Diabetes Drugs Take A BAD RAP
by Jeffrey Dach MD
You probably think of Diabetes Drugs as all lumped together as “Bad Drugs”. For many years , I certainly did. Perhaps it was the Avandia story that gave Diabetes Drugs a Bad Rap and made us think poorly of ALL Diabetes Drugs.
Upper Left Image: Photo of French Lilac Plant , the plant origin of Metformin, courtesy of Wikimedia Commons.
Avandia, the “BAD Drug” for Diabetes
Take the case of Avandia, approved in 1999, it quickly became the world’s best selling diabetes drug. However, 8 years later, the New England Journal reported that Avandia causes increased heart attack rates, and sales were suspended in Europe.(1A)
In November 2011, GlaxoSmithKline admitted they withheld safety data on Avandia and agreed to pay the US government 3 billion in civil and criminal penalties related to illegal marketing. The Avandia case gave all diabetes drugs a “Bad Rap”. The reality is that there is one diabetes drug that has stood the test of time, and is in fact a “Good Drug”. This is Metformin. Perhaps the plant origin of the drug makes it a “good drug”.
Metformin, the “Good Drug”
Is There Anyone
Who Should not Take It ?
At the May 2012 Orlando A4M Meeting, Terry Grossman, M.D. from Golden Colorado gave an excellent presentation on Metformin. Credit and thanks goes to Terry Grossman MD for sharing his talk at the meeting with all of us. Much of this article comes from Grossman’s PowerPoint slides. Dr Terry Grossman is co-author of the Ray Kurzweil book, Fantastic Voyage.
Upper Left Image : Photo of Terry Grossman MD, courtesy of Terry Grossman MD.
Metformin by Terry Grossman MD- Metformin Discovery and Approval
Discovered in the 1920’s, Metformin is currently the most widely prescribed anti-diabetic drug in the world, approved for Type Two Diabetes in 1958 for the United Kingdom (UK), in 1972 for Canada, and in 1995 by the FDA in the United States,
Metformin Origin From the Plant World, Guanidine Compounds:
Metformin comes from the plant world. The French Lilac plant (called Galega officinalis) was used for centuries as a folk medicine for the treatment of Diabetes. The active ingredient in the French Lilac plant, called guanidine compounds, were discovered and isolated in the 1920’s.
Metformin – Mechanism of Action
Master Switch which Up-Regulates AMP Kinase
At the risk of boring you with overly technical matters, here is the exact mechanism of how Metformin works its magical benefits. The actions of metformin are intimately related to AMPK, these letters stand for Adenosine Mono- Phosphate Kinase (AMP Kinase), which has been called a metabolic “master switch” involved with energy status of cells, hormone expression and protein synthesis.
Metformin Up-Regulates AMP Kinase Expression.
AMPK Affects Cellular Energy/Biochemistry
If AMPK is turned OFF: (This is BAD)
ATP is consumed
Glucose is burned for energy.
Fatty acids and cholesterol are synthesized.
This is similar to effects of HIGH insulin levels.
If AMPK is Turned ON: (This is GOOD)
ATP is created.
Fatty acids are predominantly consumed for energy.
This is similar to the effects of Caloric Restriction and LOW insulin levels.
AMPK Effects on Key Organ Systems
Pancreas: Decreases insulin secretion.
Liver: Decreases fatty acid and cholesterol synthesis.
Adipose (Storage Fat Tissue): Decreases fatty acid synthesis, increase lipolysis.
Skeletal muscle: Increases fatty acid oxidation, glucose uptake, and glycolysis
Heart muscle: Increases fatty acid oxidation, and glucose uptake
Metformin – Mechanisms of Action
1) Decreases glucose absorption from GI tract. (2)
2) Inhibits hepatic gluconeogenesis (production of sugar by the liver).
3) Increases sensitivity and number of insulin receptors.
4) Increases peripheral glucose uptake
5) Increases fatty acid oxidation.
Metformin Decreases Glucose Absorption From GI Tract
In studies using lab mice, metformin (in dosage of 250 mg/kg) given for five days decreased Glucose absorption by the GI tract by more than half. (2) These results indicate that metformin had a significant inhibitory effect on the absorption of sugar (glucose) by the gastrointestinal tract.
Metformin Inhibits Hepatic Gluco-Neogensis (Sugar Production)
Primary Action of Metformin
People with Type Two Diabetes have a Three-Fold increase in gluconeogenesis (sugar production by the liver). Metformin decreases gluconeogenesis by 36% as a result of AMPK upregulation. (3)
Metformin Increases Sensitivity and Number of Insulin Receptors
Insulin Resistance can be seen in Metabolic Syndrome, in Type two Diabetes (T2DM) and in the Aging Process.
With Insulin Resistance, higher levels of insulin are needed by the body to move glucose into the cells. Metformin is beneficial here because metformin increases both insulin sensitivity and number of insulin receptors. With Metformin use, insulin levels fall and patients often lose weight, ameliorating metabolic syndrome. (4)
Metformin Increases Fatty Acid Oxidation
When blood insulin levels are high, as in Type Two Diabetes, glucose is preferentially burned rather than fatty acids. When insulin levels decrease, fatty acids are may then be utilized (oxidized, burned, metabolized) for energy production rather than sugar (glucose). Metformin increases utilization of FAT Stores as energy for muscle (fatty acids oxidation by muscle cells). (5)
Uses of Metformin
FDA approved Use: Metformin is FDA approved for use in Type 2 Diabetes.
Off-Label Uses of Metformin
1) Polycystic ovary syndrome (PCOS)
2) Drug-induced weight gain
3) Cancer Prevention
4) Caloric restriction (CR)-mimetic
Metformin , the Diabetes Drug – 48 Million Prescriptions
Metformin is first line drug treatment for Type Two Diabetes.
Forty Eight million prescriptions for metformin were written in United States in 2010.
Metformin is the Ninth most commonly prescribed drug.
Metformin is the only anti-diabetic drug proven to prevent the Cardiovascular Complications of Type Two Diabetes.
Metformin Lowers LDL-C and Triglycerides.
Metformin does not cause weight gain, and does not cause hypoglycemia.
Metformin is Safer and Fewer Adverse Effects Compared to Other (6)
Metformin vs. Sulfonureas
Any DM Endpoint 9% 21%
Heart Attacks 15% 33%
All Cause Mortality 13% 27%
This is data is from : Ten-year follow-up of intensive glucose control in type 2 diabetes. by Holman RR, N Engl J Med. 2008 Oct 9.(6)
Metformin- Has Added Beneficial Effects
Here is a Meta-Analysis of 31 Metformin drug trials with 4,570 participants.(7)
Metformin reduced BMI (Body Mass Index) – 5.3%
Reduced Fasting Sugar – (Glucose) – 4.5%
Reduced Fasting insulin -14.4%
Reduced Triglycerides – 5.3%
Reduced LDL-C – 5.6%
Reduced New-onset diabetes – 40%
Increased HDL-C + 5%
Metformin reduces new onset Diabetes by 40% (7)
Statin Drugs or Metformin ?
For people with elevated total and LDL cholesterol, mainstream cardiologists and primary care physicians commonly prescribe statin drugs. Many of these patients may actually benefit from Metformin instead.
Metformin is useful for the patient with the “High Normal” fasting blood sugar (85-99) and elevated triglycerides. Rather than use a statin drug to alter LDL cholesterol, why not use Metformin ?
Metformin is more beneficial with fewer adverse effects than statin drugs. Statin primary prevention studies are disappointing with no reduction in all cause mortality in healthy men. On the other hand, Metformin reduces cardiovascular mortality by 40% (13) when fasting blood sugar is reduced to below 86 mg/ml, with fewer adverse effects. In addition Metformin is cancer preventive, and prolongs survival as a CR-mimetic.(CR=Caloric Restriction)
Definitions of Diabetes and Pre-Diabetes
Diabetes is defined as Fasting Glucose greater than 125 mg/ml.
and a 2 hr Post prandial glucose (after a meal) greater than 200 mg/ml.
and a Hemoglobin A1C (Hb A1c) greater than 6.5 mg/ml
Pre-diabetes is defined as a Fasting Glucose 100-124 mg/ml.
and a 2 hr Post prandial serum glucose 140-199 mg/ml.
amd a Hb A1c in the 5.7 – 6.4 range.
Type II Diabetes is NOW at Epidemic Levels (8)
There has been a 10-fold increase in Type Two Diabetes worldwide over the past 27 years. The number of Type Two Diabetics has increased from 30 million in 1985, to 300 million in 2012.
1.9 million people were diagnosed with Type Two Diabetes (T2 DM) in 2010. This is one person every 16 seconds.(8) Currently in the United States, 26 million Americans are Diabetic. Almost a third of the over-65 population is diabetic.
Lifetime Risk of Diabetes is Substantial
The estimated lifetime risk of developing diabetes for individuals born in 2000 is about thirty per cent (32.8% for males and 38.5% for females).(9)
Increased All-Cause Mortality With Diabetes- Two and a Half Times
Morbidity Risk Reduction With Metformin (11)
Metformin use producing each one per cent reduction in Hemoglobin A(1c) was associated with risk reductions of the following (11)
One Per Cent Hgb A1C Reduction Associated With Reduction of (11)
21% for any end point related to diabetes.
21% for deaths related to diabetes.
