Title: Type 2 Diabetes Across Generations: From Pathophysiology to Prevention and Management
1Type 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
2Diabetes Mellitus
- Characterized by insufficient insulin secretion,
resistance to insulin, or both - Type 1 complete absence of insulin due to
autoimmune destruction of the ß-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
3Pathophysiology
- Excess calories- but obesity does not equal
diabetes - Subcutaneous adipose tissue vs. visceral adipose
tissue and organs - Islet ß-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
4Pathophysiology
- 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
5Medications
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es-a-report/
6- BUT... continued ß-cell dysfunction
- Need to sustain glycemic control, halt declining
ß-cell function, improve insulin activity, while
avoiding hypoglycemia and severe side effects
7The 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
8GLP-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
9Non-incretin ß-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 ß-cells - Potentiate glucose induced insulin secretion and
improved glucose tolerance in animals
10In the Kidneys
- The kidneys reabsorb glucose in the proximal
tubule, mostly through sodium-glucose-cotransporte
r 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
11Bromocriptine
- 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
12Others
- 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
13Conclusion
- 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 ß-cell function - Metformin likely to remain first-line