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Diabetes

Dr Muries
Barham

Diabetes mellitus (DM) is a group of


diseases characterized by high levels
of blood glucose resulting from
defects in insulin production, insulin
action, or both.
The effects of diabetes mellitus
include longterm damage,
dysfunction and failure of various
organs.

Diabetes
Diabetes mellitus may present with
characteristic symptoms such as thirst,
polyuria, blurring of vision, and weight loss.
In its most severe forms, ketoacidosis or a
nonketotic hyperosmolar state, in absence of
effective treatment, death.
Often symptoms are not severe, or may be
absent, and consequently hyperglycaemia
sufficient to cause pathological and functional
changes may be present for a long time
before the diagnosis is made.

Diabetes Long-term Effects


The longterm effects of diabetes mellitus
include progressive development of the
specific complications of retinopathy,
nephropathy that may lead to renal
failure, and/or neuropathy with risk of
foot ulcers, amputation, Charcot joints,
and features of autonomic dysfunction,
including sexual dysfunction.
People with diabetes are at increased risk
of cardiovascular, peripheral vascular and
cerebrovascular disease.

Glucose Tolerance
Categories
FPG
Plasma glucose
(mg/dL)

h PPG (OGTT)-2

240

Diabetes
Mellitus

220

200
180

Diabetes
Mellitus

160

14
0
126

120

IFG

100
80

IGT

Normal

Normal

60
American Diabetes Association. Diabetes Care. 2004;27(suppl 1):S5-S10

Classification of Diabetes Mellitus


by Etiology
Type 1

-cell destructioncomplete lack of insulin

Type 2

-cell dysfunction and insulin resistance

Gestational

-cell dysfunction and insulin


resistance during pregnancy

Other specific types

Genetic defects of -cell function


Exocrine pancreatic diseases
Endocrinopathies
Drug- or chemical-induced
Other rare forms

A. Genetic defects of cell


function
characterized by mutations in:
1.Hepatocyte nuclear transcription factor
(HNF) 4 (MODY 1)
2.Glucokinase (MODY 2)
3.HNF-1 (MODY 3)
4.Insulin promoter factor-1 (IPF-1; MODY 4)
5.HNF-1 (MODY 5)
6.NeuroD1 (MODY 6)

A. Genetic defects of cell


function
7. Mitochondrial DNA
8. Subunits of ATP-sensitive
potassium channel
9. Proinsulin or insulin conversion

B. Genetic defects in insulin


action

1. Type A insulin resistance


2. Leprechaunism
3. Rabson-Mendenhall syndrome
4. Lipodystrophy syndromes

C. Diseases of the exocrine


pancreas
pancreatitis, pancreatectomy,
neoplasia, cystic fibrosis,
hemochromatosis, fibrocalculous
pancreatopathy, mutations in
carboxyl ester lipase

D. Endocrinopathies
Acromegaly, Cushing's
syndrome, glucagonoma,
pheochromocytoma,
hyperthyroidism,
somatostatinoma,
aldosteronoma

E. Drug- or chemicalinduced

pentamidine, nicotinic acid,


glucocorticoids, thyroid hormone,
diazoxide, Beta-adrenergic agonists,
thiazides, phenytoin, Alfa-interferon,
protease inhibitors, clozapine

F. Infections
congenital rubella,
cytomegalovirus,
coxsackie

G. Uncommon forms of
immune-mediated diabetes
"stiff-person" 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

IV. Gestational diabetes


mellitus (GDM)
Glucose intolerance may develop during
pregnancy. Insulin resistance is related to
the metabolic changes of late pregnancy,
and the increased insulin requirements
may lead to IGT. GDM occurs in ~4% of
pregnancies in the United States; most
women revert to normal glucose
tolerance post-partum but have a
substantial risk (3060%) of developing
DM later in life.

Screening for GDM


Screen for undiagnosed type 2
diabetes at the first prenatal visit
in those with risk factors, using
standard diagnostic criteria.

