39 Questions
What is the primary trigger for insulin secretion?
Increased glucose levels
Which type of insulin is normally catabolized by insulinase produced by the kidney?
Human insulin
Why does oral glucose elicit more insulin secretion than IV glucose?
Gut hormone release
What is the structure of human insulin?
51 amino acids connected by 1 disulfide bridge
Which insulin preparation is modified to have prolonged action?
Lantus
What is the main effect of increased ATP levels in β-cells?
Induces an influx of Ca2+
Why does oral administration of glucose elicit more insulin secretion?
Causes gut hormone release augmenting the insulin response
How does metformin enter the cell?
Through SLC22A1 and inhibiting mitochondrial complex I
What is the result of inhibiting mitochondrial complex I by metformin?
Reduced ATP levels and accumulation of AMP
How do α-Glucosidase inhibitors like acarbose and miglitol delay carbohydrate digestion?
By competitively inhibiting α-glucosidase activity
What is the pharmacokinetics of acarbose used as an α-Glucosidase inhibitor?
Poorly absorbed and remains in the intestinal lumen
Which enzyme hydrolyses oligosaccharides to monosaccharides in the intestine?
Alpha-glucosidase
What is a common adverse effect of α-Glucosidase inhibitors like acarbose and miglitol?
Flatulence, diarrhea, cramping
What is the mechanism of action of metformin on gluconeogenesis?
Suppresses gluconeogenesis by reducing enzyme activity and gene expression
How does the change in energy charge induced by metformin affect AMPK activation?
Activates AMPK due to low ATP levels
What is the primary function of GLP-1 in relation to insulin secretion?
It stimulates insulin secretion
What is the primary purpose of combining short-acting and longer-acting insulin preparations?
To achieve a consistent and sustained lowering of glucose levels
Which of the following statements about regular insulin is true?
It is produced using genetically engineered bacteria
How does GLP-1 affect glucagon secretion?
It suppresses glucagon secretion
What happens to native GLP-1 after parenteral administration?
It is rapidly degraded by dipeptidyl peptidase-IV (DPP-IV)
Compared to regular insulin, ultrashort-acting insulin preparations like lispro, aspart, and glulisine have:
A more rapid onset of action
When should lispro insulin be administered in relation to a meal?
15 minutes before the meal
Which of the following is a mechanism of insulin action?
It binds to specific high-affinity membrane receptors with tyrosine kinase activity
Which of the following statements about glulisine insulin is true?
It can be given up to 20 minutes after starting a meal
What is the effect of insulin on glucose transport in muscle cells?
It increases glucose transport
Which of the following is NOT an action of insulin on adipose tissue?
It increases gluconeogenesis
What is the primary difference between lente insulin and isophane (NPH) insulin?
Lente insulin is combined with protamine, while NPH is not
What is the goal of insulin therapy in diabetic patients?
To mimic the normal basal, prandial, and post-prandial secretion of insulin
Which of the following statements about lente insulin is true?
It is a combination of regular insulin and ultralente insulin
What is the purpose of combining insulin with protamine in the case of isophane (NPH) insulin?
To delay the onset of action and prolong its effectiveness
Which of the following is NOT an action of insulin on the liver?
It increases triglyceride synthesis
Which drug class for treating Type 2 Diabetes stimulates the release of insulin from pancreatic islet cells?
Sulfonylureas
What is the most common adverse effect associated with Sulfonylureas?
Hypoglycemia
How do Sulfonylureas increase the sensitivity of insulin receptors on target cells?
By blocking potassium channels in beta-cell membranes
Which Sulfonylurea has the shortest duration of action?
Tolbutamide
What is the primary mechanism of action of Sulfonylureas on beta-cells?
Blocking ATP-sensitive potassium channels
In what way do Sulfonylureas affect glucagon secretion?
Reduce glucagon secretion
What happens in cases of hepatic or renal insufficiency with Sulfonylureas?
Increased risk of hypoglycemia
How do Sulfonylureas impact insulin receptors in target tissues?
Increase the binding of insulin to target tissues
Study Notes
GLP-1 and Insulin
- GLP-1 stimulates insulin secretion, suppresses glucagon secretion, slows gastric emptying, reduces food intake, increases β cell mass, maintains β cell function, improves insulin sensitivity, and enhances glucose disposal.
- The glucose-lowering effects of GLP-1 are preserved in type 2 diabetics.
- However, native GLP-1 is rapidly degraded by dipeptidyl peptidase-IV (DPP-IV) after parenteral administration.
- GLP-1 receptor (GLP-1R) agonists and DPP-IV inhibitors have shown promising results in clinical trials for the treatment of type 2 diabetes.
Mechanism of Insulin Action
- Insulin binds to specific high-affinity membrane receptors with tyrosine kinase activity.
- Phosphorylation cascade results in the translocation of Glut-4 (and some Glut-1) transport proteins into the plasma membrane.
- It induces the transcription of several genes resulting in increased glucose catabolism and inhibits the transcription of genes involved in gluconeogenesis.
- Insulin promotes the uptake of K+ into cells.
Action of Insulin on Various Tissues
- Liver: ↓ glucose production, ↑ glucose transport, ↑ glycolysis
- Muscle: ↑ glucose transport, ↑ glycolysis
- Adipose: ↓ glucose production, ↑ glucose transport, ↑ lipogenesis, ↑ lipoprotein lipase activity, ↑ TG synthesis, ↑ glycogen deposition, ↓ intracellular lipolysis, ↑ protein synthesis
Insulin Therapy
- The goal of insulin therapy is to mimic the normal basal, prandial, and post-prandial secretion of insulin.
- Short-acting forms are usually combined with longer-acting preparations to achieve this effect.
- Rapid Onset and Ultrashort-acting Preparations:
- Regular insulin: short-acting, soluble, crystalline zinc insulin, usually given subcutaneously, rapidly lowers glucose levels.
- Lispro, Aspart & Glulisine preparations: classified as ultrashort-acting forms with an onset more rapid than regular insulin and a shorter duration.
- Intermediate–acting Insulin Preparations:
- Lente insulin: amorphous precipitate of insulin with zinc ion combined with 70% ultralente insulin, onset is slower but more sustained than regular insulin.
- Isophane NPH insulin: suspension of crystalline zinc insulin combined with protamine (a polypeptide), conjugation with protamine delays its onset of action and prolongs its effectiveness.
Type 2 Diabetes Treatment
- Classes of Oral Hypoglycemic Drugs:
- Sulfonylureas
- Biguanides
- Thiazolidinediones
- Alpha-glucosidase inhibitors
- Meglitinides
- Sulfonylureas:
- Stimulate release of insulin from pancreatic islet cells
- Increase sensitivity of insulin receptors on target cells
- Most common adverse effect is hypoglycemia
- Alpha-Glucosidase Inhibitors:
- Acarbose and miglitol: delay carbohydrate digestion by competitively inhibiting α-glucosidase
- Pharmacokinetics: Acarbose is poorly absorbed, remaining in the intestinal lumen; Miglitol is absorbed and excreted by the kidney
- Adverse Effects: GUESS (flatulence, diarrhea, cramping)
Metformin
- Enters the cell through transporters such as SLC22A1
- Inhibits mitochondrial complex I, resulting in reduced ATP levels and an accumulation of AMP
- Activates AMPK, which suppresses fat metabolism and possibly also contributes to the reduced gluconeogenic gene expression
Test your knowledge on the mechanism of insulin secretion in response to glucose levels. Learn how elevated glucose levels lead to increased ATP levels in β-cells, resulting in insulin release through a series of cellular events.
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