Experimentally Induced Hyperinsulinemia Fails to Induce Polycystic Ovary Syndrome-like Traits in Female Rhesus Macaques
Abstract
:1. Introduction
2. Results
2.1. Metabolic Observations
Glucoregulatory Effects of Chronic Insulin Therapy
2.2. Metabolic Challenge Tests
Frequently Sampled Intravenous Glucose Tolerance Tests (FSIGTT) and Minimal Modeling
2.3. Body Weights and Blood Chemistry Panels
2.4. Menstrual Cycle
2.5. Ovarian Androgen Stimulation Test (at ~3–5 Months of Treatment)
2.6. Gonadotropin-Releasing Hormone (GnRH) Test of Pituitary Gonadotropin Release
3. Discussion
4. Materials and Methods
4.1. Animals
4.2. Experimental Design
4.3. Metabolic Observations
4.3.1. Body Weight, and Select Glucoregulatory, Lipid and Hepatic Parameters
4.3.2. Assessment of Serum Binding of Insulin after 6–7 Months of Exogenous Insulin Treatment
4.4. Metabolic Challenge Test
Frequently Sampled Intravenous Glucose Tolerance Test (FSIGTT) at 3–4 Months of Treatment
4.5. Reproductive Observations
Menstrual Cycle Assessment
4.6. Endocrine Challenge Tests
4.6.1. Ovarian Androgen Stimulation Test at 3–5 Months of Treatment
4.6.2. GnRH Test at 4–6 Months of Treatment
4.7. Assay Procedures
4.8. Statistical Analysis
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Hormone Treatment | Time (Months) Following Study Onset | ||||||
---|---|---|---|---|---|---|---|
Female Group | 0 | 1 | 2 | 3 | 4 | 5 | 6 |
Fasted insulin (pmol/L) | |||||||
Diluent group | |||||||
Control | 160 ± 12 | 333 ± 35 | 397 ± 30 | 374 ± 66 | 270 ± 25 | 215 ± 3 | 220 ± 4 |
PCOS-like | 375 ± 71 | 305 ± 40 | 371 ± 92 | 410 ± 78 | 337 ± 48 | 220 ± 2 | 216 ± 3 |
Insulin group a | |||||||
Control | 182 ± 49 | 338 ± 106 | 557 ± 98 | 622 ± 130 | 841 ± 195 | 880 ± 115 | 890 ± 106 |
PCOS-like | 267 ± 91 | 403 ± 105 | 442 ± 123 | 610 ± 102 | 793 ± 151 | 926 ± 52 | 996 ± 36 |
Fasted glucose (mmol/L) | |||||||
Diluent group | |||||||
Control | 3.1 ± 0.1 | 3.1 ± 0.1 | 3.0 ± 0.1 | 3.0 ± 0.1 | 3.0 ± 0.1 | 3.2 ± 0.1 | 3.2 ± 0.1 |
PCOS-like | 2.9 ± 0.1 | 3.2 ± 0.2 | 3.0 ± 0.2 | 3.1 ± 0.2 | 3.3 ± 0.2 | 3.4 ± 0.2 | 3.3 ± 0.2 |
Insulin group b | |||||||
Control | 2.9 ± 0.2 | 3.0 ± 0.1 | 2.8 ± 0. | 2.8 ± 0.2 | 3.2 ± 0.1 | 3.2 ± 0.1 | 3.3 ± 0.1 |
PCOS-like | 5.3 ± 1.5 | 5.1 ± 1.3 | 4.1 ± 0.8 | 4.6 ± 1.0 | 5.4 ± 1.3 | 5.1 ± 0.8 | 4.7 ± 0.9 |
Afternoon glucose (mmol/L) | |||||||
Diluent group | |||||||
