Hypertension is a major health problem with widespread and sometimes devastating consequences. According to previous statistics, it has been estimated that 26.4% of the adult population has hypertension – defined as systolic blood pressure of 140 mmHg or diastolic blood pressure of 90 mmHg – and the total number of adults with hypertension is approximately one billion worldwide. This number is predicted to increase to a total of 1.56 billion in 2025 1,2. Epidemiological studies have shown that hypertension is present in 25% of urban and 10% of rural patients in India 3. The prevalence of hypertension in Kashmir is about 20% 4.
Extensive epidemiological work and treatment trials have documented that the higher the blood pressure, the higher the risk of dying from cardiovascular disease, that is, stroke, heart attack, and heart failure.
Worldwide, 57 million disability-adjusted life years (3.7% of total) are attributed to high blood pressure. Globally, 51% of stroke and 45% of ischemic heart disease deaths are attributable to high systolic blood pressure 5. In addition, hypertension is a major risk factor for heart failure, aneurysms of the arteries (e.g. aortic aneurysm), and peripheral arterial disease, and is a cause of chronic kidney disease. For prevention and treatment, it is very important to have an accurate understanding of the pathophysiology of disease. Traditionally, hypertension has been classified into two groups: essential or primary and secondary hypertension.
Primary (essential) hypertension is diagnosed in the absence of an identifiable secondary cause, for example, renovascular disease, aldosteronism, pheochromocytoma, etc. Approximately 90–95% of adults with hypertension have primary hypertension, whereas secondary hypertension accounts for around 5–10% of the cases 6. From a historical perspective, the understanding of the pathophysiology of hypertension has changed considerably. The pathophysiological methods that have been studied include hormonal, genetic, and autacoids.
One important mechanism proposed in the pathophysiology of essential hypertension is the role of insulin resistance with compensatory hyperinsulinemia. Hyperinsulinemia, which occurs as a compensation for insulin resistance, is postulated to mediate increased blood pressure in essential hypertension through multiple mechanisms, such as stimulation of sympathetic nervous system activity and renal tubular sodium reabsorption 7,8.
To confirm the role of insulin resistance and hyperinsulinemia in the pathogenesis of essential hypertension, several studies have been carried out, especially in the last three decades. Most of the studies have established a significant relationship between insulin resistance/hyperinsulinemia and hypertension 9–17, but some population studies have not been able to discern a significant relationship between hyperinsulinemia and hypertension 18–20.
As no data in this respect are available from our part of the world, our study focuses on establishing the role of insulin resistance and compensatory hyperinsulinemia in a hypertensive Kashmiri population.
Materials and methods
This study was carried out at SKIMS, a tertiary care hospital, from December 2010 to October 2012. A total of 100 individuals aged above 18 years were recruited prospectively for this study; 50 were newly detected cases of essential hypertension attending the medical outpatient department and 50 were age-matched and sex-matched normal healthy individuals. Informed consents were sought from all patients and controls.
Patients who had a BMI of at least 25 kg/m2, diabetes mellitus type 2, dyslipidemia, malignant hypertension, congestive heart failure, secondary hypertension, pregnant women, and patients already on antihypertensive treatment were excluded from this study. In addition, all cases and controls were evaluated for secondary hypertension and diabetes mellitus.
Arterial blood pressure was measured according to the standard criteria of recommendations for indirect measurement of arterial blood pressure by the American Heart Association and Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC VII). The participants were seated with the arm supported at the heart level and, on average, two or more readings on different occasions were taken.
Fasting blood glucose was assessed using an Olympus AU640 procedure (Olympus corporation, Tokyo, Japan). Serum insulin concentration was measured using an insulin electrochemiluminescence immunoassay developed by Roche Diagnostics (Mannheim, Germany) for the Elecsys and cobas e immunoassay analyzer (Roche Diagnostics, Mannheim, Germany).
