Context: Glucagon-like peptide-1 (GLP-1) and glucose-dependentinsulinotropic polypeptide are incretins secreted from enteroendocrinecells postprandially in part to regulate glucose homeostasis.Dysregulation of these hormones is evident in type 2 diabetesmellitus (T2DM). Two new drugs, exenatide (GLP-1 mimetic) andsitagliptin [dipeptidyl peptidase (DPP) 4 inhibitor], have beenapproved by regulatory agencies for treating T2DM. Liraglutide(GLP-1 mimetic) and vildagliptin (DPP 4 inhibitor) are expectedto arrive on the market soon.
Evidence Acquisition: The background of incretin-based therapyand selected clinical trials of these four drugs are reviewed.A MEDLINE search was conducted for published articles usingthe key words incretin, glucose-dependent insulinotropic polypeptide,GLP-1, exendin-4, exenatide, DPP 4, liraglutide, sitagliptin,and vildagliptin.
Evidence Synthesis: Exenatide and liraglutide are injectionbased. Three-year follow-up data on exenatide showed a sustainedweight loss and glycosylated hemoglobin (HbA1c) reduction of1%. Nausea and vomiting are common. Results from phase 3 studiesare pending on liraglutide. Sitagliptin and vildagliptin areorally active. In 24-wk studies, sitagliptin reduces HbA1c by0.6–0.8% as monotherapy, 1.8% as initial combination therapywith metformin, and 0.7% as add-on therapy to metformin. Vildagliptinmonotherapy lowered HbA1c by 1.0–1.4% after 24 wk. Theirmajor side effects are urinary tract and nasopharyngeal infectionsand headaches. Exenatide and liraglutide cause weight loss,whereas sitagliptin and vildagliptin do not.
Conclusions: The availability of GLP-1 mimetics and DPP 4 inhibitorshas increased our armamentarium for treating T2DM. Unresolvedissues such as the effects of GLP-1 mimetics and DPP 4 inhibitorson β-cell mass, the mechanism by which GLP-1 mimetics lowersglucagon levels, and exactly how DPP 4 inhibitors lead to adecline in plasma glucose levels without an increase in insulinsecretion, need further research.
Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropicpolypeptide (GIP), termed "incretins," are enteroendocrine hormonesreleased into the bloodstream from L and K cells dispersed throughoutthe gastrointestinal tract in response to ingested nutrients.They provide the additional stimulus to insulin secretion duringoral glucose ingestion that is not present with iv glucose infusion(1, 2). These incretins increase insulin secretion in a glucose-dependentmanner through activation of their specific receptors on β-cells.
In newly diagnosed type 2 diabetes mellitus (T2DM) with relativelygood glycemic control [glycosylated hemoglobin (HbA1c) 6.9%],both GIP and GLP-1 secretion in response to glucose and mixedmeal challenges are the same or even increased when comparedwith healthy subjects (3, 4). However, in long-standing T2DMwith poor glycemic control (HbA1c8–9%), the GLP-1 responseis decreased, whereas GIP secretion is unchanged (5, 6, 7).In addition, insulin response to exogenous GLP-1 is 3- to 5-foldlower in T2DM. However, acute GLP-1 administration is able toincrease insulin secretion to normal levels and to lower plasmaglucose effectively (8, 9). In contrast, exogenous GIP, evenat supraphysiological doses, has markedly reduced insulinotropicactions with little or no glucose-lowering effects in T2DM (9,10). Therefore, therapeutic strategies for T2DM within the incretinfield focused on the use of GLP-1, GLP-1 analogs, and GLP-1receptor (GLP-1R) agonists or GLP-1 mimetics, and not GIP.
GLP-1, when administered at pharmacological doses, also hasother noninsulinotropic effects beneficial for treating T2DM:suppression of glucagon secretion in the presence of hyperglycemiaand euglycemia, but not hypoglycemia, leading to improved hepaticinsulin resistance and glycemic control (11, 12); slowing ofgastric emptying and gut motility, causing delayed nutrientabsorption and dampened postprandial glucose (PPG) excursion(13); and increasing the duration of postprandial satiety, leadingto lower food intake, weight loss, and improved insulin resistance(14, 15, 16). More importantly, acute GLP-1 infusion normalizedfasting plasma glucose (FPG) in patients with long-standing,uncontrolled T2DM who were no longer responsive to sulfonylureasor metformin (17).
