Journal of In Silico & In Vitro Pharmacology

Keywords

Diabetes mellitus; Pathophysiology; Diagnosis; Management; Novel approaches

Introduction

Diabetes Mellitus (DM) is an endocrinological disorder [1-9] and not a single disorder which is a group of metabolic or heterogeneous affliction resulting from an irregularity in insulin secretions and insulin actions or both. Absence or reduced insulin in turn leads to persistent abnormally high blood sugar and glucose intolerance [10]. It is probably an oldest disease known to man. It is also referred as black-death from the 14th century.

Classification

In this section a description of types are mentioned (Table 1).

Table 1: Classification of diabetis mellitus.

Epidemiology

Type 1 diabetes is the most common type of the diabetes in people with lower age groups. The prevalence of type 1 diabetes is increasing in both prosperous and poverty countries. 85-95% of type 2 diabetes is predominant in developing countries.

In the age group between 20-79 there were about 285 million people were consider to have diabetes worldwide in the survey of 2010, by 2030 about 438 million people is expected to have diabetes in 70% of developing countries. 4 Around 7.1% are non-Hispanic whites, 8.4% are Asian Americans, 11.8% are Hispanics, 12.6% are Non-Hispanic blacks, 16.1% are American Indians and Alaska natives.

Etiology

Type 1 diabetes

Auto immune response: It is expressed as a consequence autoimmune disease [11-15], where the beta cells of pancreas are slowly demolished by the body's own immune system which reduces insulin production. In the development of type 1 diabetes both the environmental and genetic predisposing factors are significant, but the exact correlation is still unknown.

Genetical factors: Investigators have commenced at least 18 genetic positions are designated as IDDM1-IDDM18 (Insulin dependent diabetes mellitus), which are related to type 1 diabetes. The IDDM1 (Insulin dependent diabetes millites) region contains the HLA (Human leukocyte antigen) genes that encode proteins called major histocompatibility complex. In this location immune responses are affected by these genes. Other chromosomes and genes continue to be identified. We can predict the onset of clinical diabetes as much as 3 years by the appearance of ICAs frequently.

Environmental factors: Due to abrupt stress like an infection where the β-cells of pancreas falls below 5-10%. Coxsackie viruses are a family of enteric viruses which attack the intestinal tract leads to the destruction of insulin producing pancreatic β cells.

Type 2 diabetes: This kind of diabetes is also has a powerful genetic predisposition. It is suggesting that twins have 100% approaching rate for diabetes. When compared both type 1 and type 2, type 2 has 5-10% of the risk of a child for developing type 2 and 1-2% for type 1. Due to ongoing development of insulin resistance and β-cell dysfunction leads to inability of pancreas for the production of sufficient insulin to conquer insulin resistance. Nearly 85% of population with type 2 diabetes [16-18] are obese that causes insulin resistance. Particularly there is a high risk at intra-abdominal region rather than subcutaneous. To predict the risk of type 2 Body Mass Index (BMI) is used as a measure.

Pathophysiology

Type 1 diabetes

This type of diabetes is a long lasting autoimmune disease, where there is selective demolition of insulin producing pancreatic β-cells. When there is transplantation of pancreas from twin donars to chronic diabetic twin recipients in the absence of immune suppression is complicated due to elevated heterogenecity of pancreatic lesions of β-cells which are rapidly annihilated, and then there is development of massive insulitis by using infiltrating T lympocytes which measures an amnestic autoimmune reaction.

Type 2 diabetes

As a consequence of insulin resistance, abnormality of insulin production and ongoing pancreatic β-cell failure leads to insulin insensitivity which is a characteristic feature of Type 2 Diabetis Mellitus (Table 2).

Table 2: Data of venous plasma glucose.

Management

Approach considerations

Goals which includes in taking care of patients with diabetes are to eradicate the symptoms or to slow down the developing risk factors includes blood pressure and glycaemia, control of lipids which reduces macro vascular risk and stoppage of smoking and maintaining aspirin therapy.

