Diabetes mellitus is a metabolic disorder characterized by hyperglycemia, glycosuria, negative nitrogen balance and some time ketonemia causing number of complications like retinopathy, neuropathy and peripheral vascular insufficiencies. Diabetes mellitus is of two types, Insulin Dependent Diabetes Mellitus (IDDM) and Non-Insulin Dependent Diabetes Mellitus (NIDDM). Type 1 (IDDM) is an autoimmune genetic disease resulting from an absolute deficiency of insulin due to destruction of the insulin producing pancreatic b cells. Type 2 (NIDDM) is a multifactorial disease, which is characterized by insulin resistance associated not only with hyperinsulinemia and hyperglycemia but also with atherosclerosis, hypertension and abnormal lipid profile collectively called syndrome X.
Type 2 insulin resistant diabetes accounts for 90-95% of the diagnosed cases of diabetes. The risk of developing type 2 diabetes (NIDDM) increases with age, obesity, family history of diabetes, cardiovascular disease (hypertension, dyslipidaemia) and a lack of physical activity. The chronic metabolic disorder that afflicts 150 million people is set to rise to 300 million by 2025. The worldwide epidemic of type 2 diabetes (NIDDM) has been stimulating the search for new concepts and targets for the treatment of this incurable disease. Most current therapies were developed in the absence of defined molecular targets. The increasing knowledge on the biochemical and cellular alterations occurring in NIDDM has led to development of novel and potentially more effective therapeutic approaches to treat the disease.
CURRENT THERAPEUTIC APPROACHES
It is well established that proper diet, exercise, education and self monitoring make up to almost 75% of the treatment. Treatment of NIDDM is currently performed with a combination of exercise and restriction of calorie-in take or drug therapy. The primary objective of combination therapy is to achieve an additive or synergistic effect. Once a single oral agent has failed to maintain glycemic control, the next step is to add a second agent from a different class.
The most commonly used combination is metformin plus sulfonylurea. The potential side effect of weight gain seen with sulfonylureas may be minimized when used in combination with metformin. Combination rosiglitazone or pioglitazone with sulfonylureas has additive effect on glucose control as well. These combination regimens are associated with significant weight gain. Studies have showed that combination therapy with metformin and TZD improves glycemic control, insulin sensitivity and ¦Â-cell function more effectively than metformin alone. Also effective are combinations of repaglinide or nateglinide with metformin. When combination therapy with two oral agents fails to produce acceptable glycemic control, several options are available e.g. addition of bedtime intermediate-acting insulin with day-time oral agent, multiple insulin injections (most commonly split-mixed regimen), or adding a third oral agent (e.g. addition of TZD to a regimen of sulphonylureas and metformin). The decision to continue a combination regimen should be based on evidence of continuing efficacy, safety, tolerability and this should be re-evaluated at frequent intervals.
NOVEL DRUG DISCOVERY APPROACHES
Pharmaceutical companies are hunting for a blockbuster drug. A number of antidiabetic molecules are in pipeline of drug development process. In this communication instead of marketed drugs or their second generation analogues, we would like to highlight new methods or drug therapies with few examples, which are in advanced stage of development.
NON-INVASIVE INSULIN DELIVERY
At present, diabetics who require insulin to keep their blood sugar levels under tight control (target HbA1c levels of < 7%) have to administer it by injection. The need for daily repeat injections is a major drawback for diabetics. It interferes with daily activities and can lead to patients developing needle phobia. Various alternatives to injectable insulin have been investigated e.g. insulin patches, insulin pumps, oral formulations and inhaled insulin. Among alternative delivery routes, pulmonary delivery of insulin looks the most promising. Results from the phase III clinical trials suggest that Exubera, an inhaled insulin may be as effective as injected insulin and superior to oral agents in lowering blood glucose in patients with diabetes.
