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Insulin Resistance, Carbohydrate Metabolism, and Hypertension James R. Sowers, Paul R. Standley, Jeffrey L Ram, Michael B. Zemel, and Lawrence M. Resnick
sion" is characterized by fundamental metabolic abnormalities as well as by hemodynamic abnor malities. Recent observations have shown that im paired cellular responses to insulin are associated with increased vascular smooth muscle contraction, Insulin appears to attenuate the vascular response to both receptor-mediated and voltage-mediated calcium-induced contractions. Thus, insulin resist ance, and the resultant reduction in the normal at tenuating effect of insulin on vascular smooth mus cle responses, appear to be associated with abnormal vascular smooth muscle handling of cal cium and with exaggerated vascular contraction. Am J Hypertens 1991;4:466S-472S
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and atherosclerosis — such as obesity, subtle abnormali ties of glucose and lipid metabolism, and borderline hypertension — can be identified at an early a g e . " These medical disorders become increasingly overt with advancing age, their prevalence reaching epidemic pro portions in the elderly. During the past few years considerable data have accumulated that suggest these various medical problems may be linked by a common denominator—insulin resistance. " This review will focus on the role of insulin resistance as a nexus among obesity, aging, dyslipidemia, glucose intolerance, hy pertension, and accelerated atherosclerosis.
ypertension, non-insulin-dependent (type II) diabetes mellitus, obesity and dyslipidemia, and ischemic heart disease are relatively prevalent medical problems in industrialized and Westernized societies. " Many of the abnormali ties that predispose persons to coronary heart disease 1
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KEY WORDS: Hypertension, insulin resistance, obe sity, calcium, carbohydrate metabolism.
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From the Divisions of Endocrinology and Hypertension, Wayne State University, Detroit, Michigan, and Veterans Administration Medical Center, Allen Park, Michigan (JRS, PRS), the Department of Physiology, Wayne State University, Detroit, Michigan (JRS, PRS, JLR); University of Tennessee, Knoxville (MBZ), and the Cardiovascu lar Center, Cornell University, New York City (LMR). This research was supported in part by National Institutes of Health grants HD-24497 (JRS) and RR-081671 (JLR), and by Veteran's Affairs Medical Research funds (JRS, MBZ). Address correspondence and reprint requests to James R. Sowers, MD, Wayne State University School of Medicine, University Health Center 4H, 4201 St. Antoine, Detroit, MI 48201.
© 1991 by the American Journal of Hypertension, Inc.
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OBESITY AND INSULIN RESISTANCE Obesity is often accompanied by coronary heart disease risk factors such as glucose intolerance, hypertension, and hyperlipidemia, ' ' ' " but when other pa rameters are factored out, obesity remains an indepen3
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Hypertension and diabetes are common diseases in Westernized civilizations, and in the United States, the frequency of both diseases is increasing as the society ages. Factors contributing to the high preva lence and increasing frequency of these diseases in clude obesity, hyperinsulinemia and insulin resist ance, genetic factors, and abnormal cellular handling of calcium and other cations. Obesity is a strong early predictor for the development of hy pertension as a person progresses from childhood into adult life. Important factors contributing to obesity-related hypertension likely include en hanced sympathetic nervous system activity and insulin resistance and hyperinsulinemia. Recent evidence has also shown that many nonobese adults with untreated hypertension have insulin resistance and hyperinsulinemia. This observation strongly suggests that the disease called "hyperten
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associated with an acute euglycemic clamp procedure. Adolescents manifest salt-sensitivity, which could be attenuated by weight reduction and by the accompany ing reduction in insulin levels. A number of studies of obese p e r s o n s have demonstrated that weight re duction is accompanied by blood pressure reduction, even though normal salt intake is maintained. Further more, Hall et a l recently found that inducing hyperin sulinemia in dogs by chronic insulin infusion did not induce hypertension, in spite of salt retention. Thus, insulin-induced sodium retention does not play a neces sary role in the pathogenesis of hyperinsulinemia and insulin-resistance - related hypertension. 59
