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Type 1 & 2 Diabetes

Mellitus

Editing file

Objectives :
Type 1 DM:

★ Understand diabetes epidemiology in Saudi Arabia

★ Demonstrate physiology of insulin action
★ Demonstrate pathophysiology of T1DM
★ Differentiate treatment options for T1DM

Type 2 DM:

★ Explain the nature of type 2 diabetes mellitus

★ Know how to make the diagnosis in adults and pregnant Color index
★ Gain knowledge in the pathophysiology / females Original text
★ Gain knowledge in epidemiology and prevention Females slides
★ Be familiar with concepts of management including Males slides
pharmacotherapy
Doctor’s notes 438
Doctor’s notes 439
Text book
Important
Golden notes
Extra
Lecture Outline:

★ Intro
○ Insulin
○ Classification of DM
○ Clinical features of DM
○ Investigation

★ Type 1 DM
○ Definition: immune-mediated β cell destruction, usually leading to absolute insulin
deficiency.
○ Epidemiology: Accounts for 5-10% of all DM
○ Pathogenesis: Synergistic effects of genetic, immune, and environmental factors that
cause β cell destruction resulting in impaired insulin secretion. Autoimmune process is
believed to be triggered by environmental factors
○ Risk factors: Genetics + Environmental
○ Diagnosis :
○ Management: Insulin is always indicated in
people with type 1 diabetes

★ Type 2 DM You can check the Dr’s slides for more info regarding (pathogenesis & complications)

○ Definition: Ranges from predominantly insulin resistance with relative insulin deficiency to
a predominantly insulin secretory defect with insulin resistance 2o to β cell dysfunction
○ Etiology: Multifactorial (Diet, age, Obesity, Physical inactivity, Genetics, others)
○ Pathogenesis: 1. Abnormal insulin action 2. Abnormal insulin secretion
○ Diagnosis: Same as Type 1
○ Management:
■ Diet & Lifestyle modification
■ Oral Hypoglycemic drugs
■ Bariatric Surgery
 3
Introduction

Blood glucose is tightly regulated and maintained within a narrow range by insulin & glucagon. This is
essential for ensuring a continuous supply of glucose to the central nervous system.

●Insulin: the primary regulator of glucose metabolism and storage is secreted from pancreatic
β- cells into the portal circulation in response to a rise in blood glucose. The cleavage of
proinsulin (precursor molecule of insulin) produces C-peptide (connecting peptide) and insulin.
● After ingestion of a meal containing carbohydrate, normal blood glucose levels are maintained by:
○ Suppression of hepatic glucose production.
○ Stimulation of hepatic glucose uptake.
○ Stimulation of glucose uptake by peripheral tissues.
Insulin secretion in response to a glucose stimulus classically occurs in two phases (Biphasic):
- The rapid first phase represents the secretion of pre-formed insulin from granules
within the β cell. Mainly helps to prevent postprandial hyperglycemia
- Prolonged second phase is a consequence of newly synthesised insulin. It lasts over
1-2 hours until the blood glucose returns to normal
● Incretins are amino acids and hormones such as glucagon-like peptide 1 (GLP-1) and
gastrointestinal peptide (GIP) , released from the small intestines following food intake and
can augment insulin release. As a result, insulin release is greater when glucose is
administered by mouth than when the same rise in plasma glucose is achieved by
intravenous glucose infusion, a phenomenon termed the (incretin effect).

◄ Insulin secretion and action EXTRA

A.In Beta cells

Glucose enters Beta cell through facilitated diffusion mediated by GLUT2
1 (it is insulin independent)
1
Glucose get phosphorylated by glucokinase and enters Krebs cycle
2 (Glycolysis) to produce ATP
2
3 ATP closes potassium channels that normally secrets K out
3
Potassium increases intracellularly which will cause Depolarization
4
5 4 Ca channel opens (Voltage gated channel), Ca enters the cell leading to the
5 release of insulin from its vesicles by exocytosis

B.In Peripheral tissue ● Insulin & insulin-like growth factor binds to receptor and according to cell
needs it activate either one of two pathways:
Growth signal
● Cell proliferation
● Tissue development & differentiation
Metabolic signal:
● Regulation of energy metabolism (Glucose)
● It helps expressing GLUT4 to the cell membrane which facilitate
glucose entrance.
● Glucose get converted to glycogen for storage
 4
Introduction
◄ The physiology of insulin action
When The Level of Glucose is:
High Low
- Hormone: Insulin (Anabolic hormone)
- ↑ glycolysis - Hormones:
- ↑ ion uptake especially K and PO43- 1. Glucagon (Mainly)
- ↓Ketogenesis Other Counter regulatory
- Effect on Liver: hormones:
1. ↑ Glycogen synthesis 2. Glucocorticoids
2. ↓ Gluconeogenesis 3. Growth hormone
3. ↓ Glycogenolysis 4. Epinephrine
4. ↑ lipogenesis (FA synthesis) - Effect on Liver:
5. ↑ Lipoprotein synthesis 1. ↓ Glycogen synthesis
- Effect on Muscles: 2. ↑ Gluconeogenesis
1. ↑ protein synthesis 3. ↑ Glycogenolysis
2. ↓ Proteolysis - Effect on Muscles:
1. ↓ protein synthesis
- Effect on Adipose tissue: - Effect on Adipose tissue:
1. Inhibition of intracellular 1. No inhibition of intracellular
lipase > No lipolysis lipase > ↑ lipolysis > ↑ FFA
2. ↑ TGs deposition

◄ Classification of diabetes
Type 1 DM(Acute presentation) Type 2 DM(Chronic presentation)

due to a progressive insulin secretory defect on the

due to β- cell destruction, leading to absolute
Pathogenesis background of insulin resistance,Caused by obesity
insulin deficiency
mainly

Usually >30y/o: No HLA links but strong familial

Age and genetics Usually <30y/o : HLA-DR3 or DR4
predispositions

Weight 20% may be overweight/obese Virtually all BMI > 85%th percentile

Rapid Indolent
Course
From DPT-I can be indolent Virtually none found on screening

DKA (diabetic Ketonuria (33%)

35%-40%
ketoacidosis) Mild DKA (5%-25%)

5% with T1DM
Relative with DM Up to 30% may have with T2DM 74%-100% - 1st–2nd degree with T2DM
FH of T2 2-3Xs in person with T1

