Metformin For Anti-Aging & Type 2 Diabetes: Friend or Foe?

With 60 years of clinical use, Metformin is the most widely prescribed drug for the treatment of diabetes. Although, the exact molecular mechanism of action of metformin remains partly unknown despite its use for over 60 years and more than 20,000 articles in PubMed, its main mechanism of action is widely recognized as inhibition of mitochondrial complex I → low ATP → high AMP/ADP (energetic stress) → activation of AMPK (an enzyme that senses low energy levels and activates numerous pathways to restore the intracellular ATP)→ increased glucose transport into cells and glucose metabolism (increased insulin sensitivity).

As perhaps the most important cellular energy sensor, AMP-activated protein kinase (AMPK) is activated in response to a variety of conditions that deplete cellular energy levels, such as nutrient starvation, hypoxia  and exposure to toxins that inhibit the mitochondrial respiratory chain complex. In response, AMPK alters the activity of many other genes and proteins, helping keep cells alive and functioning even when they’re running low on fuel. 

The net effect of AMPK activation is inhibition of gluconeogenesis in the liver, stimulation of hepatic fatty acid oxidation, ketogenesis, stimulation of skeletal muscle fatty acid oxidation and glucose uptake, inhibition of cholesterol synthesis, lipogenesis, and triglyceride synthesis, inhibition of adipocyte lipogenesis, inhibition of adipocyte lipolysis,  and modulation of insulin secretion by pancreatic beta-cells. Activation of AMPK signifies low energy within the cell, so all of the energy consuming pathways like protein synthesis are inhibited, and pathways that generate energy are activated to restore appropriate energy levels in the cell.

Yes, Metformin activates AMPK, but it mimics energy deprived state by inhibiting the mitochondrial transport chain complex-I, which essentially poisons the mitochondria leading to ATP production mainly via glycolysis which produces only 2 ATP. On contrast, without metformin approximately 36 ATP are produced from the three stages in cellular respiration – glycolysis, the Krebs cycle (citric acid cycle), and the electron transport chain. So, cells treated with metformin become energetically inefficient, and display increased glycolysis and reduced glucose metabolism through the citric acid cycle. 

Most studies still concentrate on the liver as the main target of metformin, arguing that the blood glucose-lowering effect of metformin is mediated mainly through the suppression of hepatic glucose production. However, after oral administration, the highest concentration of metformin is not found in the liver but in the intestinal epithelium [link][link][link]. So, it is not rocket science that, preasbsorptive metformin activates AMPK in gastrointestinal cells due to mitochondrial inhibition which leads to significantly increased glucose consumption in the intestine and consequently indirectly lowers blood glucose by reducing the amount of glucose that goes into the bloodstream. So, inhibition of transepithelial glucose transport in the intestine is responsible for lowering blood glucose levels during an early response to oral administration of metformin. By the way, Metformin was more effective in lowering blood glucose levels when it was administrated orally as compared to its intravenous administration.

Furthermore, there is convincing evidence that metformin changes intestinal microbiota in humans and the gut metabolome, but the significance of this finding for whole-body glucose metabolism remains unclear. On the other hand, the activation of the glucose-lactate-glucose futile cycle during long-term treatment with metformin, which includes both the intestine and the liver, results in increased energy consumption.  Increased conversion of glucose-1-13C to glucose-1,6-13C under metformin strongly supports a futile cycle of lactic acid production in the intestinal wall, and usage of the produced lactate for gluconeogenesis in liver.

Metformin activates AMPK in liver cells, which inhibits gluconeogenesis and the liver excretes less glucose. Complex I inhibition and AMPK activation are possibly the most widely studied outcomes of metformin treatment, and they are invoked as the mechanism of metformin-mediated inhibition of hepatic gluconeogenesis & lipogenesis, decrease in triglyceride accumulation, and increase in hepatic insulin sensitivity.

Pretty smart, yes?

Metformin also activates AMPK in skeletal muscle which  increases insulin-mediated glucose uptake into skeletal muscle cells (increased insulin sensitivity). But, on the other hand, we know that when AMPK is activated by ATP depletion, AMPK switches on catabolic pathways that generate ATP while switching off anabolic pathways and other ATP-consuming processes, which restores the energy balance. So it is not rocket science, that Metformin blunts the benefits of exercise by reducing mitochondrial ATP production in skeletal muscle by as much as 48%. In simple terms, Metformin abolishes the improvement in mitochondrial respiration after exercise training.

Not only that, there are preliminary findings that metformin may inhibit skeletal muscle mass gains in response to resistance training in the elderly.  Recently in september 2019,  The MASTERS ( Metformin to Augment Strength Training Effective Response in Seniors) trial found that Metformin blunts muscle hypertrophy in response to progressive resistance exercise training in older adults.

Since cardiorespiratory fitness is one of the strongest factors for survival into old age, and since it decreases with age, the effect of metformin on this factor is concerning, because Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults. Ironically, reporting and findings of randomised trials of metformin have resulted in continuing uncertainty regarding whether it reduces risk of diabetes-related complications, particularly cardiovascular disease. Furthermore, there is a lack of cardiovascular endpoint data directly relevant to a significant proportion of the patients with type 2 diabetes worldwide for whom metformin is the recommended first-line medication.

A study of over 7,000 patients with Alzheimer’s disease showed that, metformin increased the risk of developing Alzheimer’s. In a cohort study that followed about 9300 patients with T2DM in Taiwan for up to 12 years, the risk for Parkinson’s disease (PD) or Alzheimer’s dementia was more than double during a 12-year period for those who took metformin vs those who did not — even after adjusting for multiple confounders. The use of metformin may be associated with an increased risk for dementia in older African Americans with diabetes. This research was presented at the 2018 Alzheimer’s Association International Conference, held July 22-26, 2018 in Chicago, Illinois. So, supplementation with B12 is suggested with metformin use

In simple terms, Metformin Could Be Dangerous To Your Brain.

There have even been a handful of reports of metformin-induced hepatotoxicity (toxicity in the liver). In a case of nonalcoholic liver disease, metformin was pegged as the cause of jaundice, nausea, fatigue, and unintentional weight loss, two weeks after initiating treatment, due to abnormalities in liver enzymes caused by the drug.

Imagine reductions in ATP production were observed in the brain or the heart or the GI tract which leads to neurocognitive decline, psychiatric instability, neuropathy, heart rate, rhythm and blood pressure abnormalities, along with gastrointestinal distress to name but a few. Underlying all of these symptoms, and indeed, all mitochondrial dysfunction, is an overwhelming sense of fatigue and malaise.

Moreover, when insulin producing beta cells are exposed to metformin without metabolic challenges, beta cell proliferation is known to be suppressed and apoptosis is promoted [link,link,link]. Prolonged exposure results in apoptosis either via c-JNK activation and caspase-3cascade [link] or via increasing AMPK-dependent autophagy [link]. Metformin exposure also impairs insulin secretion in primary human islets, mouse islets and, mouse and rat pancreatic beta cell lines in a normoglycaemic environment [link,link]. Therefore, metformin overdosing or exposure without metabolic challenges might result in potential beta cell toxicity. 

Metformin is excreted almost entirely unchanged in urine so reduced kidney function may lead to accumulation of both metformin and lactate and therefore, a metformin-associated lactic acidosis (MALA). So it’s not a secret that, Metformin may have an adverse effect on renal function in patients with T2D and moderate CKD. Mild to moderate renal impairment is common among metformin initiators. Even, FDA recommends against starting metformin therapy in patients with estimated glomerular filtration rate (eGFR) below 45 mL/min/1.73m2

Metformin alters immune reactivity first by damaging the mitochondrial ATP factory and reducing energy production capacity and then by inhibiting the signaling cascades that would normally respond to the danger signals.

So, what gives? Is metformin healthy and anti-aging, or not?

In a retrospective 2014 analysis of 78,241 adult type 2 diabetics in their 60s, those who took metformin lived longer, on average, than healthy controls of 90,463 without diabetes of the same age. This has led a growing body of doctors beginning to prescribe the drug off-label, so that their patients may benefit from its purported anti-aging effects. Such widespread speculation demands deeper scientific investigation.

One may ask, what about the epidemiological evidence which has linked metformin to decrease the risk of cancer and cancer-related mortality?

Studies published in 2018 and 2015 suggest that people taking metformin may have a lower risk for cancer, with some studies suggesting a reduced risk of 30% to 50%. Data from two large-scale, population-based, case-control studies of breast and colorectal cancers etiology, conducted in Northern Israel since 1998 found that, Metformin use prior to diagnosis of cancer was associated with a decrease in risk of both breast cancer (OR = 0.821, 0.726–0.928, p = 0.002) and colorectal cancer (OR = 0.754, 0.623–0.912, p = 0.004).

But, it’s also hard to tell if metformin itself lowered cancer risk in the supporting studies because other treatments and interventions may have been involved. 

But, how Metformin may work to reduce cancer?

As stated above, the main mechanism of action of Metformin is widely recognized as inhibition of mitochondrial complex I → low ATP → high AMP/ADP (energetic stress) → activation of AMPK which inhibits mTOR phosphorylation in the AMPK/mTOR signaling pathway, which may lead to the arrest of tumor cell cycle and the inhibition of cell growth and proliferation, which finally results in cell apoptosis.

Also, according to articles ‘metformin and cancer’ as the search terms published within the last 15 years to 15 February 2019 in the available databases including; Medline via PubMed and EMBASE via Elsevier, the potential anticancer activity of metformin was due to activation of AMPK .

On the other hand, cancer cells are known to be generally highly glycolytic (Warburg effect) and are thus not supposed to be very sensitive to mitochondrial poison. But, even if the proportion of mitochondrial ATP production is reduced in cancer cells, some mitochondrial ATP production exists and its reduction could be toxic. So, cancer cells exposed to metformin display a greater compensatory increase in aerobic glycolysis, highlighting their metabolic vulnerability. So, theoretically Metformin may act as an anti cancer agent.

