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Endocrinology Vol. 142, No. 3 1148-1155
Copyright © 2001 by The Endocrine Society

ARTICLES

Monounsaturated Fatty Acid Diets Improve Glycemic Tolerance through Increased Secretion of Glucagon-Like Peptide-11

Antonio S. Rocca2, Jonathon LaGreca3, Juliana Kalitsky3 and Patricia L. Brubaker

Departments of Physiology (A.S.R., J.L.G., J.K., P.L.B.) and Medicine (P.L.B.), University of Toronto, Toronto, Ontario, Canada

Address all correspondence and requests for reprints to: Patricia L. Brubaker, Ph.D., Rm 3366, Medical Sciences Building, 1 King’s College Circle, University of Toronto, Toronto, Ontario, Canada, M5S 1A8. E-mail: p.brubaker{at}utoronto.ca


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Diets enriched in monounsaturated fatty acids (MUFA)s have been shown to benefit glycemic control. Furthermore, MUFAs specifically stimulate secretion of the antidiabetic hormone, Glucagon-like peptide-1 (GLP-1) in vitro. To determine whether the MUFA-induced benefit in glycemic tolerance in vivo is due to increased GLP-1 release, lean Zucker rats were pair-fed a synthetic diet containing 5% fat derived from either olive oil (OO; 74% MUFA) or coconut oil (CO; 87% saturated fatty acids; SFA) for 2 weeks. Food intake and body weight gain were similar for both groups over the feeding period. The OO group had improved glycemic tolerance compared with the CO group in both oral and duodenal glucose tolerance tests [area under curve (AUC) 121 ± 61 vs. 290 ± 24 mM·120 min, P < 0.05; and 112 ± 28 vs. 266 ± 65 mM·120 min, P < 0.05, respectively]. This was accompanied by increased secretion of gut glucagon-like immunoreactivity (gGLI; an index of GLP-1 levels) in the OO rats compared with the CO rats (402 ± 96 vs. 229 ± 33 pg/ml at t = 10 min, P < 0.05). Tissue levels of GLP-1 and plasma insulin and glucagon levels were not different between the two groups. To determine the total contribution of GLP-1 to the enhanced glycemic tolerance in OO rats, the GLP-1 receptor antagonist exendin9–39 (Ex9–39) was infused 3 min before a duodenal glucose tolerance test. Ex9–39 abolished the benefit in glycemic tolerance conferred by OO feeding (OO+Ex9–39 vs. CO+Ex9–39, P = NS), and resulted in a deterioration of glycemic tolerance in the OO+Ex9–39 group when compared with the OO controls (AUC 331 ± 21 vs. 112 ± 28 mM·120 min, P < 0.05). To probe the mechanism by which the OO diet enhanced GLP-1 secretion, a GLP-1-secreting L cell line was incubated for 24 h with either 100 µM oleic acid (MUFA) or 100 µM palmitic acid (SFA) and subsequently challenged with GIP, a known stimulator of the L cell. Preexposure to oleic acid but not to palmitic acid significantly increased GIP-induced GLP-1 secretion when compared with controls (55 ± 12% vs. 34 ± 9%, P < 0.01). These results demonstrate that the benefit in glycemic tolerance obtained with MUFA diets occurs in association with increased GLP-1 secretion, through a mechanism of enhanced L cell sensitivity. These results suggest that diet therapy with MUFAs may be useful for the treatment of patients with impaired glucose tolerance and/or type 2 diabetes through increased GLP-1 secretion.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE INTESTINAL hormone glucagon-like peptide-1 (GLP-1) represents a potential therapeutic agent in the treatment of the insulin resistance and relative insulin deficiency that characterize type 2 diabetes. GLP-1 is one of two major incretin hormones that are secreted from the intestinal tract upon nutrient ingestion and that act to increase insulin secretion. Produced from the proglucagon molecule by tissue-specific posttranslational processing within the ileal L cell (1, 2), GLP-1 is secreted promptly after ingestion of carbohydrate and fat (3, 4). GLP-1 receptor activation within the pancreatic islets results in an increase in glucose-dependent insulin secretion, as well as inhibition of glucagon release (5, 6, 7, 8, 9, 10). This ability to decrease glucagon secretion suggests that GLP-1 therapy may also be applicable to patients with type 1 diabetes (11). GLP-1 action in the stomach also reduces gastric acid secretion and gastric motility (12, 13), thereby decreasing the rate at which ingested nutrients are absorbed, whereas in peripheral tissues, GLP-1 may increase sensitivity to insulin (14, 15, 16). Recent evidence also indicates a role for GLP-1 in the central mechanisms that contribute to satiety (17). Therefore, these actions suggest a potential role for GLP-1 in the treatment of patients with diabetes.

One approach to the therapeutic use of GLP-1 is to enhance its endogenous secretion, in an effort to avoid the compliance issues related to the necessary injections of peptide hormones. A number of studies have been performed that have examined the factors that regulate the secretion of GLP-1. These have indicated that GLP-1 secretion from the ileal L cell is governed by humoral, neural, and nutrient factors. Glucose-dependent insulinotropic peptide (GIP), a hormone released from the K cells of the duodenum, has been demonstrated to increase the secretion of GLP-1 in several experimental models (18, 19, 20), although not in humans (10), whereas somatostatin (18) and insulin (21) are inhibitory to the L cell. Agents of the nervous system such as adrenergic (22) and cholinergic (18, 23, 24) agonists, and the neuropeptide, gastrin-releasing peptide (GRP) (18, 22, 25), also stimulate GLP-1 secretion. However, as the L cells of the ileum are also exposed to luminal contents, perhaps the most important regulation of GLP-1 secretion is derived from digested nutrients, particularly carbohydrate and fat. Both carbohydrates and fat potently stimulate the secretion of GLP-1 (3, 4) and appear to act in an indirect manner because peak GLP-1 levels occur within 30 min of nutrient ingestion, a time frame that is not consistent with the delivery of these nutrients to the ileal L cell (26). However, certain fatty acids have also been shown to directly stimulate the L cell. Specifically, it has been determined that monounsaturated fatty acids (MUFA) are stimulatory to GLP-1 secretion, whereas saturated fatty acids (SFA) are not (27). Furthermore, the chain length of the fatty acid is an important factor in determining GLP-1 secretion, as only long chain MUFA (>=C16) were found to stimulate the L cell in vitro.