One major drawback of GLP-1 treatment is its short half-life(2 min) (18). GLP-1 is rapidly degraded by dipeptidyl peptidase(DPP) 4, which cleaves the N-terminal dipeptides (His7-Ala8)from GLP-1 (7–36) and renders the resulting major metaboliteGLP-1 (9–36) inactive (Fig. 1) (19, 20). In addition,neutral endopeptidase (NEP) 24.11 hydrolyzes GLP-1 at six differentplaces (21). With short half-life, bolus sc injections resultedin only a transient effect on insulin secretion and plasma glucoselevels (22).
FIG. 1. Structure of native GLP-1, exenatide, liraglutide, sitagliptin, and vildagliptin. The N-terminal dipeptide "HA" of GLP-1 is cleaved by DPP 4, and the remaining fragment does not increase insulin secretion. For exenatide the substitution of glycine for alanine at position 8 prevents the degradation by DPP 4. The free-fatty acid derivative that is attached to liraglutide is thought to promote noncovalent binding of liraglutide to albumin.
Nonetheless, in patients with T2DM, bolus sc administrationof GLP-1 before breakfast, lunch, and dinner for 7 d significantlyimproved PPG and decreased plasma lipid levels (23). Overnightiv GLP-1 infusions lowered FPG and PPG to near-normal levels,markedly improved β-cell function, and restored first-phaseinsulin secretion, the absence of which is a hallmark of T2DM(24).
Continuous sc GLP-1 infusion via a pump for 6–12 wk improvedglucose-induced insulin secretion, enhanced insulin-mediatedglucose disposal, and increased insulin pulse mass and pulsatileinsulin secretion in T2DM (25, 26). Six weeks of GLP-1 infusionalso restored first-phase insulin secretion in T2DM, therefore,demonstrating the insulinotropic potency of long-term GLP-1treatment (15).
Recent animal studies suggest that exogenous GLP-1 has the abilityto increase islet size, enhance β-cell proliferation, inhibitβ-cell apoptosis, and regulate islet growth (27, 28). Theseeffects have tremendous implication in the treatment of T2DMbecause they directly address one of the fundamental defectsin T2DM, i.e. β-cell failure.
Collectively, the aforementioned studies demonstrated the potentialof using GLP-1-based therapy for treating T2DM. Two optionsfor GLP-1-based therapies are GLP-1 mimetics resistant to DPP4 activity, therefore, a longer half-life, and agents such asDPP 4 inhibitors, which increase plasma endogenous GLP-1 levels.In this review we will focus on: 1) exenatide (GLP-1 mimetic)and sitagliptin (DPP 4 inhibitor), which have been approvedby regulatory agencies for treatment of T2DM, as well as liraglutide(GLP-1 mimetic) and vildagliptin (DPP 4 inhibitor), which areexpected to arrive on the market soon; and 2) issues that arestill open for debate regarding the actions of these agents.
Given that DPP 4 cleaves peptides with an alanine, proline,or hydroxyproline in the penultimate N-terminal position, variousmodifications of GLP-1 at His7, Ala8, or Glu9 have been investigated(29). Additional mid-chain modifications of GLP-1 to preventNEP hydrolysis are also being investigated to provide longerplasma half-life. Exenatide and liraglutide are two compoundsthat exhibit these characteristics.
Exenatide
Exenatide (synthetic exendin-4) is the only GLP-1R agonist approvedby regulatory agencies as an adjunct therapy to patients withT2DM not achieving satisfactory glycemic control. It is a 39-aminoacid peptide produced in the salivary glands of the Gila monster(Heloderma suspectum) with 53% amino acid homology to full-lengthGLP-1. It binds more avidly to GLP-1R than GLP-1 in GLP-1R-expressingcells (30). There appears to be no specific exendin-4 receptor.Exendin-4 is not a substrate for DPP 4 because it has a Gly8in place of an Ala8 (Fig. 1). In addition, it lacks some ofthe target bonds for NEP, and its secondary and tertiary structuresmay also prevent NEP hydrolysis. Exenatide, being a peptide,must be injected sc, and is eliminated by the kidneys throughglomerular filtration (31). It has a mean half-life of 3.3–4h, is detected in the plasma 15 h after sc injection, and hasbiological effect 8 h after dosing (32).
