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Etiology and Pathophysiology
The role of glucagon in weight loss-mediated metabolicimprovement: a systematic review and meta-analysis
M. P. Silvestre1,2, J. P. Goode1, P. Vlaskovsky3, C. McMahon1, A. Tay1 and S. D. Poppitt1,2,4
1Human Nutrition Unit, University of Auckland,
Auckland, New Zealand, 2School of Biological
Sciences, University of Auckland, Auckland,
New Zealand, 3Department of Statistics,
University of Auckland, Auckland, New
Zealand, and 4Department of Medicine,
University of Auckland, Auckland, New
Zealand
Received 20 August 2017; revised 30 August
2017; accepted 19 September 2017
Address for correspondence: Dr MP Silvestre,
Human Nutrition Unit, School of Biological
Sciences, University of Auckland, Auckland
92019, New Zealand.
E-mail: [email protected]
SummaryAimsThis meta-analysis aimed to investigate the role of glucagon suppression inregulating glucose homeostasis following diet or bariatric surgery.MethodsA comprehensive search of intervention and observational studies was conducted inMedline, Scopus, Web of Science, PubMed and Embase. Random effects modelmeta-analysis was performed. Primary outcomes were (i) body weight change, (ii)fasting glucagon, (iii) fasting glucose and (iv) fasting insulin concentrations.ResultsTwenty articles reporting data from 29 interventions were eligible for analysis.Bariatric surgery caused greater weight loss than diet (bariatric �29.7 kg [CI:-36.8, �22.6]; diet �5.8 kg [CI: �8.4, �3.3]; P < 0.00001), an effect that remainedsignificant after adjusting for study duration (P < 0.05). Mean fasting glucagon de-creased in parallel with weight loss (�11.8 ng/L [CI: �15.9, �7.8]; P < 0.00001)with no difference between bariatric and diet intervention. Both fasting glucose,and insulin decreased following weight loss (both P < 0.00001; glucose�1.7 mmol/L [CI: �2.0, �1.3]; insulin �50.6 pmol/L [CI: �66.5, �34.7] withgreater decrease in fasting insulin between bariatric versus diet (P = 0.01).ConclusionsSynergistic suppression of fasting glucagon and insulin resistance may act togetherto restore normoglycaemia following weight loss. Whether suppression of plasmaglucagon may contribute to increased hunger after weight loss and gradual weightregain is not yet known.
Keywords: bariatric surgery, glucagon, glucose homeostasis, traditional diet.
Abbreviations: BDP, - biliopancreatic diversion; BMI, – body mass index; CCK,– cholecystokinin.; CCT, controlled clinical trials; CT, – clinical trials;; DJBL, -duodenal-jejunal bypass liner insertion; GCGR, – glucagon receptor; GI, –gastro-intestinal; GLP-1, - glucagon-like peptide 1; IGT, – impaired glucosetolerance; ITT, – intention to treat analysis; LAGB, - laparoscopic adjustable gastricbanding; LED, – low energy diet; O-CC, – observational case–control studies;O-PC, – observational prospective cohort studies; O-XS, – observational crosssectional studies; PYY, - peptide YY; RCT, - randomized controlled trials; RIA, –radioimmunoassay; RYGBP, - Roux-en-Y gastric bypass; SG, – sleeve gastrectomy;T1D, – type 1 diabetes; T2D, – type 2 diabetes.
obesity reviews doi: 10.1111/obr.12631
© 2017 World Obesity Federation Obesity Reviews 19, 233–253, February 2018
Introduction
A global public health crisis for type 2 diabetes (T2D) isgrowing in parallel with increased obesity and increasedprevalence of sedentary lifestyles.(1) The pathophysiologyof T2D has been essentially viewed as an insulin-centredproblem with a progressive increase in insulin resistancecaused by the excess adipose mass deposition associatedwith body weight gain and obesity and a failure of β-cellinsulin secretion to compensate for insulin resistance.(2)However, similar to β-cell function, the α-cell shows anumber of characteristic abnormalities in people withT2D.(3) It is clear now that an ‘insulinocentric’ view ofglucose homeostasis is incomplete and that glucagon mayalso have an important role in the maintenance of normalplasma glucose levels.(3) In states of insulinopenia, suchas poorly controlled type 1 diabetes (T1D) or diabeticketoacidosis, insulin deficiency is associated with an in-verse elevation of plasma glucagon that can be extremelyhigh.(4,5) Most importantly, others have described abnor-mally elevated fasting glucagon levels in prediabetic sub-jects with impaired glucose tolerance,(6–9) suggesting thatthere is a critical phase of early α- cell and β-cell dysfunc-tion in prediabetic states. Glucagon plays a central role inthe response to hypoglycaemia by stimulating gluconeo-genesis and glycogenolysis, and in doing so, oppose theeffects of insulin.(10) Given that absolute or relative gluca-gon excess seems to be critical in the development and/ormaintenance of hyperglycaemia in T2D, it seems reason-able that strategies targeted to correct this abnormalityare suitable for the improvement of the glucose homeosta-sis. In line with this, a glucagon-centred view of diabeteshas re-emerged.(11,12) Treatment with glucagon receptorantagonists performed over different periods of time hasdemonstrated robust glucose-lowering effects, with someglucagon receptor antagonists producing reductions inHbA1c levels comparable to, or greater than, metformin[reviewed in (13)].
It is now well established that weight loss reduces therisk of developing T2D,(14,15) and it is also associatedwith improvements in insulin sensitivity and, potentially,β-cell function.(16) Nevertheless, only a minority of pa-tients with obesity treated with traditional weight-lossmethods (e.g. energy restricted diets, exercise and behav-ioural therapy) are able to lose a clinically relevant amountof weight and maintain the weight loss over time. Increas-ing evidence supports bariatric surgery as a powerful, al-beit invasive, intervention to induce a significant weightloss and T2D remission.(17) Although weight loss cer-tainly results in improved glucose homeostasis, surgery it-self has been proposed to trigger weight-independentmechanisms that translate into relevant metabolic im-provements.(18) Surprisingly, neither bariatric surgerynor traditional energy-restricted dietary weight-loss studies
have specifically addressed the role of glucagon as a medi-ator of improved glucose regulation and decreased risk ofT2D in response to weight change. Therefore, the aim ofthis article is to perform a systematic review of the litera-ture on the changes in glucagon following weight loss,and how these changes relate to improvements in othermetabolic markers of T2D.
Methods
This systematic review and meta-analysis was conducted ac-cording to the methods of the Cochrane Collaboration.(19)Ethical approval was not required for this research. Theprotocol of this systematic review was registered inPROSPERO (www.crd.york.ac.uk/PROSPERO) with theregistration number CRD42015025914.
Search strategy and selection criteria
A comprehensive electronic search strategy was conductedin Medline, Scopus, Web of Science, PubMed and Embase,published up to 1 May 2016, using the terms ‘glucagon’,‘type 2 diabetes’ and ‘weight loss’ under ‘MeSH terms’ orunder ‘title, abstract and key words’. Reference lists fromrelevant studies were reviewed, and authors of potentiallyeligible studies were contacted when necessary to requestfurther information regarding the study design or primaryoutcomes. The researchers hand searched any meta-analyses and systematic reviews to identify studies thatmay have been missed. Nine hundred sixty-six articles wereretrieved.
Three reviewers – M. P. S., C. M. and S. D. P. –discussed the eligibility criteria for studies to be includedand based on that, two of the three reviewers –M. P. S. and C. M. – independently assessed titles and ab-stracts of all English language studies. Studies were eligi-ble if (i) they were clinical trials, including randomizedcontrolled trials or controlled clinical trials and observa-tional studies, including prospective cohort, cross sec-tional or case–control studies; (ii) study subjects wereadults (aged ≥15 years) male and/or female and free fromacute illness, but those with T2D or non-communicablediseases in whom conditions were regarded as stable wereincluded; (iii) they reported fasting glucagon concentra-tions in relationship to body weight loss (achieved with-out pharmaceutical intervention); (iv) they providedinformation on 1 or more metabolic outcomes associatedwith T2D risk (body weight and body mass index (BMI),fasting glucose, fasting insulin); (v) studies had a durationof ≥3 days for RCTs and 3 weeks or more for observa-tional studies; and (vi) they were published as a fullmanuscript.
234 Glucagon during weight loss M. P. Silvestre et al. obesity reviews
© 2017 World Obesity FederationObesity Reviews 19, 233–253, February 2018
Data collection and validity assessment
Data collection and validity assessment were carried out in-dependently by four reviewers –M. P. S., J. P. G., C. M. andA. T. –, and any discrepancies were resolved after reviewingthe original source and by consensus with a fifth investiga-tor – S. D. P.
