Abstract
Insulin resistance is a risk factor for coronary heart disease. The protection of young women from coronary events is sharply reduced with menopause. To assess the impact of menopause on glucose tolerance, insulin resistance, body weight gain, heart size, and cardiac energy metabolism, we studied 28-week-old female SHR and Wistar-Kyoto (WKY) rats, who were either ovariectomized (SHROVX and WKYOVX ) or sham-operated (SHRSHAM and WKYSHAM ). Animals underwent blood-pressure measurement and an oral glucose tolerance test (OGTT). Hearts were weighed and assayed for metabolic enzyme activities. Female SHR were 33 % lighter and hypertensive (+ 36 mmHg), with 33 % larger hearts (when corrected for body weight differences) compared to WKY. Although ovariectomized animals of both strains were heavier overall than their sham-operated counterparts, when heart weights were corrected for body weight, both OVX strains had lighter hearts than both SHAM strains. Glucose and insulin responses during OGTT were similar between the four groups; however, free fatty acid (FFA) responses were approximately 50 % greater in SHR than WKY, although less in SHROVX than SHRSHAM . WKYOVX demonstrated 8 % lower ventricular hexokinase activity than WKYSHAM , which may reflect reduced cardiac glucose utilization. We also noted 16 % higher citrate synthase activity in WKY hearts. In conclusion, the insulin resistance characteristic of younger SHR is blunted in middle-aged female rats, although FFA responses remain elevated. Ovariectomy did not alter in vivo glucose tolerance in this group; however, sex hormones may be important in maintaining normal heart size and the potential for cardiac glucose metabolism.
Key words
Insulin Resistance - Hypertension - Cardiac Hypertrophy - Menopause
References
1
Haffner S M, Agostino R D, Saad M F, O’Leary D H, Savage P J, Rewers M, Selby J, Bergman R N, Mykkanen L.
Carotid artery atherosclerosis in type-2 diabetic and nondiabetic subjects with and without symptomatic coronary artery disease (The Insulin Resistance Atherosclerosis Study).
Am J Cardiol.
2000;
85
1395-1400
2
Wenger N K.
Coronary heart disease in women.
J Med Assoc Georgia.
1992;
81
679-681
3
Gordon T, Kannel W B, Hjortland M C, McNamara P M.
Menopause and coronary heart disease.
Ann Intern Med.
1978;
89
157-161
4
Solymoss B C, Marcil M, Chaour M, Gilfix B M, Poitras A-M, Campeau L.
Fasting hyperinsulinism, insulin resistance syndrome, and coronary artery disease in men and women.
Am J Cardiol.
1995;
76
1152-1156
5
Portaluppi F, Pansini F, Manfredini R, Mollica G.
Relative influence of menopausal status, age, and body mass index on blood pressure.
Hypertension.
1997;
29
976-979
6
Swislocki A, Tsuzuki A.
Insulin resistance and hypertension: glucose intolerance, hyperinsulinemia, and elevated free fatty acids in the lean spontaneously hypertensive rat.
Am J Med Sci.
1993;
306
282-286
7
Gaboury C L, Karanja N, Holcomb S R, Torok J, McCarron D A.
Patterns of insulin secretion and responsiveness in Wistar-Kyoto and spontaneously hypertensive rats.
Am J Hypertens.
1991;
8
661-666
8
Reaven G M, Chang H.
Relationship between blood pressure, plasma insulin and triglyceride concentration, and insulin action in spontaneous hypertensive and Wistar-Kyoto rats.
Am J Hypertens.
1991;
4
34-38
9
Hulman S, Falkner B, Freyvogel N.
Insulin resistance in the conscious spontaneously hypertensive rat: euglycemic hyperinsulinemic clamp study.
Metabolism.
1993;
42
14-18
10
Picard F, Deshaies Y, Lalonde J, Samson p, Labrie C, Belanger A, Labrie F, Richard D.
Effects of estrogen antagonist EM-652.HCl on energy balance and lipid metabolism in ovariectomized rats.
Int J Obest Relat Metab Disord.
2000;
24
830-840
11
Kumagai S, Holmang A, Bjorntorp P.
The effects of oestrogen and progesterone on insulin sensitivity in female rats.
Acta Physiol Scand.
1993;
149
91-97
12
Nolan C, Proietto J.
The effects of oophorectomy and female sex steroids on glucose kinetics in the rat.
Diabetes Res Clin Pract.
1995;
30
181-188
13
Hansen P A, McCarthy T J, Pasia E N, Spina R J, Gulve E A.
Effects of ovariectomy and exercise training on muscle GLUT-4 content and glucose metabolism in rats.
J Appl Physiol.
