Diabetes Research and Clinical Practice - Volume 120 - Supplement 1 - October 2016

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We have utilized global unbiased phosphoproteomic analysis
of insulin responsive tissues to construct a large scale map
of the insulin regulated signaling network. This has revealed
key regulatory nodes together with novel substrates of major
insulin regulated kinases such as Akt. Using machine learning
we have discovered several new Akt substrates that have
revealed novel aspects of insulin action, several of which will
be discussed. We have also applied similar approaches to
examine changes in insulin signaling and the total proteome
in adipocytes rendered insulin resistant using a range of
physiological perturbations. These studies have revealed novel
insights into the mechanism of insulin resistance, which
appears to involve the induction of an insulin sensitive
pathway in adipocytes that impairs insulin regulated glucose
metabolism.
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The metabolic consequences of fecal microbiota
transplantation (FMT) in mice
Jeroen ZOLL1, Sarah E. HEYWOOD1, Helene L. KAMMOUN 1,
Jessica MARSHALL1, Emma ESTEVEZ1,2, Borivoj ZIVANOVIC1,
Tamara L. ALLEN 1, Mark A. FEBBRAIO 1,2,
Darren C. HENSTRIDGE 1. 1Baker IDI Heart and Diabetes Institute,
Melbourne, 2Garvan Institute of Medical Research, Sydney, Australia
Background: The gastrointestinal microbiota is a community
of microorganisms that reside in the digestive tract. Studies
have suggested that the microbiota composition may contrib-
ute to the development of obesity and the metabolic syn-
drome. Exercise has been shown to alter the microbiota
composition by increasing diversity and altering specific
bacteria species. We tested whether fecal microbiota trans-
plantation (FMT) from exercise-trained mice to recipient mice
alters body composition and metabolism.
Methods: C57BL6/J mice were fed a chow or high fat diet (HFD)
for 4-weeks to induce obesity and insulin resistance. Micewere
further divided into sedentary or exercise training groups
(treadmill training for 6-weeks) while maintaining their
respective diets (four groups of donor mice; chow sedentary
or exercised and HFD sedentary or exercised). Recipient mice
were inoculated with the faeces from the respective donor
groups once a week for 6-weeks and body composition and
metabolism assessed.
Results: While the HFD led to glucose intolerance and obesity,
exercise training resulted in a small decrease in body fat and
improved glucose tolerance. FMT from the donor groups did
not alter body composition (weight, fat mss, lean mass) in any
of the recipient groups. Unexpectedly given the lack of an
effect on adiposity, glucose tolerance was disrupted in the
mice inoculated with faeces derived from mice on a HFD
irrespective of exercise status and this was associated with a
decrease in insulin-stimulated glucose clearance into white
adipose tissue and the large intestine.
Conclusion: FMT can transmit HFD-induced aspects of dis-
rupted glucose metabolism to recipient mice independently of
any change in adiposity. However, FMT from exercise trained
donor mice appears to elicit no beneficial effect.
Disclosure: No conflict of interest.
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Chronic exercise alleviates obesity-related metabolic
dysfunction by enhancing FGF21 sensitivity in adipose tissues
Aimin XU 1. 1State Key Laboratory of Pharmaceutical Pharmacology,
and Department of Medicine, University of Hong Kong, Hong Kong
Chronic exercise has beneficial effects on protecting against
obesity-related metabolic dysfunction. However, the under-
lying molecular mechanisms are incompletely understood.
Fibroblast growth factor 21 (FGF21) is a hormone mainly
derived from liver and acts on adipocytes by activating the
FGF21 receptor complex (FGFR1 and β-Klotho)-mediated
intracellular signalling. FGF21 has pleiotropic effects on
regulating glucose homeostasis, lipid metabolism and
insulin actions. Here we show that chronic exercise improves
FGF21 sensitivity by upregulating the expression of FGFR1 and
β-Klotho in adipose tissues of diet-induced obese mice. FGF21
knockout mice were refractory to several benefits of chronic
exercise, including alleviation of glucose intolerance and
insulin resistance. Exercised FGF21 knockout mice show
augmented lipolysis and free fatty acids (FFA) accumulation
in liver and muscle compared with the wild type littermates.