Selected clinical studies
Clinical trials investigating exenatide as adjuvant therapyto patients with T2DM not achieving adequate glycemic controlon metformin and/or sulfonylurea, metformin and/or thiazolidinedione,as well as comparison trials with insulin glargine and biphasicinsulin aspart, are summarized in Table 1 (33, 34, 35, 36, 37,38, 39). With exenatide 10 µg twice daily as adjuvanttherapy to oral hypoglycemic agents, a significant number ofpatients (32–62%) achieved HbA1c of 7% or less when comparedwith placebo (7–13%), glargine (48%), and biphasic insulinaspart (24%), and HbA1c reductions of 0.8–1.1% were sustainedup to 3 yr. Progressive weight loss from 1.6–2.8 kg notedat 30 wk to 5.3 kg at 3 yr was also noted. Antiexenatide antibodieswere detected in 41–49% of patients in the treatment armsbut were not associated with glycemic control (33, 34, 35, 36,37, 38).
Side effects
A metaanalysis on the randomized controlled trials with exenatideshowed that severe hypoglycemia was rare. Mild to moderate hypoglycemiawas 16 vs. 7% (exenatide vs. placebo) and more common with coadministrationwith a sulfonylurea. The most common side effects of exenatidewere nausea (57%) and vomiting (17%). Nausea was usually mildto moderate in nature, and being most common during the initial8 wk therapy and declined thereafter. Overall, 4% of patientswithdrew from the studies because of gastrointestinal side effects(40).
Liraglutide
Liraglutide is a long-acting GLP-1 analog with a substitutionof Lys34 with Arg34, and an attachment of a C-16 free-fattyacid derivative via a glutamoyl spacer to Lys26 (Fig. 1). Thefree-fatty acid derivative is thought to promote noncovalentbinding of liraglutide to albumin, therefore, increasing plasmahalf-life through protection from renal clearance and slow absorptionrate from injection site (41). Like GLP-1 and exenatide, liraglutideneeds to be injected sc. After sc injection, maximum plasmaconcentrations are reached after 10–14 h, and it has ahalf-life of 11–13 h (42, 43).
Selected clinical trials
In a 5-wk dose-escalation study, liraglutide/metformin combinationwas associated with a 0.8% reduction in HbA1c and a 70 mg/dlreduction in fasting glucose when compared with metformin alone.In addition, liraglutide/metformin significantly reduced fastingglucose (21.6 mg/dl) and body weight (2.9 kg) when comparedwith the metformin/glimepiride group, and liraglutide/placebosignificantly reduced fasting glucose (25.2 mg/dl) when comparedwith the metformin/placebo group (Table 1) (44). In a 14-wkstudy of liraglutide vs. placebo, liraglutide significantlyreduced HbA1c by 1.45, 1.40, and 0.98% in the 1.90, 1.25, and0.65-mg groups, respectively, whereas placebo group had an increaseof 0.29% in HbA1c. The percentages of patients that achievedHbA1c of 7% or less were 46, 48, 38, and 5 in the 1.9, 1.25,0.65-mg groups and the placebo group, respectively (Table 1)(45). The results from phase 3 trials have not been presentedat scientific meetings or published in peer-reviewed journals.
Side effects
Most frequently reported adverse events were nausea and vomiting,especially at the higher doses (40, 45). There is also no developmentof antibodies noted in trials up to 14 wk (45, 46, 47).
Unresolved Issues Regarding GLP-1 and GLP-1 Mimetics
1. Does GLP-1 and GLP-1 mimetics have favorable effects on β-cell mass in humans?
Studies have shown that exenatide has favorable effects on parametersof β-cell function in humans using indirect measures suchas first-phase insulin secretion and homeostasis model assessmentβ-cell index (48, 49). In rodent studies, GLP-1 inducedglucose sensitivity in glucose-resistant β-cells (50).Exenatide given to rodents in pharmacological doses appearedto have beneficial effects on β-cell mass not seen withother antidiabetic agents. However, whether exenatide has afavorable effect on β-cell mass in humans is unknown.
Exenatide prevented cytotoxic agent-induced apoptosis of rodentislets (51), and chronic treatment increased β-cell turnoverin rodents (52). GLP-1 also inhibited nonchemically inducedβ-cell apoptosis in freshly isolated human islets (53).Both decreased apoptosis and increased β-cell turnovershould and do lead to increases in islet size and β-cellnumbers. The trophic effects of exenatide on β-cells inrodents are seen with concentrations not achieved in clinicalpractice. Although markers of β-cell function show improvementin humans with chronic exenatide use of up to 3 yr (39), thisimprovement in function may be due to the restoration of glucose-competenceto β-cells and the insulinotropic, glucose-lowering, andweight-loss effects of exenatide, and not because of any directeffect of exenatide on β-cell mass.
