The Antidiabetic Properties Of Glp In Type Diabetes And Limitations To Its Therapeutic

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In patients with type 2 diabetes, the incretin effect is reduced or absent (47). GLP-1 secretion is diminished in type 2 diabetic subjects, possibly contributing to the reduced incretin effect (48). A continuous intravenous GLP-1 infusion stimulates insulin secretion and normalizes both fasting and postprandial blood glucose in patients with type 2 diabetes (29,49). A continuous subcutaneous administration for 6 weeks reduced diurnal glucose concentrations and HbA1c by 1.3% and suppressed glucagon secretion (38). Furthermore, the patients treated with GLP-1 lost approximately 2 kg of weight (Fig. 1)

The multiple actions of GLP-1 constitute a novel and attractive therapeutic principle for the treatment of type 2 diabetes by improving the postprandial metabolic situation and eliminating hypoglycemic events (Table 1) (38). The risk of hypoglycemia observed in patients treated with GLP-1 is minimal because GLP-1 only stimulates insulin secretion under hyperglycemic conditions (33,51). Intravenous infusions of GLP-1 can normalize plasma glucose in patients with type 2 diabetes. Hepatic glucose production is lowered due to the inhibition of glucagon secretion (29) and the effects on body weight are also desirable.

Effects of a single subcutaneous injection of GLP-1, however, were disappointing due to the very rapid degradation of GLP-1 in vivo (52). GLP-1 (and the other incretin, GIP) is degraded within a few minutes by the enzyme dipeptidyl peptidase-4 (DPP-4) (53,54). Due to the enzymatic degradation, only approximately 20% of the GLP-1 administered by an intravenous infusion reaches circulation intact and in a biologically active form (38,54).

Generally, either DPP-4-resistant GLP-1 receptor agonists or substances inhibiting DPP-4 could be used to utilize the therapeutic potential of GLP-1 (55).

Peptidergic GLP-1 receptor agonists (GLP-1 analogs, also termed "incretin mimetics") are currently being introduced into type 2 diabetes therapy as injectable compounds (26,55-58). On the other hand, various orally active DPP-4 inhibitors are also evaluated in clinical trials or approved in single countries (26).

GLP-1 ANALOGUES—INCRETIN MIMETICS

The first "incretin mimetic" available in the United States for the therapy of type 2 diabetic patients not optimally controlled with an oral antidiabetic therapy (sulfonylureas and/or metformin) is exenatide [Byetta®; Eli Lilly (Indianapolis, IN, U.S.A.) & Amylin Pharmaceuticals (San Diego, CA, U.S.A.)]. Exenatide is the synthetic recombinant form of the naturally occurring peptide exendin-4. Exendin-4 was discovered in the salivary gland of the Gila monster (Heloderma suspectum). It has a high amino acid sequence similarity to GLP-1 and is not cleaved by DPP-4. Exendin-4 has physiological effects comparable to GLP-1 and a biological half-life of several hours making a therapy with twice daily injections feasible (59). In clinical studies exenatide showed a significant

FIGURE 1 The entero-insular axis. Postpran-dially, insulin secretion is directly stimulated by substrates and by the strong endocrine stimulation through incretin hormones. Abbreviations: AA, amino acids; CHO, carbohydrates; FA, fatty acids; H+, protons from gastric acid. Source: From Ref. 1.

TABLE 1 Organ-Specific Effects of GLP-1

Organ/cell system

GLP-1 effect

Endocrine pancreas

Beta cells

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