But, Recent study on 55 629 T2DM patients found no evidence of a protective effect of metformin on individual cancer outcomes. In a recent 2020 cohort, metformin use was associated with increased risk of being diagnosed with prostate cancer.  After adjusting for baseline characteristics, metformin use was significantly associated with 76% and 77% increased odds of high-grade PCa and overall PCa, respectively, the investigators reported in Prostate Cancer and Prostatic Diseases.

So, when we contrast the reduction in glucose mediated by Metformin with the damage this medication does to the mitochondria and immune signaling, along with its ability to leach vitamin B12 and reduce aerobic capacity, one cannot help but wonder if we are causing more harm than good.  Metformin use is associated with an increase in methylmalonic acid (MMA) and worsening neuropathy score in patients with type 2 diabetes. Diagnosis of vitamin B12 deficiency can, however, be difficult, because functional vitamin B12 deficiency can occur regardless elevated serum B12 levels (normal reference range 140 to 450 pmol/L).

Researchers and advocates have been trying from 2015 to launch the TAME (Targeting Aging with Metformin) trial in USA nationwide that will engage over 3,000 individuals between the ages of 65-79. These trials will test whether those taking metformin will experience delayed development or progression of age-related chronic diseases—such as heart disease, cancer, and dementia—compared with those who take a placebo. Groundbreaking TAME trial, which directly targets aging as an endpoint, finally begins in November 2019, reveals lead clinician Dr Nir Barzilai. 

Whether metformin itself is a success or a failure, the trial will very likely revolutionise the way that aging research is done. Lets hope for the best.

Has the effectiveness of metformin actually been proven?

Ever since the results of the UKPDS 34 study were published in 1998, metformin has been considered as the first-line pharmacological treatment for type 2 diabetes.  Its efficacy was supposedly conclusively demonstrated in the UKPDS 34 study published in 1998 (reduction in mortality: RR=0.64; CI 95% (0.45 to 0.91) and in myocardial infarction: RR=0.61; CI 95% (0.41 to 0.89). However, these rather impressive results regarding total 10 year mortality (ARR=0.07; NNT=14) in a small subgroup of obese type 2 diabetes patients (342 in the metformin group vs. 411 patients in the conventional group) have never been reproduced .

For instance, the home study in 2009  evaluated the efficacy of metformin versus placebo (in addition to insulin). After four years of follow-up, no statistically significant difference was found for total mortality: RR=1.48; CI 95% (0.54 to 4.09) or for IDM: RR=0.99; CI 95% (0.25 to 3.90). Taking into account all the other randomized clinical trials (RCTs) having evaluated the specific effectiveness of metformin in DT2 patients, it becomes evident that although metformin is considered the gold standard, its benefit/risk ratio remains uncertain. We cannot exclude a 25% reduction or a 31% increase in all-cause mortality. We cannot exclude a 33% reduction or a 64% increase in cardiovascular mortality.

Even in 2019, Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) recommend that “Metformin remains the preferred option for initiating glucose-lowering medication in type 2 diabetes and should be added to lifestyle measures in newly diagnosed patients” referring to a single result from the UKPDS 34 study in 342 patients! 

Today 20 years after UKPDS 34 study, why no other studies cannot duplicate the positive effects of Metformin as in UKPDS 34 study?

May be, for that reason, is UKPDS study methodologically questionable? The effectiveness of metformin with regard to microvascular and macrovascular complications has never been proven in a randomized double-blind placebo-controlled clinical trial. And upon analysis of published randomized clinical trials taken as a whole, it becomes increasingly apparent that the effectiveness of metformin has not been proven, even when microvascular complications are involved. This observation leads to a more general interrogation on the fact that assessment of the clinical benefits of Metformin in general is presently lacking. 

Although metformin is not often acutely toxic, the underlying mechanisms manipulated by this drug suggest that it is likely to induce and not prevent, as is so frequently suggested, chronic illness.

To conclude, if the level of evidence concerning the efficacy of metformin is poor, and given the fact that it is proposed as firstline treatment, what are we to think of the other antidiabetic medicines? Even in 2019 American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) state “the absolute effectiveness of most oral medications rarely exceeds an 11 mmol/mol (1%) reduction in HbA1C“. 

So, it is high time to rigorously reassess antidiabetic medication on the basis not of the so-called surrogate HbA1c, but rather according to patient-relevant outcomes.

You might ask, what about the use of Metformin in PCOS?

Metformin is commonly prescribed to women with PCOS to improve the insulin sensitivity. But, Metformin has side effects such as occasional heartburn, indigestion, bloating and gas, diarrhea/constipation, weird taste in the mouth and pancreatitis, which are a common cause of treatment discontinuation.

A meta-analysis included 10 randomized controlled trials (RCTs) with a total of 845 infertile women with PCOS undergoing in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatment, found that metformin has no clinical effect on the rate of pregnancy or live birth, but reduces the risk for ovarian hyperstimulation syndrome (OHSS). A later meta-analysis, including 12 RCTs and 1,516 patients, has shown the same results: metformin does not improve assisted reproductive technology outcomes among infertile patients with PCOS. The only benefit deriving from the use of metformin was the decrease in the risk for OHSS.

In conclusion, metformin represents the main insulin sensitizing agent in the management of infertile women with PCOS, with no clear benefit in improving live birth rates. Moreover, Metformin has other downfalls.

Metformin May Predispose Your Unborn Child to Neural Tube Defects

30% of people who take metformin for PCOS are vitamin B12 deficient. If you have PCOS and insulin resistance and low levels of B12, you don’t want to take a drug which could lower those levels even more.  However, B12 deficiency can also cause an increased risk of neural tube defects in unborn children. This is important for all women, but especially those who are trying to get pregnant. One study found that mothers with a vitamin B12 deficiency were up to nine times more likely to have a baby with neural tube defect, compared to those who did not have a deficiency.

Metformin During Pregnancy Leads to Heavier Mothers and Babies

It’s been shown that metformin can cross the placental barrier and therefore potentially impact the foetus. So metformin may cause metabolic changes in babies born to mothers who have taken the drug during pregnancy. These metabolic changes could predispose the child to complications later in life. A study found that in women who took metformin during pregnancy, both mother and baby were heavier one year postpartum compared to women who were given a placebo.

Metformin can Reduce Your Energy by up to  48%

As already stated above, Studies have shown that metformin depletes the mitochondria’s ability to produce energy, meaning that you are effectively operating on half the energy that you should have. This means that when you’re taking metformin for PCOS,  then the cells in all of your essential organs, including your brain and heart, your GI tract and muscle cells are only working at half capacity. It is no wonder women taking metformin for PCOS feel so fatigued all the time.

Metformin Kills Your Gut Bacteria

Gut bacteria is essential for immune function and proper weight regulation. Read any forum about metformin and you’ll find loads of stories from women who are having to base their everyday lives around where the nearest toilet just incase they have an ‘incident’. However, what most people don’t realise is that this side effect of metformin is much worse than suffering from loose stools. The reason that metformin has this effect is because it’s actually an antibiotic which seriously affects the microbiome (community of bacteria) living in the intestine. Several human and animal studies emphasized that metformin alters the gut microbiota composition by enhancing the growth of some bacteria, such as Akkermansia muciniphila, Escherichia spp. or Lactobacillus and by decreasing the levels of some other ones like Intestinibacter. 

PPIs, metformin, NSAIDs, opioids and antipsychotics were associated with increases in either members of class  Gammaproteobacteria  (including Enterobacter, Escherichia, Klebsiella, Citrobacter, Salmonella and Proteus) or members of family Enterococcaceae. All of them are frequently isolated pathogens from blood culture samples of patients with sepsis, especially critically ill and cancer patients.

On the other hand, some suggest that metformin alleviates diabetes symptoms by killing off B. fragilis, which decreases FXR activation and the resulting production of ceramides by boosting levels of FXR-inhibiting GUDCA. However, one newer study from September 2018 does suggest that metformin causes an “increase in abundance of opportunistic pathogens and further triggers the occurrence of side effects associated with the observed dysbiosis”. 

By | 2020-06-30T18:58:22+00:00 February 13th, 2019|Uncategorized|38 Comments

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  1. zen February 13, 2019 at 08:47

    Metformin May Increase the Risk of Cognitive Impairments

    A study of over 7,000 patients with Alzheimer’s disease showed that, compared to insulin treatments, sulfonylureas, and thiazolidinediones, metformin increased the risk of developing Alzheimer’s [R].
    However, another study on approximately 1,500 people showed that the cognitive impairment associated with metformin is alleviated with vitamin B12 and calcium supplements [R].
    Vitamin B12 depletion could lead to memory and cognition issues, especially in elderly diabetics. Diabetics who have vitamin B12 depletion could suffer from confusion, memory loss, moodiness, abnormal gait, agitation, dizziness, delusions, dementia and even hallucinations. The risk of symptoms relating to a B12 deficiency increases in elderly diabetics. With age, we produce lesser stomach acid and intrinsic factor, both of which are important for digestion and absorption of Vitamin B12 from regular food sources.
    Because AMPK activity is reduced by inflammation, obesity, and diabetes, increasing AMPK activity has been viewed as a viable therapeutic strategy to improve NAFLD. AMPK is activated primarily by increases in the AMP/ATP ratio, which occurs when cellular energy status has been acutely compromised by metabolic stresses that either interfere with ATP production (e.g., mitochondrial inhibitors/uncouplers) or accelerate ATP consumption (e.g., exercise).
    When cells are chronically over-nourished, the energy-mobilizing enzymatic activity of AMPK diminishes. The outward effects manifest in the form of unwanted weight gain, diabetes, degenerative disease, and premature death.

  2. zen February 13, 2019 at 08:53

    Metformin-induced vitamin B12 deficiency can cause peripheral neuropathy.

