Diabetes mellitus, commonly known as diabetes, is a metabolic disease that causes high blood sugar. The hormone insulin moves sugar from the blood into your cells to be stored or used for energy. With diabetes, your body either doesn’t make enough insulin or can’t effectively use the insulin it does make. Untreated high blood sugar from diabetes can damage your nerves, eyes, kidneys, and other organs.

1. Diabetes Mellitus
Md. Saiful Islam
B.Pharm, M.Pharm (PCP)
North South University
Join Facebook : Pharmacy Universe

2. DIABETES
MELLITUS
• The term diabetes mellitus describes a metabolic disorder
characterized by high blood glucose levels resulting from
defects in insulin secretion, insulin action or both. Protein
and fat metabolism also hampers in diabetes mellitus.
• One of the most challenging public health problems of the
21st century
• The global prevalence of diabetes in 2000 was 2.8% and
predicted to be 4.4% by 2030.
• But global prevalence of diabetes in 2011 increased to
8.3%, and again predicted to be 9.9% by 2030.
• The present position of Bangladesh is 8th with 8.4 million
and it is expected to be 5th position in 2030 with 16.8
million of diabetic patients.

3. Symtomps:
Feeling frequent thirsty, frequent hungry, urinating
frequently, rapid weight loss, feeling extreme weekness and
fatigue, Nausia, vomiting, irritability.
Diagnosis:
Fasting blood glucose >6mmol/L
Postprandial (2hrs after breakfast) blood glucose
>7.8mmol/L Or
2 hrs after 75g glucose Solution intake: >11mmol/L
Prediabetes: Intermediate stage of diabetes; 3 types---
Impaired Fasting glucose (IFG)
Impaired glucose tolerance (IGT)
IFG-IGT

4. At a glance 2011 2030
Total World Population (Billions) 7.0 8.3
Adults (20 – 79 yrs, billions) 4.4 5.6
Diabetes and IGT (20 – 79 yrs)
Diabetes
Global prevalence (%) 8.3 9.9
No. of peoples (millions) 366 552
IGT
Global prevalence (%) 6.4 7.1
No. of peoples (millions) 280 398
Diabetes Atlas 2011

5. Region 2011
(Millions)
2030
(Millions)
Increase, %
Africa 14.7 28.0 90
Middle East and
North Africa
32.8 59.7 83
South East Asia 71.4 120.9 69
South and Central
Amertica 25.1 39.9 59
Western Pacific 131.9 187.9 42
North America and
Caribbean
37.7 51.2 36
Europe 52.6 64.0 22
World 366.2 551.8 51
IDF Atlas 2011

6. DIABETES IN BANGLADESH
• Overall prevalence of diabetes in Bangladesh – around
5%
• Predominantly type 2 diabetes mellitus
• Typical type 1 diabetes are uncommon- rising tendency
• The present position of Bangladesh is 8th with 8.4 million and it
is expected to be 5th position in 2030 with 16.8 million.
• Substantial proportion of diabetic patients are of
younger age group
• Normal to under weight
• Ketosis resistant
• Some present with pancreatic pathology- FCPD

7. TYPES OF DIABETES MELLITUS
From practical aspect: Two main types
Type 1 DM
(Insulin Dependent Diabetes
Mellitus - IDDM)
Selectively B-cell destruction
( by auto-immune or
idiopathic)
Absolute Insulin lack
Type 2 DM
(Non-Insulin Dependent Diabetes
Mellitus - NIDDM)
Insulin resistance  Insulin lack

8. Etiological classification of diabetes
(WHO 1999)
• Genetic defects of beta cell function
• Genetic defects in insulin action
• Diseases of the exocrine pancreas
[includes FCPD]
• Endocrinopathies
• Drug or chemical induced
• Infections
• Uncommon forms of immune mediated
diabetes
• Other genetic syndromes
I. Type 1 diabetes
i. Immune mediated
ii. Idiopathic
II. Type 2 diabetes
III. Other Specific Types
IV Gestational diabetes
mellitus (GDM)

9. PATHOGENESIS OF TYPE 2 DIABETES
MELLITUS
• In type 2 diabetes mellitus, impaired insulin
secretion through a dysfunction of the pancreatic β-
cell, and impaired insulin action through insulin
resistance are implicated in its pathogenesis.
• In its pathogenesis of type 2 diabetes mellitus,
insulin resistance or secretory defect can have
genetic as well as environmental origin.

