Fifty Years of Diabetes Research and Care:

Reflections and Perspectives

Pierre LEFEBVRE MD, PhD, FRCP, MAE

IDF Honorary President
WDF 2003-2014 Chairman of the Board
Emeritus (active) Professor of Medicine
University of Liège, Belgium

Dar es Salaam March 2016

Liège, BELGIUM ?
 Amsterdam

London

Cologne
Brussels Liège

Luxembourg

Paris
1955
 -The coma is an almost
hopeless complication…

-In comparison with European

countries diabetes is a rare
disease in America

-The combination of intense

application to business,
Chapter on Diabetes over-indulgence in food and
drink,with a sedentary life,
seem particularly prone to induce
the disease.

-Personally, I have never seen

recovery from a case of true
diabetes…

-The so-called diabetic phtysis

Is always tuberculosis…

-We are ignorant of the nature of

the disease
-The coma is an almost WRONG since the discovery of insulin
hopeless complication…

-In comparison with European WRONG : the USA have one of the largest
countries diabetes is a rare diabetes prevalence
disease in America

-The combination of intense TRUE

application to business,
over-indulgence in food and
drink,with a sedentary life,
seem particularly prone to induce the disease.

-Personally, I have never seen Almost TRUE

recovery from a case of true
diabetes…

-The so-called diabetic phtysis Sadly, often TRUE

Is always tuberculosis…

-We are ignorant of the nature of the disease Almost TRUE

-
 Understanding Diabetes
Fifty years ago Today
-Heredity
-Autoimmunity
-Beta cell failure vs

? insulin resistance
-Diabetes as a paracrinopathy
-We are not alone in our body
 Natural History of Type 1 Diabetes
PUTATIVE
ENVIRONMENTAL
TRIGGER

CELLULAR (T CELL) AUTOIMMUNITY

HUMORAL AUTOANTIBODIES
BETA CELL FUNCTION

(ICA, IAA, Anti-GAD65, IA2Ab, ZnT8,

etc.)
LOSS OF FIRST
PHASE
INSULIN RESPONSE
(IVGTT)
GENETIC INSULITIS GLUCOSE INTOLERANCE
PREDISPOSITION BETA CELL CLINICAL
INJURY ONSET
“PRE”-
DIABETE
S DIABETES

TIME
Courtesy Dr Jay SKYLER
1960
Luyckx et Lefebvre, 1969
 2
1

b
 Insulin

Glut4

Nucleus
www.hprd.org
Diabetes as a Paracrinopathy of the
Islets of Langerhans
Samols et al, 1983
Lefèbvre et al, 1991
Formulated by Unger and Orci, 2010
 1922
2011
1975
GLUCAGONOCENTRIC
INSULINOCENTRIC HYPOTHESIS
THE BIHORMONAL HYPOTHESIS
OF
OFDIABETES
OF DIABETES
DIABETES

InsulinGlucagon
Lack Excess

 Glucose utilization
 Lipolysis
 Proteolysis
 Hepatic glycogenolysis
 Hepatic gluconeogenesis
 Ketogenesis
 Glycogen synthesis
Courtesy RH Unger
We are not alone in our body !
Gut microbiota: an « indoor » garden that reveals secrets
through genomic approaches (microbiome)
Qin et al Nature 2010, Arumugam et al Nature 2011, Wu et al Science 2011,

1. Human cells : 30000 genes (genome)

2. Bacterial cells: 30%
1600 genes (microbiome)
3. The gut microbiota contains10 14up to 1000
bacterial cells species
in the gut (10 cells)
14

dominated by 3 (of 70) divisions:

Originally classified as gram + or gram -
 Firmicutes (E. rectale-Cl. Coccoides, Cl. leptum)
1000 species , classified upon sequences
 Bacteroidetes (Bacteroides,
homology, asPrevotella)
phyla (gender, species…)
-Firmicutes (Lactobacilli)
 Actinobacteria (Bifidobacterium)
-Bacteroidetes (Prevotella,
Bacteroides)
-Actinobacteria
4. Bacteries are classified as gram negative (LPS) or (Bifidobacterium
gram
positive spp.)

