Incretin Hormones and Type 2 Diabetes—Mechanistic Insights and Therapeutic Approaches

Abstract

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted from the gut upon nutrient stimulation and regulate postprandial metabolism. These hormones are known as classical incretin hormones and are responsible for a major part of postprandial insulin release. The incretin effect is severely reduced in patients with type 2 diabetes, but it was discovered that administration of GLP-1 agonists was capable of normalizing glucose control in these patients. Over the last decades, much research has been focused on the development of incretin-based therapies for type 2 diabetes. These therapies include incretin receptor agonists and inhibitors of the incretin-degrading enzyme dipeptidyl peptidase-4. Especially the development of diverse GLP-1 receptor agonists has shown immense success, whereas studies of GIP monotherapy in patients with type 2 diabetes have consistently been disappointing. Interestingly, both GIP-GLP-1 co-agonists and GIP receptor antagonists administered in combination with GLP-1R agonists appear to be efficient with respect to both weight loss and control of diabetes, although the molecular mechanisms behind these effects remain unknown. This review describes our current knowledge of the two incretin hormones and the development of incretin-based therapies for treatment of type 2 diabetes.

Molecular and Pathophysiological Links between Metabolic Disorders and Inflammatory Bowel Diseases

“…Glucagon-like peptide-1 (GLP-1), an incretin hormone mainly secreted from intestinal L cells, has gained attention as a key player in the pathogenesis of metabolic and inflammatory diseases due to its function in modulating ER stress and promoting anti-inflammatory signaling [48]. The insulinotropic and glucose-lowering effects of GLP-1 has long been shown to be impaired in obesity and T2D [49], and GLP-2, another co-secreted L-cell peptide hormone that improves gut epithelial proliferation and mucosal integrity, has also been found to be reduced in obese mice and humans [50,51]. Secretion of GLP-1 and GLP-2 also has been found to be impaired by chronic exposure to TNFα [52,53] and, inversely, it was reported that GLP-1 or GLP-1 receptor (GLP-1R) agonists reduce the levels of pro-inflammatory cytokines [54] and the activation of GLP-1R signaling modulates intestinal immune responses and mucosal inflammation [55].…”

“…Adipose tissue dysfunction ↓adiponectin, ↓omentin-1, ↑leptin, ↑resistin, ↑visfatin, and ↑chemerin in obesity and/or T2D * [40][41][42] ↓adiponectin, ↓omentin-1, ↓or↑leptin in IBD * [45][46][47], ↑resistin, ↑visfatin, and ↑chemerin in IBD * [44][45][46][47] Enteroendocrine cell dysfunction ↓GLP-1 [49], ↓GLP-2 [50,51], and ↑DPP-4 in obesity and T2D [56] ↑GLP-1 and ↑GLP-2 in IBD [58] ↓DPP-4 in IBD [60] Intestinal barrier dysfunction ↓ZO-1, occludin in DIO and ob/ob mice * [50,65] ↓ZO-1, occludin, claudin-1 in rodent DIO models * [66] ↓claudin-1, -3, -4, -7, -15, and ↑claudin-2 (the leaky claudin) in rodent DIO models * [67] ↓occludin, tricellulin in obese patients with T2D * [68] ↓fecal zonulin in obese patients * [69] ↓ZO-1, occludin, but no change of claudin-1 in NAFLD patients * [70] ↓claudin-4 in both CD and UC * [71] ↓claudin-5, -8 in CD * [72] ↑claudin-1 in active forms of both CD and UC * [73][74][75], but no change in inactive forms [74] ↑claudin-2 in both CD and UC * [71,72,74], ↓occludin in CD* [72,75,76], no change [74]↓ZO-1 in colonic epithelial cell culture [76] and DSS-induced colitis mice * [75] Polymorphisms of genes encoding tight junction-associated proteins in IBD patients [77,78] ↑apoptosis [79][80]…”

Pleiotropic Benefits of DPP-4 Inhibitors Beyond Glycemic Control

“…The 2 types of incretin-based therapies are glucagon-like peptide (GLP)-1 receptor agonists, and inhibitors of the incretin-degrading enzyme dipeptidyl peptidase-4 (DPP-4). 3 …”

Hepatic and Extrahepatic Insulin Clearance in Mice with Double Deletion of Glucagon-Like Peptide-1 and Glucose-Dependent Insulinotropic Polypeptide Receptors

“…In fact, due to its effect on insulin secretion, the incretin effect represents an important mechanism for the regulation of plasma insulin concentration. However, GLP-1 and GIP receptors are also expressed in other tissues, such as adipose, heart, kidney, bone, brain [3,4], and possibly liver [5] tissue, though the related functions remain mainly unknown [6].…”