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This review focuses on GLP-1 physiology and the nutritional modulation of its secretion from enteroendocrine GI cells in the context of obesity and T2D management.
It presents recent evidence on possible mechanisms by which specific foods, as well as nutrients and their by-products, could increase GLP-1 secretion, and subsequently influence appetite, food intake, and blood glucose control. Glucagon-like peptide-1 in the gut-brain-pancreas axis Synthesis, secretion, and metabolism The GI tract accomplishes several functions, namely the digestion of food, the absorption of nutrients, and the secretion of digestive juices, mucus, and peptide hormones.
The epithelium of the GI wall is composed of several cell types, including enteroendocrine cells which are a key component of the gut-brain-pancreas axis [ 12 ].
On their apical surface, enteroendocrine cells possess microvilli expressing several GPCRs that are binding to nutrients and other substrates present in the GI lumen [ 12 ]. GLP-1 is synthesized and secreted by enteroendocrine L-cells which are expressed over a large portion of the GI tract, starting in the proximal small intestine and progressively increasing in density down to the distal part of the colon.
GLP-1 is stored in secretory granules of L-cells until its secretion is triggered, and then uses endocrine and neuronal routes to exert its functions in the pancreas and central nervous system [ 10 ].
In addition to L-cells, GLP-1 is synthesized to a lesser extent by neurons of the nucleus tractus solitarius NTS of the brainstem [ 13 , 14 ]. GLP-1 is produced in two major active forms, namely GLP-1 amide and GLP-1 amide , and is resulting from the differential processing of its precursor proglucagon [ 10 ]. Its synthesis appears to be attributed to tissue-specific expression of pro-hormone convertase 1 and 3 which cleave proglucagon [ 15 ].
Proglucagon is a amino acid inactive precursor of several peptide hormones, including glucagon, oxyntomodulin and GLP-1 [ 16 ]. Proglucagon encoding gene is expressed in the intestine, the pancreas, as well as the central nervous system [ 16 ].
Several studies have confirmed that this gene produces identical messenger ribonucleic acid mRNA transcripts in these major expression sites, but is translated and processed differently, thus producing different bioactive peptides depending on the expressing tissue [ 17 — 19 ].
In the second hour, GLP-1 concentrations start to decrease gradually until the next prandial episode [ 10 ]. Postprandial GLP-1 secretion is influenced by both neuroendocrine and nutritional factors, and exhibits a two-phase release profile that is in fact very similar to that of insulin. When secreted, GLP-1 can activate vagal afferent neural fibres, as well as diffuse into nearby capillaries and then reach the systemic circulation through the portal vein [ 10 ].
Action in the pancreas One of the best-known and probably most important effects of GLP-1 is its ability to stimulate insulin secretion in response to carbohydrate consumption [ 24 — 27 ]. GLP-1 has also been shown to promote insulin gene transcription and biosynthesis [ 28 ].
GLP-1 seems to be responsible for nearly half of the total postprandial insulin secretion [ 29 ]. Nonetheless, the glucose-lowering effects of GLP-1 are not solely related to its insulinotropic effect, but also to its strong inhibition of glucagon secretion [ 10 , 31 ]. Action in the central nervous system In addition to its action in the pancreas, GLP-1 plays a role in both homeostatic and non-homeostatic regulations of food intake, which occur in distinct areas of the central nervous system [ 39 , 40 ].
The homeostatic regulation of food intake, related to short- and long-term energy status, is mainly taking place in the hypothalamus and NTS, areas which convey and integrate numerous peripheral signals [ 39 , 40 ]. The hypothalamus contains several interconnected nuclei, including the arcuate nucleus ARC , the paraventricular nucleus PVN , as well as the dorso-medial nucleus DMN [ 39 , 40 ]. Due to its anatomical position, the ARC plays a critical role in transmitting peripheral information related to energy and nutrient status to other central structures.
Indeed, the ARC is situated in the medio-basal area of the hypothalamus, where the blood-brain barrier is highly permeable, and thus likely has a greater exposition to circulating factors [ 39 ].
Nonetheless, in reason of its short half-life, endogenous GLP-1 released from L-cells is likely mostly acting on the central nervous system by indirectly stimulating neurons of the NTS and ARC via the activation of vagal afferent neurons [ 48 ]. Indeed, GLP-1Rs have been identified on neurons of the nodose ganglion of the vagus nerve [ 43 , 49 ], and the importance of this pathway in the regulation of food intake has been confirmed in rats, where vagal deafferentation decreased the effects of intraperitoneally administered GLP-1 [ 50 , 51 ].