14% for myocardial infarction.
37% for microvascular complications.
Metabolic Syndrome Increases All-Cause and CardioVascular Mortality
Meta-analysis of 87 studies involving 951,083 patients (12)
Metabolic syndrome increased Relative Risk (12)
2.35 for CardioVascular disease,
2.02 for CardioVascular disease mortality,
1.58 for total mortality
2.99 for Myocardial Infarction (heart attack)
2.27 for stroke
Increased Risk of CV Death Even with “Normal” Blood Sugar (13)
This study followed 2,000 men ages 40 to 60 years old followed over 22 years (from 1975 to 1997)(13). They found that for men with a Fasting Blood Sugar greater than 85 mg/ml, the Relative Risk of cardiovascular death increased 40%.(13) So we now have a new category called “high normal , with FBS 85 – 100 mg/ml= “high normal”
Epidemic of High Normal Fasting Blood Sugar (above 85)(14)
85% of adults have high normal blood glucose or above.
In 1976, only 25% had FBS greater than 85 mg/ml
By 2009, this number had increased to 85% (14)
Only One in Eight People Have Optimal Fasting Blood Sugar (FBS)
Fasting Blood Sugar Percent of Population
FBS > 125 Diabetes 11%
FBS 100 –124 Prediabetes 35%
FBS 86 – 99 High normal 39%
FBS 70 – 85 Optimal 13%
FBS < 69 Hypoglycemia 2%
Executive Health Patients Grossman Wellness Center
FBS Desciption Longevity ClinicPts Average
>125 T2 DM +300% risk of MI 3% 11%
100-124 Prediabetes 12% 35%
85-99 High Normal (+40% risk of MI) 60% 39%
70-84 Optimal 24% 13%
<69 Hypoglycemia 2% 2%
Off-Label Uses of Metformin
Although Metformin is FDA approved for use in Type Two Diabetes, other uses which have not been submitted is called “off-label use”. For many drugs used in the practice of medicine, off-Label use is quite common.
1) PCOS (PolyCystic Ovary Syndrome)
2) Prevents Drug-induced weight gain
3) Anti-cancer Effects
4) Caloric Restriction (CR)-mimetic
PCOS PolyCystic Ovary Syndrome
1) PCOS affects 9 per cent of young, premenopausal women. This is an epidemic.
2) PCOS is characterized by insulin resistance and hyper-insulinemia.
3) PCOS women have increased risk of Diabetes (T2DM) and Cardiovascular Disease
Benefits of Metformin in PCOS (15-17)
For the PCOS patient, Metformin lowers glucose, lowers insulin and testosterone levels. Metformin reduces the androgenic symptoms of acne and hirsutism, abdominal obesity, amenorrhea and other symptoms of PCOS. (15-17)
Metformin for Drug Induced Weight Gain From Newer Psychiatric Drugs
Weight gain is common with newer generation antipsychotics such as Clozapine (Clozaril), olanzapine (Zyprexa), Risperidone (Risperdol), quetiapine (Seroquel) and Aripiprozole (Abilify) Patients on Zyprexa gain 20 pounds of weight over three months of treatment.(18) A number of studies have shown Metformin useful in preventing this type of weight gain from anti-psychotic drugs. (19-20)
Diabetics Gain Weight From Insulin Use
When insulin or other agents are used is used for Type Two Diabetes, it is common to see weight gain of 4 kilograms (10 pounds) for each 1 per cent drop in Hemoglobin A1C. (21)
Metformin and Cancer Prevention
Virtually all cancers eats only one food, and that is Glucose, also called sugar.
Cancer cells have many times the normal number of insulin receptors on their outer cell membranes which makes the cancer cell “Gobble Up” sugar when it is available. Cancer cells are very sensitive to Insulin, and high insulin levels massively increase sugar uptake by cancer cells.
AMPK Activation by Metformin and Effect on Cancer
Metformin upregulates AMPK which blocks expression of cancer-promoting genes (22) and activates the tumor suppressor p53 gene. (22) Metformin inhibits aromatase expression in breast tissue which decreases estrogenic proliferation. (23)
Increased Cancer in Diabetes
Diabetics have increased risk of numerous types of cancers , such as
primary liver cancer, pancreatic cancer, colorectal cancer, endometrial cancer, breast cancer, and renal cancers. (24)
Metformin Use Reduced Cancer almost in HALF
In a Dutch study, 85,000 Type Two Diabetics (T2DM) on metformin or sulfonylurea were followed over ten years. The risk of a cancer diagnosis was reduced by 10% for metformin users compared to diabetics on sulfonylurea agents. Metformin users had lower risks for cancers of the esophagus, stomach, colon, liver, pancreas, lung, breast, and prostate (25)
In another study of 4,085 metformin users compared to controls, cancer was reduced by 46% for the metformin users compared to non-users. (26) An Italian study from Florence showed Metformin use reduced cancer incidence. (27) A study from MD Anderson Cancer center showed Metformin use reduce pancreatic cancer incidence by 62 per cent. (28) Another MD Anderson study shows Metformin to be beneficial to the breast cancer patient while undergoing treatment.(29)
Metformin as a CR Mimetic – Caloric Restriction
What is Caloric Restirction ?
In the race to find some type of intervention that would decelerate the aging process in animals (and humans) and prevent the onset of age-related degenerative disease, one intervention stands out as the most successful, restricting the food supply to the laboratory mouse. This is called caloric restriction. “Caloric restriction (CR) is the most robust environmental method known for decelerating aging and the development of age-related diseases.”(32)
Antiaging Potential of Metformin
In the early 1970s, Dr. Vladimir Dilman hypothesized that Metformin Compounds, the biguanides may have use as “geroprotectors” and anticancer effects (“metabolic rehabilitation”). In the early 1990s, Dr. Dilman and Ward Dean hypothesized that metformin should be considered as an “antiaging” therapy.(30)
The Metformin/AMPK Connection – CR
Metformin/AMPK use prevents cell damage, triggers cell repair, and switches our cells into “survival mode” which increases and energy (ATP) production. The cellular long term needs for protein, lipid and starch synthesis decreases.
Metformin use very closely mimics cell repair processes associated with Caloric Restriction (CR), creating a Genetic Profile (mRNA) in mice very similar to the changes in gene profile seen with Caloric Restriction (CR)(31)
Using gene chip technology, studies show Metformin affects 63 genes involved in energy production, protein synthesis, and cell growth (31-33). Metformin induced gene modifications closely mimic caloric restriction, and dramatically extends lifespan of mice by almost 40 per cent. (34)
Metformin – Precautions and Adverse effects
The major adverse effects of Metformin relate to gastrointestinal symptoms, and may affect up to half of users. Gastrointestinal side effects such as diarrhea may be reduced by beginning metformin slowly, starting with a lower dose, or using a time release formulation –
Diarrhea may be reported up to 53.2% (11.7% placebo)
Nausea/vomiting – up to 25.5% (8.3% placebo)
Gas – up to 12.1%
Weakness – up to 9.2%
Indigestion – up to 7.1%
GI discomfort – up to 6.4%
Headache – up to 5,7%
From: Drug Facts and Comparisons 2005. St. Louis, Mo:
Facts and Comparisons; 2004.
Metformin: How To Avoid Side Effects
Begin Metformin at a low dose and increase gradually. Use 250 mg Metformin Twice a Day with meals for 7 to 14 days, then increase to 500 mg twice a day with meals. Adverse effects tend to be less with metformin ER (extended release), and Diarrhea is 80% less likely.
Metformin – Metabolism and Excretion
Metformin is not bound to plasma protein or metabolized.
Most of the Metformin dose (75-90%) is excreted by kidneys within in 12 hrs.
There are no clinically relevant drug interactions, because Metformin it is not metabolized and does not interfere with the metabolism of other drugs
Other Adverse Effects – B12 malabsorption
Metformin may cause Vitamin B12 malabsorption and B12 deficiency, with increased homocysteine levels, make sure each patient supplements with B12 while taking metformin. (35-36)
Metformin Contra-indications and Safety – Less Adverse Events – Lactic Acidosis
Metformin is safer than its predecessor drug, phenformin, with a 20 fold lower incidence of fatal lactic acidosis, causing only 3 cases/per 100,000 patient years of fatal lactic acidosis, compared to Phenformin which has 64 cases. Virtually all occurring in renal failure patients. Because of this, renal failure is a contraindication to use of Metformin. (1)
Renal Failure – Lactic acidosis
Lactate serves as a Krebs cycle substrate . Metformin impedes hepatic lactate uptake as part of its action in interfering with gluconeogenesis . The slight increase in metformin-induced lactic acid is cleared by the kidneys. Therefore, renal failure is a contraindication to the use of Metformin.(37)
Other relative contraindications: Congestive Heart Failure (CHF), alcoholism, severe COPD Chronic Obstructive Lung Disease.
Clinical Considerations in using Metformin in healthy non-diabetics
1) Informed consent for off-label use
2) Check HbA1c, fasting glucose, liver and renal functuion/kidney tests
3) If FBS > 85 or Hb A1c >5.3, consider metformin
Begin with ¼ – ½ of 500 mg tablet once a day with meals x 7-14 days; then increase to twice a day x 7-14 days If tolerated, stay at 250 or increase to 500 mg twice a day
Check HbA1c, fasting glucose, liver & kidney function tests every 6 months
Generic Metformin is Very Affordable
Cost is 7 cents per 500 mg tablet, or $4.20/ month for 500 mg tablet twice a day.