Insulin resistance was determined by HOMA-IR (homeostasis model assessment of insulin resistance) and was calculated from fasting glucose and insulin concentrations using the following formula:
A cutoff of 2.5 was considered to define insulin resistance 21.
A comparison and contrast analysis of data was carried out using standard statistical methods. Data were analyzed using the Statistical Package for the Social Sciences (v. 17.0; SPSS Inc., Chicago, Illinois, USA). Quantitative data were analyzed using a two-sample independent ‘t-test’ and categorical data were analyzed using ‘Pearson’s χ2-test/Fisher’s exact test’ using the SPSS-17 software. P-values less than 0.05 were considered to be significant. All data are expressed in mean±SD.
The total study population was 100, 50 cases and 50 control participants. The mean age of the cases was 45.72±12.22 years, whereas the mean age of the controls was 42.32±12.17 years. Table 2 shows a comparison of the mean age between cases and controls. The difference between the two groups is statistically insignificant (P=0.167) (Tables 1–7).
There is a large body of experimental evidence indicating that insulin resistance and compensatory hyperinsulinemia are increased among patients with essential hypertension. Although there is considerable evidence that patients with essential hypertension are insulin resistant/hyperinsulinemic as compared with normotensive individuals 9–14, some population-based studies have not been able to discern a significant relationship between insulin resistance and hyperinsulinemia 18–20. Indeed, there is no consensus as to whether or not there is a physiological relationship between insulin resistance/compensatory hyperinsulinemia and blood pressure regulation. This positive relationship has been confirmed in several longitudinal studies, but the results are not entirely consistent. The mechanism through which insulin resistance is associated with hypertension is not known. It is believed that insulin resistance could cause hypertension through compensatory hyperinsulinemia 23. Insulin has been shown to stimulate the sympathetic nervous system, increase renal sodium retention, modulate cation transport, and induce hypertrophy of vascular smooth muscle.
Our study was a hospital-based case–control study that included 50 cases and 50 controls. Among 50 cases, 28 (56%) were men and 22 (44%) were women. The mean age of the cases was 45.72±12.23 years. The parameter used as a marker for adiposity was BMI. The mean BMI in the patients was 22.07±1.65 kg/m2 as compared with 22.26±1.63 kg/m2 in controls. The difference between the two groups was statistically insignificant (P=0.548).
The mean fasting insulin concentration in the hypertensive group was 15.33±13.76 μU/ml. Among hypertensives, the mean serum insulin level was 15.06 μU/ml in men and 15.67 μU/ml in women. Thus, there was no significant difference in fasting insulin levels between hypertensive men and women. The maximum concentration was 78.96 μU/ml. Of 50 patients, eight (16%) had hyperinsulinemia and two (4%) had hypoinsulinemia, with a reference range of 2.6–24.9 μU/ml (package insert: Roche Insulin reagent; Roche Diagnostic Corp., Indianapolis, Indiana, USA). In the control group, the mean insulin concentration was 8.02±4.08 μU/ml. Although fasting insulin concentration was significantly higher in the hypertensive than in the normotensive group, absolute hyperinsulinemia was present in only 16% of hypertensives.
Some previous studies have shown a high mean fasting insulin concentration (66.83 24, 45.99 25, and 54.8 μU/ml 26) and high percentage of hyperinsulinemics (45 24, 80 27, 74 25, and 27% 26), whereas in our study, the mean fasting insulin concentration was 15.33±13.76 μU/ml and only 16% were hyperinsulinemic.
When compared with previous studies, our study yielded mixed results. Serum insulin levels were significantly higher in hypertensives as compared with normotensives, which favors the hypothesis of the role of insulinemia in the pathogenesis of hypertension. We report a lower incidence of hyperinsulinemia (16%) and a lower mean fasting insulin level (15.33±13.76 μU/ml) when compared with studies that have shown a positive relation. Our study group had a lower mean age, lower mean BMI, and normal lipid profile. In addition, our patients were first-time detected hypertensives and had not received any antihypertensive treatment. We hypothesize that these parameters may have a confounding effect on the overall results. In addition, ethnicity may also have a role.