Control | 3.2 ± 0.3 | 3.0 ± 0.1 | 3.0 ± 0.1 | 3.1 ± 0.1 | 3.1 ± 0.1 | 3.3 ± 0.1 | 3.4 ± 0.1 |
PCOS-like | 3.0 ± 0.1 | 3.3 ± 0.1 | 3.3 ± 0.2 | 3.3 ± 0.1 | 3.4 ± 0.2 | 3.4 ± 0.2 | 3.5 ± 0.2 |
Insulin group c | |||||||
Control | 3.2 ± 0.3 | 3.2 ± 0.3 | 3.1 ± 0.1 | 3.2 ± 0.1 | 3.3 ± 0.1 | 3.2 ± 0.1 | 3.4 ± 0.1 |
PCOS-like | 5.7 ± 1.3 | 6.3 ± 2.2 | 6.0 ± 2.1 | 6.2 ± 2.3 | 5.8 ± 1.9 | 5.4 ± 0.2 | 5.5 ± 1.9 |
Female Treatment Groups | Hours 0 h | Following 2 h | Daily 4 h | Injection 24 h |
---|---|---|---|---|
Control diluent (n = 4) | 373 ± 79 | 743 ± 240 | 961 ± 261 | 476 ± 110 |
Control insulin a (n = 4) | 972 ± 321 | 672 ± 44 | 3966 ± 1340 b | 964 ± 244 c |
PCOS-like diluent (n = 5) | 522 ± 193 | 925 ± 192 | 826 ± 214 | 517 ± 152 |
PCOS-like insulin a (n = 5) | 760 ± 90 | 2125 ± 830 | 1345 ± 387 b | 927 ± 325 c |
Parameters | Control Monkeys | PCOS-like Monkeys | ||
---|---|---|---|---|
Diluent | Insulin | Diluent | Insulin | |
Gb (mmol/L) | 3.2 ± 0.2 | 3.6 ± 0.6 | 3.5 ± 0.2 | 2.2 ± 0.6 |
Ib (pmol/L) | 294 ± 117 | 478 ± 139 a | 204 ± 117 | 557 ± 139 a |
Kg (%/min) | 9.8 ± 1.5 | 4.9 ± 0.9 | 5.0 ± 1.5 | 4.4 ± 0.9 |
Sg (×10−2/min) | 4.1 ± 1.1 | 5.4 ± 1.0 | 4.1 ± 1.1 | 4.8 ± 1.0 |
SI (×10−5/min/pmol/L) | 2.0 ± 1.8 | 1.6 ± 0.9 | 3.9 ± 1.8 | 2.2 ± 0.9 |
DI (×102/min) | 4.8 ± 2.3 | 3.0 ± 0.7 b | 4.8 ± 2.3 | 0.6 ± 0.7 b |
AIRg (pmol/L) | 251 ± 58 | 233 ± 48 c | 134 ± 58 | 37 ± 48 c |
AIRtol (pmol/L) | 276 ± 72 | 520 ± 117 | 242 ± 72 | 143 ± 58 |
AUCINS (0–19) (pmol/L × 19 min × 103) | 38 ± 91 | 60 ± 11 | 27 ± 91 d | 18 ± 11 d |
AUCINS (22–180) (pmol/L × 158 min × 103) | 84 ± 38 | 183 ± 58 | 63 ± 38 | 97 ± 58 |
AUCINS (0–180) (pmol/L × 180 min × 103) | 123 ± 44 | 244 ± 69 e | 90 ± 44 | 115 ± 69 e |
AUCGLU (0–19) (mmol/L × 19 min) | 204 ± 11 | 237 ± 20 | 206 ± 11 | 211 ± 20 |
AUCGLU (22–180) (mmol/L × 158 min) | 503 ± 48 | 585 ± 100 | 547 ± 48 | 585 ± 100 |
AUCGLU (0–180) (mmol/L × 180 min) | 716 ± 50 | 819 ± 115 | 752 ± 50 | 796 ± 115 |
Basal C-peptide (nmol/L) × 10−1 | 1.9 ± 0.6 | 1.1 ± 1.4 | 1.6 ± 0.6 | 5.3 ± 1.4 |
AUCc-pep (0–180) (nmol/L × 180 min) | 33.3 ± 11.2 | 31.7 ± 2.7 | 29.3 ± 7.3 | 98.3 ± 29.0 |
Diluent Baseline | Diluent 6–7 mo | Insulin Baseline | Insulin 6–7 mo | |
---|---|---|---|---|
Body weight Control (kg) | 8.4 ± 0.6 | 8.8 ± 0.9 | 8.5 ± 0.3 | 9.0 ± 0.6 |
Body weight PCOS-like (kg) | 8.8 ± 0.3 | 8.4 ± 0.4 | 9.1 ± 0.6 | 9.5 ± 0.5 |
