Insulin resistance in African Americans

Kidney International, Vol. 63, Supplement 83 (2003), pp. S27–S30

Insulin resistance in African Americans BONITA FALKNER Thomas Jefferson University, Philadelphia, Pennsylvania, USA

Insulin resistance in African Americans. Hypertension and diabetes mellitus are the leading contributors to end-stage renal disease. African Americans suffer higher rates of renal failure as well as other vascular morbidities associated with hypertension and diabetes. Insulin resistance is strongly associated with hypertension. Insulin resistance is a component of diabetes and also precedes the clinical expression of type 2 diabetes. The relationship of blood pressure with insulin resistance, or impaired insulin action, occurs in African Americans and can be detected at young ages prior to the clinical expression of hypertension or diabetes. Through its relationship with hypertension, diabetes, and hyperlipidemia, insulin resistance is associated with endothelial dysfunction. The interface of insulin resistance with endothelial dysfunction may begin to explain the role of insulin resistance in vascular and renal pathology. The injury process, subsequent to both hypertension and diabetes, appears to be mediated by alterations tissue regulatory factors, and include vasoactive peptides such as angiotensin II, endothelin, and growth factors. Understanding the determinants that up-regulate the aberrant pathways and the early phases of these processes will be necessary to formulate strategies to effectively achieve renal protection and reduce the rates of renal failure in African Americans.

Vascular diseases, including end-stage renal disease (ESRD), strokes, and coronary artery disease (CAD), are the leading causes of death and disability in African Americans. Although African Americans appear to share with Caucasians the same conventional risk factors for vascular disease, there are a paucity of data to explain the excess prevalence and morbidity in this racial group. Both hypertension and diabetes contribute to vascular disease morbidity and mortality, and both of these disorders occur at disproportionately greater rates in African Americans compared to Caucasians [1]. The expression of vascular events is further augmented when hypertension and diabetes occur together [2]. The concept of endothelial dysfunction has developed as a model on which to examine the mechanisms and mediators of vascular injury. Pathologic stimuli, such as high blood pressure (BP), hyperlipidemia, hyperglycemia, and smoking induce oxidative stress. The oxidative stress reKey words: insulin resistance, sodium sensitivity, glucose tolerance, hypertension, diabetes mellitus, African Americans.

 2003 by the International Society of Nephrology

sults in localized alterations in endothelial cell function, including increased permeability to plasma lipoproteins, thrombogenesis, attenuation in nitric oxide bioavailability, and vasoconstriction. Abnormalities in endothelial cell function are demonstrated in the conditions of atherosclerosis, diabetes, hypertension, and tobacco use [3], all of which are high risk conditions for cardiovascular events. Endothelial dysfunction then represents an accelerated phase of vascular pathology. Insulin resistance, a condition of impaired insulin action with consequent hyperinsulinemia, is present in the clinical disorders linked with oxidative stress and endothelial dysfunction. The potential contribution of insulin resistance to nephropathy in African Americans will be discussed. INSULIN RESISTANCE AND BLOOD PRESSURE The mixed metabolic syndrome consisting of obesity, hyperinsulinemia, diabetes (or glucose intolerance), high blood pressure (BP), and dyslipidemia, is strongly associated with vascular disease [4]. The core component of this metabolic syndrome is insulin resistance, or impaired insulin-mediated glucose utilization, with consequent hyperinsulinemia [5]. Obesity may cause insulin resistance/ hyperinsulinemia due to the resistance of adipose tissue to insulin action. Alternatively, the primary defect may be one of impaired insulin-mediated uptake by peripheral muscle cells. The resulting hyperinsulinemia may then lead to obesity due to the growth promoting effects of insulin. The relationship between insulin resistance and hypertension has been well established in African Americans and other racial groups [6]. However, the association of hypertension with insulin resistance is a pathologic conundrum because in normal humans, insulin has a vasodilator effect, resulting in an increase in blood flow and a decrease in vascular resistance [7]. Clinical studies on patients with the insulin resistant conditions of obesity and type 2 diabetes have reported a blunted vasodilator response to insulin infusions [8]. These data support the concept that the condition of insulin resistance may not be limited to glucoregulatory action, but also may include vascular endothelial cell resistance to insulin action, and thereby contribute to endo-