Side effects are less with time-release formulation. Name brand metformin XR costs $1.10 per500 mg tablet, or $66 per month for 500 mg tablet twice a day.
Metformin- is there anyone who shouldn’t take it?
Type II diabetes 11% YES
Prediabetes 35% YES
High normal 39% YES
Optimal 13% ??
Hypoglycemia 2% NO
The recommended Berberine product is Dr. Jonathan V. Wright’s InsuLife-BThis is a combination supplement containing Berberine which is a botanical with profile similar to the diabetic drug Metformin. This also contains: Cinnamon (Cinnamomum cassia) bark extract, Oregon grape (Mahonia aquifolium) root extract (80% Berberine),Resveratrol,Alpha-lipoic acid,Quercetin,
Anticancer Effects of Berberine
Berberine Induces Apoptosis in Cancer Cells
Dr. Hsu from Taichung General Hospital in Taiwan published his 2007 report on the anticancer activity of berberine in Archives of Toxicolology. Dr Hsu found that Berberine induces apoptosis (programmed cell death) in human colonic carcinoma cells through generation of ROS, reactive oxygen species, and activation of JNK/p38 MAPK signalling systems.
Another report in the 2010 Journal of Cell Biochemicstry by Dr Hyun at Wonkwang University, South Korea again showed Berberine induces apoptosis in Liver cancer cells (Hepatoma HepG2) through activation of the MAPK and Caspase system after generation of ROS (reactive oxygen species).
There are literally hundreds of studies on Berberine inducing Apoptosis which can be found here.
Author: Jeffrey Dach MD
Articles with Related Interest:
Links and References
Crofford OB (August 1995). Metformin. N. Engl. J. Med. 333 (9): 588–9
Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes. Steven E. Nissen, M.D., and Kathy Wolski, M.P.H.
N Engl J Med 2007; 356:2457-2471June 14, 2007
Ikeda T, Iwata K, Murakami H. Biochem Pharmacol. 2000 Apr 1;59(7):887-90. Biochem Pharmacol. 2000 Apr 1;59(7):887-90.
Inhibitory effect of metformin on intestinal glucose absorption in the perfused rat intestine. Ikeda T, Iwata K, Murakami H. Source The Department of Medical Technology, Tottori University College of Medical Care Technology, Yonago, Japan.
In rats orally administered metformin (250 mg/kg) for 5 days, glucose absorption by the perfused intestine (375.0+/-164.3 micromol/30 min) was significantly (P<0.001) lower than that in control rats (811.0+/-83.1 micromol/30 min).
Hundal R, Krssak M et al.
Diabetes. 2000;49(12):2063–9. Diabetes. 2000 Dec;49(12):2063-9.
Mechanism by which metformin reduces glucose production in type 2 diabetes. Hundal RS, Krssak M, Dufour S, Laurent D, Lebon V, Chandramouli V, Inzucchi SE, Schumann WC, Petersen KF, Landau BR, Shulman GI.
Source Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Abstract To examine the mechanism by which metformin lowers endogenous glucose production in type 2 diabetic patients, we studied seven type 2 diabetic subjects, with fasting hyperglycemia (15.5 +/- 1.3 mmol/l), before and after 3 months of metformin treatment.
Seven healthy subjects, matched for sex, age, and BMI, served as control subjects. Rates of net hepatic glycogenolysis, estimated by 13C nuclear magnetic resonance spectroscopy, were combined with estimates of contributions to glucose production of gluconeogenesis and glycogenolysis, measured by labeling of blood glucose by 2H from ingested 2H2O. Glucose production was measured using [6,6-2H2]glucose.
The rate of glucose production was twice as high in the diabetic subjects as in control subjects (0.70 +/- 0.05 vs. 0.36 +/- 0.03 mmol x m(-2) min(-1), P < 0.0001).
Metformin reduced that rate by 24% (to 0.53 +/- 0.03 mmol x m(-2) x min(-1), P = 0.0009) and fasting plasma glucose concentration by 30% (to 10.8 +/- 0.9 mmol/l, P = 0.0002).
The rate of gluconeogenesis was three times higher in the diabetic subjects than in the control subjects (0.59 +/- 0.03 vs. 0.18 +/- 0.03 mmol x m(-2) min(-1) and metformin reduced that rate by 36% (to 0.38 +/- 0.03 mmol x m(-2) x min(-1), P = 0.01). By the 2H2O method, there was a twofold increase in rates of gluconeogenesis in diabetic subjects (0.42 +/- 0.04 mmol m(-2) x min(-1), which decreased by 33% after metformin treatment (0.28 +/- 0.03 mmol x m(-2) x min(-1), P = 0.0002). There was no glycogen cycling in the control subjects, but in the diabetic subjects, glycogen cycling contributed to 25% of glucose production and explains the differences between the two methods used.
In conclusion, patients with poorly controlled type 2 diabetes have increased rates of endogenous glucose production, which can be attributed to increased rates of gluconeogenesis. Metformin lowered the rate of glucose production in these patients through a reduction in gluconeogenesis.
Fontbonne A, Charles MA et al. 1996,
Diabetes Care 19:920-92614. Diabetes Care. 1996 Sep;19(9):920-6.
The effect of metformin on the metabolic abnormalities associated with upper-body fat distribution. BIGPRO Study Group.
Fontbonne A, Charles MA, Juhan-Vague I, Bard JM, André P, Isnard F, Cohen JM, Grandmottet P, Vague P, Safar ME, Eschwège E. Source National Institute of Health and Medical Research, INSERM U21, Villejuif, France.
Abstract OBJECTIVE: The constellation of anomalies associated with insulin resistance is a plausible additional cause of ischemic cardiovascular disease and of NIDDM. To test this hypothesis in a primary prevention trial, the effects of metformin as a potential candidate for intervention in the insulin resistance syndrome (IRS) were evaluated in 324 middle-aged subjects with upper-body obesity.
RESEARCH DESIGN AND METHODS: Trial patients were selected on the basis of a high waist-to-hip ratio. They were randomly allocated to receive either metformin or placebo, following a double-blind procedure. After 1 year of treatment, the main clinical and biological parameters of the IRS were assessed and their evolution compared between treatment groups.
RESULTS: Compared with placebo, metformin induced a significant weight loss, a better maintenance of fasting blood glucose, total and LDL cholesterol levels, and a greater decrease of fasting plasma insulin concentration. Moreover, tissue-type plasminogen activator antigen, a marker of fibrinolytic impairment, showed a significant decrease under metformin. By contrast, metformin treatment had no significant effect on blood pressure or serum triglyceride and HDL cholesterol concentrations. The main side effect of metformin was diarrhea.
CONCLUSIONS: The BIGuanides and Prevention of Risks in Obesity (BIGPRO1) results suggest that metformin would be a suitable candidate for long-term intervention for the prevention of diabetes but that its use in a trial of primary prevention of cardiovascular diseases requires either a reevaluation of its properties toward the most potentially atherogenic anomalies of the IRS or a better definition of the target population.
Fatty acid oxidation relative to storage in soleus and epitrochlearis muscle during 0–30 min of incubation
Collier C A et al. Am J Physiol Endocrinol Metab 2006;291:E182-E189 Am J Physiol Endocrinol Metab. 2006 Jul;291(1):E182-9. Epub 2006 Feb 14.
Metformin counters the insulin-induced suppression of fatty acid oxidation and stimulation of triacylglycerol storage in rodent skeletal muscle.
Collier CA, Bruce CR, Smith AC, Lopaschuk G, Dyck DJ.
Source Dept. of Human Health and Nutritional Sciences, Univ. of Guelph, Guelph, ON, Canada.
Abstract The present study examined the acute effects of metformin on fatty acid (FA) metabolism in oxidative soleus (SOL) and glycolytic epitrochlearis (EPT) rodent muscle. SOL and EPT were incubated for either 30 or 180 min in the absence or presence of 2 mM metformin and with or without insulin (10 mU/ml). Metformin did not alter basal FA metabolism but countered the effects of insulin on FA oxidation and incorporation into triacylglyerol (TAG). Specifically, metformin prevented the insulin-induced suppression of FA oxidation in SOL but did not alter FA incorporation into lipid pools. In contrast, in EPT metformin blunted the incorporation of FA into TAG when insulin was present but did not alter FA oxidation. In SOL, metformin resulted in a 50% increase in AMP-activated protein kinase alpha2 activity and prevented the insulin-induced increase in malonyl-CoA content. In both fiber types, basal and insulin-stimulated glucose oxidation were not significantly altered by metformin. All effects were similar regardless of whether they were measured after 30 or 180 min. Because increased muscle lipid storage and impaired FA oxidation have been associated with insulin resistance in this tissue, the ability of metformin to reverse these abnormalities in muscle FA metabolism may be a part of the mechanism by which metformin improves glucose clearance and insulin sensitivity. The present data also suggest that increased glucose clearance is not due to its enhanced subsequent oxidation. Additional studies are warranted to determine whether chronic metformin treatment has similar effects on muscle FA metabolism.\\
10-year follow-up of intensive glucose control in type 2 diabetes. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. Diabetes Trials Unit, Oxford Centre for Diabetes, Endocrinology, and Metabolism, Churchill Hospital, Headington, Oxford OX3 7LJ,
During the United Kingdom Prospective Diabetes Study (UKPDS), patients with type 2 diabetes mellitus who received intensive glucose therapy had a lower risk of microvascular complications than did those receiving conventional dietary therapy. We conducted post-trial monitoring to determine whether this improved glucose control persisted and whether such therapy had a long-term effect on macrovascular outcomes. METHODS:Of 5102 patients with newly diagnosed type 2 diabetes, 4209 were randomly assigned to receive either conventional therapy (dietary restriction) or intensive therapy (either sulfonylurea or insulin or, in overweight patients, metformin) for glucose control. In post-trial monitoring, 3277 patients were asked to attend annual UKPDS clinics for 5 years, but no attempts were made to maintain their previously assigned therapies. Annual questionnaires were used to follow patients who were unable to attend the clinics, and all patients in years 6 to 10 were assessed through questionnaires. We examined seven prespecified aggregate clinical outcomes from the UKPDS on an intention-to-treat basis, according to previous randomization categories.
