Diabetes Obes Metab. 2017 Mar;19(3):412-420. doi: 10.1111/dom.12836.

Effect of exenatide on postprandial glucose fluxes, lipolysis, and β-cell function in non-diabetic, morbidly obese patients.

Camastra S1, Astiarraga B1, Tura A2, Frascerra S1, Ciociaro D3, Mari A2, Gastaldelli A3, Ferrannini E3.

1 Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

2 Institute of Neurosciences, C.N.R., Padua, Italy.

3 Institute of Clinical Physiology, C.N.R., Pisa, Italy.




To investigate the effect of exenatide on glucose disposal, insulin secretion, β-cell function, lipolysis and hormone concentrations in non-diabetic, morbidly obese subjects under physiological conditions.


Patients were assigned to exenatide 10 µg twice daily (EXE, n = 15) or control (CT, n = 15) for 3 months. Patients received a meal test/tracer study (MTT) to measure endogenous glucose production (EGP), rate of oral glucose appearance (RaO), insulin secretion rate (ISR), β-cell function, hepatic insulin resistance (HIR), adipose tissue insulin resistance (AT-IR) and insulin sensitivity (IS).


Post-treatment, the EXE group showed a significant reduction in body weight (P<0.001). The postmeal time-course of glucose, insulin and ISR showed a lower peak between 60 and 180 minutes in phase with a reduction in RaO (P<0.01). After an initial similar suppression, EGP resumed at higher rates between 60 and 180 minutes (P=0.02) in EXE vs CT, while total RaO and EGP were similar throughout the MTT. In EXE, the postmeal glucagon, GLP1 and GIP responses were reduced (P<0.05). Fasting and postprandial lipolysis and β-cell function were unaltered by active treatment. HIR, AT-IR and IS were all improved after exenatide treatment (P<0.05).


In morbidly obese, non-diabetic subjects, exenatide causes weight loss, decreased postprandial glycaemia and glucagon response without changes in β-cell function. These effects are consequent upon delayed oral glucose appearance in the circulation. Exenatide treatment is also associated with an improvement in hepatic, adipose tissue and whole-body IS with no influence on postprandial lipolysis. © 2016 John Wiley & Sons Ltd.

KEYWORDS: GLP-1 receptor agonists; endogenous glucose production; exenatide; glucagon; glucose metabolism; insulin resistance; insulin secretion; lipolysis

PMID: 27898183 DOI:10.1111/dom.12836


Supplemental information:

Exenatide (EXE) is an analogue of GLP-1 that belongs to the class of GLP-1 receptor agonists (GLP-1RA); its use is approved for the treatment of type 2 diabetes (T2D). Compared to the native hormone, GLP-1RAs have a longer half life (from 2-3 h to 4-5 days) since the native GLP-1 hormone upon secretion is rapidly degraded (plasma half-life, 1-2 min) and inactivated by the enzyme DPP-4 (1).

The effects of GLP-1RA and EXE are multiple (FIGURE 1). EXE delays gastric empting [2], potentiates glucose-induced insulin secretion and improves β-cell function in diabetic patients [3-5]. EXE therapy is associated with weight loss, which contributes to the beneficial effects of EXE on both glucose and lipid metabolism. Some peripheral effects of GLP-1, like delayed glucose emptying, are probably mediated by the action of GLP-1 on the central nervous system. [1, 6]. Due to their effect on weight loss, the use of GLP-1RAs has been extended to the treatment of nondiabetic obese patients [7-9].



Figure 1. Schematic representation of the mechanisms of action of exenatide. The effects of the GLP-1 agonist exenatide occurs mostly through the engagement the GLP-1 receptors in specific tissues. The actions of exenatide in muscle, liver and adipose tissue are believed to be mediated by indirect mechanisms.


The studies on the peripheral effects of GLP-1 on glucose metabolism demonstrated that GLP-1 does not affect muscle insulin sensitivity [10-12], but improvements in both hepatic and adipose tissue insulin resistance have been observed [12-14]. Whether GLP-1 has a direct or indirect effect on liver and adipose tissue has still to be elucidated. In T2D patients, the infusion of exenatide during a mixed meal reduced the rate of oral glucose appearance and decreased endogenous glucose production (EGP) and glucagon release [2]. The acute administration of EXE decreased EGP and increased hepatic glucose uptake during the OGTT [13] .

