Module 23 Flashcards
In addition to the inconvenience, what is the disadvantage of using insulin for the treatment of obese patients with type II diabetes? Which class of oral hypoglycemic drug has a similar effect?
Insulin tends to increase appetite. If patients gain weight it makes type II diabetes worse. The sulfonylureas such as glyburide increase insulin release and have a similar effect.
Is a diet high in sugar harmful
- The answer is probably yes.
- there is increasing evidence that diets high in sugar and refined carbohydrates combined with a sedentary life style are the major contributors to obesity, type II diabetes, and metabolic syndrome.
- This is probably more of a risk factor for heart disease than fat. The food and beverage industry appear to have taken lessons from the tobacco industry.
What is the glycemic index?
- Glycemic index is a measure of how much a given food increases blood glucose. It is determined by ingesting an amount of a specific food that contains 50 grams of carbohydrate, and then for two hours the area under the curve of the glucose level above the baseline glucose level is measured. This area under the curve is compared to glucose itself, which is arbitrarily given a glycemic index of 100.
- It has several limitations. One is that a specific food will have a different effect on glucose when it is part of a meal, especially one with fat, which slows gastric emptying and decreases the rate of glucose release.
○ It also does not measure the insulin response, which may be different for different foods with the same glycemic index.
○ Fructose has a low glycemic index, and yet has a negative effect on type II diabetes. Although the glycemic index should not be taken too literally, it is true that eating foods with a large amount of sugar or rapidly metabolized starch is likely to make diabetes worse, and eating whole grains, nuts, etc is likely to decrease the risk of type II diabetes.
- It has several limitations. One is that a specific food will have a different effect on glucose when it is part of a meal, especially one with fat, which slows gastric emptying and decreases the rate of glucose release.
Which drugs can exacerbate hyperglycemia?
- The drugs include thiazide diuretics (especially diazoxide), adrenergic agents, corticosteroids, gatifloxicin (removed from the market because of this effect), olanzapine and several other antipsychotic medication, tacrolimus, protease inhibitors, abacavir, and asparaginase.
Keeping blood sugars as close to normal as possible in insulin-dependent diabetics appears to decrease many of the long term complications of diabetes; however, it also increases the risk of hypoglycemia which, when severe, can cause brain damage and even death. By what mechanisms do ß-blockers affect the risk of severe hypoglycemia in insulin-dependent diabetics?
- Hypoglycemia results in an adrenergic response, and this is associated with an increase in epinephrine, which both increases gluconeogenesis and causes symptoms such as tremor. ß-Blockers block the response to epinephrine, which prevents an increase in gluconeogenesis leading to worse hypoglycemia, and it also blocks the symptoms that would warn a patient that they are hypoglycemic so that they would know to ingest sugar.
Metformin is considered the best initial treatment for type 2 diabetes. It is inexpensive, does not promote weight gain or cause hypoglycemia, and it may be associated with lower overall mortality. However, it has a Blackbox Warning and several other cautions. What is the basis for these warnings, and what is the most recent data concerning the use of metformin under these conditions?
- Metformin inhibits complex I of the mitochondrial electron transport chain and can lead to lactic acidosis. Lactic acidosis is serious, sometimes fatal.
- The major risk factor is impaired renal function, because the major route of metformin clearance is renal, and impaired renal function markedly increases blood levels of the drug.
- Congestive heart failure, chronic liver disease, and any acute severe illness such as sepsis or a myocardial infarction also promotes lactic acid accumulation. A recent study demonstrated that metformin can be used safely in moderate chronic renal disease, congestive heart failure, or chronic liver disease. However, patients should be monitored for progression of their disease and caution is still warranted. Severe kidney disease with a glomerular filtration rate < 30 ml/min and unstable heart failure or liver disease remain contraindications
What serious diseases does metformin appear to prevent?
- Metformin inhibits mTOR and has been touted as decreasing aging. There is also evidence that the incidence of various types of cancer is lower in patients taking metformin. Metformin has some interesting properties; however, it is unlikely to be the fountain of youth.
What is the mechanism of action of acarbose, and how does that affect its adverse reaction profile? What serious adverse effect has been unexpectedly associated with acarbose?
- Acarbose inhibits alpha-glucosidase, which is involved in converting larger carbohydrates into glucose (notice the structural similarity to a starch).
- Therefore, it can cause flatulence because it results an increase in undigested carbohydrates that are metabolized by bacteria much like the effects of beans, which contain indigestible carbohydrates.
- It has also rarely been associated with severe liver injury, which is strange because its bioavailability is very low as you should be able to predict from its structure. If it cannot reach the liver, how does it damage the liver?
Other than diet and medication, what is the most important thing a type 2 diabetic can do to decrease the morbidity associated with diabetes
Moderate exercise has a significant beneficial effect on glucose tolerance. Exercise is a very important part of any therapy for diabetes and other forms of metabolic syndrome such as nonalcoholic steatohepatitis. There is a lot of controversy about the optimal type of exercise.
Sucralose (Splenda), a nonnutritive sweetener with zero calories, has no effect on glucose tolerance in obese patients (True or False).
- False. Sucralose significantly increases peak plasma glucose concentrations and the insulin area under the curve, but only in obese patients.
- Therefore, it appears that the use of artificial sweeteners in obese patients to prevent, or as part of the therapy of, type 2 diabetes is unwise. However, I have not seen this work replicated so some degree of skepticism is also warranted.
what measurement is used to determine the average degree of glycemic control, and what could lead to a falsely low estimation of the average blood sugar?
- Hemoglobin A1c (HbA1c) is a convenient way to determine the average blood glucose over a period of months. Glucose glycosylates hemoglobin, and the degree of glycosylation increases with the concentration of glucose in the blood.
- Although not a perfect measure, HbA1c is a good screening test for the average blood glucose over the life span of a red blood cell: ~120 days. If the life span of red cells is decreased for any reason, e.g blood loss or chronic renal disease, it will lead to a falsely low HbA1c level.
What is pramlintide, and how does it work?
- Pramlintide is a synthetic polypeptide analog of amylin used for the treatment of type II diabetes. It slows gastric emptying, increases satiety, and decreases the inappropriate production of glucagon. Obviously being a polypeptide it must be given parenterally.
What are exenatide and liraglutide, and how do they work? What other indication has liraglutide been approved for? From what source were the first GLP-1 agonists derived?
- These are glucagon-like protein-1 (GLP-1) agonists that mimic incretin. They increase insulin secretion, suppress glucagon secretion, and slow gastric emptying.
- Liraglutide has also been approved for weight loss in patients with a BMI > 30 or complications of obesity. Exenatide is a synthetic version of a hormone first isolated from the saliva of the Gila monster (a poisonous lizard found in the Southwestern US.)
What is sitagliptin and how does it work?
- Sitagliptin is a dipeptidyl peptidase-4 inhibitor, the enzyme involved in the breakdown of the incretin GLP-1. Therefore, it has similar effects as GLP-1 agonists, but it has the advantage of being a small molecule that can be given orally.
- However, it and the newer analogs such as saxagliptin, linagliptin, and alogliptin have been associated with a significant incidence of serious adverse reactions such as pancreatitis and joint pains.
What is canagliflozin?
- Canagliflozin is another new drug for the treatment of diabetes. It works by inhibiting the subtype 2 sodium-glucose transporter (SGLT2) in the kidney, which results in loss of glucose in the urine. You can see the sugar motif in the structure of the drug. Although it contains a sugar motif, overall it is relatively lipophilic and is well absorbed. As might be expected, an increase in urine glucose leads to an increase in the risk of urinary tract infections
