Category: glucose regulation


The increased energy required for acute moderate exercise by skeletal muscle (SkM) is derived equally from enhanced fatty acid (FA) oxidation and glucose oxidation. Availability of FA also influences contracting SkM metabolic responses. Whole body glucose turnover and SkM glucose metabolic responses were determined in paired dog studies during 1) a 30-min moderate exercise (maximal oxygen consumption of ∼60%) test vs. a 60-min low-dose 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) infusion, 2) a 150-min AICAR infusion vs. modest elevation of FA induced by a 150-min combined intralipid-heparin (IL/hep) infusion, and 3) an acute exercise test performed with vs. without IL/hep. The exercise responses differed from those observed with AICAR: plasma FA and glycerol rose sharply with exercise, whereas FA fell and glycerol was unchanged with AICAR; glucose turnover and glycolytic flux doubled with exercise but rose only by 50% with AICAR; SkM glucose-6-phosphate rose and glycogen content decreased with exercise, whereas no changes occurred with AICAR. The metabolic responses to AICAR vs. IL/hep differed: glycolytic flux was stimulated by AICAR but suppressed by IL/hep, and no changes in glucose turnover occurred with IL/hep. Glucose turnover responses to exercise were similar in the IL/hep and non-IL/hep, but SkM lactate and glycogen concentrations rose with IL/hep vs. that shown with exercise alone. In conclusion, the metabolic responses to acute exercise are not mimicked by a single dose of AICAR or altered by short-term enhancement of fatty acid supply.

Exercise vs. AICAR Infusion

With 30 min of moderate exercise, plasma glucose, insulin [4.1 ± 1.0 (before) vs. 3.0 ± 0.5 mU/l (after)], and glucagon [75 ± 17 (before) vs. 93 ± 21 ng/l (after); P = not significant (NS)] were unchanged; however, plasma FFA, lactate, and glycerol all rose significantly (P > 0.01) (Fig. 1). In contrast, with the 60-min AICAR infusion, plasma glucose fell (P = 0.05), insulin and glucagon were unchanged [insulin = 4.7 ± 0.5 (before) vs. 6.1 ± 0.8 mU/l (after), P = NS; glucagon = 53 ± 11 (before) vs. 68 ± 11 ng/l (after), P = NS], plasma FFA decreased significantly (P < 0.01), with no change in glycerol, and lactate rose sharply (P < 0.01) (Fig. 1). Thus the incremental responses of FFA and glycerol to exercise and AICAR were significantly different and in the opposite directions (Fig. 1). There was a greater than twofold increase (P < 0.02–0.01) in HGP, Rd, MCRg, and GFexog after the 30-min moderate exercise test (Fig. 2). In contrast, although these parameters also increased after the 60-min AICAR infusion (P < 0.02), the responses were considerably less (∼30–40%) and significantly (P < 0.01) smaller for the AICAR than for the exercise responses (Fig. 2). The metabolic responses to AICAR at 150 min were similar to those obtained at 60 min, with only a minor attenuation of MCRg by 150 min. SkM substrate concentrations of intracellular glucose and lactate did not change with exercise alone, whereas G6P significantly increased (change of 1.0 ± 0.3 mmol/l; P = 0.05) and glycogen decreased (change of –35 ± 36 mmol/kg dry wt; P = 0.06). In contrast, during AICAR infusion, a decrease in intracellular SkM glucose (change of –0.20 ± 0.0.9 mmol/l; P = 0.06) was noted, but no significant changes occurred in G6P, lactate, or glycogen. However, the absolute decrease of the glycogen concentration was significantly different for exercise compared with that for AICAR (change of –35 ± 36 vs. 9 ± 36 mmol/kg dry wt; P = 0.06). There were no changes in AMPK-α1 and AMPK-α2 activities with exercise or AICAR infusion (data not shown), but ACCβ-pSer221 was elevated by ∼35% [from basal level of 1.05 ± 0.02 to 1.38 ± 0.15 (P ≤ 0.05) with exercise and to 1.32 ± 0.15 (arbitrary units) (P = 0.06) with AICAR].

View larger version (17K):
In this window
In a new window

Fig. 1. Paired comparisons of absolute plasma substrate responses and incremental changes (Δ) after either 30-min moderate exercise [exer; ∼60% maximal oxygen consumption (O2max); open bars] or 60-min low-dose 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) infusion (hatched bars) in 6 dogs. A: plasma (P) glucose. B: plasma free fatty acid (FFA). C: lactate. D: glycerol. *P = 0.05; **P < 0.01 vs. the within-group basal state; ††P < 0.01 between groups.

