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Amylin Pharmaceuticals, Inc., San Diego, California 92121
Address all correspondence and requests for reprints to: Andrew A. Young, M.D., Ph.D., Amylin Pharmaceuticals, Inc., 9360 Towne Centre Drive, Suite 110, San Diego, California 92121. E-mail: ayoung{at}amylin.com.
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Abstract |
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Introduction |
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In mammals, exendin-4 is resistant to degradation by dipeptidyl peptidase-IV and has a much longer plasma half-life than GLP-1 (6), which is degraded by dipeptidyl peptidase-IV with a half-life of less than 2 min (7, 8). Due to exendin-4’s prolonged duration of action (9), prolonged pharmacokinetics (6), and high apparent in vivo potency (9), compared with GLP-1, it has received attention as a potential pharmacological candidate.
Exenatide (exendin-4) and GLP-1 share many glucoregulatory activities, including glucose-dependent enhancement of insulin secretion (10, 11, 12, 13), glucose-dependent suppression of inappropriately high glucagon secretion (12, 13, 14), slowing of gastric emptying (14, 15), and reduction of food intake (16, 17, 18). In addition, exenatide has been shown to restore first-phase insulin secretion (19, 20) and promote ß-cell proliferation and islet neogenesis from precursor cells in both in vitro and in vivo models (21).
Despite the uncertainty of a direct effect on insulin sensitive tissues (2), there is a consensus that exenatide increases whole-body insulin sensitivity in several animal models of diabetes (2, 21), including the Zucker diabetic fatty (ZDF) rat (9), a model of type 2 diabetes (22). However, the mechanism of this insulin-sensitizing effect is unclear. Glucose lowering per se, with a variety of agents, including those not classed as insulin sensitizing, has been reported to increase insulin sensitivity in diverse study designs in humans and rodents. Insulin therapy alone increased insulin sensitivity 10–39% in humans (23, 24, 25). Increases between 3 and 55% (median 32%) have been reported with thiazolidinediones (26, 27, 28, 29, 30, 31, 32), between 11 and 32% with metformin (23, 24), and from no effect (33) to a 42% increase with sulfonylureas (24, 25, 34, 35, 36, 37). Thus, one question addressed in the present study is whether the previously described effects of exenatide on insulin sensitivity, appetite, and body weight are distinct from its antidiabetic effect.
The nondiabetic obese fa/fa Zucker rat, a partially outbred strain, has the same mutation in the leptin receptor as the ZDF rat and is hyperphagic, obese, and insulin resistant (22). However, in contrast to the ZDF rat strain, plasma glucose concentrations in nondiabetic obese fa/fa Zucker rats are normal or only mildly elevated, compared with age-matched lean Zucker rats, because they are able to accommodate insulin resistance with a compensatory islet hypertrophy and hyperinsulinemia. Thus, the nondiabetic obese fa/fa Zucker rat can be used to study effects on insulin resistance that are somewhat independent of glycemic improvement.
Loss of glucose in the urine of diabetic ZDF rats, reversal of this caloric loss with glucose-lowering doses of exenatide, and a simultaneous reduction in caloric intake, are factors that confound the identification of insulin-sensitizing mechanisms in the diabetic rat model. To help identify the contribution of a decreased caloric intake, effects in exenatide-treated animals were compared with effects in pair-fed animals restricted to the same food intake. The effect of exenatide on ß-cell mass was also examined. Because ß-cell mass is sensitive to glycemia and insulin demand, effects needed to be considered in a context in which these influences were equalized or otherwise accommodated. We show here that in the nondiabetic fa/fa rat model of insulin resistance, exenatide exhibits an insulin-sensitizing effect that is partially, but not fully, attributable to changes in food intake and largely independent of glycemic improvement. Independent of effects on metabolic parameters, exenatide also exhibits a trophic effect on ß-cell mass.