We also report a significant difference in insulin resistance between the two groups. We used HOMA-IR as a measure of insulin resistance, which is calculated from fasting insulin and fasting blood glucose levels. A cutoff of 2.5 was considered to define insulin resistance 21. The mean HOMA-IR was 3.81±3.42 in the hypertensive group as compared with 1.76±0.93 among the controls. In the hypertensive group, 62% of the patients were insulin resistant as compared with the control group, in which only 24% of the participants were insulin resistant. This difference was statistically significant (P=0.0001).
From our study, the relation between insulin resistance and blood pressure appears to be significant. Insulinemia showed a weak but significant association with hypertension. Most of the studies carried out to examine the role of insulinemia in hypertension included patients without considering the duration of hypertension and BMI.
Most previous studies had reported significantly higher cholesterol and triglyceride levels in hypertensives with hyperinsulinemia. We do not report similar data as patients with dyslipidemia were excluded from the study at the outset.
Our data show that both insulin resistance and insulinemia play a role in the pathophysiology of hypertension. The exact pathophysiological mechanisms explaining the role of hyperinsulinemia and insulin resistance in essential hypertension are complex. It is considered, as already mentioned, that insulin resistance could cause hypertension through compensatory hyperinsulinemia 23. However, our data do not support this notion fully because the prevalence of hyperinsulinemia was very low. It is plausible, however, that the resistance to the vasodilator effect of insulin could lead to an increase in blood pressure. In addition, insulin resistance has been associated with impaired endothelium-dependent vasodilatation 26, which could contribute toward increased blood pressure.
As proposed by Saad et al.28, the association between insulin resistance and hypertension may not be causal. Instead, they may be linked indirectly through mechanisms of an inherited or an acquired nature. A possible link is through the sympathetic nervous system. Enhanced adrenergic tone may lead to increased insulin resistance on the one hand and an increase in blood pressure on the other. Increased levels of inflammatory markers such as tumor necrosis factor could contribute toward both insulin resistance and endothelial dysfunction 29 and underlie the link between insulin resistance and hypertension. A further possibility is that a cellular or a structural defect, genetic or acquired, may constitute the link between insulin resistance and blood pressure.
All the mechanisms mentioned above are biologically plausible. From our study, resistance to insulin action seems to be the predominant pathophysiological mechanism involved in the pathogenesis of hypertension as compared with hyperinsulinemia.
Essential hypertension is significantly associated with higher mean fasting insulin levels and insulin resistance. Hyperinsulinemia plays a possible role in the pathophysiology of essential hypertension, with insulin resistance being the likely predominant mechanism.
Conflicts of interest
There are no conflicts of interest.
1. Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J. Global burden of hypertension: analysis of worldwide data. Lancet. 2005; 365:217–223.
2. Primatesta P, Brookes M, Poulter NR. Improved hypertension management and control: results from the health survey for England 1998. Hypertension. 2001; 38:827–832.
3. Gupta R. Trends in hypertension epidemiology in India. J Hum Hypertens. 2004; 18:73–78.
4. Ahmad SZ, Malik GM. Epidemiology of hypertension in Kashmir. Paper presented at Cardiopulmonary Medicine update 1985; Srinagar: Conference of American College of Chest Physicians; 1985.
5. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002; 360:1903–1913.
6. A response to the need for comprehensive, consistent and comparable information on health risks at global and regional level. World Health Organization report, 2009. Available at: http://www.who.int/healthinfo/globalburdendisease/GlobalHealthRisksreportfull.pdf
7. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al.. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC VII report. JAMA. 2003; 289:2560–2572.
8. Reaven GM. Banting lecture 1988. Role of insulin
resistance in human disease. Diabetes. 1988; 37:1595–1607.