View larger version (19K):
In this window
In a new window

Fig. 2. Paired comparisons of absolute responses and incremental changes (Δ) of hepatic glucose production (HGP; A), metabolic clearance rate of glucose (MCRg; B), Rd (C), and glycolytic flux (GFexog; D) to 30-min moderate exercise (∼60% O2max) (open bars) or 60-min AICAR infusion (hatched bars) in 6 dogs. *P < 0.02; **P < 0.01 vs. the within-group basal state; ††P < 0.01 between groups.

IL/Hep Infusion vs. Saline and AICAR Infusions

The 150-min IL/hep infusion alone raised plasma FFA by ∼60% and glycerol by ∼80% (P < 0.05–0.01) (Table 1). This resulted in a small but significant fall in fasting glucose (P ≤ 0.05), with no changes in insulin or glucagon (Table 1). There were also no changes induced by the IL/hep infusion in HGP, Rd, and MCRg, but GFexog fell significantly (P < 0.05) by ∼20% (Table 1). The effects of increasing FA supply compared with the AICAR infusion at 150 min were different (Table 1). Plasma glucose did not change; however, in the IL/hep group, the change in plasma lactate was markedly reduced (P < 0.001) and, as expected, FFA and glycerol were raised, compared with the responses observed in the AICAR studies (P ≤ 0.05–0.01) (Table 1). The modest significant increments observed for HGP, Rd, MCRg, and GFexog with AICAR were not observed in the IL/hep studies (Table 1). There was no relationship between the changes in plasma glucagon and HGP with the combined AICAR and IL/hep groups (r = 0.40, P = 0.22). After the IL/hep infusion, there were no changes (Δ) in intramuscular substrates (Δglucose = –0.05 ± 0.27 mmol/l, ΔG6P = 0.7 ± 0.7 mmol/kg dry wt, Δlactate = 0.51 ± 0.50 mmol/l, Δglycogen = 15 ± 33 mmol/kg dry wt, and ΔACCβ-pSer221 = 0.03 ± 0.05 arbitrary units).

Table 1. Comparison of the absolute and incremental effects of 60-min and 150-min AICAR infusion and 150-min saline or IL/heparin infusion on plasma substrates and hormones, glucose turnover, and skeletal muscle substrates in 6 resting normal dogs

Exercise With or Without IL/Hep Infusion

The exercise-induced responses of plasma substrates in the presence or absence of excess FA supply were similar for plasma glucose, glycerol, lactate, insulin, and glucagon. No exercise-induced increments for plasma FA were observed in the IL/hep group, since the FFA levels were already raised preexercise above those seen postexercise for the non-IL/hep group (Fig. 3). On the background of the lipid-induced lower basal GFexog (Table 1), the glucose turnover responses to exercise were similar for the IL/hep and non-IL/hep groups for HGP, Rd, MCRg, and GFexog (Fig. 4). Only small responses in the SkM substrates with exercise performed with and without IL/hep infusion were noted [Δglucose = 0.3 ± 0.1 vs. 0.0 ± 0.2 mmol/l, ΔG6P = 0.8 ± 0.6 vs. 1.0 ± 0.3 mmol/l, Δlactate = 2.6 ± 1.1 vs. 0.0 ± 0.3 mmol/l (P = 0.07), Δglycogen = 30 ± 37 vs. –35 ± 36 mmol/kg dry wt (P = 0.09), and ΔACCβ-pSer221 = 0.29 ± 0.06 vs. 0.23 ± 0.15 arbitrary units, respectively].

View larger version (19K):
In this window
In a new window

Fig. 3. Paired comparisons of absolute responses and incremental changes of plasma substrates to 30-min moderate exercise (∼60% O2max), either in the absence [open bars, with saline (Sal)] or presence (hatched bars) of intralipid-heparin (IL/hep) infusion in 6 dogs. A: plasma glucose. B: plasma FFA. C: plasma lactate. D: plasma glycerol. *P < 0.05; **P < 0.01 vs. the within-group basal state; †P ≤ 0.06 between groups.

View larger version (21K):
In this window
In a new window

Fig. 4. Paired comparisons of absolute responses and incremental changes of HGP (A), MCRg (B), Rd (C), and GFexog (D) to moderate exercise (∼60% O2max), either in the absence (open bars) or presence (hatched bars) of IL/hep infusion in 6 dogs. **P < 0.01 vs. the within-group basal state; †P ≤ 0.05 vs. the corresponding basal study without IL/hep.


