Pharmacotherapies to manage diabesity:an update

Several pharmacotherapies have recently become available for addition to lifestyle measures to assist the management of coexistent type 2 diabetes and obesity. These are mostly administered as add-on to metformin or as alternative therapies if metformin is not appropriate. The sodium–glucose cotransporter 2 inhibitors (dapagliflozin, canagliflozin and empagliflozin) act by eliminating excess glucose in the urine. These agents provide a non-insulin-dependent mechanism to reduce hyperglycaemia and facilitate weight loss without causing frank hypoglycaemia. Their efficacy requires the individual to have adequate renal function. The glucagon-like peptide-1 (GLP-1) receptor agonists (exenatide, liraglutide, lixisenatide, dulaglutide and albiglutide [the last at the pre-launch stage at the time of writing]) are injected subcutaneously. Different members of the class offer different time courses for their onset and duration of action. Each potentiates insulin secretion and reduces glucagon secretion in a glucose-dependent manner to address prandial glycaemic excursions while avoiding interprandial hypoglycaemia. A satiety effect of these agents assists weight reduction, but delayed gastric emptying can cause initial nausea. The dipeptidyl peptidase-4 inhibitor class now comprises sitagliptin, vildagliptin, saxagliptin, linagliptin and alogliptin. These agents offer similar glucose-lowering efficacy without weight gain or hypoglycaemia by boosting the half-life of endogenous incretins, particularly GLP-1. A fixed-ratio injected combination of insulin degludec with liraglutide (IDegLira) has recently been launched and further agents to address hyperglycaemia and assist weight loss are advancing in development.

Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) is a global epidemic that poses a major challenge to health-care systems. Improving metabolic control to approach normal glycaemia (where practical) greatly benefits long-term prognoses and justifies early, effective, sustained and safety-conscious intervention. Improvements in the understanding of the complex pathogenesis of T2DM have underpinned the development of glucose-lowering therapies with complementary mechanisms of action, which have expanded treatment options and facilitated individualized management strategies. Over the past decade, several new classes of glucose-lowering agents have been licensed, including glucagon-like peptide 1 receptor (GLP-1R) agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors and sodium/glucose cotransporter 2 (SGLT2) inhibitors. These agents can be used individually or in combination with well-established treatments such as biguanides, sulfonylureas and thiazolidinediones. Although novel agents have potential advantages including low risk of hypoglycaemia and help with weight control, long-term safety has yet to be established. In this Review, we assess the pharmacokinetics, pharmacodynamics and safety profiles, including cardiovascular safety, of currently available therapies for management of hyperglycaemia in patients with T2DM within the context of disease pathogenesis and natural history. In addition, we briefly describe treatment algorithms for patients with T2DM and lessons from present therapies to inform the development of future therapies.

Seawater carbonate chemistry, mass, length and gene expression of Sepia officinalis during experiments, 2011

The specific transporters involved in maintenance of blood pH homeostasis in cephalopod molluscs have not been identified to date. Using in situ hybridization and immuno histochemical methods, we demonstrate that Na+/K+-ATPase (soNKA), a V-type H+-ATPase (soV-HA), and Na+/HCO3- cotransporter (soNBC) are co-localized in NKA-rich cells in the gills of Sepia officinalis. mRNA expression patterns of these transporters and selected metabolic genes were examined in response to moderately elevated seawater pCO2 (0.16 and 0.35 kPa) over a time-course of six weeks in different ontogenetic stages. The applied CO2 concentrations are relevant for ocean acidification scenarios projected for the coming decades. We determined strong expression changes in late stage embryos and hatchlings, with one to three log2-fold reductions in soNKA, soNBCe, socCAII and COX. In contrast, no hypercapnia induced changes in mRNA expression were observed in juveniles during both short- and long-term exposure. However a transiently increased demand of ion regulatory demand was evident during the initial acclimation reaction to elevated seawater pCO2. Gill Na+/K+-ATPase activity and protein concentration were increased by approximately 15% in during short (2-11 day), but not long term (42 day) exposure. Our findings support the hypothesis that the energy budget of adult cephalopods is not significantly compromised during long-term exposure to moderate environmental hypercapnia. However, the down regulation of ion-regulatory and metabolic genes in late stage embryos, taken together with a significant reduction in somatic growth, indicates that cephalopod early life stages are challenged by elevated seawater pCO2.