Jeff Stephens

(on behalf of the Swansea Diabetes Group)

Diabetes Research Group, Swansea University,

United Kingdom

Consultant Physician,

Morriston Hospital, Swansea, Wales, UK

Obesity, Prediabetes & Bariatric Research

(and complications)

Contents

• Overview of interested parties/investigators

• A taste of the Research work done

• Examples of research (Bariatric surgery)

• Other work related to complications

Clinical Science Basic Science

Epidemiology

& Health InformaticsClinical Trials

Exercise

& Physiology

SWANSEA & WEST WALES DIABETES RESEARCH COLLABORATION

Clinical Medicine

• Researchers

– JS, SP, RB, LW, RC, RT

• Welsh Institute of Metabolic and Obesity Surgery

– JB, SC, NJ

– Bariatric Surgery Centre for Wales, established 2010

• Students

– 4 PhD (2 prediabetes), 4 MD, 3 MSc students

• JCRF/CRU

Interested parties

• Obesity related work– Prof Dean Harris, Dr Aled Rees, Dr Jeff Davies, Dr Laura Wilkinson, Prof

Jon Barry, Mr Scott Caplin, Prof Julian Halcox, Prof Rhys Williams, Ms

Kathie Wareham, Mrs Nia Jenkins, Prof Kathie Thornton, CRU/JCRF

• Type 2 diabetes– Dr Sam Rice (AHSC fellow), Prof Gordon Lowe, Dr Raj Peter (AHSC

Fellow), Dr David Price, Dr Richard Chudleigh

• Renal disease– Dr James Chess, Dr Ashraf Mikhail

• Foot disease– Miss Claire Topliss, Dr Rebecca Thomas

• Exercise Physiology

– Prof Gareth Stratton, Dr Richard Bracken

Clinical Sciences: Collaborators

Research Students

• PhD STUDENTS

– Current: Tanisha Douglas, Dr Jenny Hayes, Dr Andrew Cunningham

– Previous: Rachel Churm, Ahmed Sabra, Richard Morton, Danielle

Jones, Ayisha Thompson, Ben Gray, Enzo Battista

• MD Student

– Current: Dr Karen Brown

– Previous: Dr Imran Alam, Dr Akhila Mallipedhi, Dr Thinzar Min

• MSc students

– Previous: David Williams, Stephanie Hanley, Ben Gray, Matthew

Daly, Max Epstein

• Many BSc students, Academic F1/CMT trainees

Funding

• Diabetes UK

• The BUPA Foundation

• Welsh Government

• Royal College of Surgeons

• KESS (European funding)

• ABMU Health Board

Examples of Obesity related Clinical Sciences

• Mallipedhi A, et al. Association between the preoperative fasting and postprandial C-peptide AUC with resolution of type 2 diabetes 6 months following bariatric surgery. Metabolism. 2015 Nov;64(11):1556-63.

• Mallipedhi A, et al. Changes in plasma levels of N-arachidonyl ethanolamine and N-palmitoyl ethanolamine following bariatric surgery in morbidly obese females with impaired glucose homeostasis. J Diabetes Res. 2015;2015:680867.

• Mallipedhi A, et al. Changes in inflammatory markers after sleeve gastrectomy in patients with impaired glucose homeostasis and type 2 diabetes. Surg ObesRelat Dis. 2014 Nov-Dec;10(6):1123-8.

• Mallipedhi A, et al. Temporal changes in glucose homeostasis and incretin hormone response at 1 and 6 months after laparoscopic sleeve gastrectomy. Surg Obes Relat Dis. 2014 Sep-Oct;10(5):860-9.

• Thomas RL, et al. Does bariatric surgery adversely impact on diabetic retinopathy in persons with morbid obesity and type 2 diabetes? A pilot study. J Diabetes Complications. 2014 Mar-Apr;28(2):191-5.

• Alam I, et al. Temporal changes in glucose and insulin homeostasis after biliopancreatic diversion and laparoscopic adjustable gastric banding. Surg ObesRelat Dis. 2011 Nov-Dec;8(6):752-63.

• Alam I, et al. Influence of bariatric surgery on indices of cardiac autonomic control. Auton Neurosci. 2009 Dec 3;151(2):168-73.

Examples of Obesity related Basic Science

• Jones DA, et al. Changes in markers of oxidative stress and DNA damage in

human visceral adipose tissue from subjects with obesity and type 2 diabetes.

Diabetes Res Clin Pract. 2014 Dec;106(3):627-33.

