Pharmacogenetics Of Diabetes Mellitus Type 2 Biology Essay

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Various environmental factors influence a persons response to medicines, but an individuals genetic makeup is the key to creating personalized drugs with greater efficacy and safety. We aimed to study the efficacy of anti-hyperglycemic drugs in association with DNA variations (SNPs) of calpain10, a diabetes type II susceptibility gene, in a Pakistani population. Data of 518 type II diabetics (age: 35-65) and 187 matched healthy controls was collected. Clinical measurements such as age, gender, BMI and duration of diabetes as well as lipid profile, FBS and serum creatinine were done according to standard protocols. A subset of the subjects aged 35-45 years with duration of diabetes <5 years was selected for a classical pharmacogenetics study. Association of calpain10 SNPs(19, 43, and 63) with anti-hyperglycemic drugs was determined. Statistical analyses were done using epi Info, SPSS and Plink programs.Prescribed antihyperglycemic drugs were independent of diabetes duration. biguanides, sulfonylureas, alpha-glucosidases, thiazolidiones and insulin were used by 35%, 24%, 1%, 4% and 36% of patients respectively. In response, the achieved FBS was <110 (5% +3.3), >110 to <126 (4% +3.1) and >126(18 %+14) for each class of drugs. Association of SNP43 was observed with biguanides (p: 0.006) and insulin ( p: 0.02), while SNP19 was associated with combined use of sulphonylureas and biguanides (P: 0.023). Biguanides and insulin were more efficacious with genotype GG of SNP43, while SNP19 responded better to combination therapy with sulphonylureas and biguanides. This information may help in prescription of the best suited drugs to patients in the future.

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INTRODUCTION :Type II diabetes is a complex and heterogeneous metabolic condition that has reached epidemic proportions, affecting more than 200 million individuals worldwide. Maintenance of near-normal blood glucose levels in patients with type II diabetes has been shown to be associated with a reduced risk of micro-vascular complications as well as a trend toward reduction of macro-vascular events. Treatment with antihyperglycemic agents is initially successful in type II diabetes, but it is often associated with a high secondary failure rate, and the addition of insulin is eventually necessary to restore an acceptable glycemic level for many patients. The molecular reasons for the different responses to anti-diabetic therapy are not clear, and the possibility that genetic factors may predispose to failure to respond adequately to oral anti-diabetic agents remains an open question

Type 2 diabetes mellitus (T2DM) can be treated with various antihyperglycemic drugs.3 T2DM is a result of 1) Insulin resistance , 2) Impaired Insulin Secretion , 3) Increased hepatic glucose production (gluconeogensis), 4) Excessive Glucose absorbtion.1, 2, 3, 8

Insulin secretion is regulated by

1) Blood Glucose, 2) Certain Amino acids , 3) GI hormones e.g. GIP 4, and 4) Other proteins e.g. calpain 10 (part of a family of proteases).5

The process of insulin secretion begins when glucose enters the B-cells of the Islets of Langerhans via GLUT-2 channels6. This glucose is phosphorylated by glucokinase to form glucose-6-phosphate. The pathway of glycolysis takes place & then large amounts ATP are generated via oxidative phosphorylation. This ATP inhibits the potassium ion channels & therefore prevents the leakage of K+ ions out, which in turn increases the membrane potential i.e. makes it more positive.7 Calcium ion channels are sensitive to this alteration in membrane potential, they open up & allow large influx of Ca++ into the B cell.7 The insulin filled vacuoles are exocytose as a result of this Ca++ influx.7 This is a first-phase secretion which consists of pre-formed vacuoles; constant stimulation leads to insulin synthesis, and therefore secretion which constitutes second-phase secretion. The drugs used in management of T2DM may target either one of these stages of insulin secretion. A few have been discussed later in this article.

a)Sulfonylureas are a class of drugs that target impaired insulin secretion in T2DM9; therefore they are also referred to as insulin secretagogues.3

