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DEFINITION OF DIABETES
MELLITUS
Common Symptoms
Classic symptoms Others sympmtoms
increased hunger fatigue
tingling or numbness
increased thirst
in hands and feet
frequent urination recurring infections
gums, skin, lung,
weight loss
urinary bladder
slow healing
blurred vision
pruritus vulvae
erectile dysfunction
Diagnosis Criteria
Diabetes Mellitus
HYPERGLYCEMIA: fluid/electrolyte
imbalance.
Polyuria
IFG or IGT
(Predabetes)
DIABETES
IFG
FPG > 100 - 125
mg/dl
A1C
IGT
2-h PG > 140 199 mg/dl
5.7% to 6.4%
CLASSIFICATION OF DIABETES
MELLITUS
1.
2.
3.
4.
Type 1 diabetes
Immune-mediated diabetes.
510% of those with diabetes;
absolute insulin deficiency (insulin dependent
diabetes, type I diabetes, or juvenile-onset diabetes)
cellular-mediated autoimmune destruction of the cells of the pancreas.
markers of the immune destruction of the -cell
include
Idiopathic diabetes.
no known etiologies
D. Endocrinopathies
F. Infections
Gestational diabetes
mellitus (GDM)
Gestational diabetes
mellitus (GDM)
Type 2 diabetes
Type 2 diabetes is characterised by:
Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Department of Noncommunicable
Disease Surveillance, World Health Organization, Geneva 1999.
Receptor:
endothelial
function
Quantity / function
Post-receptor (mostly):
Translocation of GLUT
Synthesis of GLUT
Differential Diagnosis
Type 1 and Type 2 Diabetes
Type 1 Diabetes
Type 2 Diabetes
Insulin-dependent
Initially non-insulindependent
Body weight
Usually lean
Usually obese
Clinical onset
Often acute
Subtle, slow
Ketosis-prone
Yes
No
Family history
Common
Ethnicity
minorities
Predominantly white
More common in
Frequency of HLA-DR3,
DR4, DQB1*0201, *0302
Increased
Not increased
Islet autoantibodies
(GADA, ICA, IA-2A, IAA)
Present
Absent
Insulin resistance
Impaired glucose
tolerance
Type 2 diabetes
Pathophysiology of Type 2 DM
Insulin resistance
insulin receptor number
insulin receptor kinase activity
Post-receptor defects
GLUT4 translocation from impaired signaling
Impaired islet function
Loss of first phase insulin secretion
secretion of proinsulin
Defective pulsatile insulin secretion
Deposition of islet amyloid polypeptide
Hepatic
insulin
resistance
Excessive
glucose production
Impaired
insulin
secretion
Hyperglycemia
Glycosuri
Muscle/fat
insulin
resistance
Impaired glucose
clearance
Insulin
Insulin
receptor
PPAR
Glucose
transloca
tion
RXR
Synthesis GLUT 4
mRNA
PPRE
transcription
promoter
Coding reg
Modified from Howard L. Foyt et al. Thiazolidinediones. Diabetes Mellitus: a Fundamental and Clinical Text, 2nd Ed.
Insulin resistance
Glucose
Insulin
Insulin
receptor
Translocation
X Synthesis GLUT 4
mRNA
PPAR +RXR
PPRE
promoter
Muscle
Cells
transcription
Coding reg
Modified from Howard L. Foyt et al. Thiazolidinediones. Diabetes Mellitus: a Fundamental and Clinical Text, 2nd Ed.
Increased insulin
resistance
Insulin
secreti
on
Postprandial
glucose
Hyperinsulinaem
then -cell failur
Fasting
glucose
Hyperglycaemia
Abnormal
glucose toleranc
Adapted from Type 2 Diabetes BASICS. International Diabetes Center, Minneapolis, 2000.
Insulin Resistance
Pancreas
Increased
Lipolysis
Elevated
Plasma FFA
Liver
Muscle
Adipose Tissue
Reduced
Plasma Insulin
Hyperglycemia
Courtesy of S. Smith, GlaxoSmithKline
Lipolysis
LIVER
FFA mobilization
Liver insulin
resistance
FFA oxidation
FFA oxidation
Gluconeogenesis
Glucose utilization
Hyperglycemia
Boden G. Proc Assoc Am Physicians. 1999;111:241-248.
Insulin Resistance: An
Underlying Cause of Type 2
Diabetes
Aging
Obesity and
inactivity
Genetic
abnormalities
Type 2
diabetes
Medications
INSULIN
RESISTANCE
Rare
disorders
PCOS
Hypertension
Atherosclerosis
Dyslipidemia
Reaven GM. Physiol Rev. 1995;75:473-486
Clauser, et al. Horm Res. 1992;38:5-12.
-cell dysfunction
ability of -cells to
secrete insulin
Reduced
ability of -cells to
compensate for insulin
resistance
Impaired
Genetic
and environmental
pathophysiology
Insulin resistance
Protein
glycation
-cell
(genetic background)
Amyloid
deposition
lipotoxicity
elevated FFA,TG
Management of
Diabetes Mellitus
General Therapeutic
Objectives
The principle of
management
Education of diabetes
Lifestyle management
Diet
Exercise
Interventional of pharmacology
Oral treatment
Insulin
Basic education
1.
Survival skills
2.
