DIABETES_ LECTURE

PROF. DR. DOINA CATRINOIU

Diabetes Mellitus

One of the most common noncommunicable diseases

Fourth leading cause of death in most
developed countries
More than 194 million people with diabetes
worldwide
Incidence of diabetes is increasing
estimated to rise to 333 million by 2025
To more than double in Africa, the Eastern
Mediterranean and Middle East, and South-East Asia
To rise by 50% in North America, 20% in Europe, 85%
in South and Central Americas and 75% in the Western
Pacific
: International Diabetes Federation website

Types of Diabetes Mellitus

Type 1 diabetes (insulin-dependent

diabetes)
mainly in childhood/early adult life
10-20% of cases

Type 2 diabetes (non-insulin-dependent

diabetes)

usually develops in the middle-age/elderly

incidence increasing at a younger age
80-90% of cases

At least 50% of all people with

diabetes are unaware of their condition
: International Diabetes Federation website

CLASSIFICATION OF DIABETES
Impaired glucose tolerance without
diabetes (IGT)
Primary diabetes mellitus

Insulin dependent (IDDM or Type 1)

Noninsulin dependent (NIDDM or Type 2)

Malnutrition-related diabetes mellitus

(MRDM)
Secondary diabetes mellitus

Pancreatic disease
Endocrine disorders
Drug therapy
Inherited disorders

Secretia de insulina

Gluc

ose

Basal-bolus therapy attempts to recreate physiological insulin secretion

Predicted plasma insulin concentration
profile (mU/l)

Rapid-acting insulin
Basal insulin
Total

Time of day

Diabetes is defined biochemically

by the following criteria

A fasting venous plasma glucose

level greater than 7.8 mmol/litre
(126 mg/dl) on more than one
occasion;

or A 2-hour (plus one other)

venous plasma glucose level in
excess of 11.1 mmol/litre (200
mg/dl) in a formal 75 g oral
glucose tolerance test (GTT).

Clinical features of diabetes at

diagnosis

Type 1
Type 2
Polyuria and thirst ++
+
Weakness or fatigue ++
+
Polyphagia with weight loss++

Recurrent blurred vision +

++
Vulvovaginitis or pruritus +
++
Peripheral neuropathy +
++
Nocturnal enuresis ++

Often asymptomatic
++

A diagnostic algorithm for diabetes

mellitus

Blood glucose > 200 mg/dl

Classical
Symptoms* +

Blood glucose 100 -200 mg/dl

DIABETES
A
S
Y
M
P
T
O
M
A
T
I
C

Fasting plasma glucose

> 126 mg/dl
Fasting plasma glucose
109-125 mg/dl
postprandial plasma
glucose > 200mg/dl
Blood glucose > 200 mg/dl
"occasionally"

2-h Plasma glucose after

"OGTT" > 200 mg/dl
and/or
Fasting plasma glucose >
126 mg/dl

INVESTIGATIONS

Blood glucose is the key to diagnosis in

diabetes.
Glycosylated haemoglobin and other
proteins: measurement of these proteins
reflects the degree of diabetic control in
the previous 4-6 weeks and is of value in
long-term management and control .

INVESTIGATIONS

Urine testing for glucose-glucose will

be found in the urine only when it rises
above the renal threshold (usually about
10 mmol/l
Urine testing for ketone bodies the
presence of ketones suggests loss of
control.
Proteinuria is a reflection of the
development of renal complications and
is an early indicator of diabetic renal
disease Multiple test strips allow rapid
testing for all these substancesin urine.

INVESTIGATIONS

Proteinuria is a reflection of the

development of renal complications and
is an early indicator of diabetic renal
disease Multiple test strips allow rapid
testing for all these substancesin urine.
Microalbuminuria is a very sensitive
marker of early and potentially reversible
renal impairment; it is the term given to
the presence of protein below the level of
detection with the stick methods, that is
200 mg/litre.

