Metformin For Diabetes and Related Conditions

This article  here discusses the role of metformin in the treatment of insulin resistance, prediabetes, type 1 and 2 diabetes, metabolic syndrome, obesity, non-alcoholic fatty liver disease, neurodegenerative disorders, dementia, and even cancer.

Metformin - A Plant Derived Medicinal

"Goat's rue, French lilac, Italian fitch, and professor weed are all names for the same plant: Galega officinalis. This perennial herb, 3 feet tall and with purple, blue, or white flowers, was used in folk medicine to treat diabetes starting in the Middle Ages, maybe earlier. Though it gave rise to metformin, one of the most popular diabetes medications in the world, G. officinalis is now widely considered poisonous. In the early 20th century, researchers isolated a compound from G. officinalis called guanidine, which could lower blood glucose levels in animals but was also toxic. Chemists found that they could make the compound more tolerable by bonding two guanidines together, forming a biguanide. Metformin is one such biguanide, first synthesized in 1929 and then clinically developed in the late 1950s by the French physician Jean Sterne, who gave it its first trade name, Glucophage ("glucose eater")." here

Metformin's Mechanisms of Action

"Metformin acts primarily at the liver by reducing glucose output and, secondarily, by augmenting glucose uptake in the peripheral tissues, chiefly muscle." This is important since much of the hyperglycemia (elevated blood glucose) of prediabetes, type 1 and type 2 diabetes is due to this increased glucose production by the liver both by glycogenolysis (breakdown of liver glycogen to glucose) and gluconeogenesis (new glucose production from precursors including amino acids, glycerol, lactic acid, and acetone). Another important contributor to hyperglycemia particularly in insulin resistance and its associated diseases including prediabetes, and type 2 diabetes mellitus (T2DM) is insulin resistance of the muscle cells which reduces the capacity of the muscle cells to take up and utilize glucose. Metformin helps to overcome the insulin resistance in the muscle cell resulting in increased muscle glucose uptake. See this review article for additional details. here 

This paper here further elaborates on this defect in insulin resistance and diabetes: “In the diabetic state, there is inadequate suppression of postprandial glucagon secretion resulting in elevated hepatic [liver] glucose production. Importantly, exogenously administered insulin is unable both to restore normal postprandial insulin concentrations in the portal vein and to suppress glucagon secretion [by the alpha-cells] through a paracrine effect. This results in an abnormally high glucagon-to-insulin ratio that favors the release of hepatic [liver] glucose. These limits of exogenously administered insulin therapy are well documented in individuals with type 1 or type 2 diabetes and are considered to be important contributors to the postprandial hyperglycemic [elevated blood glucose] state characteristic of diabetes.”

The role metformin plays in reducing hepatic (liver) glucose production may be particularly useful in those who choose to use a low carb ketogenic diet as part of their diabetes therapy. This is because the reduced dietary carbohydrate intake requires less insulin, either endogenous or exogenous. When insulin is reduced, particularly in the case of exogenous (injected) insulin, glucagon is increased. The combination of reduced insulin and increased glucagon does stimulate hepatic (liver) glucose production. This may be the only less desirable effect of lower insulin endogenous insulin secretion or exogenous insulin requirements. However, at least metformin is available and safe with relatively few minor side-effects to address the increased hepatic (liver) glucose production due to the elevated glucagon-to-insulin ratio that is inherently present in diabetes and might be made slightly worse by a low carbohydrate ketogenic diet.

Metformin for Insulin Resistance, Glucose Intolerance, and PreDiabetes

In reality, insulin resistance, glucose intolerance, and prediabetes are essentially synonyms or at least describe slightly different degrees of the same phenomenon. Insulin resistance means that the body's tissues become numb (resistant) to the effect of insulin. The exact cause of insulin resistance is still under investigation, but many scientists think that accumulation of fatty acids in the liver (non-alcoholic fatty liver disease), muscle and pancreas is the primary cause of insulin resistance. Insulin resistance, glucose intolerance, and prediabetes are associated with increased and varying risk of developing type 2 diabetes mellitus. "The best evidence for a potential role for metformin in the prevention of type 2 diabetes comes from The Diabetes Prevention Program (DPP) trial. Lifestyle intervention and metformin reduced diabetes incidence by 58% and 31%, respectively, when compared with placebo." here 

Metformin Suppresses Inflammation

"The benefits of metformin on macrovascular complications of diabetes, separate from its conventional hypoglycemic effects, may be partially explained by actions beyond glycemic control, particularly by actions associated with in- flammatory and atherothrombotic processes. Metformin can act as an inhibitor of pro-inflammatory responses through direct inhibition of NF-kB by blocking the PI3K– Akt pathway. This effect may partially explain the apparent clinical reduction of cardiovascular events not fully attributable to metformin’s anti-hyperglycemic action. Metformin has antioxidant properties which are not fully characterized. It reduces reactive oxygen species by inhibiting mitochondrial respiration and decreases advanced glycosylation end product (AGE) indirectly through reduction of hyperglycemia and directly through an insulin-dependent mechanism. Metformin has been proposed to cause a mild and transient inhibition of mitochondrial complex I which decreases ATP levels and activates AMPK-dependent catabolic pathways, increasing lipolysis and ß-oxidation in white adipose tissue and reducing [gluconeogenesis]. The resultant reduction in triglycerides and glucose levels could decrease metylglyoxal production through lipoxidation and glycoxidation, respectively." here 

Metformin - Effects on Lipid Profile

"Metformin is associated with improvements in lipoprotein metabolism, including decreases in LDL-C, fasting and postprandial triglycerides, and free fatty acids." here 

Metformin - Effects on Blood Pressure

"The hypertension [elevated blood pressure] associated with diabetes has an unclear pathogenesis that may involve insulin resistance. Insulin resistance is related to hypertension in both diabetic and non-diabetic individuals and may contribute to hypertension by increasing sympathetic activity, peripheral vascular resistance, renal [kidney] sodium retention, and vascular smooth muscle tone and proliferation.

