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Metabolicalchemy.comThe first drug I’m going to talk about is one that’s been around for years and its primary use is to help control blood sugar in type 2 diabetics. What’s interesting - if you are struggling with your weight and carry an excess of 20 pounds of fat, you may already be on the verge of being diabetic. You are most certainly insulin resistant at this point, however, and this is something you should talk with your doctor about if you’re interested in a medicinal way to control your blood sugar, reduce your appetite and yes even lose weight. In some instances doctors will even prescribe Glucophage to someone wanting to lose weight because they understand that Metformin (the standard name for the drug, Glucophage is the brand name) has been used for years safely and has helped many people who were developing diabetes to regain their health. Metformin works in a couple of unique ways. The first is that it inhibits the absorption of sugar in the intestines. It doesn’t stop it completely but a fairly decent amount of sugar in the foods you eat will never make it to your bloodstream because it’s been blocked in the stomach. Be warned however, this effect also effects digestion in general which means a lower dose should be used at first until a person’s digestion gets used to it. Otherwise diarrhea and bloat occur. Metformin also interacts with insulin receptors inside of muscle, fat and organs and makes the cells more sensitive to insulin. Insulin is the gate keeper of blood sugar. Our cell walls will not allow free entry of glucose (blood sugar) inside the cell except for times of extreme starvation or recently exercised muscles (exercise is the perfect natural prescription for high blood sugar by the way and eradicates the need for any kind of prescription intervention, but I digress). Insulin is the key that opens that gate, allowing blood sugar to enter the cell where, hopefully, it’s used for energy.
Overtime our bodies begin to get tired of the constant insulin signals to open the door. They have plenty of sugar and don’t need anymore, so the cells begin to ignore insulin’s messages. This is where the real process of insulin resistance, metabolic syndrome x, obesity and diabetes begin to set in. Our body’s only other response is to make more insulin OR WORSE, make more FAT CELLS to soak up this excess blood sugar (and this is where the actual visible signs of metabolic syndrome take shape, no pun intended). So we can stop it in a number of ways and one of the slickest ways is to employ an insulin sensitizer like Metformin. Metformin also blocks a process in the liver called Gluconeogenesis, which is a fancy way of saying it stops the liver from making blood sugar. The liver has a special ability to take stored glycogen and muscle protein and turns it into blood sugar. When someone begins to develop pre-diabetic symptoms, and if you’re overweight and have been for a while this is probably the case, the liver will often begin making too much blood sugar! So not only have cells become insensitive to blood sugar but the liver begins to pump out hordes more of it! Well Metformin is a very potent inhibitor of this process and this is a good thing so long as you have healthy kidneys (more on this later).
So what can be expected from using Metformin? I took it for a few months and noticed some of the following observations. I did experience bloat and diarrhea but this subsided once I started splitting my doses and taking it with meals, in the middle of it actually. I also noticed a profound sense of appetite control. A good solid meal would fuel me for hours and because my blood sugar was kept under control, my insulin was kept quiet and this prevented hunger pangs from coming along before dinner time. I could have even skipped dinner but I was ultimately trying to maintain my muscle so I knew I needed to eat. It’s also been speculated, and in some instances there are studies to back this up, that metformin encourages the release of adiponectin, the hormone released by fat cells to tell the brain that every thing's OK and it’s OK to lower appetite and increase fuel burning. Between this and leptin sensitivity increases you are looking at a very powerful and favorable change in the neuro-chemistry of hunger and appetite, one that will surely benefit those who struggle with the dips and dives of their blood sugar and the ensuing hunger it can cause.
I also noticed much fuller muscles. It was as if for the first time in a long time, my muscles were getting gorged with glycogen and staying pumped longer. I had more strength in the gym and could push out more reps than I had been able to in a long time. Unfortunately I also noticed one other bummer of an effect. Lowered testosterone. Do you remember how I was telling you that Metformin lowers the production of blood sugar made by the liver (gluconeogenesis)? Well that same effect also causes the liver to stop producing certain enzymes needed to turn DHEA into testosterone. It also increases SHBG (sex hormone binding globulin). This means that the Testosterone I do have floating around in my bloodstream was being bound up and made inactive by this excess SHBG. Now, for some men this is never a problem. In women with PCOS (poly-cystic ovarian syndrome) it can be a godsend. For men on HRT this is often never really a problem because they can increase their dosage of Testosterone to counteract the lowered Free Testosterone.