Increase in polycystic ovary syndrome, Acanthosis

Comorbid Thyroid, adrenal, vitiligo, celiac
nigricans

C- peptide C-peptide can be preserved at DX , eventually it Normal or increased

Used to differentiate
between T1DM and T2DM will disappear (more useful in T2)

Antibody 85% 15% (reported as high as 30%)

Ethnicity Whites predominate NA, AA, HA, Asian, Pacific Islander

 5
Introduction
◄ Classification of diabetes cont’
Gestational diabetes mellitus (GDM)

● Diabetes diagnosed in the second or third trimester of pregnancy that is not clearly overt diabetes
● After delivery blood glucose will return to normal. Each time they become pregnant there will be a 10% more
risk for developing permanent DM

Specific types of diabetes due to other causes:

● Monogenic diabetes syndromes: ● Diseases of the exocrine pancreas:

○ Such as neonatal diabetes and ○ Such as cystic fibrosis
maturity-onset diabetes of the young ● Drug or chemical induced diabetes:
[MODY] , which develops under the ○ Such as in the treatment of HIV/AIDS or after organ
age of 25 years, and neonatal diabetes transplantation
that presents during first 6 months of life. ○ E.g. SLE or RA due to steroids treatment (Improving
the primary disease will solve the problem)

◄ Clinical features

1 Acute presentation
● Children and young adults often present with a 2–6-week history of the classic triad of symptoms:

Polyuria Weight loss

due to the osmotic diuresis that results when due to fluid depletion and accelerated
blood glucose levels exceed the renal threshold breakdown of fat and muscle secondary to
insulin deficiency.
Thirst and polydipsia
Physiological response to diuresis to maintain
plasma volume

2 Subacute presentation
The clinical onset may be prolonged over several months or years, particularly in older people. Thirst,
polyuria and weight loss are usually present, but the individual may complain of other symptoms such as
lack of energy, visual blurring secondary to swelling of lens due to osmosis caused by hyperglycemia
(owing to glucose- induced changes in refraction), or pruritus vulvae or balanitis (inflammation of the
glans, or the head, of the penis) due to Candida infection. Because Candida albicans thrives under
increased glucose conditions

3 Complications
Complications as the presenting feature These include:
● Staphylococcal skin infections
● Retinopathy noted during a visit to the optician (Retinal Screening is recommended at the time of
diagnosis of type 2 and after 5 years in type 1)
● Polyneuropathy causing tingling and numbness in the feet
● Erectile dysfunction
● Arterial disease, resulting in myocardial infarction or peripheral gangrene (non-traumatic
amputation
 6
Introduction

4 Asymptomatic
Asymptomatic diabetes It is estimated that approximately half of people with diabetes are unaware of
their condition. up to one- third of diagnoses are made as an incidental finding and several countries have
introduced screening programmes to identify those with asymptomatic undiagnosed diabetes.

Once considered, diabetes is easy to diagnose.

◄ Investigations The diagnostic approach is the same for both T1 & T2

● Indications for testing:

- all symptomatic patients
- Asymptomatic patients with any of the following characteristics:
>45 years of age, History of pre-diabetes or gestational diabetes, Obese patients
● This may be by a laboratory measurement of:
1. fasting plasma glucose (FPG >120) (Specific)
2. (random glucose>200) (Sensitive)
3. 2-hour plasma glucose after a 75- g oral glucose tolerance test (OGTT>200) (Sensitive & Specific)
4. The use of glycated haemoglobin (HbA1c>6.5)was introduced as an alternative method in 2011. it
is also used to guide treatment decisions.
● The diagnostic criteria recognize two further categories of abnormal glucose concentrations:
1. impaired fasting glycaemia (IFG)
2. impaired glucose tolerance (IGT)
● Collectively these have been described as ‘pre-diabetes’ but this is not strictly accurate
because the majority will never develop diabetes. (⅓ will develop DM)
● Neither IFG nor IGT are clinical entities in their own right but they identify people who are at
high risk of diabetes and cardiovascular disease.
● Individuals with IGT have a similar risk of cardiovascular disease as those with frank
diabetes, but do not develop microvascular complications.

This criteria will diagnose DM but will not

differentiate between T2DM and T1DM.
One abnormal laboratory value is diagnostic in
symptomatic individuals; two values are needed
in asymptomatic people. The glucose tolerance
test is only required where there is diagnostic
uncertainty and for diagnosis of cystic
fibrosis-related diabetes and gestational diabetes.

IFG and IGT are associated with insulin resistance syndrome or syndrome X:
- insulin resistance - Dyslipidemia (High triglycerides and\or low HDL)
- Hyperinsulinemia - Hypertension
- Obesity
 7
Introduction

Glycosuria:
● Cannot be used to diagnose diabetes, but requires further investigation.
● It is commoner in older people, who have an altered renal threshold for glucose.
● It may also occur in familial renal glycosuria, which is a monogenic disorder affecting function of the
sodium–glucose co- transporter (SGLT2) and found in about 1 : 400 of the population.

● Other investigations:
○ No further tests are needed to diagnose diabetes, but measurement of C-
peptide and islet autoantibodies can help determine the type of diabetes.
○ C- peptide can be measured in blood or urine; it is often present when type 1
diabetes is diagnosed but disappears with time and is a more useful
investigation in people with a duration of diabetes longer than 5 years.

● Routine investigations:
○ include urine testing for protein, a full blood count, urea and electrolytes, liver biochemistry
and random lipids.
● Secondary causes:
○ Investigations of secondary causes of diabetes or associated autoimmune disease may be
appropriate

Type 1 DM

◄ What is Diabetes ?
● Diabetes is a complex, chronic illness requiring continuous medical care with multifactorial
risk-reduction strategies beyond glycemic control. Ongoing patient self-management education and
support are critical to preventing acute complications and reducing the risk of long-term
complications.

