Dear Rajaram.

It's DPP4 inhibitors. Dipeptidyl peptidase-4 (DPP4), also known as adenosine deaminase complexing protein 2 or CD26 (cluster of differentiation 26). DPP4 plays a major role in glucose metabolism. It is responsible for the degradation of incretins such as GLP-1. In the serum in various neoplasms DPP4 inhibitors have emerged as a new class of oral antidiabetic agents. DPP-4 inhibition prevents the inactivation of glucagon-like peptide 1 (GLP-1), which increases levels of active GLP-1. This increases insulin secretion and reduces glucagon secretion, thereby lowering glucose levels. Several DPP-4 inhibitors are in clinical development. The different DPP-4 inhibitors are distinctive in their metabolism (saxagliptin and vildagliptin are metabolized in the liver and sitagliptin is not) and their excretion.

For more detail experimental work you can access my paper with following link;

http://www.sciencedirect.com/science/article/pii/S0944711312003194

Dear Rajaram,

Following targets are new such as Protein tyrosine phosphatase-1B (PTP-1B), Glucagon like peptide receptors agonists, & Dipeptidyl peptidase-4 (DPP4).

The latest target are Sodium-Glucose Co-transporter 2 (SGLT2) inhibitors that inhibit the reabsorption of glucose in the kidney, thereby increasing glucose excretion and lowering blood glucose. DPP4 inhibitors are old now.

Sodium-dependent glucose co-transporters are now recognized as potential targets for treating hyperglycemia in Type II diabetes. There are 2 types of these transporters, SGLT-1 are found on the intestinal mucosa, and SGLT-2 are located in the proximal tubules of the nephron. SGLT-2 play a role in the reabsorption of glucose filtered by the glomeruli, inhibition leads, blocking glucose reabsorption and reducing blood glucose leves. In hyperglycemia they become saturated and glucose will appear in urine. Several selective SGLT-2 inhibitors are now being evaluated as antidiabetic drugs. Canaglifozin has been approved by the FDA in 2013. Other drugs belonging to this group are dapaglifozin, tologlifozin and ipraglifozin. These drugs have the advantages of being taken orally, having a low risk for hypoglycemia and weight loss. Multicentre clinical studies are needed to prove their cardiovascular safety, whether they can be used as adjunt to othe antidiabetic drugs, and whether they can be used in renal or hepatic impairments.

Can I use multitargets?

Yes, you can aim for Multiple targets to control glycemia. However, need to consider the cost of multiple agents and interactions. Metformin, is the single agent that acts through 4 different targets, although the main mechanism is reduction in hepatic glucose production, so if tolerated and not contraindicated, this agent should be one of the agents.

In India the herbal and polyherbal medicines are existing more than 5,000 years to cure various diseases. When we talk about diabetes it is a metabolic disorder and affects whole parts of the body. The specific targeted drugs can not help in this case. Can we use those herbal or polyherbal medicines to cure diabetes?

Already few drugs are available in market which have different mechanism of actions such as Metformin + Glibenclamide, Metformin + Glimepiride, Metformin + Gliclazide, etc.all this formulations are multiple targets mechanism.

Rajaram, most important is lifestyle modification in Type 2 diabetes, especially proper diet, weight reduction (if overweight or obese) and regular physical exercise programs. Yes, there are multiple allopathic medications that act through different mechanisms to control glycemia in diabetics. The only medication so far to shown overall CV benefit is metformin. The DPP4-inhibitors are undergoing this test at present to see if they improve CV risk profile or not. Newer Kids on the block are not fully assessed in this regard. Concerning herbals and polyherbals, I do not have the knowledge to answer this question and herbalist may be able to answer this better. Keeping in mind, that most of herbal medications have not gone through a rigurous testong as there allopathic counterdrugs do and often with herbal agents there are testimonials and based on these testimonials it is hard to make a sound and evidence based recommendation. However, there was a study published few years ago, that showed that the "orange-peel" has chemical compounds that have similar effect as DPP4 inhibitors and I beleive some company in India was going to see if they could utilize this simple resource effectively as an alternative to current expensive DPP4 inhibitors.

Thank you sir

Dear Rajaram,

Herbal formulations are quite effective particularly in T2DM. For more detail you can download our article from below given link:

http://www.omicsonline.org/scientific-reports/1948-593X-SR-688.pdf

Of course many herbs contain active constituents that make them effective for the treatment of diabetes. Generally speaking, many of the very efficient drugs are from plant origin. The problem is that there is a misconception that because they are natural they will be safe. This is not true. In order to use plants or herbs for treatment, they must be subjected to intensive studies to prove their safety, the exact amount needed, how they will be prepared, the exact dose and the possible adverse effects. Besides, there must studies on the outcome of their use in combination with conventional antidiabetic drugs; they may be antagonistic or synergistic. In both cases , dose adjustement will be necessary. Moreover, when herbs are used, they are usually in the form of a mixture containing different plants with a lot of active constituents.

Dear Samira Saleh,

I agree that the herbal medicines require scientific validation (bioactivity and toxicity). But in my point of view

The following standard protocol has been carried out for many centuries

1. Selection of the medicinal plants (active part, Age and month of the collection)

2. The preparation has standard protocols

3. The treatment durations and dosage

4. Multitargeted approaches mostly used in herbal or polyherbal medications.

5. Still the same type of treatment in process (There is no adverse effect)

Moreover many of the reported medicinal plants are consumed as food daily.