The mechanism of action of sulfonylureas is that these drugs inhibit the ATP-sensitive K+ ion channels, hence acting like glucose in their action. They also reduce serum glucagon levels & increase insulin sensitivity by increasing binding of insulin to its receptors.1

This drug has been available since 1954 and is the first-line oral antihyperglycemic drug but not in obese patients3. It has first, second & third generation agents2 which differ in potency, safety & pharmacokinetics. The 1st generation drugs e.g. chlorpropamide have the longest half-life. 2nd generation drugs e.g. glyburide have greater potency, are safer & have better pharmacokinetics. Whereas, the 3rd generation drugs e.g.glimepiride are used as part of combination drug. All sulfonylureas are given orally and bind strongly with albumin in plasma. They are metabolized in liver & excreted via kidney.

Adverse effects include hypoglycemia1, hyperinsulinemia1, and obesity1 & hypersensitivity reaction in people with sulfa allergies3. In rare conditions dermatological disorders2, GI disturbances2 & CVS complications have also been reported especially with tolbutamide where there is a 2.5 times greater risk2. Drug interactions also takes place with drugs that either displace sulfonylurea from plasma protein e.g. sulfonamides11, or decrease excretion e.g. probenecid, or reduce metabolism in liver e.g. warfarin1, 10. Loss of efficacy with time is overcome by increasing dose.

b) Another way to manage T2DM is by controlling metabolic glucose production, this is the principle of the mode of action for metformin. Metformin (glucophage) is available in Pakistan since 1998. It falls in the same drug class as phenformin. Metformin is considered a first line agent and is significantly useful in people with known insulin resistance

GLUCOPHAGE® (metformin hydrochloride tablets) and GLUCOPHAGE® XR (metformin hydrochloride extended-release tablets) are oral antihyperglycemic drugs used in the management of type 2 diabetes. Metformin hydrochloride (N, N-di methyl imido dicarbon imidic diamide hydrochloride) is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents.

Patients having type 2 diabetes treated with metformin have a significantly lower rate of gluconeogenesis, approximately one-third, when compared to non-medicated type 2 diabetes patients.[12][13] Metformin activates AMP-activated protein kinase (AMPK), a liver enzyme that plays a significant role in the signaling pathways involved in insulin release and activity, and the metabolism of glucose in the body;[14] activation of AMPK is essential for metformin's inhibitory effect on the production of glucose by liver cells.[15] Recent research has further explained metformin's mode of action and has showed that activation of AMPK, by an increase in the amount of cytosolic AMP[17], leads to an increase in the expression of SHP (Small heterodimer partner), which inhibit the expression of the liver gluconeogenic genes PEPCK and Glucose-6-phosphatase.[16] The mechanism by which metformin increase the activity of AMPK remains unsure; however, It has been hypothesized that it does not increase the amount of total AMP or total AMP/ATP; instead increases the amount of cytosolic AMP.

Besides suppressing hepatic glucose production, metformin enhances peripheral glucose uptake by increasing insulin sensitivity, and by promoting improved insulin binding to its receptors [20] thereby decreasing oxidation of fatty acids. AMPK as described above also plays a role, as metformin administration increases AMPK activity in skeletal muscle. [21] AMPK's are known to cause increased GLUT-4 translocation, resulting in an increased insulin-independent glucose uptake. Some metabolic actions of metformin are AMPK independent; a recent study found that "the metabolic actions of metformin in the heart muscle can occur independent of changes in AMPK activity and may be mediated by p38MAPK- and PKC-dependent mechanisms.[22] Metformin also decreases absorption of glucose from the gastrointestinal tract.[19]

Metformin causes a few gastrointestinal side effects including nausea, metallic taste, diarrhea and abdominal discomfort [18]. These can be avoided if the dose is increased slowly, and taking the drug with meals. A small amount of weight loss, possibly due to drop in net caloric intake due to appetite repression and/or a reduction in hyperinsulinemia is suggested. Falling in the same drug class as phenformin, the reported incidence of lactic acidosis is surprisingly low, 0.03 per 1000.

