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CNS mechanisms in insulin resistance TREATMENT kick-off, Madrid June 2017 Jan Eriksson, MD Prof Uppsala University, Dept of Medical Sciences jan.eriksson@medsci.uu.se Clinical Diabetes and Metabolism Research group 2017 Jan W Eriksson, MD,

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  1. CNS mechanisms in insulin resistance TREATMENT kick-off, Madrid June 2017 Jan Eriksson, MD Prof Uppsala University, Dept of Medical Sciences jan.eriksson@medsci.uu.se

  2. Clinical Diabetes and Metabolism Research group 2017 Jan W Eriksson, MD, prof F Anders Karlsson, MD, prof em Maria K Svensson, MD, prof (20%) Casimiro C-Lopez, Assoc prof Niclas Abrahamsson, MD PhD Maria J Pereira, PhD Dariush Mokhtari, PhD Gretha Boersma, PhD Xesus Abalo, PhD Petros Katsogiannos, MD PhD fellow Per Lundkvist, MD PhD fellow Kristina Almby, MD PhD fellow Cherno Sidibeh, PhD fellow Prasad Kamble, PhD fellow Cátia M Marques, PhD fellow Assel Sarsenbayeva, PhD fellow Carola Almström, RN Anna Ehrenborg, RN Sofia Löfving, RN Caroline Woxberg, RN Monika Gelotte, RN Jan Hall, BMA

  3. Adiposity promotes and aggravates diabetes – new treatment options? ? Adipose tissue

  4. Dysregulated tissue metabolism in Insulin resistance and MetSy. Insulin Neuro- secretion  endocrine (T2DM) activation (HPA, ANS etc) Hyperglycemia Dyslipidemia Vascular dysfunction FFA release  Adipokines Glucose and Visceral and VLDL production  Ectopic fat Glucose, lipid and energy utilisation  Mitochondrial dysfunction

  5. Research vision Metabolic dysregulation via adipose-gut-brain axes

  6. Research strategy Interventional and observational approach Type 2 Development Manifest & Reversal diabetes Progression • • • Prediab subjects T2D Clinical interv. In vitro • • • Experimental: Experimental: Experimental: Human adi- Dexamethason; Immuno- High glucose & Novel drug cand. pose tissue suppr; Antipsychotics insulin Gene-silencing • • • Prediab subj T2D subj, Drug trials, PoC In vivo • • Adverse drug staging. Diet Challenge • • effects Complications Bariatric surgery tests • Diet Imaging Large cohorts and registries , for ’ omics ’, Validation morbidity, mortality. Large clinical trials.

  7. Examples of translational research PET/MR imaging. In vivo and in vitro metabolism. Adipose morfology and function. Whole body insulin sensitivity (M-value), reduced in T2DM. White = High glucose uptake rate Before 4 wks after obesity surgery Cell differentiation Fat biopsies

  8. PET/MR study. Increased FDG uptake in brain of T2D subjects during hyperinsulinemia 25 28 Brain Control Brain [18F]FDG tissue influx rate T2D * 26 r = -0.552, p<0.05 ( ki=ul plasma/ml tissue min) 20 [18F]FDG tissue influx rate ( ki=ul plasma/ml tissue min) 24 22 15 20 10 18 16 5 14 12 0 0 2 4 6 8 10 12 14 16 Brain * p<0.05 M-value (mg/kg lbm/min) Boersma GJ et al, EASD oral presentation 2016

  9. Brain areas accounting for inverse correlation of FDG uptake with whole-body insulin sensitivity (M-value) Boersma GJ et al, EASD oral presentation 2016

  10. Hypoglycemia Reduced ANS response Pre Post

  11. Attenuated response of counterregulatory hormones post-GBP Abrahamsson N et al, Diabetes 2016

  12. There is a role of psychosocial factors in insulin resistance and T2DM Low educational level ( Lidfeldt J et al, Diab Obes Metab 2003 5:106-12. Eriksson JW et al, DISS submitted) Single living ( Lidfeldt J et al, Diab Obes Metab 2003 5:106-12) Lack of social network/support ( Norberg M et al, Diab Res Clin Pract 2007) Low sense of coherence (Agardh EE et al, Diab Care 2003 26:719-24) Work stress (Agardh EE et al, Diab Care 2003 26:719-24) Socioeconomic status vs MetSy and ANS dysfunction (Brunner E et al, Circulation 2002 106:2659-65; Circulation 2005 111:3071-77) Sleeping disorders ( Spiegel K et al Lancet 1999; 354: 1435-1439) Acute psychotic stress (inversely correlated with β -cell function and insulin sensitivity) ( Shiloah E et al, Diabetes Care 2003; 26: 1462-1467) Stressful life events ( Mooy JM et al, Diabetes Care 2000; 23: 197-201)

