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| Question | Answer |
| 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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