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

of T2D subjects during hyperinsulinemia

Brain

[18F

]FD

G tis

sue influx r

ate

(

ki=

ul pla

sm

a/m

l tissue m

in)

0

5

10

15

20

25Control T2D *

Brain

M-value (mg/kg lbm/min)

0 2 4 6 8 10 12 14 16

Bra

in [

18F

]FD

G tis

sue influx r

ate

( ki=

ul pla

sm

a/m

l tissue m

in)

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

sensitiv

ity

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