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Effects on Sympathetic Nervous System Enhanced sympathetic nervous system activity is another mecha nism proposed for the increased prevalence of hyper tension associated with obesity. - - Indeed, for nondiabetic obese persons, reducing weight has been shown to reduce plasma norepinephrine, plasma insu lin, and blood pressure. It has been suggested that hyperinsulinemia — which exists in many nonobese, nondiabetic patients with essential hyperten sion as well as in obese persons —could ele vate blood pressure by stimulating the sympathetic ner vous s y s t e m . However, acute or subacute insulin infusions that simulate physiologic hyperinsulinemia do not elevate blood p r e s s u r e and have recently been shown to decrease peripheral vascular resistance even with increasing sympathetic nerve activity. These observations suggest that hyperinsulinemia, per se, does not cause hypertension, in spite of its relatively acute or subacute effects on the sympathetic nervous system. 61
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HYPERINSULINEMIA Obesity is often accompanied by hyperinsulinemia, which is thought to reflect peripheral insulin resistance with a secondary increase in insulin secretion to main tain euglycemia. The degree of insulin resistance and hyperinsulinemia is most pronounced in both children and adults with predominantly upper-body obesity. Several mechanisms have been suggested for the strik ing relationship of central obesity to hyperinsulinemia and insulin resistance. Data from one study suggest that central obesity is associated with hyperinsulinemia linked to both insulin resistance and reduced hepatic extraction of insulin. Abdominal, upper-body fat also appears to be more metabolically active, showing in creased lipolysis and release of more free fatty acids. These products may interfere with decreased insulin clearance and may exacerbate hypertriglyceridemia. Hyperinsulinemia associated with insulin resistance in obese persons, particularly those with central obesity, could directly elevate blood pressure by several mecha nisms. During the 1970s it was reported that adminis tering insulin during euglycemic clamp studies caused substantial sodium retention in healthy young men, and data have since accumulated to suggest a proximal as well as a distal tubular site of insulin action in mediat ing tubular sodium chloride reabsorption. The data from studies conducted by Racchini et al suggest that obese adolescents are also sensitive to the sodium-retaining consequences of hyperinsulinemia 51
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GLUCOSE TOLERANCE ABNORMALITIES Only recently has it been appreciated that subtle abnor malities of carbohydrate intolerance, suggestive of insu lin resistance, are relatively common among nonobese patients with essential h y p e r t e n s i o n . Using the euglycemic insulin clamp technique, insulin resistance has been found in lean persons with essential hyperten sion and clinically normal glucose tolerance. Hyper insulinemia with insulin resistance has also very re cently been observed to be an early manifestation of and predictor of early (first trimester) manifestation of preg nancy-induced hypertension. The physiology of the insulin resistance associated with essential hypertension has been partially charac terized. This resistance site is located primarily in pe ripheral tissues, such as muscle, rather than in the liver. It also appears to be limited to nonoxidative pathways of intracellular glucose disposal. Whether these abnormali ties are inherited or are acquired in conjunction with hypertension secondary to environmental influences is not known. However, since essential hypertension has a 19-2672
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dent risk factor for premature mortality. As pointed out by Kaplan, obesity is increasing in the United States; the relationship between obesity and hyperten sion becomes apparent during childhood, " and obe sity has increased by 54% among 6- to 11-year-olds and by 39% among 12- to 17-year-olds over the past 16 years. Moreover, about 40 % of children who are obese at age 7 and 70% of obese adolescents will become obese adults. Blood pressure tends to rise along with body weight, and increasing adiposity — even from an early age — is a major contributor to the development of hypertension. " Upper-body obesity, which is sometimes referred to as android or central obesity, is determined by waist-tohip-girth ratio measurement or by computerized axial tomography. This type of obesity is more closely related to type II diabetes, - - ' hypertriglyceridemia and low high-density lipoprotein cholesterol, - hypertension, and premature coronary heart dis ease ( C H D ) . An increased prevalence of central obesity may explain the higher prevalence of hyperten sion and type II diabetes in the black population, particu larly among black women, as a function of increasing age. - Further, a striking relationship between in sulin resistance and the development of hypertension in blacks has recently been reported.
