Personalized Diabetes Treatment based on

pathophysiology-oriented biomarkers
Prof. Andreas Pftzner , MD, PhD
CEO and Medical Director
PFTZNER Science & Health Institute
Parcusstrae 8, 55116 Mainz
Germany

Figure 3

Diabetes prevalence 1980/2014

1980:

108 Mio. Patients worldwide

Egypt: 1.5 Mio. diagnosed cases
(ranked No. 17 in the world)

2014:

422 Mio. Patients worldwide

Egypt: 8.7 Mio. diagnosed cases
(ranked No. 9 in the world)

The Lancet 2016 387, 1513-1530DOI: (10.1016/S0140-6736(16)00618-8)

NCD RiskFactor Collaboration Group, Lancet 2016; 387:1513-1530

The Current Problem

Current Treatment Targets

HbA1c < 6.5 %

To reduce incedence or progression of secondary complications

Treatment Guideline for People with Type 2 Diabetes

IDF Guideline 2012

Targeting Hba1c A Surrogate for Glycemia

Reaching target did not reduce
mortality in the ACCORD, ADVANCE
and VADT Studies

He died
with a perfectly
controlled
HbA1c

Pathophysiology-oriented Diabetes Therapy vs. Blood Glucose Cosmetics

Our diagnostic and therapeutic approach:

Beyond Glucose Control
Measurement of circulating functional proteins
1. To understand and document the degree of severity of the
underlying deteriorations leading to diabetes
2. To directly measure the individual vascular risk of the patient
(and not only to provide a theoretical risk percentage)
3. To monitor the success of a consecutive personalized treatment
and to direct modifications.

Insulin Resistance, Beta-Cell Dysfunktion & Visceral Obesity

Anti-insulin hormones

Adiponectin

Insulin resistance

Insulinrequirement

Adipogenesis
Beta-Cell

Insulin

Pftzner A, Schneider C, Forst T. Exp Rev Cardiovasc Ther 2006;4:44559

Insulin Resistance, Beta-Cell Dysfunktion & Visceral Obesity

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, Beta-Cell Dysfunktion & Visceral Obesity

Anti-insulin hormones

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

High blood pressure

10

Pftzner et al., Cardiology Reviews 22:30-34, 2005

Kintscher et al., Diabetes Stoffw. Herz 15:31-45, 2006

Insulin Resistance, Beta-Cell Dysfunktion & Visceral Obesity

Anti-insulin hormones

Insulin resistance

Insulin
requirement

adiponectin

Adipogenesis
Fat cell

-Celldysfunction

hyperglycemia

Insulin
Proinsulin

IL-6, TNF etc.

Atherosclerosis
Atherosclerosis
Atherosclerosis

Pre-adipocytes
Stem cell

Free
Fatty acids

Dyslipidemia

Angiotensin

High blood pressure

11

Pftzner et al., Cardiology Reviews 22:30-34, 2005

Kintscher et al., Diabetes Stoffw. Herz 15:31-45, 2006

Potential Biomarkers

eNOS

MAPK

Anti-insulinemic hormones Adiponectin

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

Pftzner et al., Cardiology Reviews 22:30-34, 2005

Kintscher et al., Diabetes Stoffw. Herz 15:31-45, 2006

Anti-insulinemic hormones

Insulin Resistance
Insulinrequirement

HbA1c

-Cell
Dysfunction

Blood glucose

Insulin
Proinsulin

Intact
Proinsulin

Hyperglycemia

IL-6, TNF etc.

Atherosclerosis
Atherosclerosis

Atherosclerosis

hsCRP

diponectin
Adiponectin

Adipogenesis
Lipid Cell

BMI

Pre-Adipocyte
Stem Cell

Free
Fatty Acids

Dyslipidemia
Lipids

Angiotensin

Hypertension
Blood pressure

Pftzner et al., Cardiology Reviews 22:30-34, 2005

Kintscher et al., Diabetes Stoffw. Herz 15:31-45, 2006

Insulin Production in the -Cell

Proinsulin --->

Insulin +

C-Peptide

Plasma

ribosome

vesicles
Exozytosis of the vesical content at the cell membrane
14
Pftzner et al., Diabetes Technol. Ther., 2004

Qualitative -Cell Secretion Disorder in Type 2 Diabetes

Proinsulin --->

Insulin +

C-Peptide

Pathologically increased insulin secretion

Plasma

ribosome

Pftzner et al., Diabetes Technol. Ther., 2004

Intact Proinsulin and Insulin Resistance

Intact proinsulin is a highly specific indicator of insulin resistance

50

Intact Proinsulin [pmol/]