10. Complications of Diabetes Mellitus:
Two Types: Macro-vascular and Micro-vascular complications
Macro-vascular complications:
Atherosclerosis, Cardiovascular disease, Stroke, Amputation of limbs
Micro-vascular complications:
Retinopathy: Loss of vision
Nephropathy: Kidney Failure
Neuropathy: Nervous system dysorder

11. Glucose uptake mechanism of Muscle cells:
1) Glucose delivery to the muscle cell, 2) glucose transport through the membrane
and 3) glucose phosphorylation and metabolism

12. GLUCOSE UPTAKE MECHANISM OF MUSCLE
CELLS:
Two types: a) Insulin dependent and b) Insulin independent
Insulin Dependent Mechanism:
After secretion insulin binds into the insulin receptor which
locates on the cell membrane and transmits signal inside the
cells. Through signal transduction mechanism finally GLUT4
containing vescicles activates and releases GLUT4 which then
organizes in the cell membrane and helps to glucose uptake into
the cell from capillary vescles.
Insulin Independent Mechanism:
During excercise, muscle cell produces NO, ROS (Reactive
oxygen species) and activates AMPK (AMP-activated protein
kinase) which help to release GLUT4 from it’s vescicles and
organizes in the membrane to uptake glucose from extra cellular
environment.

13. Pancreatic -Cell: Insulin Secretion
GLUT2
Glucose
GLUCOKINASE
Pyruvate
GLYCOLYSIS
Amino acids
ATP
ADP
+
SUR1
KIR6.2
K+
HNF
4
HN
F3

V
+
Ca2+
Transcription, translation
and maturation of insulin
Insulin secretion
++
HN
F1

IPF-
1
Insulin
++
Ca2+
Nucleus
KATP channel
VDCC Glucose Metabolism
CREB
Mitochondria

14. Mechanism of insulin secretion
 Beta cells membrane has glucose transporter protein
 Glucose enters the beta cells
 Glucose -6 phosphate formed
 Utilized to produce ATP
 ATP inhibits ATP- sensitive Potassium channels
 Depolarization of cell membrane
 Voltage gated calcium channels open
 Calcium enters into beta-cells
 Insulin secrets from beta-cells
 Amino acids have similar mechanism of stimulation of
insulin secretion

15. Another mechanism of Insulin secretion
The roles of PKA
Glucose
GLUT2
AC


Gs
GPCR
Active
PKA
R
C
Exocytosis of Insulin
Ca Channel,
L-type
Ca2+
Transcription
Insulin
MLC
ANN-1
SYN-1
SNAP25
CSP
SNAPIN
K+
SUR1
KIR6.2
CREBc-JUN
H3
cAMP
+
Nucleus
KATP
complex
inactive
PKA

16. Mechanisms:
Glucose-induced insulin secretion is potentiated by
activation of GPCR (G-protein coupled receptors).
When hormones like glucagon, GLP-1, epinephron binds to
the G-protein couple receptors, which activates adenylyl
cyclase and produces cAMP from ATP.
This cAMP then activates protein kinase A (PKA) which
activates proteins involved in insulin secretion from
pancreatic beta-cells.

17. Cyclic AMP and PKA activation
R
cAMP
R
cAMP
PKA
inactive
R
C
R
C Activation of effectors responses
for specific cellular functions
PKA
active
PKA
active
Hormones,
Peptides...

AC

Gs
ATP
cAMP
Cell
PO4
GPCR
PO4

18. Insulin secretion & beta cells biology
Glucose
GLUT2
AC


Gs
GPCR
PKA
active
R
C
AKAP
Exocytosis of Insulin
Calcium channel,
L-type
Transcrip
tion
Insulin
MLC
ANN-1
SYN-1
SNAP25
CSP
SNAPIN
K+
SUR1
KIR6.2
CREBC-JUN
H3
cAMP
+
Nucleus
Role of sub-cellular localization of PKA ?

19. Subcellular localization of PKA
through AKAPs
cAMP
+
PKA Tetramer
(inactive)
R
C
R
C
Active PKA
AKAP
CC
AKA
P
Specific Organelles (Substrates)
Specific Organelles (Substrates)
Stimulus (Hormones via
GPCR)
+
RR

20. AKAPs at different organelles in cells

21. C
C
R
R
Tethering domain
AKAP
Subcellular localization
Inhibitory peptide
C
C
R
R