LECTURE 1

DIABETES MELLITUS
Language - English
Associate Professor, candidate of Medical Sciences
Oksana Konstantinovna Melekhovets

Department of Endocrinology, Sumy State University,

Ukrane
 DIABETES MELLITUS
a group of heterogeneous
diseases characterized by
high levels of blood
glucose resulting from
defects in insulin
production, insulin action,
or both
 Number of People with Diabetes (millions)
for 2000 and 2010 and the % Increase

26.5
32.9
14.2 84.5
24%
17.5 132.3
23% 57%

The number9.4 of adults with diabetes in the world is

to increase by 122%, from 135 million in
estimated14.1
50%1995 to 300 million in 2025
15.6
22.5
44%
1.0
1.3
33%

Zimmet P, Nature 2001;414(6865):782-7 World: 2000: 151 million

King H, Diabetes Care 1998;21(9):1414-31 2010: 221 million  Increase: 46%
The Insidence of Type 1 DM
 Diabetes Mellitus

1) Type 1 diabetes
2) Type 2 diabetes
3) Specific types
4) Gestational diabetes

¨ Complications :
- Stroke
- Heart attack
- Kidney disease
- Eye Disease
- Nerve Damage
Classification of Diabetes Mellitus
(stage)
Degrees of severity:
mild degree
moderate degree
severe degree.

State of compensation:
compensation;
subcompensation;
decompensation.
Testing :
Fasting Plasma Glucose Test Oral Glucose Tolerance Test
(FPG) - (cheap, fast) (OGTT)
*fasting B.G.L. tested for 2 hrs after
*> 110 mg/dl signals glucose-rich drink
diabetes (6,1 mmol/l)
*>200 mg/dl signals
diabetes (11,1 mmol/l)

Glycated Hemoglobin test

A1C

¨ 80 to 90 mg per 100 ml, is the normal fasting blood glucose

concentration in humans and most mammals which is
associated with very low levels of insulin secretion.
 Insulin is a small protein consisting of an A
A chain chain of 21 amino acids linked by two disulfide
(S—S) bridges to a B chain of 30 amino acids.

Beta cells have channels in their plasma

membrane that serve as glucose
detectors. Beta cells secrete insulin in
response to a rising level of circulating
glucose.
B chain
 Action of Insulin on
Carbohydrate Metabolism
Facilitates the transport of glucose into
muscle and adipose cells

Facilitates the conversion of glucose to

glycogen for storage in the liver and
muscle.

Decreases the breakdown and release of

glucose from glycogen by the liver
 Action of Insulin on
Protein Metabolism

Stimulates protein synthesis

Inhibits protein breakdown; diminishes

gluconeogenesis
 Action of Insulin
on Fat Metabolism
Fat
Stimulates lipogenesis- the transport of
triglycerides to adipose tissue

Inhibits lipolysis – prevents excessive

production of ketones or ketoacidosis
Insulin affects many organs:
amino acids protein
It stimulates skeletal muscle uptake synthesis
fibers.

It stimulates liver cells. glycogen

glucose
synthesis
uptake
It acts on fat cells

It inhibits production of certain fat

enzyme. synthesis

In each case, insulin triggers

enzyme glycogen
these effects by binding to the production breaking
insulin receptor.
 Fasting Blood Glucose Level:
The "gold standard" for diagnosing
diabetes is an elevated blood sugar level
after an overnight fast (not eating anything
during 8 h).
A value above 110 mg/dl on at least two
occasions typically means a person has
diabetes.
Normal people have fasting sugar levels
that generally run between 65 -100 mg/dl.
 Fasting blood glucose
1979 National Diabetes Data Group:
7.8 mmol/l
Classification and diagnosis of
(140 mg/dl)
diabetes mellitus
1985 World Health Organization:
7.0 mmol/l
Diabetes Mellitus: Report of a
(126 mg/dl)
WHO Study Group
1997 The Expert Committee on the
Diagnosis and Classification of
Diabetes Mellitus
6.1 mmol/l
1999 World Health Organization: (110 mg/dl)
Definition, Diagnosis and
Classification of Diabetes Mellitus
and its Complications
Postprandial plasma glucose
1979 National Diabetes Data Group:
Classification and diagnosis of
diabetes mellitus