2. What is the mechanism by which GLP-1 and GLP-1 mimetics lower glucagon secretion from -cells?
Elevated fasting and postprandial plasma glucagon levels throughoutthe day are a feature of T2DM (54), and exenatide treatmentlowers both (55). The ability for exenatide and GLP-1 to lowerglucagon levels in patients with T2DM most likely contributesto its overall glucose-lowering effect. In addition, by virtueof enhancing endogenous insulin secretion concurrently withsuppressing glucagon secretion, a more physiological insulinto glucagon ratio in the portal vein should be established,resulting in better suppression of hepatic glucose output. WhetherGLP-1 and GLP-1 mimetics lower glucagon secretion from -cellsthrough direct or indirect mechanisms is still unclear.
The presence of GLP-1R on human -cells has not been directlyinvestigated. Overnight iv GLP-1 administration to fasted subjectswith type 1 diabetes mellitus resulted in the lowering of plasmaglucagon levels that was postulated to be a direct effect ofGLP-1 on -cells (56). However, given that plasma C-peptide levelswere doubled by GLP-1 infusion, an indirect action mediatedby the stimulatory effect of GLP-1 on residual neighboring β(or ) cells resulting in intraislet paracrine inhibition ofglucagon release is also plausible, though at considerably lowerinsulin concentrations than in healthy or T2DM subjects. A transgenicmodel of β-cell dysfunction also favors a paracrine effectof GLP-1 on glucagon secretion. Mice with a β-cell-specificmutation of the pdx-1 gene had defective insulin secretory andglucagon suppressive responses to exenatide, both of which werepresent in wild-type mice (57). This strongly suggests thata β-cell secreted factor is absolutely necessary for GLP-1-mediatedsuppression of glucagon secretion.
Rodent data on the presence or absence of GLP-1R on -cells arenot convincing either way. Neither GLP-1Rs nor their transcriptscould be detected in purified rat -cells (58, 59). Direct GLP-1application to rat -cells did not alter glucagon secretion orcause an increase in cAMP levels. However, GLP-1R expressionwas detected by immunocytochemistry in a subpopulation (20%)of glucagon-positive cells in dispersed rat islets (60). Becausethis is a small number of cells and the cells were not obtainedwith precise methodology, such as laser-captured microscopy,contaminating cells may be the source of the GLP-1R expression.
Furthermore, GLP-1 was also recently reported to elicit an increasein the cAMP content and glucagon secretion in an -cell linetransfected with the GLP-1Rs (61). Therefore, if -cells actuallycontain GLP-1Rs, increased glucagon secretion would be the expectedresponse to elevated plasma GLP-1 levels or exenatide therapy.Finally, neuronal control of glucagon secretion through theautonomic nervous system is well recognized, and this pathwaymay be mediated by GLP-1. Therefore, GLP-1 and exenatide infusionmay cause glucagon suppression in vivo via feedback from vagalafferents where neuronal networks are intact but not in vitrofrom dispersed -cells or cell lines. Regardless, the mechanismunderlying suppressed plasma glucagon levels by exenatide isan interesting area of research and may offer insights as tohow glucagon secretion might be controlled in T2DM.
If pharmacological levels of exogenous GLP-1 can lower bloodglucose in T2DM, it is logical to assume that supraphysiologicallevels of endogenous active GLP-1 (aGLP-1) can also lower bloodglucose. No secretagogue of L cells has been specifically developed,though clear headway has been made in elucidating how food productsbring about GLP-1 secretion from L cells (Fig. 2) (62, 63, 64).Compared with wild-type mice, DPP knockout mice have elevatedfasting incretin levels, lower plasma glucose, and higher plasmainsulin levels after a glucose challenge (65). There has beenimmense interest at disrupting DPP 4 activity in humans to increaseplasma aGLP-1 levels. Sitagliptin and vildagliptin are two suchDPP 4 inhibitors.
