The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 13 No. 4 • August 2010

Diabetes, Insulin Resistance
Fructose-Induced Liver Gluconeogenesis Nearly Normalized by L-Carnitine

A key problem in diabetes is the failure of the liver to stop generating glucose, a process called gluconeogenesis. When blood sugar is low (such as when fasting during sleep), the liver is supposed to create glucose (either by breaking down glycogen or synthesizing glucose from amino acids), but when blood sugar is increased (as it is following a meal), gluconeogenesis by the liver is supposed to be inhibited by the insulin released following the meal. But, as diabetics typically are insulin resistant, the insulin signal is ineffective in stopping the liver from continuing to churn out glucose.

Hence, natural substances that attenuate gluconeogenesis can be highly beneficial for people who are insulin resistant. A recent paper1 describes a study of the effect of L-carnitine on gluconeogenesis in rats. Male Wistar rats were divided into four groups of six rats each. One group was fed a control diet, a second group was fed a high fructose* diet, the third group was fed the high fructose diet plus L-carnitine (CA) (300 mg of CA/kg body weight/day i.p.), and the fourth group received the control diet plus the same dose of supplemental CA. The diet and supplementation regimen ran 30 days.

* 60 g fructose/100 g diet is a very high fructose diet.

The results showed that the fructose-fed rats had significant increases of the circulating gluconeogenic substrates such as glycerol, lactate, and pyruvate as compared to the control rats. The L-carnitine (CA) supplementation to fructose-fed rats significantly reduced those levels as compared to the untreated fructose-fed rats. Liver cells from the fructose-diet fed rats produced significantly more glucose from pyruvate, lactate, glycerol, fructose, and alanine as compared to the liver cells from rats on the control diet. But the liver cells from the fructose-fed rats also supplemented with CA produced normal levels of glucose similar to the levels of the control animals.

The authors state: “The abnormalities associated with fructose feeding such as increased gluconeogenesis, reduced glycogen content and other parameters were brought back to near normal levels by CA.” “The benefits observed could be attributed to the effect of CA on fatty acyl-CoA transport.” The latter refers to the fact that CA transports fatty acids into the mitochondria for oxidation. Under conditions of CA deficiency, there is an excess of free fatty acids in the bloodstream, which inhibits the uptake and metabolism of glucose in skeletal muscle and the heart.1

As the authors explain, “[f]atty acid supply to the liver plays an important role in determining both the ability of insulin to suppress glucose production and the rate of gluconeogenesis.”1

It is also interesting to note the suggestion made recently2 that increased fructose intake may be a risk factor for dementia. The authors cite an animal study showing that a high fat/refined sugar diet even for a short duration (in this case, 2 months) was found to be associated with reduced hippocampal levels of brain-derived neurotrophic factor (BDNF), an important molecule in learning and memory) and impaired spatial memory. Another recent study they cite found that in overweight and obese women, high fructose intake was associated with increased de novo lipogenesis (the synthesis of triglycerides), lipid peroxidation, and gluconeogenesis. They also describe two animal studies suggesting that “insulin resistance status induced by high fructose intake and/or the insulin resistance syndrome (i.e., metabolic syndrome) is linked to cognitive decline and neurodegeneration, namely AD [Alzheimer disease] type pathology.” However, they note that no human studies have been performed on the short-term and long-term effects of fructose on cognition and dementia risk, although there has been preliminary evidence from subjects with type 2 diabetes of an association between insulin resistance and brain structural changes along with deficits in cognitive performance.3

We both take CA, in the form of acetyl-L-carnitine, 2 grams per day, to improve our insulin sensitivity and also for possible protection against cognitive decline.3,4


  1. Rajasekar and Anuradha. Fructose-induced hepatic gluconeogenesis: effect of L-carnitine. Life Sci 80:1176-83 (2007).
  2. Stephan et al. Perspective: Increased fructose intake as a risk factor for dementia. J Gerontol A Biol Sci Med Sci 65(8):809-14 (2010).
  3. Juliet et al. Carnitine: a neuromodulator in aged rats. J Gerontol A Biol Sci Med Sci 58(11):970-4 (2003).
  4. Ames and Liu. Delaying the mitochondrial decay of aging with acetylcarnitine. In: Alesci S et al, eds. Carnitine: the Science Behind a Conditionally Essential Nutrient. New York, NY: Ann N Y Acad Sci;1033:108-16 (2004).

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