AICAR BLOWOUT SALE! Contact us for purchase options

     100 mg: $45

     1000 mg: $350

     3 grams: $800

shipping: $20 flat rate worldwide

AICAR, aminoimidazole carboxamide ribonucleotide, acts as an agonist to AMP-activated protein kinase; AMP-activated protein kinase, also known as AMPK, is an enzyme with an important role in cellular homeostasis and energy regulation.[1]  AMPK acts through a variety of means to ultimately stimulate liver fatty oxidation, ketogenesis, beta-cell modulation of insulin secretion, and other functions within the body.  AICAR has been shown to stimulate glucose uptake and reduce apoptosis by reducing reactive oxygen compounds within cells.[2][3]

In a breakthrough study in 2008, Narkar et al of the Salk Institute discovered that AICAR significantly improves the performance of mice in endurance-type exercise by converting fast-twitch muscle fibers to the more energy-efficient, fat-burning, slow-twitch type. They also found that AICAR and GW1516, when given to “sedentary” mice, activated 40% of the genes that were turned on when mice were given GW1516 and made to exercise. As a result a publicity storm about “exercise pills” and “exercise in a pill” ensued.  The World Anti-Doping Agency now lists both compounds on their prohibited list (since 2009), and the lead researcher of the breakthrough study cooperated in providing data to make possible a urinalysis test to detect AICAR.[4][5]

Figure 5 Likely effects of AICAR (and other AMPK activators) on glucose homoeostasis in vivo

AICAR (1) stimulates glucose uptake into muscle through the membrane recruitment of Glut4, (2) inhibits hepatic glucose output and triacylglycerol synthesis, (3) inhibits both glucose uptake and lipolysis by adipose tissue, (4) acutely suppresses insulin release from pancreatic islets, and (5) activates glucose-responsive neurons in the paraventricular and arcuate nuclei of the hypothalamus, potentially stimulating appetite. Effects (1)–(4) probably explain the glucose-lowering effects of AICAR (and contribute to the effects of metformin and glitazones) and are likely to be beneficial in Type II diabetes. Effects (4) and (5) may be contra-indicated. FA, fatty acids.

AICAR has a number of other experimental/clinical and research chemical uses as it is expressed in a variety of tissue types.  Bai et al found that “data demonstrate that AICAR-initiated AMPK activation may represent a promising alternative to our current approaches to suppressing intestinal inflammation in IBD.”[6]

Guo et al found “results suggest[ing] a mechanism by which AICAR inhibits the proliferation of EGFRvIII expressing glioblastomas and point toward a potential therapeutic strategy for targeting EGFR-activated cancers.”[7]

An original study by Pold et al offers additional hope that AICAR could offer important treatment potential for humans:

Five-week-old, pre-diabetic ZDF rats underwent daily treadmill running or AICAR treatment over an 8-week period and were compared with an untreated group. In contrast to the untreated, both the exercised and AICAR-treated rats did not develop hyperglycemia during the intervention period. Whole-body insulin sensitivity, as assessed by a hyperinsulinemic-euglycemic clamp at the end of the intervention period, was markedly increased in the exercised and AICAR-treated animals compared with the untreated ZDF rats (P < 0.01). In addition, pancreatic beta-cell morphology was almost normal in the exercised and AICAR-treated animals, indicating that chronic AMPK activation in vivo might preserve beta-cell function. Our results suggest that activation of AMPK may represent a therapeutic approach to improve insulin action and prevent a decrease in beta-cell function associated with type 2 diabetes.[8]


[1]Corton JM, Gillespie JG, Hawley SA, Hardie DG. “5-aminoimidazole-4-carboxamide ribonucleoside. A specific method for activating AMP-activated protein kinase in intact cells?”. Eur. J. Biochem. 229 (2): 558–65.  1995.

[2]Lemieux K, Konrad D, Klip A, Marette A. “The AMP-activated protein kinase activator AICAR does not induce GLUT4 translocation to transverse tubules but stimulates glucose uptake and p38 mitogen-activated protein kinases alpha and beta in skeletal muscle”. Faseb J. 17 (12): 1658–65. 2003.

[3]Kim JE, Kim YW, Lee IK, Kim JY, Kang YJ, Park SY.  “AMP-activated protein kinase activation by

5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) inhibits palmitate-induced endothelial cell apoptosis through reactive oxygen species suppression”. J. Pharmacol. Sci. 106 (3): 394–403. 2008.

[4]Narkar VA, Downes M, Yu RT, Embler E, Wang YX, Banayo E, Mihaylova MM, Nelson MC, Zou Y, Juguilon H, Kang H, Shaw RJ, Evans RM. “AMPK and PPARdelta agonists are exercise mimetics”. Cell 134 (3): 405–15. 2008. [5]WADA 2009 Prohibited List: WADA PROHIBITED LIST PDF (PDF Document).

[6]Bai A, Yong M, Ma Y, Ma A, Weiss C, Guan Q, Bernstein C, Peng Z. Novel Anti-Inflammatory Action of 5-Aminoimidazole-4-carboxamide ribonucleoside with protective effect in DSS-induced acute and chronic colitis. J Pharmacol Exp Ther. 2010 Mar 17.