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Materials and Methods |
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Treatment regimen
Studies were initiated when the rats were approximately 9 wk of age, after at least 1 wk of acclimatization to the animal facility. Fasting plasma samples for measurement of glucose, insulin, lipids, and hemoglobin A1c (HbA1c) were collected from the topically anesthetized tail (Hurricaine: 20% topical benzocaine solution, Beutlich, Waukegan, IL) on d 0, 14, 28, and 41 from rats fasted approximately 15 h. Food intake and body weight were measured daily. On d 0, animals were distributed on the basis of matched HbA1c into the following three treatment groups: vehicle, 100 µl of 0.9% saline twice daily (BID) fed ad libitum (CON, n = 11); exenatide, 3 µg/kg BID fed ad libitum (EX, n = 10); and pair-fed vehicle, 100 µl of 0.9% saline BID pair fed with EX rats (PF, n = 10). Treatment was continued for 6 wk and discontinued 24 h before the animals underwent a euglycemic hyperinsulinemic clamp procedure. The purpose of the 24-h delay was to ensure that a negligible fraction of the estimated 600 pM maximum concentration after sc dosing remained, thereby allowing the residual effect of treatment on insulin sensitivity and ß-cell function to be measured, uncontaminated by ongoing incretin activity. For the sc exenatide dose used in the present study, a 24-h period encompasses approximately 16 half-lives (6), leaving approximately 0.01 pM (a concentration unassociated with any reported response) at the time of the clamp.
Hyperinsulinemic euglycemic clamp procedure
Clamp procedures (38) were performed after an overnight fast (CON, n = 9; EX, n = 9; PF, n = 8). Five rats that completed 6 wk of treatment and contributed plasma analytes did not complete the clamp procedure. The rats were tracheotomized and catheterized via the femoral artery to record arterial pressure (Biopac Systems, Santa Barbara, CA) and for glucose/lactate measurements (YSI 2300 STAT analyzer; YSI Inc., Yellow Springs, OH) and via the femoral vein for infusion of recombinant human insulin (Humulin R, Eli Lilly, Indianapolis, IN) and 20% glucose. Animals were maintained under isoflurane anesthesia for the entire procedure, starting 60 min before glucose infusion (t = –60 min). Saline (0.9% at 1 ml/h) was infused into the femoral artery to maintain fluid homeostasis, starting at t = –60 min. At t = –30 min, the rats were administered an iv 180 nmol/kg (30 U/kg) bolus of insulin, followed by a continuous infusion (14.5 mmol/liter; 2.4 U/ml) at a rate of 0.6 nmol/kg·min (100 mU/kg·min). Plasma glucose concentrations were monitored every 10 min. When glucose concentrations approached euglycemia, 20% glucose was infused at a variable rate to maintain glucose concentrations of 5.8 mM (105 mg/dl) (start at t = 0 min). The clamp was continued for a further 3 h. Samples for glucose were taken at intervals starting at t = –60 min and ending at t = 180 min. Samples for insulin measurements were taken at t = 0, 45, 150, and 180 min. The insulin sensitivity index (ISI) at 180 min was calculated by dividing the glucose infusion rate required to maintain euglycemia by the steady-state plasma insulin concentration.
Assays
For the 6-wk treatment period, endogenous rat insulin was quantitated using a rat insulin RIA (Linco Research Inc., St. Charles, MO). For the clamp studies, human insulin was quantitated using a human insulin RIA (Linco). The Cobas Mira Plus (Roche Diagnostics, Indianapolis, IN) was used for fasting glucose and lipid measurements. The DCA2000 (Bayer Corp., Elkhart, IN) was used for measuring HbA1c.
Histological assessment of ß-cell mass
A subset of rats completing the clamp procedure was killed by isoflurane overdose and cervical dislocation (CON, n = 5; EX, n = 6; PF, n = 5). The pancreas was removed from each animal, cleared of fat and lymph nodes, weighed, and fixed in 3.7% formaldehyde in PBS (pH 7.4), for 60 min in a flattened position. Each pancreas was separated into gastrosplenic (head) and duodenal/biliary (body) portions, and tissue was sequentially transferred to 15 and 30% sucrose, and Tris-buffered saline tissue-freezing media (Fisher Scientific, Los Angeles, CA) and frozen at –70 C before sectioning.