1985 World Health Organization:

1999 Diabetes Mellitus: Report of a 11.1 mmol/l
WHO Study Group (200 mg/dl)
1997 The Expert Committee on the
Diagnosis and Classification of
Diabetes Mellitus
 Diagnosis contd.
In order to be diagnosed with diabetes:
Person must have symptoms of diabetes +
Causal plasma glucose >200 mg/dl
Fasting blood glucose of >110 mg/dl
2-hour plasma glucose >200 mg/dl on oral
glucose test
Criteria for the Diagnosis of Diabetes
The classic symptoms of diabetes (polyuria,
polydepsia, and unexplained weight loss) plus
random plasma glucose concentration  200
mg/dl (11.1 mmol/l).
OR
FPG  126 mg/dl (7.0 mmol/l).
– Fasting is defined as no caloric intake for at least 8h.
OR
2-h PG  200 mg/dl (11.1 mmol/l) during OGTT
– The test should be performed as described by W HO
using a glucose load containing equivalent of 75-g
anhydrous glucose dissolved in water.
Glucose tolerance tests may lead to one
of the following diagnoses:

Normal Response
Impaired Fasting Glucose
Impaired Glucose Tolerance
 Hemoglobin A1c
A good indicator of blood glucose control.
Indicates glysimic control over the
preceding 2-3 months.
Performed 2 times a year.
A hemoglobin of 6% indicates good control
and level >8% indicates action is needed.
 Etiologic Classification of
Diabetes Mellitus
I. Type 1 diabetes
(β-cell destruction, usually leading
to absolute insulin deficiency)
  
A. Immune-mediated
B. Idiopathic
Pathophysiology of T1DM

antibodies
attack islets!
The bulk of the pancreas is an exocrine gland
secreting pancreatic fluid into the duodenum
after a meal.
Inside the pancreas are millions of clusters of
cells called islets of Langerhans. The islets are
endocrine tissue containing four types of cells.
In order of abundance, they are:
beta cells, which secrete insulin and amylin;
alpha cells, which secrete glucagon;
delta cells, which secrete somatostatin
gamma cells, which secrete a polypeptide.
 Auto-immune and HLA Markers
· high incidence of HLA DR 3/4, DQ B1 and
DQ A1
islet cell antibodies (ICA)
· insulin autoantibodies (IAA)
· antibodies to GAD 65 (glutamic acid
decarboxylase)
· evidence of T-cell reactivity to pancreatic
islet cell antigens.
· autoimmune markers differ in the various
age groups
· highest incidence of IAA in <5 year age
group.
 II. Type 2 diabetes
may range from predominantly
insulin resistance with relative
insulin deficiency to a
predominantly insulin secretory
defect with insulin resistance
 Type 2

Obesity& Genetic
Insulin susceptibility
resistance
 The progressive nature of
type 2 diabetes
Normal Impaired Type 2 Late type 2
glucose diabetes diabetes
tolerance complications
Insulin
sensitive
Hyperglycaemia

Normal insulin
secretion Insulin
resistance
Normoglycaemia
β-cell
exhaustion

Insulin resistance

Fasting plasma glucose

Insulin sensitivity
Insulin secretion Adapted from Bailey CJ et al. Int J Clin Pract 2004;58:867–876.
Groop LC. Diabetes Obes Metab 1999;1 (Suppl. 1):S1–S7.
III. Other specific
types of diabetes
Genetic defects of β-cell function
  characterized by mutations in:
Hepatocyte nuclear transcription factor
(HNF) 4α (MODY 1)
Glucokinase (MODY 2)
HNF-1α (MODY 3)
Insulin promoter factor (IPF) 1 (MODY 4)
HNF-1β (MODY 5)
NeuroD1 (MODV6)
Mitochondrial DNA
Proinsulin or insulin conversion
[MODY - maturity onset of diabetes of
the young]
 Родословная семьи с MODY

СД
с 30 лет

СД СД СД
с 6 лет с 10 лет с 14 лет

Пробанд Сибс
МАУ(N до 20 мг/л) 4 600
HbA1c (N до 6,4%) 6,8 6,9
ICA (N отр) 60 64
Инсулин (Ед/сутки) 17 9
Genetic defects in insulin
action