Furthermore, the effects of chronic exercise on enhancement
of adiponectin production and fatty acids oxidation were
abrogated in FGF21 knockout mice. Additionally, adipose
tissue β-Klotho specific knockout mice are also refractory to
the beneficial effects of exercise on attenuating diet-induced
systemic lipotoxicity, glucose intolerance and insulin resist-
ance. Collectively, chronic exercise-induced improvement of
FGF21 sensitivity in adipose tissues can prevent excessive FFA
influx and promote FFA oxidation in liver and muscle, leading
to reduced lipotoxicity and enhanced systemic glucose toler-
ance and insulin sensitivity.
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Laparoscopic sleeve gastrectomy versus Roux-en-Y gastric
bypass for the treatment of type 2 diabetes: 12month results of
a double-blind, randomised trial
R. MURPHY1, N.J. EVENNETT2, M.G. CLARKE2, S.J. ROBINSON2,
B. JONES2, D.D. KIM3, R. CUTFIELD3, L.D. PLANK4,
H. HAMMODAT2, M.W.C. BOOTH2. 1Department of Medicine,
University of Auckland, 2Department of Surgery, North Shore
Hospital, 3Department of Endocrinology, North Shore Hospital,
4Department of Surgery, University of Auckland, Auckland, New
Zealand
Introduction: It is unclear which of the two most commonly
performed types of bariatric surgery, laparoscopic sleeve
gastrectomy (LSG) or laparoscopic Roux-en-Y gastric bypass
(LRYGB), is most effective for obese patients with type 2
diabetes (T2D).
Objectives: To examine the comparative ad interim effective-
ness of LSG or LRYGB at 1 year in achieving improvement in
T2D using different HbA1c thresholds.
Methods: Single-centre, double-blind (assessor and patient),
parallel, randomized, clinical trial conducted in Auckland,
New Zealand. Eligibility criteria included age 20–55 years, T2D
of at least 6 months duration and BMI 35–65 kg/m2 for at least 5
years. Recruitment of 114 patients completed in October 2014.
Randomization 1:1 to LSG (n = 58) or LRYGB (n = 56) used
random number codes disclosed to the operating surgeon
after induction of anesthesia. A standard medication adjust-
ment schedule was used during post-operative metabolic
assessments scheduled for 5 years when primary outcome of
T2D remission defined by HbA1c <42 mmol/mol without
diabetes medications, is to be analysed.
Results: Ad interim analysis at 1 year showed 109/114
completed 12 month follow up. Participants included 17%
Maori, 8% Pacific and 55% were women. Mean (±standard
deviation) HbA1c pre-operatively was 63 mmol/mol±16 with
29% on insulin therapy and 65% on oral glucose lowering
therapy alone. Proportions achieving HbA1c <39 mmol/mol,
<42 mmol/mol, <48 mmol/mol, or <53 mmol/mol without the
use of diabetes medication in LSG vs LRYGB were 43% vs 38%
(p = 0.56), 49% vs 52% (p = 0.85) and 72% vs 75% (p = 0.83), and
77% vs 80% (p = 0.82) respectively. Mean (±standard deviation)
weight loss at 1 year was less after LSG than after LRYGB:
34.0 ± 13.1 kg and 39.6 ± 11.6 kg respectively, (p = 0.02).
Conclusions: LSG and LRYGB achieve similar prevalence
of T2D remission despite significantly greater weight loss at
1 year after LRYGB. Longer term follow up is required to
determine the durability of these results.
Speech Abstracts / Diabetes Research and Clinical Practice 120S1 (2016) S1–S39 S24