New therapeutic strategies for the treatment of type 2 diabetes mellitus based on incretins

Abstract

Orally ingested glucose leads to a greater insulin response compared to intravenously administered glucose leading to identical postprandial plasma glucose excursions, a phenomenon referred to as the "incretin effect". The incretin effect comprises up to 60% of the postprandial insulin secretion and is diminished in type 2 diabetes. One of the very important gastrointestinal hormones promoting this effect is glucagon-like peptide 1 (GLP-1). It only stimulates insulin secretion and normalizes blood glucose in humans under hyperglycemic conditions, therefore it does not cause hypoglycemia. Other important physiological actions of GLP-1 are the inhibition of glucagon secretion and gastric emptying. It further acts as a neurotransmitter in the hypothalamus stimulating satiety. In vitro and animal data demonstrated that GLP-1 increases beta-cell mass by stimulating islet cell neogenesis and by inhibiting apoptosis of islets. In humans, the improvement of beta-cell function can be indirectly observed from the increased insulin secretory capacity after GLP-1 infusions. GLP-1 represents an attractive therapeutic principle for type 2 diabetes. However, native GLP-1 is degraded rapidly upon exogenous administration and is therefore not feasible for routine therapy. The first long-acting GLP-1 analog ("incretin mimetic") Exenatide (Byetta) has just been approved for type 2 diabetes therapy. Other compounds are being investigated in clinical trials (e.g. liraglutide, CJC1131). Dipeptidyl-peptidase IV inhibitors (DPP-IV inhibitors; e.g. Vildagliptin, Sitagliptin) that inhibit the enzyme responsible for incretin degradation are also under study.

Figure 1. The Enteroinsular Axis

Postprandially, insulin secretion is directly stimulated by substrates, neuro-transmission (through entero-pancreatic nerves activated by chymus and intestinal distension), and by strong endocrine stimulation through incretin hormones. CHO: carbohydrates. AA: amino acids. FA: fatty acids. H⁺: hydrogen from gastric acid production. α-cells produce glucagon, β-cells insulin, δ-cells somatostatin, and PP-cells pancreatic polypeptide. (Modified according to [2]).

Figure 2

The figure represents plasma glucose, insulin, and glucagon levels after intravenous administration of 1.2 pmol kg-1 min-1 GLP-1 in 10 type 2 diabetic patients. The time interval of continued GLP-1 infusion (●) and placebo administration (○) was 240 min. Asterisk (*) indicates a significance level of p < 0.0001 (modified according to [15]).

Figure 3. Blood glucose and body weight at baseline, after 1 week and after 6 weeks treatment with either a continuous subcutaneous infusion of GLP-1 or placebo

The graphs show blood glucose profiles over a day during week 0, 1 and 6, the bars represent the loss in body weight in percentages (modified according to [24]).

Figure 4. Native GLP-1 and possible molecular changes to create long-acting incretin mimetics

The amino acid sequence of native GLP-1 is shown in the one-letter code. Also, the N-terminal cleavage site of DPP-IV is depicted by an arrow. The schematic molecular changes of the currently available incretin mimetics are shown.

Figure 5. Glycemic control in subjects with type 2 diabetes treated with metformin and a sulfonylurea plus exenatide or placebo (ITT population)

A: HbA1c values over the course of the study (raw data). B: Change in HbA1c over 30 weeks. * Adjusted p < 0.0001 compared with placebo. Week 30 changes in HbA1c values from baseline were -0.77 ± 0.08% (10-µg arm; adjusted p < 0.0001 vs. placebo), -0.55 ± 0.07% (5-µg arm; adjusted p < 0.0001 vs. placebo), and 0.23 ± 0.07% (placebo arm). C: Week 30 change in HbA1c stratified by baseline HbA1c. For subjects with baseline HbA1c < 9%, baseline HbA1c values were 7.92 ± 0.04% (n = 169), 7.91 ± 0.04% (n = 172), and 7.94 ± 0.04% (n = 172) for the 10-µg exenatide, 5-µg exenatide, and placebo arms, respectively. The corresponding values for subjects with baseline HbA1c ≥ 9% were 9.86 ± 0.07% (n = 72), 9.75 ± 0.07% (n = 73), and 9.75 ± 0.07% (n = 75). D: Effects of exenatide on body weight. Subjects in the 10-µg exenatide b.i.d. treatment arm received 5 µg exenatide b.i.d. during weeks 0-4. Subjects in all treatment arms were maintained on metformin-sulfonylurea therapy. * p < 0.001 compared with placebo treatment. Data are means ± SE (reproduced from [49]).