Replacing SUs with incretin-based therapies for type 2 diabetes mellitus: challenges and feasibility

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Filip K Knop, Jens Juul Holst, Tina Vilsbøll

Type 2 diabetes mellitus (T2DM) is a progressive disease characterized by insulin resistance, a steady decline in glucose-induced insulin secretion (most likely caused by a progressive decrease in functional beta-cell mass), and inappropriately regulated glucagon secretion; in combination, these effects result in hyperglycemia. In 1958, sulfonylurea (SU) was introduced to the market as one of the first oral treatments for T2DM. Since then, the ability of SU to stimulate the release of insulin from pancreatic beta-cells by the closure of ATP-sensitive K+-channels has been employed as one of the most widespread treatment options for T2DM. However, SUs are associated with weight gain and a risk of hypoglycemia, and the one-track antidiabetic mechanism of SUs often results in patients being treated with additional antidiabetic drugs. In recent studies, SU has proven to be associated with increased beta-cell apoptosis, suggesting that SU may actually accelerate the progressive decrease in beta-cell mass, thereby promoting the need for insulin replacement. In contrast, the newly developed incretin-based therapies for T2DM employ the beta-cell-preserving properties of incretin hormones - glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). More importantly, incretin-based therapies potentiate glucose-stimulated insulin secretion and may restore reduced glucose-induced insulin secretion in T2DM. Furthermore, the insulinotropic effects of GLP-1 and GIP are glucose-dependent, reducing the risk of hypoglycemia. GLP-1 inhibits glucagon secretion and decreases gastrointestinal motility, in turn reducing food intake and body weight. This feature review focuses on the challenges and feasibilities of replacing SU with incretin-based therapy in patients with T2DM.

Original languageEnglish
JournalI Drugs: the Investigational Drugs Journal
Volume11
Issue number7
Pages (from-to)497-501
Number of pages5
ISSN1369-7056
Publication statusPublished - Jul 2008

    Research areas

  • Diabetes Mellitus, Type 2, Gastric Inhibitory Polypeptide, Glucagon-Like Peptide 1, Humans, Hypoglycemic Agents, Incretins, Molecular Mimicry, Sulfonylurea Compounds

ID: 132048859