    Arms and feet could tingle or feel numb due to depletion of Vitamin B12, which is critical for nerve insulation. Our nerves are like electric wires and we need Vitamin B12 to keep the protective sheath of the nerves healthy. Metformin interferes with B12 absorption in the body. This leads to nerves becoming extra sensitive, almost like having a short circuit. If nerves get deadened instead, one could feel numbness or that ‘pillow walking’ feeling diabetics often complain about.
    Researchers found that 40% of type 2 diabetes patients using metformin had vitamin B12 deficiency or were in the low-normal range for the essential vitamin. And 77% of metformin users with vitamin B12 deficiency also had peripheral neuropathy, a common form of nerve damage associated with type 2 diabetes.

  3. zen February 13, 2019 at 08:54

    Metformin Inhibits Exercise-Induced Insulin Sensitivity

    The drug that makes your body think it’s working out. If you are on prescription metformin and you are initiating an exercise program . . .The energy you use during a sustained workout is funded in large part by free fatty acids in your bloodstream, metformin decreases this compound by 10-20%. Metformin cause cells to take up more glucose, and prevents release of stored forms of glucose from muscle and liver cells. This, in essence, blocks the ability of cells to release stored forms of glucose. Our metabolism runs on a debt-repayment economy; therefore, blocking stored glucose comes at a cost, which interferes with exercise performance, resulting in higher heart rates and greater fatigue under exercise conditions.

  4. zen February 13, 2019 at 08:55

    Metformin Inhibits Exercise Adaptations

    A study just published in Aging Cell reports that metformin blunts the benefits of exercise training: Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults.
    Participants, average age 62, were randomized to either metformin or placebo, and undertook aerobic exercise training for 12 weeks. This isn’t a surprise, since it’s already known one way in which metformin works is by inhibition of Complex 1 in mitochondria. (Ref) By inhibiting mitochondria, the powerhouses of the cell, less ATP is formed, which activates AMPK, an energy sensor. In turn, AMPK activates many processes that contribute to better metabolism, including lower insulin and glucose and increased fat burning.
    The blunting effect of metformin on exercise was not small either. Increase in VO2max in the metformin group was only about 50% that of the placebo group. The improvement in whole-body insulin sensitivity in the metformin group was zero, compared to a significant increase in the placebo group.
    Another study, “Metformin and Exercise in Type 2 Diabetes”, determined the effects of metformin on the metabolic response to sub-maximal exercise, the effect of exercise (relevant to activity patterns of type 2 diabetics) on plasma metformin concentrations, and the interaction between metformin and exercise on the response to a standardized meal. There is evidence that suggests that the benefits of exercise and metformin aren’t cumulative. In a study whose results were noted in this one, the reductions in diabetic risk were similar in a lifestyle that combined metformin and lifestyle modifications to the metformin or lifestyle alone groups. And in fact, the two adjustments may have contradictory effects on diabetes. First, metformin reduces blood glucose levels. But exercise tends to increase levels of glucagon, the hormone that deals with low blood sugar. When the two are combined, glucagon concentrations become significantly higher as the body tries to compensate for the effect of metformin. Second, by increasing the heart rate, metformin has the potential to lower some patients’ selected exercise intensity, which means it could lead to the prescription of lower exercise workloads than are commonly recommended. So, the combination of exercise and metformin, both common prescriptions for diabetics, is likely less effective at lowering the glycemic response to a meal than metformin alone.
    The cancer research suggests that Metformin reduces any gains in insulin sensitivity that normally would be achieved from exercise.
    According to one study, physical exercise can increase insulin sensitivity by up to 54% in insulin resistant individuals, unless of course, they are taking Metformin. Metformin abolishes any increased insulin sensitivity gained by exercise. Metformin also reduces peak aerobic capacity, reducing performance and making exercise more difficult.
    Metformin reduces mitochondrial ATP production in skeletal muscle by as much as 48%. Sit with that one for a moment, a 48% reduction in cell fuel. Imagine functioning at only half capacity. This would make basic activities difficult at best and exercising to lose weight a very unlikely proposition. Moreover, despite claims to the contrary, Metformin does not appear to be an especially effective tool for weight loss, netting a reduction of only 5-10 pounds over 4-8 months. Regular exercise and a healthy diet net on average a loss of 5-10 pounds per month for most people and are significantly more effective at reducing diabetes and associated health complications without the potential side effects.
    Metformin abolishes the improvement in mitochondrial respiration after aerobic exercise training. Metformin attenuates the improvement in physiological function after aerobic exercise training. The study reasoned that the cellular energy sensor AMPK would have increased activity due to the energetic stress of metformin preventing the increase in mitochondrial respiration in response to the energetic demands of exercise training.
    Since cardiorespiratory fitness is one of the strongest factors for survival into old age, and since it decreases with age, the effect of metformin on this factor is concerning.
    Surprisingly, a study in rats found little evidence for additive effects of combining metformin and aerobic exercise training on outcomes of obesity, type 2 diabetes, and NAFLD and actually suggest potential impairments in exercise-induced hepatic mitochondrial adaptations.

  5. zen February 19, 2019 at 14:55

    Even after 60 years, why we still do not fully understand the mechanism of action of Metformin?

    Metformin inhibits hepatic gluconeogenesis is probably beyond doubt, but exactly how it does so is unclear. Whether other actions on the gastrointestinal tract and perhaps even a gut–brain–liver axis are more important is hotly debated. Many discuss the impact of metformin on mitochondrial function and AMPK activity in the liver, as well as AMPK-independent effects.

    The evidence that metformin actually alters the underlying diabetes disease process is lacking. Mainly on the basis of the UK Prospective Diabetes Study (UKPDS) randomised trial and open follow-up results, we believe that metformin reduces the incidence of macrovascular disease at least in obese individuals, but are uncertain whether this is purely a glucose-lowering effect or whether metformin has other pleomorphic effects.

    This ignorance of the inner workings of the drug have triggered many endeavors to uncover how exactly it works – but the results are often contradictory. The study “Cardiovascular and metabolic effects of metformin in patients with type 1 diabetes (REMOVAL): a double-blind, randomized, placebo-controlled trial” found that while metformin may play a very wide role in managing cardiovascular risks, it doesn’t necessarily improve glycemia, and it had no average effect on insulin requirement. In fact, while there were two deaths in the placebo group, there were five among the patients allocated to metformin.

    But, the cardiovascular risk management also falls under scrutiny under certain conditions. True, metformin may be beneficial when used on its own. But, according to the study “Reappraisal of Metformin Efficacy in the Treatment of Type 2 Diabetes”, when combined with sulphonylurea (another common antidiabetic medication), metformin can actually result in an increased risk of cardiovascular complications and all-cause mortality. Studies are inconclusive at the time being, but the drug has been shown to have no proven efficacy against microvascular complications. And the possibility that metformin is not effective shouldn’t be dismissed out of hand. After all, the first molecule of this type, phenformin, did induce cardiovascular risk, and pharmacologically speaking, there’s little difference between phenformin and metformin.

    All that to say, the specific efficacy of metformin to prevent death or cardiovascular disease has not been proven beyond reasonable doubt by current studies. So metformin may not be the best comparator for evaluating hypoglycemic drugs – and that’s not even the end of the story.

  6. zen February 19, 2019 at 15:05

    Why Metformin Might Not Be Safe For PCOS?

    Have you been prescribed metformin for PCOS and are wondering what the side affects are? Metformin is often described as a ‘safe’ drug, but this might not be the case.
    There are some much more sinister side effects of metformin that aren’t so widely publicised. These include:
    – Depleting our bodies of essential nutrients.
    – Increasing the risk of having a baby with a neural tube defect by up to 9 times.
    – Reducing energy levels by almost 50%.
    – Killing beneficial gut bacteria.
    Metformin and PCOS can cause a vitamin B12 deficiency which is associated with insulin resistance. However, B12 deficiency can also cause an increased risk of neural tube defects in unborn children. This is important for all women, but especially those who are trying to get pregnant.

    One study found that mothers with a vitamin B12 deficiency were up to nine times more likely to have a baby with neural tube defect, compared to those who did not have a deficiency.

  7. zen February 19, 2019 at 15:06

    Does Metformin Leads to Heavier Mothers and Babies During Pregnancy?

    It’s been shown that metformin can cross the placental barrier and therefore potentially impact the foetus. However, what’s also concerning is that there have been few studies that have looked at potential postnatal effects on the baby.

    Although there is no conclusive evidence, some studies have indicated that metformin may cause metabolic changes in babies born to mothers who have taken the drug during pregnancy. These metabolic changes could predispose the child to complications later in life.

    For example, one study found that in women who took metformin during pregnancy, both mother and baby were heavier one year postpartumcompared to women who were given a placebo.

    In addition, a study on mice found that baby mice exposed to metformin in the womb suffered from a damaged metabolism later in life and were more likely to become obese.

    Let’s think about that evidence for a moment. Metformin is a drug that we know disrupts the normal communication in the body, can cross the placental barrier, and may potentially lead to metabolic disruption in babies. I’m not sure how that passed ethics approval.

  8. zen February 19, 2019 at 15:15

    Does Metformin Kills Your Gut Bacteria?

    Several human and animal studies emphasized that metformin alters the gut microbiota composition by enhancing the growth of some bacteria, such as Akkermansia muciniphila, Escherichia spp. or Lactobacillus and by decreasing the levels of some other ones like Intestinibacter. In-vitro studies also demonstrated a direct action of metformin on the growth of A. muciniphila and Bifidobacterium adolescentis.
    Gut bacteria is essential for immune function and proper weight regulation. Read any forum about metformin and you’ll find loads of stories from women who are having to base their everyday lives around where the nearest toilet just incase they have an ‘incident’.

    However, what most people don’t realise is that this side effect of metformin is much worse than suffering from loose stools. The reason that metformin has this effect is because it’s actually an antibioticwhich seriously affects the microbiome (community of bacteria) living in the intestine.

