Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) belong to a group of gastrointestinal hormones called incretins. Insulin released from the beta cells of the islets of Langerhans after ingestion of food is the major regulator of GIP and GLP-1 secretion [10]. Both hormones show complementary action of the β-cells of the pancreas by acting through different but related receptors [11]. GLP-1 is secreted from endocrine L-cells mainly found in the distal ileum and colon, while GIP is released from K-cells located in the duodenum and jejunum [11]. GLP-1 secretion is stimulated by activation of a number of intracellular signals, including PKA (protein kinase A), PKC (protein kinase C), calcium, and MAPK (mitogen-activated protein kinase) [11]. GLP-1 release is regulated by cell membrane channels: glucose stimulates GLP-1 secretion via K_ATP (adenosine triphosphate-sensitive potassium) channel closure [12], while nonmetabolizable carbohydrates using mechanisms dependent on sodium-glucose cotransporters 1 and 3 [13]. Many forms of GLP-1 are released in vivo, including GLP-1(1-37) and GLP-1(1–36)NH₂, which are inactive, and GLP-1(7–37) and GLP-1(7–36)NH₂, which are biologically active. GLP-1(7–36)NH₂ consists of the majority of GLP-1 circulating in the human body [14,15].

The human GIP gene comprises six exons and has been localized on the long arm of chromosome 17 [11]. Previous studies demonstrated that bioactive form of GIP (42-amino acid) is released from its 153-amino acid proGIP precursor via PC 1/3 (prohormone convertase 1/3)-dependent posttranslational cut [16]. The GIP sequence is highly conserved, with more than 90% amino-acid sequence identity in humans and other vertebrates. [11] The GIP receptor (GIPR) initially was isolated from a rat brain, but nowadays we know that it is also expressed throughout the digestive tract, pituitary, lungs, trachea, kidneys, bones, thymus, spleen, endothelial cells, thyroid, adrenal cortex, testis, and central nervous system [17]. It was previously demonstrated that the secretion of GIP may increase via β-adrenergic stimulation, K⁺-mediated depolarization, rise of intracellular Ca²⁺ concentration, and activation of adenyl cyclase [18]. Studies have shown that ahead of gastrin, secretin, and cholecystokinin, GIP and GLP-1 are predominant incretin hormones in humans [10].

For the first time, the intestinal peptide GIP was isolated from porcine upper small intestine about 50 years ago [19], and it was discovered about 10 years later that two GLP-1 fragments were potent regulators of insulin secretion [20]. Both hormones are elevated after an oral glucose load or meal consumption in healthy humans and nowadays are commonly known for regulating glycemic level by increasing insulin secretion, inhibiting glucagon release, and delaying stomach emptying [21]. However, the increase in incretins after meals is disproportionately low in people with type 2 diabetes (DM 2) [22]. Although the reasons for this phenomenon are not fully explained, several mechanisms are postulated. Because insulin increase appears to be the main regulator of GIP and GLP-1 release, and insulin secretion in DM 2 patients is reduced due to beta cells dysfunction, it can be assumed that diminished effect of incretins in DM 2 can be associated with β-cell dysfunction rather than with a direct impairment of incretins secretion or activity [23,24]. In addition, acute elevation of glucose concentration (due to continuous insulin deficiency) in diabetic patients has been shown to reduce postprandial GLP-1 response [24,25]. Another postulated mechanism is specific loss of GIP activity. It may seem that glucose-induced insulin release impairment appears to be comparable to the corresponding GIP-induced insulin secretion defect. It is possible that the inability of GIP to increase insulin secretion during hyperglycemia is primarily due to the lack of glucose amplification of insulin release in DM 2 patients [26,27]. The insulinotropic GIP and GLP-1 inefficiency in diabetics is perhaps related with an additional (not yet explored) mechanism of action rather than with a specific defect in GIP regulation. Further research is required to clarify these mechanisms.

For many years it was known that intravenous GIP or GLP-1 administration could normalize hyperglycemia in DM 2 patients [22]. Hence, GLP-1 receptor agonists (GLP-1 RAs) have been widely used as an oral treatment of DM 2 for several years [28,29]. Exenatide was introduced for the treatment of DM 2 in 2005 and liraglutide was approved for use four years later. [30] Besides these two, many other GLP-1 agonists like Semaglutide, Efpeglenatide, Dulaglutide, Albiglutide, and Lixisenatide have been recently synthesized [31]. Besides efficacy in reducing hyperglycemia, GLP-1 RAs have many additional benefits. One of their advantages over older insulin secretagogues, such as sulfonylureas or meglitinides, is lower risk of hypoglycemia development [32]. In addition, constant intake of GLP-1 stimulates weight loss and reduces appetite by inhibiting gastric emptying [32].

Apart from the undoubted impact of GIP and GLP-1 on carbohydrates metabolism, their receptors were also expressed in organs and cells such as duodenum, liver, kidneys, peripheral and central nervous system, adipocytes, osteoblasts, and myocytes [11,33].

Both GIP and GLP-1 are rapidly inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4) with a blood half-life of only a few minutes [22]. DPP-4, also known as CD 26 (cluster of differentiation 26), was discovered over 50 years ago [55]. DPP-4 belongs to the adipokines family and appears an important molecular biomarker that is strongly correlated with metabolic syndrome [56]. DPP-4 expression was proved to positively correlate with body mass index (BMI) and adipocyte size and activity in both subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) [56]. In the same study, circulating DPP-4 concentration in insulin-sensitive obese patients was significantly lower than in those with insulin resistance [56]. However, it has not yet been fully explained which tissue is the source of circulating DPP-4. It is also known that DPP-4 is involved in metabolism and release of broad range of molecules such as chemokines, vasoactive peptides, neurokinins, and growth factors [57]. DPP-4 is also associated with cancer biology and is useful as a marker of various tumors, with its level strongly correlated with neoplasia [58]. Additionally, DPP-4 inhibitors were found to have an anti-inflammatory effect via inhibition of monocyte activation and chemotaxis [59] and are involved into inhibition of the development of endothelial dysfunction and thus prevent atherogenesis in nondiabetic apolipoprotein E-deficient (ApoE^−/−) mice [60].

Apart from pleiotropic actions, DPP-4 plays the most important role in glucose metabolism [61]. By breaking down endogenous incretins GIP and GLP-1, it increases plasma glucose level both in fasting and fed conditions and is also responsible for less postprandial insulin burst [62]. Therefore, drugs that are DPP-4 inhibitors delay the breakdown of endogenous incretins GIP and GLP-1 and are successfully used to combat insulin-resistance and DM 2 management [29].

GIP, GLP-1 and DPP-4 inhibitors have not only positive pleiotropic effects on the whole human body. Incretin-based therapy has recently been shown to be associated with an increased risk of pancreatic cancer in diabetes patients [63].

The currently known physiological effects of GIP, GLP-1, and DPP-4 on animal and human tissues are presented on Figure 1.