2 | THE INCRETIN EFFECT
Oral glucose leads to a greater stimulation of insulin secretion than an intravenous glucose infusion even when the same plasma glucose concentration profiles (“isoglycaemia”) are achieved (Figure 1A,C,E, G).4 This phenomenon is called the incretin effect and is attributed to the fact that oral glucose leads to the release of incretin hormones (glucose-dependent insulinotropic polypeptide, GIP, and glucagon-like peptide-1, GLP-1) from specialized entero-endocrine cells in the gut (coupled to the absorption of glucose), while intravenous glucose does not.4,5 The gut hormones released in response to nutrient absorption are endocrine signals to the islets of Langerhans in the pancreas, augmenting insulin secretion and modulating glucagon secretion whenever plasma glucose concentrations are above a threshold value of approximately 66 mg dL−1. The physiological stimulation of insulin secretion through incretin hormones is substantial,7 while physiological degrees of hyperglycaemia are a rather weak stimulus for insulin release.4
The estimate of the contribution of incretin hormones to insulin secretory responses after oral glucose administration depends on the dose of glucose employed, and may vary between 25% and 75%.
Of the three signals originating from the gut and reaching the endocrine pancreas (substrates such as glucose, incretin hormones, and neural signals transmitted by the autonomic nervous system, Figure 2),5 incretin hormones make the most substantial contribution under physiological circumstances.
2.1 | Incretin hormones (GIP, GLP-1)
Glucose-dependent insulinotropic polypeptide was purified using a bioassay measuring the inhibition of gastric acid secretion, and hence the old name “gastric inhibitory polypeptide”.9 The main function later was identified as glucose-dependent augmentation of insulin secretion.10 GIP is produced in K cells, which are single cells located to the mucosa in the duodenum and upper jejunum.9
2.2 | Secretion of incretin hormones in healthy human subjects
GIP and GLP-1 have low (basal) plasma concentrations in the low picomolar range (10−12 mol L−1) in fasting human subjects. GIP and GLP-1 plasma concentrations start to rise a few minutes after nutrient intake, reach a peak after approximately 1 h, and reach basal concentrations again after several hours. Nutrients that stimulate the secretion of GIP and GLP-1 are glucose and other carbohydrates including sucrose and starch, triglycerides, and some amino acids as well as proteins.4,16 Protein is a comparatively weak stimulus.
GLP-1 secretion from L cells occurs early after nutrient intake, almost in parallel with GIP secretion, despite the more distal location of L cells.4,13
Both GIP and GLP-1 are substrates of DPP-4 and are physiologically degraded and inactivated by DPP-4.
2.3 | Insulinotropic activitiy of incretin hormones in healthy human subjects
Both GIP and GLP-1 stimulate insulin secretion in a glucosedependent manner.7,24 ß cells have GIP and GLP-1 receptors in their cell membranes, which, once stimulated by the binding of their respective ligands, are coupled to adenylate cyclase, which enhances cyclic AMP (adenosine monophosphate) production and thus activates protein kinase A.25 This pathway cannot initiate the release of pre-formed insulin secretory granules from ß cells, which requires closing of potassium channels, depolarization, and calcium ion influx, as initiated by hyperglycaemia. Therefore, insulinotropic actions of incretin hormones always require a permissive degree of hyperglycaemia.
The role of incretin hormones is to augment the insulin secretory responses initiated by hyperglycaemia. Therefore, incretin hormones cannot provoke episodes of hyperglycaemia. The absolute glycaemic threshold below which GLP-1 cannot stimulate insulin secretion, even at supra-physiological concentrations, was identified as approximately 66 mg dL−1.24 Conversely, the higher the glucose concentrations, the greater the degree of augmentation.