◄ DM Epidemiology and Burden

● Diabetes was the 7th leading cause of death in 2010 behind Ischemic heart disease (1st leading
cause) and chronic Kidney disease (6th leading cause). Recall DM increases the risk of IHD and CKD.
● Type 1 diabetes is a disease of insulin deficiency and accounts for 5–10% of all cases of diabetes. It
typically presents in childhood and young adulthood, reaching a peak incidence around the time of
puberty, but can present at any age.
 Type 1 DM 8

◄ Pathogenesis
● T1DM is the result of interactions of genetic, environmental, and immunological factors that
ultimately lead to the destruction of the pancreatic Beta cells and insulin deficiency.
● It can develop at any age, but most commonly < 30
● Type 1 diabetes is associated with other organ-specific autoimmune diseases including
autoimmune thyroid disease, coeliac disease, Addison’s disease and pernicious anaemia.
● The precise molecular mechanisms that lead to type 1 diabetes are incompletely understood but
involve the triggering of a selective autoimmune destruction (Most, but not all, individuals have
evidence of islet-directed autoimmunity) of the insulin producing cells of a genetically predisposed
individual.
● Initially, autoantibodies directed against pancreatic islet constituents appear in the circulation and
often predate clinical onset by many years.
● The islet antigens include:
○ insulin itself, the enzyme glutamic acid decarboxylase (GAD), protein tyrosine phosphatase
(IA-2, also known as ICA512), the cation transporter ZnT8 and tetraspanin 7.
● This is followed by a phase of asymptomatic loss of β cell secretory capacity:
○ histologically, this is characterized by a chronic inflammatory mononuclear cell infiltrate of T
lymphocytes and macrophages in the islets, known as insulitis . Eventually, when the
remaining β cells are no longer able to produce enough insulin to meet the body’s needs,
diabetes symptoms start to develop.

Note that T1DM arrow is uni-directional

and has rapid onset (unlike T2DM which
has indolent course). T1DM pts need
insulin for SURVIVAL unlike T2DM.

Quick Recap
● Insulin is anabolic Hormone
● T1DM is genetic predisposition .ex (HLA-DR3 or DR4) , result in B cell destruction and insulin
deficiency
● T2DM caused by obesity mainly, result in Insulin Resistance
● When do T2DM symptoms appear? When the patient loses ⅔ of the Beta cell mass
● Symptoms are the same in both types of Diabetes
● FPG and HBA1C are the most specific Diagnostic Tests
 Type 1 DM 9

◄ Risk factors

Genetics

● Increased susceptibility to type 1 diabetes is inherited but the disease is not genetically
predetermined. The identical twin of a person with type 1 diabetes has a 30–50% chance of
developing the disease, which implies that non- genetic factors must also be involved.
● The risk of developing diabetes by age 20 years is greater with a father with diabetes (5–7%) than
with a mother with diabetes (2–5%).
● If one child in a family has type 1 diabetes, each sibling has a 4–6% risk of developing diabetes.
● This risk rises to about 20% in siblings with the same human leukocyte antigen (HLA) genotype as
the proband.
● HLA genes are highly polymorphic and modulate the body’s immune defence system.
● More than 90% of people with type 1 diabetes carry HLA- DR3-DQ2, HLA- DR4-DQ8 or both, as
compared with some 35–40% of the background population. By contrast, certain HLA alleles
confer protective effects, for example DQB1*0602.

Environmental

● Maternal factors, such as gestational infection and older age

● Viral infections, including enteroviruses such as Coxsackie B4
● Exposures to dietary constituents, such as early introduction of
cow’s milk and relative deficiency of vitamin D
● Environmental toxins e.g. alloxan, Vacor
● Childhood obesity
● Psychological stress.

◄ Presentation Click here to go back to slide 4

Blurred Lack of energy Constant

vision and fatigue hunger

Excessive Bedwetting Frequent Sudden

thirst Urination weight Loss1

◄ Diagnosis Click here to go back to slide 5

1-Sudden weight loss is more specific for T1DM, the reason behind this is that T1DM pts are insulin deficient (Recall that
insulin has an anabolic effect). T2DM may also present with weight loss but this would occur very late, unlike T1DM which
presents from the beginning.
 Type 1 DM 10

◄ Management
◄ Goals of therapy
Through appropriate meds and education
● Eliminate symptoms related to hyperglycaemia
● Reduce risk or eliminate diabetes complications such as diabetic
ketoacidosis and hypoglycaemia with effective management when
they do occur.
● Allow patient to achieve as normal lifestyle as possible
● Avoidance of iatrogenic side-effects,such as hypoglycaemia.
● Regular physical activity, healthy diet, fast and long acting insulin Insulin treatment allows for a dramatic
are necessary in treating T1DM recovery in patients with Type 1 diabetes
With insulin treatment there is weight
gain because of the ability of the
tissues to use glucose

◄ Insulin is necessary for survival

● Type 1 diabetes is an autoimmune disease leading to β-cell destruction, lack of insulin production
and a need for life-long insulin therapy. Insulin is always indicated in people with type 1 diabetes and
is often needed in those with type 2 diabetes as the condition progresses.
● Until 1922, the treatment for Type 1 diabetes was a ‘starvation diet’ – reducing patients to emaciation
and subjecting them to a life of misery.
● Prior to discovery of insulin in 1921, the life expectancy of people with type 1 diabetes was only 3–4
months.
● The work of John Macleod, Frederik Banting and Charles Best with their patient, Elizabeth Hughes
(right), led to the widespread use of insulin injections as a treatment for Type 1 diabetes.
● The philosophy of insulin therapy is to mimic the normal physiological secretion of insulin as
closely as possible. This involves the use of both long-acting insulin to replicate the basal
secretion of insulin and short-acting insulin to cover mealtimes.

◄ Insulin deficiency
● In type 1 Diabetes:
There is a loss of both first and second phase of insulin secretion.
● In type 2 Diabetes:
In the early stage of the disease there is loss of the first phase of
insulin secretion. Phase 2 will become wider then it will gradually
reduce to reach a stage of severe insulinopenia.

The basal/bolus insulin concept

Basal Insulin Bolus Insulin (Mealtime or Prandial)

- Suppresses glucose production between - Limits hyperglycemia after meals

meals and overnight - Immediate rise and sharp peak at 1 hour
- 50% of daily needs - 10% to 20% of total daily insulin requirement
at each meal
 Type 1 DM 11

◄ Management cont’
Types of insulin

Insulin type (trade name) Onset Peak Duration Characteristics

Bolus (preprandial or mealtime) insulins

Enter the circulation more rapidly than

Rapid-acting insulin analogues (clear)
human soluble insulin, and also
● Insulin aspart (NovoRapid®) 9-20min 1-1.5h 3-5h
disappear more rapidly.
● Insulin glulisine (Apidra®) 10-15min 1-1.5h 3.5-5h
-5-10 minutes before meal
● Insulin lispro (Humalog®) U-100 U-200 10-15min 1-2h 3-4.75h
-Used in ER in Case of DKA
● Faster-acting insulin aspart (Fiasp®) 4min 0.5-1.5h 3-5h

The use of short- acting insulin analogues

in people with type 1 diabetes reduces
total and nocturnal hypoglycaemic
episodes and improves glycaemic control
Short-acting insulins (clear)
as judged by postprandial glucose
● Insulin regular [Humulin®-R,
30min 2-3h 6.5h concentrations and HbA1c.
Novolin® ge Toronto]
15min 4-8h 17-24h Used for pre-meal injection in multiple
● Insulin regular (Entuzity® (U-500)
dose regimens, during medical
emergencies, and in patients using insulin
pumps.
-Can be used by pregnant women

Basal insulins

Has the advantage that it can be

premixed with soluble insulin to form
Intermediate-acting (cloudy) stable mixtures (biphasic insulins).
● Insulin neutral protamine Its use is hampered by variability from one
1-3h 5-8h Up to 18h
Hagedorn (Humulin® -N, Novolin® injection to another, the need to
ge NPH) resuspend the insulin prior to injection
and a peak action, which generally occurs
in the middle of the night.