MUFA diets are being increasingly advocated for use in the treatment of patients with type 2 diabetes. Previously, diets high in carbohydrate content were recommended to patients with diabetes, primarily to decrease the cardiovascular risks associated with high levels of saturated fat (28). However, diets high in carbohydrate may be detrimental to glycemic control (29). In contrast, several studies have demonstrated that diets with increased proportions of MUFAs, compared with high carbohydrate diets, produce improvements in glycemic control and also provide benefit to lipid profiles [e.g. decreased triglycerides and very low-density lipoprotein (29, 30, 31, 32, 33, 34, 35)]. Glucagon levels are also elevated in patients who are fed diets high in carbohydrates compared with high MUFA diets (29). Given the benefits to glucose homeostasis produced by the many actions of GLP-1, and the finding that MUFAs potently stimulate the secretion of GLP-1 in vitro, the present study was undertaken to explore the potential link between increased GLP-1 secretion and the benefits in glycemia induced by diets containing MUFAs compared with SFAs.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Diets and feeding
Lean Zucker male rats (Fa/?; Charles River Laboratories, Inc. Canada Inc., St. Constant, Canada) were used at 7–8 weeks of age in all experiments. All animal procedures were approved by the Animal Care Committee of the University of Toronto. The animals were acclimatized in individual cages with free access to food and water for 1 week. Chow was provided in separate canisters, which were used to determine daily food intake. Subsequent to the acclimatization period, groups of animals were pair-fed on synthetic diets enriched with either MUFAs or SFAs. The dietary composition and energy content of each diet are listed in Table 1Go. In brief, each diet was composed of 75% carbohydrates, 20% protein, and 5% fat (Harlan Teklad, Madison, WI). The fat component of the MUFA diet was derived entirely from olive oil (74% MUFA), whereas the fat component of the SFA diet was derived entirely from coconut oil (87% SFA). All other constituents of the synthetic diets were identical between the two groups. Rats were maintained on the synthetic diets for a period of 2 weeks during which food intake and body weight were monitored daily. Following the 2-week feeding period, rats were fasted overnight (commencing at 1700) and underwent experiments the following day (commencing at 0900). Fasting glycemia was 4.5 ± 0.3 mM across all experiments.


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  		Table 1. Composition and energy content of synthetic rat diets

 
Glucose tolerance tests
Oral glucose tolerance tests (OGTT) were performed on conscious animals. In brief, a bolus of 10% glucose was administered by gastric gavage at a dose of 1 g/kg body weight. Tails were anesthetized with Xylocaine (Astra Pharma, Mississauga, Ontario, Canada) and blood samples were obtained at t = 0, 10, 20, 30, 60, 90, and 120 min for determination of blood glucose using a One Touch Basic blood glucose monitoring system (Lifescan Canada Ltd., Burnaby, British Columbia, Canada).

Duodenal glucose tolerance tests (DGGT) were also performed to avoid any potential effects of GLP-1 on gastric emptying (13). Rats were anesthetized with 60 mg/kg pentobarbital, and the portal vein was cannulated for blood sampling. A bolus of 10% glucose (1 g/kg body weight) was injected into the duodenum, and blood samples were obtained from the tail vein as for the OGTT. In addition, blood was also collected from the portal vein into 10% (vol/vol) Trasylol (5000 Kalikrein Inactivating Units/ml; Bayer Corp., Inc., Etobicoke, Ontario, Canada)-EDTA (12 mg/ml)-diprotin A (34 µg/ml; Calbiochem, La Jolla, CA), and plasma was stored at -20 C until time of RIA. In some experiments, Ex (9–39) (Bachem California, Inc., Torrance, CA), a GLP-1 receptor antagonist (36), or vehicle control was administered as a bolus dose through a jugular cannula at a dose of 18.3 nmol/kg (61.7 µg/kg), 3 min before the administration of duodenal glucose. This protocol was derived from a similar study in which Ex (9–39) infusion antagonized the effect of GLP-1 on glycemic profiles in rats (37).

GLUTag cell cultures
The GLUTag cell line is an L cell model derived from intestinal tumors induced in transgenic mice by expression of the SV40 large T antigen under the control of the proglucagon promoter (38). GLUTag cultures were maintained in DMEM with 10% FBS. At the time of experiment, GLUTag cells were trypsinized and plated into 24-well culture plates and allowed to grow to 60–80% confluence. The cells were then rinsed with HBSS and exposed to either normal experimental media (DMEM with 1% FBS; control), or experimental media containing either 100 µM oleic or palmitic acid (Sigma, St. Louis, MO) for 24 h. Media was then removed and replaced with either normal experimental media or media containing 100 nM human GIP (Bachem California, Inc. Torrance, CA) for 2 h. Following the incubation period, media were collected in trifluoroacetic acid (TFA) to a final concentration of 0.1% and small peptides and proteins were extracted by reversed-phase adsorption on a C18 silica cartridge (C18 Sep-Pak, Waters Associates, Milford, MA). The recovery of intact proglucagon-derived peptides with this protocol is greater than 88% (39).