RESULTS:Between-group differences in glycated hemoglobin levels were lost after the first year. In the sulfonylurea-insulin group, relative reductions in risk persisted at 10 years for any diabetes-related end point (9%, P=0.04) and microvascular disease (24%, P=0.001), and risk reductions for myocardial infarction (15%, P=0.01) and death from any cause (13%, P=0.007) emerged over time, as more events occurred. In the metformin group, significant risk reductions persisted for any diabetes-related end point (21%, P=0.01), myocardial infarction (33%, P=0.005), and death from any cause (27%, P=0.002).
CONCLUSIONS : despite an early loss of glycemic differences, a continued reduction in microvascular risk and emergent risk reductions for myocardial infarction and death from any cause were observed during 10 years of post-trial follow-up. A continued benefit after metformin therapy was evident among overweight patients.
Salpeter SR, Buckley NS, Kahn JA, Salpeter EE.
Am J Med. 2008 Feb; 121(2):149-157. Santa Clara Valley Medical Center, San Jose, CA 95128, USA.
We performed a meta-analysis of randomized controlled trials to assess the effect of metformin on metabolic parameters and the incidence of new-onset diabetes in persons at risk for diabetes.
METHODS:We performed comprehensive English- and non-English-language searches of EMBASE, MEDLINE, and CINAHL databases from 1966 to November of 2006 and scanned selected references. We included randomized trials of at least 8 weeks duration that compared metformin with placebo or no treatment in persons without diabetes and evaluated body mass index, fasting glucose, fasting insulin, calculated insulin resistance, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, and the incidence of new-onset diabetes.
RESULTS: pooled results of 31 trials with 4570 participants followed for 8267 patient-years showed that metformin reduced
body mass index (-5.3%, 95% confidence interval [CI], -6.7–4.0),
fasting glucose (-4.5%, CI, -6.0–3.0),
fasting insulin (-14.4%, CI, -19.9–8.9),
calculated insulin resistance (-22.6%, CI, -27.3–18.0),
triglycerides (-5.3%, CI, -10.5–0.03), and
low-density lipoprotein cholesterol (-5.6%, CI, -8.3–3.0%), and
increased high-density lipoprotein cholesterol (5.0%, CI, 1.6-8.3) compared with placebo or no treatment.
The incidence of new-onset diabetes was reduced by 40% (odds ratio 0.6; CI, 0.5-0.8), with an absolute risk reduction of 6% (CI, 4-8) during a mean trial duration of 1.8 years.
CONCLUSION:Metformin treatment in persons at risk for diabetes improves weight, lipid profiles, and insulin resistance, and reduces new-onset diabetes by 40%. The long-term effect on morbidity and mortality should be assessed in future trials.
CDC, Jan 26, 2011.
Press Release Number of Americans with Diabetes Rises to Nearly 26 Million More than a third of adults estimated to have prediabetes
Nearly 26 million Americans have diabetes, according to new estimates from the Centers for Disease Control and Prevention (CDC). In addition, an estimated 79 million U.S. adults have prediabetes, a condition in which blood sugar levels are higher than normal, but not high enough to be diagnosed as diabetes. Prediabetes raises a person’s risk of type 2 diabetes, heart disease and stroke. Diabetes affects 8.3 percent of Americans of all ages, and 11.3 percent of adults aged 20 and older, according to the National Diabetes Fact Sheet for 2011. About 27 percent of those with diabetes—7 million Americans—do not know they have the disease. Prediabetes affects 35 percent of adults aged 20 and older. In 2008, CDC estimated that 23.6 million Americans, or 7.8 percent of the population, had diabetes and another 57 million adults had prediabetes. The 2011 estimates have increased for several reasons: More people are developing diabetes. Many people are living longer with diabetes, which raises the total number of those with the disease. Better management of the disease is improving cardiovascular disease risk factors and reducing complications such as kidney failure and amputations. Hemoglobin A1c is now used as a diagnostic test, and was therefore incorporated into calculations of national prevalence for the first time. The test, also called glycated hemoglobin, measures levels of blood glucose (sugar) over a period of two to three months. Because of this change, estimates of populations with diabetes and prediabetes in the 2011 fact sheet are not directly comparable to estimates in previous fact sheets. In a study published last year, CDC projected that as many as 1 in 3 U.S. adults could have diabetes by 2050 if current trends continue. Type 2 diabetes, in which the body gradually loses its ability to use and produce insulin, accounts for 90 percent to 95 percent of diabetes cases. Risk factors for type 2 diabetes include older age, obesity, family history, having diabetes while pregnant (gestational diabetes), a sedentary lifestyle, and race/ethnicity. Groups at higher risk for the disease are African-Americans, Hispanics, American Indians/Alaska Natives, and some Asian-Americans and Pacific Islanders.
JAMA. 2003 Oct 8;290(14):1884-90.
Lifetime risk for diabetes mellitus in the United States. Narayan KM, Boyle JP, Thompson TJ, Sorensen SW, Williamson DF. Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Division of Diabetes Translation, Atlanta, Ga, USA. firstname.lastname@example.org Although diabetes mellitus is one of the most prevalent and costly chronic diseases in the United States, no estimates have been published of individuals’ average lifetime risk of developing diabetes.
OBJECTIVE:To estimate age-, sex-, and race/ethnicity-specific lifetime risk of diabetes in the cohort born in 2000 in the United States.
DESIGN, SETTING, AND PARTICIPANTS: Data from the National Health Interview Survey (1984-2000) were used to estimate age-, sex-, and race/ethnicity-specific prevalence and incidence in 2000. US Census Bureau data and data from a previous study of diabetes as a cause of death were used to estimate age-, sex-, and race/ethnicity-specific mortality rates for diabetic and nondiabetic populations.
MAIN OUTCOME MEASURES:Residual (remaining) lifetime risk of diabetes (from birth to 80 years in 1-year intervals), duration with diabetes, and life-years and quality-adjusted life-years lost from diabetes.
RESULTS:The estimated lifetime risk of developing diabetes for individuals born in 2000 is 32.8% for males and 38.5% for females. Females have higher residual lifetime risks at all ages. The highest estimated lifetime risk for diabetes is among Hispanics (males, 45.4% and females, 52.5%). Individuals diagnosed as having diabetes have large reductions in life expectancy. For example, we estimate that if an individual is diagnosed at age 40 years, men will lose 11.6 life-years and 18.6 quality-adjusted life-years and women will lose 14.3 life-years and 22.0 quality-adjusted life-years.
CONCLUSIONS:For individuals born in the United States in 2000, the lifetime probability of being diagnosed with diabetes mellitus is substantial. Primary prevention of diabetes and its complications are important public health priorities.
16-year excess all-cause mortality of newly diagnosed type 2 diabetic patients: a cohort study by Lars J Hansen*†, Niels de Fine Olivarius† and Volkert Siersma†
The Research Unit for General Practice and Section of General Practice, Department of Public Health, University of Copenhagen, Copenhagen, Denmark
BMC Public Health 2009, 9:400
BMJ. 2000 Aug 12;321(7258):405-12.
Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study.
Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, Hadden D, Turner RC, Holman RR. Diabetes Trials Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Radcliffe Infirmary, Oxford OX2 6HE.
OBJECTIVE:To determine the relation between exposure to glycaemia over time and the risk of macrovascular or microvascular complications in patients with type 2 diabetes. DESIGN: Prospective observational study.
Setting: 23 hospital based clinics in England, Scotland, and Northern Ireland. Participants: 4585 white, Asian Indian, and Afro-Caribbean UKPDS patients, whether randomised or not to treatment, were included in analyses of incidence; of these, 3642 were included in analyses of relative risk.
OUTCOME MEASURES: Primary predefined aggregate clinical outcomes: any end point or deaths related to diabetes and all cause mortality. Secondary aggregate outcomes: myocardial infarction, stroke, amputation (including death from peripheral vascular disease), and microvascular disease (predominantly retinal photo-coagulation). Single end points: non-fatal heart failure and cataract extraction. Risk reduction associated with a 1% reduction in updated mean HbA(1c) adjusted for possible confounders at diagnosis of diabetes.
RESULTS:The incidence of clinical complications was significantly associated with glycaemia.