  9. zen February 19, 2019 at 15:18

    Does metformin effect on hormones?

    Research studies have reported metformin’s effects on a variety of hormones, including a reduction in testosterone in men and lowering of thyroid stimulating hormone (TSH) in both men and women.

    In a small study involving 12 men taking 850 milligrams of metformin twice daily for two weeks, researchers discovered a significant decrease in levels of total testosterone, free testosterone and 17-hydroxyprogesterone, as well as an increase in sex hormone binding globulin (SHBG) and DHEA-S. There weren’t any changes noted in fasting blood sugar or insulin levels, LH, FSH, blood pressure, or weight. Because the study length was limited to two weeks, researchers concluded that more study would be needed to determine the long-term effects of metformin on testosterone and other androgen levels.

    Similar androgen-lowering effects have been seen in women with PCOS, a condition in which androgen levels rise for reasons as yet unknown.

    TSH was lowered significantly in those who were hypothyroid and on metformin for at least a year. This effect occurred in hypothyroid individuals taking L-thyroxine (T4) with metformin, and hypothyroid individuals who took no L-thyroxine. It also happened to individuals with normal thyroid function who took this patent medicine. The researchers concluded that thyroid function should be reevaluated in patients on metformin 6 to 12 months after therapy begins. Other studies have found similar results.

    But a recent study involving 828 individuals with normal thyroid function who were taking metformin also concluded that metformin did not affect their TSH levels. Since this study and prior studies partially conflict, it’s best to know your own thyroid status if you decide to use metformin.

    And if you’re a man, check your testosterone and free testosterone levels before starting metformin – if you decide to do so – and again a few weeks later.

  10. zen May 31, 2019 at 13:02

    Why Metformin down-regulates mitochondrial complex I?

    Metformin down-regulates mitochondrial complex I activity in intact liver cells and stimulates AMPK activity in muscle cells. As shown by El-Mir et al. (2), hepatocytes exposed to millimolar concentrations of metformin have lower activity of complex I. This effect is indirect because it manifests only in intact cells and not in isolated mitochondria or permeabilized hepatocytes. As reported by Fryer and colleagues (3), treating muscle cells with metformin up-regulates AMPK, presumably via liver kinase B1 (LKB1), indicating an indirect effect of metformin on AMPK. Although metformin’s direct molecular target remains unknown to date, metformin’s effect on complex I likely affects cellular bioenergetics, resulting in knock-on effects, such as an increase in the AMP:ATP ratio, which, in turn, stimulates AMPK activity (as indicated by the gray arrow). Additional studies have shown that metformin decreases liver gluconeogenesis and increases insulin-mediated glucose uptake into skeletal muscle cells.
    Although the interest around metformin has been significantly revived during the last years, principally due to the potential repositioning of this antidiabetic drug for the treatment of cancer, it still remains crucial to better decipher the mechanism by which it inhibits the mitochondrial respiratory-chain complex 1, notably the exact nature of their interaction. Elucidating this aspect may advance our understanding of how metformin regulates cellular energetics and be decisive for optimizing future drug development and therapeutic interventions, notably for cancer patients.

  11. zen May 31, 2019 at 13:08

    Why Metformin Users Need to Pay Attention to Vitamin B12?

    Alarming new research is showing a relationship between long-term metformin use and vitamin B12 deficiency, yet most health care providers rarely check B12 status in metformin users. A lack of vitamin B12 can result in serious and permanent neurological and nerve damage. Here’s what to know about vitamin B12 if you take metformin.
    A new analysis of the DDPOS published in the Journal of Clinical Endocrinology and Metabolism looked at B12 levels of individuals with prediabetes who took 850 mg Metformin twice daily and compared them to those taking a placebo. Vitamin B12 levels were assessed at 5 and 13 years.

    Results from the DDPOS showed that long-term metformin use increased the risk for vitamin B12 levels. At 5 years, 5.2 percent of the metformin users had low serum B12 levels. At 13 years, 9.2 percent of metformin users had low B12 levels. When controlling for age, sex, and BMI, there was a 13 percent increased risk of B12 deficiency for each year of total metformin use.

    It is believed that metformin can affect the absorption of vitamin B12 in the ileum of the small intestine. Not only were vitamin B12 levels affected in the DDPOS study, but homocysteine levels, a marker of cardiovascular risk, were increased over time in metformin users.

    Other studies have shown that metformin can affect levels of vitamin B12 in as little as three months of use. A systematic review and meta-analysis looked at individuals with type 2 diabetes and women with PCOS who took metformin. Their results found the higher the metformin dose, the more deficient people were in vitamin B12 and that metformin reduced vitamin B12 levels in both long (≥3 years) and short (<3 years) term use.

    The average dose of metformin for women with PCOS is 1,500 mg to 2,000 mg daily. The majority of women with PCOS take high doses of metformin for long-term use, increasing their risk for a vitamin B12 deficiency.

    If you take metformin, ask your doctor to check your vitamin B12 levels annually and supplement your diet with vitamin B12 to prevent complications of a deficiency.

  12. zen May 31, 2019 at 13:58

    Does metformin cause hair loss?

    On rare occasions, people have reported a link between metformin and thinning hair or hair loss. However, it is unclear whether metformin is directly responsible for this issue or if other factors play a role.

    For example, a 2017 case report in Current Drug Safety described how a 69-year-old man with type 2 diabetes suddenly lost his eyebrows and eyelashes.

    The man took a combination of metformin, and another diabetes medication called sitagliptin.

    Doctors used clinical tests to rule out any systemic or skin diseases that might be contributing to hair loss. The authors of the report concluded that there was a possible association between the medication and hair loss.

    However, as this case study involved just one person, it is difficult to move from these findings to a general trend suggesting a significant relationship between metformin and hair loss.

    Metformin might also reduce the risk of hair loss in people who take it to treat PCOS, according to a randomized clinical trial from 2016.

    As hair loss can be a symptom of PCOS, treating the condition can reduce its effects.

  13. zen June 10, 2019 at 10:54

    How does metformin cause Vitamin B12 deficiency?

    Three theoretical mechanisms of action regarding the contribution of metformin to the lowering of B12, a water-soluble vitamin, have been postulated; it may be one or any combination of these that contributes to a diminished B12 level. The first posits that this is due to blocking by metformin of the calcium channels in the distal ileum that normally allow absorption of the vitamin B12-intrinsic factor (B12-IF) complex by altering the membrane potential.2 The hydrophobic tail of metformin binds to the hydrocarbon core of the cell membrane, imparting a net positive charge; this, in turn, repels calcium that is necessary for transporting B12 across the ileal-lumen interface.18 The second mechanism details the modification of normal bacterial flora, resulting in bacterial overgrowth and impeded passage of B12-IF into the bloodstream.19 A third pathway describes metformin changing the B12-IF complex by binding to it structurally.19 Each of these potential influences lessens the amount of B12 that passes through the distal ileal wall.13

    Though poorly understood, low vitamin B12 levels cause a diminution of the myelin that coats the peripheral nerves, perhaps through the attenuated methylation of myelin, which subsequently disrupts the transmission of action potentials. Nonhomogeneous myelin manifests as peripheral neuropathy.8 Vitamin B12 functions as a coenzyme in the transfer of a methyl group from 5-methyl-tetrahydrofolate to tetrahydrofolate, creating methionine with the enzyme methionine synthase.20 Methionine and adenosine triphosphate are essential in assembling 5-adenosyl methionine, which is the primary methyl donor in the methylation reactions involving amines, proteins, and phospholipids (including sphingomyelin) in the myelin sheath. Thus, a deficiency of B12 leads to diminished methylation in myelin and, subsequently, the development of peripheral neuropathy.20 Once this process occurs, it is extremely difficult to reverse and correct. Low vitamin B12 levels that are symptomatic exhibit a confounding clinical similarity to diabetic peripheral neuropathy.5

  14. zen July 10, 2019 at 07:42

    The effects of metformin on pancreatic beta cells remain controversial

    Pancreatic beta cells act as the controller of glucose homeostasis in the human body by secreting insulin in response to glucose or nutrient stimulation. In humans, these pancreatic beta cells are fully differentiated by the end of the first trimester and the eventual total beta cell mass is generated via the proliferation of existing beta cells through the second and third trimesters as well as very shortly after birth [28]. In the previously mentioned clinical scenario where metformin is administered in pregnancy, both progenitors and mature pancreatic beta cells may be exposed to metformin (Fig. 1). Gregg et al. showed that in utero exposure to metformin leads to more cells expressing Pdx1 (a pancreatic progenitor marker), but less cells expressing Ngn3 (a later pancreatic endocrine progenitor marker) in mouse embryos [29]. As the endocrine progenitors are the precursors of mature pancreatic beta cells, the decrease in endocrine progenitor population will likely cause a decrease in the eventual proportion of mature beta cells.

    Metformin has recently been shown to confer protective effects on mouse pancreatic beta cells exposed to fatty-acid induced stress [30] and chronic high glucose exposure [31]. The studies proposed that metformin preserves glucose-stimulated insulin secretion (GSIS) by maintaining the ATP/ADP ratio within the beta cells, and prevents beta cell failure by activating the AMPK signalling pathway, supressing C/EBPβ expression and ameliorating ER stress [32,33]. Currently, the mechanism(s) by which metformin protects pancreatic beta cell under metabolic stress remain rudimentary.

    Converse to these positive effects, when beta cells are exposed to metformin without metabolic challenges, beta cell proliferation is known to be suppressed and apoptosis is promoted [30,34,35]. Prolonged exposure results in apoptosis either via c-JNK activation and caspase-3 cascade [34] or via increasing AMPK-dependent autophagy [30]. Metformin exposure also impairs insulin secretion in primary human islets, mouse islets and, mouse and rat pancreatic beta cell lines in a normoglycaemic environment [34,35]. Therefore, metformin overdosing or exposure without metabolic challenges might result in potential beta cell toxicity. However, it is conceivable that immature foetal pancreatic cells may respond differently to adult cells and there could be additional or detrimental effects instead, although this remains to be determined.