The outcomes of interest were pre-specified. Primary out-comes were defined as those considered relevant or com-monly reported: (i) BMI/body weight change, (ii) fastingglucagon concentration, (iii) fasting glucose concentrationand (iv) fasting insulin concentration. Secondary outcomesincluded: methods of weight reduction, i.e. traditionalweight loss versus bariatric surgery.
The risk of bias was assessed at the study level taking intoaccount the randomization process, quality of allocationconcealment, blinding, selective outcome reporting, samplesize, attrition rates, use of an intention-to-treat (ITT) analy-sis, completeness of outcome data and comparability ofsubjects’ baseline characteristics. This assessment was essen-tially qualitative. All the selected studies employed sensitive,reproducible assays; hence, no studies were excluded basedon the methodology. Only two studies reported patients onglucose lowering medications. (20,21) The data were aggre-gated based on summary estimates in alphabetic order ofthe first author in each study for diet and bariatric surgeryseparately and series of meta-analysis carried out.
Of the 996 retrieved articles, 27 articles were reviewed(Fig. 1). Five additional articles were retrieved using manualsearch, resulting in 32 articles reviewed. Of these, 20 full textarticles were included in this analysis, comprising 29 studies.
Data analysis
A meta-analysis was conducted using Review Manager(RevMan) version 5.3. (Copenhagen: The NordicCochrane Centre, the Cochrane Collaboration, 2014) toaddress the changes in body weight, glucagon, glucoseand insulin between weight loss studies. Effect sizes foreach study were computed using random effects model,(22) in which effect size is calculated under the assump-tion that samples were collected from a non-homogeneouspopulation. Subgroup analysis and a meta-regressionmodel (using Comprehensive Meta-Analysis Pro, USA)were performed to address the heterogeneity of thechanges in glucagon and of the weight loss. Factors suchas duration were considered in this analysis. Meta-regressions usually differ from simple regressions in twoways. First, larger studies have more influence on the rela-tionship than smaller studies because studies are weightedby the precision of their respective effect estimate. Second,it is wise to allow for the residual heterogeneity among in-tervention effects not modelled by the explanatory vari-ables. This gives rise to the term ‘random-effects meta-regression’, because the extra variability is incorporatedin the same way as in a random-effects meta-analysis.(23) A fixed effect model was also performed to comparethe results with the random effect model. Sensitivity anal-ysis was carried out to assess the effect of within patientcorrelation ρ, on the results of the meta-regression. ρvalues of �0.1 or higher were investigated. Data werepresented as standard error of the mean difference.Standard deviation of the mean fasting glucagon and
Figure 1 Flow diagram for identification of eligible studies. Twenty articles featuring 19 studies (one study was published in two articles) were included inthe present meta-analysis. Some studies reported results from more than one intervention. As a result, 29 interventions were assessed independently forthe purpose of the analysis.
Glucagon during weight loss M. P. Silvestre et al. 235obesity reviews
© 2017 World Obesity Federation Obesity Reviews 19, 233–253, February 2018
body weight was estimated from 95% confidence intervalswhen required(19) or from median and from interquartilerange(24) when required.
Role of the funding source
The Health and Research Council of New Zealand had norole in study design, data collection, data analysis, datainterpretation or writing of the report. The correspondingauthor had full access to all the data in the study and hadfinal responsibility for the decision to submit for publication.
Results
Description of the studies included in the systematicreview
Twenty published articles were selected, comprising 19studies reporting 29 individual weight-loss interventions(Fig. 1).
The sample size varied from 7 to 36 individuals, with ahigher percentage of females in most studies, such that 12of the 19 studies comprised >50% women.(20,25–36)Mean baseline BMI ranged from 29 to 58 kg/m2 and atthe end of each intervention BMI ranged from 28 to42 kg/m2. Overall, study duration ranged from 2 weeks to13 months, where 13 studies had a duration of 2 to26 weeks,(20,21,28–34,36–40) and six studies had a dura-tion of 1 year or longer.(25–27,35,41,42) Only bariatric in-terventions had duration of greater than 26 weeks.
In 12 of the 19 studies, participants suffered from obe-sity and T2D(21,25,27,28,30,33,36–40,42); in threestudies, they suffered from obesity but not T2D (obesebut non diabetic [OND]);(26,32,34) whereas the remain-ing four studies had participants from both groups.(20,29,35,41)
In order to achieve weight loss, 10 studies investigatedthe effect of bariatric surgery exclusively(20,21,25–27,29,35,40–42); five studies were exclusively diet interven-tion(34,36–39); and four studies compared bariatric surgeryand diet intervention. (28,30–33) Dietary studies used stan-dard food items or prescribed diets, (34,36–39) both ofwhich were provided for the participants in all studies, ex-cept for Villareal et al. 2008. (34) Three of the four studiesthat compared diet with bariatric surgery used acommercially available low energy diet (LED) with an en-ergy content of 3.3 to 4.4 MJ/d,(28,30,32) while the fourthstudy used regular food items, with an energy content(4.6 MJ) comparable to the studies where a commercialLED was used.(33)
Roux-en-Y gastric bypass (RYGBP) was the primarybariatric surgical procedure, performed in9(20,25,26,28,30,32,35,40,41) of the 14 studies. In termsof other surgical weight loss methods, one study performed
duodenal-jejunal bypass liner insertion(21); one study per-formed biliopancreatic diversion(33); one study performedeither RYGBP or sleeve gastrectomy (SG)(42); one studyperformed either SG (BMI ≤50 kg/m2) or biliopancreatic di-version (BMI >50 kg/m2)(27); and one study performedlaparoscopic adjustable gastric banding.(29)
Most studies measured serum/plasma glucagon concen-trations using a commercially available radio-immunoassay(RIA) methodology from Linco Research®/Millipore®(St Louis & St Charles, USA)(25–28,30–32,34,37–41); twostudies followed the multiplex immunoassay methodologyusing either a Bio-Plex® system from BioRad® (Veenendaal,The Netherlands)(21) or a Milliplex MAP® (Luminex®system), from Millipore® (St Chalres, USA)(42); one studyassessed plasma glucagon using Endocrine Sciences®(Calabasas, USA)(20); and one study assessed plasmaglucagon using Diagnostic® (Los Angeles, USA).(36) Twostudies performed an in-house RIA using the antibodyAb4305.(29,35) One study performed an enzyme-linkedimmunoabsorbent assay from Santa Cruz Biotech®(Milan, Italy).(33)
For the purpose of the meta-analysis, each intervention(diet or bariatric surgery) was considered independently,regardless of the study in which they were performed. Con-sequently, 29 interventions from the 20 articles retrievedwere assessed.
Weight loss improved the fasting metabolicoutcomes: glucagon, glucose and insulin
Seventeen of 18 bariatric interventions described in Table 1reported statistically significant weight loss, of between 3%and 35% of baseline body weight.(21,25–33,35,40–42)Conversely, only 4 of 11 dietary interventions resulted insignificant weight loss between 3% and 11%(28,30,34,37) or a significant decrease in BMI of 11%,(33) and the remaining seven reported non-significantweight loss of 1% to 7%.(31,32,36–39) Fig. 2a presentsthe forest plot meta-analysis for change in body weight inthe dietary and bariatric surgery subgroups. It is a generalfinding that most bariatric studies resulted in significantweight loss while most diet studies did not. When methodswere combined, diet and bariatric surgery together pro-moted significant weight loss (�20.31 kg, P < 0.00001)but very high heterogeneity (total I2 = 96%, P < 0.00001;Fig. 2a). In subgroup analysis, bariatric surgery resulted insignificantly greater weight loss compared to diet interven-tion (29.69 vs. 5.83 kg, I2 = 97.4%, P < 0.00001), suggest-ing that the different weight-loss methods contributed to theoverall heterogeneity of the data. When evaluated indepen-dently, within the diet subgroup, different interventionmethods produced similar weight loss (I2 = 52%,P = 0.03), however within the bariatric subgroup different
236 Glucagon during weight loss M. P. Silvestre et al. obesity reviews
© 2017 World Obesity FederationObesity Reviews 19, 233–253, February 2018
Tab
le1
Stu
diesincludedin
themeta
-analysis
Referen
ceAim
Des
ign
Interven
tion
Partic
ipan
tsDuration
BWT
(kg)
BMI
(kg/m
2)
Gluco
se
(mmol/L)
Insu
lin
(pmol/L)
Gluca
gon
(ng/L)
Gluca
gon
assa
ytype
Diet
Cam
pos
etal.
