diabetes

1. first oral agent for T2D
2. used since 50s
3. bind to SUR1= close KATP channel
4. side effects
   1. weight gain
   2. hypoglycemia
5. cost effective option
6. Non-sulfonylrea secretagogues
   1. Unlike sulfonylureas, these stimulate first-phase insulin release in a glucose-sensitive manner

1. bind to SUR1= close KATP channel

1. target SUR1

Nota:

•  Incretins are gastrointestinally secreted insulinotropic hormones that play an important role in glucose homeostasis - they are involved in augmentation of b-cell secretion of insulin and in suppression of glucagon secretion by the alpha cell.   

1. The incretin effect

   Nota:

   • the altered release of insulin following oral ingestion of glucose when compared with intravenous glucose challenge, even though the glucose concentration achieved in plasma may be equivalent. 
   1. two gut hormones are mainly responsible for the incretin effect- glucose-dependent insulinotropic peptide (GIP) and GLP-1.
2. GLP1
   1. an incretin that is released from intestinal L-cells in response to nutrients
   2. actions
      1. Delays gastric emptying, increase insulin sensitivity and reduce glucose production
      2. Reduce glucose peak after a meal
      3. Acts on the brain to reduce appetite and increases cardiac output
      4. may reduce b-cell apoptosis and promote b-cell proliferation/neogenesis

         Nota:

         • increase b cell numbers and hence increase insulin secretion 
      5. decreases postprandial glucagon secretion from pancreatic alpha cells, which helps to maintain the counter regulatory balance between insulin and glucagon
      6. decreases beta cell workload
   3. rapidly degraded by the enzyme DPP4
   4. drugs for diabetes
      1. exenatide and liraglutide are GLP-1 receptor agonists that are resistant to DPP-4 inhibition.
      2. DPP-4 inhibitors eg vildagliptin and sitagliptin cause increased endogenous GLP-1

1. pioglitazone and rosiglitazone
2. Agonists of PPARγ nuclear receptors in adipose tissue
   1. PPARγ
      1. regulates fatty acid storage and glucose metabolism
      2. stimulate lipid uptake and adipogenesis by fat cells
3. Alter gene regulation of lipid and glucose metabolism
4. Reduce circulating free fatty acids by 20-40%
5. Enhance insulin-receptor signalling in muscle and adipose tissue and therefore reduce insulin resistance
6. Reduced lipotoxicity and glucotoxicity of β-cells
7. Inhibit hepatic gluconeogenesis
8. Increase HDL cholesterol, reduce LDL density
9. 10y on the market
10. may have favourable effects on b-cell function by reducing exposure of the b-cells to the increased free fatty acid environment, i.e., lipotoxicity, which is postulated to contribute greatly to b-cell death
11. Side effects oedema and weight gain

1. metformin

   Nota:

   • only agent in this class had multiple actions 
   1. Well known drug- 20 years on the market
   2. Reduces circulating free fatty acids
   3. Reduces hepatic gluconeogensis and increases insulin sensitivity in skeletal muscle
   4. Acts via activation of AMP kinase, with further downstream effects on SREBP-1 and acetyl-CoA carboxylase; precise mechanism not fully elucidated
      1. Sterol Regulatory Element-Binding Proteins (SREBPs) are transcription factors
         1. increase fatty acid uptake
         2. SREBP1 expression was significantly reduced in type 2 diabetic subjects
   5. very robust effect to reduce hyperglycemia
   6. recommended as the first line treatment of diabetes with lifestyle changes
   7. direct effects on hepatic glucose and lipid metabolism
   8. Mechanism not precisely known
   9. Side effects; gastrointestinal intolerance, i.e., nausea, abdominal pain and diarrhoea.

Nota:

• Acarbose is an alpha glucosidase inhibitor in the intestinal brush border that prevents breakdown of complex carbohydrates to monosaccharides and reduces postprandial (after meal) hyperglycaemia

1. Inhibits α-glucosidase (enzyme) in brush border of small intestine

   Nota:

   •    These enzymes hydrolyse disaccharides to monosaccharides so they can be absorbed through the small intestine   
2. slow glucose absorption from the gut
3. some GI side effects
4. acarbose is associated with a significant reduction in the risk of CVD and hypertension

1. amylin

   Nota:

   •     Amiylin is co-secreted with insulin but reduced in patients with type 2 diabetes   
2. Inhibits glucagon secretion
3. Delays gastric emptying
4. Increases satiety- promote weight loss

Nota:

• SGLT2  (sodium glucose transporter) 

1. SGLT2
   1. SGLT2 mediates renal tubular glucose reabsorption
   2. exclusivley expressed in Proximal tubule
   3. possibly overexpressed in T2DM
2. Low affinity, high capacity
3. SGLT2 inhibition allows more glucose to be excreted in the urine instead of reabsorbed by the kidney
4. new drug
5. Selective inhibition of SGLT2 increases urinary glucose excretion by inhibiting renal glucose reabsorption