Cholesterol Control (mg/mL) | 150 ± 13 | 137 ± 4 | 172 ± 10 | 151 ± 7 |
Cholesterol PCOS-like (mg/mL) | 157 ± 14 | 162 ± 14 | 116 | 140 ± 9 |
Triglyceride Control (mg/mL) | 158 ± 55 | 55 ± 19 | 130 ± 36 | 235 ± 32 |
Triglyceride PCOS-like (mg/mL) | 191 ± 28 | 88 ± 42 | 363 | 185 ± 95 |
AST Control (mU/mL) | 31 ± 5 | 36 ± 10 | 42 ± 7 | 32 ± 14 |
AST PCOS-like (mU/mL) | 25 | 22 | 29 | 42 ± 2 |
ALT Control (mU/mL) | 33 ± 6 | 32 ± 4 | 51 ± 21 | 33 ± 7 |
ALT PCOS-like (mU/mL) | 43 | 27 | 9 | 20 ± 6 |
Hormone Ratio Treatment | Time (Hours) Following 200IU Intramuscular Injection of rhCG | |||
---|---|---|---|---|
Female Group | 0 | 24 | 48 | 72 |
Androstenedione:Dehydroepiandrosterone | ||||
Diluent | ||||
Control | 6.8 ± 1.6 | 6.5 ± 2.9 | 7.7 ± 2.1 | 17.4 ± 11.0 |
PCOS-like | 2.7 ± 0.2 | 6.3 ± 1.4 | 4.5 ± 0.9 | 1.8 ± 0.5 |
Insulin | ||||
Control | 2.4 ± 0.8 | 3.5 ± 1.3 | 2.8 ± 0.4 | 2.3 ± 0.5 |
PCOS-like | 7.2 ± 2.1 | 6.6 ± 2.6 | 7.8 ± 2.2 | 5.6 ± 2.4 |
Testosterone:Androstenedione × 10−2 | ||||
Diluent | ||||
Control | 1.6 ± 0.2 | 1.9 ± 0.5 | 2.3 ± 0.6 | 2.1 ± 0.3 |
PCOS-like | 1.5 ± 0.2 | 1.2 ± 0.1 | 1.6 ± 0.4 | 1.4 ± 0.2 |
Insulin | ||||
Control | 1.7 ± 0.5 | 1.1 ± 0.2 | 1.1 ± 0.2 | 1.1 ± 0.1 |
PCOS-like | 1.0 ± 0.4 | 0.7 ± 0.4 | 0.9 ± 0.5 | 0.8 ± 0.4 |
Testosterone:Estradiol | ||||
Diluent | ||||
Control | 15.4 ± 2.9 | 11.3 ± 3.2 | 27.8 ± 12.5 | 19.8 ± 2.7 |
PCOS-like | 12.4 ± 6.5 | 7.3 ± 1.5 | 14.3 ± 1.3 | 12.3 ± 1.1 |
Insulin | ||||
Control | 18.7 ± 5.9 | 8.3 ± 2.6 | 14.5 ± 5.5 | 11.9 ± 3.5 |
PCOS-like | 22.3 ± 6.8 | 15.5 ± 8.3 | 19.1 ± 6.6 | 25.3 ± 10.9 |
Estradiol:Progesterone × 10−2 | ||||
Diluent | ||||
Control | 23.5 ± 11.5 | 2.7 ± 0.9 | 10.0 ± 8.3 | 8.0 ± 4.4 |
PCOS-like | 38.9 ± 17.3 | 7.9 ± 2.5 | 4.5 ± 1.0 | 4.0 ± 0.3 |
Insulin | ||||
Control | 11.3 ± 6.4 | 4.3 ± 1.4 | 3.0 ± 0.9 | 5.9 ± 1.5 |
PCOS-like | 4.3 ± 1.3 | 4.4 ± 1.4 | 3.6 ± 1.0 | 3.3 ± 1.6 |
Hormone Treatment | Time (Minutes) Following GnRH Injection | |||||||
---|---|---|---|---|---|---|---|---|
Female Group | 0 | 2 | 5 | 10 | 20 | 30 | 40 | 60 |
LH (ng/mL) | ||||||||
Diluent | ||||||||
Control | 1.2 ± 0.4 a | 1.2 ± 0.3 | 1.3 ± 0.4 | 1.4 ± 0.4 c | 1.3 ± 0.4 | 1.4 ± 0.4 | 1.3 ± 0.4 | 1.3 ± 0.4 |
PCOS-like | 1.3 ± 0.4 a | 2.3 ± 0.8 | 2.7 ± 1.0 | 2.7 ± 1.0 c | 2.8 ± 0.9 | 2.6 ± 0.8 | 2.5 ± 0.8 | 2.4 ± 1.0 |
Insulin | ||||||||
Control | 1.1 ± 0.3 a | 1.1 ± 0.3 | 1.4 ± 0.4 | 1.5 ± 0.3 c | 1.6 ± 0.4 | 1.6 ± 0.4 | 1.7 ± 0.5 | 1.5 ± 0.4 |