Frozen tissue sections 15 µm thick were prepared from pancreata using a model OTF cryostat (Bright Instruments Co. Ltd., Cambridgeshire, UK) and placed on Superfrost/Plus slides (Fisher Scientific) at –20 C. Fifty consecutive sections from each block of tissue (two per pancreas) were prepared. Insulin was detected immunohistochemically using a guinea pig antihuman insulin serum (Linco) as the primary antibody. Relative to human insulin, this serum is 46% cross-reactive to rat insulin and does not detectably react with glucagon, somatostatin, or pancreatic polypeptide. For imaging, an antiguinea pig secondary antibody was conjugated with CY2 (Jackson ImmunoResearch Laboratories Inc., West Grove, PA) on the tissue sections (each sixth specimen of consecutive sections). Each section was also counterstained with hematoxylin (S3309, Dako, Carpinteria, CA) and mounted in aqueous media with antifading agents (Biomeda BM-M01, Fisher Scientific). Slides were read using a BH2 fluorescent microscope with a SpotRT digital camera (Olympus, Temecula, CA) and analyzed using Image-Pro Plus 4.1 software (DataCell Ltd., North Chelmsford, MA). Ten sections for each pancreas were stained and examined blindly by two investigators. Six representative sections for each pancreas were chosen for analysis. Each whole section was assayed for the presence and quantity of ß-cells, and a minimum of 120 images of ß-cells per pancreas were assayed.
ß-Cell area was quantitated using the total area immunostained for insulin in multiple representative tissue sections from both portions of the pancreas, similar to the methodology described in Finegood et al. (39). This system consisted of an Olympus BH2 fluorescent microscope (x10 objective) equipped with a SpotRT digital camera (Olympus) and Image-Pro Plus 4.1 software (DataCell Ltd.). The system was pixel calibrated. The relative cross-sectional area of ß-cells was determined by quantitation of the area occupied by fluorescently labeled ß-cells (all fields with ß-cells present, a minimum of 20 images) and the cross-sectional area of all tissue determined on hematoxylin-stained slides. ß-Cell areas were determined by marking the threshold of the captured image for green fluorescence and the total tissue for blue color. ß-Cell mass per piece was estimated as the product of the cross-sectional area of ß-cell/total tissue and the weight of the pancreas piece before fixation. Total ß-cell mass was the sum of the estimates from the two pieces of pancreas. ß-Cell mass determinations were performed in a blinded fashion by two individuals. Total ß-cell mass was calculated by multiplying total pancreatic weight by the fraction of the pancreatic cross-section occupied by insulin-containing cells.
Statistical analysis
Statistical significance between groups was evaluated by unpaired Student’s t test or testing for general effects by one-way ANOVA followed by Tukey-Kramer multiple comparisons (InStat, version 3.06, GraphPad Software Inc., San Diego, CA). Monotonic association was tested using Spearman’s rank correlation (InStat, version 3.06, GraphPad Software). All values are presented as mean ± SEM.
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Results |
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. By design, all treatment groups had similar baseline HbA1c values. After 6 wk of treatment, EX and PF obese fa/fa Zucker rats remained well matched with regard to average daily food intake, body weight, HbA1c, fasting plasma glucose concentration, fasting plasma insulin concentration, and fasting plasma total cholesterol concentration (P > 0.05 for each analyte). In contrast, food intake, body weight, HbA1c, and fasting plasma insulin concentration were all significantly reduced in EX and PF, compared with the corresponding values in the CON group (P < 0.05 for each analyte). Weight gain was significantly less in EX and PF rats (166 ± 8 and 181 ± 11 g, respectively), compared with weight gain in CON rats (237 ± 6 g; P < 0.001 for each comparison).
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Fasting plasma insulin concentration similarly increased in CON rats (P < 0.001 vs. baseline). Values in EX and PF rats did not change and thus became different from CON at 6 wk (P < 0.001 for each comparison).
Fasting plasma total cholesterol concentrations increased over 6 wk in all treatment groups (P < 0.03 vs. baseline) but did not differ among treatment groups (P > 0.05 for each comparison). Neither were there differences among groups in posttreatment fasting plasma high-density lipoprotein (HDL) concentrations (P > 0.05 for each comparison), even though plasma HDL concentrations increased in all groups (P < 0.001 vs. baseline).