(35)
, (34)
Ass
essgluco
se
andpan
crea
tic
horm
ones
followingBWT
loss
RCT
Diet
3400
kJ/d
for14
d(%
CHO
=25
,
%P=48
,%F=27
)
OND
n=10
1Age=40
±
13ye
ars
6Fan
d4M
14d
1B=13
5±17
14d=12
7
δ=�6
%
1B=48
±7
14d=NA
1B=5.5±0.8
14d=4.8
δ=�1
3%*
1B=23
7±14
0
14d=14
2
δ=�4
0%*
1,2B=86
±7
14d=86
±7
δ=0%
RIA
(Millipore,
StC
harle
s,
USA)
Gan
non
etal.(39
)
Ass
essLo
BAG
for
glyca
emic
control
duringBWT
mainten
ance
RCT-
XO
Con
trol
Diet
%en
CHO
=55
%P=15
%F=30
LoBAG
Diet
%en
CHO
=20
%P=30
%F=50
T2D
Duration=4
±2ye
ars
n=8
Age=63
±
4ye
ars
M
16wee
ksB=99
±5
16wee
ks=98
±5
δ=�1
%
B=98
±5
16wee
ks=96
±4
δ=�2
%
B=31
±1
16wee
ks=NA
δ=NA
B=31
±1
16wee
ks=NA
δ=NA
B=10
±0.616
wee
ks=8.8
±0.6
δ=�1
2%
B=9.3±0.7
16wee
ks=6.6
±0.4
δ=�2
9%**
B=72
±12
16wee
ks=72
±12
δ=0%
B=72
±12
16
wee
ks=72
±12
δ=0%
B=95
±11
16wee
ks=91
±7
δ=�4
%
B=91
±8
16wee
ks=94
±7
δ=+3%
RIA
(Linco
Res
earch,
St
Louis,
USA)
Gan
non
etal.(20
)
Ass
essLo
BAG
for
glyca
emic
control
duringBWT
mainten
ance
CT
LoBAG
Diet
%en
CHO
=30
%P
=30
%F=40
T2D
Duration=4±
0ye
ars
n=8
Age=63
±3
years
M
10wee
ksB=90
(75–
109)
10wee
ks=89
(75–
109)
δ=�1
%
B=29
±1
410
wee
ks=29
δ=0%
B=11
.2±0.7
10wee
ks=8.1
±0.6
δ=�2
8%*
4B=~82
10wee
ks=~98
δ=+20
%
B=89
±20
10wee
ks=85
±18
δ=�4
%
RIA
(Linco
Res
earch,
St
Louis,
USA)
Laferrère
etal.(28
)
Ass
essglyca
emic
controlfollowing
BWTloss
CCT
Diet
4200
kJ/d
toac
hiev
e10
kg
weight
loss
T2D
Duration=2±
2ye
ars
n=10
1Age=47
±
7ye
ars
F
55±10
d1B=11
1±10
65d=10
1±10
δ=�9
%***
1B=43
±4
65d=40
±4
δ=�7
%***
1B=7.8±1.165
d=6.3±1.0
δ=�1
9%***
1B=19
2±
10865
d=
110±50
δ=�4
3%***
1B=72
±11
65d=59
±16
δ=�1
8%*
RIA
(Linco
Res
earch,
St
Louis,
USA)
Low
etal.
(36)
Ass
essBWTloss
followingen
ergy
restric
tionviahigh
CHO
orMUFA
diet
CCT
Diet
CHO
%C
=70
%P=
20%F=10
MUFA
%C
=10
%P=20
%F=70
T2D
CHO
n=8
1Age=51
±
5ye
ars
4M
and4F
MUFA
n=9
1Age=55
±
3ye
ars
5Fan
d4M
12wee
ksB=11
0±9
6wee
ks=10
2
δ=�7
%
12wee
ks=10
0
δ=�9
%
B=10
2±5
6wee
ks=95
δ=�7
%
12wee
ks=95
δ=�7
%
B=37
±2
512
wee
ks=34
δ=�8
%
B=36
±2
5E=34
δ=�6
%
B=11
.2±2.4
6wee
ks=8.8±3.3
δ=�2
1%*
12wee
ks=9.1±3.5
δ=�1
9%*
B=12
.6±3.2
6wee
ks=8.0±3.1
δ=�3
7%*#
12wee
ks=8.5±3.1
δ=�3
3%*
B=13
0±15
6wee
k=82
±
10 δ=�3
7%*
12wee
ks=77
±8
δ=�4
1%*
B=11
4±12
6wee
ks=71
±7
δ=�3
8%*
12wee
ks=80
±10
δ=�3
0%*
B=13
2±10
6wee
ks=10
5
±11
δ=�2
0%*
12wee
ks=99
±10
δ=�2
5%*
B=12
7±10
6wee
ks=11
0
±9
δ=�1
3%*
12wee
ks=
105±9
RIA
(Diagno
stic,
LosAng
eles
,
USA)
(Con
tinue
s)
Glucagon during weight loss M. P. Silvestre et al. 237obesity reviews
© 2017 World Obesity Federation Obesity Reviews 19, 233–253, February 2018
Tab
le1
(Con
tinue
d)
Referen
ceAim
Des
ign
Interven
tion
Partic
ipan
tsDuration
BWT
(kg)
BMI
(kg/m
2)
Gluco
se
(mmol/L)
Insu
lin
(pmol/L)
Gluca
gon
(ng/L)
Gluca
gon
assa
ytype
δ=�1
7%*
Marfella
etal.(33
)
Ass
essBWTloss
andglyca
emic
controlp
ostd
iet
ITDiet
Rec
ommen
ded
intake
=4,60
0kJ
/d
for10
kgloss
%en
CHO
=55
,
%F=30
,%P=15
T2D
Duration=3±
6ye
ars
n=20
1Age=46
±
6ye
ars
11Fan
d9M
160
±10
dB=NA
70d=NA
δ=NA
1B=44
±3
70d=39
±3
δ=�1
1%**
1B=7.1±0.7
70d=5.9±0.8
δ=�1
7%**
1B=17
8±68
70d=12
7±50
δ=�2
9%**
1B=70
±13
70d=66
±11
δ=�6
%
ELISA
(D.B.A.,
San
taCruz
Biotech
,
Milan,
Italy)
Nuttall
etal.(37
)
Ass
essBWTloss
followingfasting
orCHO-freediet
RCT-
XO
Diet
%P=15
,%F=82
,
%C
=<3,for72
h
Fast
for72
h
T2D
Duration=6±
2ye
ars
n=7
Age=60
±
3ye
ars
M
5wee
ksB=97
±4
5wee
ks=95
±3
δ=�2
%
B=96
±3
5wee
ks=93
±3
δ=�3
%###
B=31
±2
55wee
ks=31
δ=0%
B=31
±2
55wee
ks=30
δ=�3
%
B=10
.9±1.05
wee
ks=8.3±
0.8
δ=�2
4%
B=10
.9±1.0
5wee
ks=6.3±0.6
δ=�4
2%
B=12
5±10
5
wee
ks=14
6
±28
δ=+17
%
B=12
5±10
5
wee
ks=97
±14
δ=�2
2%
B=74
±5
5wee
ks=71
±11
δ=�4
%
B=74
±5
5wee
ks=83
±14
δ=+12
%
RIA
(Linco
Res
earch,
purch
ased
by
Millipore,
St
Cha
rles,
USA)
Vetteret
al.
(30)
Ass
essglyca
emic
controlfollowing
BWTloss
CCT
Diet
4,40
0kJ
/d
toac
hiev
e10
%
loss
1T2
D
Duration=3±
3ye
ars
n=10
1Age=52
±12
5M
and5F
186
±24
d1B=12
2±21
110d=10
9±6
δ=�1
1%***
B=42
±4
110d=37
±1
δ=�1
2%***
B=8.5±0.411
0d
=7.2±0.5
δ=�1
5%*
B=19
7±23
110d=15
1±13
δ=�2
3%
B=64
±7
110d=47
±4
δ=�2
7%**
RIA
(Millipore,
StC
harle
s,
USA)
Villarea
l
etal.(34
)
Ass
esseffect
of
LED
andBWT
loss
on
pan
crea
tic
endoc
rine
func
tion
RCT
Con
trol
diet
Diet
Low
energydiet
(ene
rgydeficit3,
100kJ
/d;%
F=30
,
%C
=50
,%P=20
;
goa
l10%
wtlos
s)
OND
n=2,
IGTn=7
(n=9)
Age=71
±2
6Fan
d3M
OND
n=2,
IGT
n=13
(n=15
)
Age=69
±1
11Fan
d4M
26wee
ksB=10
1±6
326
wee
ks=10
1
δ=0%
B=99
±4
326
wee
ks=90
δ=�9
%###
B=38
±2
B=38
±1
B=5.5±0.2
26wee
ks=5.7
δ=�
+4%
B=5.6±0.2
26wee
ks=5.4
δ=�4
%#
8B=~92
26wee
ks=~98
δ=+7%
8B=~11
0
26wee
ks=~74
δ=�3
3%
8B=~13
9±6
26wee
ks=14
0±7
δ=+1%
8B=15
1±9
26wee
ks=14
2±7
δ=�6
%
Dou
ble-
antib
odyRIA
(Linco
Res
earch,
St
Louis,
USA)
Bariatric
Bos
eet
al.