[7]Guo D, Hildebrandt IJ, Prins RM, Soto H, Mazzotta MM, Dang J, Czernin J, Shyy JY, Watson AD, Phelps M, Radu CG, Cloughesy TF, Mischel PS.  The AMPK agonist AICAR inhibits the growth of EGFRvIII-expressing glioblastomas by inhibiting lipogenesis.Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):12932-7.

[8]Pold R, Jensen LS, Jessen N, Buhl ES, Schmitz O, Flyvbjerg A, Fujii N, Goodyear LJ, Gotfredsen CF, Brand CL, Lund S. Long-term AICAR administration and exercise prevents diabetes in ZDF rats.  Diabetes. 2005 Apr;54(4):928-34.

*The latter article is intended for educational / informational purposes only. THIS PRODUCT IS INTENDED AS A RESEARCH CHEMICAL ONLY. This designation allows the use of research chemicals strictly for in vitro testing and laboratory experimentation only. Bodily introduction of any kind into humans or animals is strictly forbidden by law.

Role of AMPK2 in basal, training-, and AICAR-induced GLUT4, hexokinase II, and mitochondrial protein expression in mouse muscle

Am J Physiol Endocrinol Metab 292: E331–E339, 2007. First published September 5, 2006;

We investigated the role of AMPK2 in basal, exercise training-, and AICAR-induced protein expression of GLUT4, hexokinase II (HKII), mitochondrial markers, and AMPK subunits. This was conducted in red (RG) and white gastrocnemius (WG) muscle from wild-type (WT) and 2-knockout (KO) mice after 28 days of activity wheel running or daily AICAR injection. Additional experiments were conducted to measure acute activation of AMPK by exercise and AICAR. At basal, mitochondrial markers were reduced by 20% in 2-KO muscles compared with WT. In both muscle types, AMPK2 activity was increased in response to both stimuli, whereas AMPK1
activity was increased only in response to exercise. Furthermore, AMPK signaling was estimated to be 60–70% lower in 2-KO compared with WT muscles. In WG, AICAR treatment increased HKII, GLUT4, cytochrome
c, COX-1, and CS, and the 2-KO abolished the AICARinduced increases, whereas no AICAR responses were observed in RG. Exercise training increased GLUT4, HKII, COX-1, CS, and HAD protein in WG, but the 2-KO did not affect training-induced increases. Furthermore, AMPK1, -2, -1, -2, and -3 subunits were reduced in RG, but not in WG, by 30–60% in response to exercise training. In conclusion, the 2-KO was associated with an 20% reduction in mitochondrial markers in both muscle types and abolished AICAR-induced increases in protein expression in WG. However, the 2-KO did not reduce traininginduced increases in HKII, GLUT4, COX-1, HAD, or CS protein in WG, suggesting that AMPK2 may not be essential for metabolic adaptations of skeletal muscles to exercise training.

5-adenosine monophosphate-activated protein kinase-2; glucose transporter-4; 5-aminoimidazole-1--D-ribofuranoside; exercise training; mitochondrial proteins; skeletal muscle

BIOCHEMICAL ADAPTATIONS of skeletal muscle to regular physical activity include an increase in mitochondrial oxidative enzyme capacity and an increase in key proteins involved in glucose uptake, such as glucose transporter-4 (GLUT4) and hexokinase II (HKII) (41, 51). The intracellular pathways involved in eliciting these exercise training-induced increases in protein expression and mitochondrial content remain largely unknown. The 5-AMPactivated protein kinase (AMPK) has been proposed as a signaling molecule involved in transmitting an “exercise signal” to the nuclei of the muscle cell (15, 49). This is in part based on the finding that AMPK is activated by in vitro electrical induced contractions of rodent skeletal muscle (8, 44) and by in vivo exercise in human (11, 50) and rodent skeletal muscle (48).
Chronic activation of AMPK by the adenosine analog 5-aminoimidazole- 4-carboxamide-1--D-ribofuranoside (AICAR) or the creatine analog -guanadinopropionic acid (-GPA) in resting rat and mouse muscles increases transcription of metabolic genes and expression of metabolic enzymes as well as mitochondrial density mimicking effects of exercise training (4, 15, 20, 49, 52). The observation that pharmacologically induced upregulation of peroxisome proliferator-activated receptor-  coactivator-1 (PGC-1) and -aminolevulinate synthase mRNA, cytochrome c (cyt c) protein, and mitochondrial density is abolished in mouse muscle overexpressing a kinasedead AMPK construct suggests a causal role of AMPK in these responses (52). The AMPK-dependent increase in PGC-1 is of particular interest because this nuclear transcription modulator is shown to be important in coordinating muscular adaptations in lipid oxidation and mitochondrial function to exercise training (23, 24) and to be involved in regulating GLUT4 protein expression (28, 30).
Several studies indicate that AMPK increases content of target proteins by increasing transcriptional activity of their respective genes. For instance, arterial infusion of AICAR in rodent hindlimb muscle stimulates HKII and uncoupling protein- 3 (UCP3) gene transcription (43), and an acute injection of AICAR increases muscle GLUT4 mRNA in rodents (5). Furthermore, a chronic treatment of rat with -GPA treatment is followed by an increase in nuclear respiratory factor-1 (NRF-1) DNA binding activity correlated by an increase in expression of NRF-1 targets and mitochondrial density in muscle (4).
NRF-1 is activated by binding with PGC-1, which in turn leads to increased transcription of nuclear genes encoding subunits of the mitochondrial respiratory chain and components of the mitochondrial transcription and replication machinery (for review, see Refs. 22 and 42).
Altogether, it seems evident that activation of AMPK in resting muscle specifically increases the protein content of several metabolic enzymes as well as mitochondrial density.
Therefore, the purpose of the present study was to investigate the importance of the catalytic AMPK2 subunit in expression of HKII and GLUT4 protein, as well as mitochondrial enzymes in skeletal muscle in the basal state, and after exercise training and chronic AICAR treatment. This was investigated in AMPK2 whole body knockout (2- KO) and corresponding wild-type (WT) mice that had undertaken a 28-day program of activity wheel exercise training or daily AICAR injections.

