Pfutzner
Pfutzner
Pfutzner
pathophysiology-oriented biomarkers
Prof. Andreas Pftzner , MD, PhD
CEO and Medical Director
PFTZNER Science & Health Institute
Parcusstrae 8, 55116 Mainz
Germany
Figure 3
2014:
He died
with a perfectly
controlled
HbA1c
Anti-insulin hormones
Adiponectin
Insulin resistance
Insulinrequirement
Adipogenesis
Beta-Cell
Insulin
Anti-insulin hormone
adiponectin
Insulin resistance
Insulinrequirement
Adipogenesis
Fat Cells
Pre-Adipocytes
Beta-Cell
dysfunction
Stem cells
Insulin
Proinsulin
Pftzner A, Schneider C, Forst T. Exp Rev Cardiovasc Ther 2006;4:44559
Insulin resistance
Insulinrequirements
adiponectin
adipogenesis
Fat cells
-Celldysfunction
Insulin
Proinsulin
IL-6, TNF etc.
Atherosclerosis
Atherosclerosis
Pre-adipocytes
Sem cells
Angiotensin
Free
Fatty acids
Dyslipidemia
10
Insulin resistance
Insulin
requirement
adiponectin
Adipogenesis
Fat cell
-Celldysfunction
hyperglycemia
Insulin
Proinsulin
Atherosclerosis
Atherosclerosis
Atherosclerosis
Pre-adipocytes
Stem cell
Free
Fatty acids
Dyslipidemia
Angiotensin
Potential Biomarkers
eNOS
MAPK
Insulin Resistance
Adiponectin
Insulinrequirement
HbA1c
-Cell
Dysfunction
C-peptide
Blood glucose
MMP-9
hsCRP
IMT
resistin
Adipogenesis
Pre-Adipocyte
Insulin
IL-6,
TNF TNF-
etc.
IL-6
Atherosclerosis
Atherosclerosis
MCP-1
Atherosclerosis
PAI-1
Lipid Cell
IntactInsulin
Proinsulin
Proinsulin
Hyperglycemia
visfatin
Stem Cell
Free
FFA
Fatty Acids
Dyslipidemia
Lipids
Angiotensin
Angiotensin
Hypertension
Blood pressure
Anti-insulinemic hormones
Insulin Resistance
Insulinrequirement
HbA1c
-Cell
Dysfunction
Blood glucose
Insulin
Proinsulin
Intact
Proinsulin
Hyperglycemia
Atherosclerosis
Atherosclerosis
Atherosclerosis
hsCRP
diponectin
Adiponectin
Adipogenesis
Lipid Cell
BMI
Pre-Adipocyte
Stem Cell
Free
Fatty Acids
Dyslipidemia
Lipids
Angiotensin
Hypertension
Blood pressure
Proinsulin --->
Insulin +
C-Peptide
Plasma
ribosome
vesicles
Exozytosis of the vesical content at the cell membrane
14
Pftzner et al., Diabetes Technol. Ther., 2004
Proinsulin --->
Insulin +
C-Peptide
Plasma
ribosome
50
III
40
Cut off
Sensitivity index
resistant: < 1,5
30
20
10
II
0
0
SI
Pftzner et al., Diabetes Care 27:682-687, 2004
Stage
description
Fasting
Insulin
Fasting Intact
proinsulin
Fasting Glucose
normal
low
normal
CV risk
II
Elevated
low
normal to elevated
elevated
IIIa
Normal to
elevated
elevated
normal to elevated
Highly elevated
IIIb
reduced
Elevated to low
(in late stage)
elevated
normal
High elevated
17
100
intact proinsulin
<1,7 pmol/l
90
1,7-3,1 pmol/l
80
70
60
0
10
15
20
25
30
Time [years]
Elevation of fasting intact proinsulin predicts development of Type 2 diabetes for up to seven
years in adult men
(Zethelius et al., Diabetes Care, 2004)
Conversion from normal glucose tolerance to T2DM in adolescents can occur rapidly, and the
onset of T2DM is heralded by increased release of intact proinsulin over up to 4 years
(Elder et al., J. Pediatr. 2015; 166:672-678)
Glucose [mg/dl]
140
120
Healthy subjects
Normalpersonen
100
Subjects who
sptere
developed type 2
Diabetespatienten
diabetes within
the next 5 years
80
60
40
20
0
0
60
120
20
OGTT/spontan:
< 15 pmol/L
Nchtern:
20
15
Healthy
subjects
Normalpersonen
Subjects
sptere who
developed
type 2
Diabetespatienten
diabetes within
the next 5 years
10
0
0
60
Zeit [min]
120
Pftzner et al. J. Diabetes Sci. Technol., 2015
21
TNF a
Resistin
Adiponectin
Leptin
Angiotensin II
PAI-1
Adiponektin ist ein endogener Insulin-Sensitizer, der in dieser Situation supprimiert wird!
