ERS40 Biochemical Basis Of Diabetes Mellitus II Flashcards
Type 2 DM Pathogenesis
Insulin resistance
—> **Impaired glucose tolerance
—> β cell try to produce more insulin to compensate
—> **β cell dysfunction (accentuate effect of insulin resistance)
—> Hyperglycaemia
—> DM
Causes of Insulin resistance:
- Obesity (over-nutrition, environmental factors)
- Genetic factors (predisposition to obesity / insulin resistance)
Special relationship between abdominal fat + insulin insensitivity
Abdominal fat
- ***High lipolytic rate (perhaps ∵ higher abundance of pro-lipolytic adrenergic receptors)
- Can produce **Cortisol locally (∵ expression of 11β-hydroxysteroid dehydrogenase type 1) —> activate **Desnutrin (another HSL)
- ***Resistant to Anti-lipolytic effect of insulin
Pro-lipolytic Adrenergic receptors on adipocytes:
—> cAMP / PKA pathway
1. Stimulate **HSL —> TAG —> DAG —> MAG —> 3 fatty acids + glycerol
2. Phosphorylate **Perilipin (a protein forming a coat on lipid droplet) —> break down Perilipin —> allow action of HSL
Anti-lipolytic pathway:
- Anti-lipolytic Adrenergic receptors on adipocytes —> oppose cAMP / PKA pathway
- Insulin receptor —> **inhibit HSL (via PP), **inhibit removal of Perilipin (via PP), ***inhibit Desnutrin —> response to insulin blunted in abdominal adipose tissue
簡單而言: Abdominal fat特性: Insulin resistance + Lipolysis prone
Altered adipocytes lipid metabolism in Obesity
Obesity —> Large amount of abdominal fat —>
- ***↑ Basal rate of Lipolysis
- ***↑ Leptin-stimulated Lipolysis
- ***↓ IRS-1 expression in cytoplasm —> ↓ sensitivity to insulin —> loss of inhibitory effect on Lipolysis
Obesity
—> Altered metabolism of TAG in these adipocytes (i.e. Overactive of Lipolysis in abdominal fat)
—> ↑ release of fatty acids
—> taken up by peripheral tissues (skeletal muscles + liver)
簡單而言: Obesity令到↑ Lipolysis —> ↑ Fatty acid
Consequence of fatty acid over-abundance in liver, skeletal muscle
Path to type 2 DM:
1. Obesity, Over-nutrition, Lack of exercise
—> Fatty acid supply»_space; utilisation
—> Accumulation of lipid metabolites / TAG (esp. in abdominal fat)
- Dysregulated Lipolysis in adipose tissue
—> ↑ Fatty acids in circulation
—> taken up by peripheral tissues (skeletal muscles + liver)
—> ↑ Fatty acid-CoA (Fatty acyl CoA) (to produce energy)
Health individual / Exercising: —> ↑ Fatty acyl CoA —> Transport into mitochondria —> β oxidation —> Acetyl CoA —> ATP
Inactive individual: —> ↑ Fatty acyl CoA —> Converted back to DAG —> ↑ TAG —> ↑ ***VLDL-TAG (liver) + ↑ ***Intramyocellular TAG (skeletal muscle)
簡單而言: Fatty acid太多積聚係Liver + Muscle —> 製造***VLDL-TAG + Intramyocellular TAG —> Hyperlipidemia
***Causes of insulin resistance: Effect of lipid metabolites on insulin receptor functions
1st possible mechanism:
Excess fatty acids in skeletal muscles
—> **DAG
—> Activation of **novel PKC in skeletal muscle
—> **Serine / Threonine phosphorylation of IRS (normally phosphorylated at Tyrosine residues)
—> make IRS **incapable of functioning as a signalling protein for insulin receptor
—> Impairment of insulin signalling downstream of IRS
—> Selective inhibition of insulin effects (only affect glucose metabolism but not fatty acids metabolism)
However, some studies showed that accumulation of DAG in skeletal muscles not always correlated with insulin resistance
—> may have other mechanisms to induce insulin resistance
—> Fatty acids may not need to convert to DAG
2nd possible mechanism:
Fatty acids (liver / skeletal muscle)
—> **↑ PPARα/δ (peroxisome proliferator activated receptor): a transcription factor
—> ↑ expression of enzymes of β-oxidation pathway
—> ↑ β-oxidation of fatty acids
—> ↑ NADH, FADH, Acetyl CoA production
—> **Saturation of electron transport chain in mitochondria
—> **Production of ROS (superoxide anions)
—> **Activation of other protein kinases
—> ***IRS phosphorylation
—> Insulin resistance
簡單而言: Lipid令到Insulin唔work
***Normal Insulin, Insulin receptor pathway on Glucose metabolism
Insulin
—> Insulin receptor
—> Phosphorylation of IRS (**If phosphorylated by other kinases e.g. PKC —> IRS inactivated)
—> Recruitment of **PI3K (lipid kinase)
—> Synthesis of **Phosphatidylinositol 3,4,5-trisphosphate (PtdIns 3,4,5-P3) (highly phosphorylated phospholipid)
—> Recruitment of **PDK to plasma membrane
Liver:
1. Activation of **AKT kinase
—> ↓ Glycogenolysis + ↑ Glycogenesis + **↓ Gluconeogenesis
Skeletal muscles:
1. Activation of ***AKT kinase
—> ↓ Glycogenolysis + ↑ Glycogenesis
- Activation of **GLUT4 translocation
—> **↑ Glucose uptake
***Normal Insulin, Insulin receptor pathway on TAG metabolism
Liver:
Insulin
—> Insulin receptor (NOT affected by insulin resistance)
—> ↑ SREBP-1c (transcription factor)