In rodents, acute intraperitoneal, subcutaneous or intravenous administration of GLP-1 and GLP-1 analogues have constantly been shown to reduced meal size, as well as cumulative food and energy intakes [ 51 — 56 ].
Similarly, in humans, acute intravenous administration of GLP-1 and GLP-1 analogues decreased appetite, hunger and food intake, and increased fullness and satiety sensations [ 57 — 62 ]. In addition to physiological energy needs, food intake is driven by non-homeostatic central pathways involved in reward processing and reward-motivated behaviours [ 63 , 64 ]. The palatability of food is a crucial determinant of the decision to eat.
As a result, highly palatable food, typically high in energy, lipids, and simple carbohydrates, can trigger food intake in the absence of physiological energy needs [ 63 , 64 ].
Several central structures, such as the orbitofrontal cortex, insula, amygdala, and striatum play an important role in the processing and evaluation of food cues [ 65 ]. Furthermore, upon food ingestion, dopaminergic neurons send projections from the ventral tegmental area to the nucleus accumbens and other forebrain areas [ 63 , 64 ]. Dopamine release in these areas of the brain is well correlated with meal pleasantness in healthy individuals with a normal body mass index [ 68 ].
Reduced consummatory food reward is associated with compensatory overeating [ 65 — 67 , 69 , 70 ]. GLP-1Rs have been identified in areas of the brain involved in anticipatory and consummatory food reward processing, and neurons of the NTS also share dense neuronal connections with these areas [ 71 , 72 ].
Recent pre-clinical and clinical studies suggest a role of GLP-1 in the modulation of food reward processing. More specifically, the exogenous administration of GLP-1 and GLP-1 analogues appears to influence dopamine neurotransmission in several central areas, and has been associated with decreased anticipatory food reward, increased consummatory food reward and decreased intake of hyperpalatable foods [ 65 , 69 , 70 , 73 — 77 ].
Glucagon-like peptide-1 as a target for obesity and type 2 diabetes management The positive influences of GLP-1 on many metabolic disturbances associated with T2D, as well as key determinants of weight loss and weight maintenance, make it a therapeutic target with good potential.
GLP-1 has been studied in relation to obesity and T2D pathophysiology and treatment. While few studies have shown contradictory results, it is generally well accepted that obesity and metabolic changes occurring with the development of T2D are associated with a decline in the postprandial secretion of GLP-1 from L-cells [ 78 — 83 ]. As a potential strategy to enhance GLP-1actions, several researchers have investigated the metabolic effects of intravenous administration of GLP-1 analogues.
Interestingly, when receiving the same dose of a GLP-1 analogue, individuals with obesity and T2D exhibited metabolic and appetite responses that were very similar to their healthy counterparts [ 57 — 59 , 62 , 84 , 85 ]. GLP-1Rs agonists are widely used for blood glucose management in individuals with T2D and have recently been approved to use for weight management in the United States [ 88 — 90 ]. Similarly, DDP-IV inhibitors are used alone or in combination with other pharmaceutical agents to inhibit the catabolic deactivation of endogenous GLP-1 [ 88 , 89 ].
All the animals tested recovered from anesthesia after the ERG recording sessions. The range of stimulus intensities extended from 1.
The ERG waveforms were recorded with a band width of 0. OPs occur as a stereotypical series of high-frequency oscillations superimposed in time on the rising phase of the b-wave in response to a high-intensity light flash. A digital band-pass filter 40— Hz was used to isolate the OP components from the original traces, 44 and the peak amplitudes of the first five wavelets were measured from baseline.
A low-pass filter 50 Hz removed the OPs and enabled direct amplitude measurements of the a-wave baseline to negative peak and b-wave a-wave trough to highest positive peak potentials. Flicker responses, tested at frequencies of 4, 8, and 16 Hz, with flash intensities of 8. The flicker responses were recorded at the end of each session to avoid light-adapting the retina.
Cell Isolation and Patch-Clamp Recording Solitary bipolar cells were isolated from the rat retina according to published protocols. After several brief washes, the tissue was triturated through a sterile pipette, and aliquots of the supernatant containing dissociated cells were placed in culture dishes with modified Ames medium.
Most animals became diabetic within 48 hours, but in some the drug took 72 hours to produce its effect. Diabetic animals also manifested polydipsia, polyuria, and glucosuria. Abdominal organomegaly was also noted, but no attempt was made to quantitate organ weights. Diabetic animals also had impaired growth relative to control animals. In contrast, age-matched diabetic animals showed no significant increase in body weight over the course of 12 weeks Fig.
