Addressing Unmet Medical Needs in Type 1 Diabetes: A Review of Drugs Under Development.

INTRODUCTION: The incidence of type 1 diabetes (T1D) is increasing worldwide and there is a very large need for effective therapies. Essentially no therapies other than insulin are currently approved for the treatment of T1D. Drugs already in use for type 2 diabetes and many new drugs are under clinical development for T1D, including compounds with both established and new mechanisms of action. Content of the Review: Most of the new compounds in clinical development are currently in Phase 1 and 2. Drug classes discussed in this review include new insulins, SGLT inhibitors, GLP-1 agonists, immunomodulatory drugs including autoantigens and anti-cytokines, agents that regenerate ß-cells and others. Regulatory Considerations: In addition, considerations are provided with regard to the regulatory environment for the clinical development of drugs for T1D, with a focus on the United States Food and Drug Administration and the European Medicines Agency. Future opportunities, such as combination treatments of immunomodulatory and beta-cell regenerating therapies, are also discussed.

Addressing unmet medical needs in type 2 diabetes: a narrative review of drugs under development.

The global burden of type 2 diabetes is increasing worldwide, and successful treatment of this disease needs constant provision of new drugs. Twelve classes of antidiabetic drugs are currently available, and many new drugs are under clinical development. These include compounds with known mechanisms of action but unique properties, such as once-weekly DPP4 inhibitors or oral insulin. They also include drugs with new mechanisms of action, the focus of this review. Most of these compounds are in Phase 1 and 2, with only a small number having made it to Phase 3 at this time. The new drug classes described include PPAR agonists/modulators, glucokinase activators, glucagon receptor antagonists, anti-inflammatory compounds, G-protein coupled receptor agonists, gastrointestinal peptide agonists other than GLP-1, apical sodium-dependent bile acid transporter (ASBT) inhibitors, SGLT1 and dual SGLT1/SGLT2 inhibitors, and 11beta- HSD1 inhibitors.

Diabetes and biomarkers.

Biomarkers play an integral part in conducting clinical trials and treating patients. In most instances, they help medical practitioners, researchers, and regulatory officials make well-informed, scientifically sound decisions. However, in clinical studies, there is often uncertainty in how much weight to place on biomarker results versus clinical outcomes. This uncertainty emanates from opposing goals of the drug approval process. On one hand, the process must ensure that all therapeutics tested are safe and that the benefits outweigh the risks. On the other hand, the process should allow therapies to be accessible to patients as quickly as reasonably possible. Judicious use of biomarkers in the drug development process can bring these goals into alignment. More efficient discovery and use of biomarkers in the development of antidiabetes drugs will depend on advancing our understanding of the pathogenesis of diabetes and especially its macrovascular complications.

Protein inhibitor of activated STAT3 inhibits adipogenic gene expression.

Protein inhibitor of activated STAT3 (PIAS3), a cytokine-induced repressor of signal transducer and activator of transcription 3 (STAT3) and a modulator of a broad array of nuclear proteins, is expressed in white adipose tissue, but its role in adipogenesis is not known. Here, we determined that PIAS3 was constitutively expressed in 3T3-L1 cells at all stages of adipogenesis. However, it translocated from the nucleus to the cytoplasm 4 days after induction of differentiation by isobutylmethylxanthine, dexamethasone, and insulin (MDI). In ob/ob mice, PIAS3 expression was increased in white adipose tissue depots compared to lean mice and was found in the cytoplasm of adipocytes. Overexpression of PIAS3 in differentiating preadipocytes, which localized primarily to the nucleus, inhibited mRNA level gene expression of adipogenic transcription factors C/EBPalpha and PPARgamma, as well as their downstream target genes aP2 and adiponectin. PIAS3 also inhibited C/EBPalpha promoter activation mediated specifically by insulin, but not dexamethasone or isobutylmethylxanthine. Taken together, these data suggest that PIAS3 may play an inhibitory role in adipogenesis by modulating insulin-activated transcriptional activation events. Increased PIAS3 expression in adipose tissue may play a role in the metabolic disturbances of obesity.