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

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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
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Diabetes 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

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Pathophysiology

• 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

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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

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Medications
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• 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

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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

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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

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Non-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

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In 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

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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

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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

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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 ß-cell function
• Metformin likely to remain first-line