INVESTIGATIONS

Serum electrolytes, blood gases,

osmolality and anion gap are all of
value in metabolic crises if there is
loss of water, sodium and potassium
and acidosis is developing, or if there
is a hyperosmolar state.
Lipid profile: elevations in serum
cholesterol are common, and
elevation of serum triglycerides is a
reflection of poor glycaemic control,
which usually reverts to normal when
euglycaemia is achieved.

PRESENTING FEATURES OF DIABETES

Acute: the typical presentation of the young

patient with IDDM; features include polyuria,
polydipsia and weight loss of short duration,
often associated with, or apparently
precipitated by, a viral infection;visual
disturbance or impairment of the conscious
level associated with severe ketoacidosis
Chronic: the typical presentation of a patient
with NIDDM; the symptoms have usually been
present for some months and often include
weight loss, thirst, excess urine volume, genital
and skin infections

PRESENTING FEATURES OF DIABETES

Coincidental discovery: routine

screening for urine or blood glucose as
part of a pre-employment medical, during
pregnancy or in local campaigns
Complications: visual disturbance or
overt retinopathy, neuropathy,
nephropathy or after major thrombotic
events such as premature stroke or
myocardial infarction

PRESENTING FEATURES OF DIABETES

Drug-related diabetes may develop in

patients on long-term steroids or thiazide
diuretics
Disease-related as in acromegaly,
Cushing's syndrome, phaeochromocytoma,
thyrotoxicosis, pancreatitis,
haemochromatosis, cystic fibrosis,
carcinoma or surgical removal of the
pancreas
Gestational: pregnancy may unmask
diabetes in a woman who is predisposed.
A full history and clinical examination are
essential to detect any of the causative
diseases and document the consequences.

PRESENTING FEATURES OF DIABETES

Patients with type 2 diabetes may
or may not have characteristic
features. The presence of obesity
or a strongly positive family
history for mild diabetes
suggests a high risk for the
development of type 2 diabetes.

DM Kendall et al. Eur J Intern Med 20, ( 2009) S329S339

Prin amabilitatea Prof. Dr. N. Hncu

Treatmentul DZ tip 2: inlocuirea deficitului

Obesitate

IGT

Diabet

[necontrolat]

Postprandial

Glicemia
(mg/dl)
126

Fasting
insulinorezistenta

Functia
-celulara
(%)

100

Insulin Level
-20

-10
0
10
20
Diabetes duration (years)

30
Adapted from IDC, Minneapolis

The Progression from CV Risk Factors to

Endothelial Injury and Clinical Events
LDL-C

BP

Risk factors

Diabetes

Smoking

Heart failure

Oxidative stress

Endothelial dysfunction

NO

PAI-1

Local mediators

VCAM

Tissue ACE-Ang II

Endothelium

ICAM cytokines
Thrombosis

Inflammation

Vasoconstriction

Growth factors
matrix

Vascular lesion
and remodelling

Proteolysis

Plaque rupture

Clinical endpoints
NO Nitric oxide

Gibbons GH, Dzau VJ. N Engl J Med 1994;330;1431-1438.

The Metabolic Syndrome and

Associated CVD Risk Factors
Hypertension
Abdominal obesity
Hyperinsulinaemia

Insulin
Resistance

Atherosclerosis

Diabetes
Hypercoagulability
Dyslipidaemia
high TGs
small dense LDL
low HDL-C

Endothelial
Dysfunction

Deedwania PC. Am J Med 1998;105(1A);1S-3S.

NCEP ATP III: The Metabolic

Recommends a diagnosis when 3 of these risk factors are present
Syndrome
Risk Factor

Defining Level

Abdominal obesity
(Waist circumference)

Men
Women
TG

>102 cm (>40 in)

>88 cm (>35 in)
150 mg/dL (1.7 mmol/L)

HDL-C

Men
Women

Blood pressure
Fasting glucose

<40 mg/dL (1.0 mmol/L)

<50 mg/dL (1.3 mmol/L)

130/ 85 mm Hg
110 mg/dL (6.0 mmol/L)
NCEP, Adult Treatment Panel III, 2001. JAMA 2001:285;2486-2497.

