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Flashcards in Insulin and Anti-Diabetics Deck (49):

What is considered the glucose set-point in the body, above and below which glucagon / insulin will maintain control?

90 mg/dL

Above 90: Insulin increases storage via uptake into skeletal muscle and liver, decreasing glycogenolysis and gluconeogenesis

Below 90: Glucagon increases glycogenolysis and gluconeogenesis


What are the incretins and what is their function?

GIP and GLP1, released by intestinal mucosal cells, respond to ingested food to increase beta-cell production of insulin for a meal


How do E / NE function in glucose homeostasis?

They act to mobilize glucose from liver under stress / exercise conditions -> prevent hypoglycemia and create many of the symptoms associated with hypoglycemia

alpha2 - inhibitory to insulin release
beta2 - enhances insulin release


What is the function of cortisol in glucose homeostasis?

Cortisol mobilizes glucose from liver and stimulates gluconeogenesis + glycogenolysis under low glucose conditions


How is insulin secretion initiated by beta-cells?

Glucose is brought into the cell according to its concentration gradient. Glycolysis causes ATP to be produced. ATP acts as a second messenger to close an ATP-sensitive K+ channel, causing a depolarization. Depolarization triggers opening of voltage-gated Ca+2 channel, allowing insulin influx


What are the four major long-term diabetes complications?

1. Cardiovascular - dysregulation of lipid metabolism and subsequent atherosclerosis
2. Retinopathy
3. Nephropathy -> high glucose levels cause kidney dmg
4. Neuropathy - deterioration of peripheral motor and sensory nerves -> bacterial ulceration and gangrene


Why is Type 1 diabetes a disease of starvation?

In the absence of insulin, glucose cannot be taken up / stored in peripheral tissues, and is instead peed out. To increase glucose in cells, cells futilely redirect and catabolize proteins / fatty acids into gluconeogenesis


What is the main cause of death in Type 1 diabetes?

Ketoacidosis -> acidification of blood due to usage of ketone bodies as primarily energy currency


Why can we not use fatty acid for gluconeogenesis?

It is important to note that animals are unable to effect the net synthesis of glucose from fatty acids. Specifically, acetyl CoA cannot be converted into pyruvate or oxaloacetate in animals. Remember that in order to initiate gluconeogenesis, we need to convert pyruvate to PEP via carboxylation of pyruvate


What is the primary difference between synthetic insulins?

Insulin preparations have different solubilities
-> regular insulin is very soluble and rapid-acting
-> other insulins can take longer to diffuse out and can maintain a stable baseline


What are the two primary forms of insulin in the body?

Monomeric - active form
Hexameric - insulin self-associates into inactive form


What is NPH insulin?

"Neutral protamine" - intermediate acting insulin mixed with protamine to slow absorption


What is Lente insulin?

Insulin with slow absorption, in amorphous insulin-zinc suspension


What is ultralente insulin?

Very slow absorption - also suspended with zinc


What two insulins are very rapidly acting and what is their mechanism?

Lispro insulin and aspart insulin

They are insulin with mutations introduced so insulin does not associate into its hexameric form


What is glargine insulin?

"Peakless" or ultra-long acting insulin that diffuses from the injection site -> favors hexameric form

Pretty much the opposite of lispro and aspart insulin


What does a general insulin regimen consist of?

A basal long-acting insulin like NPH or Lente, with usage of rapid-acting insulins like lispro insulin just before a meal to handle the post-prandial glucose surge


How do insulin pumps work?

They continuously dribble insulin at baseline, and at a meal, the patient administers an extra bolus of insulin


What are the adverse reactions of insulin?

Hypoglycemia with overdose, with possible infections at pump site if using a pump


What are the symptoms of a hypoglycemic state and what can induce it?

Sweating, tremor, blurred vision, and mental confusion

Exercise and stress can also precipitate this (exercise increases glucose uptake by cells)


If a patient is in a hypoglycemic coma and cannot eat sugar tablets or orange juice, what should be done?

Inject them with glucagon -> reverses diabetic coma.


What is an extremely important component of Type 1 diabetes management?

Self monitoring via frequent testing


What are the cutoff's for diabetes and typical treatment goal of HbA1c?

>6.5% = diabetes
Goal: Reduce to <7%


What is the definition of Type 2 diabetes, and what is intimately linked to it?

Coupling of insulin resistance with beta cell insufficiency

Intimately linked to obesity


What is metabolic syndrome X?

Panel of symptoms: visceral adiposity (very bad, around liver, stomach, heart, and pancreas), insulin resistance, dyslipidemia, hypertension


What are the hypotheses which link adiposity to insulin resistance?