2.4 | Incretin hormones and glucagon secretion
In addition to their insulinotropic activity, incretin hormones affect glucagon release. GIP has been found to stimulate glucagon secretion,26 especially at lower glucose concentrations, while GLP-1 suppresses glucagon secretion, in particular at hyperglycaemia.19 The latter leads to a reduced hepatic glucose production.27
2.5 | Physiological role of individual and combined incretin hormones in healthy human subject
There is no doubt that in healthy human subjects the insulinotropic effects of GIP and GLP-1 are additive, that is, a combined administration of GIP and GLP-1 will lead to an insulin secretory response that is equivalent to the sum of the responses elicited by GIP or GLP-1 alone.31
2.6 | Open questions in incretin physiology
Recently, the dogma that proglucagon processing leads to pancreatic glucagon in α cells in the endocrine pancreas and to GLP-1 and GLP- 2 in intestinal L cells has been challenged. Intestinal production of glucagon was suggested after total pancreatectomy in human subjects,40 and GLP-1 has been found to be present in pancreatic α cells.41
3 | ADDITIONAL BIOLOGICAL EFFECTS OF INCRETIN HORMONES
The definition of an incretin hormone entirely relates to the secretion from the gut after nutrient intake and the insulinotropic action at physiologically stimulated concentrations.5 Thus, even additional actions within the endocrine pancreas (such as the suppression of glucagon secretion, the stimulation of proinsulin biosynthesis, the stimulation of ß-cell neogenesis or proliferation, etc.) are beyond the narrow definition of an incretin hormone. However, there is ample evidence that the incretin hormones GIP and GLP-1 have additional biological effects that add important facets to their overall spectrum of activity. This is particularly true in the case of GLP-1 (Table 1,Figure 3).
3.1 | Appetite, caloric intake, body weight
GLP-1 administered into the central nervous system,43 but also into the general circulation,44 reduces appetite and food intake and increases satiety. The relevant GLP-1 receptors seem to be in the hypothalamus.45
3.2 | Triglyceride storage in adipose tissue
GIP receptor knock-out mice do not develop obesity with hypercaloric feeding.48 This and the fact that GIP induces lipoprotein lipase,49 the enzyme that releases fatty acids from chylomicron triglycerides in adipose tissue and thus promotes the elimination of chylomicron triglycerides,50 has led to the hypothesis that GIP may promote fat storage in subcutaneous adipose tissue. Mostly, this is based on animal studies, and it remains uncertain whether this translates to the human situation.
3.3 | Gastric emptying, intestinal transit
GIP has no effect on gastric emptying,51 while exogenous GLP-1, both at physiological and pharmacological concentrations, slows gastric emptying.33
3.4 | Bone metabolism
Mainly based on the phenotype of GIP and GLP-1 receptor knockout mice, a role for both incretin hormones in the formation and maintenance of bone mass has been suggested (Table 1, Figure 3).
3.5 | Cardiovascular function
GLP-1 has multiple effects in the cardiovascular system, which have been extensively reviewed.55,118 Beneficial effects of GLP-1 receptor agonists in high-risk patients have renewed the interest in elucidating the mechanisms underlying these benefits.55,118
In most cases, these effects were shown with high doses/concentrations of GLP-1. A physiological role of GLP-1 in the cardiovascular system is not known.
4 | INCRETIN HORMONES IN OBESITY
4.1 | Secretion and action of incretin hormones in obese, non-diabetic subjects
Some studies suggest that there is hypersecretion of GIP in obesity,120 which might be related to compensatory insulin hypersecretion that may occur as an attempt to overcome the metabolic consequences of insulin resistance.121 Regarding the secretion of GLP-1 in obesity, reduced increments in meal-related GLP-1 responses have been described with increasing body mass index,122–124 in particular in the presence of hepatic steatosis.125 The incretin effect has been reported to be decreased in obesity,123 even in the absence of impaired glucose tolerance or diabetes mellitus. This may be explained by a reduced responsiveness to GIP or by a reduced contribution of GLP-1 (achieving lower concentrations after physiological nutrient stimulation) to insulin secretory responses.123 Details have not been studied.