Assays
Plasma samples were analyzed by RIA for gGLI, which correlates directly with GLP-1 levels in the rat in vivo (23). Briefly, gGLI is derived by subtracting immunoreactive glucagon (IRG), determined in 0.2 ml plasma using antiserum 04A (Dr. R. H. Unger, Dallas, TX), from total glucagon-like immunoreactivity (GLI), determined using 0.1 ml plasma with antiserum K4023 (Biospacific, Emeryville, CA). Plasma insulin levels were determined using an immunoreactive insulin kit (Linco Research, Inc., St. Charles, MO).

Five-centimeter segments of ileum were homogenized in 1 N HCl containing 5% (vol/vol) HCOOH, 1% (vol/vol) TFA, and 1% (vol/vol) NaCl. Extraction of small peptides and proteins was carried out by reversed-phase adsorption, as above. Ileal and cell culture media extracts were analyzed by RIA for GLP-1 using a GLP-1 antiserum (Affiniti Research Products, Mammead, UK) directed against the carboxy-terminus of the peptide. This antiserum has been shown to recognize predominantly GLP-1 (7–36NH2) in extracts of ileum and GLUTag cells (38, 40). Protein levels in ileal extracts were assayed by the Lowry Protein method (41).

Fatty acid composition of the plasma was determined by gas chromatography in the laboratory of Dr. S. Cunnane (University of Toronto, Toronto, Ontario, Canada), as previously described (42).

Data analysis
Area-under-the-curve (AUC) of glycemic profiles was determined according to the trapezoidal rule. All data are expressed as mean ± SEM. Statistical analysis was assessed by Student’s t test or ANOVA followed by n-1 posthoc custom hypothesis tests, as appropriate, on Statistical Analysis System Software (SAS Institute, Inc., Cary, NC). Significance was established to be at the P < 0.05 level.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Food intake and body weight
Food intake during the paired feeding protocol was monitored daily and did not differ significantly between the OO group and the CO group for the duration of the feeding period (Fig. 1AGo). As a result, the two groups of rats gained weight at similar rates over the 2-week course of feeding (Fig. 1BGo). As deficiencies in the levels of essential fatty acids can cause impaired glucose tolerance (43), circulating essential fatty acids were determined in rats from each group. Levels of essential fatty acids were not significantly different between the two groups of animals (Fig. 1CGo), consistent with previous studies demonstrating that a two week feeding protocol preserves the levels of essential fatty acids (44, 45).



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  		Figure 1. Changes in food intake and body weight and essential fatty acids. Lean Zucker rats were fed diets containing either 5% olive oil (solid line) or 5% coconut oil (dashed line) for 2 weeks. A, Food intake and (B) changes in body weight are expressed. C, Levels of essential fatty acids (EFA) obtained from animals at the end of the 2-week feeding protocol are expressed as a percentage of total fatty acids.

 
Oral glucose tolerance tests
Following the 2-week feeding period, rats in both the OO and CO groups were challenged with an oral load of glucose and blood glucose was monitored over the following 2-h period. Overall, glycemic responses were reduced in rats that received the OO diet compared with those rats fed the CO diet (Fig. 2AGo). OO-fed rats displayed a lower peak in glycemia when compared with the CO group (P < 0.05). Furthermore, the OO group demonstrated better glycemic tolerance as evidenced by the return to baseline in blood glucose at t = 120 min in the OO but not the CO group (P < 0.05). When the glycemic response was quantified over the entire 120-min period, OO-fed rats were found to have a significantly reduced glycemic AUC compared with CO-fed rats (121 ± 61 vs. 290 ± 24 mM·120 min, respectively P < 0.05) (Fig. 2BGo).



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  		Figure 2. Effect of 2-week fat feeding on oral glucose tolerance test. Oral glucose tolerance test in lean Zucker rats fed diets containing either 5% olive oil (solid line) or 5% coconut oil (dashed line) for 2 weeks. The change in blood glucose above basal is depicted (fasting glycemia was 4.8 ± 0.3 and 3.0 ± 0.1 mM in OO and CO rats, respectively). B, The area under the glycemic response curves is also plotted. (*, P < 0.05).

 
Duodenal glucose tolerance tests
In a separate group of animals, DGTTs were performed to avoid the inhibitory effects of GLP-1 on gastric emptying (13). Similar results to those achieved with the OGTTs were obtained in this set of experiments (Fig. 3AGo), such that peak glycemia was again lower and blood glucose returned to baseline in OO-fed rats in contrast to the rats fed the CO diet (Fig. 3AGo). The glycemic AUC was also significantly reduced in the OO compared with the CO group (112 ± 28 vs. 266 ± 65 mM·120 min, respectively. P < 0.05) (Fig. 3BGo). During the DGTTs, blood was also sampled from the portal vein for the determination of hormone levels. Although insulin and glucagon levels were not different between the two groups of animals (Fig. 4Go), plasma gGLI levels were significantly elevated at the 10 min time-point in the OO-fed rats as compared with the CO group (402 ± 96 pg/ml vs. 229 ± 33 pg/ml respectively, P < 0.05) (Fig. 5AGo). In contrast, the ileal content of GLP-1 was not significantly different between the OO- and CO-fed rats (Fig. 5BGo).



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  		Figure 3. Effects of 2-week fat feeding on duodenal glucose tolerance tests. A, Duodenal glucose tolerance test in lean Zucker rats fed diets containing either 5% olive oil (solid line) or 5% coconut oil (dashed line) for 2 weeks. The change in blood glycemia above basal is expressed (fasting glycemia was 4.7 ± 0.5 and 4.8 ± 0.3 mM in OO and CO rats, respectively). B, The area under the glycemic response curves is also plotted. (*, P < 0.05).

 


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  		Figure 4. Insulin and glucagon levels during duodenal glucose tolerance tests. Plasma levels of (A) insulin and (B) immunoreactive glucagon (IRG) during a duodenal glucose tolerance test in lean Zucker rats fed diets containing either 5% olive oil (solid line) or 5% coconut oil (dashed line) for 2 weeks.