In a US double-blind clinical study of GLUCOPHAGE in patients with type 2 diabetes, a total of 141 patients received GLUCOPHAGE therapy (up to 2550 mg per day) and 145 patients received placebo. The results were as shown below

The occurrence of side effects like nausea, flatulence, and vomiting can further be avoided if contraindications are followed. It is contraindicated in people with a high risk of lactic acidosis: renal serum creatinine levels over 150 μmol/l [25] or hepatic impairment, respiratory insufficiency, severe infection and alcohol abuse. Any pharmacological therapy that alters either of the factors mentioned before is also considered. It should also be used cautiously in elderly especially those above 80 years of age. It is recommended to monitor renal function upon initiation and at least once a year thereafter.

It should be withheld immediately before a person has a procedure with a radio contrast dye, as the dye increases the risk of renal failure and therefore lactic acidosis [26] [27]. It should also be discontinued before surgery and can be continued immediately after if renal function is normal and the patient is stable. It is also recommended to monitor hematological parameters as it alters vitamin B12 absorption [23] [24] and therefore cause anemia. The mechanism of action is unknown but can be reversed by discontinuation of the drug.

Daily dosage should be 500 mg orally twice daily with meals. The dose can be increased every 2 weeks to 2000 mg daily.

c) The third way via which T2DM patients could manage blood glucose levels is by regulating the absorption of glucose from the diet, Alpha-glucosidase inhibitors act via this method. They are one of the five oral anti-hyperglycemic agents used in the treatment of diabetes mellitus type 2, and even pre-diabetes is the alpha glucosidase inhibitors, e.g. ACARBOSE (Precose), MITLIGOL (Glyset), and Voglibose. [1] [30] these drugs are basically saccharides which act as competitive, reversible inhibitors of various enzymes which function in the digestion of complex sugars into glucose after ingestion of a meal.

  There are certain enzymes, such as the membrane-bound alpha glucosidases which is present on the brush border of the cells of the small intestine, which breaks down oligosaccharides, disaccharides and trisaccharides into monosaccharides, especially glucose along with other sugars. The drugs in consideration inhibit those glucosidases, thereby preventing formation of excess glucose from the absorbed complex sugars, and thereby reducing the post-prandial spikes in blood glucose levels. They do not however affect either the production of insulin by the beta-cells of the pancreas, nor do they affect the action of insulin on the cells of the body…as a result, they do not induce hypoglycemia in the individual when used as a monotherapy.

Apart from acting on alpha glucosidases, they even act on pancreatic alpha amylases, which physiologically hydrolyze complex starch to oligosaccharides within the intestinal lumen. Those are then hydrolyzed to glucose and other simpler sugars by the alpha glucosidases. The drugs in question also inhibit sucrase, an enzyme which breaks down sucrose into glucose.

By inhibiting all the above mentioned enzymes, the drug helps in reducing the huge spike in blood glucose levels after a meal. These drugs should be taken at the start of meals, so that they can have an immediate effect on the blood glucose levels, and keep them in control by inhibiting the enzymes and reducing the rate of digestion of complex sugars in the body.

Their dosage should be adjusted according to the meal times, e.g. if a meal is skipped, then they should be skipped too, etc. they are best suited for people who do not have blood glucose levels very high above the baseline levels, who have very high post-meal spikes in blood glucose levels and who have irregular meal schedules. However long term vascular benefits are not shown with their use, only with the use of sulfonylureas and metformin. [31]

The major side effects of α-glucosidase inhibitors are GIT disturbances, such as flatulence, diarrhea, and abdominal cramping, which are thought to be due to the excessive unabsorbed fats present in the gastro-intestinal tract. These are however dose related and tolerance develops over time, so the initial dose should be small, and should then be suitably increased to treat the condition at hand. Patients with inflammatory bowel disease, intestinal obstruction, or colonic ulceration should not use these drugs, as they could aggravate the existing condition. Also, patients should not use metformin (a biguanide) and alpha glucosidases inhibitors concurrently, as these drugs decrease the bioavailability of metformin. [30] [31]