4.2 | Role of GIP and/or GLP-1 in the etiology of obesity
5 | ROLE OF GLP-1 IN MEDIATING EFFECTS OF BARIATRIC SURGERY ON WEIGHT LOSS AND ON GLYCAEMIC CONTROL (DIABETES REMISSION)
Surgery is used to achieve significant reductions in body weight in obese subjects, and to induce diabetes remission, if obesity is associated with type 2 diabetes. The most frequently performed procedures are Roux-en-Y gastric bypass and sleeve gastrectomy. Bariatric surgery results in major changes in the pattern of gastrointestinal hormone secretion, including the secretion of GIP and GLP-1, as well as of other gut hormones produced in the lower small intestines (e.g., peptide YY, PYY, produced in L cells like GLP-1). The most striking change is in the secretion of GLP-1: GLP-1 concentrations reach levels far above the physiological range, most likely because nutrients are rapidly delivered into distal areas of the gut characterized by a high L-cell density.128
6 | INCRETIN HORMONES IN TYPE 2 DIABETES
6.1 | Secretion of incretin hormones in type 2 diabetic subjects
Incretin hormones are secreted in subjects with type 2 diabetes much like in healthy and obese subjects.137–139.
Metaanalyses suggest that there are no systematic differences in the nutrient-induced secretion of GIP and GLP-1 between healthy and type 2 diabetic subjects,137–139 against a background of substantial inter-individual variation in secretory responses (vide supra).
6.2 | Insulinotropic activitiy of incretin hormones in type 2 diabetic subjects
While the secretion of incretin hormones is more or less normal in type 2 diabetes, the characteristic abnormalities are in the insulinotropic activities of GIP and GLP-1.
There is no doubt that physiological, and certainly pharmacological, concentrations of GLP-1 elicit insulinotropic (and glucagonostatic) effect in subjects with type 2 diabetes.19 However, the effects are reduced in magnitude as compared to healthy subjects.
6.3 | Role of incretin hormones in the pathophysiology of type 2 diabetes (reduced incretin
effect)
When the incretin effect is quantified in subjects with type 2 diabetes, it is found much reduced or absent in comparison to healthy subjects (Figure 1).3,39,147 The most likely explanation is the inability to respond appropriately to GIP19,144 (which in healthy subjects mediates the major proportion of the incretin effect, vide supra) and the rather minor role GLP-1 plays in the mediation of the incretin effect in healthy subject (so that even the relatively preserved effectiveness of GLP-1 in type 2 diabetic patients does not really matter much).31 Thus, in type 2 diabetic patients, a mechanism, which in healthy subjects contributes approximately two-thirds to the insulin secretory response after oral glucose, is largely impaired or even no longer operative. This is likely to have functional consequences.
One question arises: Does the inability to respond to GIP with an insulin secretory response represent a defect preceding (and potentially driving) the development of diabetes? Or is it a consequence of the diabetic state? Numerous studies have suggested that this defect (the inability to respond to GIP with a substantially augmented release of insulin) and a reduced incretin effect occur after the diagnosis of diabetes is established, suggesting these consequences to be secondary.148
Another question is whether the inability to secrete insulin in response to GIP is related specifically to abnormalities in the stimulus–secretion coupling for the GIP pathway, such as a reduced expression of GIP receptors or other components of the signaltransduction pathway,159 or may rather be related to more general features of the type 2 diabetic endocrine pancreas, namely reductions in ß-cell mass and functional insulin secretory capacity.4,148
While the abnormalities in the incretin system, foremost the inability of the endocrine pancreas to respond to GIP, do not seem to be involved in the progression from pre-diabetic states to manifest diabetes mellitus,148 they may well contribute to the progression that is typical for this disease. It is likely that the loss of a major physiological mechanism stimulating insulin secretion will further deteriorate glycaemic control, leading to a vicious cycle by worsening glucose toxicity, which in turn may reduce ß-cell mass and functional capacity and the expression of GIP receptors and a progressive reduction in the incretin effect (Figure 4).
7 | THERAPEUTIC POTENTIAL OF INCRETIN HORMONES IN TYPE 2 DIABETES (GLP-1 RECEPTOR AGONISTS AND DPP-4 INHIBITORS)
Based on the physiological effects described above in great detail, there is no obvious therapeutic potential for GIP in type 2 diabetes, because it has only negligible effects on insulin secretion in such patients, because it rather increases glucagon secretion, and because there are no measurable effects of even supra-physiological doses/ concentrations on plasma glucose concentrations.
On the contrary, the therapeutic potential of GLP-1 for the treatment of obesity and type 2 diabetes is obvious, since the parent compound itself is able to reduce hyperglycaemia both in the fasting and postprandial state.1,2
Referência :
(1) Diabetes Obes Metab. 2018 Feb;20 Suppl 1:5-21.