Lifestyle Management
Diet & Exercise
Exercise
Nutritional
Recomendation
Energy needs
Activity level
Infections :10-20%
Nutritional Recommendations
for All Persons with Diabetes
acute &
whole body glucose disposal longterm
risk of developing Type 2 DM
GLUT4
Recommendations of
physical activity
Sulfonylureas
Repaglinide
Pancreas
Gut
Insulin secretion
Glucose
uptake
Acarbose
Miglitol
FFA output
Hyperglycemia
Rosiglitazone
Pioglitazone
Metformin
Rosiglitazone
Pioglitazone
Liver
Hepatic
glucose
output
Rosiglitazone
Pioglitazone
Metformin
Glucose
absorption
Muscle
Glucos
e uptake
Sulfonylureas
Repaglinide
Nateglinide
Biguanides
Thiazolidinediones
Acarbose
Insulin
secretagogues
}
}
Insulin
sensitizers
Inhibitors of
CHO
absorption
Sulfonylureas :
Mechanism action
Pancreatic effect
Extrapancreatic effect
Studied in vitro and vitro
In human studies; enhances insulin-stimulated
perpheral glucose utilization in both adipose tissue
and skeletal muscle.
Sulfonylureas: Mechanism
of Action
Na+
GLUT2
Na+
K+
K+
KIR K+
K
Ca2+
Pancreatic
cell
Insulin granules
Sulfonylureas
Vm
Ca2+
Ca2+
Voltage-gated
Ca2+ channel
First Generation
Sulfonylureas
Name
Tolbutamide*
Chlorpropam
ide
Tolazamide *
Acetohexami
de*
*not available
Daily
dose
range
5003000
100500
1001000
2501500
Second Generation
Sulfonylureas
Name
Glibenclamid 1.25e
2.50
Glipizide
2.5-40
Glipizide XL
5-20
Gliclazide
40-320
Glimepiride
4-8
20
40
20
320
8
1-2
1-2
1
1-2
1
Adverse Effects of
Sulfonylureas
Severe hypoglycemia
Overdose
Early in treatment
Most common with glybenclamide
Weight gain
Erythema, skin reactions
Blood dyscrasias (abnormal cellular
elements)
Hepatic dysfunction and other GI
disturbances
Contraindications for
Sulfonylureas
Pregnancy
Surgery
Severe infections
Repaglinide and
Nateglinide
Mechanism of action:
decrease ATP-sensitive K+
conductance
Additional high affinity binding site
identified in mouse -cells for
repaglinide
Biguanide
s
First
Generation- Phenformin
Phenethylbiguanide
Adverse Effects
Lactic acidosis
Risk of cardiovascular disorder
1,1-Dimethylbiguanide
Biguanides
Mechanism of action:
antihyperglycemic
insulin resistance
Mediated by activation of 5AMP-activated
protein kinase (AMPK) in hepatocytes and
muscle
Do not increase insulin secretion
Thiazolidinediones
Antihyperglycemic
Do not increase
CH3
ROSIGLITAZONE
insulin secretion
O
NH
Increase insulin
sensitivity in liver
and muscle
PIOGLITAZONE
O
NH
Thiazolidinediones: Mechanism
of Action
Ligands
for PPAR :
Nuclear
Insulin resistance
Glucose
Insulin
Insulin
receptor
Translocation
X Synthesis GLUT 4
mRNA
PPAR +RXR
PPRE
promoter
Muscle
Cells
transcription
Coding reg
Modified from Howard L. Foyt et al. Thiazolidinediones. Diabetes Mellitus: a Fundamental and Clinical Text, 2nd Ed.
Insulin
receptor
Glucose
Transloca
ti
on
Synthesis GLUT 4
PPRE
transcription
promoter
Muscle
Cells
mRNA
+ RXR
TZ
D
A
TZV
D
PPAR
Coding reg
Modified from Howard L. Foyt et al. Thiazolidinediones. Diabetes Mellitus: a Fundamental and Clinical Text, 2nd Ed.
glucosidase inhibitors
(Acarbose)
Clinicalrise
use in postprandial glucose
Smaller
For
Adverse
effects:
Gastrointestinal
disturbances; Flatulence,
nausea, diarrhea
Use gradual dose titration
Hyperglycemic emergencies
Total pancreatectomy patients
Acute or chronic hyperglycemia provoked
by:
Infection or trauma
Steroid therapy
Endocrinopathies such as hyperthyroidism
Other types of secondary diabetes
Summary of bioavailability
characteristic of the insulin
Insulin Type
Onset
Peak Action
Duration
Ultra short
acting
Insulin
5-15
lispro/aspart minutes
1-1,5 hours
3-4 hours
Short-acting
regular
15-30
minutes
1-3 hours
5-7 hours
2-4 hours
8-10 hours
18-24 hours
Long acting
Ultralente
4-5 hours
8-14 hours
25-36 hours
Insulin
glargine
6-8 hours
24 hours
Insulin Preparations
Ultra
fast/ultra
short-acting
regular
Plasma [Insulin]
Short-acting
Lispro/aspart
NPH
Intermediateacting
lente
ultralente
Long-acting
Ultra long-
glargine
12
16
20
24
Assesment of glycemic
control
Urinalysis
Glycosuria
Urinary ketones
Glycated haemoglobin
Blood glucose
ADA1,2
AACE
3
<7
< 6.5
IDF4
(Western
Pacific
region)
< 6.5
1. ADA. Diabetes Care 2004; 27: S1535; 2. ADA Diabetes Care 2002; 25: S3549;
3. Feld S. Endocrine Pract 2002; 8 (Suppl 1): 4082; 4. Asian-Pacific Type 2 Diabetes Policy Group.
Type 2 diabetes: Practical targetsand treatment. 4th Edn; Hong Kong: Asian-Pacific Type 2 Diabetes Policy Group, 2005.
< 7%
Fasting BG
Post prandial BG
Blood pressure
LDL-cholesterol
HDL-cholesterol
Men
Women
Triglycerides