Long-acting insulin (clear)

U-100
● Insulin detemir (Levemir®)
glargine 24h, Long- acting insulin analogues reduce
● Insulin glargine U-100 (Lantus®)
Not detemir hypoglycaemia for people with both type
● Insulin glargine U-300 (Toujeo®) 90min
applicable 16–24h U-300 1 diabetes and type 2 diabetes,
● Insulin glargine biosimilar
glargine >30h particularly at night.
(Basaglar®)
degludec 42h
● Degludec U-100, U-200 (Tresiba®)

Premixed insulins1

Premixed regular insulin –NPH (cloudy)

● Humulin 30/70 A single vial or cartridge contains a fixed ratio of insulin
● Novolin® ge 30/70, 40/60, 50/50

Premixed insulin analogues (cloudy)

● Biphasic insulin aspart (NovoMix®
30) (% of rapid-acting or short-acting insulin to % of intermediate-acting insulin)
● Insulin lispro/lispro protamine
(Humalog® Mix25 and Mix50)

1- Not preferred for T1DM, although it may have some indication in pediatric. We also give premixed insulin in T2DM in case
uncontrolled diabetes and Hb1c >10
 Type 1 DM 12

◄ Management cont’
◄ Available Therapeutic Regimens
1. CT = Conventional Therapy (1 or 2 injections / day)
a. Conventional therapy is an old regimen, not recommended anymore, especially for
adults (It may have some indications in pediatrics)
2. MDI = Multiple Daily Injections (3 – 6 injections / day)
a. MDI is the preferred regimen for adults
3. CSII = Continuous S.C Insulin infusion “insulin pump “ (More flexible)

◄ Prandial and basal insulin replacement

(intermediate & short acting insulin)

Before meals : diabetic patients takes short acting insulin which is
regular insulin used to cover the daily need of the insulin after meals.
Before sleeping : no need for strong and fast action because glucose
levels before sleeping not high like after meals so, to avoid
hypoglycemia and coma the patients takes instead of short acting
insulin the insulin intermediate.

(intermediate & Ultra short acting insulin)

Same idea but the short acting insulin is replaced with the ultra-short
acting insulin which has a rapid effect As long as the body needs the
insulin as a basal level between meals , the patients take double dose of
the insulin intermediate to control the glucose level for the whole day
not only before meals or sleeping time.

(Insulin mixture(combination) = intermediate + short acting

insulin)4
Is a helpful drug to reduce the use of injections for the diabetic patients
and provide a basal level of insulin during the day and once the patient
eat a meal short acting insulin is ready.
 Type 1 DM 13

◄ Insulin complications

Hypoglycaemia insulin resistance

The most common

Weight gain (overcome by

emphasis on the need for diet and Peripheral oedema (insulin
exercise, plus addition of treatment causes salt and water
metformin) retention in the short term)

Insulin antibodies Local allergy (rare)

Lipohypertrophy or lipoatrophy at
injection sites (result of overuse
of a single injection site )

◄ The power of diabetes control

50% less 70-76% less

60% less neuropathy retinopathy
nephropathy

◄ Key messages
● Basal-bolus insulin therapies (i.e. multiple daily injections or continuous subcutaneous insulin
infusion) are the preferred insulin management regimens for adults with type 1 diabetes.
● Insulin regimens should be tailored to the individual's treatment goals, lifestyle, diet, age, general
health, motivation, hypoglycemia awareness status and ability for self-management.
● All individuals with type 1 diabetes should be counselled about the risk, prevention treatment of
hypoglycemia.
● Avoidance of nocturnal hypoglycemia may include changes in insulin therapy and increased
monitoring.
● If glycemic targets are not met with optimized multiple daily injections, continuous subcutaneous
insulin infusion may be considered. Successful continuous subcutaneous insulin infusion therapy
requires appropriate candidate selection, ongoing support and frequent involvement with the health-
care team.
● Continuous glucose monitoring may be offered to people not meeting their glycemic targets, who wear
the devices the majority of the time, in order improve glycemic control.
 Type 2 DM 14

◄ Obesity & T2DM in SA much more common than (T1DM)

● Elevated BMI (>25) is associated with an increased risk for the development of type 2 diabetes.
○ Prevalence of type 2 diabetes closely matches the prevalence of obesity.
● The prevalence of overweight was 36.9%.
○ The age-adjusted prevalence of obesity was 35.5% in KSA.
○ Females are significantly more obese with a prevalence of 44% than males 26.4% .
● The overall prevalence of DM obtained from this study is 23.7% in KSA.
○ The prevalence in males and females were 26.2% and 21.5%
○ Diabetes mellitus was more prevalent among Saudis living in urban areas of 25.5% compared
to rural Saudis of 19.5%
○ 27.9% were unaware of having DM
● Diabetes kills 1 Saudi every 30 minutes, New case diagnosed every 2 MINUTES
● More deaths than TB and breast cancer combined1
● Average life expectancy: 15 years less than non-diabetes population 2 Million

◄ Etiology
A. Diet:
● Certain dietary patterns are associated with higher or lower risks of type 2 diabetes.
● Components that increase the risk include:
dietary fat, particularly saturated fat, red and processed meat, consumption of fried food,
including French fries, increased intake of white rice and sugar-sweetened beverages.
● The following are associated with lower rates of T2DM:
Wholegrains, increased fruit and vegetable intake, fermented dairy products, oily fish and
a Mediterra- nean dietary pattern are associated with

B. Ageing:
● Pancreatic B-cell function declines with age and the incidence of type 2 diabetes
increases with age

C. Obesity:
● Obesity increases the risk of type 2 diabetes up to 80-100-fold and accounts for 80-85% of
the overall risk of developing type 2 diabetes. A central distribution of fat increases the
risk of type 2 diabetes, and so for any given level of obesity, the more visceral fat an
individual has, the higher the risk of type 2 diabetes.

