CNS mechanisms in insulin
resistance TREATMENT kick-off, Madrid June 2017
Jan Eriksson, MD Prof
Uppsala University, Dept of Medical Sciences
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
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 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
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
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