1996;
80
1605-1611
14
Kava R A, West D B, Lukasik V A, Wypijewski C, Wojnar Z, Johnson P R, Greenwood M R.
The effects of gonadectomy on glucose tolerance of genetically obese (fa/fa) rats: influence of sex and genetic background.
Int J Obest Relat Metab Disord.
1992;
16
103-111
15
Iwase M, Wakisaka M, Yoshinari M, Sato Y, Yoshizumi H, Nunoi K, Fujishima M.
Effect of gonadectomy and the development of diabetes mellitus, hypertension, and albuminuria in the rat model.
Metabolism.
1996;
45
155-161
16
Chen Y F, Meng Q C.
Sexual dimorphism of blood pressure in spontaneously hypertensive rats is androgen dependent.
Life Sci.
1991;
48
85-96
17
Reckelhoff J F, Granger J P.
Role of androgens in mediating hypertension and renal injury.
Clin Exp Pharmacol Physiol.
1999;
26
127-131
18
Schaible T F, Malhotra A, Ciambrone G, Scheuer J.
The effects of gonadectomy on left ventricular function and cardiac contractile proteins in male and female rats.
Circ Res.
1984;
54
38-49
19
Malhotra A, Buttrick p, Scheuer J.
Effects of sex hormones on development of physiological and pathological hypertrophy in male and female rats.
Am J Physiol.
1990;
259
H866-H871
20
Sharkey L C, Holycross B J, Park S, Shiry L J, Hoepf T M.
McCune SA, Radin MJ. Effect of ovariectomy and estrogen replacement on cardiovascular disease in heart failure-prone SHHF/Mcc-facp rats.
J Mol Cell Cardiol.
1999;
31
1527-1537
21
Liang H, Ma Y, Pun S, Stimpel M, Jee W S.
Aging- and ovariectomy-related skeletal changes in spontaneously hypertensive rats.
Anat Rec.
1997;
249
173-180
22
Pyorala M, Miettinen H, Halonen p, Laakso M, Pyorala K.
Insulin resistance syndrome predicts the risk of coronary heart disease and stroke in healthy middle-aged men: The 22-year follow-up results of the Helsinki Policemen Study.
Arterioscl Thromb Vasc Biol.
2000;
20
538-544
23
Hanson R l, Pratley R E, Bogardus C, Narayan K M, Roumain J M, Imperatore G, Fagot-Campagna A, Pettitt D J, Bennet P H, Knowler W C.
Evaluation of simple indices of insulin sensitivity and insulin secretion for use in epidemiologic studies.
Am J Epidemiol.
2000;
151
190-198
24
Legro R S, Finegood D, Dunaif A.
A fasting glucose to insulin ratio is a useful measure of insulin sensitivity in women with polycystic ovary syndrome.
J Clin Endocrinol Metab.
1998;
83
2694-2698
25
Crabtree B, Newsholme E A.
The activities of phosphorylase, hexokinase, phosphofructokinase, lactate dehydrogenase and the glycerol 3-phosphate dehydrogenases in muscles from vertebrates and invertebrates.
Biochem J.
1972;
126
49-58
26
Rodnick K J, Sidell B D.
Cold acclimation increases carnitine palmitoyltransferase I activity in oxidative muscle of striped bass.
Am J Physiol.
1994;
266
R405-R412
27
Hansen C A, Sidell B D.
Atlantic hagfish cardiac muscle: metabolic basis of tolerance to anoxia.
Am J Physiol.
1983;
244
R356-R362
28
Kinney LaPier T L, Swislocki A LM, Clark R J, Rodnick K J.
Voluntary running improves glucose tolerance and insulin resistance in female spontaneously hypertensive rats.
Am J Hypertens.
2001;
14
708-725
29
Iwase M, Kodama T, Himeno H, Yoshinari M, Tsutsu N, Sadoshima S, Fujishima M.
Effect of aging on glucose tolerance in spontaneously hypertensive rats.
Clin Exp Hypertens.
1994;
16
67-76
30
Walsh B A, Busch B L, Mullick A E, Reiser K M, Rutledge J C.
17β-estradiol reduces glycoxidative damage in the artery wall.
Arterioscler Thromb Vasc Biol.
1999;
19
840-846
31
Kava R A, West D B, Lukasik V A, Wypijewski C, Wojnar Z, Johnson P R, Greenwood M R.
The effects of gonadectomy on glucose tolerance of genetically obese (fa/fa) rats: influence of sex and genetic background.
Int J Obest Relat Metab Disord.
1992;
16
103-111
32
McElroy J F, Wade G N.
Short- and long-term effects of ovariectomy on food intake, body weight, carcass composition, and brown adipose tissue in rats.
Physiol Behav.
