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=0.038) and IMGD (P=0.024) 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.

Metformin's Impact on Follistatin and Oxyntomodulin in PCOS, and Comorbidities: Secondary Analysis of a Double-Blind RCT

“…Glucagon response to hypoglycemic states in PCOS patients as compared to normal controls was evaluated by Sam et al through the performance of a hypoglycemic clamp. PCOS patients displayed an increase in glucagon levels 275% higher than controls [31]. The study by Hansen et al that showed that the glucagon/insulin relationship regulates the release of hepatic Follistatin and the ndings of increased glucagon levels in pre-diabetic patients who use metformin contribute to the understanding of the negative results of the present study [32].…”

Metanephrine and Normetanephrine Urine Excretion in Patients with PCOS

“…For instance, Garcia-Rudaz et al showed increased urinary normetanephrine but not plasma or urine epinephrine, norepinephrine, and metanephrine levels in adolescent PCOS patients compared to healthy peers [18]. In adult women with the syndrome, Mehde et al described increased plasma epinephrine and metanephrine levels in comparison to healthy individuals, however, these results were not supported by other studies [17,19,20].…”

Sitagliptin decreases visceral fat and blood glucoses in women with polycystic ovarian syndrome

“…(34) The glucagon response to hypoglycemia is also potentiated in obese women with PCOS as compared to matched controls. (35) We hypothesized that sitagliptin, with its ability to potentiate post-prandial GLP-1 secretion and suppress glucagon secretion, would mitigate these undesirable post-glucose changes. We observed enhanced GLP-1 secretion during sitagliptin, but no changes in glucagon levels.…”