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38 Cards in this Set
- Front
- Back
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Describe the process of insulin production |
pre-proinsulin - ABC chain + pre signalling sequence
Pre signal cut to produce proinsulin with disulfide bond between A and B chain.
After C chain is cut from the rest, they are packaged into golgi |
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Describe the process of insulin seretion |
1) Increased glucose enters beta cell via GLUT 2 receptor.
2) Glucose under goes glycolysis to produce ATP
3) ATP sensitive K+ channel is inhibited
4) depolarization allows voltage gated Ca channel to open -> influx of Ca
5) Signalling cascade to release insulin |
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What are the effects of insulin? |
Promotes: glycolysis, glycogenesis, Protein synthesis, Glucose uptake in muscle and fat, uptake of ions (especially K+ and PO4)
Inhibits: gluconeogensis, ketogenesis, proteolysis, lipolysis, glucogenolysis |
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What is the range of predibetic FPG - fasting plasma glucose level? |
6.1-6.9 mmol/L |
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What is the prediabetic 2HPG - 2 hour plasma glucose after 75g glucose tolerance test |
7.8-11.0 mmol/L |
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What is the prediabetic A1C level |
6.0-6.4 % |
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What are the ranges of FPG, 2HPG, Random glucose and A1C level for diabetics |
FPG > 7.0 2hPG >11.1 Random glucose >11.1 A1C > 6.5% |
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What causes hyperglycemia in type 1 DM? |
Autoimmune destruction of beta cells leading to reduced insulin release
Increased release of glucagon from alpha cells due to lack of insulin inhibition |
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What are some of the risk factors of type 1 DM? |
Genetic- HLA linkage Environment - Triggering immune reaction Viral infection - Mumps, Rubella, coxackie virus B4 Chemical Toxins like (N nitroso compounds) |
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Does DKA occur in type 2 DM? |
No, because there is enough insulin to prevent DKA. |
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What are the risk factors of Type 2 DM? |
History of diabetes. NO HLA linkage
Obesity
Race: African American, Hispanic, American indian origin
Physical inactivity
Women with history of gestational diabetes, or giving birth to baby >9Ib
Hypertension with low HDL and high triglyceride |
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What are the 5 complications of diabetes? |
Neuropathy, retinopathy, CVD, Nephroapthy, Stroke |
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What is the target range of Type 1 DM patients? |
FPG level 4.0 - 7.0 2hPG level 5.0 - 10.0 A1C level below 7% |
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What is the main therapy for Type 1 DM? |
Insulin!
Either recombinant insulin that is identical with human insulin structure or modified insulin to alter the pharmacokinetics |
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How does rapid-acting and short-acting insulins work? Are they given subcutaneously? |
Have modified sequence to prevent aggregation which results in faster distribution of insulin.
E.g. insulin lispro, aspart, and gulisine
They can be given IV, subcutaneous |
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How does intermediate-acting insulin work? |
Insulin is conjugated to protein protamine to delay the absorption hence increased duration of action
e.g. NPH - insulin
They are given subcutaneously |
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How does long-acting insulin work? |
Similar- their chains are modified to have longer effect.
E.g. Insulin glargine has lower isoelectric point at the site of injection - hence takes time to be absorbed -> longer action
E.g. Insulin detemir have fatty side chain that relates well with albumin - hence decreased dissociation
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Why are longer acting insulins (including intermediate) helpful in Type 1 DM? |
They are able to provide constant basal level of insulin without having to rely on short acting insulins which increases the insulin level in short term. They are useful in achieving desired basal level |
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Compare the activity profile of regular insulin, short and longer acting insulins |
Regular insulin is slower to act than short acting insulins. They take longer to have effect and when they do, they have longer duration as well as lower glucose infusion rate
Rule of thumb: longer the acting insulins, lower glucose infusion rate, longer duration, and takes longer to have an effect |
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What is intensive therapy and why is it beneficial? |
Intensive therapy is a preferred therapeutic approach in type 1 DM where mix of short acting and intermediate/long acting insulins are given.
Short acting insulins are there to increase the insulin level post meal where as longer acting insulins are there to provide basal insulin level intact
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What are the signs of hypoglycemia |
Tachycardia, vertigo, excessive sweat (diaphoresis), confusion |
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How do you manage hypoglycemia? |
Give glucose!! 15 g of glucose ( 175 ml of juice or 2 tablespoons of raisins or 1 tablespoon of honey) |
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What is the problem with intensive treatment? |
It has higher incidence of hypoglycemia. However, its disadvantage is outbalanced by its beneficial effect of decrease complications compared to regular insulin therapy involving fixed dosage regime. |
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Describe the development of Type 2 DM |
Due to increased resistance, overproduction of insulin -> beta cells are exhausted -> decreased level of insulin
I.e. hyper-secretion of insulin initially due to hyporesponsiveness then hypo-secretion due to beta cell exhaustion |
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What is the target glucose ranges for type 2 DM? |
Same as Type 1 |
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What kind of drug is given to type 2 DM? |
Insulin sensitizer, and other drugs to deal with metabolic syndrome such as dyslipidemia and hypertesion |
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What are 4 different strategies of type 2 DM management? |
1) Decrease glucose absorption by preventing carbohydrate breakdown
2) Increase insulin sensitivity of the cell (sensitization)
3) Increase insulin production (secretagogue)
4) Hormone replacement i.e. giving exogenous insulin |
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What is methformin? |
Only available biguanides to treat type 2 DM
First level of therapy in Type 2 DM patients |
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What receptor is involved in intake of methformin into liver? |
OCT 1 - organic cation transporter 1 |
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Describe the mechanism of action of methformin |
1) Taken in by OCT-1 2) Inhibits mitochondrial complex 1 3) Increased level of AMP 4) Increased activity of AMPK pathway 5) Switches the cell from anabolic to catabolic stage hence decreased gluconeogensis or lipogensis, increase glucose and fatty acid uptake
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What is the main target of methformin? |
LIVER |
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What are rosiglitazone and piogltazone? |
Only available thiazolidinedione therapy for type 2 DM
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Where is the main site of action for thiazolidinedione? |
Adipocytes due to abundant PPAR receptor |
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What is the mechanism of action of thiazoldinedione? |
Promotes fatty acid storage as triglycerides
Decreases flux of fatty acids to liver and skeletal muscles from adipocytes which increases insulin sensitivty
NOTE: side effect include weight gain |
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Describe the mechanism of action of sulfonyl ureas and glinidies |
They are insulin secretagogues
They take advantage of ATP sensitive K+ channel
They bind to this channel, in activating it. This results in depolarization which causes voltage gated calcium channel to open. This causes calcium influx and increased release of insulin |
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What degrades Incretins GIP and GIP-1? |
DPP |
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Between GIPR agonists and DPP inhibitor, which is injectable? which is oral? |
GIP-1R agonists are injectable (~tide) e.g. Exenatide, liraglutide
DPP inhibitors are oral (~tin) e.g. sitagplitin, linaplitin |
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What are some of advantages and disadvantages of GIPR agonists over DPP inhibitor? |
Advantages Body weight - reduced Appetite - reduced CVD risk factor - reduced gastric emptying - significantly reduced
Disadvantages Nasuea, Dirrhea |