WHO: The Metabolic Syndrome

A working definition is glucose intolerance, IGT or
diabetes mellitus and/or insulin resistance together
with two or more of the following:

Raised arterial pressure 160/90 mmHg

Raised plasma triglycerides (1.7 mmol/L, 150

mg/dL) and/or low HDL-C (men <0.9 mmol/L,
35 mg/dL; women <1.0 mmol/L, 39 mg/dL)

Central obesity

Microalbuminuria (UAER 20 g/min or

albumin: creatinine ratio 20 mg/g)

Alberti KGMM for the WHO. Diabet Med 1998:15;539-553.

TREATMENT

Type 1 diabetes ONLY INSULIN is a

replacement therapy
Type 2 diabetes ORAL DRUGS+/INSULIN THERAPY

Human insulins do not closely match the

endogenous insulin response

Adapted from: Polonsky et al. J Clin Invest 1988;81:4428

Insulin analogues address the limitations of

human insulin

Adapted from: Polonsky et al. J Clin Invest 1988;81:4428

Defining glucose variability

Hypoglycaemic events
Postprandial glucose excursions
Minor fluctuations in blood glucose levels

Monnier and Colette. Diabetes Care 2008;31(Suppl.2):S1504

Nonglycemic effects of oral therapy

Cardiovascular risk
factor

Sulfonil
urea

Rapidacting
insulin
secretago
gues

Metform
in

Thiazolidindi
ones

glucosida
se
inhibitors

Insulin resistance
Hyperinsulinemia
LDL chol levels
LDL particle pattern
HDL chol levels
Triglycerides
LP (a)
PAI-1
Endothelial function
Body weight
Visceral adiposity

0
0
0
0
0
0
0
0
0

0
0
0
0
0
0
0
0
0

or 0
Large buoyant

?
0

0 or

0
0
0
0
0
0
0
0
0

Modified fromHE Lebovitz, Endocrinol clin North Am, 2001, 30: 909-933

Potential down-sides of pharmacological

treatment modalities in patients with T2DM
Potential problem

Avoid or reconsider

Unwanted weight gain

Sulphonylureas, glinides,

Gastrointestinal symptoms

Biguanides, alpha-glucosidase
inhibitors

Hypoglycemia
Impaired kidney function
Impaired liver function

Impaired cardio-pulmonary
function

glitazones, insulin

Sulphonylureas, glinides, insulin

Biguanides, sulphonylureas
Glinides, glitazones, biguanides,
alpha-glucosidase
Biguanides, glitazones

ESC, EASD Guidelines, 2007

Suggested policy for the selection of glucoselowering therapy according to the glucometabolic
situation
Post-prandial
hyperglycemia

alpha-glucosidase inhibitors, shortacting SU, glinides, short-acting regular

insulin or insulin analogs

Fasting hyperglycemia

Biguanides, long-acting SU, glitazones,

long-acting insulin or insulin analogs

Insulin resistance

Biguanides, glitazones, alphaglucosidase inhibitors

Insulin deficiency

SU, glinides, insulin

ESC, EASD Guidelines, 2007

Revisit T2DM treatment strategies:

the evolving HbA1c position
Persistent HbA1c >7%

ACTION
Realistic target:
lowest HbA1c possible without
unacceptable hypoglycaemia
Healthy individual HbA1c 46%
Achieving and maintaining HbA1c at target may require
incremental and combination therapies

Treat-to-target concept
Adapted from Rosenstock J, Riddle MC. Chapter 9: Insulin therapy in type 2 diabetes. In: Cefalu
WT, Gerich JE, LeRoith D (eds). The CADRE Handbook of Diabetes Management. New York:
Medical Information Press; 2004:14568.

