April 20
Diabetes Mellitus
Munir Gharaibeh, MD, PhD, MHPE
Faculty of Medicine
The Jordan University
August 2015
Munir Gharaibeh, MD, PhD, MHPE 1


Diabetes is a major cause of heart disease and stroke

Diabetes is a leading cause of renal failure, nontraumatic lower-limb amputations, and blindness.

Diabetes is the seventh leading cause of death in the United States
2 April 20 Munir Gharaibeh, MD, PhD, MHPE

-
-
-
10-20% of diabetics
Most commonly occurs in childhood or adolescence but may occur at any age
Mainly affects children at an age
10-14, not reported in children less than 6 months of age.
April 20 Munir Gharaibeh, MD, PhD, MHPE 3

-
-
-
-
Patients have little or no pancreatic function
Often present with ketoacidosis
Characterized by downhill course-severe type of DM with high mortality.
Easy to diagnose ( severe weight loss; easy fatigability; polyuria; polydipsia; polyphagia etc … )
4 April 20 Munir Gharaibeh, MD, PhD, MHPE

-
-
Usually associated with HLA types histocompatibility antigens and presence of β-islet cell antibodies suggesting an autoimmune-mediated destruction of insulin producing cells leading to a near total loss of endogenous insulin production.
Insulin lack could be idiopathic
April 20 Munir Gharaibeh, MD, PhD, MHPE 5

-
-
-
-
-
Type II; Maturity or Adult-onset; IIDM
Represents 80-90% of diabetics
Usually discovered accidentally after age
30-40 yrs
Most patients are obese .
More common in females as compared to males.
Patients have strong family history of DM
(?genetic background).
6 April 20 Munir Gharaibeh, MD, PhD, MHPE

-
-
-
-
Type II; Maturity or Adult-onset; IIDM
Most cases have mild polyuria and fatigue.
Ketoacidosis is rare, unless in certain circumstances of unusual stress.
Insulin blood levels could be low, normal or high.
Insulin resistance is common (prereceptor; receptor; post-receptor mechanisms)
April 20 Munir Gharaibeh, MD, PhD, MHPE 7


Early manifestations:
Polyurea, Polydipsia, Polyphagia,
Ketoacidosis (type I).

Late manifestations or complications:
Atherosclerosis, IHD, Retinopathy,
Nephropathy , Neuropathy
8 April 20 Munir Gharaibeh, MD, PhD, MHPE

-
-
-
-
Clinical manifestations
- Laboratory Tests:
Random blood sugar (RBS)
Fasting blood sugar
Glycosylated hemoglobin
Glucose tolerance test
April 20 Munir Gharaibeh, MD, PhD, MHPE 9







Ensure good patient-clinic relationship.
Control symptoms.
Prevent acute metabolic crisis of ketoacidosis and hypoglycemia.
Maintain normal growth and body weight.
Encourage self-reliance and self-care.
Eliminate risk factors: Smoking, BP, lipids .
10 April 20 Munir Gharaibeh, MD, PhD, MHPE



Prevent psychological complications:
Accept restrictions on life style.
Diet control
Monitoring blood glucose and insulin adjustment
Know manifestations of hypoglycemia & how to avoid them.
Early treatment of complications:
Photocoagulation, foot care advices...
11 April 20 Munir Gharaibeh, MD, PhD, MHPE

Type I:
Diet
+ Insulin therapy
Type II:
Diet + exercise
± Oral hypoglycemic agents
± Insulin
April 20 Munir Gharaibeh, MD, PhD, MHPE 12

RER Golgi
Insulin
Preproinsulin Proinsulin
C-peptide
Proinsulin has slight insulin-like activity (1/10 the potency of insulin)
C-peptide is devoid of any insulin-like activity
13 April 20 Munir Gharaibeh, MD, PhD, MHPE

Insulin is a protein composed of two chains.
A (21 a.a) and B (30 a.a); combined through disulfied bonds
April 20 Munir Gharaibeh, MD, PhD, MHPE 14

Ca ++ dependent
Blood glucoselevel is the major regulator.