Type A insulin resistance

Leprechaunism
Rabson-Mendenhall syndrome
Lipodystrophy syndromes   
• Leprechaunism
DIDMOAD- syndrom
(Diabetes Insipidus,
Diabets Mellitus,
Optic Atrophy,
Deafness)
Diseases of the exocrine
pancreas
pancreatitis,
pancreatectomy,
neoplasia,
cystic fibrosis, hemochromatosis,
fibrocalculous pancreatopathy
 
  Endocrinopathies

acromegaly,
Cushing's syndrome,
glucagonoma,
pheochromocytoma,
hyperthyroidism,
somatostatinoma,
aldosteronoma
  
Drug- or chemical-induced
Vacor, pentamidine, nicotinic acid,
glucocorticoids, thyroid hormone,
diazoxide, β-adrenergic agonists,
thiazides, phenytoin, α-interferon,
protease inhibitors, clozapine,
beta blockers
 
 Infections
 congenital rubella, cytomegalovirus,
coxsackie
Uncommon forms of immune
mediated diabetes—“stiff-man”
syndrome, anti-insulin receptor
antibodies
 H.Other genetic syndromes
sometimes associated with diabetes
Down's syndrome, Klinefelter's
syndrome, Turner's
syndrome,    Wolfram's syndrome,
Friedreich's ataxia, Huntington's
chorea, Laurence-Moon-Biedl
syndrome, myotonic dystrophy,
porphyria, Prader- Willi syndrome
Prader- Willi syndrome
А.К., 15 лет, делеция в 15
отцовской хромосоме
 IV. Gestational
diabetes mellitus
(GDM)
•IV. Gestational diabetes
Common Clinical Symptoms of
Hyperglycemia

The Classic Tried

Polyuria (frequently urinating)

Polydipsia (frequently thirsty)
Weight loss
 Common Clinical Symptoms
Blurred vision
Polyphagia (frequently hungry)
Fatigue
Poor wound healing (cuts, scrapes, etc.)
Dry mouth
Dry or itchy skin
Impotence (male)
Recurrent infections such as vaginal yeast
infections, groin rash, or external ear
infections (swimmers ear)  
 CHRONIC C0MPLICATIONS
Cerebrovascular
diseases
Diabetic 1.2- to 1.8-fold
retinopathy increase in stroke3
Leading cause
of blindness
in working-age Cardiovascular
adults1 disease
75% diabetic
patients
die from CV events4
Diabetic
nephropathy Diabetic
Leading cause of neuropathy
end-stage renal disease2 Leading cause of
non-traumatic lower
extremity amputations5

Fong DS, et al. Diabetes Care 2003;26 (Suppl. 1):S99–S102. 2Molitch ME, et al. Diabetes Care 2003;26 (Suppl. 1):S94–S98.
1

3
Kannel WB, et al. Am Heart J 1990;120:672–676. 4Gray RP & Yudkin JS. In Textbook of Diabetes 1997.
5
Mayfield JA, et al. Diabetes Care 2003;26 (Suppl. 1):S78–S79.
 DIABETIC
RETINOPATHY

Histology
Pathogenesis

Healthy retinal
capillaries
Diabetic capillaries:
non-perfused areas
 Identifying progession of retinopathy

Exudates/oedema =
leakage
 New Vessels

 An ‘early’ sign =
haemorrhages
Features

microaneurysms
Features

New vessels
(also get tortuous
vessels and
haemorhages)
 Nonproliferative Stage
 Dot & blot hemorrhages
 Cotton-wool spots
 Venous Loops

Preproliferative Stage
 Venous Tortuosity
 Increased retinal blood flow.
 Capillary Dropout
 Macular Edema - fluid leakage from vessels to
retina can cause localized edema. If it
presents in the macula, can cause
reduction in VA (20/20 > 20/50).
 Proliferative Stage