—> ↑ Expression of genes for **De novo lipid biosynthesis in liver
—> Fatty acids (from meal + Lipolysis in adipose tissue)
—> TAG
—> VLDL-TAG
—> VLDL packaging inhibited by insulin, so very little VLDL exported in postprandial period immediately) (*Inhibited by insulin resistance)
—> later released from liver (during fasting period)
—> taken up by peripheral adipose tissue
However, De novo fatty acid synthesis does NOT display insulin resistance —> remain intact —> continue to synthesise fatty acids —> TAG —> VLDL-TAG
Insulin resistance —> VLDL packaging cannot be inhibited —> cannot stay in liver —> ***Untimely export from liver (under insulin resistance) —> Hyperlipidemia in type 2 DM
Peripheral tissues:
- Insulin ↓ Lipolysis
—> insulin resistance —> ↑ Lipolysis into fatty acids, glycerol, glucose
Overall: Insulin resistance: Liver 1. ↑ De novo lipid synthesis 2. ↑ VLDL-TAG secretion (untimely manner) Peripheral tissues 3. ↑ Lipolysis in peripheral tissues
Type 1 DM: promote β oxidation —> DKA
Type 2 DM: inhibit β oxidation —> less DKA
***Summary of consequences of insulin resistance in liver
Liver insulin resistance
Hyperglycaemia:
- Persistent Gluconeogenesis
- Persistent Glycogenolysis
- Impaired Glycogenesis
Hyperlipidemia:
- Enhanced De novo lipid synthesis
- Enhanced VLDL-TAG secretion (untimely manner)
Overall result: Hyperglycaemia + Hyperlipidemia
簡單而言: Insulin resistance最終導致Hyperglycaemia + Hyperlipidemia
***VLDL over-secretion and Hyperlipidemia
Consequence:
1. Transfer of TAG from VLDL to HDL
—> cause ***HDL to degrade rapidly
—> HDL important for reverse cholesterol transport for cholesterol homeostasis in peripheral tissue, endothelium of vessels
- Transfer of TAG from VLDL to LDL (normally transfer to adipocytes)
—> TAG rich LDL converted to small dense LDL (via Hepatic lipase)
—> highly ***atherogenic
簡單而言: VLDL-TAG太多的後果: ↓ HDL, ↑ small dense LDL —> Atherogenic
AMP-activated kinases
Insulin / Glucagon —> Regulate Nutrient / Fuel status of tissues (Availability of fuel)
AMP-activated (i.e. energy sensing) protein kinase —> Regulate **Energy status of tissues (*How much fuel to be used)
***Effects of exercise
↑ Fatty acid utilisation
Normal: Fatty acyl CoA —> β oxidation (mitochondria in skeletal muscle) —> Acetyl CoA —> TCA cycle —> energy
Inactive / lack exercise:
Acetyl CoA
—> Malonyl CoA (by active / non-phosphorylated Acetyl CoA carboxylase)
—> inhibit transport of Fatty acyl CoA into mitochondria
—> inhibit β oxidation
—> Stop Acetyl CoA production (-ve feedback)
—> ↑ Fatty acyl CoA in skeletal muscle
—> Insulin resistance
***(超級重要: Insulin still present —> can still promote conversion of Acetyl CoA to Malonyl CoA
—> whereas Type 1 DM lack of insulin have no Malonyl CoA
Type 1 DM: promote β oxidation —> DKA
Type 2 DM: inhibit β oxidation —> less DKA)
***AMP-activated kinase dependent pathway:
Physical exercise
—> ATP —> ADP —> AMP
—> stimulate AMP-activated kinase (inactive —> active)
—> phosphorylation of Acetyl CoA carboxylase
—> inactivated Acetyl CoA carboxylase
—> stop Malonyl CoA production
—> remove inhibition of β oxidation
—> allow conversion of Fatty acyl CoA to Acetyl CoA
—> ↓ Fatty acyl CoA (consumed in physical exercise)
—> ↓ inhibitory phosphorylation of insulin receptor
—> ↓ insulin resistance
***AMP-activated kinase independent pathway:
Physical exercise
—> Translocation of GLUT4 to plasma membrane
—> ↑ glucose uptake into skeletal muscle
Strategies for treating Type 2 DM
- Sulfonylureas
- Thiazolidinediones
- Biguanides
- insulin sensitisers - DPP-4 inhibitors
- DPP-4 catalyse breakdown of incretins - Alpha-glucosidase inhibitors
- inhibit breakdown of complex carbohydrates to monosaccharides e.g. Acarbose, Miglitol
- Sulfonylureas
MOA: Bind to regulatory subunit of ATP-sensitive K channels (where ATP normally bind to) —> activate regulatory subunit —> ***inhibit ATP-sensitive K channel —> ↑ Insulin secretion
- Thiazolidinediones (TZD e.g. Rosiglitazone, Pioglitazone)
MOA:
***PPARγ Transactivation
Bind to PPARγ
—> Expression of PPAR target genes involved in adipocytes precursor differentiation to become mature adipocytes
—> Alter profile of gene expression
1. Adipocytes become more insulin-sensitive (harder to undergo Lipolysis)
2. ↑ Fatty acid uptake by adipocytes
3. Preferential differentiation of pre-adipocytes to SC rather than visceral (i.e. abdominal) adipocytes
- **PPARγ Transrepression:
4. Suppress inflammatory activities (in adipose tissue) (suppress NF-κB: a transcription factor)
- Biguanides (e.g. Metformin)
MOA:
Not clearly known
Possibly:
Activation of ***AMP-protein kinase
—> More active fatty acid oxidation, glycolysis, glycogen synthesis etc.