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significant genetic component, these subtle abnormali ties in glucose metabolism are likely linked to other in herited abnormalities such as increased sodium-lithium countertransport, decreased membrane calciumadenosine triphosphatase (ATPase) activity, and other cation transport deficiencies. - - ' 15,75-78
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or glyburide; and cells obtained from obese persons ex hibited increased intracellular calcium and lack of re sponsiveness to either insulin or glyburide in vitro. Thus, elevated intracellular calcium in tissue, particu larly in response to circulating vasoactive agonists, may be the result of genetically related abnormalities in cel lular cation metabolism that are fundamental to both insulin resistance and increased vascular resistance. Recent observations in our laboratory - - - and ear lier data - suggest that impaired cellular responses to insulin are associated with increased vascular smooth muscle tone, the physiologic hallmark of most hyper tensive states. Vessels from both insulinogenic and insulin-resistant rats - display exaggerated vasocon strictive responses to various agonists. Furthermore, our laboratory has recently reported that insulin, ad ministered in physiologic doses, attenuates the vascular contractile response to phenylephrine, serotonin, and potassium chloride, indicating that it attenuates that re sponse to both receptor-dependent and voltage-depen dent mechanisms. Calcium is generally acknowledged to be important in mediating vascular smooth muscle contractile re sponses. Insulin could accordingly attenuate contractil ity by altering the movement of calcium into vascular smooth muscle cells or by affecting the intracellular re lease of calcium from storage sites. Indeed, in skeletal muscle, insulin produces hyperpolarization, reduces cal cium currents, and shortens calcium-mediated action potentials; in vascular smooth muscle tissue, insulin regulates calcium efflux. During a recently conducted study, we observed that insulin attenuates the vascular smooth muscle cell intracellular calcium response to vasopressin and reduces calcium influx into those cells by both receptor- and voltage-operated channels. Thus, it appears that insulin regulates calcium's move ment from the extracellular to the intracellular compart ment of vascular smooth muscle. 86
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Genetic Factors
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Calcium-ATPase Activity Several investigators have shown that insulin stimulates plasma membrane calcium-ATPase activity in a number of different tissues. It may do so by increasing membrane cal modulin content, by phosphorylating calmodu lin, by increasing ATPase affinity for calcium, or by incorporating additional calcium-ATPase into the membrane. An increase in the number of active pump units in the membrane might be mediated by activating synthesis of calcium-ATPase mRNA or simulating its expression in various tissues. Since the calcium-ATPase-linked extrusion pump appears to be responsible for maintaining intracellular calcium at an optimal level, insulin resistance could lead to loss of stimu lation of this pump, with the result of increased intracel lular calcium, which in turn could ultimately lead to increased peripheral vascular resistance (Figure 2). 25
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FIGURE 1. Insulin resistance and hyperinsulinemia and al tered intracellular calcium metabolism as a nexus between genetic and environmental factors contributing to the development of hy pertension.
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Intracellular Calcium Metabolism A relationship likely exists among abnormalities in intracellular cal cium metabolism, insulin resistance, and hypertension (Figure 1). Some data suggest that "optimal" levels of intracellular calcium are necessary for the optimal cellu lar action of insulin. - - Investigations conducted by Draznin et a l , in which intracellular calcium was manipulated by varying extracellular calcium and em ploying the calcium ionophore inomycin, established an optimal range of intracellular calcium of 40 nmol/L to 370 nmol/L for insulin-mediated glucose transport. These results suggest that although increased intracel lular calcium appears to be involved in transducing the insulin signal, increasing it beyond an optimal range results in loss of the ability to transduce the signal, per haps because of the inability of insulin to appropriately modulate calcium in cells exhibiting abnormally high levels. In support of this, insulin and glucose infusions during euglycemic clamp studies of normal-weight per sons resulted in elevated intracellular calcium in isolated adipocytes and loss of cellular responsiveness to insulin
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3.
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FIGURE 2. abnormalities
f
r
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t Receptor operated I Ca transport 2 +
f Response
Vascular smooth muscle (VSM) cation transport associated with decreased cellular insulin action.