(25)
Ass
essho
rmon
e
chan
ges
12mon
thspos
t
BS
CCT
RYGBP
T2D
Duration=<5ye
ars
n=11
1Age=44
±11
F
1ye
ar1B=11
1±14
1mon
th=10
1±14
δ=�9
%*
6mon
ths=85
±13
δ=�2
3%*
12mon
ths=79
±12
δ=�2
9%*
1B=43
±5
1mon
th=39
±5
δ=�9
%*
6mon
ths=33
±5
δ=�2
3%*
E=30
±4
δ=�3
0%*
1B=7.5±1.7
1mon
th=6.2±0.7
δ=�1
7%*
6mon
ths=5.4±0.4
δ=�2
8%*
E=4.8±0.6
δ=�3
6%*
1B=17
2±70
1mon
th=11
3
±26
δ=�3
4%*
6mon
ths=67
±15
δ=�6
1%*
E=55
±19
δ=�6
8%*
1B=70
±23
1mon
th=69
±42
δ=�1
%
6mon
ths=48
±26
δ=�3
1%*
E=48
±8
δ=�3
1%*
RIA
(Millipore,
StC
harle
s,
USA)
CT
RYGBP
OND
1ye
arB=14
6±6
B=53
±2
6B=14
3(40)
6B=69
(40)
(Con
tinue
s)
238 Glucagon during weight loss M. P. Silvestre et al. obesity reviews
© 2017 World Obesity FederationObesity Reviews 19, 233–253, February 2018
Tab
le1
(Con
tinue
d)
Referen
ceAim
Des
ign
Interven
tion
Partic
ipan
tsDuration
BWT
(kg)
BMI
(kg/m
2)
Gluco
se
(mmol/L)
Insu
lin
(pmol/L)
Gluca
gon
(ng/L)
Gluca
gon
assa
ytype
Cam
astra
etal.(41
)
Ass
essmea
l-
dispos
al,w
eight
loss
andho
rmon
e
chan
ges
12mo
pos
tBS
n=11
Age=NA
Man
dF
T2D
Duration=4±
1ye
ars
n=7;
T2D
rece
ntly
diagno
sed,n
=3
(n=10
)
Age=NA
Man
dF
12mon
ths=
99±5
δ=�3
2%**
B=13
9±9
12mon
ths=
91±6
δ=�3
5%**
12mon
ths=
36±2
δ=�3
2%**
B=52
±3
12mon
ths=
34±2
δ=�3
5%**
B=5.5±0.112
mon
ths=5.1
±0.1
δ=�7
%*
B=8.8±0.9#
12mon
ths=5.0
±0.2
δ=�4
3%**
12mon
ths=44
(18)
δ=�6
9%**
6B=16
3(145
)
12mon
ths=60
(25)
δ=�6
3%**
12mon
ths=50
(23)
δ=�2
8%**
6B=69
(49)
12mon
ths=32
(16)
δ=�5
4%*#
RIA
(Millipore,
StC
harle
s,
USA)
Cam
pos
etal.
(35)
, (34)
Ass
essgluco
se
andpan
crea
tic
horm
ones
pos
t
BS
RCT
RYGBP
OND
n=12
1Age=47
±
9ye
ars
9Fan
d3M
26wee
ks1B=13
8±22
14d=12
8
δ=�7
%16mon
ths≈~
110
δ=�2
0%**
1B=48
±7
6mon
ths=NA
1B=5.3±0.7
14d=4.8
δ=�9
%*
16mon
ths=4.6
±0.6
δ=�1
0%*
1B=15
6±10
0
E=10
3
δ=�3
4%**
16mon
ths=~72
δ=�5
5%*
1,2B=83
±7
14d=88
±6
δ=+6%
16mon
ths=73
±6
δ=�1
2%*
RIA
(Millipore,
StC
harle
s,
USA)
deJo
nge
etal.(21
)
Ass
essch
anges
inglyce
mic
controlp
ostB
S
CT
DJB
LT2
D
Duration=<
10ye
ars
n=17
Age=51
±2ye
ars
14M
and3F
24wee
ksB=11
6±6
324
wee
ks=10
3
δ=�1
1%**
B=37
±1
324
wee
ks=
33 δ=�1
1%**
B=11
.6±0.5
1wee
k=9.0±
0.5
δ=�2
2%**
24wee
ks=8.6
±0.5
δ=�2
6%**
B=17
7±54
1
wee
k=15
6±
54 δ=�1
2%
24wee
ks=10
5
±22
δ=�4
1%
B=10
6±15
1wee
k=80
±15
δ=�2
5%
24wee
ks=79
±15
δ=�2
5%
Bio-Plexas
say
(BioRad
Laboratories,
Vee
nend
aal,
The
Nethe
rland
s)
Jørgen
sen
etal.(35
)
Ass
essen
doc
rine
mec
hanism
underlying
improve
men
tsin
glyce
mic
control
pos
tBS
CT
RYGBP
OND
n=12
1Age=43
±13
3M
and9F
T2D
1Duration=5±
4ye
ars
n=13
1Age=52
±9
years
7M
and6F
1ye
ar1B=12
7±15
1
wee
k=12
4±
15 δ=�2
%**
3mon
ths=10
6
±13
δ=�1
7%**
12mon
ths=95
±16
δ=�2
5%**
1B=12
9±14
1
wee
k=12
7
±13
δ=�2
%**
3mon
ths=11
2
±15
δ=�1
3%**
1B=42
±5
1wee
k=41
±5
δ=�2
%**
3mon
ths=
34±3
δ=�1
9%
12mon
ths=
31±5
δ=�2
6%**
1B=43
±51
wee
k=42
±5
δ=�2
%**
3mon
ths=
38±6
δ=�1
2%**
1B=5.5±0.61
wee
k=5.0±
0.6
δ=�9
%**
##
3mon
ths=4.9±
0.4
δ=�1
1%**
##
12mon
ths=4.9
±0.3
δ=�1
1%*
1B=8.8±2.31
wee
k=7.0±1.2
δ=�2
0%**
3mon
ths=6.8±
1.6
δ=�2
3%**
12mon
ths=6.2±
1.6
δ=�3
0%**
##
1B=82
±28
1
wee
k=49
±14
δ=�4
0%**
3mon
th=43
±14
δ=�4
8%**
12mon
ths=36
±16
δ=�5
6%**
1B=12
5±77
1
wee
k=73
±32
δ=�4
2%**
3mon
ths=58
±35
δ=�5
4%**
12mon
ths=47
±
27 δ=�6
2%**
1B=35
±14
1wee
k=38
±10
δ=+9%
3mon
ths=21
±3
δ=�4
0%**
12mon
ths=21
±7
δ=�4
0%**
1B=45
±24
1wee
k=49
±17
δ=+9%
3mon
ths=28
±7
δ=�3
8%**
12mon
ths=28
±14
δ=�3
8%**
In-hou
seRIA
usingAb43
05
(Con
tinue
s)
Glucagon during weight loss M. P. Silvestre et al. 239obesity reviews
© 2017 World Obesity Federation Obesity Reviews 19, 233–253, February 2018
Tab
le1
(Con
tinue
d)
Referen
ceAim
Des
ign
Interven
tion
Partic
ipan
tsDuration
BWT
(kg)
BMI
(kg/m
2)
Gluco
se
(mmol/L)
Insu
lin
(pmol/L)
Gluca
gon
(ng/L)
Gluca
gon
assa
ytype
12mon
ths=10
1
±20
δ=�2
2%**
12mon
ths=
34±8
δ=�2
1%**
Laferrère
etal.(28
)
Ass
essglyca
emic
controlfollowing
BWTloss
pos
tBS
CCT
RYBGP
T2D
Duration=3±
2ye
ars
n=9
1Age=45
±
10ye
ars
F
32±13
d1B=11
3±16
45
d=10
3±17
δ=�9
%***
1B=43
±6
45d=40
±7
δ=�7
%***
1B=8.0±1.7
45d=6.4±0.8
δ=�2
0%*
1B=17
2±69
45d=12
7±51
δ=�2
6%*
1B=66
±15
45d=67
±22
δ=+2%
##
RIA
(Linco
Res
earch,
St
Louis,
USA)
Marfella
etal.(33
)
Ass
essBWTloss
andglyca
emic
controlp
ostB
S
ITBPD
+paren
teral
nutrition
(6d)+diet
(sam
e
asdietg
roup
)
T2D
=3±
4ye
ars
n=36
1Age=45
±
8ye
ars
20Fan
d16
M
130