General management of diabetic patient’s education: Education must need:

• Disease process treatment option.

• Food plan.

• Physical activity plan.

• Awareness of given medication for diabetes.

• Monitoring of blood sugar levels.

• Awareness of acute and chronic issues.

• Psychosocial issues.

• Promoting health strategies.

Medical nutrition therapy: Dietary calculation is based on the body weight in pounds which is multiplied by 10 to maintain a kilo joule/kilocalorie which is essential, plus 30-100% added for physical task. The diet must include 50-55% carbohydrates, 30% fat Fiber (of which not more than 10% should be saturated fatty acids, and 15-20% proteins).

Physical activity: Inactive lifestyle is a strong risk factor for Type 2 diabetes, so exercise is useful in patients.

Type 1 diabetes

Insulins are the first choice to treat type 1 diabetes & they can be administered by injections and insulin pump. Insulins are of three type’s rapid acting, long acting and intermediate acting. Some insulins like regular insulin (HUMULIN 70/30, NOVOLIN 70/30), Insulin isophane (HUMULIN N, NOVOLIN N), and insulin glulisine (APIDRA), insulin lispro (HUMALOG), insulin aspart (NOVOLOG). Some long acting insulins are glargine (LANTUS), detemir (LEVEMIR). Pramlintide (SYMLIN) inj. is a synthetic version of a chemical free hormone which is amylin provided by β cells and some angiotensin receptor blockers; ACE inhibitors, aspirin and cholesterol lowering drugs are used.

Islet grafting was been explored as a therapy for type 1 diabetes in selected patients with inadequate glucose control despite insulin therapy. Artificial pancreas is a closed loop insulin delivery. It is linked with a continous monitor of glucose to insulin pump. The device which delivers correct amount of insulin automatically when the monitor specify the need for the pump.

Type 2 diabetes

Pharmacological therapy: Oral hypoglycaemic agents are useful in the treatment of type 2 DM and insulin also includes in it and those agents include Sulphonylureas, Alpha glucosidase inhibitors, Biguanides and Thiazolidenediones. The main aim is to correct metabolic disorder like resistance to insulin and insufficient insulin secretion. They are given in combination with a suitable diet and changes in lifestyle. They show loss of weight, increase glycaemic control [19] decrease the risk of cardiac problems (Table 3).

Table 3: Pharmacological therapy.

Best choice of drug for type 2 diabetes mellitus: Metformin does not promote weight gain and has advantageous effects on several cardiac risk factors. Accordingly, it is majorly indicated as the optional drug for most patients with type 2 diabetes. In Current guidelines from the American Diabetes Association (ADA), European Association for Study of Diabetes (EASD) and American Association of Clinical Endocrinologist (AACE) or American College of Endocrinology (ACE) recommended early initiation of metformin as first line agent for type 2 diabetes mellitus.

Combinations of antidiabetic drugs with Metformin to treat diabetes: Metformin+Sulphonyl ureas-decrease in HbA1C (0.8–1.5%) than drug alone.

• Metformin+Insulin-improve glycaemic control limit changes in body weight & reduce insulin requirements.

• Metformin+Thiazolinedinediones-decreased concentration of HbA1C & improve insulin sensitivity.

• Metformin+α-glycosidase inhibitors-decrease in HbA1C.

• Metformin+Glifozins are used in combinations now a day to treat type 2 diabetes.

New inventions developed in curingdiabetes: The current class of drugs include GLP-1 mimetics, DPP-4 Inhibitors, SGLT-2 Inhibitors, Amylin mimetics, Dual PPAR agonist.

GLP-1 mimetics (or) agonist: Glucagon like peptide (GLP-1) are mainly used in the treatment of type 2 diabetes which are given by injection to regulate glucose level there by stimulating glucose dependent secretion of insulin. GLP-1 mimetics are powerful in increasing glycaemia control and promote weight reduction by mimicing the mechanism of action of an endogenous stomach and intestinal hormones (Table 4).