Each 1% reduction in updated mean HbA(1c) was associated with reductions in risk of
21% for any end point related to diabetes (95% confidence interval 17% to 24%, P<0.0001),
21% for deaths related to diabetes (15% to 27%, P<0.0001),
14% for myocardial infarction (8% to 21%, P<0.0001), and
37% for microvascular complications (33% to 41%, P<0.0001).
No threshold of risk was observed for any end point.
CONCLUSIONS:In patients with type 2 diabetes the risk of diabetic complications was strongly associated with previous hyperglycaemia. Any reduction in HbA(1c) is likely to reduce the risk of complications, with the lowest risk being in those with HbA(1c) values in the normal range (<6.0%)
J Am Coll Cardiol. 2010 Sep 28;56(14):1113-32.
The metabolic syndrome and cardiovascular risk a systematic review and meta-analysis. Mottillo S, Filion KB, Genest J, Joseph L, Pilote L, Poirier P, Rinfret S, Schiffrin EL, Eisenberg MJ. Jewish General Hospital/McGill University, Montreal, Quebec, Canada.
OBJECTIVES:We sought to conduct a systematic review and meta-analysis of the cardiovascular risk associated with the metabolic syndrome as defined by the 2001 National Cholesterol Education Program (NCEP) and 2004 revised National Cholesterol Education Program (rNCEP) definitions.
BACKGROUND:Numerous studies have investigated the cardiovascular risk associated with the NCEP and rNCEP definitions of the metabolic syndrome. There is debate regarding the prognostic significance of the metabolic syndrome for cardiovascular outcomes. METHODS:We searched the Cochrane Library, EMBASE, and Medline databases through June 2009 for prospective observational studies investigating the cardiovascular effects of the metabolic syndrome. Two reviewers extracted data, which were aggregated using random-effects models.
RESULTS:We identified 87 studies, which included 951,083 patients (NCEP: 63 studies, 497,651 patients; rNCEP: 33 studies, 453,432 patients). There was little variation between the cardiovascular risk associated with NCEP and rNCEP definitions. When both definitions were pooled, the metabolic syndrome was associated with an increased risk of cardiovascular disease (CVD) (relative risk [RR]: 2.35; 95% confidence interval [CI]: 2.02 to 2.73), CVD mortality (RR: 2.40; 95% CI: 1.87 to 3.08), all-cause mortality (RR: 1.58; 95% CI: 1.39 to 1.78), myocardial infarction (RR: 1.99; 95% CI: 1.61 to 2.46), and stroke (RR: 2.27; 95% CI: 1.80 to 2.85). Patients with the metabolic syndrome, but without diabetes, maintained a high cardiovascular risk.
CONCLUSIONS:The metabolic syndrome is associated with a 2-fold increase in cardiovascular outcomes and a 1.5-fold increase in all-cause mortality. Studies are needed to investigate whether or not the prognostic significance of the metabolic syndrome exceeds the risk associated with the sum of its individual components. Furthermore, studies are needed to elucidate the mechanisms by which the metabolic syndrome increases cardiovascular risk.
Diabetes Care. 1999 Jan;22(1):45-9.
Fasting blood glucose: an underestimated risk factor for cardiovascular death. Results from a 22-year follow-up of healthy nondiabetic men. Bjørnholt JV, Erikssen G, Aaser E, Sandvik L, Nitter-Hauge S, Jervell J, Erikssen J, Thaulow E. Medical Department, Rikshospitalet, Oslo, Norway.
OBJECTIVE:Because of the available conflicting epidemiological data, we investigated the possible impact of fasting blood glucose as a risk factor for cardiovascular death in nondiabetic men. This study reports the results from a 22-year prospective study on fasting blood glucose as a predictor of cardiovascular death.
RESEARCH DESIGN AND METHODS:Of the 1,998 apparently healthy nondiabetic men (aged 40-59 years), a total of 1,973 with fasting blood glucose < 110 mg/dl were included in the study in which also a number of conventional risk factors were measured at baseline.
RESULTS:After 22 years of follow-up, 483 men had died, 53% from cardiovascular diseases. After dividing men into quartiles of fasting blood glucose level, it was found that men in the highest glucose quartile (fasting blood glucose > 85 mg/dl) had a significantly higher mortality rate from cardiovascular diseases compared with those in the three lowest quartiles. Even after adjusting for age, smoking habits, serum lipids, blood pressure, forced expiratory volume in 1 s, and physical fitness (Cox model), the relative risk of cardiovascular death for men with fasting blood glucose > 85 mg/dl remained 1.4 (95% CI 1.04-1.8). Noncardiovascular deaths were unrelated to fasting blood glucose level.
CONCLUSIONS:Fasting blood glucose values in the upper normal range appears to be an important independent predictor of cardiovascular death in nondiabetic apparently healthy middle-aged men.
J Atheroscler Thromb. 2009;16(6):857-61.
Fasting plasma glucose and incidence of diabetes — implication for the threshold for impaired fasting glucose: results from the population-based Omiya MA cohort study. Kato M, Noda M, Suga H, Matsumoto M, Kanazawa Y. Japan Foundation for the Promotion of International Medical Research Cooperation, Tokyo, Japan.
In 2003, the American Diabetes Association recommended that the threshold for diagnosing impaired fasting glucose (IFG) should be lowered from 6.1 mmol/L (110 mg/dL) to 5.6 mmol/L (100 mg/dL). To discuss the diagnostic threshold for IFG, the association between fasting plasma glucose (FPG) and the risk of future diabetes must be known; however, data regarding this relation in the Japanese population are scarce. The aim of this study was to determine the relation between FPG and the risk of future diabetes in the Japanese general population.
METHODS:A retrospective cohort study was conducted using data from annual health check-ups performed in Omiya city. A total of 11,369 subjects between the ages of 40-79 years who were not diabetic at baseline were followed for seven years. Diabetes was defined as FPG > or =126 mg/dL or self-report.
RESULTS:The incidence of diabetes increased as the baseline FPG level increased and a similar pattern was observed irrespective of sex or age. The hazard ratios compared with subjects with FPG <85 mg/ dL adjusted for possible confounding factors were
3.83 for 85-100
2.41- 6.08 for subjects with 100 to 104 mg/dL FPG and
7.87 ( for subjects with 105 to 109 mg/dL FPG.
CONCLUSIONS:Subjects with 100-109 mg/dL FPG have an appreciable risk of diabetes that cannot be considered as “normal” and should be notified of their potential risk of developing diabetes.
N Engl J Med. 1996 Aug 29;335(9):617-23.
Decreases in ovarian cytochrome P450c17 alpha activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome.
Nestler JE, Jakubowicz DJ. Department of Internal Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298-0111, USA.
BACKGROUND:Insulin resistance and increased ovarian cytochrome P450c17 alpha activity are both features of the polycystic ovary syndrome. P450c17 alpha, which is involved in androgen biosynthesis, has both 17 alpha-hydroxylase and 17,20-lyase activities. Increased activity of this enzyme results in exaggerated conversion of progesterone to 17 alpha-hydroxyprogesterone in response to stimulation by gonadotrophin. We hypothesized that hyperinsulinemia stimulates ovarian P450c17 alpha activity.
METHODS:We measured fasting serum steroid concentrations and the response of serum 17 alpha-hydroxyprogesterone to leuprolide, a gonadotrophin-releasing hormone agonist, and performed oral glucose-tolerance tests before and after oral administration of either metformin (500 mg three times daily) or placebo for four to eight weeks in 24 obese women with the polycystic ovary syndrome.
RESULTS:In the 11 women given metformin, the mean (+/- SE) area under the serum insulin curve after oral glucose administration decreased from 9303 +/- 1603 to 4982 +/- 911 microU per milliliter per minute (56 +/- 10 to 30 +/- 6 nmol per liter per minute) (P = 0.004). This decrease was associated with a reduction in the basal serum 17 alpha-hydroxyprogesterone concentration from 135 +/- 21 to 66 +/- 7 ng per deciliter (4.1 +/- 0.6 to 2.0 +/- 0.2 nmol per liter) (P = 0.01) and a reduction in the leuprolide-stimulated peak serum 17 alpha-hydroxyprogesterone concentration from 455 +/- 54 to 281 +/- 52 ng per deciliter (13.7 +/- 1.6 to 8.5 +/- 1.6 nmol per liter) (P = 0.01). The serum 17 alpha-hydroxyprogesterone values increased slightly in the placebo group. In the metformin group, the basal serum luteinizing hormone concentration decreased from 8.5 +/- 2.2 to 2.8 +/- 0.5 mlU per milliliter (P = 0.01), the serum free testosterone concentration decreased from 0.34 +/- 0.07 to 0.19 +/- 0.05 ng per deciliter (12 +/- 3 to 7 +/- 2 pmol per liter) (P = 0.009), and the serum sex hormone-binding globulin concentration increased from 0.8 +/- 0.2 to 2.3 +/- 0.6 microgram per deciliter (29 +/- 7 to 80 +/- 21 nmol per liter) (P < 0.001). None of these values changed significantly in the placebo group.
CONCLUSIONS:In obese women with the polycystic ovary syndrome, decreasing serum insulin concentrations with metformin reduces ovarian cytochrome P450c17 alpha activity and ameliorates hyperandrogenism. Prevents or delays onset of DM
N Engl J Med. 2002 Feb 7;346(6):393-403.
Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin.
Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM; Diabetes Prevention Program Research Group. Diabetes Prevention Program Coordinating Center, Biostatistics Center, George Washington University, 6110 Executive Blvd., Suite 750, Rockville, MD 20852, USA.