The effect of GLP-1 on lipolysis is not clear. In vitro studies showed a lipolytic effect of GLP-1 in isolated rat adipocytes [15] and in adipocytes from obese patients [16]. In vivo, GLP-1 infusion in healthy volunteers did not influence whole-body lipolysis [12]; on the contrary, in diabetic patients, EXE administration acutely enhanced the antilipolytic effect of insulin and reduced plasma FFA levels during the OGTT [13]. The same effect was observed by chronic treatment with liraglutide [17].

Few studies have analysed the impact of exenatide on glucose turnover, insulin secretion and lipolysis under physiological conditions [15, 16, 18] since this requires the use of tracers. The tracer technique, although complex, allows to accurately measure in vivo glucose and lipid metabolism and to quantify flux rates through several metabolic pathways. The infusion/ingestion of stable isotope tracers during a metabolic challenge (a mixed meal test or an OGTT) represents a powerful weapon to measure in a single test the mechanisms of action of antihyperglycemic drugs and their effects on lipid and glucose metabolism [19]. Moreover, mathematical modelling of C-peptide concentration (i.e., deconvolution) makes it possible to measure postprandial insulin secretion and its potentiation due to gastrointestinal hormones and glucose, themselves indices of β-cell function (FIGURE 2). An index of postprandial insulin sensitivity, i.e. the Oral Glucose Insulin sensitivity index OGIS [20], can be calculated using the plasma glucose and insulin levels after the mixed meal test (MTT) or OGTT.



Figure 2. Schematic representation of the mixed meal test combined with the triple-tracer technique. In the upper box are presented the main parameters derived from the mathematical modeling using C-peptide deconvolution (on the left) and from the tracer technique (on the right).


The present work employed tracer methodology in morbidly obese non-diabetic subjects before and after three months of EXE treatment to evaluate the response of glucose and lipid metabolism and β-cell function to a mixed meal test (MTT). We measured changes in glucose absorption, clearance and production, lipolysis, fasting and post meal insulin secretion and the β-cell response to the meal challenge. The combination of the mixed meal with three isotopic tracers (2 intravenous and one per os) combined with non-steady state mathematical models of tracer kinetics [21, 22], allowed us to quantify fasting and postprandial glucose and glycerol fluxes (Figure 2).

In particular the fasting and postprandial endogenous glucose production (EGP, from infused 6,6-[2H2]glucose), the rate of oral glucose appearance in the circulation after meal ingestion (RaO, from the oral glucose labeled with 1-[13C]glucose), and the fasting and postmeal lipolysis (RaGly, from the rate of glycerol appearance from infused [5H5]glycerol). In addition, indexes of insulin resistance at the level of the liver (HIR) and of the adipose tissue (AT-IR) were calculated as the product of fasting EGP and fasting RaGly, respectively, and fasting plasma insulin concentration (plasma insulin is a strong inhibitory stimulus for both EGP and lipolysis [13]).

The meal consisted of 75 g of glucose as an aqueous solution, 50 g of parmesan cheese and one 50-g egg, for a total of 585 kcal (18% protein, 31% fat and 51% carbohydrate). The choice of parmesan and egg was due to the fact that they do not contain carbohydrates. This is crucial since to follow the absorption of the ingested glucose plus its tracer, it is important to know the exact amount of glucose in the meal.

In our patients, three months of exenatide treatment (injected twice daily) led to an average weight loss of 5.5±1.0% of body weight. The glucose response to the meal ingestion was reduced with an improvement in insulin sensitivity. The tracer analysis suggested the mechanism of these metabolic changes. In the exenatide-treated patients the rate of appearance of oral glucose in the systemic circulation was clearly reduced between 2-3 hours following meal ingestion, but oral glucose was still appearing in the circulation six hours after the meal (FIGURE 3). Thus, there was no difference in the total amount recovered in the systemic circulation (FIGURE 4). This result was likely a consequence of the drug-induced delay in gastric empting, a known effect of EXE (FIGURE 1) [23, 24] and resulted in lower plasma glucose, insulin and glucagone levels. Consequently, insulin secretion rate was reduced, despite EXE, confirming that plasma glucose is the primary secretory stimulus under physiological conditions.