FIG. 2. Mechanism of action of sitagliptin, vildagliptin, and exenatide. GLP-1 is released from L cells (stained red) of the gut, and is subject to DPP 4 (stained green on endothelial cells of blood vessels of the gut) degradation in both gut and blood. Sitagliptin and vildagliptin inhibit DPP 4 action in blood and on endothelial cells. Metformin, orlistat, and -glucosidase inhibitors increase GLP-1 secretion. Exenatide, a GLP-1R agonist, increases insulin secretion from β-cells (stained green) in islets of Langerhans. The -cells in islets are stained red.
Sitagliptin
Sitagliptin, an organic molecule, appears to be selective forDPP 4 and not interact with other closely related proteases(Fig. 1) (66). Sitagliptin is rapidly absorbed, achieving peakplasma levels 1–6 h after dosing. Its half-life is 8–14h with bioavailability of 87%, with or without food (67, 68).About 80% of the dose is excreted unchanged by the kidney, with15% of the bioavailable drug metabolized by CYP3A4 and CYP2C8in the liver (67, 69). At 100 mg daily, greater than 80% ofplasma DPP 4 activity is inhibited over a 24-h period (67, 70).A dose reduction to 50 mg is needed if creatinine clearanceis less than 50 ml/min and to 25 mg if creatinine clearanceis less than 30 ml/min (71).
Selected clinical studies
Five 24-wk trials in T2DM patients examined the following: sitagliptinmonotherapy; comparison of sitagliptin monotherapy, metforminmonotherapy, and initial combination therapy of sitagliptinand metformin; sitagliptin added to ongoing pioglitazone; sitagliptinadded to ongoing metformin; and sitagliptin added to ongoingsulfonylurea and/or metformin (Table 1) (72, 73, 74, 75, 76).As initial therapy, sitagliptin/metformin combination therapyworked better than either sitagliptin or metformin monotherapywith an HbA1c reduction of 1.9% compared with 0.6–0.7%and 1.13% after 24 wk. As adjuvant therapy, sitagliptin in combinationwith metformin, glipizide, or pioglitazone yielded an HbA1creduction of 0.6–0.7% when compared with placebo.
Preliminary results from 30-wk extension trials on sitagliptinmonotherapy, initial sitagliptin combination therapy with orwithout metformin, and sitagliptin as adjuvant therapy to metforminshowed that the reduction in HbA1c was sustained at wk 54 (77,78, 79). A 52-wk trial on sitagliptin vs. glipizide as adjuvanttherapy to metformin showed a reduction in HbA1c of 0.7% inboth groups, however, the maximal HbA1c reduction was observedat 24–30 wk with a gradual increase in HbA1c from wk 30–52,which raises the issue of declining sitagliptin efficacy (80).Sitagliptin is reported to be weight neutral. Currently, thereis an ongoing study on adding sitagliptin to exogenous insulinin patients with or without metformin treatment (81).
Side effects
A pooled analysis of 5141 patients in clinical trials for 2yr or less showed that sitagliptin monotherapy or combinationtherapy (metformin, pioglitazone, sulfonylurea, or sulfonylureaand metformin) was well tolerated, and hypoglycemia occurredin the setting of combination therapy (82). The adverse eventsthat were higher with sitagliptin compared with nonexposed groupsincluded nasopharyngitis, contact dermatitis, and osteoarthritis.A systematic review and metaanalysis of incretin therapies showedthat sitagliptin has no risk of gastrointestinal adverse eventsbut has an increase risk for urinary track infection, headache,and especially nasopharyngitis (40), and may reflect a lackof DPP 4 activity required for immunosurveillance.
Vildagliptin
Vildagliptin, a selective, reversible, and competitive inhibitorof DPP 4, is a low molecular weight compound suitable for oraldosing (83, 84). After dosing, vildagliptin is rapidly absorbedand achieves peak plasma levels in 1–2 h. Its half-lifeof 2 h is shorter than sitagliptin (85, 86). Its bioavailabilityis 85% (87), and its pharmacokinetics is not affected by food(88). At 100 mg daily, it inhibits 98% of DPP 4 activities 45min after dosing and 60% at 24 h. Approximately 85% of vildagliptinis metablolized in the liver to LAY151 by hydrolysis: LAY151is inactive. The remaining 15% is eliminated unchanged by thekidneys (89). A study suggested that there was no significantdifference in exposure to vildagliptin in patients with variousdegrees of hepatic impairment (89). In 2007, the Food and DrugAdministration requested additional data on patients with renalimpairment before granting final approval of vildagliptin (90).