    Collectively, even though metformin can provide protection for pancreatic beta cells against metabolic challenges, foetal exposure to metformin might have anti-growth or restrictive effects on pancreatic beta cells, potentially resulting in a smaller beta cell mass formed during foetal development. This may reduce the individual’s ability to withstand life-long glucose or nutrient challenges, giving rise to a higher risk of earlier beta cell dysfunction which translates to the development of T2D. Nonetheless, it is important to note that these limited recent studies have only been conducted in mouse models, which may not accurately reflect the biology in human cells and organs. Hence, the effects of metformin on metabolic risks in human pancreatic beta cells remain to be determined.

  15. zen July 10, 2019 at 13:19

    Has the effectiveness of metformin actually been proven?

    Metformin is an oral antidiabetic drug (OAD) in the biguanide class [1]. It is the recommended first-line treatment for type 2 diabetes (DT2) patients [2]. Its effcacy was supposedly conclusively demonstrated in the UKPDS 34 study published in 1998 (reduction in mortality: RR0.64; CI 95% (0.45 to 0.91) and in myocardial infarction: RR0.61; CI 95% (0.41 to 0.89) [3]. However, these rather impressive results regarding total 10 year mortality (ARR0.07; NNT14) in a small subgroup of obese type 2 diabetes patients (342 in the metformin group vs. 411 patients in the conventional group) have never been reproduced [4]. For instance, the home study [5] evaluated the efficacy of metformin versus placebo (in addition to insulin). After four years of follow-up, no statistically significant difference was found for total mortality: RR1.48; CI 95% (0.54 to 4.09) or for IDM: RR0.99; CI 95% (0.25 to 3.90). Taking into account all the other randomized clinical trials (RCTs) having evaluated the specific eectiveness of metformin in DT2 patients [6], it becomes evident that metformin has not signicantly modied total mortality: RR0.99; CI 95% (0.75 to 1.31), cardiovascular mortality: RR  1.05; CI 95% (0.67 to 1.64), IDM occurrence: RR0.90; CI95% (0.74 to 1.09), cerebrovascular accidents: RR0.76; CI95% (0.51 to 1.14), cardiac insuficiency: RR1.03; CI 95% (0.67 to 1.59), peripheral vascular events: RR0.90; CI 95% (0.46 to 1.78), lower limb amputations: RR1.04; CI 95% (0.44 to 2.44) or microvascular complications: RR0.83; CI95% (0.59 to 1.17). Once an analysis without selection bias has been carried out, it becomes apparent that on the basis of clinical criteria, the efficacy of metformin has not been proven; in science, the reproducibility of results remains an essential validity criterion

  16. zen July 11, 2019 at 09:23

    Does glucose-lowering effect of metformin occurs in the gut rather than in the bloodstream?A study reported in Diabetes Care of a delayed-release from of metformin shows that the glucose-lowering effect of metformin occurs in the gut rather than in the bloodstream. The finding means that this form of the drug used to treat type 2 diabetes could be tolerated by the 40% of type 2 diabetes patients who cannot use the current formulation.

    In an article in Medical News Today, John Buse, MD, PhD, professor of medicine and lead author of the study, said, “These studies provide evidence that delivering Metformin DR to the lower bowel significantly reduces the amount of metformin in the blood, while maintaining its glucose-lowering effect.”

    Because metformin collects in the blood of patients with poor kidney function, in patients with impaired kidneys, metformin use can increase the risk of lactic acidosis, where lactic acid builds up in the bloodstream faster than it can be removed.

    There are approximately 4 million people in the United States with type 2 diabetes who, due to impaired kidneys, cannot take metformin. Results of the phase 1trial demonstrated that participants who took the DR version had half the amount of metformin in their blood compared with those who took the IR or XR versions.

    In the phase 2 trial, the effects of various doses of Metformin DR were tested compared with placebo or Metformin XR in 240 type 2 diabetes patients at various clinics. Results showed that Metformin DR was approximately 40% more potent than Metformin XR. The DR version also demonstrated a statistically significant and sustained reduction in fasting plasma glucose over 12 weeks compared with placebo.

    The treatment was generally well tolerated and side effects were similar to those known to occur with current forms of metformin.

  17. zen July 14, 2019 at 09:55

    Effects of Metformin Delayed-Release (Metformin DR)

    Improved glycemic control with minimal systemic metformin exposure: Effects of Metformin Delayed-Release (Metformin DR) targeting the lower bowel over 16 weeks in a randomized trial in subjects with type 2 diabetes.

    BJECTIVE:
    Metformin use is restricted in patients with renal impairment due to potential excess systemic accumulation. This study evaluated the glycemic effects and safety of metformin delayed-release (Metformin DR), which targets metformin delivery to the ileum to leverage its gut-based mechanisms of action while minimizing systemic exposure.

    RESEARCH DESIGNS AND METHODS:
    Participants (T2DM [HbA1c 7-10.5%], eGFR ≥60 mL/min/1.73m2, not taking metformin for ≥2 months) were randomized to QD placebo (PBO); QD Metformin DR 600, 900, 1200, or 1500 mg; or to single-blind BID Metformin immediate-release (IR) 1000 mg. The primary endpoint was change in HbA1c for Metformin DR vs. PBO at 16 weeks in the modified intent-to-treat (mITT) population (≥ 1 post-baseline HbA1c while on study drug), using a mixed-effects repeated measures model.

    RESULTS:
    571 subjects were randomized (56 years, 53% male, 80% white; BMI 32.2±5.5 kg/m2; HbA1c 8.6±0.9%; 51% metformin naive); 542 were in the mITT population. Metformin DR 1200 and 1500 mg significantly reduced HbA1c (-0.49±0.13% and -0.62±0.12%, respectively, vs. PBO -0.06±0.13%; p<0.05) and FPG (Caverage Weeks 4-16: -22.3±4.2 mg/dL and -25.1±4.1 mg/dL, respectively vs. -2.5±4.2 mg/dL p<0.05). Metformin IR elicited greater HbA1c improvement (-1.10±0.13%; p<0.01 vs. Placebo and all doses of Metformin DR) but with ~3-fold greater plasma metformin exposure. Normalizing efficacy to systemic exposure, glycemic improvements with Metformin DR were 1.5-fold (HbA1c) and 2.1-fold (FPG) greater than Metformin IR. Adverse events were primarily gastrointestinal but these were less frequent with Metformin DR (<16% incidence) vs. Metformin IR (28%), particularly nausea (1-3% vs 10%).

    CONCLUSION:
    Metformin DR exhibited greater efficacy per unit plasma exposure than Metformin IR. Future studies will evaluate the effects of Metformin DR in patients with type 2 diabetes and advanced renal disease.

  18. zen August 12, 2019 at 11:08

    Metformin does not lowers CV death, MI or stroke in T2D patients

    In patients with both type 2 diabetes (T2D) and an elevated cardiovascular risk, metformin lowers the risk of all-cause mortality but does little to protect against CV death, MI or ischemic stroke, a new evaluation of the SAVOR-TIMI 53 trial has found.

    In a post-hoc analysis of 12,156 patients enrolled in SAVOR-TIMI 53, Brian Bergmark, MD, and colleagues at Brigham and Women’s Hospital and Harvard Medical School examined whether metformin—the recommended first-line therapy for T2D in both the U.S. and Europe—is safe in patients with additional CV risk factors, like prior heart failure (HF) or chronic kidney disease (CKD).

    While it’s the gold standard for treating T2D, in reality, we’re not sure how it affects the cardiovascular system.

    “Based on recent randomized controlled trials, several of the new diabetes medications have now been granted an indication for cardiovascular risk reduction by the U.S. FDA, something metformin does not have,” Bergmark et al. said in Circulation, where their findings were published July 31. “Because professional societies’ recommendations for metformin as the first-line agent for T2D are based on wide availability, an absence of serious side effects, and low cost rather than efficacy for macrovascular outcomes, its place is now legitimately in question.”

    SAVOR-TIMI 53 was a multinational randomized controlled CV outcomes trial that compared the DPP-4 inhibitor saxagliptin with placebo in 16,492 patients with T2D and CVD or an elevated CV risk. Bergmark and his colleagues extracted data from 12,156 of those patients who had baseline biomarker samples, classifying them as either having been exposed to metformin or never having taken the drug.

    Nearly three-quarters of their patient pool was exposed to metformin, the authors reported, and an additional 13% and 11% had prior heart failure or at least moderate CKD, respectively.

    Bergmark et al. said metformin use wasn’t associated with any difference in risk for his team’s composite endpoint of CV death, MI or ischemic stroke, but the drug was linked to a 25% lower risk of all-cause mortality. The researchers didn’t find any significant relationship between metformin use and the composite endpoint or all-cause mortality in patients with prior HF or moderate to severe CKD; in fact, metformin’s positive effects were most pronounced in patients without those comorbidities.

    “While the findings from SAVOR-TIMI 53, the REACH registry and the meta-analysis are compelling in their consistency, if a potential causal relationship is to be posited, it would be helpful for there to be a biologically plausible mechanism for decreased mortality in the absence of reduction in MI or ischemic stroke,” the authors wrote. “At present, no single mechanism of this nature exists.”

    Bergmark and co-authors said that since their analysis is retrospective and observational, they can’t exclude the possibility of unmeasured confounders between the metformin-exposed and metformin-unexposed groups. They also acknowledged their patient population included “relatively few” patients with prior HF or CKD.

    “These findings emphasize the need for an adequately powered randomized trial in these high-risk patients,” they wrote.

  19. zen August 12, 2019 at 11:17

    Metformin and Exercise seem to be working against each other!

