Efficacy, safety and albuminuria-reducing effect of gemigliptin in Korean type 2 diabetes patients with moderate to severe renal impairment: A 12-week, double-blind randomized study (the GUARD Study).

AIMS: This multicentre, randomized, double-blind study investigated the efficacy and safety of gemigliptin in Korean type 2 diabetes mellitus (T2DM) patients with moderate to severe renal impairment (RI). METHODS: The study comprised a 12-week main part and a 40-week extension. We report here the results from the main part. In total, 132 patients were randomized to receive gemigliptin (n = 66) or placebo (n = 66). Changes in glycated haemoglobin (HbA1c; primary endpoint), other glycaemic control parameters (fasting plasma glucose, glycated albumin and fructosamine), lipid profiles, renal function parameters and safety profiles were evaluated. RESULTS: Baseline characteristics were comparable between the groups (mean HbA1c, 8.4% [68 mmol/mol]; age, 62.0 years; duration of type 2 diabetes, 16.3 years; estimated glomerular filtration rate, 33.3 mL/min/1.73 m2 ). At Week 12, the adjusted mean change ± standard error in HbA1c with gemigliptin was -0.82% ± 0.14% (-8.9 ± 1.5 mmol/mol), whereas it was 0.38% ± 0.14% (4.2 ± 1.5 mmol/mol) with placebo (significant between-group difference, P < .001). Other glycaemic control parameters showed beneficial changes as well. Body weight change (gemigliptin, -0.3 kg; placebo, -0.2 kg) was not significant. In the gemigliptin group, the mean decrease in urinary albumin creatinine ratio (UACR) was significant, both in patients with microalbuminuria (-41.9 mg/g creatinine, P = .03) and macroalbuminuria (-528.9 mg/g creatinine, P < .001). Drug-related adverse events were similar with gemigliptin and placebo (15% and 12%, respectively). CONCLUSIONS: A 12-week treatment with gemigliptin improved glycaemic control and provided UACR reduction in T2DM patients with moderate to severe RI. Gemigliptin was well tolerated, with no additional risk of hypoglycaemia and change in body weight.

Calmodulin interacts with MLO protein to regulate defence against mildew in barley.

In plants, defence against specific isolates of a pathogen can be triggered by the presence of a corresponding race-specific resistance gene, whereas resistance of a more broad-spectrum nature can result from recessive, presumably loss-of-regulatory-function, mutations. An example of the latter are mlo mutations in barley, which have been successful in agriculture for the control of powdery mildew fungus (Blumeria graminis f. sp. hordei; Bgh). MLO protein resides in the plasma membrane, has seven transmembrane domains, and is the prototype of a sequence-diversified family unique to plants, reminiscent of the seven-transmembrane receptors in fungi and animals. In animals, these are known as G-protein-coupled receptors and exist in three main families, lacking sequence similarity, that are thought to be an example of molecular convergence. MLO seems to function independently of heterotrimeric G proteins. We have identified a domain in MLO that mediates a Ca2+-dependent interaction with calmodulin in vitro. Loss of calmodulin binding halves the ability of MLO to negatively regulate defence against powdery mildew in vivo. We propose a sensor role for MLO in the modulation of defence reactions.