BACKGROUND:Type 2 diabetes affects approximately 8 percent of adults in the United States. Some risk factors–elevated plasma glucose concentrations in the fasting state and after an oral glucose load, overweight, and a sedentary lifestyle–are potentially reversible. We hypothesized that modifying these factors with a lifestyle-intervention program or the administration of metformin would prevent or delay the development of diabetes.
METHODS:We randomly assigned 3234 nondiabetic persons with elevated fasting and post-load plasma glucose concentrations to placebo, metformin (850 mg twice daily), or a lifestyle-modification program with the goals of at least a 7 percent weight loss and at least 150 minutes of physical activity per week. The mean age of the participants was 51 years, and the mean body-mass index (the weight in kilograms divided by the square of the height in meters) was 34.0; 68 percent were women, and 45 percent were members of minority groups.
RESULTS:The average follow-up was 2.8 years. The incidence of diabetes was 11.0, 7.8, and 4.8 cases per 100 person-years in the placebo, metformin, and lifestyle groups, respectively. The lifestyle intervention reduced the incidence by 58 percent (95 percent confidence interval, 48 to 66 percent) and metformin by 31 percent (95 percent confidence interval, 17 to 43 percent), as compared with placebo; the lifestyle intervention was significantly more effective than metformin. To prevent one case of diabetes during a period of three years, 6.9 persons would have to participate in the lifestyle-intervention program, and 13.9 would have to receive metformin.
CONCLUSIONS:Lifestyle changes and treatment with metformin both reduced the incidence of diabetes in persons at high risk. The lifestyle intervention was more effective than metformin. Restores ovulation, increases fertility
Fertil Steril. 2002 Apr;77(4):669-73.
Pregnancies following use of metformin for ovulation induction in patients with polycystic ovary syndrome. Heard MJ, Pierce A, Carson SA, Buster JE. Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Baylor College of Medicine, Houston, Texas 77030, USA.
OBJECTIVE:To assess pregnancy outcome in anovulatory infertility patients diagnosed with polycystic ovary syndrome (PCOS) who were treated with metformin. DESIGN:Case series.
PATIENT(S):Anovulatory patients (n = 48) with a diagnosis of PCOS based on clinical, diagnostic, and laboratory evaluations were enrolled in the study over a 15-month period.
INTERVENTION(S):Metformin was started at 500 mg b.i.d. for 6 weeks and then increased to 500 mg t.i.d. if no ovulation occurred. Clomiphene citrate (CC; 50 mg) was added if no ovulatory response occurred after 6 weeks.
MAIN OUTCOME MEASURE(S):Resumption of menses, presumptive ovulation, and pregnancy.
RESULT(S):Nineteen of 48 (40%) patients resumed spontaneous menses following treatment and showed presumptive evidence of ovulation with metformin alone; 15/48 (31%) required CC (50 mg) in conjunction with metformin therapy, and 10 of these 15 (67%) had evidence of ovulation; 20/48 (42%) conceived with a median time to conception of 3 months, and 7 of these 20 (35%) had spontaneous abortions (SA; 19/48 (40%) had gastrointestinal-related side effects, and 5 of 48 patients (10%) had to decrease the dosage of metformin. Only 1 patient discontinued therapy.
CONCLUSION(S):Metformin alone in patients with PCOS results in a substantial number of pregnancies, with 69% (20/29) of those who ovulated conceiving in less than 6 months.
Eur Psychiatry. 2007 Oct;22(7):453-4. Epub 2007 Aug 30.
Orally disintegrating olanzapine induces less weight gain in adolescents than standard oral tablets.
Crocq MA, Guillon MS, Bailey PE, Provost D. Centre Hospitalier, Service de Psychiatrie de l’Adolescent, BP29, 68250 Rouffach, France.
We compared the changes in weight (kg) and body mass index (BMI) (kg/m(2)) in 52 hospitalized adolescents between baseline and after 12 weeks of monotherapy with either (i) olanzapine (OLZ) orally disintegrating tablets (ODT) (N=16; 16.6 mg/day+/-4.4 [SD]), or (ii) OLZ standard oral tablets (SOT) (N=10; 18.0 mg/day+/-4.2), or (iii) risperidone (N=26; 2.8 mg/day+/-1.2). Significantly greater increases in mean weight and BMI were observed in the patients treated with OLZ SOT (8.9+/-5.1 [SD] kg; 1.9+/-0.6 kg/m(2), respectively) than in those with ODT (3.0+/-2.1 kg; 1.1+/-0.8 kg/m(2)). Similarly, OLZ ODT treatment was associated with significantly greater increases in weight and BMI than risperidone (1.0+/-1.8 kg; 0.4+/-0.7 kg/m(2)). These findings suggest that adolescents gain less weight with OLZ ODT than OLZ SOT, possibly because the former formulation shortens the time of interaction with digestive serotonin receptors mediating satiety.
Morrison JA et al. Am J Psychiatry. 2002 Apr;159(4):655-7. 39 children 10 – 17 y/o on 2nd gen antipsychotics & 10+% weight gain Half placebo, half given 500 – 850 mg metformin bid Placebo gained 4 kg; metformin no weight gain
Am J Psychiatry. 2006 Dec;163(12):2072-9.
A randomized, double-blind, placebo-controlled trial of metformin treatment of weight gain associated with initiation of atypical antipsychotic therapy in children and adolescents.
Klein DJ, Cottingham EM, Sorter M, Barton BA, Morrison JA. Division of Endocrinology, Cincinnati Children’s Hospital Medical Center, ML 7012, 3333 Burnet Ave., Cincinnati, OH 45229, USA.
OBJECTIVE:Second-generation, or atypical, antipsychotics effectively treat psychiatric illness in children and adolescents. However, weight gain and abnormalities in insulin sensitivity, including diabetes, complicate this therapy. METHOD:A 16-week double-blind, placebo-controlled trial was conducted to evaluate the effectiveness of metformin in managing weight gain in 39 subjects, ages 10-17, whose weight had increased by more than 10% during less than 1 year of olanzapine, risperidone, or quetiapine therapy. Body weight, body mass index (kilograms per square meter of height), and waist circumference were measured regularly, as were fasting insulin and glucose levels.
RESULTS:Weight was stabilized in subjects receiving metformin, while those receiving placebo continued to gain weight (0.31 kg/week). Because the study was conducted with growing children, metformin treatment resulted in reduction in z scores for both weight and body mass index. The homeostasis model assessment, a surrogate indicator of insulin sensitivity, decreased in treated subjects. Overt diabetes was diagnosed in two subjects before treatment (elevated baseline fasting glucose and insulin values) and in two placebo-treated subjects (one at week 12 and the other after study completion). One subject taking placebo developed impaired fasting glucose. Placebo treatment was associated with the need to perform oral glucose tolerance testing upon study completion, by which three additional subjects were identified with impaired glucose tolerance. No serious adverse events resulted from metformin treatment.
CONCLUSIONS:Metformin therapy is safe and effective in abrogating weight gain, decreased insulin sensitivity, and abnormal glucose metabolism resulting from treatment of children and adolescents with atypicals.
UKPDS Study Group. Lancet. 1998;352:837-853. Lancet. 1998 Sep 12;352(9131):837-53.
Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Thiazolidinediones (TZDs) such as rosiglitazone (Avandia) associated wit ave +2.8 kg
Future Oncol. 2010 March; 6(3): 457–470.
AMPK as a metabolic tumor suppressor: control of metabolism and cell growth
Zhijun Luo Department of Biochemistry, Boston University School of Medicine
Breast Cancer Res Treat. 2010 Sep;123(2):591-6.
Metformin inhibits aromatase expression in human breast adipose stromal cells via stimulation of AMP-activated protein kinase. Brown KA, Hunger NI, Docanto M, Simpson ER. Source Prince Henry’s Institute of Medical Research, P.O. Box 5152, Clayton, VIC, 3168, Australia. Kristy.Brown@princehenrys.org
Abstract AMP-activated protein kinase (AMPK) is recognized as a master regulator of energy homeostasis. In concert with the AMPK-kinase LKB1, it has been shown to provide a molecular link between obesity and postmenopausal breast cancer via its actions to inhibit aromatase expression, hence estrogen production, within the breast.
The anti-diabetic drug metformin is known to increase the activity of AMPK and was therefore hypothesized to inhibit aromatase expression in primary human breast adipose stromal cells.
Results demonstrate that metformin significantly decreases the forskolin/phorbol ester (FSK/PMA)-induced expression of aromatase at concentrations of 10 and 50 muM. Consistent with the hypothesized actions of metformin to increase AMPK activity, treatment with 50 muM metformin results in a significant increase in phosphorylation of AMPK at Thr172. Interestingly, metformin also causes a significant increase in LKB1 protein expression and promoter activity, thereby providing for the first time an additional mechanism by which metformin activates AMPK. Furthermore, metformin inhibits the nuclear translocation of CRTC2, a CREB-coactivator known to increase aromatase expression which is also a direct downstream target of AMPK.
Overall, these results suggest that metformin would reduce the local production of estrogens within the breast thereby providing a new key therapeutic tool that could be used in the neoadjuvant and adjuvant settings and conceivably also as a preventative measure in obese women.