My best solution to this was to take one dose weekly on Sundays, just to restore sensitivity once a week and prepare me for Monday when I got back into dieting (I usually took Sundays off of dieting and would eat quite a bit). One last word of warning about Metformin. It increases lactic acid accumulation. When we exercise a byproduct of energy production called lactic acid is formed. In a healthy person with good kidneys, this lactic acid is broken down into harmless material that is either recycled or dispelled through the urine. For someone with impaired kidney function though this could lead to lethal levels of lactic acid that could cause a host of health problems, one of which would ultimately end in death. I have to say I have my reservations about this one too, especially if you are an avid exerciser. Extremely high-intensity exercise, the kind of intensity I prescribe to on a regular basis, may in fact create so much lactic acid that even healthy kidneys could have a hard time keeping up. Therefore I recommend to those who really push it with high intensity training like boot camp or sprinting, to steer clear of this drug, at least during times of extreme training. Of course, if one is training in a boot camp type setting then they most likely are already experiencing great blood sugar regulation anyways. But this is purely for informational purposes and one may want to find out just how sensitive and optimized they can become, as I did.
In closing I’d like to say that Metformin is a very powerful blood sugar lowering agent that, when used appropriately, can lead to a dramatic decrease of appetite, increased insulin sensitivity and ultimately a loss of body-fat as the body begins to utilize energy once again in a very healthy fashion.
I hope this chapter gave you some things to research on your own and I hope to hear from you on the blog http://www.metabolicalchemy.com or in the forums http://www.metabolicalchemy.com/forum on this subject.
Here is a chunk of information I gathered off wikipedia at http://en.wikipedia.org/wiki/MetforminMetformin improves hyperglycemia primarily through its suppression of hepatic glucose production (hepatic gluconeogenesis). The "average" person with type 2 diabetes has three times the normal rate of gluconeogenesis; metformin treatment reduces this by over one third. Metformin activates AMP-activated protein kinase (AMPK), a liver enzyme that plays an important role in insulin signaling, whole body energy balance, and the metabolism of glucose and fats; activation of AMPK is required for metformin's inhibitory effect on the production of glucose by liver cells. Research published in 2008 further elucidated metformin's mechanism of action, showing that activation of AMPK is required for an increase in the expression of SHP, which in turn inhibits the expression of the hepatic gluconeogenic genes PEPCK and Glc-6-Pase. Metformin is frequently used in research along with AICAR as an AMPK agonist. The mechanism by which biguanides increase the activity of AMPK remains uncertain; however, research suggests that metformin increases the amount of cytosolic AMP (as opposed to a change in total AMP or total AMP/ATP).In addition to suppressing hepatic glucose production, metformin increases insulin sensitivity, enhances peripheral glucose uptake, increases fatty acid oxidation, and decreases absorption of glucose from the gastrointestinal tract. Increased peripheral utilization of glucose may be due to improved insulin binding to insulin receptors. AMPK probably also plays a role, as metformin administration increases AMPK activity in skeletal muscle. AMPK is known to cause GLUT4 deployment to the plasma membrane, resulting in insulin-independent glucose uptake. Some metabolic actions of metformin do appear to occur by AMPK-independent mechanisms; a 2008 study found that "the metabolic actions of metformin in the heart muscle can occur independent of changes in AMPK activity and may be mediated by p38 MAPK- and PKC-dependent mechanisms." ● Glucophage greatly reduces your endogenous insulin levels due to enhanced insulin
sensitivity which leads to better fat loss, reduced appetite swings.
● Glucophage blocks carbs absorption at intestinal level
● Glucophage inhibits gluconeogenesis
● Glucophage enhance insulin receptor sensitivity
● Glucophage allows the body to produce more insulin receptors
● Glucophage has an activity of about 2 hours in our body (in healthy subjects; with renal
dysfunctions it can reach 5 hours)
● Glucophage inhibits vitamin B12 absorption
● Glucophage decreases VLDL levels
Effects of short term metformin administration on androgens in normal men.