Thank you

Dear Rajaram K

I totally agree with you. If all the points you mentioned are solved and standardized, and if there are specialized herbalists that prescribe these formulations, then they are safe. I have visited New Delhi and noticed multiple herbal medicines. However, this is not the case in every country. We don't have herbalists here in Egypt. Moreover, there is no evidence-based clinical studies that support efficacy and safety on such issues.

I thank you for the clarification.

Thank you

Type 2 Diabetes Mellitus is a complex disorder with metabolic & vascular complications . Both microvascular & macrovascular complications are responsible for morbidity & mortality . The mechanism of Type 2 Diabetes Mellitus is Insulin deficiency & Insulin resistance . Insulin deficiency leads to microvascular complications & Insulin resistance leads to macrovascular complications . The benefit in prevention of complications of DM is also due to treatment of DM & also due to treatment of hypertension & Lipid disorders . Therefore , the development of newer molecules might lead to better control of DM , but they should also make an impact on morbidity & mortality . This would need long term studies to prove their benefits . Life style modifications , oral hypoglycemic agents & Insulin have made an impact on DM control & addition of hypertension & lipid control have improved survival . The end point targets in management of DM should be well defined to evaluate the newer molecules for both allopathic & herbal medicines .

SGLT2 inhibitors now started approval from USFDA. Cangliflozin, and very soon Dapagliflozin will be in the market from boerhinger.

SGLT2 target is the latest one

Most therapeutic targets for diabetes are associated with its complications. The most troubling complications associated with diabetes are the probably the vascular disorders.

New treatments for vascular conditions include stem cell therapies.

Dopamine agonists is the new probable class in oral antidiabetic agents. Bromocriptine is the drug which is approved for use in T2DM. IT acts by central mechanisms by reducing insulin resistance.

SGLT 2 inhibitors are other new agents, they act by increasing excretion of glucose from body.

Other targets are 11beta-hydroxysteroid dehydrogenase type 1 inhibitors, G protein–coupled receptor 119 agonists, Protein tyrosine phosphatase 1B inhibitors

for detailed account on newer agents in diabetes drug therapy u may refer the article http://www.genesisjournals.org/data/Articles/Pharmagene/volume1/25.pdf

That's an interesting review article

The Diabetes Drug Discovery and Beyond meeting will not only cover progress on promising pre-clinical and early clinical phase diabetes drug candidates. But this year, we will also highlight emerging therapeutic targets that probe how the underlying defects in metabolic diseases are connected. Some presentations will cover obesity, other metabolic disorders and cardiovascular disease in the context of diabetes and energy homeostasis.

Diabetes mellitus and its associated complications are major health problems in the developed world. Diabetes mellitus is associated with an increased risk of cardiovascular disease (CVD) even in the presence of intensive glycemic control. Indeed, 75% of diabetic patients will die of CVD. Patients with type 1 and type 2 diabetes mellitus have an increased risk for the 3 major types of macrovascular disease (coronary heart disease, peripheral vascular disease, and stroke).1 A striking feature of diabetic cardiovascular complications is the appearance of accelerated atherosclerosis, which anatomically resembles atherosclerosis in nondiabetic individuals but is more extensive and occurs at an earlier age. Substantial clinical and experimental evidence suggests that endothelial dysfunction is a crucial early step in the development of atherosclerosis. Evidence also suggests that it participates in plaque progression and the clinical emergence of cardiovascular events. Endothelial dysfunction is characterized by impaired endothelium-dependent vasodilation and “endothelial activation,” which is associated with a proinflammatory, proliferative, and procoagulatory milieu that promotes initiation and complications of atherogenesis.2 Endothelial dysfunction associated with insulin resistance appears to precede the development of overt hyperglycemia in patients with type 2 diabetes mellitus.3 Therefore, endothelial dysfunction may be a critical early target for the prevention of atherosclerosis and CVD in patients with diabetes mellitus or insulin resistance.2

SGLT inhibitors: a novel target for diabetes.

Abhinav Kanwal, Sanjay K Banerjee

Division of Pharmacology, Indian Institute of Chemical Technology, Hyderabad-500607, India.

Pharmaceutical patent analyst 01/2013; 2(1):77-91. DOI:10.4155/ppa.12.78

Source: PubMed

Edit

ABSTRACT Inhibiting sodium-glucose co-transporters (SGLT1/SGLT2), which have a key role in the absorption of glucose in the kidney and/or GI tract has been proposed as a novel therapeutic strategy for diabetes. Thus, screening and patenting of chemical compounds for SGLT1/SGLT2 gets more importance in the development of new drugs in diabetes. Several companies are developing SGLT inhibitors, some of which are now in various stages of clinical development. Some molecules in the pipeline, including dapagliflozin, canagliflozin, ASP1941, BI10773, LX4211, RG7201 and TS071, are at various stages of drug development. This patent review presents the overall progress carried out in the development of SGLT inhibitors over the last decade with the active participation of various pharmaceutical companies. This class of drug is anticipated to have a large impact on diabetes field and predicting to attain a blockbuster status.

Thank you

dear Rajaram The incidence of type 2 diabetes and associated serious complications continues to grow rapidly. Although several classes of anti-diabetic drugs are available, achieving and maintaining long-term glycaemic control is often challenging, and many current agents have treatment-limiting side effects. So, a significant need for novel anti-diabetic drugs remains.

Furthermore, there is a growing appreciation of the potential therapeutic value of agents that could positively affect multiple cardio-metabolic risk factors. This special focus highlights some of the most promising therapeutic targets and investigational drugs for type 2 diabetes and its complications, as well as discussing strategies to tackle the challenges in fulfilling their potential.

Numerous SGLT-inhibitors have been developed by the pharmaceutical companies however importante aspects of their true safety need more studies.