Metformin in the Treatment of Type 2 Diabetes

Diabetes mellitus is an aggregate of metabolic disorders often associated with a chronic hyperglycemic condition resulting from abnormalities in either insulin secretion or insulin action or both. Diabetes type 2 is among the two common forms of diabetes, with the other being type 1. As of 2016, the prevalence of type 2 diabetes was 8.6% in the United States, representing approximately 21 million people (Bullard et al., 2018). Type 1 diabetes is relatively uncommon when compared to type 2 diabetes and had a prevalence of only 0.55% in 2016, representing about 1.3 million people affected in the United States. It is estimated that the prevalence of diabetes will increase to 64% by the year 2025. 

Treatment of diabetes type 2 ranges from lifestyle changes combined with insulin therapy. Common drugs used in the treatment of diabetes type 2 include metformin, sulfonylureas, meglitinides, thiazolidinediones, and possibly insulin. Of all these drugs, metformin (Glucophage) is commonly used, and the paper will discuss its action in the management of diabetes type 2. 

Pathophysiology of Type 2 Diabetes Mellitus 

Under normal physiological conditions, plasma glucose concentration is maintained within a narrow range via a tightly regulated dynamic interaction between insulin tissue sensitivity and insulin secretion. When it comes to type 2 diabetes, these two mechanisms are impaired and consequently lead to impaired insulin secretion through the dysfunction of pancreatic β-cell and impaired insulin action through insulin resistance. 

Type 2 diabetes mellitus has a higher association with genetic composition as compared to type 1 (Ozougwu et al., 2013). Type 2 diabetes is much common in some ethnic groups compared to others. For instance, the condition affects about 2% of Caucasians and approaches 50% in South India. This affirms that genetic factors are more critical when compared to environmental factors in the prevalence of type 2 diabetes. 

Ozougwu et al. (2013) note that when it comes to the diabetes of the young, i.e., people aged below 25 years, the mode of inheritance is unclear. However, studies have indicated that it may result from mutations in the glucokinase gene on chromosome 7p. Glucokinase is a primary enzyme in the metabolism of glucose in the beta cells and the liver. Pancreatic abnormalities in the islet secretory cells in type 2 diabetes are usually observed in the beta, alpha, and delta cells of the islets. These defects lead to impaired insulin secretion leading to a decrease in basal secretion, decreased first and second phases of insulin response, and glucose insensitivity. 

In detail, the number of beta cells is decreased by half, and the alpha cells increase, leading to hyperglucagonemia. The pancreatic islets exhibit hyalinization and amyloid deposition, containing either islet amyloid polypeptide or amylin. The amylin is released together with the insulin, but its role in the pathogenesis of type 2 diabetes is not well now. It is, however, thought to result in insulin resistance. Insulin resistance is inadequate to cause extreme glucose resistance, but in cases of obesity, it plays a significant role. Insulin resistance by itself may be a secondary event in type 2 diabetes since it is also found in non-obese patients. However, insulin secretion may be the main event presenting as reduced insulin production. 

In summary, type 2 diabetes results from both genetic and environmental factors. However, genetic factors play a more significant role when compared to environmental factors. Type 2 diabetes is more prevalent in some ethnic groups compared to others, with the highest prevalence being 50% among South Indians and the lowest at 2% among Caucasians. Impairment of the beta cells of the pancreas leads to reduced insulin production and increased glucagon secretion, which leads to hyperglucagonemia in diabetic patients. The impairment also leads to the production of amylin, which is thought to bring about insulin resistance. All of these factors play a significant role in the development of type 2 diabetes. 

Metformin Drug Response in the Treatment of Type 2 Diabetes 

Metformin is the most prescribed drug for the treatment of individuals with type 2 diabetes since it is relatively cheap and has beneficial effects on blood glucose (Wu et al., 2017). Metformin acts primarily in the liver by reducing glucose output and augmenting glucose uptake in the peripheral tissues. Rojas and Gomes (2013) note that the effects of metformin are aided by the activation of liver kinase B1, which in turn regulates adenosine monophosphatase protein kinase. Additionally, the inhibition of mitochondrial respiration also contributes to reduced gluconeogenesis, which in turn mediates the action of metformin in the body. 

Metformin accumulates in the mitochondria up to 1000 times higher than in the extracellular medium since it carries positive charges, which aid in its absorption. Once in the mitochondria, metformin inhibits Complex 1 of the respiratory chain, which suppresses ATP production (Rena, Hardie and Pearson, 2017). Additionally, inhibition of mitochondrial function activates the cellular energy sensor AMP-activated protein kinase. It is activated by an increase in AMP: ATP and ADP: ATP ratios, which indicate a compromise in the cellular energy balance. The AMP-activated protein kinase acts to restore energy homeostasis by increasing catabolic pathways generating ATP while switching off processes consuming energy. 

