the role of glucagon in weight loss-mediated metabolic ... · medline, scopus, web of science,...

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

http://www.crd.york.ac.uk/PROSPERO

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


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



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)



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)



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)



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)



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)



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

Ass

essglyca

emic

controlfollowing

pos

tBS

2,00

0kJ

/dfor4

wee

ks;4

,000

kJ/d

for4wee

ks

n=10

1Age=54

±7

9Fan

d1M

δ=�1

0%***

δ=�9

%***

δ=�2

7%***

δ=�5

3%**

δ=�3

1%***

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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]



http://wileyonlinelibrary.com

Figure 2b (Continued)



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.



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.



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]



http://wileyonlinelibrary.com

Figure 5 (Continued)



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.



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



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



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