 Neovascularization - most prominent at

border between perfused and
nonperfused retina

 Vitreous hemorrhage due to fragility of

new vessels

 Contraction of co-existing glial tissue

may lead to retinal detachment.
 LASER
FOTOCOAGULATION
 Diabetic neuropathy is a disorder,
either clinically evident or subclinical,
that occurs in the setting of diabetes
mellitus without other causes for
peripheral neuropathy.
The neuropathic disorder includes
manifestations in the somatic and/or
autonomic parts of the peripheral
nervous system.
Definition according to the San Antonio
Conference on Diabetic Neuropathy 1988
 Classification of Diabetic
Neuropathy
 CNS Complications:
 Stroke
 Increased Risk (independent of HTN,
etc.)
 Worsened neurologic injuries/deficits
 Diabetic Encephalopathy
 Subtle cognitive defects
 Possible increased risk from repeated
episodes of severe hypoglycemia
 Peripheral Neuropathies
Mononeuropathy: involvement of a single
nerve characteristically results in foot drop,
wrist drop, or cranial nerve III, IV, or VI
paralysis
Radiculopathy: a sensory syndrome of
pain over multiple spinal nerves, mimics
zoster pain
Diabetic amyotrophy: a rare disorder
resulting in atrophy and weakness of the
pelvic girdle musculature
 Peripheral Neuropathies
 Sensory Loss
 Pain Reception
 Pain, Paresthesias
 Loss of Sensation, Occult Injuries/Ulcers
 Position/Vibratory Sense
 Ataxia
 Increased Falls Risk
 Peripheral Neuropathies

Motor Neurons
 Proximal Motor Neuropathy
 Pain/Anesthesia anterior thigh
 Difficulty rising from squat/ climbing
stairs
 Knee Buckling
 Peripheral sensorimotor
polyneuropathy
Distal, bilateral, symmetrical, stocking-glove
distribution.
Symptoms range from numbness
(“deadness”) to severe pain.
Burning, alteration of temperature sensation,
parathesias, shooting, or stabbing pains/
May worsen at night.
Minor motor involvement causing weakness.
 Physical Exam Clues to the
Diagnosis
Decrease or absent reflexes (Achilles)
Loss or diminished vibratory sensation
(128Hz tuning fork), pin prick, light touch,
or pressure perception
Muscle atrophy
Foot complications, ulcerations, blisters,
deformities (Charcot’s joint)
 Autonomic neuropathy
 Cardiovascular
 Postural Hypotension (orthostatic hypotension)

 Resting Tachycardia (alteration of heartrate

control)

 Painless MI

 Sleep Apnea
 GastroIntestinal
Autonomic Neuropathies

 Esophageal Dysmotility
 Gastroparesis
 Pylorospasm
 Intestinal - Diarrhea, Spasm
 Gall Bladder Contractility
 Anorectal Dysfunction - Incontinence
 GenitoUrinary
Autonomic Neuropathies

 Bladder Dysfunction
 Male Impotence
 Ejaculatory Disorders
 Reduced Vaginal Lubrication,
Dyspareunia
 Autonomic neuropathy
– Other:
– abnormality in perspiration,
– excessive sweating or dryness
DIABETIC NEPHROPATY
 DIABETIC NEPHROPATY
 Leading Cause of End Stage
Renal Disease (ESRD) in
developed nations.
 27.2% Dialysis Patients have
DM.
 Familial clustering occurs.
 1st STAGE

 Glomerular Hyperfiltration
 Renomegaly
 GFR up to 140% of normal
 Intermittent microalbuminuria
(with hyperglycemia)
 2st STAGE

 Early Glomerular Lesions

 Basement Membrane Thickening
 Exercise-Induced
Microalbuminuria
 Begins ~ 18-24 months after
onset DM
 Lasts 4-15 years
 3st STAGE

Microalbuminuric Stage
 30 - 300 mg albumin/Day
 GFR usually maintained 120
-140
 Associated with transited
hypertension, edema
 4st STAGE

Clinical nephropathy (permanent

hypertension, edema)
 > 300-500 mg/day
 Falling GFR
 Nephrotic Syndrome
• proteinuria>3500 mg/day
• hypoalbuminemia
• Edema
• Hyperlipidemia
 5st STAGE

 End Stage Renal Disease

 uremia
 decreased GFR <10 ml/min
 2-3 years after nephrotic
syndrome.
 DIABETIC FOOT
Pathophysiology

Angiopathy
Neuropathy
– Sensory
– Motor
– autonomic
Sensory Neuropathy
 Two mechanisms of Ulceration

– Unacceptable stress few times

 rock in shoe, glass, burn
– Acceptable or moderate stress repeatedly
 Improper shoe ware
 deformity
 Diabetic angiopathy
(peripheral artery disease )
A history of walking impairment,
claudication, ischemic rest pain, and/or
nonhealing wounds is recommended as a
required component of a standard review
for DM patients.

