25
PATHOPHYSIOLOGY OF TYPE – 2 DIABETES MELLITUS June 25, 2015 Year II Medical Students of AAU 1
1
PATHOPHYSIOLOGY OF
TYPE – 2 DIABETES MELLITUS
June 25, 2015 Year II Medical Students of AAU
2
Objectives
Understand T2DM Insulin resistance -cell dysfunction
Suspected causes Pathophysiology Metabolic changes
Treatment
4
Type 2 Diabetes Mellitus
A metabolic disorder with -- chronic hyperglycaemia
Arises from a combination of insulin resistance and
-cell dysfunction
associated with microvascular and macrovascular complications
Fasting blood glucose concentration --- > 126 mg/dl
do not require insulin to sustain life (with some exceptions)
5
Insulin resistance
The decreased ability of target tissues to respond properly to elevated insulin
Alone will not lead to type 2 diabetes i.e. only with impaired insulin secretion
Risk factor for T2DM especially in : Elderlies Obese Pregnant (gestational diabetes)
Substances produced by adipocytes include leptin and adiponectin
• Can be measured by continuous sampling of insulin/glucose
6
Cont’d…
8
-cell dysfunction
Reduced ability of -cells to secrete insulin in response to hyperglycaemia
Direct effects of inflammation on β cells arise from activation of the intraislet immune response
glucolipotoxicity and amyloid deposition result in β-cell apoptosis
Measured by Proinsulin:insulin ratio
i.e. Human pancreas incapable of renewing these cells after 30 years of age
9
Cont’d…
May be accelerated by: Toxic effects of sustained hyperglycemia Elevated free fatty acid Genetics
10
Cause of T2DM
Genetic factors- Strong component in T2DM
Mutation of IRS-1 gene KCNJ11 gene KCNQ1 gene Glucokinase genes Mitochondrial genes Insulin receptor genes
11
12
Environmental factors Aging Obesity
particularly central visceral fat obesity
Insufficient energy consumption
Alcohol drinking, Smoking
Cont’d…
13
Pathophysiology of T2DM
Bile acids activate GCBR-1 located on intestinal L cells, leading to GLP-1 secretion
GLP-1 acts both on β cells to enhance insulin secretion α cells to suppress glucagon secretion
i.e. GLP-2 activity is impaired in those with type 2 DM
14
Normally, if insulin resistance is present, β cells increase insulin output to maintain normal glucose tolerance.
However, if β cells are incapable of this task, plasma concentration of glucose increase
This leads to a decrease in glucose transport into the liver, muscle cells, and fat cells.
There is an increase in the breakdown of fat with hyperglycemia
Cont’d…
15
16
The β cell becomes increasingly dysfunctional and fails to secrete enough insulin to correct the prevailing hyperglycemia
Cont’d…
17
18
19
Metabolic changes in T2DM Mainly result of Insulin resistance
primarily on liver, muscle and adipose tissue
HyperglycemiaBy increased hepatic production of
glucoseCombined with diminished peripheral
useMinimal ketosis
Because insulin is still present
20
Hypertriacylglyceimia In liver… VLDL with TAG is secreted Chylomicrons – from dietary lipid Low lipoprotein degradation
Which is catalyzed by lipoprotein lipase in adipose tissue is low in diabetics
The plasma chylomicron and VLDL levels are elevated resulting in Hypertriacylglyceimia
Low HDL levels are also associated with type 2 diabetes.
Cont’d…
21
22
Treatment of T2DM
FOCUS --- Maintenance of blood glucose concentration Life style modification Diet control Control of overweight and obesity Education of the population Novel drugs
Yet NO CURE!!!
23
A general trend is to use oral agents that do not induce hypoglycemia (i.e. maintain the normal regulation by glucose on insulin secretion) Metformin TZD (pioglitazone) DPP4 inhibitor GLP – 1 analogs (α-glucosidase inhibitors)
Cont’d…
24
Reference Materials
o http://www.academic journals.org/JPAPo Oman Medical Journal (2012) Vol.27, No.
4:269-273o Lippincott’s Illustrated Reviews of
Biochemistry, 4th edition
Nutrition, metabolic diseases and GIT Module (IX) (NMDG2101)Biochemistry Seminar
Thank you!!!!G – 2A
Click icon to add picture