±12
dB=NA
42d=NA
δ=NA
1B=44
±3
42d=39
±3
δ=�1
1%**
1B=7.2±1.142
d=6.0±0.7
δ=�1
7%**
1B=17
8±68
70d=12
7±50
δ=�2
9%**
1B=70
±13
70d=66
±11
δ=�6
%
ELISA(D
.B.A.,
San
taCruz
Biotech
,Milan,
Italy)
Nan
nipieri
etal.(42
)
Ass
essen
doc
rine
andglyca
emic
chan
ges
pos
tBS
CT
RYGBP
SG
T2D
Duration=8±
5ye
ars
n=23
1
Age=51
±
9ye
ars
T2D
Duration=9±
6ye
ars
n=12
1
Age=57
±
7ye
ars
11M
and24
F
1ye
ar+30
d1B=11
3±20
15d=10
9±20
δ=�4
%*
13mon
ths=78
±
13 δ=�3
1%*
1B=12
4±18
15d=12
1±18
δ=�2
%*
13mon
ths=95
±
11 δ=�2
3%*
1B=42
±5
15d=40
±6
δ=�5
%*
13mon
ths=
29±4
δ=�3
1%*
1B=46
±615
d=45
±6
δ=�2
%*
13mon
ths=
36±5
δ=�2
2%*
1B=8.6±2.815
d=8.4±3.3
δ=�2
%
13mon
ths=6.1±1.9
δ=�2
9%*
1B=7.8±1.415
d=7.4±3.0
δ=�5
%
13mon
ths
=5.8±0.9
δ=�2
6%*
6B=72
(60)
15
d=90
(48)
δ=+25
%
13mon
ths=42
(30)
δ=�4
2%*
6B=10
2(78)
15d=10
8(42)
δ=+6%
13mon
ths=66
(30)
δ=�3
5%*
6B=60
(22)
15
d=72
(29)
δ=+20
%*
13mon
ths=52
(46)
δ=�1
3%
6B=48
(35)
15
d=72
(51)
δ=+50
%*
13mon
ths=58
(37)
δ=+21
%
MilliplexMAP
Kits
(Millipore,
StC
harle
s,
USA)
Rub
ino
etal.(20
)
Ass
essch
anges
inBWTan
d
gluco
se
metab
olism
CT
RYGBP
T2D
n=6
OND
n=4
(n=10
)1Age=37
±10
1M
and9F
3wee
ksB=NA
E=NA
δ=NA
1B=46
±4
3wee
ks=43
±4
δ=�7
%
1B=6.3±1.3
3wee
ks=4.7±0.3
δ=�2
5%**
1B=17
1±12
0
3wee
ks=88
±81
δ=�4
9%*
1B=66
±30
3wee
ks=70
±31
δ=+6%
RIA
(End
ocrin
e
Scien
ces,
Calab
asas
,
USA)
Swarbric
k
etal.(26
)
Ass
essho
rmon
e
chan
ges
pos
tBS
CT
RYGBP
OND
n=19
Age=41
±2
F
1ye
arB=12
6±4
1mon
th=11
3±3
δ=�1
0%****
3mon
ths=10
7±4
δ=�1
5%****
6mon
ths=95
±3
B=46
±2
1mon
ths=41
±2
δ=�1
1%****
3mon
ths=39
±2
7B=5.5±0.3
1mon
th=5.1±0.2
δ=�7
%
3mon
ths=4.9±0.1
δ=�1
1%*
6mon
ths=4.8±0.1
7B=20
0±19
1mon
ths=11
7±12
δ=�4
2%****
3mon
ths=95
±8
δ=�5
3%****
6mon
ths=83
±7
7B=98
±11
1mon
th=86
±7
δ=�1
2%
3mon
ths=73
±5
δ=�2
6%*
6mon
ths=68
±5
RIA
(Linco
Res
earch,
St
Louis,
USA)
(Con
tinue
s)
240 Glucagon during weight loss M. P. Silvestre et al. obesity reviews
© 2017 World Obesity FederationObesity Reviews 19, 233–253, February 2018
Tab
le1
(Con
tinue
d)
Referen
ceAim
Des
ign
Interven
tion
Partic
ipan
tsDuration
BWT
(kg)
BMI
(kg/m
2)
Gluco
se
(mmol/L)
Insu
lin
(pmol/L)
Gluca
gon
(ng/L)
Gluca
gon
assa
ytype
δ=�2
5%****
12mon
ths=
86±3
δ=�3
2%****
δ=�1
5%****
6mon
ths=35
±2
δ=�2
4%****
12mon
ths=31
±1
δ=�3
3%****
δ=�1
3%****
12mon
ths=4.6±0.1
δ=�1
6%****
δ=�5
9%****
12mon
ths=77
±6
δ=�6
2%****
δ=�3
1%**
12mon
ths=
63±4
δ=�3
6%****
Tsolie
tal.
(27)
Ass
esseffic
acyof
SG
andBPD
for
BWTch
angean
d
endoc
rine
chan
ges
pos
tBS
CT
SG
Ifpre-operative
BMI≤
50kg
/m2
BPD
Ifpre-operative
BMI>
50kg
/m2
1T2
DDuration=
18±7mon
ths
n=12
1Age=40
±9
years
8Fan
d4M
1T2
D
Duration=18
±
7mo
n=12
1Age=
42±12
years
7Fan
d5M
1ye
arB=NA
E=NA
δ=NA
B=NA
E=NA
δ=NA
B=44
±2
1mon
th=39
±2
δ=�1
1%*
3mon
ths=34
±2
δ=�2
3%*
12mon
ths=28
±3
δ=�3
6%*
B=58
±10
#
1mon
th=52
±9#
δ=�1
0%*
3mon
ths=45
±8#
δ=�2
2%*
12mon
ths=
32±5#
δ=�4
5%*
1B=7.9±2.1
1mon
th=5.8±
0.9
δ=�2
7%*
3mon
ths=5.3
±0.6
δ=�3
3%*
12mon
ths=5.0
±0.5
δ=�3
7%*
1B=8.7±2.7
1mo=6.6±0.6#
δ=�2
4%*
3mon
ths=5.4±
0.7
δ=�3
8%*
12mon
ths=
4.3±0.6#
#
δ=�5
1%*
1B=28
7±13
4
1mon
th=13
5
±63
δ=�5
3%*
3mon
ths=84
±35
δ=�7
1%*
12mon
ths=58
±25
δ=�8
0%*
1B=23
8±19
0
1mon
ths=11
4
±44
δ=�5
2%*
3mon
ths=67
±24
δ=�7
2%*
12mon
ths=33
±17
#
δ=�8
6%*
1B=55
±16
1mon
th=54
±19
δ=�2
%
3mon
ths=
43±15
δ=�2
2%*
12mon
ths=
38±9
δ=�3
1%*
1B=69
±19
1mon
th=83
±20
##
δ=+20
%*
3mon
ths=
61±17
#
δ=�1
2%*
12mon
ths=
51±14
#
δ=�2
6%*
RIA
(Linco
Res
earch,
St
Louis,
USA)
Umed
a
etal.(40
)
Ass
essen
doc
rine
andglyca
emic
chan
ges
pos
tBS
CT
RYGBP
T2D
(durationno
t
given
)
n=10
Age=25
–65
years
Sex
=NA
12wee
ks1B=10
3±16
30d=92
±14
δ=�1
1%*
3mon
ths=86
±12
δ=�1
7%*
1B=40
±2
30d=35
±2
δ=�1
3%*
3mon
ths=33
±2
δ=�1
8%*
1B=13
.3±5.7
30d=6.9±1.8
δ=�4
8%*
3mon
ths=6.6
±2.5
δ=�5
0%*
1B=11
5±11
7
30d=58
±21
δ=�5
0%
3mon
ths=49
±
19 δ=�5
7%
1B=78
±21
30d=87
±30
δ=+12
%
3mon
ths=87
±20
δ=+12
%
RIA
(Linco
Res
earch,
St
Louis,
USA)
Using
er
etal.(32
)
Ass
essch
anges
inBWTan
d
gluco
se
metab
olism
pos
t
BS
CT
LAGB
OND
n=3,
IGTn=3,
T2D
rece
ntly
diagno
sedn=2
(n=8)
Age=48
±3
7Fan
d1M
~6wee
ks
(4–8wee
ks)
B=12
5±6
6wee
ks=12
1
±6
δ=�3
%*
B=44
±2
56wee
ks=42
δ=�5
%
B=6.2±0.5
6wee
ks=
6.0±0.3
δ=�3
%
B=14
4±24
6wee
ks=12
8±
31 δ=�1
1%
B=56
±5
6wee
ks=49
±8
δ=�1
3%
In-hou
seRIA
(Ab43
05,
Nov
oNordisk,
Bag
sværd,
Den
mark)
Vetteret
al.
