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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #122: The Insulin Resistance Syndrome Part 3

Apr 24, 2018

Adipose-derived markers and insulin resistance

Whilst rising BMI or waist circumference are clearly linked to insulin resistance and risk for T2DM, a number of adipose-derived factors have attracted interest with respect to determining insulin resistance. Adiponectin, as recently reviewed [21], has been the most notable of these biomarkers. Adiponectin is unlike the other adipocyte hormones in that its concentrations decline with rising obesity. Therefore low levels predict higher risk for T2DM but there are a number of complexities in this relationship. First, it remains unclear if adiponectin measurement aids diabetes risk prediction. For instance, in the British Regional Heart Study men with adiponectin concentrations in the top third of the distribution had a 60% (95% CI 30–77%) lower risk of incident T2DM although adjustment for insulin resistance attenuated the association [22]. Second, in older individuals or those with increased vascular risk, high, not low, adiponectin predicted increased risk of cardiovascular disease and mortality [23]. Risk associations are thus highly context dependent.

With respect to causality, a recent Mendelian randomization study did not support a causal role for adiponectin in insulin resistance and T2DM[24]. Furthermore, other data have shown that low adiponectin in humans is more likely to be a downstream signal of hyperinsulinemia, than a causal upstream determinant of insulin resistance [25].

With respect to other adipokines, leptin has also been widely suggested as a cause of insulin resistance, but in most individuals higher leptin is a marker of percent fat mass. Due to the great degree of correlation with fat mass (i.e., information that can be gained from other simple measures of adiposity) it is unlikely to ever be used in clinical practice to predict diabetes. More interesting adipokines are: (i) IL-6, which is also released from fat cells; there is emerging evidence of a causal association of IL-6R with cardiovascular disease [26] and potentially diabetes, and (ii) PAI-1, an inhibitor of fibrinolysis [27]. There is preliminary evidence of a potential causal association with diabetes. Further work on IL-6 and PAI-1 seem warranted.

Endothelial-derived markers and insulin resistance

There is a wealth of data suggesting a potential role for endothelial dysfunction in insulin resistance. Although the direction of causality remains hotly debated, circulating elevations in some endothelial-derived factors, cell adhesion molecules, in particular E-Selectin, ICAM-1, and t-PA have been shown to predict risk for T2DM, independently of other predictors [2]. However, t-PA can also be released from the liver so its link to insulin resistance may be via differential pathways. VWF has also been linked to insulin resistance but more weakly than other parameters. Finally, microalbuminuria is often considered to reflect vascular dysfunction at the level of the kidney and, interestingly, its levels in urine have long been known to be related to insulin resistance in nondiabetic subjects [28].

Cardiac biomarkers and insulin resistance

There is emerging evidence that as well as metabolism impacting cardiac function, cardiac function may also influence metabolism. Natriuretic peptides are produced by the myocardium in response to mechanical stretch as a downstream result of a range of cardiac and vascular pathologies. A-type and B-type natriuretic peptides exert natriuretic and diuretic effects to limit elevation in blood pressure and fluid accumulation. Circulating levels of BNP and its inactive N-terminal metabolite (NT-proBNP) are used for the clinical exclusion of heart failure. However, evidence from genetic studies shows that elevated BNP protects generally healthy people from diabetes [29]. How do natriuretic peptides protect from insulin resistance? There is evidence that natriuretic peptides cause lipolysis from adipose tissue, and also result in an increase in adiponectin [30]. Thus natriuretic peptides may go some way to “explaining” the adiponectin paradox described earlier; high levels in healthy people are protective, but high levels arising from pathology are adverse signals. Whilst these latter relationships are not commonly discussed in relation to the insulin resistance syndrome, they serve to show that insulin resistance is being linked to some unexpected parameters and in different tissues from those commonly associated with insulin resistance.

Insulin resistance as cardiovascular risk factor?

Given that insulin resistance is associated with dyslipidemia, dysglycemia, high blood pressure, inflammation, thrombotic pathways, and endothelial dysfunction, many have suggested that insulin resistance must be a strong cardiovascular risk factor. Yet, the evidence base for this assumption is relatively limited and there are no large studies linking gold standard clamp-based insulin resistance measurements to subsequent cardiovascular outcomes. The multinational  relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study recently reported weak cross-sectional associations of insulin sensitivity (measured by clamp) with carotid intima media thickness in men but not in women, and insulin sensitivity was not associated with three-year changes in cIMT [31]. To address this important issue, we recently related circulating concentrations of fasting and nonfasting insulin, as well as pro-insulin, to incident coronary heart disease in a meta-analysis of 19 Western prospective studies [32]. The

findings showed that in a comparison of individuals who had circulating levels of each of these markers in the top third with those in the bottom third of the population, the odds ratio for CHD was 1.12 (95% CI 0.98–1.28) for raised fasting insulin, 1.35 (1.14–1.60) for raised nonfasting insulin, and 2.23 (1.65–3.00) for raised pro-insulin. These results also suggest that links between CHD risk and fasting or nonfasting insulin levels are likely to be more modest than previously suspected. Powerful genetic data consortia are required to address the

causal role of insulin in CVD with confidence. Clearly, this area requires further research but, currently, the best available data do not support hyperinsulinemia as a strong risk factor for vascular disease in people without diabetes.

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