Shegem NS, Nasir AM, Jbour AK, Batieha AM, El-Khateeb MS, Ajlouni KM.
National Center for Diabetes Endocrinology and Genetics, Jordan University Hospital, Amman, Jordan.
OBJECTIVE: To study the effect of metformin on androgens in normal men. METHODS: A total of
12 healthy males volunteered to participate in the study. A blood sample was obtained from each
of them and analyzed for the following: Testosterone (total and free), sex hormone binding globulin
dehydroepiandrosterone sulphate, 17-hydroxyprogesterone, luteinizing hormone, and follicle stimulating hormone. In addition, each participant was subjected to a glucose tolerance test and his insulin level was measured. Metformin 850 mg twice daily for 2-weeks was given to each subject after which the above tests were repeated. A paired t-test was used to assess the statistical significance of any observed differences before and after metformin. RESULTS: After metformin administration, there was a significant reduction in serum level of total testosterone (p=0.0001), free testosterone (P=0.002), and 17 hydroxyprogesterone (p=0.0001). There was also a significant increase in serum level of sex hormone binding globulin (p=0.009) and dehydroepiandrosterone sulphate (P=0.0008). Serum levels of luteinizing hormone and follicle stimulating hormone showed no significant changes. Similarly, there were no changes in fasting plasma glucose, fasting serum insulin, weight, or blood pressure. CONCLUSION: Metformin administration was associated with a reduction in total testosterone, free testosterone, and 17-hydroxyprogesterone and an increase in sex hormone binding globulin and dehydroepiandrosterone sulphate in normal males. The clinical significance of these findings needs further investigation.
Treatment of polycystic ovary syndrome with insulin-lowering agents.
Glueck CJ, Streicher P, Wang P.
Cholesterol Center, ABC Building, 3200 Burnet Avenue, Cincinnati, Ohio, USA. [email protected]
Early diagnosis and therapy of the underlying insulin resistance of heritable polycystic ovary syndrome
(PCOS), often manifested at menarche, facilitate the reduction and/or reversal of the reproductive and
metabolic morbidity of PCOS, as well as reduce the risk factors for cardiovascular disease. PCOS is
characterised by oligoamenorrhoea, clinical and biochemical hyperandrogenism, infertility, recurrent
miscarriage, insulin resistance, hyperinsulinaemia, gestational diabetes, impaired glucose tolerance,
Type 2 diabetes, morbid obesity, hypertension, hypofibrinolysis, hypertriglyceridaemia, low levels of high
density lipoprotein-cholesterol and a sevenfold risk increase in cardiovascular disease. Insulin sensitising-
lowering agents reduce insulin resistance and hyperinsulinaemia, reverse PCOS endocrinopathy
and ameliorate the reproductive, metabolic and cardiovascular morbidity of the disorder. The largest
literature on the subject discusses metformin. Improved pregnancy outcomes in women with PCOS
receiving metformin may be attributed to its ability to reduce insulin resistance, hyperinsulinaemia and
hypofibrinolytic plasminogen activator inhibitor activity by the enhancement of folliculogenesis and
improvement of oocyte quality.
Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type
Musi N, Hirshman MF, Nygren J, Svanfeldt M, Bavenholm P, Rooyackers O, Zhou G, Williamson JM,
Ljunqvist O, Efendic S, Moller DE, Thorell A, Goodyear LJ.
Research Division, Joslin Diabetes Center, Brigham and Women's Hospital and Harvard Medical School,
One Joslin Place, Boston, MA 02215, USA. [email protected]
Metformin is an effective hypoglycemic drug that lowers blood glucose concentrations by decreasing
hepatic glucose production and increasing glucose disposal in skeletal muscle; however, the molecular
site of metformin action is not well understood. AMP-activated protein kinase (AMPK) activity increases
in response to depletion of cellular energy stores, and this enzyme has been implicated in the stimulation
of glucose uptake into skeletal muscle and the inhibition of liver gluconeogenesis. We recently reported
that AMPK is activated by metformin in cultured rat hepatocytes, mediating the inhibitory effects of the
drug on hepatic glucose production. In the present study, we evaluated whether therapeutic doses of
metformin increase AMPK activity in vivo in subjects with type 2 diabetes. Metformin treatment for 10
weeks significantly increased AMPK alpha2 activity in the skeletal muscle, and this was associated
with increased phosphorylation of AMPK on Thr172 and decreased acetyl-CoA carboxylase-2 activity.