D. Fetal origins of diabetes:

● There is a J-shaped relationship between low weight at birth and at 12 months of age and
glucose intolerance later in life, particularly in those who gain excessive weight in
adulthood. The concept is that poor nutrition early in life impairs B-cell development
function, predisposing to diabetes later on.

E. Physical inactivity:
● Associated with an increased risk of diabetes.

1- But it’s not recorded in the death certificate bc it’s not the direct cause
 Type 2 DM 15

◄ Etiology cont’
F. Genetic susceptibility and inheritance
● Identical twins of people with type 2 diabetes have more than a 50% chance of developing
diabetes: the risk to non-identical twins or siblings is approximately 25%, confirming a
strong inherited component to the disease.
● Most of the identified genetic markers exert very modest risk and together explain less than
20% of the heritability of type 2 diabetes.

G. TNF-alpha may induce insulin resistance in obesity from the slides

● The cytokine tumour necrosis factor - 𝞪 (TNF- 𝞪) is produced from adipose tissue, and TNF-𝞪
levels are often elevated in obesity.
● Administration of TNF - 𝞪 leads to insulin resistance.
● Over-expression of TNF-𝞪 in adipose and muscle of obese, insulin resistant diabetic subjects is
positively corrrelated with insulin resistance.
● Polymorphisms at the TNF-𝞪 locus correlate with insulin resistance.
● TNF-𝞪 inhibits insulin receptor signalling in adipocytes.
● TNF-𝞪 deficiency (knockout mice) prevents diet-induced insulin resistance.

H. Other factors
● Other risk factors include urbanization, poverty, abnormal sleep patterns, environmental
toxins and mental illness, High-risk ethnic or racial group, Diabetes mellitus in a first-degree
relative, History of vascular disease

◄ Pathogenesis
★ Both defects are necessary to develop diabetes.

Abnormalities of insulin action

1
Insulin resistance, which is defined as the inability of insulin to produce its usual biological effects at
physiological concentrations. It is characterized by an impaired ability of insulin to:

Inhibit hepatic glucose output Stimulate glucose uptake into skeletal muscle

Suppress lipolysis in adipose tissue.

● The underlying mechanisms of insulin resistance are not fully understood but result from
nutrient excess.
Hyperglycemia alone will lead to
microvascular complications. If combined
with other factors (e.g. Obesity, smoking
etc.) it will lead to macrovascular
complications. Microvascular complications
causes morbidity and macrovascular causes
mortality. You should deal with (B) and (C)
not only (A), bc for example a pt with
retinopathy may become blind in 10yrs, so
refer to ophtha early.
 Type 2 DM 16

◄ Pathogenesis cont’
Abnormalities of insulin secretion
2
● As insulin resistance develops, the body's response is to increase insulin secretion and so
01 early diabetes is often associated with insulin hypersecretion.
● Insulin secretory abnormalities manifest early in the course of type 2 diabetes and progress with
time; an early sign is loss of the first phase of the normal biphasic insulin secretion.

● Even though circulating insulin concentrations are higher than in people without diabetes, they

02 are still inadequate to restore glucose homeostasis. By the time of diagnosis, at least 50% of
B-cell mass and function has been lost.
● Hyperglycaemia and lipid excess are toxic to ß cells, at least in vitro, a phenomenon known as
glucotoxicity, which is thought to cause further B-cell loss and further deterioration of glucose
homeostasis. With time, insulin secretion declines, an observation referred to as the 'Starling
curve' of the pancreas.

I. Disrupted pulsatile
insulin response
II. ↓first phase
III. ↑Proinsulin / insulin ratio
IV. ↓𝛽-cell responsiveness to
glucose
V. ↓insulin production
- ↓insulin
- ↓insulin granules

Abnormalities of 𝛽-cell Function in

Type 2 Diabetes

In summary, the
pathogenesis of type 2 DM:
Relative insulin secretion loss
and/or decrease in insulin
sensitivity (increase in insulin
resistance)

◄ Clinical features Click here to go back to slide 4

◄ Diagnosis Click here to go back to slide 5

1. Gold standard for the diagnosis of DM is HbA1C because it is stable, accurate if done in qualified lab
and has no much variability.
2. Retinopathy in DM is unique and can be used as a marker as it is different than other types of
retinopathy like in HTN and other diseases.
 Type 2 DM 17

◄ Management of T2DM

● Diet and lifestyle changes are the key to successful treatment of type 2 diabetes. Medication
should never be prescribed until lifestyle changes have been implemented.
● The three main options are metformin, a sulfonylurea or a thiazolidinedione.
● If control is inadequate (if HbA1c > 10% ) oral therapy, insulin therapy should be started without
undue delay
● DM management depends on hyperglycemia, microvascular complications and macro-vascular
together.

Better control means fewer complications

Every 1% reduction in HBA1C REDUCED RISK

Deaths from diabetes 21%

Does it work? YES see on the right Heart attacks 14%

where treatment has decreased the
microvascular complication by about Microvascular complications 37%
37% for every 1% decrease in HBA1C
Peripheral vascular disorders 43%

Diet & lifestyle modifications:

● All patients with diabetes require healthy diet therapy

● Reducing alcohol consumption and stopping smoking
● Weight management and regular exercise is encouraged to reduce cardiovascular risk
● Exercises increase muscular insulin sensitivity.
● Dietary advice:
1. Salad: 1hour BEFORE the meal
2. 1⁄4 - 1⁄2 what you are used to. No cheating. 3. 1 Fruit per meal (juice is fruit)
4. 2 DATES BID (1 extra date BID)
5. No Communal eating
6. Avoid what you can live without.

Oral Hypoglycemic drugs:

HgbA1c targets:
● 7%: Early young without atherosclerosis (AT)
● 8%: Late old
● In diabetic older patients with AT the target of HbA1C is 8% and there is no evidence that 7 better
than 8, while in younger patients with no AT the target i
 OBJ. Type 2 DM 18

Oral Hypoglycemic drugs:

Insulin Sensitizers with predominant action in the liver (Biguanides: metformin)

● Stimulate skeletal muscle glucose uptake and inhibition of hepatic gluconeogenesis

MOA
● increases insulin sensitivity, peripheral glucose utilization and reduces gluconeogenesis

● Metformin is the best-validated treatment for type 2 diabetes and appears as the first-line
pharmacological agent in all type diabetes guidelines.
Clinical ● Metformin may be given in combination with other oral diabetes treatments as well as GLP-1 receptor
use agonists or insulin. It lowers fasting plasma glucose by 2-4 mmol/L (36–72 mg/dL), corresponding to a fall
in HbA1c of 11-22 mmol/ mol (1-2%).
● Metformin has been used alongside insulin in people with type 1 diabetes but only with limited efficacy.