Decreased activity of erythrocyte membrane calciumATPase has been observed in insulin-resistant type II diabetic hypertensive patients. - This decrease was associated with an increase in erythrocyte calcium con centration, suggesting that decreased membrane cal cium efflux was partially responsible for the elevated cellular calcium levels. Reduced calcium-ATPase activ ity in erythrocytes from diabetic persons, compared with healthy controls, has also been reported. Studies by our investigative group have demonstrated de creased calcium-ATPase in erythrocyte membrane and in kidney basolateral membrane - from insulinresistant rats. Furthermore, increased intracellular cal cium was observed in erythrocytes, in skeletal muscle, and in bone cells from these animals. - Further, the regulatory effects of insulin on cell membrane calciumATPase activity are absent in an insulin-resistant non insulin-dependent diabetes rat model. These observa tions support the concept that the regulation of intracellular calcium by insulin, mediated partially by cell membrane calcium-ATPase, is impaired in states of insulin resistance and hypertension (Figure 2). In addition to effects on intracellular calcium directly mediated by changes in calcium regulatory mecha nisms, changes in intracellular calcium may also occur secondarily to modification of other cation regulatory mechanisms. Decreased activity of the ouabain-sensitive (sodium, potassium) ATPase cell membrane pump has also been observed in rat models of d i a b e t e s and in human obesity. Reduced sodium-potassium pump activity would, in turn, increase intracellular so dium. The resulting decrease in sodium gradient across the membrane would theoretically decrease sodiumcalcium exchange, with a resultant increase in intra cellular calcium (Figure 2). Thus, abnormalities in vascu lar smooth muscle cation metabolism may account, in 78
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a n d resistance in obesity a n d n o n i n s u l i n - d e p e n d e n t type II diabetes mellitus. A m J Physiol 1 9 8 2 ; 2 4 3 : E 1 5 30. F r e e d m a n DS, Srinivasan SR, Burke G L , et al: Relation of b o d y fat distribution to hyperinsulinemia in children a n d adolescents: the Bogalusa h e a r t study. A m J Clin Nutr 1 9 8 7 ; 4 6 : 4 0 3 - 4 1 0 .
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Insulin Resistance, Carbohydrate Metabolism, and Hypertension James R. Sowers, Paul R. Standley, Jeffrey L Ram, Michael B. Zemel, and Lawrence M. Resnick
sion" is characterized by fundamental metabolic abnormalities as well as by hemodynamic abnor malities. Recent observations have shown that im paired cellular responses to insulin are associated with increased vascular smooth muscle contraction, Insulin appears to attenuate the vascular response to both receptor-mediated and voltage-mediated calcium-induced contractions. Thus, insulin resist ance, and the resultant reduction in the normal at tenuating effect of insulin on vascular smooth mus cle responses, appear to be associated with abnormal vascular smooth muscle handling of cal cium and with exaggerated vascular contraction. Am J Hypertens 1991;4:466S-472S
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and atherosclerosis — such as obesity, subtle abnormali ties of glucose and lipid metabolism, and borderline hypertension — can be identified at an early a g e . " These medical disorders become increasingly overt with advancing age, their prevalence reaching epidemic pro portions in the elderly. During the past few years considerable data have accumulated that suggest these various medical problems may be linked by a common denominator—insulin resistance. " This review will focus on the role of insulin resistance as a nexus among obesity, aging, dyslipidemia, glucose intolerance, hy pertension, and accelerated atherosclerosis.
ypertension, non-insulin-dependent (type II) diabetes mellitus, obesity and dyslipidemia, and ischemic heart disease are relatively prevalent medical problems in industrialized and Westernized societies. " Many of the abnormali ties that predispose persons to coronary heart disease 1
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KEY WORDS: Hypertension, insulin resistance, obe sity, calcium, carbohydrate metabolism.