 


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  		Figure 5. Plasma levels of gGLI in animals undergoing two week feeding study. A, Plasma levels of gut glucagon-like immunoreactivity (gGLI) during a duodenal glucose tolerance test, and (B) tissue levels of glucagon-like peptide-1 (GLP-1), in lean Zucker rats fed diets containing either 5% olive oil (solid line) or 5% coconut oil (dashed line) for 2 weeks. (*, P < 0.05).

 
Duodenal glucose tolerance tests + Ex (9–39) infusions
To establish whether different GLP-1 levels between the OO- and CO-fed groups were responsible for the observed differences in glucose tolerance, DGTTs were carried out with concomitant administration of the GLP-1 receptor antagonist, Ex (9–39). Preinfusion of Ex (9–39) completely abolished the observed benefit in glucose tolerance produced by the OO diet (Fig. 6Go). Peak glucose levels were higher, glycemia remained elevated above baseline for the entire experimental period, and the glycemic AUC was elevated in OO-fed rats that received Ex (9–39) compared with OO rats receiving a saline (control) infusion (331 ± 21 vs. 112 ± 28 mM·120 min, P < 0.05; Fig. 6CGo). In contrast, Ex (9–39) treatment did not alter the glycemic response to an oral glucose challenge in CO-fed rats (272 ± 120 vs. 266 ± 65 mM·120 min [CO+Ex9 vs. CO+saline]). Plasma insulin levels were not significantly different between the OO- and the CO-fed rats throughout the experimental period (data not shown), however, after infusion with Ex (9–39), glucagon levels rose dramatically and to a similar extent in both the OO- and CO-fed animals (Fig. 7Go).



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  		Figure 6. Effect of Exendin(9–39) on duodenal glucose tolerance tests. Duodenal glucose tolerance tests in lean Zucker rats fed diets containing either 5% olive oil (solid line) or 5% coconut oil (dashed line) for 2 weeks. A, Olive oil and coconut oil groups pretreated with exendin(9–39) (18 nmol/kg; fasting glycemia was 5.2 ± 0.4 and 4.7 ± 0.1 mM in OO and CO rats, respectively) (B) olive oil group (solid line; data from Fig. 3AGo) compared with olive oil + exendin(9–39) (dashed line; data from panel A). C, Area under the glycemic excursion curve for olive oil group compared with olive oil rats receiving exendin(9–39). *, P < 0.05.

 


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  		Figure 7. Immunoreactive glucagon levels in rats receiving Exendin(9–39) infusions prior to A duodenal glucose tolerance test. Immunoreactive glucagon (IRG) levels during a duodenal glucose tolerance test. Both olive oil- (solid line) and coconut oil-fed rats (dashed line) received a bolus injection of exendin(9–39) 3 min before the duodenal glucose tolerance test.

 
Effects of MUFA and SFA on GIP-induced GLP-1 secretion in vitro
To determine the effects of chronic exposure to MUFA and SFA on the L cell response to secretagogues, GLUTag cells were preincubated for 24 h in media alone or media containing either oleic acid (MUFA) or palmitic acid (SFA). The 24-h pretreatment was then followed by a 2-h challenge with GIP, a known stimulator of GLP-1 secretion from the L cell (18, 19, 20). Pretreatment with either oleic acid or palmitic acid did not change basal secretion of GLP-1 from that observed in cells treated with media alone (Fig. 8Go). In cells preincubated with media alone, treatment with GIP resulted in a 34 ± 9% (P < 0.05) increase in GLP-1 secretion. In contrast, in cells preincubated with oleic acid, GIP not only induced a significant increase in GLP-1 secretion (by 55 ± 12%; P < 0.01), but this increase was significantly greater than that observed in cells that were preincubated with media alone (P < 0.01). Preincubation of GLUTag cells with media containing 100 µM palmitic acid diminished the subsequent GLP-1 response to the same challenge with GIP (P = NS).



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  		Figure 8. Effects of 24 hour preexposure of GLUTag cells to monounsaturated or saturated fatty acids. Cells were preincubated for 24 h with media alone or media supplemented with 100 µM palmitic or oleic acid. The cells were then challenged for 2 h with either media alone (control; open bars) or 100 nM glucose dependent insulinotropic peptide (solid bars). *, P < 0.05 and ***, P < 0.001 vs. control.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The benefits of diets rich in MUFAs have been reported to include improvements in both lipid status and glycemic control (28, 29, 30, 31, 32, 33, 34, 35, 46). However, few studies have attempted to investigate the mechanisms by which dietary MUFAs mediate these benefits. The demonstration of increased secretion of the antidiabetic hormone GLP-1 in rats following 2 weeks of feeding with an OO diet provides one mechanism for the observed benefit of MUFA to glycemic tolerance. OO feeding, in contrast to feeding with CO, was associated with improvements in glycemic tolerance in rats, as evidenced by lower glycemic AUCs in response to both oral and duodenal glucose tolerance tests. In association with the observed benefit in glycemic tolerance achieved in this study was the concomitant increase in the secretion of gGLI, a molecule released in parallel with the antidiabetic hormone GLP-1 (23). An alternative perspective on this finding is that chronic CO feeding acted to depress GLP-1 secretion in this setting. However, this seems unlikely because oleic acid, the main fatty acid constituent of OO, has been demonstrated to significantly increase GLP-1 secretion in intestinal cultures in vitro (27). Consistent with this finding, OO, but not butter, also stimulates GLP-1 secretion acutely in humans (47).