Effects on insulin sensitivity measured by euglycemic clamp
Results from hyperinsulinemic euglycemic clamps performed approximately 24 h after the last treatment and after an overnight fast are shown in Fig. 1. Plasma insulin concentrations during euglycemia (time weighted for t = 0–180 min) did not differ among EX, PF, and CON rats (180 ± 11, 184 ± 7, and 175 ± 6 nM, respectively; P > 0.05). Plasma glucose concentrations during the 60- to 180-min steady-state interval also did not differ among EX, PF, and CON rats (5.9 ± 0.1, 5.9 ± 0.1, 6.0 ± 0.1 mM, respectively; P > 0.05).
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The ISI (glucose infusion rate to plasma insulin concentration) in EX rats was 224% higher than that in CON rats (P < 0.0001) and 61% higher than in PF rats (P < 0.003). ISI was inversely related to fasting plasma insulin concentrations measured before the clamp procedure (see Table 1
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Effects on pancreas
Total pancreatic weight did not differ among treatment groups (1.98 ± 0.09, 1.95 ± 0.09, 1.76 ± 0.12 g; Fig. 2A). Absolute ß-cell mass was decreased by 36% in EX rats (115 ± 9 mg/pancreas, P < 0.02) and 26% in PF rats (134 ± 30 mg/pancreas, P > 0.05), compared with CON rats (181 ± 24 mg/pancreas), in which HbA1c, fasting insulin, and body weight were higher (Fig. 2B). Absolute ß-cell mass mirrored changes in fasting insulin levels (Spearman rank correlation R = 0.485, P = 0.057). In the absence of exenatide treatment (i.e. with CON and PF groups combined), there was a reciprocal relationship between insulin sensitivity index and ß-cell mass (see Fig. 3A). ß-Cell mass was least in the most insulin-sensitive animals (those with least insulin demand), and was greatest in those with greatest insulin demand (the most insulin-resistant animals). The reciprocity of these two factors was manifest in the product of ß-cell mass * ISI in CON and PF groups being similar. To accommodate the contribution of observed changes in insulin sensitivity in the analysis of the influence of exenatide on ß-cell mass, the product of ß-cell mass * ISI in EX was compared with that in CON and PF and was found to be greater (P < 0.02 and P < 0.03, respectively; Fig. 3B). Treatment-specific changes in unadjusted ß-cell mass occurred in parallel with changes in fasting insulin levels (Table 1). The 63% increase in (ß-cell mass * ISI) in EX rats, compared with PF rats, well matched in other metabolic measures, therefore signifies a greater ß-cell mass than would be predicted for animals of comparable insulin sensitivity.
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Discussion |
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Chronic exenatide treatment for 6 wk reduced the mild increases in HbA1c, fasting endogenous insulin, and plasma cholesterol concentrations that occur in the normal progression of this disease model, with minimal effects on fasting plasma concentrations of glucose. The matching between PF and EX groups was sufficiently precise and global to allow a robust identification of an effect of exenatide on increased insulin sensitivity independent of body weight and glycemic changes. The large increase in insulin sensitivity observed in the present study with exenatide is reminiscent of a previous report of an 88% increase in clamp insulin sensitivity and a 2.4-fold increase in muscle glucose uptake after chronic administration of GLP-1 in rats (40). Thus, chronic administration of exenatide and GLP-1 appears to be associated with increases in insulin sensitivity.
The present study is the first to show that exenatide can improve insulin sensitivity, independent of decreasing glucose and body weight, pointing to mechanisms other than reversal of glucotoxicity and lipotoxicity. A number of studies have examined the abilities of exenatide to increase pancreatic ß-cell mass in vivo (21). In a partial pancreatectomy (90–95%) rat model of ß-cell insufficiency, the daily administration of exenatide for 10 d post pancreatectomy attenuated the development of diabetes and stimulated an expansion of ß-cell mass and cell proliferation (41). In the Goto-Kakizaki rat, a genetic model of type 2 diabetes in which a deficiency in neonatal ß-cell mass results in nonfasting hyperglycemia, neonatal treatment with exenatide enhanced pancreatic insulin content and total ß-cell mass, and decreased basal plasma glucose levels (42). In neonatal Wistar rats injected with streptozotocin at birth to induce ß-cell destruction, the response to early exenatide exposure was improved islet function and mass (43). In other experiments using neonatal Sprague Dawley rats, Stoffers et al. (44) induced intrauterine growth retardation to produce neonatal rats with deficient islet cell function and mass. Exenatide treatment restored ß-cell mass and glucose tolerance to normal levels. This effect was reportedly due to enhanced ß-cell proliferation and pancreatic duodenal homeobox-1 (PDX-1) expression, compared with vehicle-treated growth-retarded rats. One report described increased ß-cell proliferation in diabetic db/db mice treated with exenatide for 15 d (45), although another study reported improved glucose tolerance and increased insulin secretion and a 1.4-fold increase in ß-cell mass in db/db mice treated with exenatide (46). Treatment with exenatide increased pancreatic expression of PDX-1, in association with enhanced islet neogenesis, stimulated insulin secretion, lowered blood glucose, and reduced HbA1c in db/db mice (47).
