Type 2 Diabetes Across Generations: From Pathophysiology to Prevention and Management

1. Type 2 Diabetes Across Generations: From Pathophysiology to Prevention and Management Nolan, Christopher J., Damm, Peter, Prentki, Marc Management of Type 2 Diabetes: New and Future Developments in Treatment Tahrani, Abd A., Bailey, Clifford J., Del Prato, Stefano, Barnett, Anthony H. The Lancet, July 9th 2011 Rachel McLaughlin University of Georgia Pharm D. candidate October 25, 2012

2. Diabetes Mellitus • Characterized by insufficient insulin secretion, resistance to insulin, or both • Type 1: complete absence of insulin due to autoimmune destruction of the β-cells of the pancreas • Type 2: resistance to insulin, leading to inadequate insulin production • ≥ 90% of all patients with diabetes • Insulin resistance characterized by increased resistance in the muscle and liver, increased gluconeogenesis in the liver, hyperglycemia, increased lipolysis, increased plasma free fatty acids and triglycerides

3. Pathophysiology • Excess calories- but obesity does not equal diabetes • Subcutaneous adipose tissue vs. visceral adipose tissue and organs • Islet β-cells (insulin) unable to compensate the excess fuel • Increased glucagon secretion, reduced incretin response • Inflammation of the adipose tissue (cytokine release) • Finally, development of peripheral insulin resistance

4. Pathophysiology • Genetic • Heritability is highly confirmed in diabetes • There are over 40 diabetes-associated loci in the genome • Environment • Intrauterine growth restriction associated with numerous adult diseases including DM2 • Women with DM2 at time of pregnancy linked to higher occurrences of diabetes and obesity in the child • Low vitamin D and B12 implicated • Diet and sedentary lifestyle

5. Medications http://healthplant.wordpress.com/2010/01/30/diabetes-a-report/

6. BUT... continued β-cell dysfunction • Need to sustain glycemic control, halt declining β-cell function, improve insulin activity, while avoiding hypoglycemia and severe side effects

7. The Incretins • Secreted in the intestines in response to nutrients in order to lower blood glucose • Stimulates insulin secretion, glucagon suppression • Slows gastric emptying and reduces food intake • Animal studies: reduces severity of MI and improves left ventricular ejection fraction • GLP-1 decreased amount in diabetics

8. GLP-1 mimetics • Exenatide (Byetta) and liraglutide (Victoza) • Once weekly Bydureon showed sustained weight loss and glycemic control for 2 years • Oral non-peptide agents that activate GLP-1 receptor have been identified and some animal studies are being done

9. Non-incretin β-cell stimulants • Glucokinase activators • Glucokinase phosphorylates glucose once in the cell and affects how fast it is metabolized and thus initiates insulin secretion • Piragliatin and other compounds increased insulin concentration and reduced glucose • But also showed some increased triglycerides and maybe hypoglycemia • Synthetic activators of certain G-protein-coupled receptors on β-cells • Potentiate glucose induced insulin secretion and improved glucose tolerance in animals

10. In the Kidneys • The kidneys reabsorb glucose in the proximal tubule, mostly through sodium-glucose-cotransporter 2 (SGLT2) • In diabetes, this may be enhanced because of SGLT2 upregulation so inhibiting SGLT2 can increase glusocuria enough to lower blood glucose • people with a familial renal glucosuria have a mutation here and have glucosuria without any complications • Dapagliflozin, canagliflozin, and others • Reduce fasting and postprandial plasma glucose and A1C • Low risk of hypoglycemia and can used in combination, including insulin

11. Bromocriptine • Sympatholytic D2 Dopamine agonist • Mediates effects via resetting of the dopaminergic and sympathetic tone in the central nervous system • Type 2 diabetics are believed to have a drop in dopaminergic tone in the early morning • Only the quick-release form (Cycloset) has been proven to lower fasting glucose and A1C, and reduced the risk of cardiovascular disease

12. Others • Bile acid sequestrants (Welchol) • Reduced A1C ~0.5% when in combination with metformin, SU, or insulin • Metabolic surgery: gastroplasty, gastric bypass, lap bands, biliopancreatic diversion • 78% of patients had resolution of their diabetes • Not any long-term outcomes studied

13. Conclusion • Type 2 diabetes will always require a patient-specific treatment plan • Side effects play a big role in the risk-benefit analysis for each patient • Promising treatments are in development to lower blood glucose and maybe preserve β-cell function • Metformin likely to remain first-line