Curiously, the benefit in glycemic tolerance observed in the MUFA-fed rats persisted for the entire experimental time period (120 min), even though GLP-1 secretion was elevated only at the early time point of the experiment (10 min). This pattern of GLP-1 secretion is consistent with stimulation of the L cell through indirect mechanisms (36, 37) because glucose is rapidly absorbed in the proximal regions of the gastrointestinal tract (36, 37). Thus, glucose does not progress to the distal location of the majority of the L cells under physiological conditions and is therefore incapable of eliciting later peaks in GLP-1 secretion. Therefore, to clearly define the contribution of increased GLP-1 secretion to the benefit in glycemic tolerance induced by MUFA feeding, experiments using a specific inhibitor of the GLP-1 receptor were undertaken. Ex (9–39) is a peptide homologue of GLP-1 isolated from the venom of the Gila monster and has been demonstrated to be a potent antagonist at the GLP-1 receptor (36, 37). Although Ex (9–39) may also interact with the GIP receptor in vitro, this only occurs at extremely high concentrations [1–10 µM (48)], and it is therefore believed that the actions of Ex (9–39) in vivo are largely mediated through the GLP-1 receptor. Ex (9–39) administration before a duodenal glucose challenge in rats fed OO completely abolished the benefit in glycemic tolerance obtained with this diet, therefore demonstrating that the beneficial effects of MUFA feeding on glucose tolerance are specific to activation of the GLP-1 receptor. A similar experiment conducted in the CO group did not significantly alter the glycemic response to the duodenally administered glucose challenge, consistent with the observation that GLP-1 secretion was not elevated in this group. It may also be postulated that the CO diet partly decreased glucose tolerance in the present study, as SFA have been associated with decreases in insulin sensitivity (49, 50). However, the results of the Ex (9–39) study clearly implicate GLP-1 as a causative factor in the enhanced glycemic tolerance conferred by MUFA feeding in the present study.

The fact that the benefit in glycemic tolerance induced by OO feeding in OGTTs was maintained in DGTTs indicates that differences in the rates of gastric emptying were not responsible for the MUFA-induced improvement in glycemic tolerance. This is an important finding, as GLP-1 is known to inhibit gastric emptying as part of its ability to improve glycemic handling (12, 13). Also, as tissue levels of GLP-1 were not significantly different between the two groups of rats, altered synthesis of GLP-1 cannot account for the increased secretion of GLP-1 observed in the OO-fed group. This is also consistent with the fact that fatty acids do not affect total cell content of GLP-1 in vitro (27). Furthermore, the increase in GLP-1 secretion in rats fed OO was not associated with alterations in the plasma levels of either insulin or glucagon. In support of this finding is a recent report that demonstrated that elevated secretion of GLP-1 did not alter insulin levels in normal humans fed a meal supplemented with OO (47). Similarly, GLP-1 administration during an OGTT in rats improves glycemic tolerance in the absence of any effect on insulin secretion (51). Given that the primary stimulator of insulin secretion is the level of glycemia, the fact that glucose levels were diminished in the OO rats despite unaltered plasma levels of insulin demonstrates that the amount of insulin secreted per unit of glycemia must have increased as a result. Therefore, the enhanced secretion of GLP-1 observed in the present study may have benefited glycemic tolerance through its stimulatory effects on the {beta} cell despite the fact that plasma levels of insulin were not different.

However, in this model it is not possible to accurately define the site of the benefit to glycemic tolerance induced by the increased secretion of GLP-1. Thus, the decreased levels of glycemia accompanied by unchanged insulin levels observed in OO-fed rats may also be explained by extrapancreatic-extragastric functions of GLP-1 acting to enhance insulin sensitivity. In support of this concept, GLP-1 has been reported to stimulate glycogen formation in liver cells (52), and GLP-1 receptors have been identified in both muscle and adipose tissue (16, 53, 54). GLP-1 also enhances insulin-dependent and insulin-independent glucose disposal in dogs and humans, respectively (14, 15, 16), although this remains controversial (55). In addition, high-MUFA diets can improve glycemic control when compared with diets high in carbohydrate (46, 56) and have been shown to enhance insulin sensitivity (35). Interestingly, the effects of the qualitative features of dietary fat on insulin sensitivity were examined recently, demonstrating that chronic feeding of diets high in MUFAs improved insulin sensitivity compared with a high SFA diet in healthy human volunteers (33). It is not known whether the dietary manipulation altered the secretion of GLP-1 in these experiments. Additionally, the experiments using the GLP-1 receptor antagonist, Ex (9–39), demonstrated that the deterioration of glycemic tolerance in OO rats was partly attributable to the elevated secretion of glucagon, consistent with a role for GLP-1 in the inhibition of secretion from the {alpha} cell. However, similar increments in glucagon release were also observed in the CO rats, without a comcomitant rise in glycemia. Therefore, the improvements in glycemic tolerance mediated by enhanced secretion of GLP-1 witnessed in the present study are likely attributable to effects on peripheral insulin-sensitive tissues.

