More and more evidence is emerging that highlights the far-reaching consequences of obesity on kidney morphology and function disorders. The prevalence of obesity is increasing by alarming proportions worldwide and more than 20% of the world population is overweight, while nearly 300 million are obese [22–24]. Driving forces for overweight and obesity include increasing sedentary lifestyle and consumption of a western diet high in fat, fructose and salt and their interaction with genetic factors and epigenetic processes [25–27]. This study shows that a hyperinsulinemic (HI: 10.85 ± 4.09 μg/ml) subgroup of well-characterized metabolic syndrome bearers-obese subject but not all obese subjects, show higher glycemic and elevated blood pressure levels when compared to lean (LS) and meanly, normoinsulinemic (NI: 5.51 ± 1.18 μg/ml, P < 0.027) groups. Here, it has been supposed that insulin resistance may result from a cluster of inflammatory and metabolic disorders with an inherent potential for hemodynamic abnormalities particularly, higher blood pressure. Also in the current study, the combination of hyperinsulinemia, higher HOMA-IR (HI: 2.19 ± 0.70 (n = 12) vs. LS: 0.83 ± 0.23 (n = 12) and NI: 0.98 ± 0.22 (n = 15), P < 0.0001) associated with lower QUICKI in HI obese when compared with LS and NI volunteers (P < 0.0001), strongly suggests the occurrence of insulin resistance and, as previously demonstrated, a defect in insulin-stimulated peripheral action [28–30]. The link between hyperinsulinemia and higher blood pressure described above does not prove the presence of causal relationships, but experimental findings have shown possible mechanisms, which may account for a putative relationship [31, 32]. Otherwise, the prevalence of hypertension in type 2 diabetes mellitus is increased 3-fold, and the coexistence of hypertension in diabetic patients greatly enhances the development of cardiovascular disease and chronic renal failure . The current study shows, although on normal range, a clear and significant increase of the arterial pressure in hyperinsulinemic obeses, characterizing a prehypertension state. Prehypertension is increasingly recognized as a risk factor for cardiovascular disease. This is supported by studies demonstrating the association of increased systolic or diastolic dysfunction in a prehypertension state in genetic or diet-induced rodent models of obesity [8–10]. It is estimated that 37% of the adult population has prehypertension and 40% of these subjects will progress to hypertension within a two-year time frame . By the way, impaired insulin stimulated uptake of glucose associated with impaired vasodilatation has been shown to be early manifestations in insulin resistant models of obesity [11–13, 24]. In this respect, increased activation of renin-angiotensin system (RAS) and enhanced oxidative stress within cardiovascular tissue in obesity are important mediators of insulin resistance and vasoconstriction . Although the precise mechanism by which arterial blood pressure enhances in HI obese subjects remain to be elucidated, taking in account our and previous findings we may suppose that systemic inflammatory response, endothelial dysfunction, sympathetic neural and renin-angiotensin overactivity and, renal fluid and electrolyte balance disorder is thought to play a dominant role in the long-term salt and water retention, vascular resistance and consequently, enhanced blood pressure.
In the past two decades, the view of adipose tissue has gone from revolutionary change from inert energy store to the biggest endocrine organ . The current study confirms that in the obese state, the plasma levels of leptin, TNF-α, IL-6 and PCR are increased, and these molecules have been shown to be associated with metabolic inflammation or neologically by metaflammation to review see [35, 36] and insulin resistance. Although mechanisms underlying this inflammatory response are not well understood, endoplasmic reticular stress is one of the cellular stress events that activate inflammatory signaling pathways including activation of JNK and mTOR [35, 36]. Also, have been shown that TNF-α and IL-6 cause systemic insulin resistance through activation of MAP kinases, protein kinase C (PKC) and SOCS-3 mediated proteasome degradation . In addition to adipose tissue dysfunction, activation of Toll-like receptor 4 (TLR-4) and perhaps other TLRs induced by nutrients excess such as saturated fatty acid, gut derived lipopolysaccharide (LPS), uric acid and/or intestinal dysbiosis contributes significantly to hepatic and systemic inflammatory response in hyperinsulinemic obeses [37, 38].