9. Landsberg L, Krieger DR. Obesity, metabolism, and the sympathetic nervous system. Am J Hypertens. 1989; 2:1255–1325.
10. Lucas CP, Estigarribia JA, Darga LL, Reaven GM. Insulin
and blood pressure in obesity. Hypertension. 1985; 7:702–706.
11. Modan M, Halkin H, Almog S, Lusky A, Eshkil A, Shefi M, et al.. Hyperinsulinemia: a link between hypertension, obesity and glucose intolerance. J Clin Invest. 1985; 75:809–817.
12. Ferrannini E, Buzzigoli G, Bonadona R. Insulin
resistance in essential hypertension. N Engl J Med. 1987; 317:350–357.
13. Shen DC, Shieh SM, Fuh M, Wu DA, Chen YD, Reaven GM. Resistance to insulin
-stimulated glucose uptake in patients with hypertension. J Clin Endocrinol Metab. 1988; 66:580–583.
14. Swislocki ALM, Hoffman BB, Reaven GM. Insulin
resistance, glucose intolerance and hyperinsulinemia in patients with hypertension. Am J Hypertens. 1989; 2:419–423.
15. Pollare T, Lithell H, Berne C. Insulin
resistance is a characteristic feature of primary hypertension independent of obesity. Metabolism. 1990; 39:167–174.
16. Skarfors ET, Lithell HO, Selinus I. Risk factors for the development of hypertension: a 10-year longitudinal study in middle-aged men. J Hypertens. 1991; 9:217–223.
17. Lissner L, Bengtsson C, Lapidus L, Kristjansson K, Wedel H. Fasting insulin
in relation to subsequent blood pressure changes and hypertension in women. Hypertension. 1992; 20:797–801.
18. Reaven GM. Relationship between insulin
resistance and hypertension. Diabetes Care. 1991; 14:33–38.
19. Mbanya J-C, Wilkinson R, Thomas T, Alberti K, Taylor R. Hypertension and hyperinsulinemia: a relation in diabetes but not in essential hypertension. Lancet. 1988; I:733–734.
20. Collins VR, Dowse GK, Finch CF, Zimmet PZ. An inconsistent relationship between insulin
and blood pressure in three Pacific Island populations. J Clin Epidemiol. 1990; 43:1369–1378.
21. Saad MF, Lillioja S, Nyomba BL, Castillo C, Ferraro R, DeGregorio M, et al.. Racial differences in the relation between blood pressure and insulin
resistance. N Engl J Med. 1991; 324:733–739.
22. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin
resistance and beta-cell function from fasting plasma glucose and insulin
concentrations in man. Diabetologia. 1985; 28:412–419.
23. Weir DM. Elecsys 2010 operators manual. 2005.Mannheim:Roche Diagnostics.
24. Lindholm LH, Ibsen H, Dahlöf B, Devereux RB, Beevers G, de Faire U, et al.. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan intervention for Endpoint Reduction in Hypertension Study (LIFE): a randomized trial against atenolol. Lancet. 2002; 359:1004–1010.
25. Bhatnagar MK, Ganesh R, Goel A, Venna NPS, Chauhan UPS. A study of hyperinsulinemia in Indian hypertensive subjects. J Assoc Physicians India. 1994; 42:57–59.
26. Zavaroni I, Mazza S, Dall’Aglio E, Gasparini P, Passeri M, Reaven GM. Prevalence of hyperinsulinaemia in patients with high blood pressure. J Intern Med. 1992; 231:235–240.
27. Reaven GM, Hoffman BB. A role for insulin
in the aetiology and course of hypertension. Lancet. 1987; 2:435–436.
28. Saad MF, Rewers M, Selby J, Howard G, Jinagouda S, Fahmi S, et al.. Insulin
resistance and hypertension. The Insulin
Resistance Atherosclerosis Study. Hypertension. 2004; 43:1324–1331.
29. Wheatcroft SB, Williams IL, Shah AM, Kearney MT. Pathophysiological implications of insulin
resistance on vascular endothelial function. Diabet Med. 2003; 20:255–268.