Eur J Intern Med. 2000 Oct;11(5):245-252. Diabetes mellitus and cancer. Czyzyk A, Szczepanik Z. Department of Gastroenterology and Metabolic Diseases, Central Clinical Hospital, University Medical School of Warsaw, ul. Banacha 1A, PL-02-097, Warsaw, Poland
Although an association between diabetes and cancer was found over 100 years ago, the issue underwent different interpretations over the subsequent decades, and only modern, prospective, epidemiological cohort and case-control studies conducted in several countries have provided reliable evidence of an increased cancer risk in diabetic patients, mainly in those with type 2 diabetes. This risk varies according to the tumor site: it is the greatest for primary liver cancer, moderately elevated for pancreatic cancer, and relatively low for colorectal, endometrial, breast, and renal cancers. The cause of the association is not clear and remains the subject of different hypotheses. The most frequently cited reason is the potential effect of insulin. Found in high concentrations, due to insulin resistance in most patients with type 2 diabetes, this hormone is believed to express a mitogenic effect. This hypothesis needs to be confirmed in appropriately programmed prospective studies, but it may already be helpful in choosing an adequate treatment for type 2 diabetes to achieve optimal metabolic control with a simultaneous reduction in hyperinsulinemia, such as diet, physical exercise, metformin, and acarbose.
Ruiter R et al. Diabetes Care 2012 Jan; 35:119
Diabetes Care January 2012 vol. 35 no. 1 119-124
Lower Risk of Cancer in Patients on Metformin in Comparison With Those on Sulfonylurea Derivatives Results from a large population-based follow-up study by Rikje Ruiter, MD Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands
OBJECTIVE Numerous studies have suggested a decreased risk of cancer in patients with diabetes on metformin. Because different comparison groups were used, the effect magnitude is difficult to estimate. Therefore, the objective of this study was to further analyze whether, and to what extent, use of metformin is associated with a decreased risk of cancer in a cohort of incident users of metformin compared with users of sulfonylurea derivatives.
RESEARCH DESIGN AND METHODS Data for this study were obtained from dispensing records from community pharmacies individually linked to hospital discharge records from 2.5 million individuals in the Netherlands. The association between the risk of cancer in those using metformin compared with those using sulfonylurea derivatives was analyzed using Cox proportional hazard models with cumulative duration of drug use as a time-varying determinant.
RESULTS Use of metformin was associated with a lower risk of cancer in general (hazard ratio 0.90 [95% CI 0.88–0.91]) compared with use of sulfonylurea derivatives. When specific cancers were used as end points, similar estimates were found. Dosage-response relations were identified for users of metformin but not for users of sulfonylurea derivatives.
CONCLUSIONS In our study, cumulative exposure to metformin was associated with a lower risk of specific cancers and cancer in general, compared with cumulative exposure to sulfonylurea derivatives. However, whether this should indeed be seen as a decreased risk of cancer for the use of metformin or as an increased risk of cancer for the use sulfonylurea derivatives remains to be elucidated.
Diabetes Care. 2009 Sep;32(9):1620-5. Epub 2009 Jun 29.
New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes.
Libby G, Donnelly LA, Donnan PT, Alessi DR, Morris AD, Evans JM.
Division of Clinical and Population Sciences and Education, University of Dundee, Dundee, UK.
The antidiabetic properties of metformin are mediated through its ability to activate the AMP-activated protein kinase (AMPK). Activation of AMPK can suppress tumor formation and inhibit cell growth in addition to lowering blood glucose levels. We tested the hypothesis that metformin reduces the risk of cancer in people with type 2 diabetes.
RESEARCH DESIGN AND METHODS:In an observational cohort study using record-linkage databases and based in Tayside, Scotland, U.K., we identified people with type 2 diabetes who were new users of metformin in 1994-2003. We also identified a set of diabetic comparators, individually matched to the metformin users by year of diabetes diagnosis, who had never used metformin. In a survival analysis we calculated hazard ratios for diagnosis of cancer, adjusted for baseline characteristics of the two groups using Cox regression.
RESULTS:Cancer was diagnosed among 7.3% of 4,085 metformin users compared with 11.6% of 4,085 comparators, with median times to cancer of 3.5 and 2.6 years, respectively (P < 0.001). The unadjusted hazard ratio (95% CI) for cancer was 0.46 (0.40-0.53). After adjusting for sex, age, BMI, A1C, deprivation, smoking, and other drug use, there was still a significantly reduced risk of cancer associated with metformin: 0.63 (0.53-0.75).
CONCLUSIONS:These results suggest that metformin use may be associated with a reduced risk of cancer. A randomized trial is needed to assess whether metformin is protective in a population at high risk for cancer.
Acta Diabetol. 2009 Dec;46(4):279-84. Epub 2008 Dec 10. Sulphonylureas and cancer: a case-control study. Monami M, Lamanna C, Balzi D, Marchionni N, Mannucci E. Department of Critical Care Medicine and Surgery, Unit of Gerontology and Geriatrics, University of Florence and Azienda Ospedaliero-Universitaria Careggi, Via delle Oblate 4, 50134, Florence, Italy.
This study was aimed at the assessment of incidence of malignancies in type 2 diabetic patients treated with different sulphonylureas.
A matched case-control study was performed. Cases were 195 diabetic patients aged 69.0 +/- 9.2 years who had an incident malignancy.
Controls were 195 diabetic patients, unaffected by cancer, who were matched with the corresponding case for age, sex, duration of diabetes, BMI, HbA1(c), comorbidity, smoking and alcohol abuse.
Exposure to hypoglycaemic drugs during the 10 years preceding the event (or matching index date) was assessed. After adjusting for concomitant therapies, exposure to metformin and gliclazide for more than 36 months was associated with a significant reduction in the risk of cancer (adj. ORs with 95% CI: 0.28 (0.13-0.57), p < 0.001, and 0.40 (0.21-0.57), p = 0.004, respectively). Conversely, use of glibenclamide for at least 36 months was associated with increased incidence of malignancies (adj. OR 2.62 (1.26-5.42); p = 0.009). Treatment with insulin, thiazolidinediones, or acarbose, was not associated with significant differences in the incidence of cancer. Long-term treatments with individual sulphonylureas could have differential effects on the risk of cancer. In particular, the possible protective effect of gliclazide, as well as the risk associated with glibenclamide, deserves further investigation.
Gastroenterology. 2009 Aug;137(2):482-8.
Antidiabetic therapies affect risk of pancreatic cancer. Li D, Yeung SC, Hassan MM, Konopleva M, Abbruzzese JL. Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Antidiabetic drugs have been found to have various effects on cancer in experimental systems and in epidemiologic studies, although the association between these therapeutics and the risk of human pancreatic cancer has not been explored. We investigated the effect of antidiabetic therapies on the risk of pancreatic cancer. METHODS:A hospital-based case-control study was conducted at M. D. Anderson Cancer Center from 2004 to 2008 involving 973 patients with pancreatic adenocarcinoma (including 259 diabetic patients) and 863 controls (including 109 diabetic patients). Information on diabetes history and other risk factors was collected by personal interview. The frequencies of use of insulin, insulin secretagogues, metformin, and other antidiabetic medications among diabetic patients were compared between cases and controls. The risk of pancreatic cancer was estimated using unconditional logistic regression analysis.
RESULTS- Diabetic patients who had taken metformin had a significantly lower risk of pancreatic cancer compared with those who had not taken metformin (odds ratio, 0.38; 95% confidence interval, 0.22-0.69; P = .001), with adjustments for potential confounders. This difference remained statistically significant when the analysis was restricted to patients with a duration of diabetes >2 years or those who never used insulin. In contrast, diabetic patients who had taken insulin or insulin secretagogues had a significantly higher risk of pancreatic cancer compared with diabetic patients who had not taken these drugs.
CONCLUSIONS:Metformin use was associated with reduced risk, and insulin or insulin secretagogue use was associated with increased risk of pancreatic cancer in diabetic patients.
29) www.ncbi.nlm.nih.gov/pmc/articles/PMC2736070/?tool=pubmed www.ncbi.nlm.nih.gov/pubmed/19487376
J Clin Oncol. 2009 Jul 10;27(20):3297-302. Epub 2009 Jun 1.
Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. Jiralerspong S, Palla SL, Giordano SH, Meric-Bernstam F, Liedtke C, Barnett CM, Hsu L, Hung MC, Hortobagyi GN, Gonzalez-Angulo AM. Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, 77030-4009, USA. Population studies have suggested that metformin use in diabetic patients decreases cancer incidence and mortality. Metformin inhibits the growth of cancer cells in vitro and tumors in vivo. However, there is little clinical data to support this. Our purpose was to determine whether metformin use was associated with a change in pathologic complete response (pCR) rates in diabetic patients with breast cancer receiving neoadjuvant chemotherapy.
PATIENTS AND METHODS:We identified 2,529 patients who received neoadjuvant chemotherapy for early-stage breast cancer between 1990 and 2007. Patients were compared by groups: 68 diabetic patients taking metformin, 87 diabetic patients not taking metformin, and 2,374 nondiabetic patients. pCR rates were compared between the three groups using chi(2) tests of independence and compared pair- wise using a binomial test of proportions. Factors predictive of pCR were assessed using a multivariate logistic regression model.