Selected clinical trials
Six clinical trials evaluated vildagliptin as initial monotherapyin comparison to placebo, metformin, rosiglitazone, or acarbose,and also as initial combination therapy with pioglitazone incomparison to vildagliptin monotherapy in drug-naive patientswith T2DM (Table 1) (91, 92, 93, 94, 95, 96, 97). Patients withworse glycemic control (HbA1c8.4 vs. 6.7%) had bigger HbA1creduction over 24 wk. Data from the extension study on the groupwith better glycemic control showed that maximum HbA1c reductionoccurred around 24–30 wk, followed by a gradual increasethereafter until wk 108 (92). As monotherapy, vildagliptin 50mg twice daily was as effective as rosiglitazone 8 mg once dailyand acarbose 100 mg thrice daily in lowering HbA1c but not aseffective as metformin 1000 mg twice daily (94, 95, 97). Initialcombination therapy with vildagliptin and pioglitazone providedbetter glycemic control than either vildagliptin or pioglitazonemonotherapy (96).
Vildagliptin is effective as adjuvant therapy when administeredto patients inadequately controlled with sulfonylurea, metformin,thiazolidinedione, or insulin therapy with HbA1c reduction of0.6, 0.9, 1.0, and 0.5%, respectively (98, 99, 100, 101). Inaddition, vildagliptin and pioglitazone were equally effectiveas adjuvant therapy for patients who were inadequately controlledon metformin, in which HbA1c reductions of 0.9 and 1.0% werenoted, respectively (102).
Side effects
The side effects from vildagliptin are comparable to that ofsitagliptin. In a systematic review and metaanalysis of incretintherapies, vildagliptin has no risk of gastrointestinal adverseevents but has an increase risk for urinary track infectionand headache (40).
1. Do DPP 4 inhibitors have favorable effects on β-cell mass in humans?
Exenatide appears to have beneficial effects on β-cellmass when given in pharmacological doses to rodents (51, 52).The effect of DPP 4 inhibitors on β-cell mass is less clear.Three-month treatment of high-fat-fed diet streptozotocin-induceddiabetic mice with des-fluoro-sitagliptin preserved β-cellsfrom apoptosis with no increase in β-cell mass (103). β-Cellsof DPP 4 knockout mice are also reported to be more resistantto the toxic effects of streptozotocin (104). But against DPP4 inhibitors being trophic factors, 8-wk treatment with vildagliptinhad no obvious effects on β-cell turnover or β-cellmass in mice (105).
2. Is the modest increase in aGLP-1 levels the sole modulator of glycemia using DPP 4 inhibitors?
DPP 4 inhibitors were developed to augment biologically active,endogenously secreted plasma GLP-1. In humans, sitagliptin,both after a single dose and after a once-daily dose for 10d, resulted in about a 2-fold increase in aGLP-1 after meal(67, 106). Furthermore, sitagliptin decreased total GLP-1 (tGLP-1)in the presence of increased aGLP-1 (107). However, whetherthe 2-fold increase in aGLP-1 is sufficient to explain the glucose-loweringeffect with reduction of HbA1c in patients on chronic sitagliptintherapy is controversial.
If DPP 4 inhibitors did lower blood glucose as a direct consequenceof increased aGLP-1 levels, plasma insulin levels would be expectedto increase as well. However, fasting and postprandial plasmainsulin and C-peptide levels were not different before and after10 d DPP 4 inhibition in both healthy and T2DM subjects (106,108, 109). Indeed, infusions of GLP-1 that result in comparableplasma aGLP-1 levels attained by DPP 4 inhibition do not induceinsulin secretion in T2DM (10). Some reviewers noted that withDPP 4 inhibitors, the same amount of insulin is secreted ata lower glucose level, or insulinogenic index is improved (110).However, any treatment that lowers plasma glucose without increasinginsulin secretion, such as weight loss, metformin, or -glucosidaseinhibitors, also improves insulinogenic indices (111, 112).
Another surprising finding is that DPP 4 inhibition does notslow gastric emptying (108) when slowed gastric emptying isa consistent finding with exogenous GLP-1 and exenatide treatments(13, 113). An explanation offered in some reviews is that thedegree of elevation of aGLP-1 is not of sufficient magnitudeto inhibit gastric emptying (110, 114). However, by the samerationale, one can extrapolate that the elevation in aGLP-1from DPP 4 inhibition is also not sufficient to bring aboutan increase in insulin secretion (108).
