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Insulin resistance and hypertension
C87
Motectdar and Celiular Endocrinology 74 (1990) C87-C89 Elsevier Scientific
MOLCEL
Publishers
Ireland.
Ltd.
02428
At the Cutting
Edge
Insulin resistance and hypertension James R. Sowers Wayne Stare University School of Medicine, Detroit, MI, U.S.A.
Key words: Insulin;
Calcium;
Hypertension
A common mechanism which may be involved in the development of hypertension in both type I and type II diabetes mellitus is a deficiency of insulin at the cellular level. Observations from a number of laboratories suggest that impaired cellular response to insulin rather than hyperinsulinemia predisposes to increased vascular smooth muscle tone (the hallmark of hypertension in the diabetic state). This review presents some of the data which suggest that there is a relationship between impaired cellular action of insulin, altered cellular calcium metabolism and the development of hypertension.
An important relationship is likely to exist between alterations in intracellular calcium ([Ca*+]i) metabolism, insulin resistance and hypertension [l-3]. There are various data suggesting that ‘optimal’ levels of [Ca2+li are necessary for maximal cellular action of insulin [2,4,5]. Investigations in which [Ca2+li is altered by varying extracellular CaZC and employing the Ca2+ ionophore ionomycin have estab~shed an optimal range of [Ca2+li of 40-370 nM for insulin-mediated glucose transport [4,5]. These results suggest that although increases in [Ca2+ji appear to be involved in transduction of the insulin signal, increasing [Ca2+li beyond an optimal range results in decreased ability to transduce the signal. Thus, decreased insulin action results from inability of insulin to modulate [Ca2+li appropriately in cells
Address for correspondence: James R. Sowers, M.D., Professor of Medicine and Physiology, Director, Endocrinology and Hypertension, Wayne State University School of Medicine, Detroit, MI, U.S.A.
0303-7207/90/$03.50
0 1990 Elsevier Scientific
Publishers
Ireland,
exhibiting abnormally high [Ca*+]i levels. Indeed, insulin and glucose infusions (euglycemic clamp studies) in normal individuals result in elevated [Ca2’]i in isolated adipocytes and loss of cellular responsiveness to insulin or glyburide, while cells obtained from obese individuals exhibit increased [Ca2+li and lack of responsiveness to either insulin or glyburide in vitro [5]. Hence, elevated [Ca2+ji and the accomp~ying insulin resistance, rather than h~e~nsuhne~a per se, may underlie the frequently observed association between obesity, type II diabetes mellitus and hypertension [l-6]. That too little insulin action at the level of vascular smooth muscle cells (VSMC) could result in elevated VSMC [Ca2+]i is indicated by several observations. Insulin blocks Ca2+ currents, shortens Ca’+-driven action potentials and results in cell membrane hype~ola~ation [7]. Studies recently performed in our laboratory show that insulin attenuates the contractile response of rat aortic vascular strips to vasoconstrictor agonists. Insulin has been shown to stimulate plasma memLtd.
C88 Insulin
Norepinephrine Angiotensin Il Serotonin
Fig. 1. Role of insulin resistance in altered cation pump activity smooth muscle contraction in the diabetic hypertensive
brane Ca2+-ATPase activity in several different tissues [2]. Insulin may increase Ca’+-ATPase activity by increasing membrane calmodulin content, by increasing phosphorylation of calmodulin, or by increasing its affinity for Cazf [2,8,9]. Finally, it is possible that insulin can mediate its effects via Ca’+-ATPase mRNA expression in various tissues [lo]. Since the Ca*+-ATPase linked Ca2+ extrusion pump appears to be responsible for the fine tuning (maintenance at an optimal level) of [Ca2+li [2], insulin resistance could lead to increases in [Ca’+], which, in turn, could then result in enhanced VSMC responses to various agonists (Fig. 1). The genetically-obese insulin resistant Zucker (‘fatty’) rat has been studied by our group to examine relationships between insulin resistance, cellular abnormalities of Ca2+ metabolism and blood pressure [ll-131. Recently the Zucker rat has been shown to have elevated blood pressure [ 11-14). We have shown that the hypertension in this obese rat strain, like that in type II diabetic individuals, is characterized by enhanced vascular responses to vasoactive agonists as well as abnormalities of cellular Ca2+ metabolism [ll131. These abnormalities of cell Ca*+ metabolism include diminished cell membrane Ca’+-ATPase
resistance
,
d
I
f Response
and accumulation of cytoplasmic free calcium leading to enhanced state. ATPase = adenosine triphosphatase: Ca = calcium.