  13. Stress response and insulin resistance Threat Stressor Defence Defeat SNS HPA Adrenaline Cortisol Noradrenaline Insulin resistance Glucose production ↑ Lipolysis ↑ P Björntorp: Stress  Hypothalamic arousal  ’ Burnout ’

  14. A role of low parasympathetic reactivity in insulin resistance? Heart rate variability in non-diabetic subjects. High insulin sensitivity, n=17 Low insulin sensitivity, n=8 Lindmark S et al, Diabet Med 2003

  15. Altered autonomic nerve activity may contribute to insulin resistance. Partly inherited? Data from 24h HRV recordings in everyday life Control T2D relative Svensson MK et al, Cardiovasc Diabetol 2016

  16. Summary of TRIM study results - prediction of T2DM • In women, but not men, work stress • Among components of the and low emotional support were in- ‘metabolic syndrome’ dependently associated with – adiposity with development of T2DM, and thus accompanying insulin psychosocial factors are of resistance and importance . – β -cell decompensation (mirrored by hyperglycemia) are core factors that predict T2DM. • Inflammation, dyslipidemia and hypertension are not independent risk markers for T2DM. Norberg M et al: Obesity 2007; J Intern Med 2006; Diab Res Clin Pract 2007

  17. Previous study on metabolic side effects of antipsychotic drugs

  18. A ’ multiple hit’ concept explaining progression of insulin resistance Healthy Insulin sensitivity Prediab Diabetes ? Glucotoxicity Lipotoxicity Neuroendocrine dysregulation Genetic & environmental background, including stress Adopted from Burén J and Eriksson JW, Diab Metab Res Rev 2005

  19. Proposed Uppsala studies in TREATMENT • Effects on antipsychotic drugs on whole body and adipose tissue metabolism in humans – In vitro study on human adipose tissue • Direct peripheral effects – In vivo study on whole body and adipose tissue metabolism • Systemic effects (central and peripheral) • Cross-talk brain-adipose-liver-muscle

  20. Further clinical work • Antidiabetic effects of bariatric surgery • Role of GLP1 as a counterregulatory hormone? • Glucose-mediated regulation of GLP1 and glucagon – basic experiments • Brain glucose metabolism – role for whole body metabolism These studies involve clamps, meal tests, imaging • SGLT2 inhibition – mechanisms in brain, liver and heart • SGLT2 inhibition – outcome study ? • Novel obesity and diabetes-preventing treatment concepts.

  21. Effects of antipsychotic drugs in vivo on adipose tissue and whole-body insulin sensitivity and beta- cell function • Treatment of control and pre/diabetes subjects with: – Placebo, aripiprazol, olanzanapine and dexamethasone treatment – 4-way cross-over. Randomized treatment orders. – Each treatment period will be 5 days followed by a 2-week washout – Dexamethasone used as positive control for diabetogenic drugs • Assessments after each treatment: ‒ Plasma glucose, insulin and lipids ‒ 3-h OGTT: glucose, insulin, C-peptide, FFA and glycerol ‒ Insulin sensitivity (Matsuda), lipolysis ‒ Arginine challenge test (beta cell function) ‒ Subcutaneous adipose tissue biopsy: metabolic function with respect to glucose uptake, lipid storage, insulin signalling and expression of inflammatory mediators

  22. Effects of antipsychotic drugs on human adipose tissue metabolism – In vitro • Human subcutaneous adipose tissue (SAT) needle biopsies • Incubation of human SAT with antipsychothic drugs – in vitro Subcutaneous adipose tissue Incubation with antipsychotic drugs E.g. olanzapine, aripiprazole • Following incubation, effects on: – Glucose transport (w/wo insulin; 14C-glucose uptake) – Lipid storage : Lipolysis and lipogenesis – Key factors involved in glucose and lipid transport and utilization , IRS1, AKT, GLUT4, FABP, FATP, ACC, FAS, HSL, perilipin etc (mRNA, protein, activity) – Inflammatory mediators , and other peptides produced by adipose tissue (e.g. leptin, adiponectin and TNF- α)

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