Metformin also acts on the intestines by increasing anaerobic glucose metabolism in enterocytes, leading to reduced glucose absorption and increased lactate delivery to the liver. Wu et al. (2017) conducted a comprehensive study on the action of metformin on the gut. The findings of the study indicate that metformin alters the gut microbiota, which in turn mediates the antidiabetic effects of the drug. The drug affects pathways with a standard biological function, and many of the metformin regulated genes encode metalloproteins or metal transporters. This effect improves glucose tolerance in an individual on metformin drug therapy. 

Recently, interests on the effects of metformin on genes have emerged. Studies have reported that metformin has some associative effects on chromosome 11 involving seven genes, one of which is the ataxia-telangiectasia mutated gene. Recessive mutations of this gene cause ataxia-telangiectasia, a condition often associated with fatty liver, insulin resistance, and diabetes (Zhou et al., 2011). Additionally, metformin affects the expression of GLUT2 in the liver and other tissues. Initially, these genes were not thought to be involved in the mechanism of metformin; however, additional studies are needed to understand this relationship better (Florez, 2017). 

Bringing the points home, metformin is a complex drug with multiple sites of action and several molecular mechanisms. Metformin acts directly or indirectly on the hepatocytes to lower glucose production and acts on the gut to increase glucose utilization. At the molecular level, metformin inhibits mitochondrial activity resulting in the activation of AMPK, which improves insulin sensitivity. The effects on the genes are not well understood, thus, necessitating the need for more studies in that particular area. 

Drug Reactions and Side Effects of Metformin 

Metformin interacts with at least 74 other different drugs. These interactions are, however, mild and lack serious effects. Dangerous drug interactions exist between metformin and ethanol, loversol, and iodinated contrast media. Metformin should be halted at least 48 hours before the administration of iodinated contrast media, lest acute renal failure may result (Glucophage, 2003). 

Shenoy (2006) notes that metformin can, at times, cause lactic acidosis in patients with acute renal failure. This condition is potentiated by ethanol on patients who consume much ethanol when using metformin. For patients on cimetidine, furosemide, or nifedipine, monitoring should be done once metformin is introduced as the drugs above tend to increase the concentration of metformin, leading to potential toxicity. 

Just like any other drug, metformin has its side effects. Common side effects reported by clients using the drug include physical weakness, diarrhea, flatulence, myalgia, nausea, vomiting, chest discomfort, dizziness, constipation, and heartburn. It is, however, essential to note that the occurrence of the above side effects varies from person to person. Gastrointestinal intolerance frequently occurs as abdominal pain, flatulence, and diarrhea. These effects subside once the dose is reduced; however, about 5% of patients fail to tolerate even the lowest dose. 

Additionally, about 10-30% of patients on metformin have impaired vitamin B12 absorption and utilization due to calcium-dependent ileal membrane antagonism, an outcome that can be overturned with supplemental calcium (Rojas and Gomes, 2013). It is important to note that this vitamin B12 deficiency is rarely associated with megaloblastic anemia (Rojas and Gomes, 2013). 

Pharmacokinetics of Metformin 

Metformin is a hydrophilic base that exists at physiological pH as the cationic species. It is not metabolized and is excreted unchanged in the urine with a half-life of about 5 hours (Graham et al., 2011). The drug is widely distributed in the body tissues, including the liver and kidney. Intestinal absorption is mediated by the plasma membrane monoamine transporter, which is expressed on the luminal side of the enterocytes. 

The hepatic uptake of metformin is mediated primarily by the OCT1 (SLC22A1) and to some extent, OCT3 (SLC22A3). Both transporters are expressed on the basolateral membrane of hepatocytes. As metformin is not metabolized in the liver, drug-drug interactions through inhibition of OCTs and MATEs are clinically appropriate (Nies et al., 2011). Genetic polymorphisms in these transporter genes impact metformin pharmacokinetics directly (Nies et al., 2011). 

The uptake of metformin from the circulation into the renal cells is facilitated by OCT2 (SLC22A2), which is expressed mainly in the basolateral membrane of the renal tubules. Renal excretion is mediated via MATE1 (SLC47A1) and MATE2-K (SLC47A2) (Gong et al., 2012). 