Gestational
Diabetes
Hyperglycemia during pregnancy
usually resolves
after birth
Complicates ~4% of all
pregnancies in the United States
High risk of perinatal morbidity
and mortality

Gestational
Diabetes

High risk of later type 2 diabetes


in both mother and baby
Diagnosed by specific glucose
tolerance test methods
Requires intensive dietary and
glycemic management

Etiologies of diabetes/hyperglycemia
in childhood
1- Type 1 DM.
2- Type 2DM.
3- Other specific types of DM:
Genetic defects in beta-cell and
in insulin receptor.

ISLET CELLS ANTIBODIES:

A heterogeneous group of AB against a


variety of cytoplasmic islet cell antigens

Not exclusively against Beta cells. Other


islet cells are also targets.

Highly positive esp. in the pre- diabetic


phase

More positive at onset than later.

Positivity decreases rapidly with


duration of diabetes .

ANTIBODIES:
ISLET CELLS

DURATION OF DIABETES

% POSITIVE

1-4 WEEKS
60-95 % *

3-9 MONTHS
50 %

1-10 YEARS
< 25 %

*Positive ICA correlate with declining C-peptide


levels &-increasing insulin requirements

ANTI GLUTAMIC ACID DECAROXYLASE ( GAD)


AB

AntiGADAntibodies

Present in 75- 84 % of
recent onset DM type 1.

Pathogenesis of Type 1
Diabetes : One Defect
No hepatic
insulin effect
Unrestrained
glucose production

Absent
insulin
secretion

Hyperglycemia

No muscle/fat
insulin effect
Impaired glucose
clearance

Less glucose enters


peripheral tissues

More glucose enters


the blood

Glycosuria

D.M. Type 1
Epidemiology in US in < 19 yr of age
population:
1. Incidence: 16/100,000/yr.
2. Prevalence: 140/100,000.
3. Mean age of onset: 11 yr in F / 12.5 yr in M.
4. Incidence by gender:
< 5 yr: increased in males;
5-10 yr: increased in females;
11-19 yr: equal in males and females.

D.M. Type 1
Pathogenesis
1. Genetic factors:
1) Major histocompatibility complex
(MHC) predisposing genes HLA-DR3,
DQB1*0201 or DR4,DQB1*0302.
protective: DQB1*0602.
2) Non- MHC genes: At least 19 genes
have been identified, 3 of them
mapped to chromosomes: 11, 15, 2.

D.M. Type 1
2. Environmental factors: e.g. Coxakie virus
infection.
3. Autoimmune:
A) T- lymphocyte- mediated destruction
(inslinitis).
B) Markers, not causative: Autoantibodies
( ICA, IAA, GAD).

D.M. Type 1
The combination of all those factors
ultimately leads to - cell destruction,
which is an insidious process that may
take up to 10 yrs before completion;
once the - cell mass is <5-10% of its
original amount, symptoms of diabetes
become manifest.

Late-Onset Type 1
Diabetes
About half of patients with type 1
diabetes are diagnosed after age 18
Autoimmune process may differ and is
slower
Often mistaken for type 2 diabetesmay
make up 10%30% of individuals
diagnosed with type 2 diabetes
Can be identified by ICA or GAD
antibodies
Oral agents are usually ineffective
insulin therapy is eventually required

The honey-moon period


Shortly

after the onset


of the disease, there
may follow a brief
period of a spontaneous
remission

called:

The honey-moon period.

The honeymoon period in type 1


diabetes mellitus

1. Characterized by evidence of
recovery of
endogenous insulin secretion.
[ presence of C-peptide in serum ]
Insulin requirements become less
and less, sometimes none.

2. Lasts for 2-3 months up to one year.


Thereafter, the disease re-appears
and the state of insulin dependency
becomes permanent for life .

Type 1.5 DM
Begins as Type 1 with DKA.
Later becomes non-insulin dependent.
No HLA predisposition.
No autoimmunity.
Occurs in certain ethnic groups, e.g.
African- Americans.

