Liver Enzymes the #1 Marker of Insulin Resistance!? What Do HbA1C & ALT, AST and GPT Tell Us About Diabesity?

Just like type II diabetes, NAFLD is a life-style disease.
While it may not be obvious, today's SuppVersity post is very closely related to Sunday's post about supplements to battle insulin resistance. The recent revelation that the liver enzymes alanine transaminase (ALT aka GPT), aspartate transaminase (AST aka SGOT) and gamma-glutamyl transpeptidase (GGT aka gamma-GT) and not free fatty acid levels are the most reliable predictors of insulin sensitivity in overweight and obese, non-diabetic adults does after all show clearly support the notion that we (scientists, doctors, patiens) should pay much more attention to the liver. It's the liver that controls blood glucose, lipids and even our hormone levels, not the adipose organ. Therefore it is in the liver, our metabolic organ #1, is where the dark diabesity magic happens.

Heal the liver, cure the insulin resistance

Just in: A recent Stanford study shows that the use of VEGF inhibitors that are usually prescribed as cancer drugs can help diabetics manage their blood glucose levels, by increasing the expression of a protein (HIF-2alpha) that's usually expressed in response to hypoxic cell death and will - as a side effect - increase the expression of insulin receptors and thus restore hepatic insulin sensitivity and the optimal function of all the regularory processes that depend on it (Conger. 2013).
Usually you will think of being overweight and undermuscled, of insulin resistant myocytes (muscle cells) and adipocytes (fat cells) and about eating too much simple sugars, whenever someone is talking about the etiology of insulin resistsance. NAFLD, i.e. non-alcoholic fatty liver disease, on the other hand, is still often thought of as one of the long-term side effects of T2DM.

A recent study from the Children's Nutrition Research Centre at the University of Queensland does however suggest that the connection between having a messed up liver and being insulin resistant does not just start much earlier, than previously thought, but is probably also directly involved in the progression from being slightly insulin resistant to being a real diabetic.

Certainly, central adiposity (=high amounts of visceral, inter-organ fat) is and will always be one of the key risk factors for the development of insulin resistance and its progression towards full blown type 2 diabetes. Whether this is mainly a function of the spatial proximity of the constantly inflamed visceral fat depot to the liver is still a matter of current research. What we do know already is however that the presence of NAFLD is an independent risk factor for cancer and heart disease (Guebre-Egziabher. 2013)

Once the liver has taken a beating, the downstream effects are profound

One thing that's for sure, though, is that the downstream effect that occur, whence the liver is beginning to take a hit are profound:
  • endocrine imbalances resulting from errors in the cytochrome enzymatic cascade that's responsible (among other things) for the conversion and clearance of all sorts of hormones
  • messed up cholesterol levels and lipid profile with increases in LDL and VLDL lipoproteins and decreases in HDL
  • chronically elevated  glucose levels due to lowered glycogen storage capabilities and a lack of control of the gluconeogenic processes in the liver that are no longer shut off when insulin is present, 
  • increased fatique that's mediated at least in parts by the accumulation and build-up of toxic metabolic byproducts and environmental toxins the liver cannot handle any longer
The list goes on and on and I bet you that all 40 overweight and obese (body mass index≥25.0kg/m²) subjects with elevated ALT and AST values in the study at hand were already suffering from these problems.
Figure 1: Correltion coefficients for blood glucose, blood insulin and HbA1C (Gray. 2013)
No wonder that the data in Figure 1 confirms that there is no other parameter - including BMI, adiponectin, blood lipids, i.e. LDL, HDL, etc., I-CAM or ghrelin (the latter are not shown in the figure) that come remotely close as far as their reliability as markers of insulin resistance and the corresponding elevations of the long-term glucose marker HbA1C are concerned.