The fact that female rats show little or no weight gain after the onset of hyperglycemia has been reported by other investigators. Control animals showed no signs of lens opacification at any time during the study, whereas mild cataracts were observed in the diabetic animals during the later stages of the study. Figure 1C shows examples of dark-field images of the lenses obtained from a control animal i and from rats after 15 and 25 weeks of diabetes ii and iii, respectively.
By 20 to 25 weeks, lenses isolated from a separate group of diabetic animals had grade III cataracts with coalescing vacuoles that extended to the posterior pole iii. In all cases, the effects were bilateral—that is, lenses from the same animal were of the same grade. Figure 2A illustrates typical ERG waveforms elicited by a brief Ganzfeld flash at various intensities from a control rat first column and a diabetic rat second column at the week time point.
Although there was a slight enhancement of the a-wave amplitude in diabetic animals, the difference was not statistically significant, nor was there a significant difference in the b-wave intensity—response function between diabetic and control animals. ERGs recorded at other time points 4, 8, and 20 weeks gave similar results data not shown.
The slopes n of the corresponding intensity—response functions were also nearly identical. Neuronal Dark Adaptation. The b-wave, generated primarily by the light-evoked radial currents of ON bipolar cells, 47 48 was used to determine whether diabetes alters the kinetics of neural adaptation in the distal retina. ERG responses to a weak test stimulus 8. The two sets of responses showed nearly equivalent peak amplitudesduring the course of dark adaptation, and plotting the normalized amplitude values of the probe response recorded during 90 seconds of dark adaptation Fig.
Oscillatory Potentials. It is well documented that diabetes leads to alterations in the OPs of the flash ERG in humans and animal models. Figure 3A shows the OP responses of the filtered ERG recordings from a control and a diabetic animal at a light intensity of 1.
At this week time point, it is apparent that the OPs from the diabetic rat differed from those of its normal counterpart. The first three wavelets appeared to be smaller, whereas the fourth and fifth tended to be greater than those in the control animal. Of interest, the times-to-peak of each wavelet were unchanged in the diabetic animals, suggesting that the amplitudes, but not the latencies of the responses were affected by the hyperglycemic condition in these female rats. The effect of diabetes on the pattern of the OP wavelets is shown in Figure 3B , which plots the averaged amplitudes of the individual OPs obtained at several light intensities for the eight control and seven diabetic rats, respectively.
In both groups of animals, the OP amplitudes increased as the light intensity was increased. However, the maximum OP amplitude was seen in the third OP in control animals, whereas OP4 had the highest amplitude in diabetic rats at all light intensities tested. The small negativity seen in OP2 when tested at 0.
An example of the changes in OP amplitude observed during a week time period is illustrated in the bar graph of Figure 3C for the fourth wavelet of the response.
At the beginning of the study week 0 , there was no statistical difference in the amplitude of OP4 between the control group and the group of animals designated for STZ injection. At the 4-week time point, the amplitude of the fourth OP had increased significantly in the diabetic animals, and the increase continued at 8 and 12 weeks after injection.
These differences persisted in a pair of diabetic and control animals that we observed for nearly 6 months data not shown. The reduction in the amplitude of the third OP in diabetic rats followed a similar time course data not shown. Flicker ERG. Responses to intermittent stimuli were recorded at frequencies of 4, 8, and 16 Hz with flash intensities of 8. The ERG responses to a flickering light contain multiple components note the small second peak that emerges in the 4-Hz recordings at 3.
The fast Fourier transform has proven valuable in this regard. When the duration of each flash is very brief i. To compare the temporal resolution of the two groups of animals, we analyzed the flicker ERG responses in the frequency domain, and the averaged results are illustrated in Figure 4B.
The three groups of graphs show the mean amplitudes of the fundamental and the second harmonic of the flicker responses at three light intensities. There were no significant changes in the implicit times for the flicker response at any stimulus intensity. It is interesting that the amplitudes of the 8-Hz component were similar, irrespective of whether they were derived as the second harmonic from a 4-Hz stimulus or as the fundamental of an 8-Hz stimulus.
Despite the fact that the 8-Hz stimulus contained double the light intensity of the 4-Hz stimulus, the small difference in 8-Hz responses suggests that rat flicker ERG responses are essentially linear. The same is true for the amplitude of the Hz response component.
Linearity in the temporal response has also been observed in the mouse flicker ERG. At higher intensities, however, significant differences in both harmonics emerged. Specifically, a reduction in the first harmonic of the 8-Hz flicker ERG was seen in diabetic rats at the intermediate intensity of 3. Accordingly, we compared the GABA-induced currents of individual bipolar cells enzymatically dissociated from normal and diabetic retinas.