Incretin-based therapy for type 2 diabetes mellitus: pancreatic and extrapancreatic effects.

The prevalence of type 2 diabetes mellitus has increased at an alarming rate in recent years. Recent estimations project that 366 million people could have diabetes by 2030. The incretin system emerges as a new target for type 2 diabetes therapy, and new molecules are being approved for its use in humans since the year 2005. These agents could be divided into 2 main groups, glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 inhibitors. Endogenous GLP-1 is an incretin hormone composed by a 30-amino acid peptide and is secreted from L-cells in distal small intestine in response to calorie intake, causing a glucose-dependent ß-cell response resulting in a restoration of the first-phase insulin response. Additionally, GLP-1 regulates glucagon production, which leads to inhibition of glucogenolysis and gluconeogenesis in the liver. Synthetic molecules such as exenatide and liraglutide have been developed to bind GLP-1 receptor and mimic GLP-1 effects in pancreatic cells and other target organs.

Insulin analogs: impact on treatment success, satisfaction, quality of life, and adherence.

A growing body of medical research has demonstrated that intensive control of serum glucose levels can minimize the development of diabetes-related complications. Success with insulin management ultimately depends on how closely a given regimen can mimic normal physiologic insulin release patterns. The new insulin analogs, including the rapid-acting analogs (aspart, lispro, glulisine), the long-acting basal analogs (glargine, detemir), and the premixed insulin analog formulations (75% neutral protamine lispro, 25% lispro; 50% neutral protamine lispro, 50% lispro; 70% protamine aspart, 30% aspart) have been formulated to allow for a closer replication of a normal insulin profile. The rapid-acting analogs can be administered at mealtimes and produce a rapid and short-lived insulin spike to address postprandial glucose elevations, while the long-acting analogs come close to the ideal of a smooth, relatively flat, 24-hour basal insulin supply, with less variability in action compared to NPH insulin. Despite these clear pharmacologic advantages, measurable clinical benefits in a complex disease such as diabetes can be hard to measure. To date, reviews of insulin analog studies have not found a dramatic overall improvement in glycosylated hemoglobin (HbA1c) outcomes compared to traditional human insulins, although all-analog basal-bolus regimens were associated with significantly lower HbA1c than all-human-insulin basal bolus regimens in some studies. Beyond HbA1c comparisons, however, insulin analogs have been shown in many instances to be associated with lower risks of hypoglycemia, lower levels of postprandial glucose excursions, better patient adherence, greater quality of life, and higher satisfaction with treatment. The long-acting basal analog insulin detemir has the additional advantage of producing less weight gain, which has been considered until now an almost inevitable consequence of insulin replacement.