The number of Americans with type 2 diabetes is expected to increase by 50% in the next 25 years; hence, the prevention of type 2 diabetes is an important objective. Recent large-scale trials (the Diabetes Prevention Program and STOP-NIDDM) have demonstrated that therapeutic agents used to improve insulin sensitivity in diabetes, metformin and acarbose, may also delay or prevent the onset of type 2 diabetes in high-risk populations. Interestingly, an early report showed that vinegar attenuated the glucose and insulin responses to a sucrose or starch load (1). In the present report, we assessed the effectiveness of vinegar in reducing postprandial glycemia and insulinemia in subjects with varying degrees of insulin sensitivity.

Our study included nondiabetic subjects who were either insulin sensitive (control subjects, n = 8) or insulin resistant (n = 11) and 10 subjects with type 2 diabetes. Subjects provided written informed consent and were not taking diabetes medications. Fasting subjects were randomly assigned to consume the vinegar (20 g apple cider vinegar, 40 g water, and 1 tsp saccharine) or placebo drink and, after a 2-min delay, the test meal, which was composed of a white bagel, butter, and orange juice (87 g total carbohydrates). The cross-over trial was conducted 1 week later. Blood samples were collected at fasting and 30 and 60 min postmeal for glucose and insulin analyses. Whole-body insulin sensitivity during the 60-min postmeal interval was estimated using a composite score (2).

Fasting glucose concentrations were elevated ∼55% in subjects with diabetes compared with the other subject groups (P < 0.01, Tukey’s post hoc test), and fasting insulin concentrations were elevated 95–115% in subjects with insulin resistance or type 2 diabetes compared with control subjects (P < 0.01). Compared with placebo, vinegar ingestion raised whole-body insulin sensitivity during the 60-min postmeal interval in insulin-resistant subjects (34%, P = 0.01, paired t test) and slightly improved this parameter in subjects with type 2 diabetes (19%, P = 0.07). Postprandial fluxes in insulin were significantly reduced by vinegar in control subjects, and postprandial fluxes in both glucose and insulin were significantly reduced in insulin-resistant subjects (Fig. 1).

These data indicate that vinegar can significantly improve postprandial insulin sensitivity in insulin-resistant subjects. Acetic acid has been shown to suppress disaccharidase activity (3) and to raise glucose-6-phosphate concentrations in skeletal muscle (4); thus, vinegar may possess physiological effects similar to acarbose or metformin. Further investigations to examine the efficacy of vinegar as an antidiabetic therapy are warranted.

Figure 1—

View larger version:

Figure 1—

Effects of vinegar (□) and placebo (⧫) on plasma glucose (AC) and insulin (DF) responses after a standard meal in control subjects, insulin-resistant subjects, and subjects with type 2 diabetes. Values are means ± SE. The P values represent a significant effect of treatment (multivariate ANOVA repeated-measures test).