● Gastrointestinal side-effects such as: anorexia, nausea, abdominal discomfort and diarrhoea. the most
common. It can also cause vitamin B12 deficiency (decreased absorption).
● The effects can be mitigated by starting at low dose and gradually increasing until the desired
therapeutic effect is achieved.
● Contraindicated in: renal impairment, cardiac failure and hepatic failure because of the risk of lactic
Adverse acidosis.
effects ● Should be stopped temporarily around surgery or during other intercurrent illnesses that may affect
lactate clearance.
● Should be avoided in people with a history of alcohol misuse.
● Should not be started in someone whose estimated glomerular filtrate (EGFR) is less than 45 mL/min per
1.73m2 and should be stopped if the eGFR falls below 30 mL/min 1.73m2.
● Does not cause weight gain and it’s not associated with with a significant risk of hypoglycemia

Sulphonylureas

Chlorpropamide, Tolazamide, Gliclazide, Glimepiride, Glibenclamide (aka glyburide) , Glipizide, Tolbutamide

● Act on the B cell to induce insulin secretion.

● They are ineffective in people without a functional B-cell mass and therefore have no effect in people
MOA
with type 1 diabetes.
● Has a long half-life and has an effect on both pre-prandial and post-prandial

● Most clinical guidelines recommend that sulphonylureas can be used as an alternative first-line agent
Clinical where metformin is contraindicated or not tolerated.
use ● As monotherapy, sulphonylureas typically reduce fasting plasma glucose by 2–4 mmol/L (36–7 to a fall in
HbA,c of 11–22 mmol/mol (1-2%). g/dL), corresponding.

● Weight gain, typically 1-4 kg, and hypoglycaemia are the most common side effects.
● The risk of hypoglycaemia is increased with longer acting sulphonylureas, excessive alcohol intake, older
age and during intercurrent infection.
Adverse ● Severe sulphonylurea-induced hypoglycaemia should be managed in hospital for up to 48 hours with
effects glucose support until the drug has cleared from the circulation.
● Contraindicated in renal failure and hepatic failre.
● Glibenclamide is best avoided in renal failure and the elderly b/c of its relatively long duration of action
(12-20 hours) and renal excretion)
 Type 2 DM 19

Thiazolidinediones : pioglitazone, rosiglitazone

● Reduce insulin resistance by interaction with peroxisome proliferator-activated receptor-gamma

(PPAR-Y), a nuclear receptor that regulates large numbers of genes, including those involved in lipid
MOA metabolism and insulin action. It leads to an improvement in glycemic control over weeks to months in
parallel with an improvement in insulin sensitivity and a reduction in FFA levels.

● Can be used as monotherapy or in combination with other antidiabetic drugs, including insulin.
● Thiazolidinediones do not cause hypoglycemia as monotherapy.
Clinical
● Pioglitazone may specifically benefit people with non-alcoholic fatty liver disease, a frequent
use co-morbidity of type 2 diabetes. As the effect on plasma glucose is indirect, thiazolidinediones may take
up to 3 months to reach their maximal effect.

● The most common adverse effect is weight gain of 5-6 kg.

● Pioglitazone may cause fluid retention (and associated edema formation and hemodilution)
precipitating heart failure.
Adverse
● Increased risk of bone fractures
effects ● May cause anemia and osteoporosis. There is possible increase in risk of bladder cancer.
● Contraindicated in pts with active hepatocellular disease and in patients with unexplained serum ALT
levels greater than 2.5 times the upper limit of normal

Meglitinides or post-prandial insulin releasers

Repaglinide, Nateglinide

● Short-acting agents that promote insulin secretion in response to meals. Mode of action Like
sulphonylureas, meglitinides act by closing the K*-ATP channel in the ß cells have a short duration of
MOA
action of less than 3 hours.
● They were designed to restore early-phase post-prandial insulin release.

● Meglitinides may be used to treat people with post-prandial hyperglycaemia with normal fasting
Clinical
glucose levels.
use ● Suitable for use in diabetic pts with IRF or with renal failure undergoing dialysis

Adverse ● Hypoglycaemia and weight gain are the most common adverse effects but these are generally less
effects severe than with sulphonylureas.

Dipeptidyl peptidase-4 (DPP4) inhibitors or 'gliptins

Sitagliptin, Linagliptin, Vlidagliptin, Alogliptin, Saxagliptin

gliptins are one of two classes of drug that improve glycaemic control by enhancing the incretin effect

● These drugs inhibit the enzyme DPP4, which prevents the rapid inactivation of glucagon-like peptide-1
MOA
(GLP-1), which in turn increases insulin secretion and reduces glucagon secretion.

● DPP-4 inhibitors are most effective in the early stages of type 2 diabetes, when insulin secretion is
relatively preserved, and are currently recommended for second-line use in combination with
Clinical
metformin or a sulphonylurea.
use ● They’re not associated with nausea because of the lesser increase in GLP-1 activity
● Weight affect neutral

● Contraindication: history of pancreatitis, and advanced kidney disease (eGFR ,30 mL/minute per 1.73m2),
Adverse except linagliptin which can be used.
effects ● Occasional reports of acute pancreatitis.
● Saxagliptin may increase the risk of heart failure and hospitalization.
 Type 2 DM 20

Sodium-glucose transporter 2 inhibitors ('flozins')

Dapaglilozin ,Empaglilozin, Canaglilozin

In addition to their effects on blood glucose, they lower body weight, improve renal dysfunction and reduce
the risk of atherosclerotic cardiovascular events and heart failure.

● They work by blocking the SGLT2 protein located in the proximal convoluted tubule of the
nephron resulting in glycosuria and thereby lowering plasma glucose concentration.
● Lower the renal threshold for glucose, consequently increasing urinary glucose
MOA
excretion.lowering blood glucose by 7-13 mmol/mol (0.6-1.2%) and facilitating weight loss
● Exactly how SGLT2 inhibitors reduce the risk of myocardial infarction, stroke, cardiovascular
death heart failure is uncertain.

