resistance TREATMENT kick-off, Madrid June 2017 Jan Eriksson, MD - - PowerPoint PPT Presentation

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, 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

Adiposity promotes and aggravates diabetes – new treatment options?

Adipose tissue

?

Dysregulated tissue metabolism in Insulin resistance and MetSy.

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

Research vision Metabolic dysregulation via adipose-gut-brain axes

Research strategy

Interventional and observational approach

Development Manifest & Reversal Progression

• Prediab subj
• Adverse drug

effects

• Diet
• T2D subj,

staging.

• Complications
• Drug trials, PoC
• Diet
• Bariatric surgery

In vivo

Challenge tests Imaging

• Prediab subjects
• Experimental:

Dexamethason; Immuno- suppr; Antipsychotics

• T2D
• Experimental:

High glucose & insulin

• Clinical interv.
• Experimental:

Novel drug cand. Gene-silencing

In vitro

Human adi- pose tissue

Large cohorts and registries, for ’omics’, morbidity, mortality. Large clinical trials.

Validation Type 2 diabetes

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

Fat biopsies Before 4 wks after obesity surgery Cell differentiation

PET/MR study. Increased FDG uptake in brain

• f T2D subjects during hyperinsulinemia

Brain

[18F]FDG tissue influx rate ( ki=ul plasma/ml tissue min)

5 10 15 20 25 Control T2D

*

Brain

M-value (mg/kg lbm/min) 2 4 6 8 10 12 14 16 Brain [18F]FDG tissue influx rate ( ki=ul plasma/ml tissue min) 12 14 16 18 20 22 24 26 28

r = -0.552, p<0.05

* p<0.05

Boersma GJ et al, EASD oral presentation 2016

Brain areas accounting for inverse correlation of FDG uptake with whole-body insulin sensitivity (M-value)

Boersma GJ et al, EASD oral presentation 2016

Pre Post Hypoglycemia Reduced ANS response

Attenuated response of counterregulatory hormones post-GBP

Abrahamsson N et al, Diabetes 2016

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)

Threat Stressor SNS HPA Adrenaline Noradrenaline Cortisol

Insulin resistance Defence Defeat P Björntorp: Stress  Hypothalamic arousal  ’Burnout’ Glucose production ↑ Lipolysis ↑

Stress response and insulin resistance

A role of low parasympathetic reactivity in insulin resistance?

Heart rate variability in non-diabetic subjects.

Lindmark S et al, Diabet Med 2003

High insulin sensitivity, n=17 Low insulin sensitivity, n=8

Altered autonomic nerve activity may contribute to insulin resistance. Partly inherited?

Data from 24h HRV recordings in everyday life

T2D relative Control

Svensson MK et al, Cardiovasc Diabetol 2016

Summary of TRIM study results

• prediction of T2DM
• Among components of the

‘metabolic syndrome’ – adiposity with accompanying insulin resistance and – β-cell decompensation (mirrored by hyperglycemia) are core factors that predict T2DM.

• Inflammation, dyslipidemia and

hypertension are not independent risk markers for T2DM.

• In women, but not men, work stress

and low emotional support were in- dependently associated with development of T2DM, and thus psychosocial factors are of importance.

Norberg M et al: Obesity 2007; J Intern Med 2006; Diab Res Clin Pract 2007

Previous study on metabolic side effects of antipsychotic drugs

A ’multiple hit’ concept explaining progression of insulin resistance

Adopted from Burén J and Eriksson JW, Diab Metab Res Rev 2005

Insulin sensitivity

Prediab Diabetes

?

Glucotoxicity Lipotoxicity Neuroendocrine dysregulation Genetic & environmental background, including stress

Healthy

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

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.

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

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
• 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)

Incubation with antipsychotic drugs E.g. olanzapine, aripiprazole Subcutaneous adipose tissue