The Rutherford clinical categories are used

to classify the degree of ischemia and
salvageability of the limb.
Critical limb ischemia is also a component
of tht Fontaine clinical classification
system.
 Critical limb ischemia
Critical limb ischemia is defined by most vascular
clinicians in patients who present with lower
extremity ischemic rest pain, ulceration, or
gangrene. In these individuals, the untreated
natural history of severe PAD would lead to major
limb amputation within 6 months.
Patients with CLI usually present with limb pain at
rest,with or without trophic skin changes or tissue
loss. The discomfort is often worse when the
patient is supine (e.g., in bed) and may lessen
when the limb is maintained in the dependent
position.
Typically, narcotic medications are required for
analgesia.
 Classification of peripheral artery
disease (PAD)
Fontaine Stage Classification of PAD

STAGE CLINICAL FINDINGS

I Asymptomatic, decreased pulses,

ankle-brachial index (ABI)<0.9
II Intermittent claudication
III Daily rest pain
IV Focal tissue necrosis

Source: Am Fam Phys 2001; 61:1027–1032, 1034.

 Classification of Peripheral Arterial Disease:
Fontaine’s Stages and Rutherford’s
Categories

Fontaine Rutherford

Stage Clinical Grade Category Clinical

I Asymptomatic 0 0 Asymptomatic
IIa Mild claudication I 1 Mild claudication
IIb Moderate-severe I 2 Moderate claudication
claudication
I 3 Severe
claudication
III Ischemic rest pain II 4 Ischemic rest pain
IV Ulceration III 5 Minor tissue loss
or gangrene IV 6 Ulceration or
gangrene
The shoes and socks should be removed;
the feet inspected; the color, temperature,
and integrity of the skin and intertriginous
areas evaluated; and the presence of
ulcerations recorded.
Additional findings suggestive of severe
PAD, including distal hair loss, trophic skin
changes, and hypertrophic nails, should
be sought and recorded.
Ulcer Classification

Wagner’s Classification

0 – Intact skin (impending ulcer)

1 – superficial uninfected
2 – deep infected
3 – osteomyelitis
4 – gangrene of toes or forefoot
5 – gangrene of entire foot
Classification
grade 2 or 3
 Patients’ Evaluation
X-ray Bony destruction (Charcot or osteomyelitis; Menceberg’
arteriites).
Ankle-Brachial and Toe-Brachial Indices, Segmental Pressure
Examination. The ABI should be measured in both legs in all
new patients with PAD of any severity to confirm the diagnosis
of lower extremity PAD and establish a baseline. (Level of
Evidence: B)
Magnetic resonance angiography of the extremities is
useful to diagnose anatomic location and degree of
stenosis of PAD. (Level of Evidence: A)
Continuous-wave Doppler ultrasound blood flow measurements
are useful to provide an accurate assessment of lower
extremity PAD location and severity, to follow lower extremity
PAD progression, and to provide quantitative follow-up after
revascularization procedures. (Level of Evidence: B)
Contrast angiography provides detailed information about
arterial anatomy and is recommended for evaluation of patients
with lower extremity PAD when revascularization is
contemplated. (Level of Evidence: B)
Patient Evaluation
Classification
grade 4
 Foot Physical Examination and
Differential Diagnosis
of Neuropathic and Neuroischemic Ulcers
Neuropathic Ulcer Neuroischemic Ulcer

Painless Painful
Normal pulses Absent pulses
Typically punched-out appearance Irregular margins
Often located on sole or edge of Commonly located on toes
foot or metatarsal head
Presence of calluses Calluses absent or infrequent
Loss of sensation, reflexes, and Variable sensory findings
vibration sense
Increase in blood flow Decrease in blood flow
(arteriovenous shunting)
Dilated veins Collapsed veins
Dry, warm foot Cold foot
Bone deformities No bony deformities
Red appearance Pale, cyanotic
Adapted from J Vasc Surg, 31, Dormandy JA, Rutherford RB, for the TransAtlanticInter-Society Consensus (TASC) Working Group, Management of peripheral
THANKS VERY MUCH