III
40

Cut off
Sensitivity index
resistant: < 1,5

30

20

10

II

Cut off Proinsulin

(< 11 pmol/l)

0
0

SI
Pftzner et al., Diabetes Care 27:682-687, 2004

The 3 Stages of -Cell Dysfunction

Staging of -Cell Dysfunction based on the degree of

insulin resistance and the composition of the
secretion product (insulin and/or proinsulin)
independent from blood glucose values

Stage

description

Fasting
Insulin

Fasting Intact
proinsulin

Fasting Glucose

normal

low

normal

CV risk

Insulin sensitive, acute secretion

failure upon challenge

II

Insulin resistance without qualitatve

secretion disorder

Elevated

low

normal to elevated

elevated

IIIa

Insulin resistance with severe -cell

dysfunction

Normal to
elevated

elevated

normal to elevated

Highly elevated

IIIb

Exhaustion of -cell secretion

reduced

Elevated to low
(in late stage)

elevated

normal

High elevated

Pftzner,A. et al. Diab.Technol.Ther.2005;7: 478-486

17

Proinsulin and CAD Risk

100
intact proinsulin

<1,7 pmol/l

Survival rate [%]

90

1,7-3,1 pmol/l

80

70

60
0

> 3,1 pmol/l (p<0,001)

10

15

20

25

30

Time [years]

non-diabetic men, n = 874, observation period: 26.7 years

Zethelius et al., Circulation. 105:2153-8 , 2002

Proinsulin Elevation predicts development of Type 2 Diabetes

Intact proinsulin independently predicts Type 2 diabetes mellitus over 27 years in men
(Zethelius et al., Diabetologia, 2003)

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)

Elevation of fasting and glucose-stimulated intact proinsulin predicts type 2 diabetes

development in Finnish men over 6 years
(Vangipurapu et al., PLOSone, 2015)

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)

Elevation of glucose-stimulated intact proinsulin in normoglycemic adult patients predicts type 2

diabetes up to five years in advance
(Pftzner et al., J. Diabetes Sci. Technol. 2015)

Elaveted intact Proinsulin is Predicitve for Type 2 Diabetes

200
180
160

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

Pftzner et al. J. Diabetes Sci. Technol., 2015

20

Elaveted intact Proinsulin is Predicitve for Type 2 Diabetes

25

Cut-off values for intact proinsulin:

< 11 pmol/L

OGTT/spontan:

< 15 pmol/L

intact Proinsulin [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

Adipokines: Secretion Products of the Pre-Adipocyte

Free Fatty acids

TNF a

Resistin

Insulin resistant adipocytes

and pre-adipocytes secret
proinflammatory hormones
and cytokines, which lead
to chronic systemic
inflammation and eventually
cause atherosclerosis

Adiponectin

Leptin

Angiotensin II
PAI-1

Adiponektin ist ein endogener Insulin-Sensitizer, der in dieser Situation supprimiert wird!

Plasma-Adiponectin and CAD Risk

p<0.01
p<0.01

12

Adiponectin (g/ml)

10

p<0.01

p<0.01

8
6
4
2
0

Men

Controls

Diabetes without CAD

Women

Diabetes with CAD

Hotta K. et al., Ather Thromb Vasc Biol, 2000

Adiponectin a Biomarker for the Activity of the Visceral Lipid Tissue

Fasting adiponectin level

Adiponectin > 10 mg/l:

low Risk

Adiponectin: 7 10 mg/l:

moderate Risk

Adiponectin < 7 mg/l:

high Risk

A successful diabetes treatment leads to normalization of glucose and HbA1c

and to
a reduced hormonal activity of the visiceral lipid tissue as indicated by an increase in
adiponectin levels

hsCRP: Accepted Biomarker for Cardiovascular Risk

0 1 mg/l:

low Risk

1 3 mg/l:

moderately elevated Risk

3 10 mg/l:

high Risk

> 10 mg/l:

unspezific Infection/ not useful for interpretation

A successful diabetes treatment results in normalization of glucose and HbA1c

and also
in a reduction of chronic systemic inflammation as indicated by a reduction in the hsCRP levels

Ridker PM, et al. N Engl J Med. 2002;347:1557-1565.

Real Diabetes Treatment or Blood Glucose Cosmetics

these patients need more than just blood glucose lowering!

