Type 2 Diabetes (incretins)

Chloe.H
Flashcards by Chloe.H, updated more than 1 year ago
Chloe.H
Created by Chloe.H over 8 years ago
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Flashcards on Type 2 Diabetes (incretins), created by Chloe.H on 04/23/2013.

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Useful 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.
Background 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.
Findings 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.
Current issues with GLP-1 therapies?: Rapidly degraded into its inactive form in the circulation by DPP-IV (a tumour suppressor gene).
Current 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.
] 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.
1: Site of action of TZDs: 2: Mode of action: 1: Liver and peripheral stores. 2: Inhibits glucose production(liver) and stimulates glucose uptake (muscle).
1: 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.
3 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).
About 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.
Definition of Diabetes Chronically raised blood glucose concentration
Causes of Type 2 Diabetes Mellitus (T2DM): * Impaired Beta cell function. * Insulin resistance.
% of DM cases that are type 2? Around 80%.
Most 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.
Pathogenesis 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.
Current therapies for diabetic retinopathy: *Strict glycemic control. *Strict blood pressure control. *Laser therapy. *
Novel treatments for diabetic retinopathy: *PKCb inhibitors. *Anti-VEGF therapy (with Avastin a monoclonal antibody targetting VEGF). *Anti-growth hormone therapy.
Facts 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.
Obesity 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.
Goals of T2DM therapeutics: *To decrease the incidence of microvascular and cardiovascular disease. *To improve Quality of Life. *To limit the burden of treatment.
HbA1C: 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.
A 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.
Role of pancreas in regulation of blood glucose concentration: Insulin Secretion.
Role of liver in regulation of blood glucose concentration: Glucose production.
Role of GIT in regulation of blood glucose concentration: Glucose absorption.
Role of peripheral stores (muscle and fat) in regulation of blood glucose concentration: Glucose uptake.
1: Site of action of sulfonylureas: 2: Mode of action: 1: Pancreas. 2: Stimulates insulin release.
1: 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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