Summary of antidiabetic interventions as

monotherapy
Interventions

Step 1: initial
Lifestyle to decrease weight
and increase activity
Metformin
Step 2: additional therapy
Insulin

Expected
decrease
in A1c
(%)
1-2
1.5
1.5-2.5

Advantages

Low cost, many

benefits
Weight neutral,
inexpensive
No dose limit,
inexpensive,
improved lipid profile
Inexpensive
Improved lipid
profile

Sulphonylureas
TZDs

1.5
0.5-1.4

Other drugs
-glucosidase inhibitors

0.5-0.8

Weight neutral

Exenatide

0.5-1.0

Weight loss

Glinides
Pramlintide

1-1.5
0.5-1.0

Short duration
Weight loss

Disadvantages

Fails for most in first year

GI side effects, rare lactic
acidosis
Injections, monitoring,
hypoglycemia, weight gain
Weight gain, hypoglycemia
Fluid retention, weight
gain, expensive
Frequent GI side effects,
expensive
Injections, frequent GI side
effects, expensive, little
experience
3x/ day dosing, expensive
Injections, frequent GI side
effects, expensive, little
experience

A consensus statement from ADA and EASD. Diabetologia, 2006, 49: 1711-21

Strategii si algoritmuri

Algorithm for the metabolic management of T2DM

Diagnosis
Lifestyle intervention + metformin
HbA1C7
%
Add basal insulin
-most efective

Add sulfonylurea
-least expensive

HbA1C7%

Add glitazone
-no hypoglycamia

HbA1C7%

Intensify insulin

Add glitazone

HbA1C7%

HbA1C7%

Add basal insulin

Add sulfonylurea

HbA1C7%
Add basal or intensify insulin

Intensive insulin + metformin +/- glitazone

A consensus statement from ADA and EASD. Diabetologia, 2006, 49: 1711-21

Management of hyperglycemia in type 2 diabetes

How do I establish and sustain glycemic control?
Lifestyle change: an
option?

Is metformin still the

first line drug?

&

Which drugs after

metformin?
Sulphonylureas, TZDs
or insulin?
And then? Three oral agents,
insulin as add-on or insulin alone?
What is the evidence for the
proposed algorithm?
Will new drugs be able to halt
the decline of beta-cell function?
RJ Heine et al. BMJ, 9 december 2006, 333: 1200-1204

Contraindications can damage your healthis

metformin a case in point?
Standard contraindications to the use of metformin should be relaxed,
and that the benefits of reducing the number of patients excluded from
using it would by far outweigh the potential risks
propose removal of the following contraindications from the list:
1. old age
2. chronic renal insufficiency (as long as GFR>40 ml/min)
3. chronic heart failure (NYHA stages I and II)
4. discontinuation of metformin therapy 2 days before surgery
and i.v. contrast medium administration
A clear re-definition of metformin contraindications will enable more
physicians to prescribe within the guidelines
The main effect of revising these contraindications and precautions will
be to bring the official guidelines into harmony with day-to-day clinical
practice
A Holstein, M. Stumwoll. Doiabetologia, 2005, 48:2454-59

Insulin

Oral agents
SIOFOR 1000

Chacra RA et al. Diabetes, Obesity, Metab, 2005, 7: 148-160

GLP-1
SNC

Stomac

Cord

Neuroprotecie
Apetitul

Cardioprotecie
Funcia cardiac

Evacuarea
coninutului gastric

Intestinul

GLP-1
Ficat
Pancreas
Producia de
glucoz

Muchi

Sensibilitate
la insulin

Secreia de insulin

esut

Secreia de glucagon

adipos

Sinteza de insulin
Proliferarea beta-celular
Preluarea i stocarea
glucozei

Apoptoza celulelor beta

Baggio LL, Drucker DJ. Gastroenterology. 2007;132:2131-2157 Reprodus cu permisiune Elsevier 2007.

Efects ofGLP-1 in healthy

subjects
Eliberare de
insulin

Insulin

50

Exenatid is not inactivated by

DPP-4
Eliberare de
insulin

Insulin

51

The basal/bolus insulin concept

Basal insulin
Suppresses glucose production between meals
and overnight
40% to 50% of daily needs

Bolus insulin (mealtime)

Limits hyperglycaemia after meals
Immediate rise and sharp peak at 1 hour
10% to 20% of total daily insulin requirement
at each meal