Impact of Interventions on Diabetes Pathophysiology

Intervention

Cell dysfunction

Visc. Fat Activity

Inflammation

Diet & Exercise

(Acarbose)

SU/Glinides
Metformin

Pioglitazone
DPPIV-Inhibitors
SGLT2-Inhibitors

GLP1-Analogs
Insulin (early)
Insulin (late)

A Personalized Treatment Approach Based on the Underlying Individual Phenotype

DET
De-Eskalation Therapy

De-Escalation Concept in Type 2 Diabetes mellitus

Improvement of glycemic control with the additional effect to

reduce the severity of the underlying deteriorations to a
lower level
by
Reducing stress and providing a relieve to the -cells, allowing
them to recover and to re-built new cells from stem cells by
providing a temporary targeted multiple drug treatment.

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

Reduction of hormonal visceral lipid tissue activity (GLP1, SGLTII-Inh.) :

Reduction of Pr-adipocyte differentiation and weight loss (GLP-1 to reduce appetite and/or renal loss of calories by
means of SGLTII-inhibitors)

Treatment of metabolic and vascualr insulin resistance (Pioglitazone):

Pioglitazone leads to an increase in adiponectin and improved insulin sensitivity in metabolism and in the vasculature

Treatment of glucose toxicity (SGLTII-Inh., Metformin):

Reducing high blood glucose values in particular after the meal can be achieved by SGLTII-inhibitors (reduction of the
kidney thershold) or by metformin (inhibition of hepatic glucose production)

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.

Patient Case: Pilot with Diabetes

W.A., male:
Profession:
Type 2 DM since:
BMI:

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

Patient Case: Pilot with Diabetes

Biomarker-Analysis 10/2012:
-Cell function:
Visceral Lipid Tissue Activity:
Chron. Syst. Inflammation:

intact Proinsulin: 12.3 pmol/L

total Adiponectin: 1.79 mg/L
hsCRP:
1.5 mg/dL

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:

Insulin glargine 10 IU, s.c.:

Liraglutide 0,6 mg, s.c.:
Pioglitazone 30 mg, p.o:
Dapagliflozin 10 mg, p.o:

0-0-0-1
1-0-0
1-0-0
1-0-0

For 3 months until re-consultation

33

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

Blutzucker im OGTT [mg/dL]

200

01/12/2012

01/10/2012

intakt Proinsulin [pmol/L]

Patient Case: Pilot with Diabetes

Lifestyle
DET

Lifestyle

6.5

HbA1c

Patient Case: Pilot with Diabetes

DET

12

Lifestyle
Epicrisis:

2h-BZ

10
Adiponektin [mg/L]

DET

Lifestyle

The DET effect could be maintained for 2 years.

Adiponectin

Increasing intact proinsulin and suppressed

adiponectin were indicators of diabetes return.

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

The patient decided to not wait until glucose goes up,

but to repeat DET immediately for 8 weeks. During
this time he only made simulator trainings and took
vacation. After the DET period, the pilot was
participating in the final professional examinations to
become an A380 pilot.

As of April 2016, this patient is the first (and only)

approved A380 pilot who carries a diagnosis of type 2
diabetes in his medical files.

hsCRP

01/10/2012

hsCRP [mg/L]

01/10/2012

Patient Case: Newly Manifested Diabetes

A.P.,female:
Profession:
Type 2 DM since:
BMI:

born. 17.02.1934
retired
January 2008
29.4 kg/m

Current treatment:

1000 mg Metformin 1-0-1

3 mg Glimepiride 1-0-0

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

for three months

Family history: mother had type 2 diabetes

After consultation, the patient decided for the DET approach
36

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]

Lifestyle & Pioglitazon 45 mg

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

intakt Proinsulin [pmol/L]

Patient Case: Newly Manifested Diabetes

Lifestyle & Pioglitazon 45 mg

40

30

20

Adiponektin

Patient Case: Newly Manifested Diabetes

30
29
28
27
26
25
24
23
22
21
20

After DET, the patient became very adherent to the

agreed lifestyle and reduced her body weight to a
normal BMI.

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

In the attempt to achieve a maximally sustained effect,

the patient continued with 45 mg pioglitazone
monotherapy.
01/03/2006

body mass index [kg/m]

Epicrisis:

Lifestyle & Pioglitazon 45 mg

DET

Since 2006, the patient has until today only measured

normal values with respect to her blood glucose
metabolism.

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

A new scientific truth does not triumph by

convincing its opponents and making them see the
light, but rather because its opponents eventually
die, and a new generation grows up that is familiar
withit.
Max Planck

41