What is diabetes?

Regulation of Plasma
Glucose Level

 Diabetes mellitus (DM) is a chronic condition

that is characterised by raised blood glucose
levels (Hyperglycemia).

1 2

How Insuline Decrease Classification of DM

Plasma Glucose Level?
1. Type 1 DM

• It is due to insulin deficiency and is formerly known as.

• Type I
• Insulin Dependent DM (IDDM)
• Juvenile onset DM

2. Type 2 DM

• It is a combined insulin resistance and relative deficiency in

insulin secretion and is frequently known as.
• Type II
• Noninsulin Dependent DM (NIDDM)
• Adult onset DM
3 4

Etiology
3. Gestational Diabetes Mellitus (GDM):

 Gestational Diabetes Mellitus (GDM) developing during some 1. Etiology of Type 1 Diabetes
cases of pregnancy but usually disappears after pregnancy.

4. Other types:

 Secondary DM

5 6
 2. Etiology of Type 2 Diabetes

7 8

a 9 10

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Characteristics Type 1 Type 2

% of diabetic pop 5-10% 90% Risk Factors

Age of onset Usually < 30 yr + some adults Usually > 40 + some obese
children
Pancreatic function Usually none Insulin is low, normal or high • Type 2 DM
Pathogenesis Autoimmune process Defect in insulin secretion,
tissue resistance to insulin,
– Family History
increased HGO
– Obesity
Family history Generally not strong Strong
– Habitual physical inactivity
Obesity Uncommon Common – Previously identified impaired glucose tolerance
History of ketoacidosis Often present Rare except in stress (IGT) or impaired fasting glucose (IFG)
Clinical presentation moderate to severe symptoms: Mild symptoms: Polyuria and – Hypertension
3Ps, fatigue, wt loss and fatigue. Diagnosed on routine
ketoacidosis physical examination – Hyperlipidemia
Treatment Insulin, Diet Diet ,Exercise
Exercise Oral antidiabetics,Insulin
13 14

Treatment
Desired outcome
- Relieve symptoms
- Reduce mortality
- Improve quality of life
- Reduce the risk of microvascular and macrovascular
disease complications
- Macrovascular complications:
Coronary heart disease, stroke and peripheral vascular disease
- Microvascular Complications:
Retinopathy, nephropathy and neuropathy
15 16

Treatment Treatment
How to achieve the goals ?
General approaches
- Near normal glycemic control reduce the risk
of developing microvascular disease - Medications
complications - Dietary and exercise modification
- Regular complication monitoring
- Control of the traditional CV risk factors such - Self monitoring of blood glucose
as smoking, management of dyslipidemia, - Control of BP and lipid level
intensive BP control and antiplatelet therapy.

17 18
 Treatment Treatment
Glycemic goals Complication monitoring

- Annual eye examination

- Annual microalbuminuria
- Feet examination
- BP monitoring
- Lipid profile

19 20

Treatment Treatment
Nonpharmacological therapy Nonpharmacological therapy

Diet
- For type 1 the goal is to regulate insulin
administration with a balanced diet
- In most cases, high carbohydrate, low fat, and low
cholesterol diet is appropriate
Activity
- Exercise improves insulin resistance and achieving glycemic
control.
- Exercise should start slowly for patients with limited activity.

- Type 2 DM patients need caloric restriction - Patients with CV diseases should be evaluated before
21 starting any exercise 22

Treatment
Pharmacological therapy

- Insulin (Type 1 and Type 2 DM)

- Sulfonylurea (Type 2 DM)
- Biguanides (Type 2 DM)
- Meglitinides (Type 2 DM)
- Thiazolidinediones Glitazones (Type 2 DM)
 a-Glucosidase inhibitors (Type 2 DM)

23 24
 Pharmacological Treatment of Type 2 DM
Strategy for Controlling Hyperglycemia
Absorption from Diet Biosynthesis in Liver
1. Sulfonylureas
a-Glucosidase Biguanides
Inhibitors Pharmacological effect
Cellular Uptake
• Stimulate the pancreatic secretion of insulin
Serum Sugar
Biguanides;
thiazolidinediones