activity, decreased vascular smooth muscle Ca”+ efflux and increased [Ca2+], 121. It has also been shown that the regulatory effect of insulin on cell membrane Ca*+-ATPase activity is markedly diminished in an insulin-resistant rat model [2], and decreased activity or erythrocyte membrane Ca2+ATPase has also been observed by our group in insulin-resistant hypertensive individuals [15]. This decrease was associated with an increase in erythrocyte Ca2+ concentration, suggesting that decreased membrane Ca*+ efflux was partially responsible for the elevated [Ca2+li. Shaefer and colleagues have also noted decreased erythrocyte Ca*+-ATPase activity in erythrocytes from type I diabetics compared with healthy controls [16]. Our group has demonstrated an impairment in vascular smooth muscle Ca2+ efflux in association with increased vascular reactivity in insulinopenic (streptozotocin-treated) rats, suggesting that it is lack of cell insulin action in both insulinopenic and insulin resistant states that is responsible for impaired Ca2+ efflux and increased resistance. Thus, an insulin-resistant state as exhibited in the Zucker obese rat may be associated with (1) increased Ca2+ influx through voltage-dependent sarcolemmal Ca* + channels, and (2) decreased
C89
production or activation of the VSMC Ca2+ATPase pump. The resulting sustained rise is characteristic of hypertension associated with NIDDM. Accordingly, it is proposed that insulin resistance is associated with impaired VSMC membrane Ca2+ transport leading to a more sustained rise in VSMC (Ca’+)i which, in turn, is associated with enhanced vascular smooth muscle contraction (Fig. 1). References [l] Sowers, J.R., Levy, J. and Zemel, M.B. (1988) Med. Clin. N. Am. 72(6), 139991414. [2] Levy, J., Zemel, M.B. and Sowers, J.R. (1989) Am. J. Med. 87 (Suppt. 6A), 7S-16s. [3] Sowers, J.R., Zemd, P.C., Bedford-Johnson, B. and Zemel, B. (submitted) J. Clin. Invest. [4] Draznin, B., Sussman, K.E., Eckel, R.H. et al. (1988) J. Clin. Invest. 28, 1848-1852. [5] Draznin, B., Sussman, K., Koa, M. et al. (1987) J. Biol. Chem. 262, 1485-1488.
(61 Levy, J., Sowers, J.R. and Zemel, M.B. (1990) Horm. Metab. Res. 22, 136-140. [7] Zierler, K. and Fong-Sen, W.U. (1988) Trans. Assoc. Am. Phys. 101, 320-325. [S] Graves, C.B., Gale, R.D., Laurino, J.P. et al. (1986) J. Biol. Chem. 261. 10429-10438. t91 Wong, E.C., Sacks, D.B., Laurino, J.P. et al. (1988) Endocrinology 123. 1830-1836. IW Sowers, J.R. (in press) Am. J. Kidney Dis. [111 Zemel, M.B., Sowers, J.R., Shehin, S. et al. (1990) Metabolism 39(7), 1-8. WI Shehin, S.E., Sowers, J.R. and Zemel, M.B. (1989) J. Vast. Med. Biol. 1, 278-282. u31 Zemel, M.B., Reddy, S., Shehin, S.E., Lockette, W. and Sowers, J.R. (1990) J. Vase. Med. Biol. 2, 81-85. H.A. (1989) (141 Kurtz, T.W., Morris, R.C. and Pershadsingh, Hypertension 13, 896-901. WI Zemel, M.B., Bedford, B.A., Zemel, PC, Marwah, 0. and Sowers, J.R. (1988) J. Hypertens. 6. 5228-5230. P61 Shaefer, W., Prieben, J., Mannhold, R. et al. (1987) Klin. Wochenschr. 65, 17-21. P71 Reddy, S., Shehin, S., Sowers, J.R. et al. (1990) J. Vast. Med. Biol. 2, 47-51.
