Diabetes Mellitus

an overview

Aly A. Abdel-Rahim, MD
Diabetes is a disorder
caused by the
presence of too much
glucose in the blood.
A first depiction of this
“sugar disease” was
described in the
“Ebers Papyrus”, a
papyrus sold to the
German Egyptologist
Georg Moritz Ebers in
1872. It was said to
have been found close
to a mummy in the
tomb of Thebes and
appears to have been
written between 3000
and 1500 BC.
 History

• Reference to diabetes was made 1550 BC.

• In the 2nd Century AD, Aretaeus gave an
excellent description of diabetes.
• Thomas Willis in the 17th Century detected the
sweet test of urine.
• Mathew in the 18th Century showed that the
sugar in urine comes from the blood.
 History

• Minkowski and Von Mering discovered

that disease of the pancreas is
responsible for diabetes to develop in the
19th century.
• In the 19th century treatment of diabetes
was confined to food regulation which
reduced urination but did not prevent
wasting and complications.
 History

• In the second half of the 19th Century, Paul

Langerhans, a German student, identified
clusters of cells within the pancreas
responsible for the production on glucose
lowering substance. “islets of
Langerhans”.
• Insulin: in Latin insula= island. So the
name was coined before the hormone was
discovered.
 History

• Banting and Best “a student” worked in

McLeod's labs in Toronto.
• In 1921they made the exocrine cells
atrophy by ligation of the pancreatic duct.
• They made aqueous extracts of the
remaining tissue keeping it cold and
filtered it.
• The extract was injected into a diabetic
dog on 30 July 1921.
 History

• They convinced
themselves that they
had discovered the
active pancreatic
hormone which
normalizes the blood
sugar.
 History

• The first person to be

treated with insulin
was Leonard
Thompson (1908-
1935). The first
injection was in 11
January 1922
 History: Noble Prize 1923

• Banting • McLeod

• Best • Collip
 Definition of diabetes

• A syndrome of chronic hyperglycaemia

with other metabolic abnormalities
together with micro and macro-vascular
complications.
 What is wrong with diabetes

• Insulin deficiency

Hyperglycaemia
• Insulin resistance
 Classification of diabetes

• Type 1DM
• Type 2DM
• IFG: impaired fasting glycaemia
• IGT: impaired glucose tolerance
• GDM: Gestational diabetes mellitus
• Secondary DM.
 Criteria of diagnosis

• FBS > 125.

• PP > 200
• OGTT.

normal:
• FBS <100
• PP <140
 T1DM

• Usually in young age

• Characterized by absolute insulin
deficiency.
• Increased catabolism and liability to
ketosis.
• Stormy presentation.
• must be treated with insulin.
 T2DM

• Usually in older age.

• Relative insulin deficiency.
• Increased insulin resistance.
• Can be treated with OHA or insulin.
• Slow onset, less likely to develop ketosis.
• May present with complications.
 MODY
Maturity onset diabetes of the youth

• A special type of diabetes similar to type 2

diabetes but develop in young age groups.
• Increased prevalence worldwide.
• Associated with increased childhood
obesity.
 Diabetes related to drugs

• Glucocorticoids
• Diazoxide.
• Thiazides.
• Phyention
• Pentamidine
 GDM
Gestational diabetes mellitus

• Diabetes discovered for the first time

during pregnancy.
• Every pregnant lady should be screened.
• Usually disappears after labor.
• Increased risk to develop T2DM later in
life.
Diabetes is a pandemic
Prevalence of diabetes in the EMME
region
Prevalence of IGT in the EMME region
Prevalence of DM & IGT by region
Estimated 10 prevalence of diabetes
Estimated 10 top number of diabetes
patients
 Social profile related to diabetes in
Egypt

• with an average income per person of

$1,490 in 2001, fighting poverty remains
a substantial challenge.
• In it dropped to $1.390 in 2003 and then
$1.310 in 2004. *
• People living under poverty line (<1 $/day)
3.7%
*WHO statistics 2005
 Social profile related to diabetes in
Egypt
• Life expectancy is 69.1 years.
• National poverty rate (% of population)
16.7 .
• Child malnutrition, weight for age (% of
under 5) 4.0 in 2003 increased to 8.6
2004.

Source: World Development Indicators database

, August 2005
 Prevalence of diabetes in Egypt

• Herman : 9.3% above 20y of age.

• Arab 4.3% above 20y of age.

• Why the difference ???

region e.g.: desert and Nubians.
 Prevalence of diabetes in Egypt

• Herman : 9.3% above 20y of age.

• Arab 4.3% above 20y of age.