  1. Ebihara K, Nakajima A: Effect of acetic acid and vinegar on blood glucose and insulin responses to orally administered sucrose and starch. Agric Biol Chem 52:1311–1312, 1988
  2. Matsuda M, DeFronzo RA: Insulin sensitivity indices obtained from oral glucose tolerance testing. Diabetes Care 22:1462–1470, 1999
  3. Ogawa N, Satsu H, Watanabe H, Fukaya M, Tsukamoto Y, Miyamoto Y, Shimizu M: Acetic acid suppresses the increase in disaccharidase activity that occurs during culture of Caco-2 cells. J Nutr 130:507–513, 2000
  4. Fushimi T, Tayama K, Fukaya M, Kitakoshi K, Nakai N, Tsukamoto Y, Sato Y: Acetic acid feeding enhances glycogen repletion in liver and skeletal muscle of rats. J Nutr 131:1973–1977, 2001



Internal Medicine, UNICAMP.



Metformin is a widely-used antidiabetic drug whose anti-cancer effects, mediated by the activation of AMPK and reduction of mTOR signaling, have become noteworthy. Chemotherapy produces genotoxic stress and induces p53 activity, which can cross-talk with AMPK/mTOR pathway. Herein, we investigate whether the combination of metformin and paclitaxel has an effect in cancer cell lines.


Human tumors were xenografted into SCID mice and the cancer cell lines were treated with only paclitaxel or metformin, or a combination of both drugs. Western Blotting, flow cytometry and immunohistochemistry were then used to characterize the effects of the different treatments.


The results presented herein, demonstrate that the addition of metformin to paclitaxel leads to quantitative potentialization of molecular signaling through AMPK and a subsequent potent inhibition of the mTOR signaling pathway. Treatment with metformin and paclitaxel resulted in an increase in the number of cells arrested in the G2/M phase of the cell cycle, decreased the tumor growth and increased apoptosis in tumor-bearing mice, when compared to individual drug treatments.


We have provided evidence for a convergence of metformin and paclitaxel induced signaling at the level of AMPK. This mechanism illustrates how different drugs may cooperate to augment anti-growth signals, and suggests that target activation of AMPK by metformin may be a compelling ally in cancer treatment.


BUY ACTOVEGIN from us $19 /5ml amp

Actovegin� is a Deproteinized Hemoderivative of Calf Blood that is obtained by ultra-filtration. The Deproteinized Hemoderivative of Calf Blood contains only physiological components, anorganic substances socle as electrolytes and essential trace elements and 30% of organic components as amino acids, oligopeptides, nucleosides, intermediary products of the carbohydrate and of the fat metabolism, and components of the cellular membranes as glycosphingolipids. One of the physiologic components of Actovegin is inositol phospho-oligosaccharides ( IPOs ). These compounds are thought to possess central and peripheral insulin effects, suggesting that a therapeutic benefit could be obtained in disorders of impaired glucose utilization. The molecular weight of the organic components is below 6000 Dalton.

The active components in Actovegin promote glucose uptake by cerebral and skeletal muscle and other cells and stimulate intrinsic glucose transport by regulating glucose carrier GluT1; Actovegin activates piruvate-dehydrogenase (PDH) and thereby leads to increased utilization of glucose by cells and formation of energy-rich substances (“insulin-like effect). (Oberermaier-Kusser et al. 1989 Actovegin also increases uptake and utilization of oxygen by hypoxic tissues and cells (which can be proven by Warburg’s test) via promoting mitochondrial respiratory function and decreases formation of lactate, as a result, it protects hypoxic tissue. (Machicao, 1993; Kununaka et al. 1991)

Acute toxicity: Acute toxicity tests in mice (NMRI mice, male and female mixed) showed that the fifty percent lethal doses (LD50, calculated as dry weight) were as follows:
-intravenous administration: 2.31 g/kg;
-intraperitoneal administration: 2.97 g/kg;
-sucutaneous administration: 5.57 g/kg;
-oral administration: 7.93 g/kg

Subchronic toxicity: Experiments performed in rabbits (Deutsche Riesenschecken rabbits, female) demonstrated that there was no evidence of either macroscopic or microscopic organic pathological changes as compared to normal control animals after infusing 20% Actovegin intravenously once a day at a dose of 7.0 ml/kg, 7 days a week, for 3 months. Actovegin has no toxicity on fertility, embryo and fetus; it has no teratogenic, mutagenic, or carcinogenic effects.

Actovegin� is a calf-blood derived hemodialysate. Since it is not a single-component drug, conducting a pharmacokinetic study is impossible. However, for its bioavailability, certain pharmacological studies in animals may provide some reference: glucose tolerance studies in rats showed that blood glucose level started to decline as early as at 5 minutes after intravenous administration of Actovegin , and the effect reached its peak at 180 minutes after administration. (Bachmann et al. 1968) improved at 15 minutes after parenteral administration of Actovegin . (Quadbeck et al. 1964)

Disturbances in the cerebral circulation and nutrition (ischemic insultus, cranio-cerebral traumas).
Disturbances of peripheral (arterial, venous) blood flow and sequels resulting from these disturbances (arterial angiopathy, ulcus cruris).
Skin graftings.
Burns, scalds, erosions.
Wound-healing impairment: torpid wounds, decubitus;
Radiation-induced skin and mucous membrane lesions (prophylaxis and therapy).

