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significant and clinically relevant worsening of insulin sensitivity with an isoenergetic plant-based high-protein diet

healthy humans that are exposed to amino acid infusions rapidly develop insulin resistance

longer term high-protein intake has been shown to result in whole-body insulin resistance [68, 118], associated with upregulation of factors involved in the mammalian target of rapamycin (mTOR)/S6K1 signalling pathway [68], increased stimulation of glucagon and insulin within the endocrine pancreas, high glycogen turnover [118] and stimulation of gluconeogenesis [68, 118].

it was recently shown in a large prospective cohort with 10 years followup that consuming 5% of energy from both animal and total protein at the expense of carbohydrates or fat increases diabetes risk by as much as 30% [69]. This reinforces the theory that high-protein diets can have adverse effects on glucose metabolism.

Another recent study showed that low-carbohydrate high-protein diets, used on a regular basis and without consideration of the nature of carbohydrates or the source of proteins, are also associated with increased risk of cardiovascular disease [70], thereby indicating a potential link between high-protein Western diets, T2DM, and cardiovascular risk.

innate immune system may be causally linked to obesity

adipose tissue contains a substantial population of macrophages, and macrophage-driven adipose inflammation contributes significantly to the pathogenesis of obesity

Collectively, activation of the innate immune system is strongly associated with ASCVD, insulin resistance, and obesity, and recent evidence suggests that much of this association can be traced to a unique family of PRRs known as TLRs

TLRs are a family of type I transmembrane receptors, currently thought to comprise at least 13 members in mammals, that specifically recognize a variety of microbial PAMPs and trigger host cellular responses

Free SFAs have indeed been demonstrated to elicit TLR4-dependent and TLR2-dependent responses in several cell types.

Endogenous SFAs released from adipocytes activate cocultured macrophages via TLR4 [18], indicating the potential for cellular crosstalk in adipose tissue. Collectively, there is a growing body of evidence that SFAs promote, whereas long chain PUFA antagonize, TLR4-dependent and TLR2-dependent signaling in multiple cell models

In an elegant study, Shi et al. [16] demonstrated that SFAs activate TLR4-dependent signaling in both macrophages and adipocytes, and mice lacking TLR4 are protected against insulin resistance driven by intravenous lipid infusion

In addition to effects in macrophages and adipocytes, SFAs can activate TLR4 in the hypothalamus, which triggers a central inflammatory response that results in resistance to anorexigenic signals

endogenous SFAs can indeed promote innate immunity and inflammatory disease

This finding strongly supports the work of Hwang and coworkers [19–22] demonstrating that ω-3 PUFAs can effectively counteract SFA-induced TLR4 activation in cultured macrophages and dendritic cells.

Thus, while glucose metabolism is negatively regulated by phosphofructokinase, fructose can continuously enter the glycolytic pathway. Therefore, fructose can uncontrollably produce glucose, glycogen, lactate, and pyruvate, providing both the glycerol and acyl portions of acyl-glycerol molecules. These particular substrates, and the resultant excess energy flux due to unregulated fructose metabolism, will promote the over-production of TG (reviewed in [53]).

Glycemic excursions and insulin responses were reduced by 66% and 65%, respectively, in the fructose-consuming subjects

reduction in circulating leptin both in the short and long-term as well as a 30% reduction in ghrelin (an orexigenic gastroenteric hormone) in the fructose group compared to the glucose group.

A prolonged elevation of TG was also seen in the high fructose subjects

Both fat and fructose consumption usually results in low leptin concentrations which, in turn, leads to overeating in populations consuming energy from these particular macronutrients

Chronic fructose consumption reduces adiponectin responses, contributing to insulin resistance

A definite relationship has also been found between metabolic syndrome and hyperhomocysteinemia

the liver takes up dietary fructose rapidly where it can be converted to glycerol-3-phosphate. This substrate favours esterification of unbound FFA to form the TG

Fructose stimulates TG production, but impairs removal, creating the known dyslipidemic profile

the effects of fructose in promoting TG synthesis are independent of insulinemia

Although fructose does not appear to acutely increase insulin levels, chronic exposure seems to indirectly cause hyperinsulinemia and obesity through other mechanisms. One proposed mechanism involves GLUT5

If FFA are not removed from tissues, as occurs in fructose fed insulin resistant models, there is an increased energy and FFA flux that leads to the increased secretion of TG

In these scenarios, where there is excess hepatic fatty acid uptake, synthesis and secretion, 'input' of fats in the liver exceed 'outputs', and hepatic steatosis occurs

Carbohydrate induced hypertriglycerolemia results from a combination of both TG overproduction, and inadequate TG clearance

fructose-induced metabolic dyslipidemia is usually accompanied by whole body insulin resistance [100] and reduced hepatic insulin sensitivity

Excess VLDL secretion has been shown to deliver increased fatty acids and TG to muscle and other tissues, further inducing insulin resistance

the metabolic effects of fructose occur through rapid utilization in the liver due to the bypassing of the regulatory phosphofructokinase step in glycolysis. This in turn causes activation of pyruvate dehydrogenase, and subsequent modifications favoring esterification of fatty acids, again leading to increased VLDL secretion

High fructose diets can have a hypertriglyceridemic and pro-oxidant effect

Oxidative stress has often been implicated in the pathology of insulin resistance induced by fructose feeding

Administration of alpha-lipoic acid (LA) has been shown to prevent these changes, and improve insulin sensitivity

LA treatment also prevents several deleterious effects of fructose feeding: the increases in cholesterol, TG, activity of lipogenic enzymes, and VLDL secretion

Fructose has also been implicated in reducing PPARα levels

PPARα is a ligand activated nuclear hormone receptor that is responsible for inducing mitochondrial and peroxisomal β-oxidation

decreased PPARα expression can result in reduced oxidation, leading to cellular lipid accumulation

fructose diets altered the structure and function of VLDL particles causing and increase in the TG: protein ratio

LDL particle size has been found to be inversely related to TG concentration

therefore the higher TG results in a smaller, denser, more atherogenic LDL particle, which contributes to the morbidity of the metabolic disorders associated with insulin resistance

High fructose, which stimulates VLDL secretion, may initiate the cycle that results in metabolic syndrome long before type 2 diabetes and obesity develop

A high flux of fructose to the liver, the main organ capable of metabolizing this simple carbohydrate, disturbs normal hepatic carbohydrate metabolism leading to two major consequences (Figure 2): perturbations in glucose metabolism and glucose uptake pathways, and a significantly enhanced rate of de novo lipogenesis and TG synthesis, driven by the high flux of glycerol and acyl portions of TG molecules coming from fructose catabolism

a series of long-term balance studies (67-69) showed that intake of the proposed safe allowance of 0.57 g (70) egg protein resulted in negative nitrogen balance, loss of lean body mass, and deteriorating serum protein and transferase values unless additional energy or nonessential nitrogen was supplied

The results of the present study suggest that the current EAR recommendations (0.66 g · kg−1 · d−1) and RDA (0.80 g · kg−1 · d−1) for protein are underestimated at 29% and 33%, respectively