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From the Divisions of Endocrinology and Hypertension, Wayne State University, Detroit, Michigan, and Veterans Administration Medical Center, Allen Park, Michigan (JRS, PRS), the Department of Physiology, Wayne State University, Detroit, Michigan (JRS, PRS, JLR); University of Tennessee, Knoxville (MBZ), and the Cardiovascu lar Center, Cornell University, New York City (LMR). This research was supported in part by National Institutes of Health grants HD-24497 (JRS) and RR-081671 (JLR), and by Veteran's Affairs Medical Research funds (JRS, MBZ). Address correspondence and reprint requests to James R. Sowers, MD, Wayne State University School of Medicine, University Health Center 4H, 4201 St. Antoine, Detroit, MI 48201.
© 1991 by the American Journal of Hypertension, Inc.
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OBESITY AND INSULIN RESISTANCE Obesity is often accompanied by coronary heart disease risk factors such as glucose intolerance, hypertension, and hyperlipidemia, ' ' ' " but when other pa rameters are factored out, obesity remains an indepen3
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Hypertension and diabetes are common diseases in Westernized civilizations, and in the United States, the frequency of both diseases is increasing as the society ages. Factors contributing to the high preva lence and increasing frequency of these diseases in clude obesity, hyperinsulinemia and insulin resist ance, genetic factors, and abnormal cellular handling of calcium and other cations. Obesity is a strong early predictor for the development of hy pertension as a person progresses from childhood into adult life. Important factors contributing to obesity-related hypertension likely include en hanced sympathetic nervous system activity and insulin resistance and hyperinsulinemia. Recent evidence has also shown that many nonobese adults with untreated hypertension have insulin resistance and hyperinsulinemia. This observation strongly suggests that the disease called "hyperten
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associated with an acute euglycemic clamp procedure. Adolescents manifest salt-sensitivity, which could be attenuated by weight reduction and by the accompany ing reduction in insulin levels. A number of studies of obese p e r s o n s have demonstrated that weight re duction is accompanied by blood pressure reduction, even though normal salt intake is maintained. Further more, Hall et a l recently found that inducing hyperin sulinemia in dogs by chronic insulin infusion did not induce hypertension, in spite of salt retention. Thus, insulin-induced sodium retention does not play a neces sary role in the pathogenesis of hyperinsulinemia and insulin-resistance - related hypertension. 59
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Effects on Sympathetic Nervous System Enhanced sympathetic nervous system activity is another mecha nism proposed for the increased prevalence of hyper tension associated with obesity. - - Indeed, for nondiabetic obese persons, reducing weight has been shown to reduce plasma norepinephrine, plasma insu lin, and blood pressure. It has been suggested that hyperinsulinemia — which exists in many nonobese, nondiabetic patients with essential hyperten sion as well as in obese persons —could ele vate blood pressure by stimulating the sympathetic ner vous s y s t e m . However, acute or subacute insulin infusions that simulate physiologic hyperinsulinemia do not elevate blood p r e s s u r e and have recently been shown to decrease peripheral vascular resistance even with increasing sympathetic nerve activity. These observations suggest that hyperinsulinemia, per se, does not cause hypertension, in spite of its relatively acute or subacute effects on the sympathetic nervous system. 61
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HYPERINSULINEMIA Obesity is often accompanied by hyperinsulinemia, which is thought to reflect peripheral insulin resistance with a secondary increase in insulin secretion to main tain euglycemia. The degree of insulin resistance and hyperinsulinemia is most pronounced in both children and adults with predominantly upper-body obesity. Several mechanisms have been suggested for the strik ing relationship of central obesity to hyperinsulinemia and insulin resistance. Data from one study suggest that central obesity is associated with hyperinsulinemia linked to both insulin resistance and reduced hepatic extraction of insulin. Abdominal, upper-body fat also appears to be more metabolically active, showing in creased lipolysis and release of more free fatty acids. These products may interfere with decreased insulin clearance and may exacerbate hypertriglyceridemia. Hyperinsulinemia associated with insulin resistance in obese persons, particularly those with central obesity, could directly elevate blood pressure by several mecha nisms. During the 1970s it was reported that adminis tering insulin during euglycemic clamp studies caused substantial sodium retention in healthy young men, and data have since accumulated to suggest a proximal as well as a distal tubular site of insulin action in mediat ing tubular sodium chloride reabsorption. The data from studies conducted by Racchini et al suggest that obese adolescents are also sensitive to the sodium-retaining consequences of hyperinsulinemia 51