Pancreas Insulin

Sulfonylureas
Meglitinide 25 26

Sulfonylureas (Cont’d) Major Pharmacokinetic Properties of Sulfonyl Ureas

Classification Eqv. Dose Duration Active metabolites

• First generation
(mg) (h)

First Generation
• e.g. tolbutamide, chlorpropamide, and acetohexamide Tolbutamide 1000-1500 12-24 Yes (p-OH derivative)

• Lower potency, more potential for drug interactions Chlorpropamide 250-375 24-60 Yes (2’-OH and 3’OH groups)

and side effects Tolazamide 250-375 12-24 No (4-COOH derivative)

• Second generation Second

generation
• e.g. glimepiride, glipizide, and glyburide Glipizide 10 10-24 No (cleavage of pyrazine ring)

• higher potency, less potential for drug interactions and Glyburide

(glibenclamide)
5 16-24 Some (trans + cis 4’-OH groups)

side effects
• All sulfonylurea drugs are equally effective in reducing the Third generation
Glimepiride 1-2 24 Yes (-OH on CH3 of R’ group)
blood glucose when given in equipotent doses. 27 28

Sulfonylureas (Cont’d) Sulfonylureas (Cont’d)

Efficacy
Drug interactions
– HbA1c: 1.5 – 1.7% reduction.
– FPG: 50 – 70 mg/dL reduction.
– PPG: 92 mg/dL reduction.

Adverse effects
– Hypoglycemia
– Hyponatremia (with tolbutamide and chlorpropamide)
– Weight gain

29 30
 2. Short-acting Secretogogues Secretogogues (Cont’d)
– Repaglinide
Adverse effect
– Nateglinide
– Incidence of hypoglycemia is very low about 0.3 %

Pharmacological effect
– Stimulation of the pancreatic secretion of insulin Drug Interactions
– The insulin release is glucose dependent and is decreased
at low blood glucose – Inducers or inhibitors of CYP3A4 affect the action of repaglinide
– With lower potential for hypoglycemia (incidence 0.3%) – Nateglinide is an inhibitor of CYP2C9
– Should be given before meal or with the first bite of each
meal. If you skip a meal don’t take the dose!
31 32

3. Biguanides 4. Glitazones (PPARg Agonists)

Metformin (Glucophage)
Pharmacological effect PPARg Agonists:
– Reduces hepatic glucose production Peroxisome proliferator-activated receptor g gonists
– Increases peripheral glucose utilization
- Rosiglitazone - Pioglitazone
Adverse effects
Pharmacological effect
– Nausea, vomiting, diarrhea, and anorexia
– Reduces insulin resistance in the periphery (Sensitize muscle and
– Phenformin: another biguanide, was taken off the market fat to the action of insulin) and possibly in the liver
because it causes lactic acidosis in almost 50% of patients – The onset of action is slow taking 2-3 months to see the full effect
– As a precaution metformin should not be used in patients – Edema and weight gain are the most common side effects. (no
with renal insufficiency, CHF, conditions that lead to hepatotoxicity)
hypoxia 33 34

