Correcting hepatic insulin resistance
This analysis suggests that healthful measures which tend to correct hepatic insulin resistance may favourably impact the vascular and metabolic health of subjects with high TMAO. Evidently, sustained remediation of the visceral obesity which often underlies hepatic insulin resistance should be helpful in this regard; nonetheless, it is easier to recommend this than to achieve it! By improving the insulin sensitivity of hypertrophied adipocytes, thiazolidinediones such as pioglitazone tend to improve hepatic insulin resistance in people with diabetes by quelling excessive fatty acid efflux from adipocytes, even though they tend to increase body fat mass somewhat.78–81
Hormones and medications which boost hepatic AMPK activity tend to improve impaired hepatic insulin sensitivity. AMPK achieves this, at least in part, by downregulating mTORC1 activity, which acts indirectly to promote phosphorylations of insulin receptor substrate-1 that impede transmission of the insulin signal.82 Also, by promoting oxidative disposal of FFAs while suppressing lipogenesis, AMPK could be expected to lessen hepatic diacylglycerol synthesis, thereby getting to the root of hepatic insulin resistance.83 84 The favourable impact of metformin on hepatic insulin resistance in diabetes is thought to be mediated by activation of AMPK.85–88 The phytochemical nutraceutical berberine, widely used in China for the management of type 2 diabetes, is likewise thought to improve glycaemic control via activation of AMPK, and has been shown to counter hepatic insulin resistance in diabetic hamsters.89–93
Both adiponectin and glucagon-like peptide-1 (GLP-1) act on the liver to stimulate AMPK activity; moreover, they have been shown to combat hepatic insulin resistance, and work in various ways to promote vascular and metabolic health.94–106 Hence, elevated TMAO may often be a marker for suboptimal adiponectin and/or GLP-1 activity. The antidiabetic drug pioglitazone tends to boost the diminished adiponectin secretion of hypertrophied adipocytes.107 108 It seems likely that plant-based diets of rather low-protein content can increase adiponectin production, as these boost the liver’s production of fibroblast growth factor-21, one of whose major functions is to promote adiponectin secretion by adipocytes.109 110 Such diets are also useful for preventing or correcting the obesity that often underlies hepatic insulin resistance.111–113
With respect to GLP-1, acarbose, dietary lente carbohydrate, bile acid sequestrants and certain prebiotics can boost GLP-1 production, drugs inhibiting plasma dipeptidyl peptidase-4 can prolong its half-life, and injectable GLP-1 receptor agonists can mimic its bioactivity.114–117
PPARalpha agonists, such as fenofibrate, also promote hepatic fatty acid oxidation, owing to induction of a range of mitochondrial enzymes (including carnitine palmitoyl transferases-1a and -2, fatty acyl-CoA dehydrogenase, UCP-2) which catalyse such oxidation.118 119 Moreover, PPARalpha agonism also acts indirectly to stimulate AMPK in the liver and other tissues by boosting adiponectin production in adipose tissue; PPARalpha enhances hepatic synthesis and release of fibroblast growth factor-21, which in turn stimulates adiponectin synthesis in adipocytes.120–123 Not surprisingly, fenofibrate has been shown to decrease hepatic levels of diacylglycerol and alleviate hepatic insulin resistance in rodents fed diets high in fat and/or fructose.124–128 Moreover, fenofibrate therapy has been shown to reduce risk for CV events in patients with metabolic syndrome.118
There is recent evidence that the carotenoid antioxidant astaxanthin can also serve as a PPARalpha agonist, and, both in rodents and humans, alleviate the dyslipidaemia associated with metabolic syndrome.129–135 In obese mice, astaxanthin has been reported to improve hepatic insulin resistance.136 Krill oil provides esterified forms of astaxanthin which have superior bioavailability, as well as health-protective omega-3 fatty acids, oxidised forms of which likewise serve as PPARalpha agonists.137–140 Moreover, krill oil supplementation has been found to beneficially modulate serum lipid profile–including, intriguingly, a reduction in LDL cholesterol–in controlled clinical trials.141 Krill oil, even when compared with fish oil, suppresses hepatic steatosis in rodents.142–144 This may be due to its astaxanthin content, which is not found in fish oil. Moreover, krill oil, but not fish oil, reduces diacylglycerol and ceramide content in the liver.145 The phospholipid fraction of krill oil has also been noted to reduce hepatic glucose production, unlike fish oil.146 Thus, krill oil, being a source of highly bioavailable form of astaxanthin, appears to have additional advantages for reducing hepatic steatosis and hepatic insulin resistance compared with fish oil.
In brief, if this analysis is accurate, various measures which alleviate hepatic insulin resistance–correction of visceral obesity, activation of 5' adenosine monophosphate-activated protein kinase (AMPK) with metformin or berberine, activation of PPARalpha with fenofibrate or astaxanthin, amplification of adiponectin production with pioglitazone or plant-based diets, and clinical strategies which boost the production or bioactivity of GLP-1, could be expected to decrease elevated TMAO while also decreasing the risk for vascular events and diabetes associated with this risk factor. Figure 1 summarises these relationships.
Figure 1Measures which increase adiponectin, increase GLP-1 activity, control metabolic syndrome and activate hepatic AMPK or PPARalpha may decrease elevated TMAO and associated vascular/metabolic risk. GLP-1, glucagon-like peptide-1; TMAO, trimethylamine-N-oxid.