(30)
CCT
RYGBP
1T2
D=5±3
years
159
±12
d1B=12
1±24
71d=10
9±6
B=43
±6
71d=39
±1
B=8.6±0.4
71d=6.3±0.5
B=19
5±35
71
d=91
±13
B=62
±6
71d=43
±4
(Con
tinue
s)
Glucagon during weight loss M. P. Silvestre et al. 241obesity reviews
© 2017 World Obesity Federation Obesity Reviews 19, 233–253, February 2018
Tab
le1
(Con
tinue
d)
Referen
ceAim
Des
ign
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242 Glucagon during weight loss M. P. Silvestre et al. obesity reviews
© 2017 World Obesity FederationObesity Reviews 19, 233–253, February 2018
Figure 2 Forest plot presenting meta-analysis of the mean difference and standard error (SE) in (a) absolute body weight (kg), (b) fasting glucagon (ng/L),(c) fasting glucose (mmol/L) and (d) fasting insulin (pmol/L), following weight loss interventions. N = 29 interventions, except for Fig. 2a (N = 26), whereonly 26 interventions were assessed due to lack of data on body weight (kg) in two interventions from Marfella et al. (33) and one intervention from Rubinoet al. (20); and for Fig. 2d (N = 28) due to lack of data for fasting insulin in Campos et al. ((31,32); not estimable). Z-score at the bottom of the plot representsthe overall effect for a random effect model. Heterogeneity of the results was measured by τ
2, χ2, degrees of freedom (df) and I2. Subgroup differenceswere tested and presented as χ
2, degrees of freedom (df) and I
2. Results were found significant when P < 0.05. “Weight” corresponds to the percentage
of contribution of each intervention to the overall effect. [Colour figure can be viewed at wileyonlinelibrary.com]
Glucagon during weight loss M. P. Silvestre et al. 243obesity reviews
© 2017 World Obesity Federation Obesity Reviews 19, 233–253, February 2018
Figure 2b (Continued)
244 Glucagon during weight loss M. P. Silvestre et al. obesity reviews
© 2017 World Obesity FederationObesity Reviews 19, 233–253, February 2018
intervention methods resulted in high heterogeneity inweight loss (I2 = 94%, P < 0.00001).
Figure 2b presents meta-analysis of the change in fastingglucagon concentration in the 29 interventions, whichshowed a significant decrease following weight loss(�11.8 ng/L; P < 0.00001), with some degree of heteroge-neity (total I2 = 58%). Ten of 18 bariatric interventions re-ported a statistically significant decrease of 12% to 54%in circulating glucagon, (25–27,30–32,35,41) as did 4 ofthe 11 diet interventions, (28,30,36) where glucagon de-creased by 17% to 27%. Subgroup analysis to investigatethe effect of the two weight-loss methods (Fig. 2b) showedthat both bariatric and diet interventions resulted in compa-rable changes in fasting glucagon concentration. Meandecrease in glucagon was 12.02 ng/L for bariatric and10.53 ng/L for diet intervention (test for subgroup differ-ences, I2 = 0%, P = 0.76).
To further understand metabolic improvements followingweight loss, meta-analysis of the changes in fasting glucose(Fig. 2c), and fasting insulin (Fig. 2d) was performed. As ex-pected, both parameters significantly decreased followingweight loss (both, P < 0.00001; glucose �1.66 mmol/L;insulin �50.60 pmol/L). Subgroup analysis showed thatthese changes were significant irrespective of the weight lossmethod and that fasting glucose and insulin were bothsignificantly improved after dietary (P < 0.00001 andP = 0.002, respectively) and bariatric intervention(P < 0.00001 and P < 0.00001, respectively). However,change in glucose was similar between methods (test forsubgroup differences, I2 = 0%, P = 0.55, Fig. 2c) whereas in-sulin changes were significantly greater for bariatric inter-ventions when compared to diet interventions (test forsubgroup differences, P = 0.01, I2 = 83.5%, Fig 2d). Nota-bly, when analysed independently, fasting insulin presented
low degree of heterogeneity within diet interventions(I2 = 55%, P = 0.02) but not within bariatric interventions(I2 = 81%, P < 0.00001; Fig. 2d).
Greater weight loss results in long term greaterglucagon improvements
To better understand the potential association betweenweight loss and improvements in fasting glucagon, we per-formed a meta-regression of changes in body weight on im-provements in fasting glucagon (Fig. 3). Body weight losswas positively correlated with improvements in fasting glu-cagon (P < 0.01).It is important to note that 2 to 4 weeks after bariatric
surgery, there was an acute rise of 6% to 50% in fasting glu-cagon reported in 7 of the 18 bariatric interventions,(20,31,32,35,40,42) although this was only statistically sig-nificant for the bariatric interventions performed byNannipieri et al., with 20% and 50% increase for RYGBPand SG, respectively, 2 weeks after surgery (Table 1). Theabsence of short term data in the other interventionsprevented analysis of these acute effects in more detail.
Addressing heterogeneity: study duration as aconfounding variable
The high degree of heterogeneity led to an investigation ofpotential confounders. A random effect meta-regressionmodel was used to investigate whether the heterogeneity ofthe data could be explained by the duration of the studies,because the maximum duration of diet interventions was26 weeks, while maximum duration of bariatric interven-tion was 56 weeks. The significantly greater change in bodyweight following bariatric surgery was driven in great part
Figure 3 Meta-regression of the effect of body weight change on change in fasting glucagon. N = 26 interventions due to lack of data on body weight (kg)in two interventions from Marfella et al. (33) and one intervention from Rubino et al. (20). Data on Z-score represents the overall effect for a random effectmodel. Diet interventions are represented by circles, and bariatric surgery interventions are represented by squares.
Glucagon during weight loss M. P. Silvestre et al. 245obesity reviews
© 2017 World Obesity Federation Obesity Reviews 19, 233–253, February 2018
by the longer study duration (P < 0.00001, Fig. 4a). Studyduration was also significantly correlated with changes infasting glucagon (P < 0.05, Fig. 4b), but this effect was lostwhen analysed over only 26 weeks (data not shown). Studyduration was not correlated with the changes observed infasting glucose (P = 0.6, Fig. 4c) or fasting insulin(P = 0.9, Fig. 4d).
To further understand the effect of diet versus bariatricsurgery in improving fasting glucagon and glucose homeo-stasis following weight loss, series of meta-analysis wereconducted for diet and bariatric interventions of matchedduration of 26 weeks. Figure 5a shows significant weightloss (�12.78 kg, P < 0.00001) with high heterogeneity(total I2 = 91%, P < 0.00001; Fig. 5a). In subgroup analysis,bariatric surgery resulted in significantly greater weight lossover 26 weeks compared to diet intervention (�18.89 vs.�5.83 kg, I2 = 95.3%, P < 0.00001).
Figure 5b presents meta-analysis of the change in fastingglucagon concentration, which showed a significant de-crease following 26 weeks of weight loss (�10.43 ng/L;P < 0.00001), with some degree of heterogeneity (totalI2 = 58%, P = 0.0002). Subgroup analysis showed no differ-ences between weight loss methods of diet and bariatric sur-gery (I2 = 0%, P = 0.9).
Fasting glucose (Fig. 5c) and fasting insulin (Fig. 5d) bothsignificantly decreased following 26 weeks of weight loss(�1.51 mmol/L, P < 0.00001; �40.51 pmol/L for insulin,P = 0.0009) with minimal heterogeneity between diet andbariatric study groups (glucose I2 = 0% P = 0.93, insulinI2 = 0.8% P = 0.32).