STEM CELLS TRANSPLANTS
The technique involves transplanting cells into the livers of diabetes sufferers, putting an end to the need for daily insulin injections. Even with daily injections, some type 1 sufferers are unable to control their blood glucose levels and frequently lapse into potentially fatal diabetic comas. After two injections, the cells kick start the body's insulin production and no more treatment is needed. At present, patients have to take a cocktail of anti-rejection drugs for the rest of their lives to stop their bodies destroying the transplanted cells. Adult stem cells, with the potential to become islet cells, are found in the pancreas. These could be reproduced in the laboratory to provide large numbers of cells. Taken from the patient being treated, they would not be rejected and immuno-suppressants would no longer be needed.
PPAR DUAL/PAN AGONISTS
Simultaneously activating PPAR¦Á/¦Ã dual agonists and PPAR¦Á/¦Ã/¦Ä pan agonist, we can reduce atherogenic triglycerides, raise cardioprotective HDL levels and improve insulin resistance. Thus, they address many of the core features seen in people with metabolic syndrome and may help to reverse the underlying disease process and its adverse clinical sequelae. PPAR dual agonists tesaglitazar, naveglitazar and muraglitazar are under phase 3 clinical study. Our laboratory is also actively involved in synthesizing PPAR dual agonists with additive antioxidant property.
DPP- IV INHIBITORS
Inhibitors of dipeptidyl peptidase IV (DPP IV) are increasingly interest of diabetologists as they may be established as new member of oral antidiabetics, designed to lower the blood glucose and prevent the progressive impairment of glucose metabolism in patients with impaired glucose tolerance and type 2 diabetes. Incretin hormones play important role in normal and pathological blood glucose homeostasis. The role of DPP-IV in the inactivation of glucagons like peptide-I (GLP-I), one of the most important incretin hormone is well known. Thus, optimization of this class of drugs may well contribute the first mechanistic attempt to provide effective therapy of the disease by lowering of glycaemia without increase in body weight. Vildagliptin (LAF 237) is now in phase 3 development for the treatment of type 2 diabetes.
GLP-1
Released from cells in the gut in response to food, GLP-1 (glucagons like peptide-1) binds to receptors on beta cells of the pancreas, thereby stimulating the release of insulin. Since stimulation of insulin secretion occurs only in the presence of elevated blood glucose concentrations and not during periods of normal or low blood-glucose concentrations, the risk of hypoglycaemia should be greatly reduced with GLP-1. Exenatide may enable type 2 diabetics to control their blood-glucose levels while reducing or eliminating the risk of hypoglycaemia and weight gain.
PTP-1B INHIBITORS
Protein tyrosine phosphatase (PTP-1B) is well described component of negative regulation of insulin receptor signaling and enhances insulin sensitivity, improves glucose tolerance and obesity. PTP-1B inhibitors with good pharmacokinetics and pharmacodynamics have been identified and are in different clinical trial stages. ISIS 113715 a potent PTP-1B inhibitor is in phase 2 clinical study.
GSK-3 INHIBITORS
The inhibition of glycogen synthase kinase-3 (GSK-3) offers considerable potential for treatment of diabetes since this lowers plasma glucose levels increases insulin sensitivity and may also be insulinotrophic. Despite the promise of GSK-3 inhibitors in multiple, serious and unmet clinical conditions, in starting only pharma companies Vertex and Chiron were developing GSK-3 inhibitors. But now Novo Nordisk and GlaxoSmithKline are also involved in the field, and the latter has developed of two structurally distinct compounds, SB-216763 and SB-415286, with nanomolar potency.
RESEARCH ON ALTERNATIVE MEDICINES
Plants have been an exemplory source of medicine. Indian plants which are more effective and have been studied in relation to diabetes are: Allium sativum (aloe), Gymnema sylvestre (gurmar booti), Momordica charantia (karela), Ocimum sanctum (tulsi), Pterocarpus marsupium (vijaysaar), Syzigium cumini, Tinospora cordifolia, Trigonella foenum graecum (methi), Eugenia jambolana (jamun) etc. Extensive research is being carried out to find the lead from plants responsible for antidiabetic activity.
Though science has come through a long way of drug discovery and therapeutic approaches for diabetes, yet we are lacking a permanent treatment of diabetes forever. So it is responsibility of scientists to come up with new concepts and targets for treatment of this incurable disease.
- (The authors are with National Institute of Pharmaceutical Education and Research (NIPER), Mohali, Punjab)