Microbiome is specific for each individuals,

Courtesy Nathalie Delzenne but common core are present in all persons
Gut microbiota are associated with diseases
Inflammatory Obesity
Bowel
diseases

Rheumatoid Diabetes
arthritis

Autism Athero-
sclerosis

Multiple
sclerosis Asthma Colon
Cancer

Metabolic diseases Heart diseases Cancer

Neurological disorders Autoimmune diseases Airway diseases
By courtesy of M. Arumugam and O. Pedersen
 High-fat food alters intestinal bacteria flora, promotes low-grade
inflammation and triggers insulin resistance

Gut Blood Inflammation

Insulin sensitivity

High-fat food
Lipogenesis
Pro-
+ inflammatory Inflammation
cytokines
Steatosis
Selective gut Macrophage Insulin sensitivity
bacteria
Proinflammatory
cytokines
Inflammation
Macrophage infiltration

Toll-like receptor 4
CD14 receptor
LPS Bacterial lipopolysaccharides

Cani PD & Delzenne NM. Current Pharmaceutical Design 15:1546-1558, 2009

Cani PD et al. Diabetologia 50:2374-2383,2007
Gut microbiota based interventions
It is possible to preserve the gut microbiota?

 Coloscopic replacement with a

mixture of cultured or fresh ’healthy’
bacteria species?

 Oral prebiotics

 Oral probiotics

 Irradications

 Individualizing the gut treatment

dependent on host genotype profiles

Courtesy Oluf Pedersen

Clinical Issues
Controling blood glucose does matter
Fifty years ago Today
• The work of J.PIRART • Hb A1c
• Blood glucose monitoring
• Devices

•
Good control

Fair control

Bad Control
Introduced at about the same time, some
40 years ago, HbA1c and Blood Glucose
Monitoring ( BMG ) have JOINTLY been
the greatest progress in diabetes care since
the discovery of insulin in 1921
 HbA1C Target

BGM Tool to reach the target

 Insulin therapy
Fifthy years ago
All animal insulins
Soluble vs NPH or « Lente »
Glass seringes
Painful needles
Above all « Dirty insulin »
Today
Human insulin (synthesized or
animal « humanized »)
Disposable seringes and needles
Insulin « pens »
Insulin pumps
Artificial pancreas
Exotic ways of administration
Basic needs vs
Sophistication ?
 DiAs (Diabetes Assistant)
Closed-loop insulin delivery using smart-phone technology
Courtesy Professor Eric Renard,Montpellier 2013
Management of Type 2 Diabetes mellitus

Prior to 1955 : Largely neglected

« Benign », « Maturity-onset »…
1955-1995 : Essentially glucose control-
oriented
After 1996 and UKPDS :
-Insulin not too late
-Consider treating obesity (first ?)
-Multifactorial
-Type 2 DM considered as a ( the ?)
main cause of cardio-vascular
morbidity and mortality
 Oral antidiabetic drugs

Fifty years ago Today

None…then… Metformin: first line !
Sulfonylureas Sulfonylureas, still there !
Biguanides « Innovations » ?
Mechanisms of Action of Different Diabetes
Therapies

Increase Increase
Insulin Glucose
Secretion Uptake
• Sulfonylureas
• Meglitinides
• Phenylalanine
Blood •Glitazones

Derivatives
• GLP-1 agonists
Glucose
• DPPIV inhibitors Delay
Glucose
Decrease Absorption
Hepatic •Biguanides ·a-Glucosidase
Glucose •Glucagon inhibitors Inhibitors
Output
 New options

• CB1 antagonists (Rimonabant, Teranabant…) :

a failure
• SGLT2 inhibitors (Glifozines) :
- a physiological non-sense …
-drug-induced glycosuria largely compensated
for by glucagon–induced increase in liver glucose output…
• The paradigme :
« Non-inferiority » vs Metformin
 EMPA-REG OUTCOME ®
CV death
HR 0.62
(95% CI 0.49, 0.77)
p<0.0001

Cumulative incidence function.