Of some interest was the finding that GLP-1 secretion in the OO-fed rats was elevated above basal levels very early during the glucose challenge. Similar rapid increments in GLP-1 secretion have also been observed in humans (3, 4). These findings are inconsistent with the fact that nutrients do not reach the ileal L cell within this time frame (26) and have led to the hypothesis that the early phase of nutrient-induced GLP-1 secretion may be mediated indirectly (57, 58). Indeed, previous studies from our lab have demonstrated that proximal nutrients are incapable of stimulating GLP-1 secretion in the absence of the distal gut (36, 37). In the rat, this indirect regulation of GLP-1 secretion is mediated through complex interactions between the endocrine and nervous systems and involves the enteric hormone GIP (58) and the vagus nerve (23). However, GIP can also directly stimulate the L cell (18, 19, 20), and for this reason, was used to investigate the potential mechanism of action of MUFAs on the L cell. Exposure to oleic acid for 24 h before a 2 h challenge with GIP led to a greater stimulation of GLP-1 secretion compared with the secretion elicited by the same dose of GIP in cells preexposed to media alone. Furthermore, preexposure of the L cells to palmitic acid, a SFA, caused a blunting in the GLP-1 secretion induced by GIP. Therefore, it appears that chronic exposure to MUFAs can enhance the sensitivity of the L cell to subsequent stimulation, resulting in greater levels of GLP-1 secretion, whereas SFAs depress the secretory response to the same stimulus. The cellular mechanism(s) underlying these responses is not known, however, several factors may be speculated to play a role. For example, PKC-{zeta} has been reported to be preferentially activated by unsaturated as opposed to saturated fatty acids (59, 60) and therefore may be implicated in this process. PKC is a known intracellular mediator of GLP-1 secretion (39), and the intestinal L cell expresses the {zeta} isoform of this enzyme (Rocca, A. S., and P. L. Brubaker, unpublished observations). Alternatively, the increased L cell sensitivity to GIP induced by oleic acid may occur consequent to altered membrane fluidity (61), possibly through changes in activity of the intestinal fatty acid binding protein (I-FABP). I-FABP is present in the intestinal L cell (Rocca, A. S., and P. L. Brubaker, unpublished observations) and this molecule is known to influence cell membrane structure and function (62, 63). Further experimentation is clearly required to identify the intracellular mechanism(s) that is responsible for the MUFA-induced increase in L cell sensitivity to GIP stimulation.

In conclusion, the benefits in glycemic control that have been ascribed to diets enriched with MUFAs can be explained, at least in part, by the fact that such diets increase secretion of the antidiabetic hormone GLP-1. Manipulation of dietary fatty acid composition to increase the proportion of MUFAs relative to SFA, may therefore be a useful approach with which to increase the secretion of GLP-1 in patients with impaired glucose tolerance or type 2 diabetes.


   Footnotes
 
1 This work was supported by an operating grant from the Canadian Diabetes Association. Back

2 Supported by graduate studentships from the Banting and Best Diabetes Centre and the Department of Physiology, University of Toronto, and by an Ontario Graduate Studentship. Back