Cephalexin and Metformin Interactions 

Jayasagar et al. (2002) note that when metformin is consumed together with cephalexin, the effects of metformin are amplified. In their randomized control trial, the authors noted that individuals who consumed metformin together with cephalexin at equal doses, renal clearance of metformin were significantly reduced up to 14%. Furthermore, the authors observed that renal metformin clearance was reduced in a time-dependent manner in the presence of cephalexin, indicating that cephalexin inhibits renal tubular secretion of metformin, leading to higher serum concentrations. 

Consequently, using cephalexin together with metformin may increase the effects of metformin on its action in the body. This means that the drug-drug interactions of these two therapies may result in deficient blood sugar levels than initially desired. When combining both drugs, care should be taken to avoid overdose effects of metformin on the client. Additionally, in cases where cephalexin cannot be entirely avoided, reducing the metformin dose in combination with cephalexin can achieve desired effects on blood sugar levels when compared to a higher dose of metformin taken alone. 

Pharmacogenomics of Metformin 

Response to metformin varies significantly among different individuals, attributing the role of genetic factors. Understanding these underlying factors is one step closer to tailoring individualized treatment on patients with type 2 diabetes. The OCT1 gene involved in metformin absorption in the liver is highly polymorphic. This gene is essential in mediating the glucose-lowering effects of metformin. Shu et al. (2007) conducted a study on healthy individuals with at least one of four reduced functions of the OCT1 gene. The findings indicated that these individuals experienced reduced effects of metformin in improving glucose tolerance. 

Additionally, a follow-up study on the same group established that people with reduced function alleles had a higher area under the curve of metformin plasma concentration over time. When the reduced function variants were analyzed as a group, renal clearance of metformin increased directly proportionally to the increasing number of hypofunctioning alleles. 

The renal transporter OCT2 has less functional variables compared with OCT1. Genetic analysis identified eight non-synonymous variants in about 250 ethnically diverse samples. Leabman et al. (2002) note that non-synonymous variants had significantly more skewed allele numbers compared to synonymous variants, suggesting selection pressure against functional OCT2 variation. The effects of variation in OCT2 in respect to metformin have been studied to a lesser extent than OCT1. This, therefore, necessitates the need for more studies in this area of metformin pharmacogenetics. 

Improving Communication between Interprofessional Team Members 

Healthcare institutions are faced with the challenge of ensuring patient safety at all times. While physical barriers such as the procedural ordering of drugs have been put in place to ensure this, gaps are still present and can result in adverse effects on the patient’s wellbeing. Drug-drug interactions are common accidents that occur in all health care facilities, regardless of their size. This kind of interaction can be reduced by involving all professional cadres in the management of patients. This ensures that each professional brings a piece of relevant information that will ultimately prevent harm on the patient’s side. 

For instance, a pharmacist is conversant with drug-drug interactions but falls short when it comes to drug-nutrient interactions. In such a case, involving a nutritionist will bring in a different perspective that the pharmacist could not see. On top of that, a nurse is in charge of the patient’s care hands-on. The nurse will, therefore, report minor observations that other cadres could not see, especially when it comes to a combination of different drugs, such as cephalexin and metformin, as initially discussed. 

Improving such communication begins with having a team of competent professionals. This ensures that everyone involved has something to bring to the table when required to. Additionally, having a quality management system such as ISO 9000 adopted in the facility will ensure things are done procedurally, thus improving the quality of service and upholding patient safety. Lastly, having frequent random audits across various departments within the hospital will ensure that all healthcare providers offer effective and safe services that promote the wellbeing of the patient. 

Application of Study in a Clinical Setting 

While metformin is the preferred first line of treatment in type 2 diabetes, it does not necessarily mean it lacks some key caveats. From the paper, metformin has both beneficial and harmful effects when consumed in the body. Common errors that seem to arise from the use of metformin include drug-drug interactions. As noted, metformin combined with iodinated mediums can lead to acute renal failure. Overlooking this interaction can significantly harm the patient as they will end up being treated for a condition they did not have before. 

Consequently, when metformin is taken with cephalexin at equal doses, the effects of metformin are significantly amplified up to 14%. This means that if the metformin dose is not adjusted accordingly when taken with cephalexin, the patient will exhibit overdose like symptoms of metformin. These overdose symptoms may also increase the chances of experiencing adverse side effects such as lactic acidosis, which can aggravate acute renal failure. 

Also, as initially discussed in the paper, metformin affects different people in different ways, with some having a higher tolerance for the drug than others. This brings about the pharmacogenomic effects of the drug, necessitating the need for an individualized approach when managing a patient diagnosed with type 2 diabetes using metformin. This means that no one dosage fits all, even if the elevated blood sugars are within similar ranges. This individualized approach ensures the patient’s response to the particular drug is significantly improved, coupled with reduced adversities leading to a better quality of life. 

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