Figure 3. The major components of glycemia during the meal test are shown. The rate of oral glucose appearance (RaO; red line) in the systemic circulation was reduced after exenatide treatment (panel B) compared to pre-treatment (panel A) in the second and third hour following meal ingestion. Glucose was still appearing in circulation six hours after meal ingestion. Endogenous glucose production (EGP; blue line) was less suppressed after exenatide treatment (panel B) compared to pre-treatment (panel A). The plasma glucose profile measured during the meal test is shown as a grey shadow. Data are mean±SEM.


Regarding the endogenous glucose release (EGP), in the first 3 hours after meal EGP was less suppressed compared to pre-treatment and to non-treated groups despite a reduction of postprandial glucagon concentration, which has a strong stimulatory effect on EGP. This result is only apparently contradictory and can be explained by the fact that the glucagon/ insulin ratio, i.e. the balance between the hormonal stimulatory and inhibitory effects, was increased after 3 months of EXE.

Another finding of this study is that exenatide, in our patients with obesity but with preserved β-cell function, did not change any parameter of β-cell function, despite the changes in postmeal glucose fluxes and in the temporal pattern of postprandial insulin secretion.

With regard to lipolysis, the rate of lipolysis was unchanged in the exenatide group after the mixed meal despite lower insulin levels, suggesting an improvement in adipose tissue insulin sensitivity, i.e. the postprandial antilipolytic effect of insulin. In agreement with this result, the fasting and meal-derived indices of insulin sensitivity (HIR, AT-IR, OGIS) confirmed the improvement in insulin action on EGP, lipolysis, and glucose uptake following exenatide treatment.

In summary, exenatide treatment determines, in addition to weight loss, an improvement in hepatic, adipose tissue, and whole-body insulin sensitivity in non-diabetic morbidly obese patients. Furthermore, by slowing gastric empting, exenatide delays oral glucose appearance and postprandial glycemic excursions, maintaining the total amount of ingested glucose recovered in the systemic circulation. Insulin secretion rate follows a similar pattern, whereby endogenous glucose production is less suppressed in the 2nd and 3rd hour postmeal, very likely as a result of the reduced insulin-to-glucagon ratio. These changes occur without any alteration of β-cell function.



Figure 4. Area under the curve (AUC) of the rate of oral glucose appearance in the systemic circulation (AUC RaO). The bars on the left show the AUC of the RaO calculated between 0 and 180 minutes after meal ingestion before treatment (blue) and after exenatide treatment (green). The bars on the right show the AUC of the RaO calculated over the six hours following meal ingestion before (blue) and after exenatide treatment (green). Data are mean±SEM.