Motectdar and Celiular Endocrinology 74 (1990) C87-C89 Elsevier Scientific
MOLCEL
Publishers
Ireland.
Ltd.
02428
At the Cutting
Edge
Insulin resistance and hypertension James R. Sowers Wayne Stare University School of Medicine, Detroit, MI, U.S.A.
Key words: Insulin;
Calcium;
Hypertension
A common mechanism which may be involved in the development of hypertension in both type I and type II diabetes mellitus is a deficiency of insulin at the cellular level. Observations from a number of laboratories suggest that impaired cellular response to insulin rather than hyperinsulinemia predisposes to increased vascular smooth muscle tone (the hallmark of hypertension in the diabetic state). This review presents some of the data which suggest that there is a relationship between impaired cellular action of insulin, altered cellular calcium metabolism and the development of hypertension.
An important relationship is likely to exist between alterations in intracellular calcium ([Ca*+]i) metabolism, insulin resistance and hypertension [l-3]. There are various data suggesting that ‘optimal’ levels of [Ca2+li are necessary for maximal cellular action of insulin [2,4,5]. Investigations in which [Ca2+li is altered by varying extracellular CaZC and employing the Ca2+ ionophore ionomycin have estab~shed an optimal range of [Ca2+li of 40-370 nM for insulin-mediated glucose transport [4,5]. These results suggest that although increases in [Ca2+ji appear to be involved in transduction of the insulin signal, increasing [Ca2+li beyond an optimal range results in decreased ability to transduce the signal. Thus, decreased insulin action results from inability of insulin to modulate [Ca2+li appropriately in cells
Address for correspondence: James R. Sowers, M.D., Professor of Medicine and Physiology, Director, Endocrinology and Hypertension, Wayne State University School of Medicine, Detroit, MI, U.S.A.
0303-7207/90/$03.50
0 1990 Elsevier Scientific
Publishers
Ireland,
exhibiting abnormally high [Ca*+]i levels. Indeed, insulin and glucose infusions (euglycemic clamp studies) in normal individuals result in elevated [Ca2’]i in isolated adipocytes and loss of cellular responsiveness to insulin or glyburide, while cells obtained from obese individuals exhibit increased [Ca2+li and lack of responsiveness to either insulin or glyburide in vitro [5]. Hence, elevated [Ca2+ji and the accomp~ying insulin resistance, rather than h~e~nsuhne~a per se, may underlie the frequently observed association between obesity, type II diabetes mellitus and hypertension [l-6]. That too little insulin action at the level of vascular smooth muscle cells (VSMC) could result in elevated VSMC [Ca2+]i is indicated by several observations. Insulin blocks Ca2+ currents, shortens Ca’+-driven action potentials and results in cell membrane hype~ola~ation [7]. Studies recently performed in our laboratory show that insulin attenuates the contractile response of rat aortic vascular strips to vasoconstrictor agonists. Insulin has been shown to stimulate plasma memLtd.
C88 Insulin
Norepinephrine Angiotensin Il Serotonin
Fig. 1. Role of insulin resistance in altered cation pump activity smooth muscle contraction in the diabetic hypertensive
brane Ca2+-ATPase activity in several different tissues [2]. Insulin may increase Ca’+-ATPase activity by increasing membrane calmodulin content, by increasing phosphorylation of calmodulin, or by increasing its affinity for Cazf [2,8,9]. Finally, it is possible that insulin can mediate its effects via Ca’+-ATPase mRNA expression in various tissues [lo]. Since the Ca*+-ATPase linked Ca2+ extrusion pump appears to be responsible for the fine tuning (maintenance at an optimal level) of [Ca2+li [2], insulin resistance could lead to increases in [Ca’+], which, in turn, could then result in enhanced VSMC responses to various agonists (Fig. 1). The genetically-obese insulin resistant Zucker (‘fatty’) rat has been studied by our group to examine relationships between insulin resistance, cellular abnormalities of Ca2+ metabolism and blood pressure [ll-131. Recently the Zucker rat has been shown to have elevated blood pressure [ 11-14). We have shown that the hypertension in this obese rat strain, like that in type II diabetic individuals, is characterized by enhanced vascular responses to vasoactive agonists as well as abnormalities of cellular Ca2+ metabolism [ll131. These abnormalities of cell Ca*+ metabolism include diminished cell membrane Ca’+-ATPase
resistance
,
d
I
f Response
and accumulation of cytoplasmic free calcium leading to enhanced state. ATPase = adenosine triphosphatase: Ca = calcium.