CI, confidence interval; HR, hazard ratio.
Zinman et al. N Engl J Med 2015:373:2117-2128. 37
 The management of diabetes
Fifty years ago
Almost exclusively the
paternalistic model:
The physician decided was the
most appropriate treatment
was and told the patient what
to do.
Today
-Evidence-based medicine
-Guidelines
-Patient education
-Patient autonomy
-Individualized care, so-called
« Precision Medicine »
 About GUIDELINES:
UN Inquiry into the « Arms to Iraq » affair
• Lady Thatcher: Guidelines are exactly what they say they
are.They are guidelines. They are not the law.

• Question: But do they have to be followed?

• Lady Thatcher: Of course they have to be followed, but they

are not strict law. That is why they are guidelines and not the
law, and , of course, they have to be applied according to the
circumstances…
 Three Inventions
Cochrane A, Effectiveness and Efficiency: Miller LV, Goldstein J, More efficient care of
Random Reflections on Health Services, 1972 diabetic patients in a county-hospital setting.
N Engl J Med. 1972 ;286:1388-91
Guyatt G, et al. Evidence-based medicine.
A new approach to teaching the practice of WHO definition: 1998
medicine. JAMA 1992 ; 268 : 2420-5.

Evidence- Patient
Based Education
Medicine

Principle of
Autonomy
Tom Beauchamp and James Childress,
Principles of Biomedical Ethics , 1979

Courtesy Dr Gérard Reach

 Four models of the physician-patient relationship

I decide for you In addition,

I tell you
Paternalistic Deliberative
model model my preferences

Informative Interpretative
model model I give you facts
I give you facts and help you
to find
your preferences

Emanuel EJ,Emanuel LL, Four models of the physician-patient relationship JAMA.

1992;267:2221-6
Through patient education,
care is neither a paternalism nor a manipulation

I decide for you In addition,

I tell you
Paternalistic Deliberative my
model model preferences

Sympathy
Informative Interpretative
model Empathy model
I give you facts
I give you facts and help you
to find
Patient
your preferences
education

Courtesy Dr Gérard Reach

Hyperglycemia

Medical and
social consequences
of diabetes
Percent and number of men with and without CVD experiencing
catastrophic spending and impoverishment, India, 2004

30
25

20 1.4 to 2.0 million

Percent

10
10
5 0.6 to 0.8 million
2
0
Catastrophic Impoverishment

CVD No CVD
Source: Mahal et al 2010
Catastrophic spending >30% HH income in one year; Impoverishment from above poverty line to below
during year
What in the next 50 years ?
 Global Risk Landscape 2010
Likelihood and Severity of Economic Loss

4 Slowing of Chinese Economy

5 Fiscal Crisis
6 Asset Price Collapse
7 Retrenchment from Globalization
29 Pandemic
30 Infectious diseases
31 Chronic diseases

World Economic Forum 2010

Iceland April 2010
RESERVE SLIDES
Paul LANGERHANS
1847-1888

Berlin 18/02/1869

I admit frankly that I am

not able to explain the
nature and function of
these cells…
Professor
Lelio Orci,
Geneva
 Beta-cell
Alpha-cell

Human islet. Courtesy Lelio Orci

Lelio ORCI

Rat pancreas:
Left ventral part
Right dorsal part
Unique arrangement of
Alpha and Beta cells in
Human Islets of Langerhans

Bosco et al
Diabetes 2010, 59:1202-10
 b-cell extensions intercalate between a-cells

Bosco et al. 2010. Diabetes 59: 1202

A B C

D E
60

Frequency (%)
40

20

0
beta apha-beta alpha
wrapping wrapping
alpha beta