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Type 2 Diabetes (incretins)
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- 1Useful effects of GLP-1 receptor:1: Increases insulin release from B-cells.
2: Increases insulin synth- glucose dependent.
3:Decreases glucagon secretion = decreased glucose prodn in the liver = improved glycemic control.
4:Increased insulin sensitivity in muscle and fat.
5:Increased B-cell mass.
6:Delays gastric emptying.
7:Promotes satiety = weight loss. - 2Background to the Blonde et al study in 'Diabetes' in 2006 on effects of Byetta (exenatide, Eli-Lilly), a GLP-1 mimetic:Study on T2DM patients. Exenatide = 1st GLP-1 mimetic FDA approved. Synthetic version of exendin-4, a 39 amino acid peptide with many glucoregulatory actions like GLP-1.
- 3Findings of the Blonde et al study in 'Diabetes' in 2006 on effects of Byetta (exenatide, Eli-Lilly), a GLP-1 mimetic:A decrease in HbA1C levels an body weights observed. After 30weeks at 10ug 40% of those with HbA1c >7% were <7%. Decreases also in CV risk, HDL-C, triglycerides and diastolic BP.
- 4Current issues with GLP-1 therapies?:Rapidly degraded into its inactive form in the circulation by DPP-IV (a tumour suppressor gene).
- 5Current DPP-IV inhibitors:Vildagliptin(Novartis) = orally effective, selective inhibitor of DPP-IV. Augments levels of GLP-1 and improves glucose tolerance. Mari et al study (2004) = Vildagliptin decreases day-long glucose levels and glucagon levels and augments plasma levels of intact active GLP-1 and GIP. Improves B-cell function by increasing insulin secretion at any given glucose level.
- 6] What do incretins do:Incretins = gut hormones secreted in response to a meal. Induce satiety and promote growth of new beta cells in the pancrease. Role is to augment glucose-stimulated insulin release from pancreas. Effect decreased in T2DM.
- 71: Site of action of TZDs: 2: Mode of action:1: Liver and peripheral stores.
2: Inhibits glucose production(liver) and stimulates glucose uptake (muscle). - 81: Site of action of incretins: 2: Mode of action:1: pancreas, liver, and GIT.
2: Augment glucose stimulated insulin release. Decreases glucagon secretion (in a glucose dependent manner). Promotes growth of beta cells. - 93 problems found with traditional therapies (not incretins):1: In T2Dm Beta cell function usually decreases regardless of intervention (UKPDS, Diabetes, 1995).
2: # of meds usually increases with duratio of disease (Turner et al, 1999).
3: With insulin, sulfonylurea & metformin therapies long-term glycemic control is lost (UKPDS, Lancet, 1998). - 10About Glucagon-like Peptide 1 Receptor antagonists (GLP-1s):Based on the modulation of the incretin system. Recent on the market (DeBlock & Van Gaal, Lancet, 2009). GLP-1 is a 30 amino acid peptide.
- 11Definition of DiabetesChronically raised blood glucose concentration
- 12Causes of Type 2 Diabetes Mellitus (T2DM):* Impaired Beta cell function.
* Insulin resistance. - 13% of DM cases that are type 2?Around 80%.
- 14Most NB clinical features of T2DM?*microangiopathy: retinopathy(leading cause of working age blindness), nephropathy (leading cause of end-stage renal disease), neuropathy.
*Atheroslcerosis.
*Osteoporosis.
*Limb loss. - 15Pathogenesis of Diabetic retinopathy:*Hypoglycaemia = cell wall dysfunction.
*Increased vascular permeability.
*large proteins in ECM.
*Retinal oedema and loss of vision.
*Subretinal exudates = fibrosis occurs.
*Permanent loss of vision due to ischemia. - 16Current therapies for diabetic retinopathy:*Strict glycemic control.
*Strict blood pressure control.
*Laser therapy.
* - 17Novel treatments for diabetic retinopathy:*PKCb inhibitors.
*Anti-VEGF therapy (with Avastin a monoclonal antibody targetting VEGF).
*Anti-growth hormone therapy. - 18Facts on diabetic nephropathy:*A microvascular kidney disease.
*Develops several years after onset of diabetes.
*Between 25-40% of diabetics will develop it.
*Develops in 4 stages.
*Ultimately leads to ESRF requiring dialysis and transplant.
*Novel therapies include antiGF beta and CTGF. - 19Obesity and T2DM:~80% of T2DM patients are obese. Goal is to lower blood pressure and cholesterol in these patients and increase insulin sensitivity in this cohort to decrease their chance of becoming diabetic.
- 20Goals of T2DM therapeutics:*To decrease the incidence of microvascular and cardiovascular disease.
*To improve Quality of Life.
*To limit the burden of treatment. - 21HbA1C:HbA1C is an integrated average of glucose levels over the last 8-10 weeks measured in DM2 patients. A level over 7% is considered at-risk of complications.
- 22A 1% decrease in HbA1C levels means a decrease of:*21% decreased risk of death.
* 14% decreased risk of heart attack.
*37% decreased risk of microvascular complications.
*43% decreased risk of peripheral vascular disorders. - 23Role of pancreas in regulation of blood glucose concentration:Insulin Secretion.
- 24Role of liver in regulation of blood glucose concentration:Glucose production.
- 25Role of GIT in regulation of blood glucose concentration:Glucose absorption.
- 26Role of peripheral stores (muscle and fat) in regulation of blood glucose concentration:Glucose uptake.
- 271: Site of action of sulfonylureas: 2: Mode of action:1: Pancreas.
2: Stimulates insulin release. - 281: Site of action of Biguanides (eg Metformin) : 2: Mode of action:1: Liver and peripheral stores.
2: Inhibits glucose production (liver) and stimulates glucose uptake (muscle).
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- Fichas sobre Type 2 Diabetes (incretins), creado por Chloe.H el 23/04/2013.
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- Chloe.H
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