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ENDOCRINE
HORMONE
Insulin, Glucagon &
Diabetes mellitus
Islet
Pancreas
Insulin secretagogue
• Sulphonylureas
• Meglitinides,
•GLP-1
a cell
b cells
Pancreas – 3 types of cells
1. a cell (5-10%) – secrete glucagon
2. b cells (70-80%) – secrete insulin
3. d cells (5%)
– secrete somatostatin
Diabetes
Diabetes mellitus is a heterogeneous group of
metabolic disorders characterized by hyperglycemia
resulting from defects in insulin secretion, insulin
action, or both.
(American Diabetes Association 2001)
Defective Insulin secretion
Absolute insulin
Defective Insulin action
Diabetes
Symptoms of Diabetes
1. Polydipsia (Excessive thirst, dry mouth)
2. Polyuria (excessive urination)
3. Tiredness, fatigue, irritability
4. Recent change in weight.
5. Polyphagia (increased food consumption)
6. Blurring of vision
7. Nausea, headache
Complication of Diabetes
• Diabetes is a complex heterogeneous disease where multiple levels of abnormalities are
present in various tissues.
• Defects of diabetes mellitus include long-term damage, dysfunction and failure of
various organs.
• The major long-term complications of diabetes mellitus are macrovascular and
microvascular diseases such as nephropathy, retinopathy and neuropathy
1. Macrovascular complication
- Coronary and peripheral vascular disease
- hypertension
2. Microvascular complication
- Retinopathy with potential blindness
- Neuropathies with risk of foot ulcer, amputation.
- Nephropathy that may lead to renal failure.
- Reduce resistance to infection
Diabetes - classification
1. Type 1 (IDDM)
2. Type 2 (NIDDM)
3. MODY (Maturity-onset diabetes)
4. Gestational diabetes
Type 1 diabetes
• Type 1 diabetes is defined by an absolute requirement of exogenous
insulin results from the autoimmune destruction of insulin-secreting
pancreatic B c ells.
• Type 1 diabetes prone to ketoacidosis and exogenous insulin is required
to prevent ketosis.
Type 2 diabetes
• Type 2 diabetes is characterized by a relative insulin deficiency due to
insulin secretory defect with insulin resistance.
• Ketoacidosis is absent.
• Common risk factors: obesity, genetics.
Etiology/causes of Diabetes
Type 1 Diabetes
• The common causes of type 1 diabetes (90% cases) is autoimmune
destruction of B cells.
Environmental factors
(virus and dietary component
Genetic factors
(HLA antigen)
Autoimmune destruction of B cell
Type 2 Diabetes
•
Obesity
•
Insulin resistance
•
Genetic factors (family history of diabetes)
HLA, Human leukocyte antigen
Important feature of type 1 and type 2 diabetes
Clinical & other
Type 1
Type 2
Age of onset
Usually <30
Usually >40
Weight
Non-obese
Usually obese
Ketosis
Common
Rare
Plasma glucose level
High
Mild to
features
moderate
Islet cell mass
Severely
Moderately
reduced
reduced
Autoantibodies
Present
Absent
Family history of
Uncommon
Common
diabetes
Mechanism of insulin secretion
Insulin
AA, arachadonic acid; AC, adenylyl cyclase; Ach, acetylcholine; CaM PK,
calmodulin-dependent kinase; CCK, cholecystokinin; DAG, diacylglycerol;
GK, glucokinase; GIP, gastric inhibitory polypeptide; Gp, G protein; IP3,
inositol 1,4,5-triphosphate; PKA, protein kinase A; PKC, protein kinase C;
PLA2, phospholipase A2; PLC, phospholipase C.
M/A of Sulphonylurea
GLP, GIP
PDE
5-AMP
Insulin release
Ach, CCK
+
RX871024
Troglitazone
Ca2+
Insulin secretion
Imidazoline compd (RX871024) DAG level & activates PKC
Diabetes therapy
The goal of diabetes management
is
to
achieve
as
near
normoglycemia as in practicable.
1. Diet
2. Insulin
3. Oral hypoglycemic agents
(sulphonylyurea or biguanide)
Antidiabetic drugs
1. Sulphonylurea (insulin secretagogue)
First generation
 tolbutamide
 tolazamide
 acetohexamide
Second generation
Drugs in pipeline

glucagon-like-peptide 1 (GLP- 1)
and analogues
 glibenclamide

 glipizide
 gliclazide
gastric inhibitory polypeptide (GIP)
and analogues

Amylin
2. Biguanide
 metformin
 phenformin
 buformin
3.
a-glucosidase inhibitors
 acarboseibitor
4. Thiazolidinediones (insulin sensitizers)
 troglitazone
 pioglitazone
 rosiglitazone
5. Meglitinides (insulin secretagogue)
 repaglinide
Principal modes and sites of action of antidiabetic drugs
Liver
glucose output
• Metformin
•Thiazolinediones
Pancreas
 Insulin secretion
• Sulphonylureas
• Meglitinides,
•GLP-1
Gut
Delayed glucose absorption
• a-glucosidase inhibitors
(eg. Acarbose)
• Metformin, GLP-1
Muscle & Adipose tissue
 Peripheral glucose uptake
• Metformin
 Insulin sensitivity
•Thiazolidinediones, Amylin
Antidiabetic drugs: main modes of action
Drug
Main actions
Insulin
Sulphonylureas
 HGO peripheral glucose
utilization
 Insulin release
Metformin*
 Insulin resistance
Acarbose§
 Rate of carbohydrate digestion
Troglitazone
 Actions of insulin
Repaglinide
 Postprandial insulin release
*Biguanide; §a
glucosidase inhibitor, thiazolidinedione;
 non-sulfonylurea insulin release. HGO, hepatic glucose
output.
M/A of Sulphonylurea
Sulpholylurea
GLP, GIP
Extendin
PDE
5-AMP
IBMX
Piperazine
GLP-1 receptor agonist : Extendin (newer drug)
Insulin release
Ach, CCK
+
RX871024
Troglitazone
Ca2+
Imidazoline compd (RX871024) DAG level & activates PKC
Insulin secretion