● can be used as monotherapy but are used more typically in combination with all other
antidiabetes drugs.
● Beneficial effect include weight reduction, positive cardiovascular outcome (all cause mortality,
Clinical
nonfatal stroke , and nonfatal MI),and lower hospitalization for heart failure.
use
● This class has become rapidly established in clinical practice and in type 2 diabetes guidelines
because of their cardiovascular benefits, weight loss and low risk of hypoglycaemia. SGLT2
inhibitors are licensed as adjunctive therapy to insulin in type 1 diabetes.

● The most common adverse effects are genital candidiasis and dehydration.
Adverse ● .Associated with risk of diabetic ketoacidosis, dehydration, increased incidence of genitourinary
effects tract infection “fungal”.
● Canagliflozin :- increased risk of fracture and toe amputation.

Alpha-glucosidase inhibitors

Acarbose ,Miglitol ,Voglibose

● Prevent a-glucosidase, the last enzyme involved in carbohydrate digestion, from breaking
MOA down disaccharides to monosaccharides. This slows the absorption of glucose after a meal
and lowers post-prandial glucose.

● Can be used as monotherapy or in combination with all other antidiabetes drugs, they are not
Clinical
widely used because of their limited efficacy and gastrointestinal side-effects.
use
● Doesn’t cause hypoglycemia and it is weight neutral

Adverse ● The major side-effects are gastrointestinal and include flatulence, abdominal distension and
effects diarrhoea, as unabsorbed carbohydrate is fermented in the bowel.
 Type 2 DM 21

GLP-1 receptor agonist

Exenatide: Liraglutide: Lixisenatide

Twice daily once daily Dulaglutide
2 doses: 5 mg- 10 mg 3 doses: 0.6, 1.2, 1.8 mg Semaglutide
weight reduction HbA1c :0.8- 1.8 Albiglutide

GLP-1 receptors are a heterogeneous class of drugs that act by enhancing the incretin effect.

● GLP-1 is produced in intestinal L cells and is secreted in response to nutrients

● GLP-1 stimulates insulin secretion in a glucose dependent fashion, inhibits inappropriate
hyperglucagonemia, slows gastric emptying, reduces appetite and improves satiety
● It has a very short life in plasma (1 to 2 minutes) due to aminoterminal degradation by the enzyme (DPP4)
MOA ● Unlike DPP-4 inhibitors that restore physiological GLP-1 levels, GLP-1 receptor agonists achieve
pharmacological levels and are therefore more potent that DPP-4 inhibitors. In addition to their effects
on the pancreas to increase insulin secretion and decrease glucagon, they also act on the hypothalamus
to reduce appetite and food intake leading to weight loss. The size of effect has led to the licensing of
liraglutide as an anti-obesity treatment.

● Despite the need for injection, clinical guidelines endorse their use and GLP-1 receptor agonists are now
widely used in combination with other antidiabetic agents, as second- or third-line therapies. They
Clinical should not be combined with DPP-4 inhibitors as the DPP-4 inhibitor does not confer any additional
use benefit.
● Beneficial effect include weight reduction, positive cardiovascular outcome (all cause mortality, non fatal
stroke, and non fatal MI ) and reduction HbA1c

The most common side-effects of GLP-1 receptor agonists are gastrointestinal and include nausea and vomiting,
bloating and diarrhoea. There is a low risk of hypoglycaemia but this may occur if GLP-1 receptor agonists are
Adverse
combined with insulin or sulphonylureas. GLP-1 receptor agonists should not be used in people with a history of
effects pancreatitis because of a risk of acute pancreatitis. It may also induce weight loss (approx. 3-6kg) but most
pts will regain the weight once the medication is stopped

Recommend treatment Algorithm for Middle East

The choice of medication depends on a few things: Note that in the triple
1- Socio-economic status: For example if the pt is a driver therapy there are 10 drug
then you shouldn’t use SUs, insulin. Or if the pt is the one groups, and in each group
paying for the meds, you shouldn’t use expensive drugs. If there are at least 4-5
the pt lives alone or blind then you shouldn’t give insulin drugs. if you were to
2- Presence of vascular complications: For example if you choose 3meds from these
give insulin and they develop hypoglycemia → fall → groups, there will be 1440
break their leg, this is probably worse than DM itself.
possible combination
3- Patient age
(And it’s impossible to
4- Disease duration
5- History of hypoglycemia determine what fits the pt
best).
 Type 2 DM 22

◄ Management of T2DM cont’

Complications of Bariatric Surgery:

● Bariatric or metabolic surgery is a treatment option for people with severe obesity. The National
Institute for Health and Care Excellence (NICE) recommends consideration of surgery in those with a
(BMI) higher than 40 kg/m2 , or in those with a BMI of more than 35 kg/m 2 and co-morbidities,
such as diabetes.
● Not recommended, Why?:
○ Bc it’s SURGERY
○ In 5yrs most of the pts will regain all the weight they’ve lost.
○ It’s not effective in those who have been suffering from DM for a long time bc they probably already
have extreme insulin deficiency

● Atelectasis and pneumonia ● Gallstones

1- Complications ● Deep vein thrombosis ● Failure to lose weight
of all ● Pulmonary embolism ● Intractable
Procedures ● Wound infection vomiting/kwashiorkor (B1)
● Gastrointestinal bleeding ● Mortality (0.1%–2%)

● Band slippage
2- Complications ● Band erosion
of Gastric ● Esophageal dilatation
banding ● Band or port infections
procedure ● Port disconnection
● Port displacement

● Anastomotic leak with peritonitis ● Nutrient deficiencies (iron,

3- Complications ● Stomal stenosis calcium,folic acid, vitamin B12)
of Gastric ● Marginal ulcers ● Dumping syndrome
bypass ● Staple line disruption ● Small bowel obstruction:
Internal hernia - Adhesions

● Anastomotic leak with peritonitis

● Protein-calorie malnutrition
4- Complications
● Calcium, iron, folic acid, fat soluble vitamin (A,D,E,K) deficiencies
of
● Dehydration
Biliopancreatic
● Steatorrhea
diversion
● Small bowel obstruction:
Internal hernia - Adhesions
 Take home Messages 23

Type 1:

● Type 1 DM is often sudden, while Type 2 DM is typically gradual.

