|Image 1: "Diabetesity" is prevalent almost every-|
where in the USA (CDC data from 2007)
Coming from scientists from the Universities College of Pharmacy and Health in Atlanta and the School of Pharmacy and Health Performance at the University of Atlanta is a review (Ryan. 2011) of the therapeutic use(-fulness) of Liraglutide, a subcutaneously administered glucagon-like peptide 1 (GLP-1) agonist that has already been approved for the treatment of diabetes type II in the US and Europe. The drug itself is structurally similar to GLP-1 with artificial modifications that slow absorption and DPP-4 degradation, while increasing aggregation and non-covalend albumin binding. The result, a fine-tuned version of neuroendocrine glucose-increasing hormone GLP-1, which is produced in the enteroendocrine K cells in the duodenum and jejunum and has a much shorter half-life of only 5 to 7 minutes, has been shown to increase glucose-dependend insulin release by 34%-118%, while reducing postprandial glucagon levels by 20% . Furthermore, ...
Liraglutide reduced PPG levels because of its ability to delay gastric emptying and increase satiety, which has been shown to decrease a single-meal intake by 28% (95% CI, 0.73–0.94).In the 13 randomized human studies the authors reviewed, the synergy of improved beta-cell function, insulin release and glucose uptake along with a satiety-induced reduction in food intake alone facilitated a medial weight loss which ranged from a meager 30g to statistically significant, yet by no means earth-shattering 3.24kg.
Note: In all honesty (and despite all my antipathies against big pharma), some of the more recent data on Metformin seems to indicate that the latter would be the preferred choice for treatment of diabetes, it would, however not work as synergistically with AICAR, because it has lately been found that Metformin appears to share the same working mechanism, i.e. AMPK activation (for a recent review cf. Violett. 2011)In spite of its negligible effects on weight loss, Ligraglutide, due to its ability to effectively manage blood glucose levels and restore insulin sensitivity, could set the scene for an effective dietary and exercise intervention, which would not only entail weight loss, but could eventually make the use of the GLP-1 analogue obsolete.
|Figure 1: Weight of fat pads in g/100g body weight in AICAR (intraperitoneal injections @ 0.7g/kg body weight) treated vs. control male Wistar rats after 4 and 8 weeks of treatment (data adapted from Gaidhu. 2011)|
Attention! In the May issue of Drug Testing and Analysis (Thevis. 2011), Mario Thevis and his colleagues from the Center for Preventive Doping Research - Institute of Biochemistry at the German Sport University in Cologne report that the powdered form of AICAR they had purchased from dubious Internet sources along with GW1516 another AMPK agonist and PPARδ modulator and a SARM (MK-2866), back in 2010, and which had passed customs mislabeled as containing ‘amino acids’ and ‘green tea extract' did in fact contain the inosine monophosphate intermediate 5-Aminoimidazole-4-carboxamide ribotide. Yet, of the 100mg of white powder the scientists received, only 45% contained the active ingredient. In this context it is also noteworthy, that a) AICAR is not yet approved as a drug by any federal agency, I know of, so that your doctor could not even prescribe it at the moment and b) it is not even likely that it will ever be approved, because BigPharma won't be interested in a naturally occurring and thus non-patentable peptide that could potentially reduce the sales of blood pressure, diabetes and cholesterol medications to zero.The underyling mechanism of AICAR by which AICAR mimmics exercise is an increase in the synthesis of inosine monophosphat, in the synthesis of which 5-Aminoimidazole-4-carboxamide ribotide(AICAR) itself, is an intermediate. The ensuing chronic AMP-kinase activation is similar to what would be seen in one of the cyclists during the Tour de France or other ultra-endurance athletes, as AMPK, which by the way is an m-TOR antagonist is significantly promoted by chronic endurance exercise (cf. Caligari. 2011).
|Figure 2: Inguinal mytochondrial density in AICAR (intraperitoneal injections @ 0.7g/kg body weight) treated vs. control male Wistar rats after 4 and 8 weeks of treatment (data adapted from Gaidhu. 2011)|
Did you know? The inhibitory effect of AMP-kinase activity on the m-TOR complex may inhibit muscle growth. On the other hand, AICAR also inhibits the proliferation of cancer cells by the very same mechanism (Rattan. 2005).Furthermore, AICAR induced "time-dependent and depot-specific regulation of AMPK phosphorylation and fatty acid oxidation" and increased "[a]mbulatory activity and whole-body energy expenditure (EE)". And although the increase in energy expenditure was significant (+36%) only during the active (dark) cycle of the rats (cf. figure 3), the synergistic effect of the AICAR induced metabolic changes "led to significant reductions in VC and SC adiposity", what is yet really astonishing is that these effects were not accompanied by any "energy-sparing mechanisms that oppose long-term fat loss", which is where the previous analogy of the Tour de France cyclists breaks down: Real chronic endurance exercise - and overtrained dieters will know that - will very well induce energy-sparing mechanisms which will initially stall weight loss and eventually set you up for the dreaded "Yoyo"-effect of cardio-driven (over-)dieting.
|Figure 3: Energy expenditure of male Wistar rats in kcal/h in week 8 of treatment with saline (control) or AICAR @ 0.7g/kg body weight (data adapted from Gaidhu. 2011)|