3. How might DPP 4 inhibition lead to a decline in plasma glucose levels without an increase in insulin secretion?
DPP 4 inhibition results in lower postprandial plasma glucagonlevels (108, 109, 115). However, the reduced glucagon secretionis not evident in the fasting state when it would be most beneficialto decrease nocturnal hepatic glucose output. The postprandialglucagon suppressive effects of DPP 4 inhibitors, whereas significantlydifferent from placebo, are small and short lived, and the levelsare much higher than in nondiabetic subjects, therefore, unlikelyto account for the full antihyperglycemic effect.
The following is speculation by the authors. Many endogenouscompounds are subject to DPP 4 modification, resulting in theiractivation or inactivation, and any of these unknown qualitiesmight have effects on glucose homeostasis (116, 117). If indeedthe glucose-lowering effects of DPP 4 inhibition are mediatedby GLP-1, one would expect to see maximum clinical effects ofone dose of DPP 4 inhibitor on PPG and insulin levels immediatelyafter a meal when GLP-1 secretion is at its maximum. However,this is not the case because no clinical effects on glucose,insulin, glucagon, or C-peptide levels over a 2-h post-mealperiod were observed after one dose of sitagliptin (67). However,after 4 wk sitagliptin, PPG levels were significantly reducedover a 24-h period in the treatment group, but insulin and C-peptidelevels were comparable between treatment and placebo groups(118). This phenomenon may signify accumulation, over time,of one or more DPP 4 products that have effects on glucose uptake.
GLP-1 is known to have effects on the gut-hepatoportal-brainneural axis. Sitagliptin should directly inhibit DPP 4 activityat the level of the vascular endothelium in the gut, resultingin greater activation by GLP-1 of sensory neurons originatingin the nodose ganglion, where GLP-1R gene expression has beenshown to occur (119, 120). It should also cause higher aGLP-1levels to enter the portal system after eating with subsequentactivation of the vagal hepatic nerves (121). GLP-1R mRNA ispresent on nerve terminals of the portal vein in rodents (120),and there are GLP-1-modifiable glucose sensors in the hepatoportalbed (122). Dog studies had shown that direct infusion of GLP-1into the portal vein results in increased glucose uptake (123,124). Against gut-neuronal pathways being the likely cause ofthe improved glucose homeostasis with DPP 4 inhibition is this– gastric emptying is not altered. GLP-1 is thought toinfluence gastric emptying through interacting with afferentsensory neurons. Therefore, if DPP 4 inhibition were of suchmagnitude as to influence neuronal pathways through greaterGLP-1R activation, one would also expect to see effects on gastricemptying, which is not the case.
4. Was the development of DPP 4 inhibitors, which are not specific for GLP-1 and actually resulted in decreased tGLP-1 secretion, really needed to increase plasma aGLP-1 levels?
There are other hypoglycemic agents that cause a minor increasein plasma GLP-1 levels but were thought to not contribute totheir antihyperglycemic effect. Three-day treatment with phenforminresulted in elevated levels of gut-derived glucagon-like immunoreactivity(measured before a RIA specific for GLP-1 was available) bothduring fasting and in response to intraduodenal glucose infusionsin T2DM (125). One-week metformin treatment in healthy subjectsresulted in dramatic increases in postprandial glucagon-likeimmunoreactivity levels when compared with baseline (126). Furthermore,a 2-wk course of metformin in obese nondiabetic volunteers resultedin a statistically significant increase in aGLP-1 levels duringan oral glucose load performed under euglycemic-hyperinsulinemicclamp when compared with baseline (127). aGLP-1 levels duringboth fasting and after the oral glucose load did not changeafter a single 850 mg dose of metformin but were significantlyincreased after 4 wk metformin in obese patients with and withoutT2DM (128). Subsequently, metformin was found to inhibit DPP4 activity in patients with T2DM (129). Similarly, metforminwas found to decrease DPP 4 activity, increase aGLP-1 levels,and improve insulin secretory capability to exogenous GLP-1administration in diabetic mice (130). However, on a molar basis,specific DPP 4 inhibitors are 15–20 times more effectiveat reducing DPP 4 activity than metformin. A recent study ofhealthy subjects showed the following: both postprandial tGLP-1and aGLP-1 levels were increased 2-fold with metformin; aGLP-1levels were increased 2-fold but tGLP-1 levels were diminishedby a third with sitagliptin; and aGLP-1 levels were increased4-fold and tGLP-1 increased by 1.6-fold with metformin/sitagliptin(107).