1. Toxicity of circulating fats
2. Endocrine effects of adipose tissue -> release of leptin, resistin, and TNFa / IL-6 which control inflammation
3. Inflammation from ectopic fat storage -> in liver and visceral organs, causes insulin resistance


Historically, what was the mainstay of Type 2 diabetes treatment? What is their mechanism of action?


They bind ATP-sensitive K+ channel in beta cells, reducing its conductance. This stimulates insulin release from pancreas (requires functional Beta cells)

-> basically, they act like glucose in stimulating insulin


What are the three sulfonylureas primarily being used today?

1. Glimepiride
2. Glipizide
3. Glyburide


What are the adverse reactions of sulfonylureas?

1. Induction of severe hypoglycemia
2. Stimulation of appetite (due to hypoglycemia) -> weight gain
3. High failure rate as disease progresses (beta cell failure)


What are the meglitinides?



What do meglitinides do and why might they be preferable to sulfonylureas?

Rapid-acting and short duration sulfonylurea-like compounds -> block the ATP-sensitive K+ channel.

Taken at mealtimes to blunt post-prandial blood glucose surge.

Less likely to induce hypoglycemia -> just skip a pill if you are going to skip a meal (won't induce hypoglycemia like sulfonylureas would because these are shorter acting)


What is the current first line treatment for diabetes and what is its mechanism of action?

A biguanide called metformin

Lowers blood glucose levels without stimulating insulin release.

1. Reduces gluconeogenesis (reduced liver output)
2. Enhances insulin action on peripheral tissues (reduces resistance)

unknown molecular mechanism


What are the adverse effects of metformin use and who is it contraindicated in?

GI disturbances -> dose-related, especially at start of therapy
Lactic acidosis (from decreased usage of lactate in gluconeogenesis)
-> avoid in renal disease, liver disease, or alcoholics


What are the benefits of metformin use?

No associated hypoglycemia risk
May lead to weight loss due to anorexia side effect
May be used with sulfonylureas -> beneficial synergy


What are the thiazolidinediones (TZDs) also called? What drugs are in this class?


1. Rosiglitazone
2. Pioglitazone


What is the mechanism of action of the TZDs and what drug are they similar to?

Similar to metformin, in that they reduce insulin resistance without posing hypoglycemia risk

Mechanism: activate PPARy receptor, expressed in white adipocytes which is a nuclear transcription factor. This suppresses the release of resistin from white adipocytes


What are the adverse effects of glitazones? How does this relate to their usage

This keeps them from being used alot, only used as second line in combination:
1. Hepatotoxicity
2. Congestive heart failure from 3. Edema
4. Weight gain -> significant
5. Heart attack
6. Bone loss


Why is simply injecting GLP-1 into diabetic patients not a good treatment option? What are the advantages of incretins?

It has a very short half-life

Incretins increase insulin secretion (like sulfonylureas or meglitinides) but still require a high blood glucose, and thus will not induce hypoglycemia


What enzyme metabolizes GLP-1 in the human body?

DPP-4 protease


What drug is a GLP-1 homolog isolated from Gila monster?

Exenatide - resistant to DPP-4 protease


What drug is a human GLP-1 with a mutation making it DPP-4 resistant?


More effective -> given once daily injection


What are the actions of exenatide and liraglutide?

Induces insulin release, depresses glucagon release -> good for post-prandial surge

Also: Blunts appetite by delaying gastric emptying
-> associated with significant weight loss!
->liraglutide even approved for obesity


What are exenatide / liraglutide given with? Adverse effect?

Approved for combination use with sulfonylureas and metformin, may cause nausea

Also may induce hypoglycemia if given in combination with sulfonylureas


What drug is a DPP-4 inhibitor, and what is its primary benefit over the GLP-1 homologs? What is its main side effect?

Sitagliptin (Januvia)

Can be taken orally, does not show GI disturbances.

However, no associated weight loss :/

Side effect: Acute pancreatitis


What is SGLT2 vs SGLT1?

Both combine to reabsorb all glucose if blood level is <200 mg/dL

SGLT2 - high capacity, low affinity transporter in kidney, co-transports sodium and glucose

SGLT1 - low capacity, high affinity, prevents hypoglycemia by taking up glucose from urine when your body REALLY needs it


What are the SGLT2 inhibitors?


end in -gliflozin


What are the clinical uses / benefits of SGLT2 inhibitors?

Taken orally, modest HbA1c reduction in combination with metformin.

Also reduces CVD outcomes and may promote weight loss due to excretion of glucose


What are the risks of SGLT2 inhibitors?

Urinary tract yeast infections -> due to glucose in urine
Diabetic ketoacidosis (rare, perhaps from hypoglycemia)


When is insulin therapy for T2DM used, and what drug is typically given?

Typically glargine insulin in early severe stages (very long acting), in combination with metformin

Full insulin replacement is only used in very severe disease -> beta cell failure