• Why the difference ???

region e.g.: desert and Nubians.
 Diagnosis

• How to diagnose diabetes:

1. Signs and symptoms
2. Blood glucose test
3. OGTT
4. HbA1c
 Diagnosis

• Most people are diagnosed with diabetes

when they are suspected to have symptoms of
polyurea, polydepsia, fatigue, loss of weight.
• This is confirmed by fasting or PP blood
glucose.
• In case of doubt OGTT may be done.
• Urine testing should not be used in diagnosis.
 Diagnosis

• Peers and medical ‘advisors’ should be aware

of the following:
• T1DM & T2DM are two distinct diseases.
• T1DM is stormy at presentation, delay in
diagnosis can be disastrous.
• Among the presentations of T1DM could be
some non-specific symptoms like vomiting,
abdominal pain….
 Diagnosis

• T2DM may present with late symptoms,

like numpness, disturbed vision,
generalized oedema.
• Patients with hypertension, dyslipidaemia,
MI and family history of diabetes are very
likely to develop T2DM.
Pathophysiology of T1DM

Absence of insulin secretion

Failure to use glucose as a fuel

Hyperglycaemia & using fat

Ketosis
 Pathophysiology of T1DM

• Possible contributing factors:

1. Autoimmune disease.
2. HLA typing
3. Viruses
4. chemicals
 Pathophysiology of T1DM

• Remission.

• The honeymoon period

 Pathophysiology of T2DM

Insulin resistance

hyperinsulinaemia

Relative hypoinsulinaemia

Hyperglycaemia, dyslipidaemia, atherosclerosis, HTN

 Pathophysiology of T2DM

• Causes of insulin resistance:

1. Hereditary.
2. Decreased glucose transporters.
3. Decreased insulin receptors
4. Post receptor mechanisms
5. Chemical mediators e.g. TNFα
 Pathophysiology of T2DM

• Loss of first phase of insulin secretion.

• Delayed insulin release.
Insulin
Insulin
Insulin
Insulin
 Insulin

• Action of insulin:
1. On glucose metabolism
2. On amino acid metabolism
3. On lipid metabolism
 Insulin

• Short acting
 Insulin

• Intermediate acting
 Insulin

• Peak less insulin

• Act for 24 hours no peak
 Insulin

• Premixed insulin
 Insulin

• Preparation of human insulin:

 Insulin

• Preparation of human insulin:

 insulin

• Plasmid preparation
 Insulin

• Absorption
 Insulin

• Variation of absorption:
1. Type
2. Dose
3. Site of preparation
4. Temperature.
5. circulation
 Insulin

• Storage of insulin
 Insulin

• injection
 insulin

• injection:
 insulin

• Devices
 Insulin

• Side effect:
1. Hypoglycaemia
2. Atrophy
3. Hypertrophy
4. Sensitivity
5. Weight gain
 Diet

• Rules:
1. Balanced meal
2. Maintain body weight
3. Adequate nutrition
4. Regular meal time.
Diet
OHA
 OHA

• Sulphonylureas:
1. Mode of action
2. Side effect
3. Differences
4. Use
 OHA

• Metformin:
1. Action
2. When to use
3. Side effects
4. Warning.
 OHA

• Acarbose
1. Action
2. Effect
3. Side effect use
 OHA

• Non Sulphonylureas insulin

secreatgauges:
1. Repaglinide
2. Natiglinide.
 OHA

• Insulin sensitizers:
1. Mode of action
2. Effect
3. Side effect
4. use
 Oral Antihyperglycemic Therapy for
Type 2 Diabetes: Scientific Review

• 63 published studies reviewed

• Individually, oral agents lower A1c 1-2 %
• In comparisons, roughly equal effects
• In combination, roughly additive effects
• Long-term benefits demonstrated only for
– Metformin and Sulfonylureas

SE Inzucchi. JAMA 2002; 287:360-372.

 Sulfonylureas
e.g. Chlorpropamide, Glyburide

• Mechanism
– Increase insulin secretion by pancreas
• Advantages
– Well established, Decrease microvascular
risk, Convenient dosing
• Disadvantages
– Hypoglycemia, Weight gain
• FDA Approval for combination therapy
– Metformin, TZD, acarbose

Adapted from SE Inzucchi, JAMA 2002; 287:360-372.

Nateglinide
 Non-SU Secretagogues
e.g. Nateglinide, Repaglinide

• Mechanism
– Increase insulin secretion by pancreas
• Advantages
– Targets post-prandial glycemia
• Disadvantages
– TID dosing, No long-term data
• FDA Approval for combination therapy
– Metformin
Adapted from SE Inzucchi, JAMA 2002; 287:360-372.
 Biguanides
e.g. Metformin

• Mechanism
– Decrease hepatic glucose production
• Advantages
– Well established, Weight loss, No hypoglycemia,
Decrease micro & macrovascular risk, Convenient
dosing, [Also prevents diabetes]
• Disadvantages
– GI distress, Lactic acidosis, Contraindications
• FDA Approval for combination therapy
– Insulin, SU and non-SU secretagogues, TZD

Adapted from SE Inzucchi, JAMA 2002; 287:360-372.