3 Supported by summer studentships from the Banting and Best Diabetes Centre, University of Toronto. Back

Received August 31, 2000.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Holst JJ, Bersani M, Johnsen AH, Kofod H, Hartmann B, Orskov C 1994 Proglucagon processing in porcine and human pancreas. J Biol Chem 269:18827–18833[Abstract/Free Full Text]
  2. Dhanvantari S, Seidah NG, Brubaker PL 1996 Role of prohormone convertases in the tissue-specific processing of proglucagon. Mol Endocrinol 10:342–355[Abstract]
  3. Elliott RM, Morgan LM, Tredger JA, Deacon S, Wright J, Marks V 1993 Glucagon-like peptide-1(7–36)amide and glucose-dependent insulinotropic polypeptide secretion in response to nutrient ingestion in man: acute post-prandial and 24-h secretion patterns. J Endocrinol 138:159–166[Abstract]
  4. D’Alessio D, Thirlby R, Laschansky E, Zebroski H, Ensinck J 1993 Response of tGLP-1 to nutrients in humans. Digestion 54:377–379
  5. Drucker DJ, Philippe J, Mojsov S, Chick WL, Habener JF 1987 Glucagon-like peptide I stimulates insulin gene expression and increases cyclic AMP levels in a rat islet cell line. Proc Natl Acad Sci USA 84:3434–3438[Abstract/Free Full Text]
  6. Mojsov S, Weir GC, Habener JF 1987 Insulinotropin: glucagon-like peptide I(7–37) co-encoded in the glucagon gene is a potent stimulator of insulin release in the perfused rat pancreas. J Clin Invest 79:616–619
  7. Holst JJ, Orskov C, Vagn Nielsen O, Schwartz TW 1987 Truncated glucagon-like peptide I, an insulin-releasing hormone from the distal gut. FEBS Lett 211:169–174[CrossRef][Medline]
  8. Kreymann B, Ghatei MA, Williams G, Bloom SR 1987 Glucagon-like peptide-1 7–36: a physiological incretin in man. Lancet 2:1300–1304[Medline]
  9. Komatsu R, Matsuyama T, Namba M, Watanabe N, Itoh H, Kono N, Tarui S 1989 Glucagonostatic and insulinotropic action of glucagonlike peptide I-(7–36)-amide. Diabetes 38:902–905[Abstract]
  10. Nauck MA, Heimesaat MM, Orskov C, Holst JJ, Ebert R, Creutzfeldt W 1993 Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin Invest 91:301–307
  11. Creutzfeldt WOC, Orskov C, Kleine N, Holst JJ, Willms B, Nauck MA 1996 Glucagonostatic actions and reduction of fasting hyperglycemia by exogenous glucagon-like peptide I(7–36) amide in type I diabetic patients. Diabetes Care 19:580–586[Abstract]
  12. Schjoldager BTG, Mortensen PE, Christiansen J, Orskov C, Holst JJ 1989 GLP-1 (glucagon-like peptide 1) and truncated GLP-1, fragments of human proglucagon, inhibit gastric acid secretion in humans. Dig Dis Sci 34:703–708[CrossRef][Medline]
  13. Schirra J, Katschinski M, Weidmann C, Schäfer T, Wank U, Arnold R, Göke B 1996 Gastric emptying and release of incretin hormones after glucose ingestion in humans. J Clin Invest 97:92–103[Medline]
  14. D’Alessio DA, Kahn SE, Leusner CR, Ensinck JW 1994 Glucagon-like peptide 1 enhances glucose tolerance both by stimulation of insulin release and by increasing insulin-independent glucose disposal. J Clin Invest 93:2263–2266
  15. D’Alessio DA, Prigeon RL, Ensinck JW 1995 Enteral enhancement of glucose disposition by both insulin-dependent and insulin-independent processes—a physiological role of glucagon-like peptide I. Diabetes 44:1433–1437[Abstract]
  16. Sandhu H, Wiesenthal S, MacDonald PE, McCall R, Tchipashvili V, Rashid S, Satkunarajah M, Irwin DM, Shi ZQ, Brubaker PL, Wheeler MB, Vranic M, Efendic S, Giacca A 1999 Glucagon-like peptide-1 increases insulin sensitivity in depancreatized dogs. Diabetes 48:1045–1053[Abstract]
  17. Turton MD, O’Shea D, Gunn I, Beak SA, Edwards CMB, Meeran K, Choi SJ, Taylor GM, Heath MM, Lambert PD, Wilding JPH, Smith DM, Ghatei MA, Herbert J, Bloom SR 1996 A role for glucagon-like peptide-1 in the central regulation of feeding. Nature 379:69–72[CrossRef][Medline]
  18. Brubaker PL 1991 Regulation of intestinal proglucagon-derived peptide secretion by intestinal regulatory peptides. Endocrinology 128:3175–3182[Abstract]
  19. Brubaker PL, Schloos J, Drucker DJ 1998 Regulation of glucagon-like peptide-1 synthesis and secretion in the GLUTag enteroendocrine cell line. Endocrinology 139:4108–4114[Abstract/Free Full Text]
  20. Damholt AB, Buchan AMJ, Kofod H 1998 Glucagon-like-peptide-1 secretion from canine L-cells is increased by glucose-dependent insulinotropic peptide but unaffected by glucose. Endocrinology 139:2085–2091[Abstract/Free Full Text]
  21. Fischer KD, Dhanvantari S, Drucker DJ, Brubaker PL 1997 Intestinal growth is associated with elevated levels of glucagon-like peptide-2 in diabetic rats. Am J Physiol 273:E815–E820
  22. Dumoulin V, Dakka T, Plaisancie P, Chayvialle J-A, Cuber J-C 1995 Regulation of glucagon-like peptide-1-(7–36)amide, peptide YY, and neurotensin secretion by neurotransmitters and gut hormones in the isolated vascularly perfused rat ileum. Endocrinology 136:5182–5188[Abstract]
  23. Rocca AS, Brubaker PL 1999 Role of the vagus nerve in mediating proximal nutrient-induced glucagon-like peptide-1 secretion. Endocrinology 140:1687–1694[Abstract/Free Full Text]
  24. Balks HJ, Holst JJ, Von zur Mühlen A, Brabant G 1997 Rapid oscillations in plasma glucagon-like peptide-1 (GLP- 1) in humans: cholinergic control of GLP-1 secretion via muscarinic receptors. J Clin Endocrinol Metab 82:786–790[Abstract/Free Full Text]
  25. Roberge JN, Gronau KA, Brubaker PL 1996 Gastrin-releasing peptide is a novel mediator of proximal nutrient-induced proglucagon-derived peptide secretion from the distal gut. Endocrinology 137:2383–2388[Abstract]
  26. Ferraris RP, Yasharpour S, Lloyd KCK, Mirzayan R, Diamond JM 1990 Luminal glucose concentrations in the gut under normal conditions. Am J Physiol 259:G822–G837
  27. Rocca AS, Brubaker PL 1995 Stereospecific effects of fatty acids on proglucagon-derived peptide secretion in fetal rat intestinal cultures. Endocrinology 136:5593–5599[Abstract]
  28. Garg A, Grundy SM, Unger RH 1992 Comparison of effects of high and low carbohydrate diets on plasma lipoproteins and insulin sensitivity in patients with mild NIDDM. Diabetes 41:1278–1285[Abstract]
  29. Garg A, Grundy SM, Koffler M 1992 Effect of high carbohydrate intake on hyperglycemia, islet function, and plasma lipoproteins in NIDDM. Diabetes Care 15:1572–1550[Abstract]
  30. Garg A 1994 High-monounsaturated fat diet for diabetic patients. Diabetes Care 17:242–246[Medline]