Data of the effects of metformin on blood pressure are variable, with neutral effects or small decreases in systolic blood pressure and diastolic blood pressure. In the BIGPRO1 trial carried out in upper-body obese non-diabetic subjects with no cardiovascular diseases or contraindications to metformin, blood pressure decreased significantly more in the IFG/IGT [impaired fasting glucose/impaired glucose tolerance] subgroup treated with metformin compared to the placebo group." here  

Metformin and Neuroprotection

"Alzheimer’s disease (AD), one of the most common neurodegenerative diseases, has been termed type 3 diabetes. It is a brain specific form of diabetes characterized by impaired insulin actions and neuronal insulin resistance that leads to excessive generation and accumulation of amyloid oligomers, a key factor in the development of AD. The human brain is characterized by an elevated oxidative metabolism and low antioxidants enzymes, which increases the brain’s vulnerability to oxidative stress. Oxidative stress has been implicated in a variety of neurological diseases, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis disease. Mitochondrial dysfunction has a pivotal role in oxidative stress. In this setting, the permeability transition pore (PTP) acts as a regulator of the apoptotic cascade under stress conditions, triggering the release of apoptotic proteins and subsequent cell death. It was reported that metformin prevents PTP opening and subsequent cell death in various endothelial cell types exposed to high glucose levels. Metformin could interrupt the apoptotic cascade in a model of ectoposide-induced cell death by inhibiting PTP opening and blocking the release of cytochrome-c. These events together with other factors from the mitochondrial intermembrane space are critical processes in the apoptotic cascade." here  

Metformin and Cancer

"Patients with type 2 diabetes have increased risks of various types of cancer, particularly liver, pancreas, endometrium, colon, rectum, breast, and bladder cancer. Cancer mortality is also increased. Many studies showed reduced incidence of different types of cancer in patients as well a reduced cancer-related mortality in patients using metformin (see Table 3 below). The underlying mechanisms of tumorigenesis in T2DM seem to be related to insulin resistance, hyperinsulinemia, elevated levels of IGF-1, and hyperglycemia with the latter driving ATP production in cancer cells through the glycolytic pathway, a mechanism known as the Warburg effect.

Metformin significantly reduces tumorigenesis and cancer cell growth although how it does it is not well understood. It may be due to its effects on insulin reduction and hyperinsulinemia, and consequently on IGF-1 levels, which have mitogenic actions enhancing cellular proliferation,but may also involve specific AMPK- mediated pathways. Patients with type 2 diabetes who are prescribed metformin had a lower risk of cancer compared to patients who did not take it. The reduced risk of cancer and cancer mortality observed in these studies has been consistently in the range of 25% to 30%. An observational cohort study with type 2 diabetics who were new metformin users found a significant decrease in cancer incidence among metformin users (7.3%) compared to controls (11.6%). In an observational study of women with type 2 diabetes, a decreased risk of breast cancer among metformin users was only seen with long-term use. Metformin use is associated with lower cancer-related mortality. A prospective study (median follow-up time of 9.6 years) found that metformin use at baseline was associated with lower cancer-related mortality and that this association appeared to be dose dependent." here  

Metformin: an old but still the best treatment for type 2 diabetes, Rojas and Gomes, Diabetology & Metabolic Syndrome 2013, 5:6

Metformin - Contraindications

The following contraindications for metformin use primarily occur in acutely ill hospitalized patients. "Metformin is contraindicated in patients with diabetic ketoacidosis or diabetic precoma, renal failure or renal dysfunction, and acute conditions which have the potential for altering renal function such as: dehydration, severe infection, shock or intravascular administration of iodinated contrast agents, acute or chronic disease which may cause tissue hypoxia (cardiac or respiratory failure, recent myocardial infarction or shock), hepatic insufficiency, and acute alcohol intoxication in the case of alcoholism and in lactating women. Several reports in literature related an increased risk of lactic acidosis with biguanides, mostly phenformin, with an event rate of 40–64 per 100,000 patients years whereas the reported incidence with metformin is 6.3 per 100,000 patients years." here  In stable outpatients, chronic kidney disease (depending on the stage) is a contraindication to metformin use, but your physician will be familiar with this contraindication. "Metformin may be continued or initiated with an eGFR of 60 mL/min per 1.73 m2 but renal func- tion should be monitored closely (every 3–6 months). The dose of metformin should be reviewed and reduced (e.g. by 50% or to half-maximal dose) in those with an eGFR of 45 mL/min per 1.73 m2, and renal function should be monitored closely (every 3 months). Metformin should not be initiated in patients at this eGFR. The drug should be stopped once eGFR falls to 30 mL/min per 1.73 m2. Frid et al. supports these recommendations through findings that above 30 ml/min/1.73 m2 metformin levels rarely goes above 20 mmol/l, which seems to be a safe level." here  

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