1987;
39
361-365
33
Delorme J, Benassayag C, Christeff N, Vallette G, Savu L, Nunez E.
Age-dependent responses of the serum non-esterified fatty acids to adrenalectomy and ovariectomy in developing rats.
Biochim Biophys Acta.
1984;
17
6-10
34
Caprio S, Boulware S, Diamond M, Sherwin R S, Carpenter T O, Rubin K, Amiel S, Press M, Tamborlane W V.
Insulin resistance: An early metabolic effect of Turner’s syndrome.
J Clin Endocrinol Metab.
1991;
72
832-836
35
Gravholt C H, Naeraa R W, Nyholm B, Gerdes L U, Christiansen E, Schmitz O, Christiansen J S.
Glucose metabolism, lipid metabolism, and cardiovascular risk factors in adult Turner’s syndrome. The impact of sex hormone replacement.
Diabetes Care.
1998;
21
1062-1070
36
Pasquali R, Gambineri A, Anconetani B, Vicennati V, Colitta D, Caramelli E, Casimirri F, Morselli-Labate A M.
The natural history of the metabolic syndrome in young women with the polycystic ovary syndrome and the effect of long-term oestrogen-progestagen treatment.
Clin Endocrinol.
1999;
50
517-527
37
Davidge S T, Zhang Y, Stewart K G.
A comparison of ovariectomy models for estrogen studies.
Am J Physiol.
2001;
280
R904-R907
38
Niggeschulze A, Kast A.
Maternal age, reproduction and chromosomal aberrations in Wistar derived rats.
Lab Anim.
1994;
28
55-62
39
Mattheij J A, Swarts J J.
Quantification and classification of pregnancy wastage in 5-day cyclic young through middle-aged rats.
Lab Anim.
1991;
25
30-34
40
Matt D W, Lee J, Sarver P L, Judd H L, Lu J K.
Chronological changes in fertility, fecundity and steroid hormone secretion during consecutive pregnancies in aging rats.
Biol Reprod.
1986;
34
478-487
41
Hashimoto R, Kimura F.
Puberty and ovulatory release of gonadotropins in spontaneously hypertensive rats.
Endocrinol Jpn.
1989;
36
675-680
42
Brown-Grant K, Exley D, Naftolin F.
Peripheral plasma oestradiol and luteinizing hormone concentrations during the oestrous cycle of the rat.
J Endocrinol.
1970;
48
295-296
43
Lorenz R P, Picchio L P, Weisz J, Lloyd T.
The relationship between reproductive performance and blood pressure in the spontaneously hypertensive rat.
Am J Obstet Gynecol.
1984;
150
519-523
44
Pedersen S B, Bruun J M, Kristensen K, Richelsen B.
Regulation of UCP1, UCP2, and UCP3 mRNA expression in brown adipose tissue, white adipose tissue, and skeletal muscle in rats by estrogen.
Biochem Biophys Res Commun.
2001;
288
191-197
45
Toth M J, Poehlman E T, Matthews D E, Tchernof A, MacCoss M J.
Effects of estradiol and progesterone on body composition, protein synthesis, and lipoprotein lipase in rats.
Am J Physiol Endocrinol Metab.
2001;
280
E496-E501
46
Swislocki A LM, Kinney LaPier T L, Khuu D T, Fann K Y, Tait M, Rodnick K J.
Metabolic, hemodynamic, and cardiac effects of captopril in young, spontaneously hypertensive rats.
Am J Hypertens.
1999;
12
581-589
47
Scheuer J, Malhotra A, Schaible T F, Capasso J.
Effects of gonadectomy and hormonal replacement or rat hearts.
Circ Res.
1987;
61
12-19
48
Lopaschuk G D, Belke D D, Gamble J, Itoi T, Schonekess B O.
Regulation of fatty acid oxidation in the mammalian heart in health and disease.
Biochim Biophys Acta.
1994;
1213
263-276
49
Christe M E, Rodgers R L.
Altered glucose and fatty acid oxidation in hearts of the spontaneously hypertensive rat.
J Mol Cell Cardiol.
1994;
26
1371-1375
50
Paternostro G, Clarke K, Heath J, Seymour A M, Radda G K.
Decreased GLUT-4 mRNA content and insulin-sensitive deoxyglucose uptake show insulin resistance in the hypertensive rat heart.
Cardiovasc Res.
1995;
30
205-211
A. Swislocki, M.D., F.A.C.P.
Medical Service (612/111) · VA Northern California Health Care System ·
150 Muir Road · Martinez, CA 94553 · USA ·
Phone: + 1 (925) 372-20 70 ·
Fax: + 1 (925) 372-21 85
Email: arthur.swislocki@med.va.gov