12
Adiponectin (g/ml)
10
p<0.01
p<0.01
8
6
4
2
0
Men
Controls
Women
low Risk
Adiponectin: 7 10 mg/l:
moderate Risk
high Risk
0 1 mg/l:
low Risk
1 3 mg/l:
3 10 mg/l:
high Risk
> 10 mg/l:
Cell dysfunction
Inflammation
SU/Glinides
Metformin
Pioglitazone
DPPIV-Inhibitors
SGLT2-Inhibitors
GLP1-Analogs
Insulin (early)
Insulin (late)
DET
De-Eskalation Therapy
29
DET Targets
Relieving the -cells (Insulin, GLP-1, DPPIV-Inh.):
Continuous small scale supply of insulin (e.g. with a basal insulin or fixed doses of a short-acting prandial insulin prior
to each meal), additional improvement of insulin processing by GLP-1 agonists or DPPIV-inhibitors
To avoid hypoglycemia, all drugs are initially given in the lowest possible dose. Dose increases in one or two of the
selected drugs are subject to the results of the biomarker screening and to better target the individual phenotype
of the patient.
D
30
DET Procedure
1.
Comprehensive diagnosis (history, physical examination, ECG, pulse wave velocity, impedance balance,
routine biochemistry, cardiodiabetes biomarkers, liver biomarkers, glucose challenge test, genetic diagnosis
(food intolerance, atherosclerosis risk)
2.
Selection of drugs and their doses in correlation with the individual patient situation (biomarker results,
willingness of the patient to adhere to temporary injections, cognitive skills of the patient, etc.)
3.
Patient education regarding the drugs and lifestyle (diet & exercise).
4.
Regular contact with the patient for the next 12 weeks
5.
Repetition of the diagostic procedures lister under 1. (except for history and genetic testing) two days after
stopping any diabetes medication. Selection of drugs for the maintenance treatment (also treatment for
hypertension and lipud disorders, if applicable) together with the patient and under consideration of the new
laboratory results.
born 16.03.1964
Airline Pilot
2005
28.9 kg/m
Current treatment:
850 mg Metformin
3 mg Glimepiride
Lab 10/2012:
HbA1c: 7.2 %
OGTT: 0 h: 119 mg/dL
1 h: 292 mg/dL
2 h: 234 mg/dL
1-0-1
1-0-0
Airline medical service plans to put him on additional basal insulin with insulin glargine (basal
insulin supported oral treatment, BOT)
However, insulin-treated pilots are grounded and not allowed to fly anymore according to
international air traffic regulations
32
Diagnosis:
Severe insulin resistance with stage III -cell dysfunction and moderately elevated cardiovasular risk
Patient decide to undergo a de-escaletion treatment:
Individual drug combination:
0-0-0-1
1-0-0
1-0-0
1-0-0
01/08/2014
01/10/2014
01/12/2014
01/02/2015
01/04/2015
01/06/2015
01/08/2015
01/10/2015
01/08/2014
01/10/2014
01/12/2014
01/02/2015
01/04/2015
01/06/2015
01/08/2015
01/10/2015
01/04/2014
01/02/2014
01/12/2013
01/10/2013
01/08/2013
01/06/2013
01/04/2013
01/02/2013
01/06/2014
BMI
01/06/2014
01/04/2014
29.5
29
28.5
28
27.5
27
26.5
26
25.5
25
24.5
01/02/2014
DET
01/12/2013
2
7.5
01/10/2013
01/08/2013
01/06/2013
10
01/04/2013
12
01/02/2013
14
01/12/2012
FBG
01/10/2012
100
HbA1c [%]
Blood Glucose in
glucose challenge
01/12/2012
Intact Proinsulin
BMI [kg/m]
01/10/2015
01/08/2015
01/06/2015
Lifestyle
01/10/2012
01/10/2015
01/08/2015
01/06/2015
01/04/2015
01/02/2015
DET
01/04/2015
01/02/2015
01/12/2014
01/10/2014
01/08/2014
01/06/2014
01/04/2014
01/02/2014
01/12/2013
01/10/2013
01/08/2013
Lifestyle
01/12/2014
01/10/2014
01/08/2014
01/06/2014
01/04/2014
01/06/2013
150
01/02/2014
0
01/04/2013
DET
01/12/2013
5.5
01/02/2013
250
01/10/2013
50
01/12/2012
2h-BG
01/08/2013
01/06/2013
01/04/2013
01/02/2013
01/10/2012
01/12/2012