• Prior SL, et al. Total antioxidant status before and after bariatric surgery for type 2

diabetes mellitus. Metabolism. 2009;58(9):1366.

• Huth C, et al. Joint analysis of individual participants' data from 17 studies on the

association of the IL6 variant -174G >C with circulating glucose levels,

interleukin-6 levels, and body mass index. Ann Med 2008; 27:1-21

• Ghrelin mediated lipid retention and insulin resistance in human visceral adipose tissue

• Cell-derived extracellular vesicles: do they play a role in obesity driven inflammation?

Examples of other Obesity related work

• Handley JD, et al. Changes in Cognitive Function Following Bariatric Surgery: a

Systematic Review. Obes Surg. 2016 Oct;26(10):2530-7.

• Handley JD, et al. Bariatric surgery as a treatment for idiopathic intracranial

hypertension: a systematic review. Surg Obes Relat Dis. 2015 Nov-

Dec;11(6):1396-403.

• Efficacy of bariatric surgery for ‘hidden’ victims of domestic violence.

Examples of Prediabetes related work

• Gray BJ, et al; Prosiect Sir Gâr Group. A non-exercise method to determine

cardiorespiratory fitness identifies females predicted to be at 'high risk' of type 2

diabetes. Diab Vasc Dis Res. 2017 Jan;14(1):47-54.

• Gray BJ, et al. A workplace-based risk assessment improves predicted lifetime

cardiovascular disease risk in male steelworkers. Public Health. 2016 Apr 27.

• Gray BJ, et al; Prosiect Sir Gâr Group. Different type 2 diabetes risk assessments predict dissimilar numbers at 'high risk': a retrospective analysis of diabetes risk-assessment tools. Br J Gen Pract. 2015 Dec;65(641):e852-60.

• Gray BJ, et al; Prosiect Sir Gâr Group. Cardiorespiratory fitness is a stronger indicator of cardiometabolic risk factors and risk prediction than self-reported physical activity levels. Diab Vasc Dis Res. 2015 Nov;12(6):428-35.

• Gray BJ, et al; Prosiect Sir Gâr Group. 'Prosiect Sir Gâr': workplace-based

cardiovascular disease and diabetes risk assessments. Occup Med (Lond).

2014 Oct;64(7):549-56.

• Gray BJ, et al; Prosiect Sir Gâr Group. Predicted 10-year risk of cardiovascular

disease is influenced by the risk equation adopted: a cross-sectional analysis. Br

J Gen Pract. 2014 Oct;64(627):e634-40.

• Gray BJ, et al. Prevalence of undiagnosed cardiovascular risk factors and 10-year CVD risk in male steel industry workers. J Occup Environ Med. 2014 May;56(5):535-9.

• Diabetes UK Annual Conference Committee, since 2015

• Organising committee for the Association of Obesity Meeting 2016

• Organised and hosted the British Obesity and Metabolic Surgery Society

Meeting in Cardiff 2015

• Contributions and teaching on the University of South Wales Obesity

Diploma/MSc

• Set up and lead of the Welsh Institute of Metabolic and Obesity Surgery

• Phase 3 Industry clinical trial collaboration

• PocketMedic patient on-line education prescriptions

• Prosiect Sir Gar

• Membership of the RCP Wales Obesity Strategy Group

• Contribution to Global Report on Diabetes. World Health Organisation,

2016, ISBN 978 92 4 156525 7.

Other contributions to Obesity from Swansea

A taste of clinical science relating

to Bariatric surgery

Sleeve gastrectomyGastric bypass

SOS study – weight loss

Sjostrum et al NEJMed 2007;357:741-52

SOS study – results at 2 years

LSG…. More than restriction !

Mallipedhi A, Prior SL, Barry JD, Caplin S, Baxter JN, Stephens JW. Temporal

changes in glucose homeostasis and incretin hormone response at 1 and 6

months after laparoscopic sleeve gastrectomy. Surg Obes Relat Dis. 2014 Sep-

Oct;10(5):860-9.