Factors/drugs ↑ release:
Glucose; AAs; FAs; GH; glucagon; ACTH; sulfonylureas; β-adrenergics, cholinergic drugs …

Factors/drugs ↓ release:
α-adrenergics; anticholinergics; phenytoin; alloxan; streptozocin.
April 20 Munir Gharaibeh, MD, PhD, MHPE 15

Mechanism of Action of Insulin
Insulin binds to its receptor leading to phosphorylation of insulin-receptor complex which in turn starts many protein -kinase activation cascades .
These include: translocation of Glu transporter-4 to the plasma membrane and influx of glucose, glycogen synthesis, glycolysis and fatty acid synthesis.
16 April 20 Munir Gharaibeh, MD, PhD, MHPE

April 20 Munir Gharaibeh, MD, PhD, MHPE 17

-
-
-
-
-
-
-
-
↑ Glucose uptake or transport into muscles and adipocytes.
↑ Glucose oxidation by muscles.
↓ Hepatic gluconeogenesis.
↑ Hepatic glycogen synthesis and storage.
↓ Glycogenolysis.
↑ AA uptake and protein synthesis by muscles and liver.
↓ Lipolysis.
↓ Ketogenesis.
18 April 20 Munir Gharaibeh, MD, PhD, MHPE

Natural:
Bovine
Porcine.
Human: limited supply, short t
1/2 and has problems of poor stability.
Biosynthetic: rHI
April 20 Munir Gharaibeh, MD, PhD, MHPE 19

Potency:
Human > porcine > bovine
Allergy:
- Bovine > porcine > human(proinsulin is a major contaminant).
Insulins are classified according to duration of action (DOA)
20 April 20 Munir Gharaibeh, MD, PhD, MHPE

Factors Affecting Insulin Absorption
-
Site of injection: abdomen > arm > buttocks > thigh.
- Exercise increases blood flow at site.
- Depth of injection.
- Concentration and dose of insulin.
- Addition of protamine or isophane to insulin preparations delays absorption and hence duration of action.
21 April 20 Munir Gharaibeh, MD, PhD, MHPE

-
-
-
Ultra-rapid onset; very short acting:
O (hr) P (hr) DOA (hr)
Insulin Lispro
Insulin Aspart
Insulin Glulisine
0.25-0.5 0.5-1 3-4
-
-
Rapid onset and short acting:
Crystalline zinc 0.3-0.7 2-4 5-8
(Regular; Soluble)
Insulin zinc prompt
(Semilente)
22 April 20 Munir Gharaibeh, MD, PhD, MHPE

-
-
Intermediate onset and action:
Insulin zinc suspension 1-2 6-12 18-24
(Lente)
Isophane insulin suspension
(NPH; Humulin)
-
-
Slow onset and action:
Protamine zinc suspension 4-6 14-20 24-36
Extended insulin zinc suspension
(Ultralente)
23 April 20 Munir Gharaibeh, MD, PhD, MHPE

Peakless Insulins:
Insulin Glargine 1-2 24-36
Insulin Detemir
Mixed insulins:
Int. + short 0.5-1 3-8 20-24
Int. + long 2-4 4-16 22-24
April 20 Munir Gharaibeh, MD, PhD, MHPE 24


Advantages of peakless insulins over intermediate-acting insulins:
- Constant circulating insulin over 24hr with no pronounced peak.
- Reduced risk of hypoglycemia (especially nocturnal hypoglycemia).
- Clear solution that does not require resuspension before administration.
25 April 20 Munir Gharaibeh, MD, PhD, MHPE

April 20 Munir Gharaibeh, MD, PhD, MHPE 26

April 20 Munir Gharaibeh, MD, PhD, MHPE 27

All insulin preparations are mainly given S.C; except regular insulin, insulin Glulisine & insulin Aspart , which can also be given IV
April 20 Munir Gharaibeh, MD, PhD, MHPE 28

Methods of insulin administration
- Insulin Syringes
- Pre-filled insulin pens
- Insulin Jet injectors
- External insulin pump
Methods under clinical trials:
- Oral tablets
-
- Inhaled aerosol
Intranasal,
-
Transdermal
- Buccal spray
April 20 Munir Gharaibeh, MD, PhD, MHPE 29