  31. Riccardi G, Parillo M 1993 Comparison of the metabolic effects of fat-modified vs low fat diets. Ann NY Acad Sci 683:192–198[CrossRef][Medline]
  32. Low CC, Grossman EB, Gumbiner B 1996 Potentiation of effects of weight loss by monounsaturated fatty acids in obese NIDDM patients. Diabetes 45:569–575[Abstract]
  33. Riccardi G, Rivellese AA 2000 Dietary treatment of the metabolic syndrome–the optimal diet. Br J Nutr [Suppl 1] 83:S143–S148
  34. Wright J 1998 Effect of high-carbohydrate versus high-monounsaturated fatty acid diet on metabolic control in diabetes and hyperglycemic patients. Clin Nutr [Suppl 2] 17:35–45
  35. Parillo M, Rivellese AA, Ciardullo B, Giasso A, Genovese S, Riccardi G 1992 A high-monounsaturated-fat/low-carbohydrate diet improves peripheral insulin sensitivity in non-insulin-dependent diabetic patients. Metabolism 41:1373–1378[CrossRef][Medline]
  36. Schirra J, Sturm K, Leicht P, Arnold R, Göke B, Katschinski M 1998 Exendin(9–39)amide is an antagonist of glucagon-like peptide-1(7-36)amide in humans. J Clin Invest 101:1421–1430[Medline]
  37. Kolligs F, Fehmann H-C, Göke R, Göke B 1995 Reduction of the incretin effect in rats by the glucagon-like peptide 1 receptor antagonist exendin (9–39) amide. Diabetes 44:16–19[Abstract]
  38. Drucker DJ, Jin T, Asa SL, Young TA, Brubaker PL 1994 Activation of proglucagon gene transcription by protein kinase A in a novel mouse enteroendocrine cell line. Mol Endocrinol 8:1646–1655[Abstract]
  39. Brubaker PL 1988 Control of glucagon-like immunoreactive peptide secretion from fetal rat intestinal cultures. Endocrinology 123:220–226[Abstract]
  40. Tucker JD, Dhanvantari S, Brubaker PL 1996 Proglucagon processing in islet and intestinal cell lines. Regul Pept 62:29–35[CrossRef][Medline]
  41. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ 1951 Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275[Free Full Text]
  42. Cunnane S, Ryan MA, Craig KS, Brooks S, Koletzko B, Demmelmair H, Singer J, Kyle DJ 1995 Synthesis of linoleate and alpha-linolenate by chain elongation in the rat. Lipids 30:781–783[CrossRef][Medline]
  43. Opara EC, Hubbard VS 1993 Essential fatty acids (EFA): role in pancreatic hormone release and concomitant metabolic effect. J Nutr Biochem 4:498–509[CrossRef]
  44. Dyer JR, Greenwood CE 1991 Dietary essential fatty acids change the fatty acid profile of rat neural mitochondria over time. J Nutr 121:1548–1553
  45. Innis SM 2000 Essential fatty acids in infant nutrition: lessons and limitations from animal studies in relation to studies on infant fatty acid requirements. Am J Clin Nutr 71:238S–244S
  46. Campbell LV, Marmot PE, Dyer JA, Borkman M, Storlien LH 1994 The high-monounsaturated fat diet as a practical alternative for NIDDM. Diabetes Care 17:177–182[Abstract]
  47. Thomsen C, Rasmussen O, Lousen T, Holst JJ, Fenselau S, Schrezenmeir J, Hermansen K 1999 Differential effects of saturated and monounsaturated fatty acids on postprandial lipemia and incretin responses in healthy subjects. Am J Clin Nutr 69:1135–1143[Abstract/Free Full Text]
  48. Gremlich S, Porret A, Hani EH, Cherif D, Vionnet N, Froguel P, Thorens B 208 1995 Cloning, functional expression, and chromosomal localization of the human pancreatic islet glucose-dependent insulinotropic polypeptide receptor. Diabetes 44:1202–1211[Abstract]
  49. Hunnicutt JW, Hardy RW, Williford J, McDonald JM 1994 Saturated fatty acid-induced insulin resistance in rat adipocytes. Diabetes 43:540–545[Abstract]
  50. Manco M, Mingrone G, Greco AV, Capristo E, Gniuli D, De Gaetano A, Gasbarrini G 2000 Insulin resistance directly correlates with increased saturated fatty acids in skeletal muscle triglycerides. Metabolism 49:220–224[CrossRef][Medline]
  51. Hendrick GK, Gjinovci A, Baxter LA, Mojsov S, Wollheim CB, Habener JF, Weir GC 1993 Glucagon-like peptide-1-(7–37) suppresses hyperglycemia in rats. Metabolism 42:1–6[Medline]
  52. Valverde I, Morales M, Clemente F, López-Delgado MI, Delgado E, Perea A, Villanueva-Peñacarrillo ML 1994 Glucagon-like peptide 1: a potent glycogenic hormone. FEBS Lett 349:313–316[CrossRef][Medline]
  53. Wheeler MB, Lu M, Dillon JS, Leng X-H, Boyd III AE 1993 The rat glucagon-like peptide 1 receptor can couple to adenylyl cyclase, phospholipase C and the free cytosolic calcium level. Digestion 54:348–349[CrossRef]
  54. Valverde I, Mérida E, Delgado E, Trapote MA, Villanueva-Peñacarrillo ML 1993 Presence and characterization of glucagon-like peptide-1(7-36)amide receptors in solubilized membranes of rat adipose tissue. Endocrinology 132:75–79[Abstract]
  55. Orskov L, Holst JJ, Moller J, Orskov C, Moller N, Alberti KGMM, Schmitz O 1996 GLP-1 does not acutely affect insulin sensitivity in healthy man. Diabetologia 39:1227–1232[Medline]
  56. Garg A, Bantle JP, Henry RR, Coulston AM, Griver KA, Raatz SK, Brinkley L, Chen YD, Grundy SM, Huet BA 1994 Effects of varying carbohydrate content of diet in patients with non-insulin-dependent diabetes mellitus [see comments]. JAMA 271:1421–1428[Abstract]
  57. Roberge JN, Brubaker PL 1991 Secretion of proglucagon-derived peptides in response to intestinal luminal nutrients. Endocrinology 128:3169–3174[Abstract]
  58. Roberge JN, Brubaker PL 1993 Regulation of intestinal proglucagon-derived peptide secretion by glucose-dependent insulinotropic peptide in a novel enteroendocrine loop. Endocrinology 133:233–240[Abstract]
  59. Nakanishi H, Exton JH 1992 Purification and characterization of the zeta isoform of protein kinase C from bovine kidney. J Biol Chem 267:16347–16354[Abstract/Free Full Text]
  60. Wilkinson SE, Hallam TJ 1994 Protein kinase C: is its pivotal role in cellular activation over-stated. Trends Pharmacol Sci 15:53–57[CrossRef][Medline]
  61. Goldberg EM, Zidovetzki R 1998 Synergistic effects of diacylglycerols and fatty acids on membrane structure and protein kinase C activity. Biochemistry 37:5623–5632[CrossRef][Medline]
  62. Catala A, Arcemis C, Cerruti A 1994 Interaction of rat liver microsomes containing saturated or unsaturated fatty acids with fatty acid binding protein: peroxidation effect. Mol Cell Biochem 137:135–139[CrossRef][Medline]
  63. Woodford JK, Jefferson JR, Wood WG, Hubbell T, Schroeder F 1993 Expression of liver fatty acid binding protein alters plasma membrane lipid composition and structure in transfected L-cell fibroblasts. Biochim Biophys Acta 1145:257–265[Medline]



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