Current Therapies and Emerging Targets for the Treatment of Diabetes

Abstract

Concurrent with the spread of the western lifestyle, the prevalence of all types of diabetes is on the rise in the world's population. The number of diabetics is increasing by 4-5% per year with an estimated 40-45% of individual's over the age of 65 years having either type II diabetes or impaired glucose tolerance. Since the signs of diabetes are not immediately obvious, diagnosis can be preceded by an extended period of impaired glucose tolerance resulting in the prevalence of beta-cell dysfunction and macrovascular complications. In addition to increased medical vigilance, diabetes is being combatted through aggressive treatment directed at lowering circulating blood glucose and inhibiting postprandial hyperglycemic spikes. Current strategies to treat diabetes include reducing insulin resistance using glitazones, supplementing insulin supplies with exogenous insulin, increasing endogenous insulin production with sulfonylureas and meglitinides, reducing hepatic glucose production through biguanides, and limiting postprandial glucose absorption with alpha-glucosidase inhibitors. In all of these areas, new generations of small molecules are being investigated which exhibit improved efficacy and safety profiles. Promising biological targets are also emerging such as (1) insulin sensitizers including protein tyrosine phosphatase-1B (PTP-1B) and glycogen synthase kinase 3 (GSK3), (2) inhibitors of gluconeogenesis like pyruvate dehydrogenase kinase (PDH) inhibitors, (3) lipolysis inhibitors, (4) fat oxidation including carnitine palmitoyltransferase (CPT) I and II inhibitors, and (5) energy expenditure by means of beta 3-adrenoceptor agonists. Also important are alternative routes of glucose disposal such as Na+-glucose cotransporter (SGLT) inhibitors, combination therapies, and the treatment of diabetic complications (eg. retinopathy, nephropathy, and neuropathy). With may new opportunities for drug discovery, the prospects are excellent for development of innovative therapies to effectively manage diabetes and prevent its long term complications. This review highlights recent (1997-2000) advances in diabetes therapy and research with an emphasis on small molecule drug design (275 references).

SGK1 inhibitor reverses hyperglycemia partly through decreasing glucose absorption

“…Fujita et al (1998) reported that intestinal glucose absorption through SGLT1 was increased in 6-week-old OLETF rats before the onset of insulin resistance and hyperinsulinemia. An SGLT1 inhibitor has been shown to counteract hyperglycemia and obesity (Wagman & Nuss 2001). In accordance with previous studies, this study also detected enhanced intestinal SGLT1 expression in db/db mice.…”

“…This process could eventually potentiate the development of hyperglycemia and diabetes. Conversely, inhibitors of SGLT1 have been shown to counteract obesity (Wagman & Nuss 2001).…”

Synthesis of tartaric acid analogues of FR258900 and their evaluation as glycogen phosphorylase inhibitors

“…3 Although several drugs are in clinical use for symptomatic treatment of T2DM, 4,5 these therapies are inadequate for 30-40% of the patients. 6 Among several investigational fields to diminish hepatic glucose output in T2DM, glycogen phosphorylase (GP) as a main regulatory enzyme of glycogen metabolism has become a validated 50 target. 2 Protein crystallographic studies have shown that endogenous and synthetic modulators can bind to six major sites in GP: the catalytic, the inhibitor, the allosteric (or AMP-binding), the glycogen storage, and the new allosteric sites, 7 as well as the newly discovered benzimidazole site.…”

Prenylated Flavonoids with PTP1B Inhibitory Activity from the Root Bark of Erythrina mildbraedii

“…Since it has been suggested that compounds that reduce protein tyrosine phosphatase 1B (PTP1B) activity or expression levels can used for the treatment of either type 2 diabetes or obesity, [1][2][3][4][5] there have been found a number of natural products reported to possess suppressive effects on PTP1B enzyme in our program searching for anti-diabetes agents from nature. [6][7][8][9][10][11][12][13][14][15][16] Previously, we found that an EtOAcsoluble extract of the root bark of Erythrina mildbraedii exhibited inhibitory effect on PTP1B activity and demonstrated that prenylated flavonoids are principles of this extract.…”