Miglitol
 Alpha-Glucosidase Inhibitors
e.g. Acarbose, Miglitol

• Mechanism
– Decrease gut carbohydrate absorption
• Advantages
– Targets post-prandial hyperglycemia, No
systemic absorption, [Also prevents diabetes]
• Disadvantages
– GI distress, TID dosing, No long-term data
• FDA Approval for combination therapy
– Sulfonylureas

Adapted from SE Inzucchi, JAMA 2002; 287:360-372.

 Thiazolidindiones
e.g. Pioglitazone, Rosiglitazone

• Mechanism
– Increase peripheral glucose disposal
• Advantages
– Physiologically “correct,” Convenient dosing,
[Also prevents diabetes]
• Disadvantages
– Liver toxicity, Liver monitoring, Weight gain,
Edema, No long-term data
• FDA Approval for combination therapy
– Insulin, sulfonylurea, metformin
Adapted from SE Inzucchi, JAMA 2002; 287:360-372.
 Retail Price ($ per month) of Selected
Antidiabetic Regimens

• Chlorpropamide 500 mg qD 18
• Glyburide (generic) 10 mg bid 48
• Glimepiride 8 mg qD 56
• Acarbose 100 mg tid 68
• Metformin (generic) 850 mg tid 78
• Nateglinide 120 mg tid 90
• Rosiglitazone 8 mg qD 130
• Repaglinide 4 mg tid 160
www.drugstore.com, August 2003
 Acute complications
of Diabetes Mellitus
Hypoglycaemia
 Hypoglycaemia

• Most common complication of diabetes

– 100% of Type 1 patients affected
– ~ 10%/year severe (requiring assistance)
– much less common in Type 2
• Multiple causes:
– exercise/activity drug overdose
– reduced food intake alcohol use
– delayed meal
 Symptoms of Hypoglycemia

Adrenergic Neuroglycopenic
tachycardia dizziness
palpitations confusion
sweating sleepiness
tremor coma
hunger seizure
 Hypoglycemia
Symptoms and Signs
• Sweating, tremors, pounding heart beats.
• Pallor, cold sweat, irritability
• May develop coma.

107
 Prevention of Hypoglycemia

• Consistent meal times, appropriate to drug

regimen
• Consistent carbohydrate intake, or matched
to drug dose
• Adjustments for extra exercise
– extra food, e.g. 15 gm carb/30 min
– reduce drug, e.g. prior dose by 20-30%
• Accurate drug dosing
• Blood glucose monitoring
 Treatment of Hypoglycemia

• Oral carbohydrate:
– 10-15 gms, repeat after 15 minutes if needed
– glucose tabs preferred; food acts slower, adds
unneeded calories (fat, protein)
• IV Glucose
– 20-50 cc of D50
• Glucagon
– 1 mg IM
Hyperosmolar Hyperglycemic
Nonketotic Syndrome
 Hyperosmolar Hyperglycemic
Nonketotic Syndrome

Clinical presentation
Severe hyperglycemia (BG > 600)
No or minimal ketosis
Hyperosmolarity
Profound dehydration
Altered mental status
 Causes of HHNS

• Drugs: glucocorticoids, diuretics

• Acute stressors: infection, burns, CVA,
MI, gastroenteritis
• Other chronic disease: renal, heart, old
stroke
• Procedures: surgery
 Prevention of HHNS

• Awareness of the syndrome

• Maintenance of adequate hydration
• Control of blood glucose during acute
stress with insulin
DIABETIC KETOACIDOSIS
 Diabetic Ketoacidosis

• An acute, life threatening metabolic acidosis

complicating IDDM and some cases of NIDDM with
intercurrent illness (infection or surgery)
• Usually coupled with an increase in glucagon
concentration with two metabolic consequences:
– 1) Maximal gluconeogenesis with impaired
peripheral utilization of glucose
– 2) Activation of the ketogenic process and
development of metabolic acidosis.
 Diabetic Ketoacidosis

• Usually seen in Type 1 DM, but CAN

OCCUR in Type 2
• Often with acute stress, such as infection,
MI, etc.
• Recurrent DKA almost always related to
omission of insulin, psychosocial problems
• Preventive measures same as for HHNS
 Clinical Presentation

