Effects of the Long-Acting Human Glucagon-Like Peptide-1 Analog Liraglutide on {beta}-Cell Function in Normal Living Conditions

doi:10.2337/dc07-0310

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Emerging Treatments and Technologies
Original Article

Effects of the Long-Acting Human Glucagon-Like Peptide-1 Analog Liraglutide on ß-Cell Function in Normal Living Conditions

Andrea Mari, PHD¹, Kristine Degn, MD, PHD², Birgitte Brock, MD, PHD², Joergen Rungby, MD, DMSC², Ele Ferrannini, MD³ and Ole Schmitz, MD, DMSC²

¹ National Research Council Institute of Biomedical Engineering, Padua, Italy
² Department of Endocrinology and Diabetes, University Hospital, University of Aarhus, Aarhus, Denmark
³ National Research Council Institute of Clinical Physiology, University of Pisa, Pisa, Italy

Address correspondence and reprint requests to Andrea Mari, Institute of Biomedical Engineering-CNR, Corso Stati Uniti 4, 35127 Padova, Italy. E-mail: andrea.mari{at}isib.cnr.it

Abbreviations: GLP, glucagon-like peptide • ISR, insulin secretion

INTRODUCTION

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Liraglutide is a long-acting glucagon-like peptide (GLP)-1 analog,which exerts its glucose-lowering action through multiple mechanisms(1). One important feature of liraglutide is its ability toenhance ß-cell function. The effects on ß-cellfunction have been demonstrated using standardized ß-cellfunction tests based on intravenous glucose administration (2–4).However, these studies may not reflect the modes of action ofliraglutide during normal living. To assess the effects of liraglutideon ß-cell function in normal living, we have useda validated ß-cell model to analyze 24-h triple-mealexperiments.

RESEARCH DESIGN AND METHODS—

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RESEARCH DESIGN AND METHODS--
RESULTS--
CONCLUSIONS--
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This study includes data used for a different analysis in aprevious publication (3), where the experimental protocol, approvedby the local ethics committee and performed in accordance withthe Helsinki Declaration, was described in detail.

Thirteen type 2 diabetic patients (five women and eight men)were examined. Their mean ± SD age was 56.4 ±9.2 years, BMI was 31.2 ± 3.6 kg/m², last measured A1Cbefore inclusion was 7.3 ± 0.4% (normal range <6.4%),and the duration of diabetes was 3.0 ± 2.6 years.

The study is a randomized, double-blind, placebo-controlled,crossover trial, with a washout period of 6–7 weeks betweentreatments. After inclusion, the patients discontinued theiroral hypoglycemic agents (sulfonylurea and metformin) for 2weeks before the study. Liraglutide (6 µg/kg body wt)or placebo was injected subcutaneously into the abdomen oncedaily (at $~$ 0745 h) for 9 days. After 7 days of treatment, thepatients where hospitalized at 2200 h. On the next day, whilecontinuing treatment, three standard meals were served at 0800,1200, and 1800 h. Breakfast contained 2,660 kJ (protein 14%,carbohydrate 55%, and fat 31%), lunch 2,865 kJ (protein 16%,carbohydrate 50%, and fat 34%), and dinner 3,397 kJ (protein28%, carbohydrate 53%, and fat 19%). Blood was collected atvarying intervals for determination of glucose, insulin, andC-peptide, which were measured as previously described (3).

ß-Cell function
ß-Cell function was assessed using a model that describesthe relationship between insulin secretion (ISR) and glucoseconcentration (5,6). The model expresses ISR (in picomoles perminute per squared meter of body surface area) as the sum oftwo components. The first component represents the dependenceof ISR on absolute glucose concentration and is characterizedby a dose-response function relating the two variables. Characteristicparameters of the dose response are the mean slope within theobserved glucose range, denoted as ß-cell glucosesensitivity, and ISR at a fixed reference glucose value of 9mmol/l (approximately the mean basal glucose value in the wholegroup). The dose response is modulated by a potentiation factor,which accounts for several potentiating mechanisms (prolongedexposure to hyperglycemia, nonglucose substrates, gastrointestinalhormones, neurotransmitters, and liraglutide). The potentiationfactor is set to be a positive function of time and is constrainedto average unity during the experiment; thus, it expresses therelative potentiation of the secretory response to glucose.Changes in the potentiation factor were evaluated as the foldchange over a given time interval. The second ISR componentrepresents the dependence of ISR on the rate of change of glucoseconcentration and is expressed by a single parameter, denotedas rate sensitivity, which is related to early insulin release(5,6). The model parameters were estimated from glucose andC-peptide concentration by regularized least squares, as previouslydescribed (5,6).

Statistical analysis
Data and results are presented as means ± SD or as median(interquartile range) for non–normally distributed ISRparameters. Differences between liraglutide and placebo weretested using the Wilcoxon's signed-rank test (significance levelP < 0.05). Associations were tested by standard linear regression.