LSG: Pre & postoperative changes

Measurement Baseline 1 month P 6 months P

Weight (kg) 152.0 (31.7) 136.3 (28.5) <0.001 118.8 (27.2) <0.001

BMI (kg/m2) 51.9 (9.2) 46.6 (28.5) <0.001 41.1 (8.9) <0.001

Waist (cm) 144 (20) 135 (19) <0.001 118 (18) <0.001

Cholesterol (mmol/L) 4.2 (0.9) 5.4 (1.1) 0.76 4.6 (1.2) 0.16

LDL-C (mmol/L) 2.3 (0.8) 2.5 (1.0) 0.28 2.7 (1.0) 0.09

HDL-C (mmol/L) 1.2 (0.3) 1.1 (0.3) 0.01 1.3 (0.3) 0.17

HbA1c (%)

HbA1c (mmol/mol)

6.8 (1.4)

51 (15.3)

6.1 (0.7)

43 (7.7)

0.004

0.004

5.9 (1.3)

41 (14.2)

0.02

0.02

FPG (mmol/L) 7.0 (2.6) 5.7 (1.1) 0.04 5.7 (3.2) 0.28

2h Glucose (mmol/L) 11.1 (4.6) 7.8 (3.4) 0.002 6.4 (4.9) 0.003

LSG: Changes in insulin sensitivity

Baseline 1 month P 6 months P

Fasting insulin

(mU/L)

18.1 (4.8) 13.3 (3.1) 0.009 9.6 (2.5) 0.001

Fasting C-peptide

(pmol/L)

4.2 (0.6) 3.6 (0.4) 0.15 3.1 (0.8) 0.01

HOMA-IR 0.394 (0.11) 0.250 (0.07) 0.19 0.220 (0.08) 0.04

HOMA-S% 351.3 (112.0) 380.9 (97.8) 0.23 443.7 (173.1) 0.03

Hepatic insulin

clearance

0.20 (0.03) 0.27 (0.06) 0.02 0.33 (0.08) <0.001

LSG: Temporal changes during 2-hr OGTT

-Plasma glucose

0

2

4

6

8

10

12

14

16

18

0 15 30 45 60 120

Pla

sm

a g

luco

se (

mm

ol/

L)

Time (mins)

∆ AUC

1 mth, p=0.01

6 mths, p=0.003

*

*

**

*

*

*

*

LSG: Temporal changes during 2-hr OGTT

-Plasma C-peptide

0

2

4

6

8

10

12

14

16

18

0 15 30 45 60 120

C-p

ep

tid

e (

pm

ol/

L)

Time (mins)

*

* *

*

**

*

*

∆ AUC

1 mth, p <0.001

6 mths, p=0.04

LSG: Temporal changes during 2-hr OGTT-Plasma GLP-1

0

5

10

15

20

25

30

0 15 30 45 60 120

GL

P-1

(p

Mo

l/L

)

*

*

*

*

*

*

*

*

**

Time (mins)

∆ AUC

1 mth, p <0.001

6 mths, p <0.001

Beta cells: Enhances

glucose-dependent

insulin secretion

GLP-1 secreted upon

the ingestion of food

Promotes satiety and

reduces appetite

Stomach:

Slows gastric emptying

Alpha cells:

Postprandial

glucagon secretion

1. Nauck MA et al. Diabetologia 1986; 29: 46‒52. 2. Drucker DJ. Diabetes 1998; 47: 159‒169. 3. Flint A et al. J Clin Invest 1998; 101: 515‒520. 4. Larsson H et al. Acta Physiol Scand 1997; 160:

413‒422. 5. Nauck MA et al. Diabetologia 1996; 39: 1546‒1553.

GLP-1 secreted upon

the ingestion of food

Liver:

Glucagon reduces

hepatic glucose output

GLP-1 effects in humans: Understanding the

glucoregulatory role of incretins1–5

Bariatric Surgery & glucose homeostasis:

5 year outcome

5 years primary endpoint (HbA1c <6% with or without medication)

• 5% of the medical therapy group • 29% of the RYGB group • 23% of the LSG group

What has yet to established?

• Limited literature on detailed examination of long-termeffect (≥5years) of bariatric surgery on glucose-insulinhomeostasis .

• Long-term effect (≥5years) of bariatric surgery on GLP-1and GIP secretion.

• Role of incretin hormones in the remission of diabetes.− An increased GLP-1 response after RYGB does not explain

the improvement in glucose control (Steven et al, 2016).