5. a-Glucosidase Inhibitors
- Acarbose - Miglitol II. Oral hypoglycemic and
Pharmacological effect other drugs, used
• Prevent the breakdown of sucrose and complex
carbohydrates
in DM type 2
– The net effect is to reduce postprandial blood glucose rise
– The effect is limited to the luminal side of the intestine with
limited systemic absorption. Majority eliminated in the feces.
– Postprandial glucose conc is reduced.
– FPG relatively unchanged.
– Average reduction in HbA1c: 0.3-1.0%
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1. Biguanides:
Metformin
•usually first line drug for type 2 DM
•reduces intestinal glucose absorption
•stimulates anaerobic glycolysis
•stimulates glucose uptake
•enhances insulin receptor binding
2. Sulfonylureas
I generation:
•Chlorpropamide and Tolbutamide (Out)
II generation:
•Glibenclamide (Maninil: tab. 5 mg)
•Gliclazide (Diaprel MR)
•Glipizide
•Gliquidone
Sulfonylureas –
important drug interactions:
•displacement from protein binding sites
– salicylates and sulphonamides
•interference with hepatic metabolism
– inducers: rifampicin, phenytoin
– inhibitors: cimetidine
•reduction of renal elimination
– allopurinol, salicylates
Metformin
•excreted exclusively
by the kidney
•does not increase weight
and preferable in the obese
•GI side effects
•rarely
lactic acidosis
Mechanism of action
•promote enhanced insulin release
from the pancreas
•leads to a reduction in hepatic
glucose production
Unwanted effects
•Hypoglycemia, weight gain
•facial flushing following
alcohol ingestion
3. Meglitinides: stimulate the release of insulin
from pancreas by closing ATP-dependent
potassium channels.
- Nateglinide
- Repaglinide
4. Glucosidase inhibitors
- Acarbose (Gluco Bay): p.o.
•Inhibits intestinal alpha-glucosidase
•Decreases intestinal absorption
of the mono- and polysaccharides.
•Produces flatulence and diarrhoea.
 6. Glucagon-like peptide-1 (GLP-1)
5. Thiazolidinediones (TZDs) agonists (in type 2 DM): increase
They increase tissue insulin sensitivity pancreatic secretion of insulin:
but have serious ADRs and the EMA Exenatide
recommended in Sept (2010) that they Bydureon (s.c./7 days):
be suspended from the EU market: $323/4 doses, resp.
$4200 per year
- Rosiglitazone (Avandia)
has high cardiovascular risks.
- Pioglitazone causes bladder tumors.
- Troglitazone causes hepatitis.

7. Inhibitors of Dipeptidil
Liraglutid peptidase-4 (DPP-4): prevent
degradation of incretin GLP-1
is a GLP-1
Sitagliptin (p.o.)
agonist,
which reduces, Vildagliptin (p.o.)
BM, HbA1C,
and systolic
Liraglutid blood pressure,
and improves
beta cell function
of the pancreas
(s.c. once a day)

8. Inhibitors of reabsorption
of glucose (SGLT2 inhibitors): p.o.
•Canagliflozin blocks in renal proximal
tubule sodium / glucose co-transporter
protein 2 (SGLT2), which re-absorbed
90% of the filtrated glucose.
The result is increased glucosuria and
plasma glucose levels are lowered.
ADRs: Hypoglycaemia, vulvovaginal candidiasis
urinary tract infections, polyuria, frequent urination.
 Pharmacotherapy :Type 2 DM Pharmacotherapy :Type 2 DM

Obese Patients >120% LBW:

General considerations:
- Consider therapeutic life style changes (TLC) for Metformin or glitazone
all patients with Type 2 DM
Add SU or short-acting insulin
- Initiation of therapy may depend on the level of HbA1C secretagogue
- HbA1C < 7% may benefit from TLC

- HbA1C 8-9% may require one oral agent

- HbA1C > 9-10% my require more than one oral agent Add Insulin or glitazone

49 50

Pharmacotherapy :Type 2 DM Pharmacotherapy :Type 2 DM

Non-obese Patients <120% LBW: Elderly Patients with newly diagnosed
DM :
SU or short-acting insulin
secretagogue SU or short-acting insulin
secretagogue or a-glucosidase
inhibitor or insulin
Add Metformin or
glitazone

Add or substitute insulin

Add Insulin
51 52

Pharmacotherapy :Type 2 DM Clinical Trials: Diabetes Mellitus

Early insulin resistance :
1- Diabetes Prevention Program
Metformin or glitazone
• Population: Over-weight patients with impaired
glucose tolerance.

Add glitazone or metformin

• Intervention: Low-fat diet and 150 min of exercise
per week.
Add SU or short-acting insulin
secretagogue or insulin • Results: Decrease the risk of progression to Type 2
53 DM by 58% 54
 Pharmacotherapy :Type 1 DM Insulin
Pharmacological effect:

The choice of therapy is simple Anabolic Anticatabolic

- Glucose uptake - Inhibits gluconeogenesis

All patients need Insulin - Glycogen synthesis- Inhibits glycogenolysis
- Lipogenesis - Inhibits lipolysis
- Protein synthesis - Inhibits proteolysis
- Triglyceride uptake - Inhibits fatty acid
oxidation
55 56

Insulin (Cont’d) Insulin (Cont’d)