This does also mean that the study at hand would refute the results of previous experiments which suggest that the mobilization of FFA in the circulation promotes insulin resistance, however
Please remember: AST, ALT & CK will be elevated after workouts so take a couple of days off before you get blood work done.
"this [particular] study found no direct correlations between FFA and markers of insulin sensitivity. Furthermore, there were no clear correlations between markers of insulin sensitivity (glucose, insulin, HbA1C, or HOMA scores) and physical activity or self-reported fatigue. Fatigue scores were correlated with C-reactive protein, suggesting that inflammation may play a role, although there was no significant correlation with ICAM-1"(Gray. 2013)
Overall the currently data from the Gray study does therefore clearly support the notion that there is a  direct "link between liver function, adiposity, and the development of IR [insulin resistance]" (Gray. 2013) that goes well beyond the common understanding of 'adiposity begets insulin resistance, insulin resistance triggers NAFLD'.

Figure 2: Liver tissue in rodents fed a hypercaloric high sucrose diet with (B) and w/out (A) taurine.  Taurine inhibited the development of hepatic steatosis (Gentile. 2011)
Bottom line: While the results of the study at hand certainly shift the focus away from the fat cells and towards the liver, they do not change the fact that "insulin resistance and the subsequent development of T2DM remain primarily lifestyle disorders" (Gray. 2013). In other words, if you followed all the "non-quick fix" tips from part I of the "Restore & Keep Insulin Sensitivity" series, in the first place - you would not have to worry about insulin resistance or non-alcoholic fatty liver disease (NAFLD).

Still, with a new emphasis on the involvement of the liver, the way we approach insulin resistance with supplements may in fact change... Although, when you come to think about it two of the top-supplements from the first and second serving of insulin sensitizing supplements, you will realize that many of them (e.g. alpha lipoic acid, taurine, berberine, etc.) are also known "liver protectors" (Gentile. 2011; Valdecantos. 2012).

Similar data on both improvements in liver health and insulin sensitivity is available for NAC (Haber. 2003) and milk thistle (Maghrani. 2004), as well. It is thus not too far off to assume that whatever you do to protect your liver is also going to have beneficial effects on your glucose metabolism; and what's even better it will improve your blood lipids, make your that your endocrine system works optimally, protect you against the constant assault of environmental toxins and reduce your chance of being carried off by diabetes, cancer and heart disease... still not convinced? Well, then think about something my good friend Carl Lanore likes to say "liver has the words 'to live' or 'life'" in it ;-)

  • Gentile CL, Nivala AM, Gonzales JC, Pfaffenbach KT, Wang D, Wei Y, Jiang H, Orlicky DJ, Petersen DR, Pagliassotti MJ, Maclean KN. Experimental evidence for therapeutic potential of taurine in the treatment of nonalcoholic fatty liver disease. Am J Physiol Regul Integr Comp Physiol. 2011 Dec;301(6):R1710-22.
  • Gray B, et al., Liver enzymes but not free fatty acid levels predict markers of insulin sensitivity in overweight and obese, nondiabetic adults, Nutr Res. 2013 [published ahead of print]
  • Guebre-Egziabher F, Alix PM, Koppe L, Pelletier CC, Kalbacher E, Fouque D, Soulage CO. Ectopic lipid accumulation: A potential cause for metabolic disturbances and a contributor to the alteration of kidney function. Biochimie. 2013 Jul 27.
  • Haber CA, Lam TK, Yu Z, Gupta N, Goh T, Bogdanovic E, Giacca A, Fantus IG. N-acetylcysteine and taurine prevent hyperglycemia-induced insulin resistance in vivo: possible role of oxidative stress. Am J Physiol Endocrinol Metab. 2003 Oct;285(4):E744-53. Epub 2003 Jun 10.
  • Maghrani M, Zeggwagh NA, Lemhadri A, El Amraoui M, Michel JB, Eddouks M. Study of the hypoglycaemic activity of Fraxinus excelsior and Silybum marianum in an animal model of type 1 diabetes mellitus. J Ethnopharmacol. 2004 Apr;91(2-3):309-16.
  • Conger K. Approved cancer drug potentially could help treat diabetes, researchers find. <> retrieved September 16, 2013.
  • Valdecantos MP, Pérez-Matute P, González-Muniesa P, Prieto-Hontoria PL, Moreno-Aliaga MJ, Martínez JA. Lipoic acid improves mitochondrial function in nonalcoholic steatosis through the stimulation of sirtuin 1 and sirtuin 3. Obesity (Silver Spring). 2012 Oct;20(10):1974-83.
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