Diabete therapeutic targets

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BlutzuckermessungResearch of mechanisms regulating the concentration of glucose in the blood in the past decade allowed to define new therapeutic targets for the treatment of one of the most common diseases in the industrialized world

Caterina Lucchini

Type II diabetes mellitus is among the most prevalent non-communicable diseases in the world. Metformin, sulfonylureas and insulin are the traditional treatments proposed for the pharmacological control of blood glucose in these patients. Research in the last decade has discovered new targets for type II diabetes, some of whom have reached the clinical application.

Glucagon-like peptide 1

In humans, glucagon-like peptide-1 (GLP-1) is secreted after food intake to reduce the concentration of glucose in the blood by acting on the processes of insulin secretion and glucagon release. GLP-1 is also involved in delaying gastric emptying, suppress the appetite and potentially inhibit apoptosis of β cells of the pancreas. GLP-1 is degraded by the body after two/three minutes of its release into the circulation. In the last years several studies were conducted to try to understand whether and how it could be used in the treatment of patients with diabetes. Biologic GLP-1 has limited application in the therapeutic field because of a very short half-life and the need of parenteral administration. In order to overcome these limitations, several studies were conducted which led to two pharmacological strategies. The first consists in the use of inhibitors of dipeptidyl peptidase 4 (DPP4) with the aim of increase the plasma levels of GLP-1 by preventing the proteolytic digestion. The second approach involves the production of receptor agonists of GLP-1, other molecules structurally similar to GLP-1 able to bind and thus to activate the receptor. Unlike the native molecule, GLP-1 agonists have an increased half-life and can be administered subcutaneously. The pharmaceutical market has launched several molecules of receptor agonists classified as short-term and long-term analogues. The molecules of the two classes differ mainly in the pharmacokinetic characteristics, mechanism of action, efficacy and tolerability of the compounds. The short-life drugs are based on modifications of the peptide GLP-1 to make it resistant to cleavage by DPP4. The modification involves a substitution of amino acids in second and third N-ter positions. These compounds activate the receptor for approximately 6 hours after administration (the peptide still has a limited half-life because is subject to the renal elimination). Lixisenatide and exenatide are two short term analogues. Another approach is based on binding GLP-1 to plasma albumin, which also prevents renal excretion. In the case of the drug liraglutide this binding to albumin is facilitated through the attachment of a fatty acid chain to GLP-1, leaving less than 1% of GLP-1 free in plasma. In the case of drug albiglutide the albumin binding is achieved through a process of fusion of the two molecules. GLP-1 conjugate can be achieved not only thanks to albumin but also promoting a binging with the Fc fragment of an IgG (dulaglutide) or with microspheres that allow a prolonged release over time of GLP-1 (exenatide-LAR). Researchers have also attempted to pair the administration of GLP-1 with that of zinc, which slows the absorption of the peptide from the subcutaneous tissue, but in 2010 this approach has been blocked due to massive side effects. The development of this class of drugs has broadened the range of treatments available for the treatment of type II diabetes, providing the ability to control blood glucose levels without the risk of hypoglycemia, and coupling a reduction in body weight.

High-density lipoprotein (HDL)

High plasma levels of HDL protect against atherosclerotic vascular disease: studies of the past decade, however, have also shown anti-diabetic properties of HDL. Clinical and experimental evidence suggest that HDL can reduce blood glucose level by stimulating the secretion of pancreatic β cells and by activating the AMP-AMPK pathway (which leads to increased uptake of glucose into muscle cells). The effect that the increase in HDL-induced pharmacologically has on the prevention and management of type II diabetes is still poorly known, and studies began recently. Among the various studies, the trial ILLUMINATE (Investigation of Lipid Level Management to Understand ITS Impact in Atherosclerotic Event) is the one that most revealed a possible relationship between the levels of HDL and glucose metabolism. This trial compares the effects of the CETP inhibitor torcetrapib combined with atorvastatin vs atorvastatin alone in cases of major cardiovascular events. In a retrospective analysis of more than 6000 patients with type II diabetes enrolled in the study it was seen that an increase of more than 70% of the levels of HDL leads to a significant improvement in the control of blood glucose levels. The data, although interesting, remain to be confirmed due to the limitations of a retrospective study. Currently there are two ongoing phase III clinical trials of two other CETP inhibitors, anacetrapib and dalcetrapib in which the possible effect of diabetic patients will be tested in a prospective manner.

Sodium-glucose cotransporter 2 (SGLT2)

In patients with type II diabetes mellitus in which the renal re-absorption of glucose is increased, inhibitors of sodium-glucose co-transporter 2 (SGLT2) (expressed in the kidneys) can improve glycemic control and act as potential anti-diabetic drugs. The SGLT family includes twelve members localized in the epithelium of the stomach and in the tubular cells of the kidney. Among the different members, SGLT2 is abundantly expressed in the renal segment S1. Once glucose enters the tubular cells, passes through the basolateral membrane into the interstitium and from there via the cotransporter SGLT2 is released into the blood stream. The idea is thus to increase the glycosuria to reduce glycaemia, by administering inhibitors of SGLT2. Phlorizin is the first natural inhibitor extracted from the root bark of the apple tree. It has been discovered in 1835 but its rapid degradation in the gastrointestinal tract did not allow the use as a drug. Other molecules of interest are dapagliflozin and canagliflozin, both resistant to degradation by gastric enzymes and recently placed on the market. On the contrary sergliflozin and remogliflozin have not been included in clinical trials, perhaps because of their structure which makes them very susceptible to hydrolysis by the enzyme β-glucosidase. Both ipragliflozin and empagliflozin are currently under study and reached the primary endpoint of reducing the levels of HbA in patients with type II diabetes mellitus. On the basis of current knowledge regarding the pharmacokinetics and pharmacodynamics of SGLT2 inhibitors in patients with diabetes, these agents can be used as second-line treatment or in triple therapy. Mono-therapy can be explored as a possibility for young patients whose diagnosis has just been concluded with a mild hyperglycemia and in need for weight control.

Bibliography

  • Meier JJ. GLP-1 receptor agonists for indivudualized treatment of type 2 diabetes mellitus. Nat Rev Endocrinol 2012;8:728-742.
  • Ferrannini E, Solini A. SGLT2 inhibition in diabetes mellitus: rationale and clinical prospects. Nat Rev Endocrinol 2012;8:495-502.
  • Drew BG et al. The emerging role of HDL in glucose metabolism. Nat Rev Endocrinol 2012; 8:237-245.
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