The kidney as a new target for antidiabetic drugs: SGLT2 inhibitors.

WHAT IS KNOWN AND OBJECTIVE: A novel class of antidiabetic drugs - SGLT2 (Na(+) /glucose cotransporter type 2) inhibitors - target renal reabsorption of glucose and promote normal glucose levels, independent of insulin production or its action at receptors. We review this new mechanistic approach and the reported efficacy and safety of clinical testing of lead compounds. METHODS: Information was obtained from various bibliographic sources, including PubMed and others, on the basic science and the clinical trials of SGLT2 inhibitors. The information was then summarized and evaluated from the perspective of contribution to a fuller understanding of the potential and current status of the lead clinical candidates. RESULTS AND DISCUSSION: Diabetes mellitus is a spectrum of disorders that involves inadequate insulin function resulting in adverse health sequelae due to acute and chronic hyperglycaemia. Current antidiabetic pharmacotherapy primarily addresses either insulin production at the pancreatic ß-cells or insulin action at insulin receptors. These drugs have less than full clinical effectiveness and sometimes therapy-limiting adverse effects. The third major component of glucose balance, namely elimination, has not been a significant therapeutic target to date. SGLT2 inhibitors are a novel approach. WHAT IS NEW AND CONCLUSION: A sufficient number of clinical trials have been conducted on sufficiently chemically diverse SGLT2 inhibitors to reasonably conclude that they have efficacy (HbA1c reductions of 0·4-1%), and thus far, the majority of adverse effects have been mild and transitory or treatable, with the caveat of possible association with increased risk of breast cancer in women and bladder cancer in men.

Vitamin D and type 2 diabetes mellitus.

WHAT IS KNOWN AND OBJECTIVE: The deleterious effect of vitamin D deficiency on bone health has long been known. More recent studies suggest a deleterious effect of low vitamin D (hypovitaminosis D) on general health. And specific studies propose an association between hypovitaminosis D and the aetiology and progression of type 2 diabetes (T2DM). Given a commonly assumed lack of toxicity of vitamin D, routine measurement of plasma vitamin D and supplementation is rapidly becoming accepted general practice. COMMENT: Authoritative practice guidelines have raised the level of vitamin D that is to be considered minimal for optimum health. This recommendation was based on a wealth of information and definitive evidence for skeletal benefits of vitamin D, but there was a lack of compelling evidence that hypovitaminosis D is causally related to extra-skeletal health outcomes such as diabetes. Hence, vitamin D supplementation for the purpose of achieving a level consistent with good health is evidence based, but measurement and supplementation for the purpose of preventing or treating T2DM is not. WHAT IS NEW AND CONCLUSION: Although the maintenance of adequate vitamin D levels is desirable for all patients, we conclude that routine measurement of vitamin D level in every patient or initiating high-dose supplementation for the purpose of preventing or treating T2DM is not evidence based.

ß-lactamase inhibitors display anti-seizure properties in an invertebrate assay.

Antibiotics containing a beta-lactam ring (e.g. ceftriaxone) display anti-glutamate effects that underlie their efficacy in animal models of central nervous system (CNS) diseases [Rothstein JD, Patel S, Regan MR, Haenggeli C, Huang YH, Bergles DE, Jin L, Dykes Hoberg M, Vidensky S, Chung DS, Toan SV, Bruijn LI, Su ZZ, Gupta P, Fisher PB (2005) Nature 433:73-77]. We hypothesized that the structurally related beta-lactamase inhibitors (clavulanic acid, tazobactam)--which also contain a beta-lactam ring--will mimic ceftriaxone efficacy in an invertebrate (planarian) assay designed to screen for anti-seizure activity [Rawls SM, Thomas T, Adeola M, Patil T, Raymondi N, Poles A, Loo M, Raffa RB (2009) Pharmacol Biochem Behav 93:363-367]. Glutamate or cocaine administration produced planarian seizure-like activity (pSLA). Glutamate- or cocaine-induced pSLA was inhibited by ceftriaxone, clavulanic acid, or tazobactam, but not by the non-beta-lactam antibiotic vancomyocin. The present findings indicate beta-lactamase inhibitors display efficacy, and mimic ceftriaxone activity, in an invertebrate anti-seizure screen. These results suggest beta-lactamase inhibitors--particularly ones such as clavulanic acid that display enhanced brain penetrability, oral bioavailability, and negligible anti-bacterial activity--might offer an attractive alternative to direct antibiotic therapy for managing CNS diseases caused by increased glutamate transmission and provide a solution to the growing concern that ceftriaxone will be of only limited utility as a CNS-active therapeutic because of its intolerable side effects.