01/10/2012
Lifestyle
6.5
HbA1c
12
Lifestyle
Epicrisis:
2h-BZ
10
Adiponektin [mg/L]
DET
Lifestyle
Adiponectin
01/10/2015
01/08/2015
01/06/2015
01/04/2015
01/02/2015
01/12/2014
01/10/2014
01/08/2014
01/06/2014
01/04/2014
01/02/2014
01/12/2013
01/10/2013
01/08/2013
01/06/2013
01/04/2013
01/02/2013
01/12/2012
10
9
8
7
6
5
4
3
2
1
0
01/10/2015
01/08/2015
01/06/2015
01/04/2015
01/02/2015
01/12/2014
01/10/2014
01/08/2014
01/06/2014
01/04/2014
01/02/2014
01/12/2013
01/10/2013
01/08/2013
01/06/2013
01/04/2013
01/02/2013
01/12/2012
hsCRP
01/10/2012
hsCRP [mg/L]
01/10/2012
A.P.,female:
Profession:
Type 2 DM since:
BMI:
born. 17.02.1934
retired
January 2008
29.4 kg/m
Current treatment:
Lab 03/2006:
HbA1c: 11.0 %
OGTT: 0 h: 130 mg/dL
1 h: 274 mg/dL
2 h: 202 mg/dL
Intact Proinsulin:
Total adiponectin:
hsCRP:
14.3 pmol/L
2.3 mg/L
1.7 mg/dL
Treatment:
Insulin glargine 10 IU:
Liraglutide 0.6 mg:
Pioglitazone 45 mg:
Metformin 500 mg:
001
100
100
101
01/04/2013
01/09/2013
01/02/2014
01/07/2014
01/12/2014
01/05/2015
01/10/2015
01/03/2016
01/09/2013
01/02/2014
01/07/2014
01/12/2014
01/05/2015
01/10/2015
01/03/2016
01/01/2012
01/08/2011
01/03/2011
01/10/2010
01/05/2010
01/12/2009
01/07/2009
01/02/2009
01/09/2008
01/11/2012
0
01/04/2013
01/06/2012
1.5
01/11/2012
hsCRP
01/06/2012
0.5
01/01/2012
01/08/2011
4
2
01/03/2011
2.5
01/10/2010
Intakt Proinsulin
10
01/05/2010
10
01/12/2009
01/07/2009
12
01/02/2009
3.5
01/04/2008
DET
01/09/2008
14
01/04/2008
4
01/11/2007
01/11/2007
01/06/2007
01/06/2007
01/01/2007
50
01/01/2007
10
01/08/2006
HbA1c
01/03/2006
60
Adiponektin [mg/L]
01/08/2006
16
hsCRP [mg/L]
01/03/2016
01/10/2015
01/05/2015
01/12/2014
01/07/2014
01/02/2014
01/09/2013
01/04/2013
01/11/2012
01/06/2012
01/01/2012
01/08/2011
01/03/2011
12
01/03/2006
01/03/2016
01/10/2015
01/05/2015
01/12/2014
01/07/2014
01/02/2014
01/09/2013
01/04/2013
01/11/2012
01/06/2012
01/01/2012
01/08/2011
01/03/2011
01/10/2010
01/05/2010
01/12/2009
01/07/2009
01/02/2009
01/10/2010
01/05/2010
01/12/2009
01/07/2009
01/02/2009
01/09/2008
01/04/2008
01/11/2007
01/06/2007
01/01/2007
01/08/2006
01/03/2006
HbA1c [%]
DET
01/09/2008
01/04/2008
01/11/2007
01/06/2007
01/01/2007
01/08/2006
01/03/2006
40
30
20
Adiponektin
30
29
28
27
26
25
24
23
22
21
20
BMI
01/03/2016
01/10/2015
01/05/2015
01/12/2014
01/07/2014
01/02/2014
01/09/2013
01/04/2013
01/11/2012
01/06/2012
01/01/2012
01/08/2011
01/03/2011
01/10/2010
01/05/2010
01/12/2009
01/07/2009
01/02/2009
01/09/2008
01/04/2008
01/11/2007
01/06/2007
01/01/2007
01/08/2006
Epicrisis:
DET
Conclusions
Type 2 Diabetes is a complex disease with underlying disorders that progressively deteriorate over time
if not adequately treated (-Cell dysfunction, Insulin resistance, increased hormonal activity of the
visceral lipid tissue, chronic systemic inflammation).
Next to determination of common routine biochemical parameters, the additonal determination of
specific cardiodiabetes markers (intact proinsulin, adiponectin, hsCRP) help to understand the
severity of the underlying disorders and allow to determine the indivitual phenotype of the patient.
Based on this information, a individually taylored treatment can be defined and in case of a sufficient
remaining -cell function an attempt can be undertaken to re-boot the metabolism by means of a
temporary de-escalation treatment with multiple drugs.
In many cases, the application of a DET has helped to stop disease progression and sometimes have
even allowed the metabolism to return to normal or at least to delay the onset or progression of
secondary disease complications.
39
41