These data suggest that metformin and sitagliptin increase aGLP-1levels through different mechanisms. Most likely metformin increasesGLP-1 levels through both inhibition of DPP 4 and secretionfrom L cells. The mechanism by which metformin might increaseGLP-1 secretion is speculative. Biguanides have inhibited glucoseabsorption (131, 132). We hypothesize that this decrease inglucose absorption would prolong exposure of the sweet tastereceptors on intestinal L cells (recently found to be the modulatorsof GLP-1 secretion from L cells) to glucose, resulting in theprolonged activation of the sweet taste receptors and secretionof GLP-1 (Fig. 2) (62).
Although metformin increases GLP-1 secretion, it is still unclearwhether this increase has any glucose-lowering effect. It iswell accepted that metformin lowers glucose levels by suppressinghepatic glucose output, mediated through kinase LKB1 in theliver (133, 134). Therefore, it is also reasonable to ask whethersitagliptin, which increases aGLP-1 by the same amount as metformin,is actually lowering glucose through aGLP-1. However, giventhe synergistic effect of metformin and sitagliptin, both interms of increase in aGLP-1 levels and lowering of HbA1c (0.8%with sitagliptin alone, 1.3% with metformin alone, and 1.8%with metformin/sitagliptin), combination therapy might actuallyhave a meaningful impact in glucose lowering through the GLP-1mechanism (73, 78, 107).
Summary
Exenatide, as adjuvant therapy in T2DM, led to sustained HbA1creduction of 1.0%, and improved β-cell function and weightloss. It is inconvenient to use, but long-acting forms withonce-weekly injection, such as long-acting release exenatideformulation are under development (135). Liraglutide loweredHbA1c by 1.5% in a 14-wk study, but phase 3 studies are notyet available in peer-reviewed journals.
The advantage of DPP 4 inhibitors is their availability in oralform. Sitagliptin monotherapy led to HbA1c reduction of 0.6–0.7%after 54 wk. Vildagliptin monotherapy lowered HbA1c by 0.9–1.4%after 24 wk. However, patients with mild T2DM on low-dose vildagliptinshowed a return of HbA1c to pretreatment levels after 108 wk.A similar trend was seen in sitagliptin. Long-term data on sitagliptinand vildagliptin are needed to evaluate whether their glucose-loweringeffects are sustained. Both DPP 4 inhibitors are weight neutral,and their effects on other DPP 4 substrates need further research.
A better understanding of the effects of GLP-1 and GLP-1 mimeticson β-cell mass in humans and the mechanism of action bywhich they lower glucagon secretion from -cells are needed.Finally, more work is needed to elucidate how DPP 4 inhibitorsimprove insulin sensitivity in humans.
Footnotes
Address all correspondence and requests for reprints to: JosephineM. Egan, M.D., F.R.C.P.I., National Institute on Aging, NationalInstitutes of Health, 5600 Nathan Shock Drive, Baltimore, Maryland21224-6825. E-mail: eganj@grc.nia.nih.gov.
The writing of this special feature was supported by the IntramuralResearch Program of the National Institutes of Health (NIH),National Institute on Aging.
The views expressed in this manuscript are those of the authorsand do not reflect those of the NIH.
Disclosure Summary: The authors have nothing to declare.
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) (62, 63, 64). Compared with wild-type mice, DPP knockout mice have elevated fasting incretin levels, lower plasma glucose, and higher plasma insulin levels after a glucose challenge (65). There has been immense interest at disrupting DPP 4 activity in humans to increase plasma aGLP-1 levels. Sitagliptin and vildagliptin are two such DPP 4 inhibitors. 
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Abstract
Introduction
6.9%], both GIP and GLP-1 secretion in response to glucose and mixed meal challenges are the same or even increased when compared with healthy subjects (
-cells?
) cells resulting in intraislet paracrine inhibition of glucagon release is also plausible, though at considerably lower insulin concentrations than in healthy or T2DM subjects. A transgenic model of β-cell dysfunction also favors a paracrine effect of GLP-1 on glucagon secretion. Mice with a β-cell-specific mutation of the pdx-1 gene had defective insulin secretory and glucagon suppressive responses to exenatide, both of which were present in wild-type mice (