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GLUCOSE TOLERANCE ABNORMALITIES Only recently has it been appreciated that subtle abnor malities of carbohydrate intolerance, suggestive of insu lin resistance, are relatively common among nonobese patients with essential h y p e r t e n s i o n . Using the euglycemic insulin clamp technique, insulin resistance has been found in lean persons with essential hyperten sion and clinically normal glucose tolerance. Hyper insulinemia with insulin resistance has also very re cently been observed to be an early manifestation of and predictor of early (first trimester) manifestation of preg nancy-induced hypertension. The physiology of the insulin resistance associated with essential hypertension has been partially charac terized. This resistance site is located primarily in pe ripheral tissues, such as muscle, rather than in the liver. It also appears to be limited to nonoxidative pathways of intracellular glucose disposal. Whether these abnormali ties are inherited or are acquired in conjunction with hypertension secondary to environmental influences is not known. However, since essential hypertension has a 19-2672
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dent risk factor for premature mortality. As pointed out by Kaplan, obesity is increasing in the United States; the relationship between obesity and hyperten sion becomes apparent during childhood, " and obe sity has increased by 54% among 6- to 11-year-olds and by 39% among 12- to 17-year-olds over the past 16 years. Moreover, about 40 % of children who are obese at age 7 and 70% of obese adolescents will become obese adults. Blood pressure tends to rise along with body weight, and increasing adiposity — even from an early age — is a major contributor to the development of hypertension. " Upper-body obesity, which is sometimes referred to as android or central obesity, is determined by waist-tohip-girth ratio measurement or by computerized axial tomography. This type of obesity is more closely related to type II diabetes, - - ' hypertriglyceridemia and low high-density lipoprotein cholesterol, - hypertension, and premature coronary heart dis ease ( C H D ) . An increased prevalence of central obesity may explain the higher prevalence of hyperten sion and type II diabetes in the black population, particu larly among black women, as a function of increasing age. - Further, a striking relationship between in sulin resistance and the development of hypertension in blacks has recently been reported.
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significant genetic component, these subtle abnormali ties in glucose metabolism are likely linked to other in herited abnormalities such as increased sodium-lithium countertransport, decreased membrane calciumadenosine triphosphatase (ATPase) activity, and other cation transport deficiencies. - - ' 15,75-78
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or glyburide; and cells obtained from obese persons ex hibited increased intracellular calcium and lack of re sponsiveness to either insulin or glyburide in vitro. Thus, elevated intracellular calcium in tissue, particu larly in response to circulating vasoactive agonists, may be the result of genetically related abnormalities in cel lular cation metabolism that are fundamental to both insulin resistance and increased vascular resistance. Recent observations in our laboratory - - - and ear lier data - suggest that impaired cellular responses to insulin are associated with increased vascular smooth muscle tone, the physiologic hallmark of most hyper tensive states. Vessels from both insulinogenic and insulin-resistant rats - display exaggerated vasocon strictive responses to various agonists. Furthermore, our laboratory has recently reported that insulin, ad ministered in physiologic doses, attenuates the vascular contractile response to phenylephrine, serotonin, and potassium chloride, indicating that it attenuates that re sponse to both receptor-dependent and voltage-depen dent mechanisms. Calcium is generally acknowledged to be important in mediating vascular smooth muscle contractile re sponses. Insulin could accordingly attenuate contractil ity by altering the movement of calcium into vascular smooth muscle cells or by affecting the intracellular re lease of calcium from storage sites. Indeed, in skeletal muscle, insulin produces hyperpolarization, reduces cal cium currents, and shortens calcium-mediated action potentials; in vascular smooth muscle tissue, insulin regulates calcium efflux. During a recently conducted study, we observed that insulin attenuates the vascular smooth muscle cell intracellular calcium response to vasopressin and reduces calcium influx into those cells by both receptor- and voltage-operated channels. Thus, it appears that insulin regulates calcium's move ment from the extracellular to the intracellular compart ment of vascular smooth muscle. 86
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Calcium-ATPase Activity Several investigators have shown that insulin stimulates plasma membrane calcium-ATPase activity in a number of different tissues. It may do so by increasing membrane cal modulin content, by phosphorylating calmodu lin, by increasing ATPase affinity for calcium, or by incorporating additional calcium-ATPase into the membrane. An increase in the number of active pump units in the membrane might be mediated by activating synthesis of calcium-ATPase mRNA or simulating its expression in various tissues. Since the calcium-ATPase-linked extrusion pump appears to be responsible for maintaining intracellular calcium at an optimal level, insulin resistance could lead to loss of stimu lation of this pump, with the result of increased intracel lular calcium, which in turn could ultimately lead to increased peripheral vascular resistance (Figure 2). 25
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FIGURE 1. Insulin resistance and hyperinsulinemia and al tered intracellular calcium metabolism as a nexus between genetic and environmental factors contributing to the development of hy pertension.