Table 4: Drugs used.

DPP-4 inhibitors (Gliptins): It is a new class of oral diabetic drugs which help in weight loss as well as decrease in blood sugar level and they work by an enzyme which destroys a group of gastrointestinal hormones called incretins. DPP-4 inhibitors are prescribed for type 2 diabetes mellitus patients who do not well respond to metformin and sulphonyl ureas.

Amylin analogues or agonist: These are injectables which are used in treating both type 1 & type 2 Diabetes and are administered before meals.They inhibit the release of glucagon while eating, slows food emptying from the stomach. Pramlintide acetate (SYMLIN) is the class of drug available in US which is administered by subcutaneous injections. In the UK it is unapproved by National institute for health and care excellence (NICE) because it can significantly raise the risk of severe hypoglycaemia (Table 5).

Table 5: Different brands used.

SGLT- 2 inhibitors: Selective sodium glucose transporter-2 is used to treat type 2 diabetes mellitus. These agents lower the kidney glucose margin levels resulting in an increased amount of glucose which will be excreted in the urine (Table 6).

Table 6: SGLT-2 inhibitors.

Dual PPAR agonist (Peroxisome Proliferator Activated Receptor): Nuclear receptor PPAR γ agonists are used to reduce hyperglycemia combained with metabolic syndrome & type 2 Diabetes. It was the main target of fibrate drugs which is a class of amphipathic carboxylic acids. Being potent in normalisation of sugar levels in blood, now a days PPAR γ agonist in thiazolidinedione type will have many worst adverse effects like fluid retention, oedema and congestive heart failure (Table 7).

Table 7: Dual ppar agonist.

Removal drugs of type 2 diabetes from the market: In 2006 inhaled insulin was given license for use but it was withdrawn from the market because it has less encouragement. Troglitazone (REZULIN) was not recommended & removed from market due to its potential high hepatotoxicity [20-23]. Phenformin & buformin causes severe lactic acidosis, rosiglitazone (AVANDIA) causes high risk of heart attack & death, but continues to be available in the US, pioglitazone (ACTOS) worsen the heart failure in some patients, due to these reasons these drugs are eliminated from the market.

Conclusion

This review acts as a brief introduction for diabetes which is a growing health care problem affecting individual’s health, health care system and the economy of the whole world. In the hospital the health professionals will meet patients with diabetes. It is the role of them to be properly educated about diabetes and the most current recommended treatments. New drugs are developing to treat diabetes and these important roles have a great impact on the prevention and management of this disease which improves patient’s quality of life.