1. Muscogiuri G, DeFronzo RA, Gastaldelli A, Holst JJ. Glucagon-like Peptide-1 and the Central/Peripheral Nervous System: Crosstalk in Diabetes.Trends Endocrinol Metab. 2017;28(2):88-103.
2. Cervera, A., Wajcberg E, Sriwijitkamol A, et al., Mechanism of action of exenatide to reduce postprandial hyperglycemia in type 2 diabetes. Am J Physiol Endocrinol Metab, 2008; 294: E846-52.
3. Schnabel CA, Wintle M, Kolterman O. Metabolic effects of the incretin mimetic exenatide in the treatment of type 2 diabetes. Vasc Health Risk Manag 2006; 2:69-77.
4. Mari A, Nielsen LL, Nanayakkara N, et al Mathematical modeling shows exenatide improved beta-cell function in patients with type 2 diabetes treated with metformin or metformin and a sulfonylurea. Horm Metab Res 2006; 38:838-44.
5. Gastaldelli, A., Brodows R.G., D’Alessio D. The effect of chronic twice daily exenatide treatment on beta-cell function in new onset type 2 diabetes. Clinical Endocrinology, 2014; 80: 545-53.
6. Daniele G, Iozzo P, Molina-Carrion M, et al. Exenatide Regulates Cerebral Glucose Metabolism in Brain Areas Associated With Glucose Homeostasis and Reward System. Diabetes. 2015; 64(10):3406-12
7. Pi-Sunyer X, Astrup A, Fujioka K, et al. for the SCALE Obesity and Prediabetes NN8022-1839 Study Group A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management N Engl J Med 2015; 373:11-22
8. Wilding JP, Overgaard RV, Jacobsen LV, et al. Exposure-response analyses of liraglutide 3.0 mg for weight management. Diabetes Obes Metab 2016; 18:491-9.
9. Nuffer WA, Trujillo JM. Liraglutide: A New Option for the Treatment of Obesity. Pharmacotherapy. 2015; 35: 926-34.
10. Orskov L, Holst JJ, Moller J, et al.  GLP-1 does not acutely affect insulin sensitivity in healthy man. Diabetologia 1996; 39:1227-32.
11. Ahren B, Larsson H, Holst JJ. Effects of glucagon-like peptide-1 on islet function and insulin sensitivity in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1997; 82:473-8.
12. Seghieri M, Rebelos E, Gastaldelli A, et al. Direct effect of GLP-1 infusion on endogenous glucose production in humans. Diabetologia. 2013; 56:156-61.
13. Gastaldelli A, Gaggini M, Daniele G et al. Exenatide improves both hepatic and adipose tissue insulin resistance: A dynamic PET study. Hepatology. 2016; 64 (6); 2028-37
14. Prigeon RL, Quddusi S, Paty B, D’Alessio DA. Suppression of glucose production by GLP-1 independent of islet hormones: a novel extrapancreatic effect. Am J Physiol Endocrinol Metab 2003; 285:E701-7.
15. Ruiz-Grande C1, Alarcón C, Mérida E, Valverde I. Lipolytic action of glucagon-like peptides in isolated rat adipocytes. Peptides. 1992;13 :13-6.
16. Sancho V, Trigo MV, MartínDuce A, et al. Effect of GLP-1 on D-glucose transport, lipolysis and lipogenesis in adipocytes of obese subjects: International Journal of Molecular Medicine. 2006; 17: 1133-1137
17. Armstrong MJ, Hull D, Guo K, et al. Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatohepatitis. J Hepatol. 2016; 64:399-408.
18. Cersosimo E, Gastaldelli A, Cervera A, et al. Effect of Exenatide on Splanchnic and Peripheral Glucose Metabolism in Type 2 Diabetic Subjects. J Clin Endocr Metab 2011; 96: 1763-70..
19. Camastra S . Translational Research Methods for Diabetes, Obesity and Cardiometabolic Drug Development: A Focus on Early Phase Clinical Studies Andrew J. Krentz, Lutz Heinemann, Marcus Hompesch (Eds); Editrice Springer 2007; Pharmaceutical Medicine, 2016, Volume 30, Issue 3, pp 165–167
20. Mari A, Pacini G, Murphy E, Ludvik B, Nolan JJ. A model-based method for assessing insulin sensitivity from the oral glucose tolerance test. Diabetes Care. 2001; 24:539-48. Erratum in: Diabetes Care. 2014; 37(7):2063
21. Gastaldelli A, Coggan A. R, Wolfe R.R. Assessment of methods for improving tracer estimation of non-steady-state rate of appearance. Journal of Applied Physiology. 1999; 87:1813-1822
22. Camastra, S. Muscelli, E. Gastaldelli, et al. E. Long-term effects of bariatric surgery on meal disposal and β-cell function in diabetic and nondiabetic patients. Diabetes. 2013; 62: 3709-17.
23. Linnebjerg, H., S. Park, P. A. Kothare, M. E. et al. Effect of exenatide on gastric emptying and relationship to postprandial glycemia in type 2 diabetes. Regul. Pept. 2008; 151:123–129.
24. Kolterman OG, Buse JB, Fineman MS, et al., Synthetic exendin-4 (exenatide) significantly reduces postprandial and fasting plasma glucose in subjects with type 2 diabetes. J Clin Endocrinol Metab, 2003. 88: 3082-9.