Treatments for Diabetes Mellitus II

1. Treatments for Diabetes Mellitus II Brittany Garrett

2. Type II diabetes In 2001, 7.9% of the American population was living with diabetes mellitus; this population is expected to almost double by the year 2010. Diabetes mellitus is the result of metabolic dysfunction. Onset starts with the overproduction of unutilized glucose that leads to abnormal insulin resistance and impaired insulin secretion. Islet B-cells that produce and secrete insulin eventually cannot keep up with the need for insulin and become dysfunctional resulting in their degradation.

3. Effects of Diabetes Mellitus

4. Effects of Diabetes Mellitus • Usually the first symptom is inception of hyperglycemia caused by a deficiency in insulin secretion. • This is often in conjunction with effects such as; dyslipidemia, abnormalities in carbohydrates, fat, and protein metabolism, resulting in weight gain, and an elevation in blood pressure. • Over time these dysfunctions can cause irreversible damage to; kidneys, eyes, heart, blood vessels, and nerves. • This damage can lead to blindness, vascular clotting, myocardial infarction, stroke, amputation and even death.

5. Insulin Analogues • When developing an insulin analogue, researcher seek to alleviate side effects of past therapies such as nocturnal hypoglycemia and metabolic control. • At the present there are two short-acting analogues on the market, insulin aspart and insulin lispro.

6. Structure of Analogues compared to Structure of Insulin

7. Long acting Analogues • Unlike short acting analogues, glargine has a constant action of up to 24 hours • Structural changes make the analogue less soluble at a physiological PH, thus mimicking basal insulin release

8. Side effects of insulin analogues Thus far, no negative side effects have been found in human cases of analogue usage. Side effects have been shown in animal studies with both long and short term action analogues revealing an elevated risk of mammary gland tumors. Research on these particular analogues was abandoned and no other analogues have shown similar side effects in humans.

9. Peroxisome Proliferator-activated Receptors (PPARS) • Belong to the steroid/thyroid retinoid receptor superfamily, and therefore, are expected to effect metabolic functions involved in diabetes. • They form active heterodimers with the 9-cis-retinoic acid receptor allowing them to regulate target genes in DNA. • Two important subtypes PPAR alpha and PPAR gamma are involved in regulating lipid metabolism and energy balance.

10. PPAR alpha and PPAR gamma • PPAR alphas are lipoprotein regulators expressed in catabolic tissues such as the liver, kidney, heart and skeletal muscles • PPAR gamma is primarily expressed in adipose tissue, however, it is occasionally active in skeletal muscle, kidney, and intestine • PPAR gamma’s activation is known to be accompanied with the modulation of genes involved in fat derived hormones that effect body metabolism.

11. PPAR • Differences between the PPAR alpha and gamma binding sites lie within the exchange of the Tyrosine in PPAR alpha and substitution for a histadine in PPAR gamma. • Ligands with bulky head groups such as TZDs have shown more affinity to the PPAR alphas because of interaction with the larger tyrosine group resulting in a disruption of the hydrogen bonding with the other amino acids.

12. Dual agonists • Researchers hypothesised that a dual agonist for these receptors, can potential exhibit the positive effects of both. • KRP-297 and Tesaglitazar are dual agonists that are still in clinical trials . • Studies of these agonists are fairly recent and therefore, no dual agonist are on the market at this time, but they give strong possibilities for the treatment of diabetes in the future

13. TZDs • Patent testing has shown that oral TZD treatment enhances the effects of insulin on glucose. • The correct mechanism for the action of TZD is still not know but drugs such as rosiglitazone and pioglitazone are on the market and shown effective in patients. • Like any drug these agents have side effects such as weight gain and an increase in subcutaneous fat mass. • For most patients, weight increase is minimal but sometimes the weight gain is accompanied with an increase in plasma volume resulting in edema

14. GLP-1 • GLP-1 is a hormone released from L- cells in the intestine as a reaction to meal ingestion. This release causes the inhibition of gastric motility and gastric acid secretions. GLP-1 is responsible for enhanced insulin secretions after oral ingestion of glucose by the release of islet B-cells in the pancreas.

15. Exendin-4 • An agonist currently studied is the exendin-4 peptide which is isolated from the venom of a Gila monster. • Exendin-4 has a 9 amino acid proline-rich C-terminal tail, which is thought to stabilize the molecule at the receptor binding site. • Exendin-4 is a very potent peptide with potency up to 10 times greater than that of natural GLP-1 and has a longer half-life.

16. Liraglutide • Liraglutide is a series of acylated derivatives of GLP-1 that have long acting effects. • Liraglutide works by self-association and noncovalent binding of plasma albumin fatty acid binding sites • Albumin acts as a buffer reservoir to insure the binding of liraglutide to the active site. • This binding causes a pharmacokinetic profile with slow absorption and a long half-life of eight hours • Administered intravenously once a day

17. Dipeptidyl Pepidase 4 (DPP4) • Dipeptidyl peptidase 4 (DPP4) is a “nonclassical serine protease” that is ubiquitously expressed in increased levels in the kidney and in lower levels in many areas including; the liver, pancreas, placenta, thymus, spleen, epithelium cells, vascular endoplasm, and lymphoid and myeloid cells • DPP-IV works by cleaving the N-terminal two amino acids causing GLP-1 to give an inactive amide. Through these trials it was determined that an amine at position two is absolutely required for inhibition. Two N-substituted glycine derivatives; DPP728 and LAF237 have been studied in depth for their inhibitory effects.

18. Ribbon Diagram of DPPIV

19. DPP728 • DPP728 was given on a trial basis to patients for a period of a month on a daily dosage of 300mg. • It showed a decrease in fasting and prandial glucose over a period of twenty-four hours. • Transient pruritus localized to the palms was noted in some subjects though the reason for this effect is not known.

20. LAF237 • LAF237’s efficient once a day doses. • This inhibitor was also administered over a period of four weeks with a dosage of 100mg. Fasting was also decreased, along with postprandial glucose, and postprandial glucagon levels. The presence of Pruritus of the palms was not shown over the course of this trial.

21. Future focuses for treatment of Diabetes mellitus • Now that many of the mechanisms for metabolic dysfunction are understood, researchers can develop better drugs to alleviate adverse effects. • Future drug development aims to increase the duration of drug action thus decreasing the amount of times the drug needs to be administered for effectiveness. • Researchers are also focused on developing the most efficient and easy method of admission to target areas. By improving these current problems with the development of new drugs, hopefully future treatment of the diabetes mellitus will be a more efficient and satisfying experience for patients.