    Both exercise and metformin have been shown to independently improve glycemic control and insulin sensitivity in diabetics; the former has also been shown to drive cardiovascular improvements. Multiple studies have shown, however, that the combination of metformin and exercise leads to an inferior response compared to either intervention alone. For example:

    One study showed metformin alone and exercise alone led to 55% and 90% improvements in skeletal muscle insulin sensitivity, respectively. Significantly, however, metformin + exercise led to a smaller improvement at 30% (3).
    Metformin combined with exercise led to smaller improvements in both hsCRP and systolic blood pressure — and thus a smaller reduction in cardiovascular risk — than either intervention alone. (ibid)
    Adding metformin to exercise blunted subjects’ increase in VO2max by 50% compared to 10 weeks of exercise alone. Subjects also reported greater perceived exertion than controls while exercising and taking metformin, which further indicates a reduction in cardiovascular improvement. These reduced improvements in aerobic fitness were associated with blunted improvements in muscular insulin sensitivity (4).
    Similar effects have been seen with statins, where aerobic exercise training alone in overweight/obese adults improved VO2max by 10%, but when combined with statins therapy, VO2max improved by only 1.5% (5).
    3. Malin, SK, et al. Independent and combined effects of exercise training and metformin on insulin sensitivity in individuals with prediabetes. Diabetes Care 35.1(Jan. 2012): 131-6.

    4. Malin, SK, et al. Metformin’s effect on exercise and postexercise substrate oxidation. Int J Sport Nutr Exerc Metab. 20.1(Feb. 2010): 63-71.

    5. Mikus CR, et al. Simvastatin impairs exercise training adaptations. J Am Coll Cardiol. 62.8(Aug. 2013): 709-14.

  20. zen September 29, 2019 at 14:03

    Metformin-Induced Lactic Acidosis (MILA): Review of current diagnostic paradigm.

    High levels of metformin are the primary cause of illness.
    (1) Acute metformin overdose
    Acute poisoning may lead to MILA in the absence of renal dysfunction.
    Precise amount of metformin required to do this is unclear, but seems to be high (e.g. >20 grams).3
    Patients with acute ingestion look fine initially, but deteriorate subsequently (“toxin bomb”).
    (2) Subacute accumulation of metformin due to renal failure
    Metformin is renally cleared.
    Progressive renal failure (with GFR << 30 ml/min) eventually leads to metformin accumulation and toxicity. These patients may present with marked lactic acidosis, yet have fairly preserved hemodynamics and look OK.

  21. zen September 29, 2019 at 14:05

    Metformin associated lactic acidosis: a case series of 28 patients treated with sustained low-efficiency dialysis (SLED) and long-term follow-up

    Metformin associated lactic acidosis (MALA) is a well-known serious side effect of biguanides.
    Definition:
    Patient on metformin develops an acute life-threatening illness (e.g. septic shock, cardiogenic shock).
    Metformin amplifies the degree of lactic acidosis, but it’s not the sole cause of the illness.
    Risk factors include renal insufficiency, higher doses of metformin, and alcoholism.

  22. zen September 29, 2019 at 14:07

    metformin-induced lactic acidosis vs. DKA

    Compared to isolated DKA, patients with metformin-induced lactic acidosis have greater degree of hyperlactatemia, with less extensive ketoacidosis.
    It can be very difficult to sort this out in some situations. When in doubt, treat both conditions (the treatment for DKA may actually improve MILA/MALA). More on treatment of this below.
    other causes of lactic acidosis, for example:
    Shock of any etiology (septic shock, adrenal insufficiency, cardiogenic shock, etc.)
    Acute mesenteric ischemia
    Seizure
    Liver failure
    Thiamine deficiency
    Medications
    HIV antiretrovirals
    Linezolid
    Propylene glycol
    Propofol infusion syndrome
    Beta-adrenergic medications (e.g. albuterol, epinephrine)
    Massive acetaminophen overdose

  23. zen October 14, 2019 at 07:00

    Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors: A Clinician’s Guide

    SGLT2 inhibitors are an insulin-independent class of oral antihyperglycemic medication that clinicians use in the treatment of type 2 diabetes. Multiple landmark clinical trials support the effectiveness of SGLT2 inhibitors in reducing blood glucose levels, but it is important to understand when to properly utilize them. SGLT2 inhibitors are the most beneficial as an adjunct medication in addition to metformin in patients with a history of cardiovascular or renal disease who need further hemoglobin A1c reduction. The novel mechanism of action also demands clinicians be aware of the side effects not typically experienced with other oral antihyperglycemic drugs, such as genital tract infections, lower leg amputations, electrolyte disturbances and bone fractures. On top of their benefits in type 2 diabetes, novel uses for SGLT2 inhibitors are being uncovered. Diabetic patients with non-alcoholic fatty liver disease, who are at an increased risk of cirrhosis and hepatocellular carcinoma, experience a clinically significant reduction in serum alanine aminotransferase levels. SGLT2 inhibitors are also effective at lowering body weight in obese individuals and decreasing systolic blood pressure. Dual SGLT1/SGLT2 inhibitors are currently being investigated as possibly the first oral medication for type 1 diabetes.

  24. zen October 14, 2019 at 08:02

    Vitamin B12 deficiency is high among T2DM patients on metformin therapy

    Introduction: Metformin is the most widely administered anti-diabetic medication among type 2 diabetes mellitus (T2DM) patients. However, metformin induces vitamin B12 malabsorption which may increase the risk of vitamin B12 deficiency among T2DM patients. We determined the prevalence of vitamin B12 deficiency and related risk factors among Ghanaian T2DM patients on metformin therapy.

    Methods: This cross-sectional study recruited 196 T2DM patients attending the outpatient diabetic clinic at the Effia Nkwanta Regional Hospital, Ghana. Fasting venous blood was collected for biochemical analysis. Vitamin B12 deficiency was defined as serum B12 <100 pg/ml and methylmalonic acid (MMA) ≥ 0.4µmol/L.

    Results: The prevalence of vitamin B12 deficiency based on serum vitamin B12, MMA, and the combination of both methods were 32.1%, 14.8%, and 14.3%, respectively. Longer duration of metformin use [5-9 years; aOR= 2.83, 95% CI (1.03-7.81), p=0.045 and ≥10 years; aOR= 4.17, 95% CI (1.41-12.33), p=0.010], higher daily dose of metformin [1000-2000 mg/day; aOR= 1.34, 95% CI (0.25-2.74), p=0.038 and >2000 mg/day; aOR= 1.13, 95% CI (0.39-2.97), p=0.047], and very high body fat [aOR= 2.98, 95% CI (1.47-6.05), p=0.020] were significantly associated with increased odds of vitamin B12 deficiency. For daily dose of metformin, a cutoff value of 1500 mg/day presented with a sensitivity, specificity, and AUC of 71.4%, 40.1%, and 0.54 (95% CI, 0.53-0.54), respectively, in predicting vitamin B12 deficiency. A ≥ six (6) years duration of metformin therapy presented with a sensitivity, specificity, and AUC of 70.4%, 62.9%, and 0.66 (95% CI, 0.57-0.75), respectively, in predicting vitamin B12 deficiency.

    Conclusion: Vitamin B12 deficiency is high among T2DM patients on metformin therapy in Ghana. There is the need for regular monitoring of vitamin B12 levels especially in T2DM patients on metformin daily dose of ≥ 1500 mg for duration of therapy ≥ 6 years.

  25. zen October 16, 2019 at 09:49

    delayed-release from of metformin shows that the glucose-lowering effect of metformin occurs in the gut rather than in the bloodstream.

    A study reported in Diabetes Care of a delayed-release from of metformin shows that the glucose-lowering effect of metformin occurs in the gut rather than in the bloodstream.

    Delayed‐release metformin has been shown to induce clinically significant effects on blood glucose and enhanced secretion of incretin peptide hormones, despite minimal systemic exposure.

    In the phase 2 trial, the effects of various doses of Metformin DR were tested compared with placebo or Metformin XR in 240 type 2 diabetes patients at various clinics. Results showed that Metformin DR was approximately 40% more potent than Metformin XR. The DR version also demonstrated a statistically significant and sustained reduction in fasting plasma glucose over 12 weeks compared with placebo.

    The treatment was generally well tolerated and side effects were similar to those known to occur with current forms of metformin.

  26. zen December 15, 2019 at 09:20

    Metformin use at the time of first AMI is associated with increased risk of cardiovascular disease and death in patients with T2DM

    Background
    The use of metformin after acute myocardial infarction (AMI) has been associated with reduced mortality in people with type 2 diabetes mellitus (T2DM). However, it is not known if it is acutely cardioprotective in patients taking metformin at the time of AMI. We compared patient outcomes according to metformin status at the time of admission for fatal and non-fatal AMI in a large cohort of patients in England.

    Methods
    This study used linked data from primary care, hospital admissions and death registry from 4.7 million inhabitants in England, as part of the CALIBER resource. The primary endpoint was a composite of acute myocardial infarction requiring hospitalisation, stroke and cardiovascular death. The secondary endpoints were heart failure (HF) hospitalisation and all-cause mortality.

    Results
    4,030 patients with T2DM and incident AMI recorded between January 1998 and October 2010 were included. At AMI admission, 63.9% of patients were receiving metformin and 36.1% another oral hypoglycaemic drug. Median follow-up was 343 (IQR: 1–1436) days. Adjusted analyses showed an increased hazard of the composite endpoint in metformin users compared to non-users (HR 1.09 [1.01–1.19]), but not of the secondary endpoints. The higher risk of the composite endpoint in metformin users was only observed in people taking metformin at AMI admission, whereas metformin use post-AMI was associated with a reduction in risk of all-cause mortality (0.76 [0.62–0.93], P = 0.009).

    Conclusions
    Our study suggests that metformin use at the time of first AMI is associated with increased risk of cardiovascular disease and death in patients with T2DM, while its use post-AMI might be beneficial. Further investigation in well-designed randomised controlled trials is indicated, especially in view of emerging evidence of cardioprotection from sodium-glucose co-transporter-2 (SGLT2) inhibitors.