April 20 Munir Gharaibeh, MD, PhD, MHPE 30

April 20 Munir Gharaibeh, MD, PhD, MHPE 31

-
-
-
-
Hypoglycemia; manifested as symptoms of sympathetic ove ractivity.
Lipodystrophy
Allergy
Induration
32 April 20 Munir Gharaibeh, MD, PhD, MHPE

April 20 Munir Gharaibeh, MD, PhD, MHPE 33

-
-
-
-
Biguanides
Metformin
Only effective in type II DM (effects require insulin).
↓ CHO absorption.
↓ Hepatic gluconeogenesis; ↑ glycolysis.
↓ Glucagon release.
↑ Peripheral utilization of glucose.
34 April 20 Munir Gharaibeh, MD, PhD, MHPE

-
-
-
-
-
Side effects:
Nausea and vomiting, metallic taste.
Abdominal pain and diarrhea.
Hypoglycemia is rare.
Lactic acidosis.
↓ Vitamin B
12 absorption.
April 20 Munir Gharaibeh, MD, PhD, MHPE 35

Tolbutamide
First Generation t
1/2
DOA
7 6-12
Chlorpropamide
Tolazamide
Acetohexamide
34 24-72
7 12-16
5 12-18
36 April 20 Munir Gharaibeh, MD, PhD, MHPE

Second Generation t
1/2
DOA
Glyburide (Glibenclamide) 4 20-24
Glipizide 3 14-16
Gliclazide
Glimeperide
8 10-15
5 18-22
37 April 20 Munir Gharaibeh, MD, PhD, MHPE

-
-
-
-
-
-
-
-
↑ Insulin release (major MOA) (Receptormediated effect)
↑ Number of β-cells and insulin receptors.
↑ Peripheral cells sensitivity to insulin effect.
↑ Insulin binding to its receptors.
↑ Insulin affinity to its receptors.
↓ Hepatic gluconeogenesis.
↓ Glucagon release.
↑ Somatostatin release .
38

-
-
-
Mechanism of Action of Sulfonylureas
Bind to receptors linked to ATP-ase sensitive
K + ion channel; causing depolarization and opening of voltage dependent Ca ++ channels and influx of Ca ++ .
Ca ++ binds to Calmodulin which activates kinases that cause exocytosis of insulin from the secretory granules.
Beta cells sense glucose more efficiently, producing more insulin.
39 April 20 Munir Gharaibeh, MD, PhD, MHPE

K
ATP
Channel Structure and Function glucose
ATP-sensitive K + Channel (K
ATP
Channel)
Sulfonylurea Receptor Inwardly Rectifying
K + Channel
Voltage-dependent
Ca 2+ Channel
Membrane
Depolarization
NBF K +
ATP NBF glucose metabolism insulin secretion
NBF
Nucleotide Binding Fold = site of ATP/ADP binding
Ca 2+
Influx
Four copies of each subunit combine to form an active K
ATP channel
April 20 http://www.musc.edu/~rosenzsa
Munir Gharaibeh, MD, PhD, MHPE 40


Sulfonylureas differ in potency, bioavailability, duration, tolerance, extent of protein binding, and metabolic fate.

Sulfonylureas have many interactions:
Propranolol, sulfa drugs, oral anticoagulants, aspirin,
↑ effects of sulfonylureas
-
-

Clinical uses:
DM
Nocturnal enuresis (Glyburide → ↑ ADH release)
41 April 20 Munir Gharaibeh, MD, PhD, MHPE

-
-
-
-
-
Hypoglycemia, like insulin.
Nausea, vomiting, dizziness.
Allergy, due to sulfa moiety.
Agranulocytosis.
Hepatic dysfunction.
April 20 Munir Gharaibeh, MD, PhD, MHPE 42

Acarbose
Miglitol (more potent)
Effective in type II DM
↓ CHO absorption
Inhibit α-glucosidase , an enzyme in the brush border of intestine responsible for breakdown of CHO, and hence ↓ glucose absorption.
↓ Fasting and postprandial hyperglycemia.
43 April 20 Munir Gharaibeh, MD, PhD, MHPE

↓ Insulin secretion, thus sparing β-cells.
Reduce incidence and risk of atherosclerosis in diabetics
Taken before or with meals.
Could be given with insulin and sulfonylureas.
Cause abdominal pain and diarrhea.
44 April 20 Munir Gharaibeh, MD, PhD, MHPE