activity, decreased vascular smooth muscle Ca”+ efflux and increased [Ca2+], 121. It has also been shown that the regulatory effect of insulin on cell membrane Ca*+-ATPase activity is markedly diminished in an insulin-resistant rat model [2], and decreased activity or erythrocyte membrane Ca2+ATPase has also been observed by our group in insulin-resistant hypertensive individuals [15]. This decrease was associated with an increase in erythrocyte Ca2+ concentration, suggesting that decreased membrane Ca*+ efflux was partially responsible for the elevated [Ca2+li. Shaefer and colleagues have also noted decreased erythrocyte Ca*+-ATPase activity in erythrocytes from type I diabetics compared with healthy controls [16]. Our group has demonstrated an impairment in vascular smooth muscle Ca2+ efflux in association with increased vascular reactivity in insulinopenic (streptozotocin-treated) rats, suggesting that it is lack of cell insulin action in both insulinopenic and insulin resistant states that is responsible for impaired Ca2+ efflux and increased resistance. Thus, an insulin-resistant state as exhibited in the Zucker obese rat may be associated with (1) increased Ca2+ influx through voltage-dependent sarcolemmal Ca* + channels, and (2) decreased
C89
production or activation of the VSMC Ca2+ATPase pump. The resulting sustained rise is characteristic of hypertension associated with NIDDM. Accordingly, it is proposed that insulin resistance is associated with impaired VSMC membrane Ca2+ transport leading to a more sustained rise in VSMC (Ca’+)i which, in turn, is associated with enhanced vascular smooth muscle contraction (Fig. 1). References [l] Sowers, J.R., Levy, J. and Zemel, M.B. (1988) Med. Clin. N. Am. 72(6), 139991414. [2] Levy, J., Zemel, M.B. and Sowers, J.R. (1989) Am. J. Med. 87 (Suppt. 6A), 7S-16s. [3] Sowers, J.R., Zemd, P.C., Bedford-Johnson, B. and Zemel, B. (submitted) J. Clin. Invest. [4] Draznin, B., Sussman, K.E., Eckel, R.H. et al. (1988) J. Clin. Invest. 28, 1848-1852. [5] Draznin, B., Sussman, K., Koa, M. et al. (1987) J. Biol. Chem. 262, 1485-1488.
(61 Levy, J., Sowers, J.R. and Zemel, M.B. (1990) Horm. Metab. Res. 22, 136-140. [7] Zierler, K. and Fong-Sen, W.U. (1988) Trans. Assoc. Am. Phys. 101, 320-325. [S] Graves, C.B., Gale, R.D., Laurino, J.P. et al. (1986) J. Biol. Chem. 261. 10429-10438. t91 Wong, E.C., Sacks, D.B., Laurino, J.P. et al. (1988) Endocrinology 123. 1830-1836. IW Sowers, J.R. (in press) Am. J. Kidney Dis. [111 Zemel, M.B., Sowers, J.R., Shehin, S. et al. (1990) Metabolism 39(7), 1-8. WI Shehin, S.E., Sowers, J.R. and Zemel, M.B. (1989) J. Vast. Med. Biol. 1, 278-282. u31 Zemel, M.B., Reddy, S., Shehin, S.E., Lockette, W. and Sowers, J.R. (1990) J. Vase. Med. Biol. 2, 81-85. H.A. (1989) (141 Kurtz, T.W., Morris, R.C. and Pershadsingh, Hypertension 13, 896-901. WI Zemel, M.B., Bedford, B.A., Zemel, PC, Marwah, 0. and Sowers, J.R. (1988) J. Hypertens. 6. 5228-5230. P61 Shaefer, W., Prieben, J., Mannhold, R. et al. (1987) Klin. Wochenschr. 65, 17-21. P71 Reddy, S., Shehin, S., Sowers, J.R. et al. (1990) J. Vast. Med. Biol. 2, 47-51.