● Diabetes type 1 childhood onset typically < 20 years. Peaks at age 4–6 years and 10–14 years.
● Weak familial predisposition in Type 1. Strong familial predisposition in Type 2.
● “If you buy 4 DiaMonds and only pay for 3, you get 1 for free:” DR4 and DR3 are associated
with Diabetes Mellitus type 1. Type 2 DM has no HLA association.
● Classic symptoms (i.e., polyuria, polydipsia, polyphagia, weight loss) are common in Type 1
DM, sometimes happen in Type 2 DM.
● A thin appearance is typical for patients with T1DM.
● Gold standard for the diagnosis of DM is HbA1C.
● MDI = Multiple Daily Injections (3 – 6 injections / day) is the preferred regimen for adults
with Type 1 DM.
● The most common complication of insulin use is Hypoglycemia.

Type2:

● Obesity accounts for 80-85% of the overall risk of developing type 2 diabetes
● The pathogenesis of type 2 DM: Relative insulin secretion loss and/or decrease in insulin
sensitivity (increase in insulin resistance)
● Possible cutaneous signs of insulin resistance:
Benign acanthosis nigricans.
Acrochordons.
● Diabetes mellitus should be suspected in patients with recurrent cellulitis, candidiasis,
dermatophyte infections, gangrene, pneumonia (particularly tuberculosis reactivation),
influenza, genitourinary infections (UTIs), osteomyelitis, and/or vascular dementia.
● Medication should never be prescribed until lifestyle changes have been implemented.
● IMP: when you diagnose a pt with DM2 start management with diet & lifestyle
modifications and reassess in the next visit. If the HbA1c is still high -> start monotherapy
(metformin) & reassess after ~ 3 months. If there are contraindications for metformin,
choose a different noninsulin antidiabetic, depending on patient factors
● The three main options are metformin (1st line) , a sulfonylurea or a thiazolidinedione.
● If control is inadequate (if HbA1c > 10% )oral therapy, insulin therapy should be started
without undue delay
● DM management depends on hyperglycemia, microvascular complications and
macro-vascular together.

Reference: AMBOSS+ Slides.

 Summary

Type 1 DM Type 2 DM

● Autoimmune destruction of
● Characterized by resistance to
pancreatic Beta cells in genetically
susceptible individuals and the action of insulin and an
triggered by some environmental inability to produce sufficient
Pathogenesis
factors. insulin to overcome this ‘insulin
● Characterized by a severe resistance’.
deficiency of insulin. ● Obesity play a major role
● Not related to obesity

● Factors that act as a trigger for the ● obesity

autoimmune response. ● Sedentary lifestyle
● E.g infection with mumps virus, ● PCOS
Risk factors
coxsackie B virus Rotavirus or EBV. ● Metabolic syndrome
● HLA- DR3-DQ2, HLA- DR4-DQ8 ● Impaired glucose tolerance
genes or both ● Impaired fasting glucose

polyuria
Polydipsia
Weight loss
Clinical
Blurred vision
presentation
Fungal infections
frequent urination
Numbness, tingling of hands and feet

1. fasting plasma glucose (FPG) (Specific)

2. random glucose (Sensitive)
3. 2-hour plasma glucose after a 75- g
Diagnosis oral glucose tolerance test (OGTT)
(Sensitive & Specific)
4. The use of glycated haemoglobin (HbA1c)
5. Glycosuria

● Bolus (preprandial or mealtime)

● Diet and lifestyle changes
insulins : rapid acting and short
acting insulin ● The three main options are
● Basal insulin : intermediate and metformin, a sulfonylurea or a
Management long acting insulin thiazolidinedione.
● Premixed insulin ● If control is inadequate on oral
● MDI = Multiple Daily Injections (3 – 6 therapy, insulin therapy should
injections / day) is the preferred
be started without undue delay
regimen for adults
 Lecture Quiz

Q1: A 29-year-old man presents to his GP complaining of being constantly thirsty, tired and visiting the toilet more
often than usual during the last 4 days. He has noticed his clothes have become more baggy and he now needs to
tighten his belt. His parents both have diabetes requiring insulin therapy. A fasting plasma glucose result is most likely
to be:
A. 9.0 mmol/L
B. 6.0 mmol/L
C. 16.3 mmol/L
D. 5.0 mmol/L
E. 3.0 mmol/L

Q2: A 41-year-old man has been recently diagnosed with type 2 diabetes and has been following a plan of lifestyle
measures to improve his diet and increase his level of exercise. On returning to clinic, his BMI is 23, fasting plasma
glucose 9.0 mmol/L, blood pressure 133/84 mmHg and HbA1c of 7.1 per cent. The most appropriate treatment option
is:
A. Metformin
B. Sulphonylurea
C. Insulin
D. Exenatide
E. Further diet and exercise

Q3: Risk factors for T2DM include all of the following except :
A- Advanced age
B- obesity
C- Smoking
D- physical inactivity

Q4: Which of the following diabetic drugs acts by decreasing the amount of glucose produced by the liver ?
A- Sulfonylureas
B- Meglitinides
C- Biguanides
D- alpha glucosidase Inhibitor

Q5: A 47-year-old woman complains of weight loss. She has a family history of type 1 and type 2 diabetes but has
never been diagnosed herself despite the finding of islet cell antibodies. In the last few months, however, she has
noticed progressively increasing polyuria and polydipsia and 5 kg of weight loss. Her fasting plasma glucose is 8
mmol/L and urine dipstick shows the presence of ketones. The most likely diagnosis is:

A. Type 1 diabetes
B. Non-ketotic hyperosmolar state
C. Type 2 diabetes
D. Occult malignancy
E. Latent autoimmune diabetes of adults (LADA)

Q6 : Which of the following regimens offers the best blood glucose control for persons with type 1
diabetes?

A- A single anti-diabetes drugs

B- Once daily insulin injections
C- A combination of oral anti-diabetic medications
D- Three or four injections per day of different types of insulin.

Answers: Q1: A | Q2:B| Q3:C | Q4: C | Q5:E | Q6:D Answers Explanation File!
 GOOD LUCK !

This work was originally done by 438 Medicine team:

Team - Raghad AlKhashan - Mashal AbaAlkhail

Leaders - Amirah Aldakhilallah - Nawaf Albhijan

Member : Rahaf Alshabri - Razan Alzohaifi -

Noura Alturki - Amirah Aldakhilallah
Note taker : Njoud Alali - Mashal
AbaAlkhail - Rema Almutawa - Arwa Alemam

Edited by 439 Medicine team:

Team - Shaden Alobaid - Hamad Almousa

Leaders - Ghada Alabdi - Naif Alsulais

Member : Abdulaziz Alrabiah2

Note taker : Mohammed beyari2

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