Insulinotropic agents

Carroll MF, Gutierrez A, Castro M, Tsewang D, Schade DS. Targeting postprandial hyperglycemia a comparative study of insulinotropic agents in type 2 diabetes. J Cin Endocrinol Metab 2003 88 5248-54. 

Insulinotropic agents directly stimulate the release of insulin from pancreatic j3-cells, and are thus useful only in the treatment of NIDDM. The drugs in this class are often divided into the subclasses of sulfonylureas and glinides. These compounds are structurally related and share a common mechanism of action, and are described together. 

Table 1.3 Structures and Properties of Insulinotropic Agents Sulfonylureas... 

Structure-Activity. The more recently introduced insulinotropic agents are complex, richly functionalized molecules, the optimized products of many extensive synthetic and pharmacological investigations (101-117) of structure-activity relationships (SAR). Common features found in potent compounds (102,103, 106) of this class are summarized in Fig. 1.2, illustrated by the use of glyburide, repaglinide, and nateglinide as reference structures. The relationship to other compounds in Table 1.3 is readily apparent. 

Exogenous insulin or insulinotropic oral agents such as sulphonylureas are not suitable for improving insulin resistance. Non-insulinotropic hypoglycaemic medication such as biguanides and/or acarbose, however, is recommended if diet alone fails to achieve sufficient metabolic control. It is still controversial, however, whether the reduction of endogenous insulin also reduces the synthesis of islet amyloid polypeptide (IAPP) sufficiently to slow down the progression of NIDDM (Clark et al., 1987). 

Because diabetes is a heterogeneous disease, each patient must be treated individually. More studies, however, are necessary to determine which of several available sulphonylureas is most appropriate in clinical treatment. The evidence of the relative efficacy of sulphonylureas, however, is still inconclusive. The blood glucose-lowering effect has always been primarily attributed to their insulinotropic action. In subjects not previously exposed to sulphonylureas, close association between the appearance of the drug in the plasma after a single dose and the release of insulin has been amply demonstrated. Sulphonylureas, however, also seem to exert potent extra-pancreatic effects. This may explain why, in two recent reports, these agents were found to also be beneficial in the management of insulin-dependent diabetes. 

Although the marketed sulfonylureas are all well absorbed, they differ in the time required to reach maximum blood levels (Table 1.3) and in metabolic fate and in rate and mode of elimination. These differences can have important implications for safe use of the various drugs. Accumulation of these agents in vivo can lead to extended episodes of serious or fatal hypoglycemia through overstimulation of insulin release. Insulinotropic drugs, for instance, which are metabolized to active compounds that are eliminated solely by renal excretion, pose a serious risk of hypoglycemia in renally compromised individuals. 

Fig. 6. (continued). In other cases, especially if a more potent drug is to be added, which relies on a similar mechanism (e.g., incretin-mediated insulinotropic activity), one of the previously used antidiabetic agents may need to be discontinued (e.g., when adding a sulfonylurea or an incretin mimetic to a patient previously treated with a DPP-4 inhibitor). Note that sufficient study results (see Fig. 5) are not available for all mentioned combinations to provide a sound scientific basis for their use outside clinical studies. 

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