Bariatric surgery & Incretin hormone response

• 2 to 7 folds increase in GLP-1 response after bariatric surgery

References Type of surgery number Duration (months)

Korner et al (2009) RYGB vs LAGB 35 12

Laferrer et al (2007) RYGB 8 1

Novaes et al (2015) BPD 10 12

Mallipedhi et al (2014) LSG 22 6

• Conflicting observations on GIP response after bariatric surgery

References Type of surgery

number Duration(months)

Effect on GIP

Laferrer et al (2007) RYGB 8 1 Increase

Guidone et al (2006) BPD 10 1 Decrease

Mallipedhi et al (2014) BPD 10 6 No change

Mallipedhi et al (2014) LSG 22 6 No change

Changes in Measures of Obesity At 5 years:Min et al, unpublished 2018

100110120130140150160

Baseline1 month 6months

5 years

Bo

dy

wie

ght

(kg)

Mean changes in body weight

-60

-50

-40

-30

-20

-10

0

1 month 6 months 5 years

Perc

enta

ge

Mean changes in % EWL

P value <0.001

110

120

130

140

150

160

Cir

cum

fere

nce

(cm

)

Mean changes in hip & waist circumferences

Hip

Waist

P value <0.001

35

40

45

50

55

60

Baseline 1 month 6months

5 years

BM

I (kg

/m2)

Mean changes in BMI

P value <0.001

P value <0.001

Changes in markers of glycaemia at 5 yearsMin et al, unpublished 2018

Mean ±SD shown. *Median & IQR shown. p1: p comparing baseline & 1 month; p2: p comparing baseline & 6 months; p3: p comparing baseline & 5 years.

Changes in diabetes

medicationsBaseline 1 month 6 months 5 years p

None (%) 4 (23) 10 (63) 10 (59) 9 (53)

0.381Oral agents/ GLP-1 (%) 11 (65) 5 (31) 6 (35) 7 (41)

Insulin ± Oral agents/ GLP-1

(%)2 (12) 1 (6) 1 (6) 1 (6)

Baseline 1 month p1 6 months p2 5 years p3

FPG* (mmol/L) 7.3 (5.9, 9.2) 5.7 (4.8, 6.8) 0.007 5.4 (4.5, 6.9) 0.016 6.4 (5.5, 9.0) 0.085

2hr-PG (mmol/L) 13.1 ±5.7 8.8 ±3.8 0.005 9.2 ±6.6 0.022 9.4 ±5.5 0.004

HbA1c (%) 7.4 ±1.6 6.4 ±1.1 0.006 6.2 ±1.4 0.004 6.4 ±1.4 0.001

HbA1c (mmol/mol) 58 ±18 47 ±12 45 ±15 46 ±15

Results: Changes in insulin sensitivityMin et al, unpublished 2018

Baseline 1 month p1 6 months p2 5 years p3

Fasting Insulin** (mU/L) 28 (20, 39) 13 (8, 26) 0.017 10 (6, 21) 0.065 17 (6, 34) 0.327

Fasting CP** (pmol/ml) 1.4 (0.9, 1.6) 1.2 (0.8, 1.6) 0.802 0.8 (0.6, 1.1) 0.279 0.5 (0.3, 0.7) 0.02

2-hr CP (pmol/ml) 3.2 ±1.5 3.2 ±1.8 0.443 2.8 ±1.7 0.786 1.9 ±1.4 0.042

HOMA%S* 1.6 ±0.3 1.7 ±0.3 0.072 1.8 ±0.5 0.006 1.8 ±0.4 0.016

HOMA-IR* 0.4 ±0.2 0.2 ±0.3 0.071 0.1 ±0.4 0.007 0.2 ±0.4 0.016

HOMA%B 97 ±50 157 ±86 0.01 123 ±58 <0.00

1

82 ±62 0.377

Data are presented as mean ±SD otherwise stated. **Data are presented as median and interquartile range. *log transformed datap1: p value comparing baseline and 1 month; p2: p value comparing baseline and 6 months; p3: p value comparing baseline and 5 years.

Results: Changes in GLP-1 during the 2-hr OGTTMin et al, unpublished 2018

0

5

10

15

20

25

0 30 60 90 120

GLP

-1 (

pm

ol/

L)

Time poit during OGTT (minute)

Baseline

1 month

6 month

5 year

*** **

**** **

*

*

Baseline 1 month 6 months 5 years p1m p6m p5y

GLP-1 AUC0-30 1.7 ±1.3 4.7 ±3.0 7.0 ±4.6 2.4

±1.6

0.001 0.001 0.098

GLP-1 AUC0-60 4.5 ±3.5 13.0 ±7.7 15.1 ±9.0 4.5

±3.0

<0.001 <0.001 0.914

GLP-1 AUC 6.1 ±4.6 19.7 ±11.5 23.0 6.8 <0.001 <0.001 0.618

Mean and SE shown. Comparison made between 1 month, 6 months and 5 years time point values to baseline.*p<0.05 for 1-month visit.**p<0.05 for 6-months visit.***p<0.05 for 5-years visit.