Addressing heterogeneity: Inclusion of participantssuffering from obesity but not type 2 diabetes (OND)
Inclusion of T2D participants as well OND participants canbe seen as a contributing factor for the variability in thedata. To further address this potential source of heterogene-ity, we conducted sensitivity analysis in which we (i)reanalysed the data, excluding studies where subject groupwas OND only and (ii) where subject group was bothOND and T2D (Supporting Information). The sensitivityanalysis resulted in no differences in heterogeneity and Z-scores for body weight changes (as expected; Supporting In-formation I). Minor differences in heterogeneity for changein glucagon concentration were seen; noting that these dif-ferences were exclusively in the subgroup diet intervention,in which heterogeneity reduced from 76% to 71% with Z-score improving from 2.42 to 2.60 (Supporting Information
Figure 4 Meta-regression of the effect of study duration on the mean change in (a) body weight, (b) fasting glucagon, (c) fasting glucose and (d) fastinginsulin. N = 29 interventions except for Fig. 4a, where only 26 interventions were assessed due to lack of data on body weight (kg) in two interventions fromMarfella et al. (33) and one intervention from Rubino et al. (20) and for Fig. 4d due to lack of data for fasting insulin in Campos et al. (31,32). Data on Z-scorerepresents the overall effect for a random effect model. A vertical red line indicates a duration of 26 weeks, which was the maximum duration for all dietstudies. Data presented in a red squared box on Fig. 4a,b is relative to a maximum of 26-week duration only. All the studies with a duration greater than26 weeks were bariatric surgery interventions. Diet interventions are represented by circles, and bariatric surgery interventions are represented bysquares.
246 Glucagon during weight loss M. P. Silvestre et al. obesity reviews
© 2017 World Obesity FederationObesity Reviews 19, 233–253, February 2018
Figure 5 Forest plot presenting meta-analysis of the mean change and standard error (SE) in (a) absolute body weight (kg), (b) fasting glucagon (ng/L),(c) fasting glucose (mmol/L) and (d) fasting insulin (pmol/L), following weight-loss interventions that provided data for a maximum duration of 26 weeks.N = 24 interventions, except for Fig. 5a (N = 21) due to lack of data on body weight (kg) in two interventions from Marfella et al. (33) and one interventionfrom Rubino et al. (20) and for Fig. 5d (N = 23) due to lack of data for fasting insulin in Campos et al. (31,32). Z-score at the bottom of the plot represents theoverall effect for a random effect model. Heterogeneity of the results was measured by τ
2, χ
2, degrees of freedom (df) and I
2. Subgroup differences were
tested and presented as χ2, degrees of freedom (df) and I2. Results were found significant when P < 0.05. “Weight” corresponds to the percentage of
contribution of each intervention to the overall effect. [Colour figure can be viewed at wileyonlinelibrary.com]
Glucagon during weight loss M. P. Silvestre et al. 247obesity reviews
© 2017 World Obesity Federation Obesity Reviews 19, 233–253, February 2018
Figure 5 (Continued)
248 Glucagon during weight loss M. P. Silvestre et al. obesity reviews
© 2017 World Obesity FederationObesity Reviews 19, 233–253, February 2018
II). Larger differences in heterogeneity were seen forchange in blood glucose concentration, as expected, withoverall heterogeneity reducing from 77% to 61%(Supporting Information III). Heterogeneity for the sub-group diet reduced from 66% to 42%, but this was notstatistically significant (P = 0.09; Supporting InformationIII); and heterogeneity for subgroup bariatric reduced from82% to 69%, with Z-score improving from 7.34 to 7.64(Supporting Information III). Finally, this analysis resultedin minor differences in heterogeneity and Z-scores forfasting insulin; where overall heterogeneity increased from83.5% to 86.8% following reanalysis (SupportingInformation IV).
Discussion
This systematic review and meta-analysis assessed the evi-dence for an association between fasting plasma glucagonand weight loss-mediated metabolic improvements,achieved through both: diet and bariatric surgery. Previ-ously shown to be elevated in obesity and dysglycaemicstates(6–9) alongside the characteristic pattern ofhyperinsulinaemia and insulin resistance, our current anal-ysis showed that fasting glucagon concentrations appearto be responsive to changes in adiposity, decreasing fol-lowing weight-loss concomitant to a decrease in fastingglucose and fasting insulin. Opposing the effects of insulinand preventing hypoglycaemia and, potentially also an-orexia, insulin-induced suppression of glucagon may beenhanced by weight loss as insulin sensitivity improves.Moreover, we found that change in fasting glucagon isnot dependent on method of body weight loss (diet orbariatric surgery) but rather absolute weight loss, withgreater weight loss promoting greater hormonesuppression.
Glucagon, secreted from pancreatic α-cells, acts as acounter-regulatory hormone of blood glucose alongside in-sulin, promoting elevation of blood glucose through hepaticglycogenolysis and gluconeogenesis during periods ofhypoglycaemia.(43–48) Besides secretion in response tolow plasma glucose levels, plasma concentration of gluca-gon is modulated directly by insulin through regulation ofglucagon gene expression and also at an intra-islet levelinhibiting secretion when insulin levels increase, e.g. post-prandially in response to a meal.(49) Glucagon secretionalso rises postprandially following increases in circulatinglevels of amino acids and fatty acids, as well as in responseto adrenergic stimulation and to some regulatory peptides.(50) Whether glucose primarily controls glucagon releasedirectly, via glucose sensing and metabolism in α-cells, or in-directly, through β-cell and insulin secretion, or even thoughneural activity under normoglycaemic, hyperglycaemic orhypoglycaemic conditions, has not yet been precisely eluci-dated in vivo. It has been shown that insulin action is
essential to exert the suppressive effect of glucose on α-cellsand that in its absence glucose is unable to suppress gluca-gon release.(49) Notably, however, both OND individualsand patients with T2D typically exhibit normal to slightlyelevated fasting glucagon levels(51–53) in comparison withhealthy lean individuals, and in parallel with raised fastingglucose and insulin concentrations.(54) This fastinghyperglucagonaemia in T2D and obesity, likely a conse-quence of the increased adiposity and lipid deposition, inturn contributes to the hyperglycaemia characteristicallyobserved in the insulin resistance/hyperinsulinaemic state.In line with this observation, it is unsurprising that this sys-tematic review identified fasting glucagon concentrationsthat were variable at baseline but which improved signifi-cantly in the medium-term to long-term following weightloss. This decrease probably contributed synergistically tothe hypoglycaemic action of insulin and, in turn, improvedglycaemic control.As expected, diet and bariatric interventions resulted in
marked body-weight reduction that was accompanied bymetabolic improvements. Surgery caused significantlygreater body-weight loss than diet, but this effect was con-founded by the longer duration of the bariatric studies.Nevertheless, when a meta-analysis was undertaken forstudies of matched duration (26 weeks), bariatric surgerystill resulted in greater weight loss than diet. This is in linewith that previously reported in the literature.(55) Possiblemechanisms by which weight loss surgery maintains energyrestriction and weight loss includes secretion of gastrointes-tinal hormones (glucagon-like peptide 1 [GLP-1], peptideYY [PYY] and cholecystokinin [CCK]) and/or appetitesuppression,(56–58) but causality is yet to be established.Indeed, it has consistently been shown that the secretionof the anorexigenic hormones, GLP-1 and PYY, is in-creased after RYGB (56–58) while secretion of CCK hasshown some inconsistent results. (56) Conversely, theplasma concentration of ghrelin – the well-knownappetite-inducing hormone – is reduced during the firstmonths after surgery but later increases along with the re-duction in body weight. (56,59) Similarly, there is a limitedamount of evidence suggesting that glucagon can also sup-press appetite. Early studies reported suppression of hun-ger and decreased food intake following glucagonadministration in humans (60–62) and rats.(63) This the-ory was later supported by the fact that glucagon levels in-crease following a meal, as discussed earlier. (50) Theprecise mechanism for the potential anorexigenic effect ofglucagon is still unclear, but more recent studies in sheepsuggested that glucagon acts directly in the central nervoussystem to inhibit food intake. (64) It is possible that asustained fall in fasting glucagon following weight loss ispart of a defence mechanism to increase hunger during aperiod of energy restriction and hence may contribute tothe issue of weight regain.
Glucagon during weight loss M. P. Silvestre et al. 249obesity reviews
© 2017 World Obesity Federation Obesity Reviews 19, 233–253, February 2018
Interestingly, despite the greater weight loss driven by thelong study duration, bariatric surgery did not cause greaterimprovement than diet intervention in either fasting gluca-gon or glucose, with both methods equally effective overmedium-term and long-term follow-up. We believe thatthe changes in fasting glucagon are a result of an adaptiveand compensatory mechanism, and as such, it does makesense that the fall in fasting glucagon concentration stabi-lizes over time, even in the face of greater weight loss, asa response to the fasting glucose stabilization. This raisesthe hypothesis that some degree of weight loss (achievedthrough diet) causes some improvement in glucagon, butthat greater weight loss (achieved through bariatric sur-gery) does not further suppress glucagon. Conversely, bar-iatric surgery did improve fasting insulin when comparedto diet in these long term interventions. Notably, however,when fasting insulin was analysed for matched durationof 26 weeks, there was no difference between bariatricand diet methods, as for both glucagon and glucose. Unex-pectedly, two of the studies reported significant improve-ments in fasting glucose in the absence of a change infasting insulin or glucagon concentration. These were shortduration bariatric studies(21,40) of 12 and 24 weeksrespectively, with less weight loss than other bariatric stud-ies.(25–27,35,41,42) Possibly, improved insulin sensitivitymay account for the hypoglycaemia, but this cannot bedetermined in this analysis.