PCOS-like | 1.0 ± 0.2 a | 1.3 ± 0.1 | 1.6 ± 0.1 | 1.6 ± 0.1 c | 1.6 ± 0.1 | 1.7 ± 0.1 | 1.7 ± 0.1 | 1.6 ± 0.1 |
FSH (ng/mL) | ||||||||
Diluent | ||||||||
Control | 1.8 ± 0.3 b | 1.6 ± 0.2 | 1.9 ± 0.4 | 1.7 ± 0.4 c | 1.8 ± 0.4 | 1.7 ± 0.3 | 1.8 ± 0.5 | 1.8 ± 0.4 |
PCOS-like | 3.9 ± 1.3 b | 4.5 ± 1.5 | 4.5 ± 1.5 | 4.8 ± 1.6 c | 5.4 ± 1.6 | 5.2 ± 1.4 | 5.3 ± 1.5 | 5.3 ± 1.5 |
Insulin | ||||||||
Control | 2.8 ± 1.6 b | 2.8 ± 1.5 | 2.7 ± 1.5 | 2.8 ± 1.4 c | 2.7 ± 1.0 | 2.7 ± 1.1 | 2.9 ± 1.5 | 2.9 ± 1.4 |
PCOS-like | 3.0 ± 1.0 b | 2.9 ± 0.8 | 3.3 ± 1.0 | 3.2 ± 0.8 c | 3.3 ± 0.8 | 3.2 ± 0.6 | 3.5 ± 0.9 | 3.5 ± 0.9 |
LH:FSH ratio | ||||||||
Diluent | ||||||||
Control | 0.8 ± 0.2 | 0.8 ± 0.2 | 0.7 ± 0.2 | 0.8 ± 0.2 | 0.8 ± 0.2 | 0.8 ± 0.2 | 0.8 ± 0.2 | 0.7 ± 0.2 |
PCOS-like | 0.4 ± 0.1 | 0.5 ± 0.1 | 0.6 ± 0.1 | 0.6 ± 0.1 | 0.5 ± 0.1 | 0.5 ± 0.1 | 0.5 ± 0.1 | 0.4 ± 0.1 |
Insulin | ||||||||
Control | 0.5 ± 0.1 | 0.5 ± 0.1 | 0.7 ± 0.2 | 0.7 ± 0.1 | 0.7 ± 0.1 | 0.7 ± 0.1 | 0.8 ± 0.1 | 0.6 ± 0.1 |
PCOS-like | 0.6 ± 0.2 | 0.7 ± 0.3 | 0.8 ± 0.3 | 0.7 ± 0.3 | 0.7 ± 0.2 | 0.7 ± 0.2 | 0.7 ± 0.2 | 0.6 ± 0.2 |
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Zhou, R.; Bruns, C.M.; Bird, I.M.; Kemnitz, J.W.; Dumesic, D.A.; Abbott, D.H. Experimentally Induced Hyperinsulinemia Fails to Induce Polycystic Ovary Syndrome-like Traits in Female Rhesus Macaques. Int. J. Mol. Sci. 2022, 23, 2635. https://doi.org/10.3390/ijms23052635
Zhou R, Bruns CM, Bird IM, Kemnitz JW, Dumesic DA, Abbott DH. Experimentally Induced Hyperinsulinemia Fails to Induce Polycystic Ovary Syndrome-like Traits in Female Rhesus Macaques. International Journal of Molecular Sciences. 2022; 23(5):2635. https://doi.org/10.3390/ijms23052635
Chicago/Turabian StyleZhou, Rao, Cristin M. Bruns, Ian M. Bird, Joseph W. Kemnitz, Daniel A. Dumesic, and David H. Abbott. 2022. "Experimentally Induced Hyperinsulinemia Fails to Induce Polycystic Ovary Syndrome-like Traits in Female Rhesus Macaques" International Journal of Molecular Sciences 23, no. 5: 2635. https://doi.org/10.3390/ijms23052635
APA StyleZhou, R., Bruns, C. M., Bird, I. M., Kemnitz, J. W., Dumesic, D. A., & Abbott, D. H. (2022). Experimentally Induced Hyperinsulinemia Fails to Induce Polycystic Ovary Syndrome-like Traits in Female Rhesus Macaques. International Journal of Molecular Sciences, 23(5), 2635. https://doi.org/10.3390/ijms23052635