  27. zen December 15, 2019 at 12:49

    What are the risks of taking metformin?

    Side effects of metformin include:
    physical weakness (asthenia)
    diarrhea.
    gas (flatulence)
    symptoms of weakness, muscle pain (myalgia)
    upper respiratory tract infection.
    low blood sugar (hypoglycemia)
    abdominal pain (GI complaints), lactic acidosis (rare)
    low blood levels of vitamin B-12.

  28. zen December 16, 2019 at 07:20

    Diabetes association urges authorities to test metformin drugs for cancer-causing contaminant

    Metformin, a drug used to treat Type 2 diabetes, was once heralded as a first-in-class treatment for which there was no substitute. Now it is sparking international concerns over a contaminant that may cause cancer.

    The debate has taken off in South Korea as well, and on Friday the Korean Diabetes Association urged the nation’s drug safety authority to test every drug containing metformin.

    The potentially carcinogenic impurity, called N-nitrosodimethylamine or NDMA, had previously been detected in valsartan, a blood pressure drug, and in peptic ulcer drugs ranitidine and nizatidine. This resulted in global recalls of the original drugs and numerous copy drugs.

  29. zen January 21, 2020 at 07:27

    Metformin-induced increases in GDF15 are important for suppressing appetite and promoting weight loss

    Metformin is the most commonly prescribed medication for type 2 diabetes, owing to its glucose-lowering effects, which are mediated through the suppression of hepatic glucose production (reviewed in refs. 1,2,3). However, in addition to its effects on the liver, metformin reduces appetite and in preclinical models exerts beneficial effects on ageing and a number of diverse diseases (for example, cognitive disorders, cancer, cardiovascular disease) through mechanisms that are not fully understood1,2,3. Given the high concentration of metformin in the liver and its many beneficial effects beyond glycemic control, we reasoned that metformin may increase the secretion of a hepatocyte-derived endocrine factor that communicates with the central nervous system4. Here we show, using unbiased transcriptomics of mouse hepatocytes and analysis of proteins in human serum, that metformin induces expression and secretion of growth differentiating factor 15 (GDF15). In primary mouse hepatocytes, metformin stimulates the secretion of GDF15 by increasing the expression of activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP; also known as DDIT3). In wild-type mice fed a high-fat diet, oral administration of metformin increases serum GDF15 and reduces food intake, body mass, fasting insulin and glucose intolerance; these effects are eliminated in GDF15 null mice. An increase in serum GDF15 is also associated with weight loss in patients with type 2 diabetes who take metformin. Although further studies will be required to determine the tissue source(s) of GDF15 produced in response to metformin in vivo, our data indicate that the therapeutic benefits of metformin on appetite, body mass and serum insulin depend on GDF15.

  30. zen January 21, 2020 at 08:11

    Metformin could increase risk of stroke by up to 48%.

    In spite of its long history, we identified only 13 studies, including just over 2000 patients with type 2 diabetes allocated to metformin, that addressed our study question, and only four randomised-controlled cardiovascular endpoint trials simply comparing metformin with placebo among patients with type 2 diabetes. Metformin monotherapy appears safe and, while there is a suggestion of benefit, there remains uncertainty about whether it reduces risk of cardiovascular disease. According to our review it is possible that metformin reduces risk of all-cause mortality by up to 16% but it could increase risk of stroke by up to 48%. Metformin is the recommended first-line treatment worldwide for patients with type 2 diabetes. However, in contrast to some newer treatments, cardiovascular endpoint trial data for metformin are largely derived from small studies among relatively young, overweight/obese, North American and Northern European patients with poorly controlled diabetes. Metformin demonstrates cardiovascular safety as per the 2008 FDA guidance, but its use for prevention of cardiovascular disease among older individuals, those with HbA1c less than 8% (63.9 mmol/mol), non-white ethnic groups and people living outside North America and Northern Europe is not well supported by trial evidence. Furthermore, while not specifically covered in this review, there remains concern about the observed increased risk of mortality associated with the addition of metformin to sulfonylurea treatment [14, 15].

    The reports of all included trials either suggested the possibility of bias or provided insufficient information to allow risk of bias to be assessed. The one trial that appeared to exhibit low risk of bias for all but one criterion seemed to be compromised by clinically important baseline differences between study groups [22]. The majority of data for this review came from the UKPDS [21], a seminal trial concerning the effectiveness and safety of treatments for type 2 diabetes, albeit exhibiting a number of previously discussed limitations that might influence its interpretation [28]. These include the small size (only 342 patients were allocated to metformin), lack of placebo and double-blinding, ‘subgroup’ nature of the analysis with updated statistical significance thresholds, potential for between-group differences in management of other cardiovascular risk factors, unacceptably poor level of glycaemic control in the comparison group by current standards, and attrition over the near 18-year follow-up. Including data from the long-term follow-up of the UKPDS [21] introduces a number of assumptions that may lead to underestimation of effects, in particular the extent of any ‘legacy effect’ of treatment with metformin in the early part of the trial. However, a sensitivity analysis replacing the longer term follow-up with the original UKPDS trial data [12] increased the width of the 95% CIs but did not significantly change our findings.

  31. zen February 18, 2020 at 07:00

    Higher doses of metformin associated with lower risk for AMD

    A population-based, retrospective cohort study showed an association between metformin and a lower risk for age-related macular degeneration.

    “We found that metformin was associated with a lower risk of AMD and that the risk-lowering trend was significantly associated with a higher dose of metformin,” Yu-Yen Chen, PhD, of the department of ophthalmology at Taichung Veterans General Hospital in Taiwan, and colleagues wrote in Journal of Ophthalmology.

    They next evaluated whether the lower risk for AMD among users was dose responsive. Investigators used patient prescription records to analyze treatment duration, total dose and average dose of metformin.

    Overall, 45,524 patients used metformin. The incidence of AMD was significantly lower in the metformin group (3.4%) vs. the non-user group (5.6%).

    Results showed that age was a significant risk factor for AMD in both univariate and multivariate analyses (HR for patients older than 70 years vs. those younger than 50 years = 6.44). Patients with hypertension, hyperlipidemia, coronary artery disease and obesity had a significantly higher risk for developing AMD. The risk for AMD in patients with diabetic retinopathy significantly increased in both analyses (HR = 1.51).

    Data revealed that longer duration of metformin use and higher total and average doses of metformin were associated with a lower risk for AMD.

    “The underlying mechanism remains unclear but may be related to the antioxidative and anti-inflammatory properties of metformin,” the researchers wrote.

    Chen and colleagues suggested further prospective studies and basic research be conducted to clarify possible explanations of the association between metformin and a lower risk for AMD development. – by Erin T. Welsh

    Disclosures: The authors report no relevant financial disclosures.

  32. zen February 18, 2020 at 07:02

    Metformin Activates the AMPK-mTOR Pathway by Modulating lncRNA TUG1 to Induce Autophagy and Inhibit Atherosclerosis

    Background: Metformin has been shown to inhibit the proliferation and migration of vascular wall cells. However, the mechanism through which metformin acts on atherosclerosis (AS) via the long non-coding RNA taurine up-regulated gene 1 (lncRNA TUG1) is still unknown. Thus, this research investigated the effect of metformin and lncRNA TUG1 on AS.
    Methods: First, qRT-PCR was used to detect the expression of lncRNA TUG1 in patients with coronary heart disease (CHD). Then, the correlation between metformin and TUG1 expression in vitro and their effects on proliferation, migration, and autophagy in vascular wall cells were examined. Furthermore, in vivo experiments were performed to verify the anti-AS effect of metformin and TUG1 to provide a new strategy for the prevention and treatment of AS.
    Results: qRT-PCR results suggested that lncRNA TUG1 expression was robustly upregulated in patients with CHD. In vitro experiments indicated that after metformin administration, the expression of lncRNA TUG1 decreased in a time-dependent manner. Metformin and TUG1 knockdown via small interfering RNA both inhibited proliferation and migration while promoted autophagy via the AMPK/mTOR pathway in vascular wall cells. In vivo experiments with a rat AS model further demonstrated that metformin and sh-TUG1 could inhibit the progression of AS.
    Conclusion: Taken together, our data demonstrate that metformin might function to prevent AS by activating the AMPK/mTOR pathway via lncRNA TUG1.

  33. zen February 18, 2020 at 07:04

    Metformin reduces cardiovascular risk in patients with T2DM

    New analysis continues to build the case for metformin and cardiovascular benefits.

    Metformin has been recommended as first-line therapy for type 2 diabetes mellitus (T2DM) by the American Diabetes Association and European Association for the Study of Diabetes. Although metformin has proven benefits in reducing plasma glucose levels and reducing microvascular complications, its effect on cardiovascular complications in patients with T2DM is less clear. One meta-analysis found that following treatment with metformin, there were reduced cardiovascular mortality, all-cause mortality, and cardiovascular events in patients with coronary artery disease. Newer studies are being conducted that are comparing dual anti-glycemic regimens vs. metformin monotherapy. Therefore, if metformin can prove to have cardiovascular benefits, its use will be further supported.

    This meta-analysis was conducted by searching Pubmed, Embase, and CNKI (China National Knowledge Infrastructure) databases for articles published between 1980 to 2019 on the association of cardiovascular risk following metformin treatment in patients with type 2 diabetes mellitus. Metformin users were compared to non-users with T2DM. The Newcastle-Ottawa Scale (NOS) was used to assess the quality of the case-control and cohort studies. The inclusion criteria for each study was the following: 1. evaluate the association of cardiovascular risk following metformin treatment in patients with T2DM; 2. inclusion of sufficient data or the data can be acquired from the manuscript or supplementary materials to calculate ORs and 95% CIs; 3. the publication was a cohort study; 4. the study was published in English. The studies had high levels of heterogeneity between them (I^2 = 96.5% for mortality, and I^2 = 98.5% for incidence). There were no factors that could influence initial heterogeneity.