RESULTS:The rate of pCR was 24% in the metformin group, 8.0% in the nonmetformin group, and 16% in the nondiabetic group (P = .02). Pairwise comparisons between the metformin and nonmetformin groups (P = .007) and the nonmetformin and nondiabetic groups (P = .04) were significant. Comparison of the pCR rates between the metformin and nondiabetic groups trended toward but did not meet significance (P = .10). Metformin use was independently predictive of pCR (odds ratio, 2.95; P = .04) after adjustment for diabetes, body mass index, age, stage, grade, receptor status, and neoadjuvant taxane use.
Diabetic patients with breast cancer receiving metformin and neoadjuvant chemotherapy have a higher pCR rate than do diabetics not receiving metformin. Additional studies to evaluate the potential of metformin as an antitumor agent are warranted.
Dilman, Vladimir, and Dean, Ward.
The Neuroendocrine Theory of Aging, The Center for Bio-Gerontology, Pensacola, Florida, 1992
31) physiolgenomics.physiology.org/content/23/3/343.long physiolgenomics.physiology.org/content/23/3/343.full.pdf
Physiol Genomics. 2005 Nov 17;23(3):343-50.
Identification of potential caloric restriction mimetics by microarray profiling.
Dhahbi JM, Mote PL, Fahy GM, Spindler SR. Department of Biochemistry, University of California, Riverside, California
To facilitate the development of assays for the discovery of pharmaceuticals capable of mimicking the effects of caloric restriction (CR) on life- and healthspan (CR mimetics), we evaluated the effectiveness of glucoregulatory and putative cancer chemopreventatives in reproducing the hepatic gene expression profile produced by long-term CR (LTCR), using Affymetrix microarrays. We have shown that CR initiated late in life begins to extend lifespan, reduce cancer as a cause of death, and reproduce approximately three-quarters of the genomic effects of LTCR in 8 wk (CR8). Eight weeks of metformin treatment was superior to CR8 at reproducing LTCR-like gene expression changes, maintaining a superior number of such changes over a broad range of statistical stringencies, and producing more Gene Ontology terms overlapping those produced by LTCR. Consistent with these results, metformin has been shown to reduce cancer incidence in mice and humans. Phenformin, a chemical cousin of metformin, extends lifespan and reduces tumor incidence in mice. Taken together, these results indicate that gene expression biomarkers can be used to identify promising candidate CR mimetics.
32) sens.org/node/1821 Spindler SR et al.
Rapid identification of candidate CR mimetics using microarray.
Biogerontology 2003 4(Suppl 1):
Rapid identification of candidate CR mimetics using microarrays
S.R. Spindler, J.D. Dhahbi, P.L. Mote, H.J. Kim, T. Tsuchiya University of California, Riverside, Department of Biochemistry, 5478 Boyce Hall, Riverside, CA 92521, U.S.A.
Quantitative changes in the activity of genes can control the rate of aging and the development of age-related diseases in invertebrates and mammals. Caloric restriction (CR) is the most robust environmental method known for decelerating aging and the development of age-related diseases. CR is widely viewed as acting slowly and incrementally to prevent the accumulation of deleterious age-related physiological changes. CR is also widely thought to be less effective in older animals. Using survival and high-density microarray studies we demonstrate that CR acts rapidly and reversibly to establish a pattern of gene expression temporally associated with enhanced life span and reduced tumor incidence in mice. CR was fully effective at extending life span and reducing tumor incidence when begun in old animals. The results indicate that therapies mimicking the gene expression effects of CR may be rapidly effective, even in old animals. To investigate this possibility, we screened three glucoregulatory pharmaceuticals and a soy isoflavone extract (a putative chemopreventative) for their ability to mimic the effects of long-term CR on gene expression using hepatic RNA, since most of these mice die of liver tumors. The glucoregulatory pharmaceuticals and the combination of two of these pharmaceuticals produced a significant number of changes in hepatic gene expression identical to those produced by long-term and/or short-term CR. The most extensive overlap with CR was obtained from metformin. The gene expression changes common to metformin and CR were associated with xenobiotic metabolism, cellular stress, energy metabolism, biosynthesis, signal transduction, and the cytoskeleton. The changes are consistent with enhanced apoptosis and protein turnover, and reduced tumor incidence and cellular stress. These results suggest that metformin is potential CR-mimetic. Others have shown that phenformin, a glucoregulatory pharmaceutical structurally and functionally similar to metformin, extends the lifespan of mice by 23%, and reduces cancer as a cause of death from 80% to 20% (1). Others recently have presented preliminary evidence that metformin extends the lifespan of rats (2). Therefore, agents that reproduce the long-term CR signature in microarray assays are candidate CR mimetics. 89
Cell Cycle. 2008 Sep 1;7(17):2769-73. Epub 2008 Sep 11.
Metformin slows down aging and extends life span of female SHR mice.
Anisimov VN, Berstein LM, Egormin PA, Piskunova TS, Popovich IG, Zabezhinski MA, Tyndyk ML, Yurova MV, Kovalenko IG, Poroshina TE, Semenchenko AV. N.N.Petrov Research Institute of Oncology, St. Petersburg, Russia.
Studies in mammals have led to the suggestion that hyperglycemia and hyperinsulinemia are important factors both in aging and in the development of cancer. It is possible that the life-prolonging effects of calorie restriction are due to decreasing IGF-1 levels. A search of pharmacological modulators of insulin/IGF-1 signaling pathway (which resemble effects of life span extending mutations or calorie restriction) could be a perspective direction in regulation of longevity.
Antidiabetic biguanides are most promising among them.
Here we show the chronic treatment of female outbred SHR mice with metformin (100 mg/kg in drinking water) slightly modified the food consumption but decreased the body weight after the age of 20 months, slowed down the age-related switch-off of estrous function, increased mean life span by 37.8%, mean life span of last 10% survivors by 20.8%, and maximum life span by 2.8 months (+10.3%) in comparison with control mice. On the other side, treatment with metformin failed influence blood estradiol concentration and spontaneous tumor incidence in female SHR mice. Thus, antidiabetic biguanide metformin dramatically extends life span, even without cancer prevention in this model.
Arch Intern Med. 2002 Feb 25;162(4):484-5.
Metformin and vitamin B12 deficiency.Gilligan MA.
Metformin is a drug increasingly used as a first-line treatment for type 2 diabetes mellitus. In this country, there is less experience with the drug than in England and Europe, where it has been used for decades. The drug is well tolerated in most patients. The primary adverse effect discussed in the North American literature is lactic acidosis, which is seen in patients with renal insufficiency and those undergoing radiologic procedures using contrast dye. Another well-documented but little-discussed adverse effect, notably omitted from an article in the ARCHIVES on laboratory diagnosis of B12 deficiency,1 is biguanide-associated decreased levels of vitamin B12. The following case highlights this problem.
Letters to the Editor
Use of Metformin Is a Cause of Vitamin B12 Deficiency Am Fam Physician. 2004 Jan 15;69(2):264-266.
Salpeter S, Greyber E, et al. Arch Int Med. 2003;163(21):2594–602 Arch Intern Med. 2003 Nov 24;163(21):2594-602.
Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus: systematic review and meta-analysis. Salpeter SR, Greyber E, Pasternak GA, Salpeter EE. Source Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
Metformin therapy for type 2 diabetes mellitus has been shown to reduce total mortality rates compared with other antihyperglycemic treatments but is thought to increase the risk of lactic acidosis. The true incidence of fatal and nonfatal lactic acidosis associated with metformin use is not known.
METHODS:A comprehensive search was performed to identify all comparative trials or observational cohort studies published between January 1, 1959, and March 31, 2002, that evaluated metformin therapy, alone or in combination with other treatments, for at least 1 month. The incidence of fatal and nonfatal lactic acidosis was recorded as cases per patient-years for metformin treatment and for placebo or other treatments. In a second analysis, lactate levels were measured as a net change from baseline or as mean treatment values for metformin and comparison groups.
Pooled data from 194 studies revealed no cases of fatal or nonfatal lactic acidosis in 36 893 patient-years in the metformin group or in 30 109 patients-years in the nonmetformin group. Using Poisson statistics with 95% confidence intervals, the probable upper limit for the true incidence of lactic acidosis in the metformin and nonmetformin groups was 8.1 and 9.9 cases per 100 000 patient-years, respectively. There was no difference in lactate levels for metformin compared with placebo or other nonbiguanide therapies.
CONCLUSION:There is no evidence to date that metformin therapy is associated with an increased risk of lactic acidosis or with increased levels of lactate compared with other antihyperglycemic treatments if the drugs are prescribed under study conditions, taking into account contraindications.
Aging (Albany NY). 2011 Apr;3(4):348-62.
Gerosuppressant Metformin: less is more
Javier A. Menendez,1,2 Sílvia Cufí,1,2 Cristina Oliveras-Ferraros,1,2 Luciano Vellon,3 Jorge Joven,4 and Alejandro Vazquez-Martin1,2 1 Catalan Institute of Oncology, Girona (Catalonia, Spain) 2 Girona Biomedical Research Institute, Girona (Catalonia, Spain) 3 Fundación INBIOMED, Cell Reprogramming Unit, San Sebastián (Basque Country, Spain) 4 Centre de Recerca Biomèdica, Hospital Universitari Sant Joan de Reus, Institut d’Investigaciò Sanitària Pere Virgili, Universitat Rovira i Virgili, Reus (Catalonia, Spain)
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