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thelial dysfunction. Thus, the hypertension-insulin resistance linkage could be due to endothelial dysfunction, resulting in an imbalance in vasoactive peptides that favor vasoconstriction. An alternative concept to explain insulin resistance with the progression of hypertensive vascular disease is based on primary changes in peripheral vessels. While BP elevations per se play a role in the development of vascular hypertrophy, Folkow proposed that structural changes in peripheral vessels could be seminal events in raising vascular resistance and systemic BP [9]. This concept is further described by Julius, who proposed that it is subjects with increased sympathetic tone and a hyperkinetic circulation who progress to chronic hypertension through alterations in vessel structure that include hypertrophy of the muscular layer of the vascular wall and vascular rarefaction [10]. This theory proposes that the changes in vascular configuration decrease the microcirculatory supply to skeletal muscle and increase the diffusion distance between the vessel and the metabolizing cell. As a result of these tissue changes there would be a reduction in the delivery of glucose to the muscle cell, thereby creating a state of relative insulin resistance. Despite the competing theories on the causal relationship between hypertension and insulin resistance, it is possible that the determining aspect is linked with growth, development, and vascular aging. There is evidence that the early phase of BP elevation is marked by sympathetic overactivity [11]. There is also a consistent trend in higher BP levels among African Americans from childhood, through adolescence, into adulthood [12], and there is a consistent co-segregation of insulin resistance with higher BP [13]. Thus, it is plausible that alterations in vascular growth and structure mediate the observed relationships between insulin resistance and BP; with expression of endothelial dysfunction occurring as glucose regulation shifts toward diabetes. The various pathogenic pathways engaged by endothelial dysfunction then accelerate the vascular injury. INSULIN RESISTANCE AND SODIUM SENSITIVITY The role of sodium in blood pressure regulation may be relevant in African Americans, a group that expresses more salt sensitivity [14]. Insulin resistance with hyperinsulinemia is associated with sodium sensitivity [15]. In healthy young African Americans, we have found that plasma insulin concentration correlates significantly with BP sensitivity to sodium. Both BP sensitivity to sodium and plasma insulin level predict change in BP over a five year interval, suggesting that hyperinsulinemia contributes to the expression of the sodium sensitivity phenotype [16]. Hyperinsulinemia augments renal tubular sodium reabsorption [17]. A net gain in sodium balance

can lead to a volume dependent pressor effect, which, transmitted to the renal vasculature, could contribute to hyperfiltration. Alternatively, the hyperfiltration may be due to failure in autoregulation of the renal vasculature. Kotchen et al found an increase in glomerular filtration rate (GFR) in response to norepinephrine infusions among hypertensive African Americans, suggesting a reduced capacity to protect the glomeruli from pressure stress [18]. Similarily, Price et al reported a blunted vasoconstrictor response to angiotensin II infusion in a sample of healthy African Americans [19]. These changes were eliminated following captropril treatment, suggesting an altered intrarenal renin system in African Americans. This pattern is consistent with the phenotype of “nonmodulation” [20], a phenotype associated with insulin resistance. A candidate vasoconstrictor peptide that could be relevant to insulin resistance and renal disease in African Americans is endothelin-1 (ET-1). In vitro studies have found that, in addition to vasoconstriction, ET-1 stimulates mitogenesis in vascular smooth muscle and mesangial cells, and also stimulates angiotensin II [21]. Insulin stimulates ET-1 gene expression, [22] and higher plasma levels of ET-1 have been reported in clinical conditions of insulin resistance [23]. Plasma ET-1 levels also are reported to be higher in African American men compared to Caucasian men [24] and in hypertensive African Americans compared to hypertensive Caucasians [25]. Based on these reports and the contribution of ET-1 to regulation of sodium and water balance, Ergul proposed that ET-1 may be turned on in salt-sensitive hypertension and contribute to renal disease in African Americans [26]. INSULIN RESISTANCE AND GLUCOSE TOLERANCE Insulin resistance is a component of type 2 diabetes mellitus, and generally precedes the clinical expression of diabetes. Concurrent hypertension in patients with type 2 diabetes occurs frequently, and when these two disorders occur within patients, the risk for nephropathy is augmented [2]. It is quite possible that the pathogenic mechanisms that mediate vessel and tissue injury are underway prior to full clinical expression of diabetes or hypertension. In a cohort of young adult African Americans, none of whom were known diabetics, we detected 28% of the sample with either impaired glucose tolerance (IGT) or undetected diabetes based on an oral glucose tolerance test [27]. When the sample was stratified by glucose tolerance status as normal glucose tolerant (NGT), IGT, or diabetic (DM), there was a linear upward shift in BP as glucose tolerance deteriorated from NGT to IGT to DM. The upward linear trend in BP remained significant after adjustment for obesity. The measures of insulin sensitivity by insulin clamp also