    In total, 16 studies were included, and 25 comparisons met the inclusion criteria. Total participants included 1,160,254 patients with T2DM and 708,843 patients with T2DM who were taking metformin. The study results found statistical evidence of significantly decreased cardiovascular risk to be associated with metformin treated patients (OR = 0.57, 95% CI = 0.48-0.68), both with the mortality (OR = 0.44, 95% CI = 0.34-0.57) and incidence (OR = 0.73, 95% CI = 0.59-0.90). In the sub-group analysis, metformin proved to have a significantly decreased cardiovascular risk when compared to sulfonylureas (OR = 0.50, 95% CI = 0.38-0.64), both with the mortality (OR = 0.34, 95% CI = 0.17-0.67) and incidence (OR = 0.70, 95% CI = 0.55-0.89).

    This study indicates that treatment with metformin in a person with T2DM is associated with decreased cardiovascular risk, both with the mortality and incidence, and that metformin is more effective than sulfonylureas in reducing risk. Limitations of the study were possible bias, and only studies that reported OR’s and 95% CI’s were included. The large population and time support the results of this study. Future studies can focus on subgroup analysis on which community receives the most significant benefit from metformin.

  34. zen February 18, 2020 at 07:07

    Metformin prolonged the survival of hepatocellular carcinoma (HCC) patients with T2D after the curative treatment of HCC

    Six retrospective cohort studies were included for analysis: Four studies with curative treatment for HCC (618 patients with metformin and 532 patients with other anti-hyperglycemic agents) and two studies with non-curative treatment for HCC (92 patients with metformin and 57 patients with other anti-hyperglycemic agents). Treatment with metformin was associated with significantly longer OS (OR1yr=2.62, 95%CI: 1.76–3.90; OR3yr=3.14, 95%CI: 2.33–4.24; OR5yr=3.31, 95%CI: 2.39–4.59, all P<0.00001) and RFS (OR1yr=2.52, 95%CI: 1.84–3.44; OR3yr=2.87, 95%CI: 2.15–3.84; all P<0.00001; and OR5yr=2.26, 95%CI: 0.94–5.45, P=0.07) rates vs. those of other anti-hyperglycemic agents after curative therapies for HCC. However, both of the two studies reported that following non-curative HCC treatment, there were no significant differences in the OS and PFS rates between the metformin and non-metformin groups (I2>50%).

    Conclusions
    Metformin significantly prolonged the survival of HCC patients with T2D after the curative treatment of HCC. However, the efficacy of metformin needs to be further determined after non-curative therapies for HCC patients with T2D.

  35. zen February 18, 2020 at 07:26

    Metformin may trigger both antitumorigenic and protumorigenic effects

    The evidence collected so far clearly shows that, apart from blocking cancer cell proliferation, metformin may influence tumor progression by modulating TME. This may be achieved indirectly, as metformin-induced metabolic changes in cancer cells reflect on the phenotype of non-malignant cells in a tumor mass. For example, by elevating oxygen concentration in cancer cells, metformin causes downregulation of HIF1-mediated endothelial cell proliferation, and by reducing cancer cell energy charge it promotes PD-L1 degradation in cancer cells, boosting cytotoxic T-cells (Fig. 1). On the other hand, metformin has also shown to directly skew the phenotype of TME populations, such as macrophages and T-cells, by modulating their cytokine production, for example, via the NF-kB pathway.

    We are only starting to understand the complexity of the effects metformin may have on different TME populations, which were reported to depend not only on the cell and tissue type, but also on parameters such as the hypoxic status of a tumor mass or the oncogene driving the progression. Moreover, since metformin has recently shown the optimal antitumorigenic performance in hypoglycaemia [18], and nutrient availability is known to significantly skew the functions of non-malignant cells in a tumor [62], it will be particularly important to evaluate the effect of metformin on TME populations when the treatment is implemented upon fasting conditions.

    As the molecular and biochemical mechanisms underlying the metformin mode of action are emerging, it is clear they will need to be investigated not only in cancer cells, but also in the non-malignant populations of TME. For the time being, it is reasonable to conclude that metformin may trigger both antitumorigenic and protumorigenic effects in the case of endothelial cells and macrophages, suggesting that combinatorial therapeutic approaches should be foreseen in certain cases to increase its efficacy. On the other hand, the current literature generally agrees on the fact that metformin promotes cytotoxic functions of T lymphocytes, underlining the importance of using immunocompetent models and patient-derived data to draw conclusions on the final outcome of metformin treatment in cancer.

  36. zen February 18, 2020 at 07:31

    Metformin Reduces the Senescence of Renal Tubular Epithelial Cells in Diabetic Nephropathy via the MBNL1/miR-130a-3p/STAT3 Pathway

    Senescence of renal tubular epithelial cells plays an important role in diabetic nephropathy, but the mechanism is unknown. Metformin may alleviate diabetic nephropathy by reducing this senescence. This study is aimed at clarifying the effects and mechanism of metformin on the senescence of renal tubular epithelial cells in diabetic nephropathy. We found that metformin reduced the expression of senescence-associated gene P21 in high-glucose-induced (30 mmol/L) renal tubular epithelial cells and decreased the β-galactosidase positive staining rate (decreased 16%, ). Metformin was able to reduce senescence by upregulating the expression of RNA-binding protein MBNL1 and miR-130a-3p and reducing STAT3 expression. MBNL1 prolonged the half-life of miR-130a-3p, and miR-130a-3p could negatively regulate STAT3 by binding to its mRNA 3UTR. In db/db diabetic mice, we found an enhanced senescence level combined with low expression of MBNL1 and miR-130a-3p and high expression of STAT3 compared with db/m control mice during nephropathy development. Meanwhile, metformin (200 mg/kg/day) could increase the expression of MBNL1 and miR-130a-3p and decreased STAT3 expression, thus reducing this senescence in db/db mice. Our results suggest that metformin reduces the senescence of renal tubular epithelial cells in diabetic nephropathy via the MBNL1/miR-130a-3p/STAT3 pathway, which provided new ideas for the therapy of this disease.

  37. zen February 24, 2020 at 09:11

    Combination of metformin and berberine represses the apoptosis of sebocytes in high‐fat diet‐induced diabetic hamsters and an insulin‐treated human cell line

    Obesity and insulin resistance affect metabolic reactions, but their ensuing contributions to macrophage metabolism remain insufficiently understood. We investigated the contributions of berberine and metformin combination to the inhibition of sebocyte apoptosis in high‐fat diet‐induced diabetic hamsters and an insulin‐treated human cell line. Golden hamsters were fed a high‐glucose high‐fat diet and administered a 6‐week treatment with a combination of metformin and two concentrations of berberine (100 or 50 mg·kg−1). Body weights of treated hamsters were remarkably reduced compared with those of controls. Histological examination indicated that berberine repressed liver fat accumulation. Moreover, insulin and glucose concentrations were noticeably decreased by the combination treatments. In glucose tolerance tests, hamsters receiving berberine displayed higher tolerance to glucose, compared with the control group. Sebocytes isolated from high‐fat diet‐induced diabetic hamsters and insulin‐treated human sebocytes displayed elevated cell death rates, which were attenuated by berberine and metformin treatments. Further studies showed that the effects of metformin and berberine on cellular apoptosis were mediated via the Bik pathway. Thus, berberine may effectively decrease circulating glucose levels, ameliorate insulin resistance, reduce body weight, and attenuate sebocyte apoptosis in diabetic hamsters, potentially decreasing vulnerability to the cardiovascular complications of diabetes.

    Significance of the study
    The present data indicate that insulin stimulates changes in the expression levels of cell death‐associated proteins, which participate in sebaceous gland diseases during obesity or diabetes. The anti‐apoptotic effects of BBR and MET in sebaceous gland cells are regulated partially by Bik expression. To the best of our knowledge, this study is the first to suggest cell death counteracting effects of BBR in hamster and human sebocytes as well as to propose BBR as an innovative therapeutic agent for insulin‐related sebaceous gland diseases, including acne.

  38. zen June 7, 2020 at 06:38

    Metformin promotes excretion of blood sugar from the large intestine into the stool.

    Metformin is the most frequently prescribed drug for diabetes in the world. The mechanism by which this drug lowers blood sugar concentration is not clear.
    In a bioimaging study on humans, metformin was found to promote the “excretion of sugar into the stool”.
    This newly discovered action of metformin may explain some of the drug’s biological effects and contribute to the development of new medication for diabetes.
    A research team led by Kobe University Graduate School of Medicine’s Professor OGAWA Wataru (the Division of Diabetes and Endocrinology) and Project Associate Professor NOGAMI Munenobu (the Department of Radiology) has discovered that metformin, the most widely prescribed anti-diabetic drug, causes sugar to be excreted in the stool.

    Metformin has been used for more than 60 years, and is the most frequently prescribed drug for diabetes in the world. Administration of metformin lowers blood sugar levels, but the mechanism behind this effect is not clear. Metformin’s mode of action has thus been actively researched over the world.

    Taking advantage of the new bio-imaging apparatus PET-MRI, the research team revealed that metformin promotes the excretion of blood sugar from the large intestine into the stool. This is a completely new discovery that has never previously been predicted.

    The current finding may explain metformin’s biological actions for which the underlying mechanism is unknown, and contribute to the development of new drugs for diabetes.

    These findings were published on June 3, 2020 in the online edition of Diabetes Care, a medical journal published by the American Diabetes Association.

    Previous studies using PET-CT showed that FDG was accumulated in the intestines of patients taking metformin. It was however assumed that FDG (sugar) was accumulated in the “wall of the intestine” without sufficient evidence because PET-CT cannot separately show the wall and the inside the intestine. In the current study, the new imaging technology PET-MRI allowed the research team to investigate the accumulation in the wall and the inside of the intestine (stool) separately, revealing for the first time that metformin-induced accumulation of sugar occurred exclusively inside the intestine.

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