The increase in AMPK alpha2 activity was likely due to a change in muscle energy status because
ATP and phosphocreatine concentrations were lower after metformin treatment. Metformin-induced
increases in AMPK activity were associated with higher rates of glucose disposal and muscle glycogen concentrations. These findings suggest that the metabolic effects of metformin in subjects with type 2 diabetes may be mediated by the activation of AMPK alpha2.
Metformin increases insulin-stimulated glucose transport in insulin-resistant human skeletal
Galuska D, Zierath J, Thorne A, Sonnenfeld T, Wallberg-Henriksson H.
Department of Clinical Physiology, Karolinska Hospital, Stockholm, Sweden.
The effect of metformin (0.1 mM) on glucose transport was investigated in healthy control and in insulin-
resistant human skeletal muscle. Muscle samples (200-400 mg) were obtained from the rectus abdominis
muscle (abdominal surgery) or from the vastus lateralis portion of the quadriceps femoris muscle (open
biopsy technique) from 8 healthy controls (age 38 +/- 4 yrs, BMI 23 +/- 1) and from 6 insulin-resistant
subjects (age 53 +/- 5 yrs, BMI 30 +/- 2). Metformin had no effect on basal or insulin-stimulated (100
microU/ml) 3-0-methylglucose transport in incubated muscle strips from healthy subjects. Muscle tissue
from the insulin resistant group did not respond to 100 microU/ml of insulin (0.73 +/- 0.17 for basal and
0.81 +/- 0.22 mumol x ml-1 x h-1 for insulin-stimulation, NS). Basal glucose transport was unaffected
by metformin, whereas insulin-stimulated (100 microU/ml) glucose transport was increased by 63% in
the insulin-resistant muscles (0.73 +/- 0.17 in the absence vs 1.19 +/- 0.18 mumol x ml-1 x h-1 in the
presence of metformin, p less than 0.05). In conclusion, metformin abolishes insulin-resistance in human
skeletal muscle by normalizing insulin-stimulated glucose transport accross the muscle cell membrane.
The mechanism for this effect remains to be elucidated
Metformin: a review of its pharmacological properties and therapeutic use.
In a survey, the pharmacological and clinical documentation of metformin is presented and discussed,
and the present state of knowledge relating to metformin-associated lactic acidosis is reviewed. The
use of metformin in the treatment of diabetes is based on clinical experience over twenty years. It has
been well documented that metformin is effective in maturity-onset diabetes both as monotherapy
and in combination with a sulphonylurea. An advantage of metformin treatment is the tendency to
weight reduction and the absence of significant hypoglycemia; blood glucose levels are reduced only
to normal. The disadvantages are the gastro-intestinal side effects and the potential risk of vitamin B
12 and folic acid deficiency during long-term use. Metformin-associated lactic acidosis is a very rare
complication, which has mainly occured in patients with serious renal insufficiency or other contra-
indications to the use of metformin. The association between phenformin and lactic acidosis has led to
withdrawal of this biguanide in several countries. Metformin differs from phenformin in certain important
respects, and the normal use of metformin does not involve the risk of side effects disproportionate to
the intended effect. Further experimental studies are required to substantiate pharmacokinetics and
metabolic effects of metformin in man.
Our next chapter will discuss one very promising drug in the fight against obesity, a drug that has been used to protect hearts for years now and may prove to be the ultimate anti-fat-gain medicine of the 21st century. Stay tuned.
Nutrition Volume 19, Numbers 11/12, 200316. Carpenter KC, Roberts S, Sternberg S. Nutrition and immune function: a 1992size, the place of residence of the subjects whether living at homeor in institutions, and the baseline status of the subjects. In several17. Sano M, Ernesto C, Thomas RG, et al. A controlled study of selegiline, alpha-studies, single nutrients were used. Zinc supplements c