A systematic review and meta-analysis from Buchwaldet al., (2009) showed that T2D improved or resolved in87% of participants who underwent bariatric surgery forweight loss,(17) highlighting the success of this approach.Interestingly, diet intervention has been shown to matchinsulin-mediated glucose clearance after RYGBP whencomparable restriction of energy intake(65) and/or weightloss(30) is achieved. Few studies have succeeded in directlycomparing changes in glucose metabolism following bariat-ric surgery and diet intervention,(28,31,65) with compari-sons challenged by the difficulties of matching cumulativeweight loss and degree of energy restriction. This makes itdifficult to assess whether surgery per se may have dietindependent effects on improved glucose metabolism. Inour current meta-analysis, surgery was not shown to be su-perior to diet for improvement in fasting glucagon, insulinor glucose for matched study duration. Moreover, we didnot observe differences in weight-loss-related improvementin glucose metabolism between the different bariatric pro-cedures, although there was a paucity of comparative stud-ies, other than RYGBP or SG, which prevents firmconclusions being made. While the type of diet interventionalso did not seem to play an important role in changes infasting glucagon, there was insufficient data to drawconclusions.
Notable in several of the bariatric interventions presentedin Table 1, there are unexpected acute changes in glucagon
following weight loss. Seven bariatric interventions showedan acute increase in fasting glucagon 1–4 weeks after sur-gery, which then reversed in the longer term.(20,27,31,32,35,40,42) Other research groups investigatingchange in peptide concentration following surgery have alsoreported this outcome.(41,66–68) Because fasting glucoseand insulin declined immediately following bariatric surgeryin all studies (except Nannipieri et al. (42)), we hypothesisethat glucagon concentration may have increased as an acuteadaptive response to the rapid decrease in plasma glucose,possibly acting through a non-insulin-mediated mechanism.It is possible that glucose homeostasis during weight loss iscontrolled under a feedback-loop system between glucose,insulin, glucagon and other factors discussed earlier, whereeach parameter senses lack of equilibrium and functions to-wards its restoration by sensing other metabolites.Glucagon-mediated increased hepatic gluconeogenesis andglycogenolysis would be expected to ‘normalize’ glycaemiato its high pre-surgical concentration and may be a homeo-static response to weight loss. Following this period of ad-aptation, fasting glucagon may then gradually decline inparallel with circulating glucose concentrations. Interest-ingly, an acute increase in secretion of gastrointestinal hor-mones PYY, CCK and GLP-1 immediately after bariatricsurgery has also been well documented,(69) but becausethese incretin peptides have been shown to inhibit glucagonsecretion,(13,70,71) it seems unlikely that this can explainthe acute rise in glucagon. Other mechanisms underpinningearly hyperglucagonemia post-surgery remain to bedemonstrated.
With respect to analytical laboratory methods, identify-ing changes in glucagon secretion can be challenging. Asdiscussed earlier, glucagon increases hepatic glucose outputunder conditions of hypoglycaemia/fasting, and its secretionis inhibited in response to a meal. However, the physiologi-cal decrease in plasma glucagon in response tohyperglycaemia may be outside the limits of detection, withcirculating concentrations lowered by only 1–2pmol/L(3.5–7 pg/mL).(72) Clearly assays with sensitivity >5pmol/L (17.4 pg/mL) are unsuitable to detect such smallchanges in hormone concentration. ‘Specific assays’ for glu-cagon are directed against the free, unextended and un-abridged C-terminus of glucagon, based on theassumption that molecules exposing this region are mainlyderived from the pancreatic α-cells. However, the pancreasis not the only origin of glucagon with studies of intestinalmucosa reporting small concentrations of fully processedglucagon in this tissue.(73) Accurate measurements of glu-cagon could be performed using a sandwich enzyme-linkedimmunosorbent assay approach, but such assays have notbeen developed so far and would not solve the problem ofpancreatic-origin versus intestinal-origin glucagon. To date,the best-performing assay for glucagon is the LincoResearch/Millipore® RIA kit, but its accuracy at a low
250 Glucagon during weight loss M. P. Silvestre et al. obesity reviews
© 2017 World Obesity FederationObesity Reviews 19, 233–253, February 2018
concentration range does not appear to be adequate underconditions in which, for instance, glucagon secretion is sup-pressed.(74) For this reason, we restricted the present sys-tematic review to glucagon in the fasting state andexcluded changes in postprandial glucagon concentrationswhere analytical limits of detection may prevent accurateconclusions being drawn.
One of the limitations of this meta-analysis is the hetero-geneity of the studies. To address this issue, subgroup anal-ysis based on method of weight loss was performed, and arandom-effects model and meta-regression addressed the as-sociation between glucose homeostasis and study duration.Furthermore, sensitivity analysis were performed by remov-ing studies that included OND participants only or ONDand T2D participants, hence, addressing the variability ofthe study participants. The results of this analysis suggestedthat only fasting glucose changes were affected by the inclu-sion of participants without T2D. Excluding them from thedata set did not compromise the results or conclusions ofthe analysis, but it improved the data by reducing heteroge-neity. Sensitivity analysis were also undertaken to under-stand if the use of glucose lowering medication could haveaffected the overall result. No differences were seen whenstudies reporting patients on glucose lowering medication(20,21) were excluded from the original analysis (data notshown). In addition, the majority of the studies althoughwell designed did not include plasma glucagon as a primaryoutcome variable, and many studies had only short follow-up that limits conclusions on weight-loss maintenance andlong-term metabolic adaptation. Finally, the majority ofstudies were of small sample size and hence lacked statisticalpower to detect small changes in body weight and metabolicoutcome. For example, change in body weight of 7–9%wascommonly reported as not statistically significant, yet5–10% weight loss is clinically relevant and likely impor-tant in terms of metabolic improvement.(75)
Conclusions
In this systematic review of weight-loss interventionsreporting changes in fasting glucagon concentration, bothdiet and bariatric surgery, caused significant weight loss that,as expected, resulted in improvement in several aspects ofglucose metabolism, including decrease in fasting glucagonconcentration. In turn, this is expected to contribute to im-proved glucose tolerance. While bariatric surgery was moreeffective than diet in decreasing body weight irrespective ofduration of intervention, it was not superior to diet in im-proving glucose homeostasis. When measured, long-termfasting glucose and glucagon improvements did not differ be-tween bariatric surgery and diet interventions. Unexpectedly,bariatric surgery led to an acute increase in glucagon secre-tion in parallel to the predicted hypoglycaemic andinsulinaemic response, possibly a direct response to the acute
drop in blood glucose that in turn promotes hepatic glucoseoutput, preserving glucose homeostasis and preventinghypoglycaemia. The underpinning mechanism of surgicallymediated glucagon secretion, however, is unknown. In turn,whether the long-term suppression of plasma glucagon fol-lowing weight loss may contribute to increased hunger andgradual weight regain is not yet known.
ContributionsM. P. S. developed the study design, searched the literature,collected and assessed the validity of the data, performedthe statistical analysis, interpreted the data, wrote the manu-script and produced the figures; J. P. G. collected and assessedthe validity of the data, reviewed and harmonized the datacollection, contributed to the statistical analysis and to theproduction of figures; P. V. contributed to the statistical anal-ysis; C. M. searched the literature, collected and assessed thevalidity of the data; A. T. collected and assessed the validityof the data, reviewed and harmonized the data collection;S. D. P. revised the literature search, solved the discrepanciesin data collection and validity assessment, contributed to thedata interpretation and revised the full manuscript.
Disclosures
M. P. S. was funded by the Health and Research Council ofNew Zealand (HRC; #14/191). As the corresponding au-thor, S. D. P. holds the Fonterra Chair in Human Nutritionat the University of Auckland and receives funding fromHRC (#14/191), National Science Challenge High ValueNutrition Program (MBIE #3710040) and the Riddet Cen-tre of Research Excellence (CoRE), New Zealand.
Conflict of interest statement
No conflict of interest was declared.
Acknowledgements
This systematic review and meta-analysis was funded by theHealth and Research Council of New Zealand (HRC) grantnumber 14/191. We would like to acknowledge Prof. PeterMullins for his statistical advice.
Supporting information
Additional Supporting Information may be found online inthe supporting information tab for this article. https://doi.org/10.1111/obr.12631
Data S1. Supporting informationData S2. Supporting informationData S3. Supporting informationData S4. Supporting informationData S5. Supporting information
Glucagon during weight loss M. P. Silvestre et al. 251obesity reviews
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