Strength Onset and duration of effect

- The number of units/ml Changing the properties of insulin preparation can

e.g. U-100 , U-20, U-10 alter the onset and duration of action
- Lispro: (Monomeric) absorbed to the circulation
Source very rapidly
- Pork: Differs by one a.a. - Aspart: (Mono- and dimeric) absorbed to the
circulation very rapidly
- Beef-Pork
- Regular: (Hexameric) absorbed rapidly but slower
- Human (recombinant DNA technology) than lispro and aspart
57 58

Insulin (Cont’d) Insulin (Cont’d)

Onset and duration of effect Onset and duration of effect
- Rapid-acting insulin
- Lent insulin: Amorphous precipitate of insulin and
zinc and insoluble crystals of insulin and zinc. - e.g. Insulin lispro and insulin aspart
Releases insulin slowly to the circulation - Short-acting insulin
- e.g. Regular insulin
- NPH: R-insulin + Protamine zinc insulin. Releases
- Intermediate-acting insulin
insulin slowly to the systemic circulation
- e.g. NPH and Lente insulin
- Insulin glargine: Prepared by modification of the - Long-acting insulin
insulin structure. Precipitate after S.C. injection to - e.g. Insulin Glargine
form microcrystals that slowly release insulin to the
- Mixture of insulin can provide glycemic control over
systemic circulation (N.B. cannot be mixed with other
extended period of time
insulins)
59 - e.g. Humalin 70/30 (NPH + regular) 60
 Insulin (Cont’d) Insulin (Cont’d)
Adverse effects
Drugs interfering with glucose tolerance
- Hypoglycemia
- Treatment: • The most significant interactions are with drugs that alter
the blood glucose level:
- Patients should be aware of symptoms of hypoglycemia
- Oral administration of 10-15 gm glucose - Diazoxide
- IV dextrose in patients with lost consciousness
- 1 gm glucagon IM if IV access is not available - Thiazide diuretics
- Corticosteroids
- Skin rash at injection site - Oral contraceptives
- Treatment: Use more purified insulin preparation
- Streptazocine
- Lipodystrophies (increase in fat mass) at injection site - Phenytoin
- Treatment: rotate the site of injection • All these drugs increase the blood glucoseconcentration.
• Monitoring of BG is required
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Insulin (Cont’d) Pharmacotherapy :Type 1 DM

Methods of Insulin Administration The goal is:

• Insulin syringes and needles To balance the caloric intake with the
glucose lowering processes (insulin and
• Pen-sized injectors exercise), and allowing the patient to live
as normal a life as possible
• Insulin Pumps

63 64

Pharmacotherapy :Type 1 DM Pharmacotherapy :Type 1 DM

Breakfast Lunch Supper

Concentration

- -The insulin regimen has to mimic the physiological

Insulin

secretion of insulin

- With the availability of the SMBG and HbA1C

Time of day tests adequacy of the insulin regimen can be
assessed
Normal insulin secretion during he day
- More intense insulin regimen require more intense
- Constant background level (basal) monitoring
- Spikes of insulin secretion after eating
65 66
 Pharmacotherapy :Type 1 DM Pharmacotherapy :Type 1 DM

Example:
Modification
1- Morning dose (before breakfast): - NPH evening dose can be moved to bedtime
Regular + NPH or Lente - Three injections of regular or rapid acting insulin
before each meal + long acting insulin at bedtime (4
2- Before evening meal: injections)
Regular + NPH or Lente - The choice of the regimen will depend on the patient

Require strict adherence to the timing of meal and

injections
67 68

Pharmacotherapy :Type 1 DM Pharmacotherapy :Type 1 DM

How much insulin ? Example: For a 50 kg patient

- A good starting dose is 0.6 U/kg/day
- The total dose should be divided to:
- 45% for basal insulin
- 55% for prandial insulin
The prandial dose is divided to
- 25% pre-breakfast
- 15% pre-lunch
- 15% pre-supper
- The total dose = 0.6X50 = 30 U/day
- 13.5 U for basal insulin (45% of dose)
- Administered in one or two doses
- 16.5 U for prandial insulin (55% of dose)
The 16.5 U are divided to:
- 7.5 U pre-breakfast (25%)
- 4.5 U pre-lunch (15%)
- 4.5 U pre-supper (15%)
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Pharmacotherapy :Type 1 DM Pharmacotherapy :Type 1 DM