Mode of action
Actovegin produces an organ-unrelated increase of the cellular energy metabolism. The activity is confirmed by measurement of the increased uptake and of the elevated utilization of glucose and oxygen. These two effects are coupled and they result in a rise of the ATP-turnover and thus in a greater provision of energy in the cell. In deficiency states with impairment of the normal functions of the energy metabolism (hypoxia, substrate deficiency) and in states of increased energy requirement (reparation, regeneration) Actovegin promotes the energy-dependent processes of the functional metabolism and of the conservation metabolism. An increase of the blood supply is seen as a secondary effect

Effects related to therapeutic indication:
Effects related to glucose transport
-The IPO fraction of Actovegin demonstrated a positive effect on glucose carrier activity( GLUT1) in the plasma membrane
-Actovegin stimulated glucose uptake in cerebral tissues, as well as other isolated animal tissues
Effects related to glucose utillization
-The IPO fraction of Actovegin activated glucose oxidation as well as the PHD complex
-The IPO fraction of Actovegin acts indirectly on the citric acid cycle by causing increased formation of acetyl COA
Effects related to oxygen uptake on energy metabolism
-Actovegin increased the respiratory capacity of mitochondria
-Actovegin improved oxygen uptake in Anesthetized dogs
-Actovegin demonstrated a positive effect on cerebral metabolism of rats under conditions of Hypoxia

Safety of Actovegin

The manufacturer Nycomed Austria GmbH confirms that all measures are in place to guarantee the TSE safety of Actovegin. According to the actual guideline EMEA/410/01 final (issued in February 2001, replacing CPMP/BWP/1230 REV.1) and the Final Opinion of the Scientific Steering Committee on the geographical BSE risk (issued in July 200) the safety of a medicinal product is determined by several important factors:

1. Animals as source of material: the most satisfactory source of materials is from countries which are free of BSE and have appropriate surveillance systems. Materials may be used from countries with a low BSE incidence. The calf blood used as raw material for Actovegin derives from calves born, raised and slaughtered in Australia. Australia is officially categorised as BSE � and Scrapie free country by the OIE (World Organization for Animal Health) and the SSC (Scientific Steering Committee of the European Union). Surveillance systems are in place.

2. Parts of animal bodies and body fluids used as starting materials: tissues and body fluids are categorised in four categories (from category I = high infectivity like brain to category IV= safest category, no detectable infectivity like blood and milk). Actovegin is manufactured from calf blood, blood is in the safest tissue category IV.

3. Age of animals: the sourcing from young animals is seen as very important safety factor. The blood used as raw material for Actovegin production derives from calves below six months of age. The calves were never fed animal carcasses fodder and are declared fit for human consumption, as all proven by veterinary certificates. Moreover the traceability of every Actovegin batch back to the individual calves as blood donors is ensured. The mother cows (dams) of the calves are also known.

4. A production process should be designed which is thought to remove or inactivate TSE agents. Validation studies are currently not generally required. The manufacturing process of Actovegin is BSE validated, thus proven to be capable of removing hypothetically present TSE agents.

5. A risk analysis was performed according to the PhPMA system showing that Actovegin is absolutely BSE safe. Moreover Actovegin is a natural drug with proven efficacy and also a general favourable safety profile over decades. These benefits cannot be substituted by a chemical drug. In conclusion, Actovegin is BSE safe and fullfills even more safety measures than required by actual guidelines



Actovegin® is a biological drug manufactured from a natural source: it is a calf blood hemodialysate. Its therapeutic benefits stem from a variety of pharmacodynamic actions that can be summarized to a common goal, i.e. the enhancement of cellular metabolism; this results from an insulin-like activity mediated by Inositol-phospho-oligosaccharides. Actovegin®

Actovegin-Ergogenic Aid or Not results in beneficial effects in several pathophysiological clinical settings including malfunction of the blood circulation and trophic disturbances in the brain, impairment of peripheral blood circulation and associated diseases, dermal transplants and acute and chronic wounds. Here, we give an overview of the pharmacodynamic actions of calf-blood hemidialysate and its beneficial effects in a variety of clinical settings.

