0.04) and IMGD (P = 0.02) predicted the differential glucagon response to hypoglycemia in separate regression models, however, neither parameter remained an independent predictor in a combined model. Principal Conclusions Glucagon responses were increased in PCOS, whereas other CRR did not differ. Women with PCOS were insulin resistant under hypoglycemic conditions and higher postabsorptive lactate levels in PCOS were consistent with this finding. Insulin resistance may have contributed to exaggerated glucagon response to hypoglycemia in PCOS.

AB - Context Premenopausal women have blunted counter-regulatory hormone responses (CRR) to hypoglycemia compared to men. Postmenopausal women have CRR similar to men; the premenopausal pattern can be restored by estrogen. However, glucagon and pancreatic polypeptide (PP) responses remain lower in postmenopausal women than in men. Since hyperandrogenemia contributes to the metabolic phenotype of polycystic ovary syndrome (PCOS), we hypothesize that CRR to hypoglycemia especially of glucagon and PP is exaggerated in premenopausal women with PCOS compared to premenopausal control women. Study Subjects and Methods Ten obese women with PCOS and 9 control women of similar ethnicity, age and BMI underwent determination of CRR in response to hypoglycemia during 180-min 60 mU/m2/min insulin dose hypoglycemic clamp with isotopic assessment of endogenous glucose production (EGP). To assess CRR to hypoglycemia, glucagon, cortisol, growth hormone (GH), epinephrine, norepinephrine, PP, lactate, free fatty acid (FFA), β-hydroxybutyrate, and glycerol levels were sampled at 15-min intervals throughout the clamp. Main Findings Incremental glucagon levels were ~ 3-fold higher during hypoglycemia (P = 0.03) in PCOS. Postabsorptive, steady-state and incremental GH, cortisol, epinephrine, norepinephrine, PP, FFA, glycerol and β-hydroxybutyrate did not differ. At target glucose levels of ~ 52 mg/dL, insulin mediated glucose disposal (IMGD) was decreased by ~ 40% (P = 0.02) in PCOS, compared to control women, despite ~ 20% higher steady-state insulin levels (P = 0.03). Neither postabsorptive nor steady-state EGP differed. However, postabsorptive lactate levels were ~ 50% higher (P = 0.02). PCOS status (P = 0.04) and IMGD (P = 0.02) predicted the differential glucagon response to hypoglycemia in separate regression models, however, neither parameter remained an independent predictor in a combined model. Principal Conclusions Glucagon responses were increased in PCOS, whereas other CRR did not differ. Women with PCOS were insulin resistant under hypoglycemic conditions and higher postabsorptive lactate levels in PCOS were consistent with this finding. Insulin resistance may have contributed to exaggerated glucagon response to hypoglycemia in PCOS.

KW - Counter-regulatory hormones

KW - Hypoglycemia

KW - Polycystic ovary syndrome

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JO - Metabolism: Clinical and Experimental

JF - Metabolism: Clinical and Experimental

ER -

Exaggerated glucagon responses to hypoglycemia in women with polycystic ovary syndrome

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