Results: Changes in GIP during the 2-hr OGTTMin et al, unpublished 2018

50

150

250

350

450

550

650

750

0 30 60 90 120

GIP

(p

g/m

L)

Time point during OGTT (minutes)

Baseline

1 month

6 month

5 year

** * *

*

Baseline 1 month 6 months 5 years p1m p6m p5y

GIP AUC0-30 (pg/mL/hr) 135 ±59 133 ±88 142 ±87 246 ±139 0.522 0.628 0.002

GIP AUC 0-60 (pg/mL/hr) 340 ±155 309 ±146 330 ±205 551±308 0.211 0.363 0.01

GIP AUC0-120 (pg/mL/hr) 547 ±312 501 ±291 558 ±446 824 ±518 0.135 0.452 0.03

Mean and SE shown. Comparison made between 1 month, 6 months and 5 years time point values to baseline.P value for 1-month visit and 6-months visit not significant.*p<0.05 for 5-years visit.

LSG…. Effects on inflammation and oxidative stress!

Temporal effects of laparoscopic sleeve gastrectomy on adipokines,

inflammation and oxidative stress in subjects with impaired glucose

homeostasis

Jeffrey W Stephens, Thinzar Min, Gareth Dunseath, Rachel Churm, Jonathan D

Barry, Sarah L Prior.

Accepted by SOARDS, March 2019

Measurement Baseline 1monthaP 6months

bP

Weight(kg) 148.3(27.7) 128.8(26.6) <0.001 114.4(24.1) <0.001

BMI(kg/m2) 50.4(7.2) 43.7(6.7) <0.001 38.7(6.4) <0.001

A1c(mmol/mol)c 57.0[46.0-89.3] 46.0[38.5-56.0] <0.001 40.0[36.0-49.0] <0.001

Fastingglucose(mmol/L)c 7.1[5.9-11.7] 5.6[4.6-6.8] <0.001 5.2[4.5-5.8] <0.001

2-hourglucose(mmol/L)c 13.4[9.2-18.4] 8.8[5.2-12.7] <0.001 5.8[4.2-9.4] <0.001

Fastinginsulin(mU/L)c 21.8[13.7-29.5] 12.0[8.9-19.3] <0.001 5.4[9.0-14.1] <0.001

HOMA-IRc 3.1[1.9-4.1] 1.61[1.22-2.56] <0.001 1.33[0.83-1.91] <0.001

HOMA-%Sc 32.4[24.5-52.3] 62.3[39.0-81.7] <0.001 75.5[52.3-121.0] <0.001

LSG: Effects on clinical measurements (n=55)

Measurement Baseline 1month aP 6months bP

CRP(ng/mL) 6.9

[4.1-17.0]

5.0

[2.3-14.3]

0.183 4.4

[1.9-9.9]

<0.001

IL6(pg/mL) 4.2

[2.4-8.0]

3.8

[2.3-8.0]

0.032 3.1

[1.7-7.3]

0.002

Adiponectin

(ng/mL)

7.6

[5.2-10.5]

7.1

[5.0-11.6]

0.07 11.0

[7.0-14.3]

0.003

Leptin(pg/mL) 41.7

[26.7-61.9]

31.0

[15.1-43.4]

<0.001 19.5

[10.9-38.3]

<0.001

TBARS(ng/mL) 58.6

[33.4-99.2]

46.9

[33.1-72.7]

0.053 46.8

[33.8-66.9]

0.007

LSG: Effects on Inflammation (n=55)

Mechanisms of diabetes resolution

Early• Restoration of GLP-1 response• Calorie restriction• Improved insulin sensitivity

Later• Weight loss• Improved insulin sensitivity• ? GIP response

Examples of other work relating to “complications”

• Cardiovascular genetics

– Collaboration with UCL

• Foot amputation risk in Wales

– Jenny Hayes

• Renal disease and cardiovascular disease

– Karen Brown

• Osteoporosis and diabetes risk associated with inhaled corticosteroid therapies

– Dundee University

Future plans

• Work with the exercise strand to look at a DPP in Wales

• Continue clinical and basic science research

• More involvement in clinical trials

• Further understanding of the role of bariatric surgery and metabolic dysfunction

• The role of gut microbiota in diabetes and “metabolic dysfunction”

Thank you!