Diabetes mellitus (DM) is a metabolic disorder consists of two major types namely type I and type II. It is characterized by negative nitrogen balance, hyperglycaemia, hyperlipaemia, glycosuria, and sometimes ketonaemia. Insulin, is a hormone that is secreted by groups of cells within the pancreas called islet cells. It facilitates in the absorption of glucose from the blood stream into the inside of the cell when insulin binds to the insulin receptor on the cell.
Type II diabetes occurs when the peripheral tissue cells do not respond to insulin or when the body does not produce a sufficient amount of insulin. In a patient having DM type II the glucose levels will build up in the blood instead of being circulated among the cells supposingly in a person without DM type II.
Type II diabetes is a heterogeneous disorder. Patients may either have maturity-onset diabetes of youth, latent adult-onset autoimmune diabetes, or have it secondary to rare genetic disorders. The disease can be influenced by genetics or environmental factors. Its inheritance can be polygenic in which the onset of the disease can be controlled by the interaction or simultaneous presence of several abnormal genes.
One of the genetic causes is polymorphism or abnormal genes related to insulin resistance and impaired insulin secretion. In the body, the insulin receptor is called tyrosine kinase receptor. The interior portion of insulin receptor with kinase activity will be activated when the hormone insulin binds to the extracellular portion of the receptor. Intracellular events will occur allowing glucose to move into the cell. In a presence of a gene that modifies the insulin receptor resulting in a decreased of it's action, the person will prone to develop insulin resistance. Thus he or she will be more susceptible to DM type II.
The other reason that might contribute to the development of DM type II is sedentary lifestyle and poor diet maintenance. Due to the dietary intake, the insulin secretion is high however it will not be utilized due to inactive lifestyle. The cells are not deprived of energy. Consequently, the body body decreases the amount of insulin receptors since the body is not in need of energy. As the insulin receptors decreases, the cellular response to insulin will follow suit. Cells of other tissues for instance muscle, liver and adipose will also become insulin resistant.
Other factors that will influence insulin sensitivity and insulin secretions are age, obesity cases, gender, ethnicity, physical fitness, smoking and also fat distributions.
Patients with DM type II need to regulate their diet and maintain a healthy lifestyle. On top of that, oral medications are also available for the treatment of DM type II such as Sulfonylureas, Thiazolidinediones, Meglitinides, Alpha-glucosidase inhibitors, GLP-agonists and Insulin. These medications have side effects in which including nausea, vomiting, and diarrhea (GLP-agonists), weight gain and swelling of the feet and ankle (Thiazolidinediones).
Ongoing studies on pharmacogenomics provide better understanding of drug responses that facilitate in the development of antidiabetic drugs with greater efficacy and safety. In the development of anti-diabetic drugs, several molecular targets had been used for instance enzymes and receptors. Since DM type II is also associated with the risk of cardiovascular disease, many pharmacological targets that have been identified need to be studied further for its liability in terms of clinical management.
One of the targets is the enzyme PTEN phosphatase that negatively regulates PI-3 kinase. PI3-kinase or also known as Akt signaling cassette is important in the response to growth factors especially on insulin-like molecules. Misregulation of it is a characteristic feature of many forms of human cancer and also diabetes.
By altering PI3-kinase/Akt signaling, growth will be affected. There are other changes will be observed when photoreceptors mutant for PI-3 kinase antagonist PTEN (tensin and phosphatase homologue deleted on chromosome demonstrated altered morphology in apical light-sensing structures namely rhabdomeres. It is then associated with the selective activation of Akt signaling in the apical region that result from the loss of specific isoform of PTEN that localizes to focal adhesion structures flanking the domain as shown in the diagram
Current study on cultured kidney epithelial cells showed that differential regulation of PI-3 kinase in apical/basolateral domains is fundamental in other types of epithelial cells and by limiting the activity of this cassette is important for normal apical morphology. In both studies it was suggested that the signaling cassette controls shuttling of proteins to and from the apical surface in a process more similar in glucose transporter shuttling.
Your browser may not support display of this image.Another molecular target is the receptors which are peroxisome proliferator-activated receptors (PPAR). There are three subtypes PPAR nuclear fatty acid receptors that have been recognized, namely alpha, beta/delta and gamma. PPAR alpha involves in fatty acid uptake mostly in the heart ad liver. PPAR beta/delta participates in fatty acid oxidation in muscle. PPAR gamma helps in glucose and lipid uptake, stimulate glucose oxidation, reduce free fatty acid level and reorganizing insulin resistance. There are synthetic ligands for PPAR alpha and gamma that have been used in treating patients with DM type II and pre-diabetic insulin resistance which are fibric acid and thiazolidinediones. The usage of PPAR agonists for the case of heart disease in metabolic syndrome and DM type II have its own issues of safety and clinical indication which is still undecided.
An attractive therapeutic target namely β3-adrenoceptor (β3-AR) existed in gastrointestinal tract, prostate, plasma membrane of white and brown adipocytes, human heart, near-term myometrium and brain. This receptor physiological role in adipocytes is recognized in rodents where it is the predominant subtype in both white and brown adipocytes. In obese animals, weight loss without the reduction of food intake was observed in the administration of β3-AR agonist. Anti-diabetic effect in rodent models of DM type II has been exerted by β3-AR agonist.
In chronic treatment, the animals have a reduced case of hyperglycaemia, hyperinsulinaemia, and hyperlipidaemia. Although the mechanism related to anti-diabetic effect of β3-AR agonist has not been fully understood, the effect may be a result of consequence of improved peripheral insulin sensitivity. It was observed that the tissue that was responsible for the effect was brown and white adipose tissue. Also, the effect of anti-diabetic does not occur together with anti-obesity effects of the drugs at dose levels that do not cause weight loss. By chronic administration of β3-AR agonist, insulin-stimulated glucose uptake in rodents was increased.
These observations on the effects of β3-AR created much interest in the development of compounds for the treatment of obesity and DM type II in humans. However, clinical studies had been conducted that gave unsatisfactory results due to the inconsistent distribution of white and brown adipocytes in humans and rodents and poor selectivity of the compounds for the human β3-AR. They study gave an useful insights into the pharmacology of β3-ARs though β3-AR agonist is not very practical for the treatment of diabetes and obesity as therapeutic targets.