References

1. Kumar PJ, Clark M (2002) Textbook of Clinical Medicine.Pub: Saunders (London), pp: 1099-1121.
2. Ahmed AM (2002) History of diabetes mellitus. Saudi Med J 23: 373-378.
3. Clinical Pharmacy and Therapeutics (2011) Roger walker and Cate whittlesea (5th edn.).
4. Evaluation of the Characteristics of Safety Withdrawal of Prescription Drugs from Worldwide Pharmaceutical Markets-1960 to 1999. Therapeutic Innovation & Regulatory Science 35: 293-317.
5. Ford ES, Zhao G (2010) Prevalence and correlates of metabolic syndrome based on a hormonius definition among adults in the US. J Diabetes 2: 180-193.
6. Morgan M, Deoraj A, Felty Q, Yoo C, Roy D (2016) Association between Exposure to Estrogenic Endocrine Disruptors-Polychlorinated Biphenyls, Phthalates, and Bisphenol A and Gynecologic Cancers- Cervical, Ovarian, Uterine Cancers. J Carciong Mutagen 7: 275
7. Lyons RA, Benvenuti L (2016) Deposition and Distribution Factors for the Endocrine Disruptor, 4-Nonylphenol, in the Sierra Nevada Mountains, California, USA. J Environ Anal Toxicol 6: 388.
8. Messinaa G, AValenzano A, Moscatelli F, Triggiani AI, Capranica L, et al. (2015) Effects of Emotional Stress on Neuroendocrine and Autonomic Functions in Skydiving. J Psychiatry 18: 280.
9. Utku N, Pape UF (2016) Neuroendocrine Tumors. J Mult Scler 3: 193.
10. Jahan S, Fariduddin M, Sultana N, Aktar Y, Hasan M, et al. (2015) Predictors of Post-Partum Persistence of Glucose Intolerance and Its Association with Cardio-Metabolic Risk Factors in Gestational Diabetes Mellitus. J Diabetes Metab 6: 609.
11. Reuveni D, Gertel-Lapter S, Aricha R, Mittleman M, Fuchs S, et al. (2016) Erythropoietin Ameliorates Experimental Autoimmune Myasthenia Gravis. J Clin Exp Neuroimmunol 1: 108.
12. Zou L, Karim RM, Wang YF (2016) The Research Progress of Long Noncoding RNAs in Autoimmune Diseases. J Neurol Neurophysiol 7: 359.
13. Yanqiang W, Bingjun Z, Zhengqi L, Xueqiang H (2016) Neuromyelitis Optica Spectrum Disorders with Autoimmune Diseases. J Mult Scler (Foster City) 3: 167.
14. Allen HB, Shaver CM, Etzler CA, Joshi SG (2015) Autoimmune Diseases of the Innate and Adaptive Immune System including Atopic Dermatitis, Psoriasis, Chronic Arthritis, Lyme Disease, and Alzheimer’s Disease. Immunochem Immunopathol 1: 112.
15. Zhang Y (2013) Emerging Vitamin D Receptor-Centered Patterns of Genetic Overlap across Some Autoimmune Diseases and Associated Cancers. J Genet Syndr Gene Ther 4: e123.
16. Tiki T (2016) Prevalence and Associated Factors of Depression among Type 2 Diabetes Mellitus Patients on Follow up at Ambo General Hospital, Oromia Regional State, Ethiopia, Institutional Based Cross Sectional Study. J Depress Anxiety 6: 259.
17. Yamada H, Suzuki D, Kakei M, Kusaka I, Ishikawa S (2016) Close Association of Hypoadiponectinemia and Increased Insulin Resistance in Non-Obese Japanese Type 2 Diabetes with Visceral Adiposity. J Metabolic Synd 5: 215.
18. Nealon RS, Sukala WR, Coutts RA, Zhou S (2016) The Effect of 28 Days of Beta-alanine Supplementation on Exercise Capacity and Insulin Sensitivity in Individuals with Type 2 Diabetes Mellitus: A Randomised, Double-blind and Placebo-controlled Pilot Trial. Sports Nutr Ther 2: 111.
19. Asmaa MN, Samira SZ, Aliaa MM, Bassem HG (2016) The Relationship between Hypomagnesaemia and Glycemic Control in Children with Type 1 Diabetes Mellitus. J Diabetes Metab 7: 693.
20. Lai Y, Lai J (2016) Severe Liver Toxicity in a Lung Cancer Patient Treated with Erlotinib: A Case Report and Literature Review. J Cancer Sci Ther 8: 268-273.
21. Vinken M (2012) Connexins: Mediators, Targets and Biomarkers of Liver Toxicity. J Clinic Toxicol 2: e108.
22. Rath R, Tevatia S (2016) Pharmacokinetic Study of Isoniazid and Rifampicin in Patients Suffering from Antitubercular Drugs (ATD) Induced Hepatotoxicity. J Bioequiv Availab 8: 290-293.
23. Nandi S (2016) Adjuvant Phytotherapy against Antitubercular Drug Induced Hepatotoxicity. J Bioanal Biomed 8: e147.