Monitoring Monitoring
- Most Type 1 patients require
0.5-1.0 U/kg/d
- The initial regimen should be modified
based on:
- Symptoms
- SMBG
- HbA1C
71 72
 Pharmacotherapy :Type 1 DM Pharmacotherapy :Type 1 DM
Insulin Pump Therapy Insulin Pump
- This involves continuous SC administration of
short-acting insulin using a small pump
- The pump can be programmed to deliver basal
insulin and spikes of insulin at the time of the
meals
- Requires intense SMBG
- Requires highly motivated patients because
failure to deliver insulin will have serious
consequences 73 74

Diabetes Mellitus Complications Diabetes Mellitus Complications

1. Hypoglycemia
2. Diabetes retinopathy
- Cause: Missing meals or excessive exercise or too
much insulin
- Symptoms: Tachycardia, palpitation, sweating, - Microaneurysm
nausea, and vomiting. Progress to mental confusion, - Hemorrhage
bizarre behavior and coma
- Exudates
- Treatment: Candy or sugar
- Retinal edema
IV glucose
- other
Glucagon 1 gm IM
- Identification: MedicAler bracelet
75 76

Diabetes Mellitus Complications Diabetes Mellitus Complications

3. Diabetes nephropathy Diabetes nephropathy (Cont’d)

- 30-40 % of all type 1 DM patients develop - All diabetic patients should be screened annually for
nephropathy in 20 years microalbuminurea to detect patients at high risk of
developing progressive diabetic nephropathy
- 15-20 % of type 2 DM patients develop nephropathy
- Tight glycemic control and management of the blood
- Manifested as:
pressure can significantly decrease the risk of
- Microalbuminuria developing diabetic nephropathy.
- Progressive diabetic nephropathy leading to end-
stage renal disease - ACE-inhibitors are recommended to decrease the
progression of nephropathy
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 Diabetes Mellitus Complications Diabetes Mellitus Complications
4. Diabetes neuropathy 5. Peripheral vascular disease and foot ulcer
Incidence of gangrene
of the feet in DM is 20
fold higher than control
group due to:
- Ischemia
- Peripheral neuropathy
Autonomic neuropathy: - Secondary infection
- Manifested by orthostatic hypotension, diabetic
diarrhea, erectile dysfunction, and difficulty in
urination. 79 80

Special Patient Population Special Patient Population

1. Adolescent Type 2 DM
- Type 2 DM is increasing in adolescent
- Lifestyle modification is essential in these patients
- If lifestyle modification alone is not effective,
metformin the only labeled oral agent for use in
children (10-16 years)
2. Gestational DM
- Dietary control
- If blood glucose is not controlled by dietary control,
insulin therapy is initiated
- One dose of NPH or NPH + regular insulin (2:1) given
before breakfast. Adjust regimen according to SMBG.
- Sulfonylureas: Effective, but require further studies to
demonstrate safety.

81 82

Special Situations Special Situations

3. Diabetic ketoacidosis
Diabetic ketoacidosis (Cont’d)
- It is a true emergency
- Diagnosis
- Usually results from omitting insulin in type 1 DM or - Hyperglycemia, acidosis, low serum
increase insulin requirements in other illness (e.g. bicarbonate, and positive serum ketones
infection, trauma) in type 1 DM and type 2 DM - Abnormalities:
- Dehydration, acidosis, sodium and
- Signs and symptoms:
potassium deficit
- Fatigue, nausea, vomiting, evidence of
- Patient education is important
dehydration, rapid deep breathing, fruity breath
odor, hypotension and tachycardia 83 84
 Special Situations
Diabetic ketoacidosis (Cont’d)
Management:
- Fluid administration: Rapid fluid administration to
restore the vascular volume,
- IV infusion of insulin to restore the metabolic
abnormalities. Titrate the dose according to the blood
glucose level.
- Potassium and phosphate can be added to the fluid if
needed.
Follow up:
- Metabolic improvement is manifested by an
increase in serum bicarbonate or pH. 85