By Chad Robertson B.Sc (KIN), B.Sc (PHARM)

There has been a great deal of hype in the media of late regarding the drug Actovegin after reports that a world renown physician who treated Tiger Woods is under investigation for apparently using it. My intentions of this article is to educate the public on the pharmacological properties of Actovegin and how to derive the same clinical applications using natural nutrients. As reported, Actovegin is a protein free blood derived extract from calf used for treating dementia, cerebrovascular insufficiency, and periperal vascular resistance. It is manufactured by a European based pharmaceutical company, Nycomed Austria

Properties of Actovegin

An extensive Medline literature search revealed older German and Russian studies focusing on Actovegin’s physiologic effects on glucose metabolism and cerebral circulation. There are no reports on its use in improving athletic performance and scant reviews for it’s treatment of sports related injuries. Nevertheless, since its introduction, the athletic community has realized the potential of Actovegin to increase mitochondrial ATP energy production through increased glucose and oxygen utilization.

Improvement of glucose metabolism

Jacob S et. al. (1996) was one of the first to show that Actovegin stimulated the uptake of glucose into adipocytes by inositol-phosphate-oligosaccharides (IPO), a key component of Actovegin. IPO is thought to possess insulin-mimicking effects by regulating glucose carrier activity 1, 2. Improvements in glucose tolerance occurs without affecting endogenous serum insulin levels and this effect was seen in diabetics rather than those with normal carbohydrate metabolism 3.

Increase peripheral blood flow

Restrictions in peripheral blood flow due to arterial occlusive disease results in muscle pain during rest and exercise. A study was undertaken to determine the effects of intravenous (IV), intraarterial (IA) Actovegin administration and physical exercise on peripheral arterial occlusive disease 4.

Over a four week period, patients who received IA injections achieved a pain free walking distance of 44.9% compared to 37.8% in the IV group. However, physical exercise showed improvements in pain free walking distance of 66.9% although the results were not considered significant compared to IA Actovegin.

Hypoxic states and dementia

The parietal cortex is responsible for processing visual information and spatial directed attention and shrinkage to the area leads to dementia. It appears Actovegin improves the cognitive processing in the parietal cortex in age associated memory impairment 5. Kanowski S et. al. 1995 showed improvements in organic brain syndrome patients in social behavior and mental performance with injections of Actovegin compared to placebo 6.

Actovegin improves energy metabolism in hypoxia by increasing uptake of glucose and oxygen 7.

Sports injuries

Rapid recovery times from sports related injuries are important for athletes. Local injections of Actovegin has been shown to significantly shorten recovery time in muscle injury compared to placebo 8.

How does Actovegin compare to ACS

Autologous Conditioned Serum (ACS) is produced by physical and chemical stimulation of whole blood to increase the concentration of specific growth factors such as FGF-2, TGF-beta1 and HGF. During muscle regeneration, a host of growth factor are involved in the repair process but FGF-2, TGF-beta 1, and HGF are key regulators of muscle satellite cell activation. Wright-Carpenter 2004 compared the effects of ACS against Actovegin/Traumeel (control) for muscle strains. Local injections of ACS shortened recovery time to healing (as shown on MRI scans) and showed an almost complete regression of edema and bleeding after 14 days compared to the control group which only possessed mild effects 9.

Comparison to alternative products

It is interesting to note how Actovegin’s biochemical and physiological properties compares to other products currently used in similiar disease states.

R-Lipoic Acid

Actovegin has been proposed to increase glucose utilization by regulating glucose transporter protein (GLUT-1). Lipoic acid mimics insulin action by affecting GLUT-1 and GLUT-4 10. Glut-1 involves glucose transport into red blood cells and the brain whereas Glut-4 transports glucose into fat and muscle cells and has a greater impact on blood sugar levels than Glut-1.

Skeletal muscle depends on insulin to transport glucose into myocytes where it is used to produce energy. During exercise, muscle contractions upregulate expression of GLUT-4 thereby reducing blood sugar levels and overcoming insulin resistant skeletal muscle 11. Another important property of Lipoic acid is it’s ability to strengthen antioxidant defenses by increasing glutathione and protect against exercise induced oxidative stress 12.


The hypoglycemic properties of taurine appear to be much greater after glucose supplementation rather than administration before a glucose challenge 13. Taurine acts by stimulating the secretion of insulin from pancreatic beta cells in addition to protecting it from lipid peroxidation through it’s antioxidant action. Taurine’s antioxidant property also extends to skeletal muscles where it may enhance exercise performance by attenuating damage to muscle tissues induced by exercise 14.


Vinpocetine, a derivative from the periwinkle plant, has been used as a nootropic to enhance mental function and as a drug to treat cerebral ischemia. Like Actovegin, vinpocetine can increase cerebral blood flow in ischemic stroke patients especially in areas which concentrated the drug the most 15. However, it’s effect on the metabolic rate of glucose in the brain is minimal and the clinical use of vinpocetine in dementia is not conclusive 16.


Similiarities exists between Actovegin and the natural products lipoic acid, taurine and vinpocetine to improve blood flow and increase glucose disposal. Current well designed studies on it’s use in sport injuries and enhancement of performance has yet to be conducted.