Pathogenesis of Type 2
Diabetes : Two Defects
Hepatic
insulin
resistance
Excessive
glucose production

More glucose enters


the blood stream

Impaired
insulin
secretion

Hyperglycemia

Glycosuri

Muscle/fat
insulin
resistance
Impaired glucose
clearance

Less glucose enters


peripheral tissues

Loss of early-phase insulin secretion in


type 2 DM

120
100

Normal
20
glucose

80
60
40
20
0

30 0 30 60 90 120
Time )minutes(

Ward WK et al. Diabetes Care 1984;7:491502

Type 2 diabetes
Plasma insulin )U/ml(

Plasma insulin )U/ml(

Pattern of insulin secretion is altered early in type 2 diabetes

120
100

20 g glucose

80
60
40
20
0
30 0 30 60 90 120
Time )minutes(

MODY
MODY is non-insulin requiring form
of diabetes,occurring in children and
young adults,resulting from genetic
defect in beta-cell function,and
inherited in autosomal dominant
trait(AD)

MODY is non-insulin requiring


form of diabetes, occurring in
children and young adults,
resulting from genetic defect in
beta-cell function, and inherited
in autosomal dominant trait(AD)

MODY
MATURITY ONSET
YOUNG (MODY)

DIABETES

OF

THE

- Clinical presentation partly similar to type 2


DM but occurring in young age group-mostly
adolescents
- Autosomal dominant inheritance;
different gene defects described
- All relatively rare.

Clinical Features

Obesity

Insulin resistance Autoimmunity

Type 1

No

No

Yes

Type 2

Yes

Yes

No

MODY

No

No

No

Genetic heterogeneity in MODY


Clinical Features of Heterozygous State

MODY

Type
Mody1

Gene
HNF-4

Diabetes;microvascular complication, reductions


in serum triglycerides,apolipoproteins.
Impaired fasting glucose, impaired glucose
tolerance, diabetes, normal proinsulin-to-insulin
.ratio in serum

Mody2

Glucokinase

Mody3

HNF-1

Diabetes, microvascular complication, renal


. glycosuria

Mody4
Mody5

IPF-1
HNF-1

.Diabetes
Diabetes;renal cysts and renal dysfunction,internal
genital . abnormalities

Mody6

NeuroD1,OR
BETA2

.Diabetes

Glucose Tolerance Categories


FPG
Plasma glucose
(mg/dL)

h PPG (OGTT)-2

240

Diabetes
Mellitus

220

200
180

Diabetes
Mellitus

160

140
126

120

IFG

100
80

IGT

Normal

Normal

60
American Diabetes Association. Diabetes Care. 2004;27(suppl 1):S5-S10

Type 1 Diabetes Mellitus


This form of diabetes is immunemediated in over 90% of cases and
idiopathic in less than 10%. The rate
of pancreatic B cell destruction is
quite variable, being rapid in some
individuals and slow in others.

Type 1 diabetes is usually associated with


ketosis in its untreated state. It occurs at
any age but most commonly arises in
children and young adults with a peak
incidence before school age and again at
around puberty. It is a catabolic disorder
in which circulating insulin is virtually
absent, plasma glucagon is elevated, and
the pancreatic B cells fail to respond to all
insulinogenic stimuli.

Criteria for the Diagnosis of


Diabetes Mellitus
Symptoms of diabetes plus random
blood glucose concentration 11.1
mmol/L (200 mg/dL)aor
Fasting plasma glucose 7.0 mmol/L
(126 mg/dL)bor
Two-hour plasma glucose 11.1
mmol/L (200 mg/dL) during an oral
glucose tolerance testc

aRandom is defined as without regard


to time since the last meal.
bFasting is defined as no caloric intake
for at least 8 h.
cThe test should be performed using a
glucose load containing the equivalent
of 75 g anhydrous glucose dissolved in
water; not recommended for routine
clinical use.

Risk Factors for Type 2


Diabetes Mellitus
Family history of diabetes (i.e., parent
or sibling with type 2 diabetes)
Obesity (BMI 25 kg/m2)
Habitual physical inactivity
Race/ethnicity
Previously identified IFG or IGT
History of GDM or delivery of baby
>4 kg

Risk Factors for Type 2


Diabetes Mellitus
Hypertension (blood pressure 140/90
mmHg)
HDL cholesterol level <35 mg/dL
(0.90 mmol/L) and/or a triglyceride
level >250 mg/dL (2.82 mmol/L)
Polycystic ovary syndrome or
acanthosis nigricans
History of vascular disease