RESULTS—

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Liraglutide decreased mean and nocturnal (2300–0800 h)plasma glucose levels (from 9.7 ± 3.3 to 7.8 ±2.1 and from 8.3 ± 2.7 to 6.8 ± 1.5 mmol/l, respectively,P < 0.01) (Fig. 1A), whereas the decrease in fasting glucosedid not reach statistical significance (9.6 ± 2.8 vs.8.6 ± 2.4, P = 0.15). Mean plasma insulin (173 ±132 vs. 161 ± 87 pmol/l) and C-peptide (1.6 ±0.8 vs. 1.6 ± 0.6 nmol/l) concentrations and total insulinsecretion (median 274 [interquartile range 126] vs. 304 nmol/m²[92]) did not change; in contrast, modeling analysis predicteda marked effect on the ß-cell dose response (Fig. 1B).In particular, the ß-cell dose response was shiftedupwards and steeper, as reflected by a significant increasein glucose sensitivity (from 38 [51] to 54 pmol/min per m² permmol/l [59], P < 0.01) and in insulin secretion at 9 mmol/lglucose (from 189 [225] to 322 pmol/min per m² [265], P <0.0005). Liraglutide also significantly increased the fold riseof potentiation factor induced by breakfast (from 0800 to 1100h), from 1.2 (interquartile range 0.7) to 2.1-fold (1.2), P< 0.002 (Fig. 1C). The change in rate sensitivity was notsignificant (0.5 [0.4] vs. 0.1 nmol/m² per mmol/l [0.5]).

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Figure 1— A: Plasma glucose and insulin concentrations during placebo (solid line and •) and liraglutide (broken line and ${circ}$ ). Time is relative to the beginning of the test (0800 h). Data are means ± SE. B: Dose response with placebo (solid line and •) and liraglutide (broken line and ${circ}$ ). The dose responses are plotted over a glucose range corresponding approximately to the observed glucose excursions. The slope of the dose response is glucose sensitivity. C: Potentiation factor during placebo (solid line and •) and liraglutide (broken line and ${circ}$ ). Data are means ± SE. The dashed areas represent the dose response (B) and the potentiation factor (C) in normal subjects, redrawn from ref. 6.

In a multivariate regression model, the treatment-induced changesin insulin secretion at 9 mmol/l glucose and glucose sensitivity(log transformed) were independent predictors of the correspondingchanges in mean glucose levels (standardized correlation coefficients–0.49 for insulin secretion at 9 mmol/l glucose and –0.49for glucose sensitivity, explained variance 65%, P < 0.005).

CONCLUSIONS—

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The novel finding is that liraglutide treatment significantlyenhances ß-cell function evaluated under conditionsof normal living and that the ß-cell function improvementis related to the improvement in glucose levels.

The modes of ß-cell function improvement are similarto those observed after a single liraglutide dose with the useof the graded glucose infusion test (2), i.e., an upward shiftand a steeper slope of the ß-cell dose-response curve.In addition, the current data show that liraglutide also improvedpotentiation of insulin secretion during the first meal by restoring,in part, the potentiation peak, which is markedly blunted indiabetes (5). This phenomenon is similar to what has been observedwith exenatide (7) and is suggestive of a potentiating effectmediated by analogous mechanisms, possibly by direct stimulationof the GLP-1 receptor.

However, in comparison with a group of normal subjects in whichß-cell function was assessed with similar experimentaland data analysis methods (6), in our diabetic patients neitherthe ß-cell dose response nor potentiation were normalized(Fig. 1), in contrast with previous observations based on anintravenous test (2). In fact, glucose sensitivity with liraglutidewas still well below normal (median 54 [interquartile range59] vs. 84 pmol/min per m² per mmol/l [41] in ref. 6, P <0.05), and the initial potentiation peak remained considerablyblunted. Although these abnormalities might have been overestimateddue to the younger age of the control group, the finding stressesthe importance of assessing ß-cell function underphysiological conditions of ß-cell stress.

Footnotes

Published ahead of print at http://care.diabetesjournals.orgon 27 April 2007. DOI: 10.2337/dc07-0310.

A table elsewhere in this issue shows conventional and SystèmeInternational (SI) units and conversion factors for many substances.

The costs of publication of this article were defrayed in partby the payment of page charges. This article must thereforebe hereby marked "advertisement" in accordance with 18 U.S.CSection 1734 solely to indicate this fact.

Received for publication February 14, 2007. Accepted for publication April 21, 2007.

References

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Degn KB, Juhl CB, Sturis J, Jakobsen G, Brock B, Chandramouli V, Rungby J, Landau BR, Schmitz O: One week's treatment with the long-acting glucagon-like peptide 1 derivative liraglutide (NN2211) markedly improves 24-h glycemia and ${alpha}$ - and ß-cell function and reduces endogenous glucose release in patients with type 2 diabetes. Diabetes 53:1187–1194, 2004[Abstract/Free Full Text]
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Mari A, Tura A, Gastaldelli A, Ferrannini E: Assessing insulin secretion by modeling in multiple-meal tests: role of potentiation. Diabetes 51 (Suppl. 1):S221–S226, 2002
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