Insulin sensitivity and insulin secretion are mutually related such that insulin resistance is compensated by increased insulin secretion. Mathematical analyses of the relationship between insulin sensitivity and insulin secretion has revealed a hyperbolic function, such that the product of the two variables is constant (48, 49). The product (insulin secretion * insulin sensitivity) is usually called the disposition index (50), which is a measure of the power (open-loop gain) of insulin-mediated glucose control. This reciprocal relationship describes the compensatory increase in ß-cell function in the insulin resistance of obesity, pregnancy, and glucocorticoid administration, whereas deviation below the hyperbola identifies defective ß-cell function as an underlying cause of impaired glucose tolerance and type 2 diabetes. The converse analysis of insulin sensitivity and insulin secretion has shown a down-regulation of ß-cell function after increases in insulin sensitivity with weight reduction and exercise (48). Correct judgment of changes in insulin secretory function therefore needs to acknowledge this inverse relationship and requires interpretation in the context of changes in insulin sensitivity and, hence, insulin demand.
To our knowledge, the present work is the first to relate histologically imaged ß-cell mass to insulin sensitivity, quantified in clamp experiments. To the extent that ß-cell mass is an index of insulin secretory capacity, the (ß-cell mass * ISI) product used in the present work is analogous to disposition index, and in the two saline-treated groups (i.e. in the absence of exenatide) was constant (see Fig. 3B). The effect of exenatide in the present experiments was to increase ß-cell mass above that appropriate for the prevailing insulin sensitivity, resulting in a near doubling of the (ß-cell mass * ISI) product. This result is analogous to the increase in disposition index that has been previously reported for GLP-1 (51) and a GLP-1 analog (52) and predicts more powerful glucoregulatory control.
The mechanisms underlying the increase in insulin sensitivity with exenatide remain elusive. Neither exenatide (53) nor GLP-1 (54) has an acute effect on insulin sensitivity measured by clamp in humans, and because neither compound reproducibly activates insulin-sensitive tissues (2), chronic insulin-sensitizing effects are likely to be indirect. A possible effect in liver (55) is debatable, based on the absence of GLP-1 receptors in liver (56) and absence of a specific effect of intraportal (vs. peripheral) GLP-1 on hepatic substrate fluxes (57). The association between exenatide dose and reduction in fasting lactate (9) does, however, point to lactate-generating tissues (especially muscle as the predominant carbohydrate sink) as being involved in the changes in insulin sensitivity.
Summary
In summary, in a nondiabetic rodent model of hyperphagic insulin resistance, we have shown combined effects of exenatide to increase whole-body insulin sensitivity and increase insulin sensitivity-adjusted ß-cell mass. It is likely that the combination of these effects contributes to the antidiabetic actions of exenatide in animal models of diabetes (58) and possibly humans with type 2 diabetes (59, 60).
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Acknowledgments |
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Footnotes |
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First Published Online December 23, 2004
Abbreviations: BID, Twice daily; CON, ad libitum-fed vehicle control; EX, ad libitum-fed exenatide-treated; GLP, glucagon-like peptide; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein; ISI, insulin sensitivity index; PF, pair-fed vehicle control; ZDF, Zucker diabetic fatty.
Received October 13, 2004.
Accepted for publication December 14, 2004.
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-induced insulin resistance in vivo and its prevention by troglitazone. Diabetes 46:1678–1683[Abstract]
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