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Intracellular Calcium Metabolism A relationship likely exists among abnormalities in intracellular cal cium metabolism, insulin resistance, and hypertension (Figure 1). Some data suggest that "optimal" levels of intracellular calcium are necessary for the optimal cellu lar action of insulin. - - Investigations conducted by Draznin et a l , in which intracellular calcium was manipulated by varying extracellular calcium and em ploying the calcium ionophore inomycin, established an optimal range of intracellular calcium of 40 nmol/L to 370 nmol/L for insulin-mediated glucose transport. These results suggest that although increased intracel lular calcium appears to be involved in transducing the insulin signal, increasing it beyond an optimal range results in loss of the ability to transduce the signal, per haps because of the inability of insulin to appropriately modulate calcium in cells exhibiting abnormally high levels. In support of this, insulin and glucose infusions during euglycemic clamp studies of normal-weight per sons resulted in elevated intracellular calcium in isolated adipocytes and loss of cellular responsiveness to insulin
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REFERENCES 1. Sowers JR, Levy J, Zemel MB: Hypertension and dia betes. Med Clin Ν Am 1988;72(6):1399-1414. 2.
3.
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FIGURE 2. abnormalities
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Vascular smooth muscle (VSM) cation transport associated with decreased cellular insulin action.
Decreased activity of erythrocyte membrane calciumATPase has been observed in insulin-resistant type II diabetic hypertensive patients. - This decrease was associated with an increase in erythrocyte calcium con centration, suggesting that decreased membrane cal cium efflux was partially responsible for the elevated cellular calcium levels. Reduced calcium-ATPase activ ity in erythrocytes from diabetic persons, compared with healthy controls, has also been reported. Studies by our investigative group have demonstrated de creased calcium-ATPase in erythrocyte membrane and in kidney basolateral membrane - from insulinresistant rats. Furthermore, increased intracellular cal cium was observed in erythrocytes, in skeletal muscle, and in bone cells from these animals. - Further, the regulatory effects of insulin on cell membrane calciumATPase activity are absent in an insulin-resistant non insulin-dependent diabetes rat model. These observa tions support the concept that the regulation of intracellular calcium by insulin, mediated partially by cell membrane calcium-ATPase, is impaired in states of insulin resistance and hypertension (Figure 2). In addition to effects on intracellular calcium directly mediated by changes in calcium regulatory mecha nisms, changes in intracellular calcium may also occur secondarily to modification of other cation regulatory mechanisms. Decreased activity of the ouabain-sensitive (sodium, potassium) ATPase cell membrane pump has also been observed in rat models of d i a b e t e s and in human obesity. Reduced sodium-potassium pump activity would, in turn, increase intracellular so dium. The resulting decrease in sodium gradient across the membrane would theoretically decrease sodiumcalcium exchange, with a resultant increase in intra cellular calcium (Figure 2). Thus, abnormalities in vascu lar smooth muscle cation metabolism may account, in 78
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