Falkner: Insulin resistance in African Americans

demonstrated greater insulin resistance as glucose tolerance deteriorated. The rates of obesity were quite high in this cohort, but consistent with the high rates of obesity among African Americans. Of note was the observation that there was no difference in body mass index, particularly among the women, between the NGT and IGT. Thus, some, but not all, individuals with obesity and hyperinsulinemia are vulnerable to the toxic effects of obesity and express the other components of the insulin resistance syndrome with rising BP, impaired glucose tolerance, and elevation in plasma lipids. When we examined urinary albumin excretion as an indicator of tissue or vessel injury, we found no difference in urinary albumin excretion between the normotensive versus the hypertensive subjects. However, the urinary albumin excretion was significantly greater in those with IGT compared to NGT regardless of their BP status. These observations suggest that the aberrant mechanisms that mediate tissue injury may be operational prior to full clinical expression of disease. Pathologic characteristics of diabetic nephropathy include hypertrophy of glomerular and tubular cells, with thickening of glomerular and tubular membranes and subsequent accumulation of extracellular matrix components. In vitro studies have shown that exposure of renal cells to high ambient glucose stimulates hypertrophy and production of collagen Types I and IV in proximal tubular and mesangial cells. The outcome of this process is the characteristic accumulation of excess matrix observed in diabetic nephropathy [28]. Transforming growth factorbeta (TGF-␤) is a tissue cytokine with multiple fibrinogenic properties. Sharma and Ziyadeh [29] and others have demonstrated increased levels of TGF-␤ in kidney cells of genetically diabetic animals as well as in streptozotocin-induced diabetic animals. The common factor that directs an increase in TGF-␤ activity in the experimental studies has been hyperglycemia. There is also some clinical evidence that this tissue cytokine may contribute to renal pathology in humans. Up-regulation of TGF-␤ activity has been reported to be associated with renal alterations in patients with hypertension [30] and in patients with diabetes [31]. Although the evidence to date suggests that hyperglycemia is involved in up-regulation of TGF-␤ activity, the necessary level of hyperglycemia and the extent to which TGF-␤ can initiate renal tissue injury in humans has not yet been determined. We explored this question in a pilot study on our cohort of young adult African Americans. Timed urine samples were collected overnight and again following an oral glucose tolerance test (OGTT). The samples were assayed for creatinine and TGF-␤. TGF-␤ excretion was calculated on eight subjects with NGT and nine cases with IGT. Figure 1 provides the TGF-␤ excretion, expressed as pg/mg creatinine in this small sample. Urinary TGF-␤ excretion at baseline (pre) and following OGTT (post) was higher

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Fig. 1. Urinary transforming growth factor-␤ (TGF-␤) excretion is presented for cases with normal glucose tolerance (NGT) and cases with impaired glucose tolerance (IGT). Overnight urine collections represent the baseline and are designated as Pre and urine collections following the OGTT are designated as Post. Urinary TGF-␤ is presented as pg/mg creatinine. Data are mean ⫾ standard deviation.

in the cases with IGT compared to NGT. Although the sample size was quite limited, these few cases indicate that renal TGF-␤ activity may be increased in the presence of mild hyperglycemia (IGT) and that, among IGT, a further increase in TGF-␤ excretion can be detected following an OGTT. More extensive investigations will be necessary to confirm these preliminary observations. If confirmed the findings would indicate that even modest levels of relative hyperglycemia along with modest levels of BP elevation could impose sufficient oxidative stress to impose endothelial dysfunction. The consequent up-regulation of tissue factors such as ET-1, angiotensin II, and TGF-␤ would then augment tissue and vessel injury. Insulin resistance appears to be an underlying platform from which these processes emanate. SUMMARY Insulin resistance, as a syndrome, occurs in African Americans as well as other ethnic groups. Among African Americans there is a consistent relationship of insulin resistance with BP, which is present from a young age and remains significant despite adjustment for adiposity. There is a linear upward trend in BP as glucose tolerance deteriorates. Insulin resistance is linked with hypertension and diabetes, two conditions that occur at disproportionately high rates among African Americans. According to the oxidative stress concept, the barotrauma from hypertension and the hyperglycemia of diabetes induce oxidative stress to the tissue. The free radicals generated then disrupt the normal regulatory balance of vascular endothelial cells. Endothelial dysfunction is

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manifest by local tissue activity with up-regulation of several factors such as ET-1, angiotensin II, or TGF-␤. These factors may initiate and accelerate the pathology. Insulin resistance can be implicated in several phases of this process, and is clearly a risk factor for nephropathy in African Americans. Future studies will be necessary to identify the critical stages for injury, and to identify more specific therapeutic targets for renal protection in this high-risk ethnic group. Reprint requests to Bonita Falkner, M.D., Thomas Jefferson University, Walnut Towers, 6th Floor, 211 South 9th St., Philadelphia, Pennsylvania 19107, USA. E-mail: [email protected]

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