Repaglinide
Nateglinide
Mitiglinide…
↑ Insulin release (similar action to sulfonylureas).
Taken before meals.
Could be taken with metformin or insulin.
Hypoglycemia is infrequent.
April 20 Munir Gharaibeh, MD, PhD, MHPE 45

Rosiglitazone (withdrawn)
Pioglitazone (has shorter t
1/2
)
Troglitazone
Used in NIDDM patients who have insulin resistance.
Peroxisome Proliferator-Activated Receptors
(PPAR) agonists.
PPAR ’ s are members of the superfamily of ligandactivated transcription factors located in adipose tissue, skeletal muscle and large intestine.
46 April 20 Munir Gharaibeh, MD, PhD, MHPE

↑ Sensitivity of peripheral tissues to insulin effect.
↓ Glucose exit or output from the liver.
↓insulin resistance.
Good for patients with ↑ insulin levels, which are also believed to be responsible for ↑
B.P,↑ lipids and atherosclerosis in patients with insulin resistance.
47 April 20 Munir Gharaibeh, MD, PhD, MHPE

April 20 Munir Gharaibeh, MD, PhD, MHPE 48

2 polypeptides which ↑ glucose absorption by gut.
1. Glucagon-like peptide-1 (GLP-1).
Produced by the L cells in ileum and colon:
A.↑ Insulin release and ↓ glucagon release following meals.
B. ↓ Gastric emptying and induction of satiety.
49 April 20 Munir Gharaibeh, MD, PhD, MHPE

April 20 Munir Gharaibeh, MD, PhD, MHPE 50

2 . Glucose-dependent insulinotropic polypeptide (GIP)
Produced by the K cells in the proximal gut
(duodenum & proximal jejunum)
Stimulates glucose-dependent insulin release from
β-cells.
Both GLP & GIP are metabolized by the enzyme dipeptidyl peptidase-4 (DPP-4) which is present in gut, liver, kidneys, lymphocytes and endothelial cells.
51 April 20 Munir Gharaibeh, MD, PhD, MHPE

Normal people Type 2 D.M patients
Incretin effect
Oral
Insulin glucose
Blood I.V
Level
Time (min) Time (min)
April 20 Munir Gharaibeh, MD, PhD, MHPE 52



Sitagliptin
Gemigliptin

Linagliptin
Orally effective selective DPP-4 inhibitors
↑ blood levels of GLP-1, GIP, insulin, and C-peptide and ↓ glucagon blood levels.
A daily oral dose reduces high blood glucose and
HbA1c levels.
Could be taken with metformin or sulfonylureas
Hypoglycemia is not common.
April 20 Munir Gharaibeh, MD, PhD, MHPE 53


Exenatide

Liraglutide
Synthetic analogs to GLP-1
↑ insulin and ↓ glucagon blood levels
Considered as an adjunct therapy to metformin or sulfonylureas in patients with type 2 DM who still have suboptimal glycemic control.
Given S.C, 60 min before meal.
54

Epalrestat
Ranirestat
Fidarestat
AR AR
Glucose Fructose Sorbitol
Sorbitol has been implicated in the pathogenesis of retinopathy, neuropathy and nephropathy
AR inhibitors proved to improve diabetic polyneuropathy.
Orally effective.
April 20 Munir Gharaibeh, MD, PhD, MHPE 55

-
Somatostatin
-
In low doses → ↓ glucagon release
Drugs Under Evaluation:
ACEI’s; ARB’s; Statins.
Pancreatic transplantation and gene therapy
April 20 Munir Gharaibeh, MD, PhD, MHPE 56

β-blockers
Salicylates, indomethacin, naproxin
Alcohol.
Sulfonamides
Clofibrate
Anabolic steroids.
Lithium
Ca ++
Ampicillin
Bromocriptine .
April 20 Munir Gharaibeh, MD, PhD, MHPE 57

β-agonists.
Thiazides and loop diuretics.
Glucocorticoids
Oral contraceptive drugs
Ca ++ channel blockers
Phenytoin.
Morphine
Heparin
Nicotine
Clonidine
Diazoxide
H
2
-receptor blockers
Munir Gharaibeh, MD, PhD, MHPE 58