 

*Neither Glyset nor Precose are currently available in generic formulations. [29]

 

**Among the AGIs, Acarbose has also been shown to decrease the risk of progressing to diabetes in subjects with impaired glucose tolerance (IGT). [34] Studies have also suggested that Acarbose could decrease the risk of cardiovascular disease, both in IGT and in diabetes. Furthermore, AGIs are very safe and are nontoxic drugs. [28] [29] [33]

 

***ACARBOSE has been shown to affect heart function positively [33] [34]

Pharmacogenetics is an emerging discipline that involves the search for genetic polymorphisms, commonly observed among the general population, which influence drug response. Candidate genes belong to three main groups:

genes encoding for drug-metabolizing enzymes and/or transporters that influence pharmacokinetics;

genes encoding for targets and/or receptors of drugs that influence pharmacodynamics;

genes encoding for proteins involved in the causal pathway of disease which are able to modify the effects of drugs.

In this work, our current understanding of genetic polymorphisms that may affect responses of patients with type II diabetes to anti-diabetic oral treatment is vital in order to translate pharmacogenetics principles into widespread clinical practice.

METHODS : Data was collected from patients of diabetes type II and healthy controls in order to study the common variations in the intron region of the Calpain10 gene. Information on allelic variants associated to the various classes of oral anti-hyperglycemic drugs used as treatment for diabetes mellitus type II in the general population was gathered.

A subset population was used for Calpain association. The subset population was on any suitable drug such as sulphonylureas, biguanides, insulin and for combined therapy with biguanides and sulphonylureas for more than three months. Fasting blood glucose samples were collected from patients and from controls as well after taking consent and ethical approval from the Aga Khan University.

Genotyping was done after extraction of genomic DNA from white blood cells according to established procedures of our lab. Briefly, PCR of three selected loci SNP 43, 19 and 63 were done using specific primers. This was followed by restriction fragment length and/or ID polymorphism. Each sample was analyzed on agarose gel electrophoresis. Association of allelic variants was done using different statistical programs such as epi Info, SPSS and Plink.

DISCUSSION :Type II diabetes mellitus, which affects 12% of the adults in Pakistani population, can be a devastating disease if not controlled properly. It is a multifactorial disease in which the vast majority of type II diabetes patients have polygenetic forms of the disease that also involve co-morbidities such as obesity, a sedentary life style, advancing age, etc. In addition to diet and exercise regimens, nine different classes of drugs are used worldwide to treat type II diabetes. To date, eleven different loci, apart from calpain10, have been identified as being involved in diabetes. Each locus contributes a small amount of risk, so large cohort studies are needed to identify the alleles at risk .

Drug-genome interaction can occur in number of ways. Genetic variation in the direct molecular target of the drug class is one type of pharmacogenetic interaction. Another class of genes are those involved in drug ADME-absorption, distribution, metabolism and excretion. ADME genes can effect molecular targets independent of the drug. Another group of genes affecting drug actions are those affecting the underlying disease. Drug response is a complex trait, also involving interaction of many genes with environmental conditions. Therefore more integrative approaches, rather than genetic association approaches alone, are needed to effectively describe drug response traits.

Our study identifies SNPs of Calpain genes associated with responses to various drugs. Further studies are required to identify the pathways of mode of action and signaling so as to elucidate the metabolism of Calpain 10 variants, so that the patient can be immediately benefited by knowledge about the polymorphisms in the genes that define the metabolic and signaling pathway associated with a drug and disease. The selection of the right drug for the patient depends on the drug's availability, cost, safety and tolerance. Personalized medicine promises a path for individually optimized treatment choices; however, this requires fine characterization of diseases and drug response. It is still early times for the field of pharmacogenomics which can lead to personalized treatment regimens, thus ensuring administration of the right drug to the right person at the right time.

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