The only hormone displaying an opposite trend is adiponectin. Here, the adiponectin measured in basal period was significantly enhanced in NI subjects when compared to HI groups (P < 0.04). The association between adiponectin and hypertension is evident in clinical studies by showing that hypoadiponectinemia is a risk factor for hypertension independent of insulin resistance and diabetes, while overexpression of adiponectin may also decrease the blood pressure in genetically obese mice [39–41]. Nevertheless, despite the well-established association of adiponectin with metabolic disorders and hypertension, very few studies address the relationship between adiponectin and hypertension at a mechanistic level. Recently, several studies have also focused on the effects of adiponectin on the sympathetic nervous system (SNS), RAS and kidney function. The role of increased SNS activity in insulin resistance and hypertension is increasingly recognized [15, 24, 31, 42]. A disproportionate activation of SNS in the obese state is proposed to play important roles in obesity-associated metabolic dysfunction . Conversely, Tanida et al.  have found that adiponectin attenuates blood pressure and sympathetic nerve activity by inhibition of leptin action in the brain. Taking in account our and the above findings, we may speculate that adiponectin, secreted from adipose tissue decreases the risk for insulin resistance, inflammation, and blood pressure elevation in a particular subgroup of normoinsulinemic obeses (Figure 6).
Surprisingly, the current report shows a similar insulin-mediated reduction of post-proximal urinary sodium excretion in lean (LS: 9.41 ± 0.68% vs. 6.38 ± 0.92%, P = 0.086) and normoinsulinemic (NI: 8.41 ± 0.72% vs. 5.66 ± 0.53%, P = 0.0025) and hyperinsulinemic obese subjects despite of persistent and pronounced insulin plasma levels in HI obese subgroup (HI: 8.82 ± 0.98% vs. 6.32 ± 0.67%, P = 0.0264), after oral glucose load, despite elevated insulinemic levels in hyperinsulinemic obeses. This exaggerated enhancement of serum insulin levels in response to an oral glucose load, associated with similar renal sodium reabsorption in NI and HI subjects, separately, could not be enough to explain the high blood pressure development in our specific HI obese subgroup. Thus, the present findings provide additional insights about mechanisms and insulin function during high blood pressure development in obese subjects, beyond of those involved in the renal sodium transport. Furthermore, the equal tubule sodium reabsorption in normoinsulinemic and hyperinsulinemic obeses observed in the current study may argue favorably to decrease renal insulin sensitivity in HI volunteers. The sodium-retaining effect of insulin has been known for a long time , but there is no consensus on the exact mechanism of action. Prior studies assume that antinatriuretic effect of insulin, predominantly in the post-proximal renal tubules [15, 45], may be due to a fall in filtration fraction, renal sympathetic nerve and/or RAS overstimulation and, suppression of natriuretic peptide release . Also, for all of experimental groups, the contribution of the glucose filtered load to tubule Na+ reabsorption via a Na+/glucose cotransport or Na+/H exchanger should also be considered. Here, the oral glucose load in LS and OS did not change the glomerular filtration rate, estimated by CCr and consequently, the filtered sodium load, suggesting that the antinatriuresis observed was mediated by direct tubular mechanisms. Our data was positively related with an increased post-proximal fractional reabsorption of sodium without enhanced tubular potassium excretion suggesting that insulin action preceded the distal segments of nephron.
Although the renin-angiotensin system (RAS) was not detailed here, the angiotensin II (AngII) effects on sympathetic activation are widely demonstrated by several studies. Under pathophysiological conditions, such as obesity-associated metabolic diseases, the overproduction of AngII plays an important role in the development and progression of insulin resistance, hyperinsulinemia and arterial hypertension. The RAS causes sustained sympathetic overactivity by modulating central neurons in the subfornical organ of the forebrain [47, 48]. Interestingly, these neural responses are associated with modulation of peripheral T cell immune responses [47, 48] suggesting a link between glucose metabolic disorders and the central regulation of systemic immune and/or inflammatory responses through brain AngII signaling and resultant increased SNS outflow. Thus, we may hypothesize that inappropriate activation of RAS and/or SNS may significantly contribute to this inflammatory response, progression of insulin resistance and kidney disorders in this specific subgroup of hyperinsulinemic obese. We also may not rule out the participation of adiponectin in this process since the plasma adiponectin level is reported to be increased and to show a positive correlation with plasma natriuretic factors in heart disorders (7,14). The current study has shown that the plasma adiponectin level was positively correlated with the enhanced natriuresis in normoinsulinemic obese subjects while it is decreased in HI subgroup. The plasma natriuretic peptide level had the same influence on adiponectin as that of the waist circumference, HDL-cholesterol, and triglycerides. We suppose that positive association between plasma adiponectin and normoinsulinemic individuals in our study that adiponectin may retard the arterial pressure increase and so, may predict a better prognosis or morbidity of cardiovascular disease, specifically on hypertension development, even in obese subjects. The precise mechanism of these phenomena remains unknown.