• Anorexia, N/V, along with polydepsia and polyuria for

about 24 hrs. followed by stupor (or coma).
• Abdominal pain and tenderness could be present
(remember DDx of acute abdomen).
• Kussmaul breathing with fruity odor “acetone”
• Sings of dehydration (↑ HR, postural BP, etc.)
• Normal or low temperature:
NB.: if fever is present it suggests infection
while leukocytosis alone is not because
DKA per se can cause fever.
 Has to be treated in Hospital
Always refer to Endocrinologist

•Insulin: is a prerequisite for recovery

•IVF: the usual fluid deficit is 3-5L
•Potassium: replacement is always necessary
•Bicarbonate:
 Acute Complications of Diabetes

SUMMARY:

• Acute complications can be prevented or

greatly reduced
• Prevention depends on effective patient
education
Chronic complications
of Diabetes Mellitus
Causes of Death Among People With
Diabetes
Cause % of Deaths

Ischemic heart disease 40

Other heart disease 15
Diabetes (acute complications) 13
Cancer 13
Cerebrovascular disease 10
Pneumonia/influenza 4
All other causes 5

Geiss LS et al. In: Diabetes in America. 2nd ed. 1995:233-257.

Complications of Diabetes: Long term
– Macrovascular
• Ischaemic heart disease – heart attacks; stroke
• Peripheral vascular disease – gangrene,
amputations
– Microvascular
• EYE – retinopathy - blindness
• NERVE - neuropathy (peripheral and
autonomic)
• KIDNEY – nephropathy; dialysis
– Infections
 Magnitude of Problem

• Diabetic retinopathy: most common cause

of blindness before age 65
• Nephropathy: most common cause of
ESRD
• Neuropathy: most common cause of non-
traumatic amputations
• 2-3 fold increase in cardiovascular
disease
 Microvascular Complications

• Diabetic retinopathy
• background retinopathy
• macular edema
• proliferative retinopathy
• Diabetic nephropathy
• Diabetic neuropathy
• distal symmetrical polyneuropathy
• mononeuropathy (peripheral, cranial nerves)
• autonomic neuropathy
 Increased risk of complications
with lack of glucose control...
Only 27% of DM US patients
on OADs have HbA1c<7%**
15

13 Retinopathy
Relative Risk

Nephropathy
11
Neuropathy
9 Microalbuminuria
7

1
6 7 8 9 10 11 12
HbA1C (%)
*Endocrinol Metab Clin 1996;25:243 - 254 (Diabetes Control Complications Trial) ** NHANES III
 chronic complications*
population based - Egyptians
• prevalence known D new D
%
– retinopathy 41.5 15.7
– nephrop. 6.7 6.8
– neuropathy 21.9 13.6
– foot ulcers 0.8 0.8
• associations
ret; nephr; neuro : ↑ glucose

*microvasc + neuropathic; n: 1451

 Retinopathy and Blindness in
Diabetes Patients
– It is estimated that retinopathy affects 80%−97% of patients
with diabetes of ≥ 15 years’ duration
– Diabetes is the leading cause of new cases of blindness in
adults*
– Diabetic retinopathy accounts for the majority of
these cases
– Minimum cost of blindness for working-age adult is
estimated at $12,769 per year
*Blindness is defined as visual acuity ≤ 20/200
Klein R, Klein BEK. In: Diabetes in America. 2nd ed. 1995:293-338.
 Diabetic Retinopathy

• Background retinopathy
– present in 90% of patients after 10 years
– asymptomatic
– red dots (microaneurysms)
– dot, blot, and flame shaped hemorrhages
– hard waxy exudates of lipid and protein
– best detected by dilated eye exam or photos
Background Retinopathy
 Diabetic Retinopathy

• Macular edema
– sight threatening edema of the macula
– usually reduces visual acuity early
– can only be diagnosed by ophthalmologic
exam
– focal photocoagulation reduces risk of
blindness by 50%
 Diabetic Retinopathy

• Proliferative retinopathy
– growth of small, fragile blood vessels that may
bleed (vitreous hemorrhage)
– associated with growth of fibrous tissue that
may cause retinal detachment
– may occur on the optic disk or elsewhere
– high risk of blindness (50% in 3 years)
– hypertension, isometric exercise, high contact
sports may increase risk of bleeding
Preproliferative Retinopathy
 Kidney Disease in Diabetes Patients

– 27,851 new cases of ESRD in diabetes patients in 1995

• 40% of all new cases in the US
– Nearly 99,000 diabetes patients required dialysis or kidney
transplantation that year
– Annual cost of ESRD:
• $45,000 in diabetic patients ages 45−64

National Diabetes Fact Sheet. November 1, 1997:1-8.

U.S. Renal Data System, USRDS 1997 Annual Data Report.