insulin and glucagon- mitsouras

Question 1

How is insulin secreted?

Answer 1

Insulin mRNA transcribed & protein synthesized in beta-cells of pancreas
insulin is stored as preproinsulin
Proteolytic processing in ER of beta cells cleaves off the signal sequence, leaving proinsulin
Mature insulin stored in cytoplasm for exocytosis–> the C petide is cleaved in the Golgi apparatus.
Mature protein is 51 aa; Alpha & Beta chain linked by disulfide bonds
Exocytosis stimulated by glucose, aminoacids & GI hormones (cholecystokinin & gastric inhibitory peptide)

Question 2

How does the insulin signaling cascade occur?

Answer 2

in the fed state, insulin is secreted. Insulin receptors on liver, muscle and adipose tissue (receptor tyrosine kinase –> RTK) bind the insulin and the receptor autophosphorylates, becoming an active receptor + hormone complex

IRS-1 binds this activated receptor and is phosphorylated

signaling proteins then bind to the phosphorylated IRS-1 and become active

downstream:
1. GLUT 4 transporters increase in number on the surface to help bring BG into cells.
2. protein phosphatase-1 is dephosphorylated and activated
3. gene expression: induction/repression

Question 3

What enzymes are induced by insulin signaling? repressed?

Answer 3

induces? 
glucokinase 
PFK-1
pyruvate kinase 
G6PD 

represses?
PEPCK

Question 4

what is the dephosphorylation of protein phosphatase-1 due to? and what enzymes are activated/ inhibited by the activation of protein phosphatase-1?

Answer 4

insulin causes the dephosphorylation of protein phosphatase-1.

it activates (by dephosphorylation) 
glycogen synthase, PDH, pyruvake kinase, PFK-1, and AcCoA carboxylase 

inhibits:
F1, 6, BPase,
glycogen phosphorylase
hormone sensitive lipase

Question 5

What stimulates the secretion of glucagon?

Answer 5

low levels of glucose and amino acids and epinephrine stimulate the alpha cells to release glucagon during fasting and starvation

glucagon binds a glucagon GPCR (g protein coupled receptor) which then activates adenylate cyclase
–> adenylate cyclase converts ATP–> cAMP
-high cAMP activates PKA
PKA phosphorylates enzymes down stream

downstream effects:

1. gene expression
2. enzyme phosphorylation

Question 6

what are the downstream effects of glucagon?

Answer 6

transcriptional regulation

induces: PEPCK
represses: glucokinase, PFK-1, pyruvate kinase

enzyme phosphorylation:
activates: glycogen phosphorylase, F1, 6, Biphosphatase, hormone sensitive lipase

inhibits:
PFK-1, glycogen synthase, pyruvate kinase, AcCoA carboxylase

Question 7

What regulates beta-oxidation and ketogenesis?

Answer 7

SUBSTRATE
the amount of FA only

Glucagon does not activate these processes

Question 8

How do catecholamines regulate blood glucose levels from the liver, adipose and muscle?

Answer 8

epinephrine and norepinephrine stimulate:
released during physical exertion, stress, cold exposure, hypoglycemia –> immediate sources of fuel

liver: stimulates glycogenolysis (glycogen phosphorylase activated)
adipose: stimulates lipolysis (hormone sensitive lipase activated)
muscle: stimulates glycogenolysis (glycogen phosphorylase)

Question 9

Type I Diabetes- description and metabolic changes

Answer 9

Also called juvenile or insulin-dependent diabetes (IDDM)
10% of diagnosed cases
Sudden onset & usually after illness
Onset during childhood or puberty
Loss of pancreatic beta-cells by autoimmune destruction
No (extremely low) insulin production
*Characterized by hyperglycemia, hypertriglyceridemia & ketoacidosis
Patients are thin
Some genetic contribution primarily in immune-related genes
- HLA genes (HLA-DR & HLA-DQ)
- IL2RA (IL2 receptor)
- CLEC16A (C-type lectin in immune cells)
- NLRP1 (apoptosis-related protein)
** Some of these gene variants are protective against and some are risk factors for T1DM

 Diabetic ketoacidosis (DKA)  is acute & life-threatening complication
 Treatment by insulin replacement therapy

Metabolic changes:

1. hyperglycemia due to decrease uptake by GLUT 4 in mm and adipose, increase in gluconeogenesis via loss of PEPCK repression
2. ketosis: increased lipolysis in adipose and increased hepatic ketogenesis
3. hypertriacylglycerolemia: excess FA’s converted to TAGs and packaged into VLDLs and due to elevated hylomicrons and VLDLs because of a decrease in lipoprotein lipase activity

Question 10

Type II diabetes

Answer 10

Also called non-insulin dependent diabetes (NIDDM)
90-95% of diagnosed diabetes cases
Onset usually 35+ years old
Children and teenagers are increasingly getting diagnosed with type 2 diabetes
Progressive disease with gradual development & insidious onset
Risk factors include age, physical activity, obesity, family history (genetics)
Insulin resistance combined with inadequate insulin secretion (dysfunctional b-cells)
Some residual insulin signaling => metabolic abnormalities milder than T1DM
*Characterized by hyperglycemia and dyslipidemia
Hyperglycemic hyperosmolar state (HHS) is a life-threatening complication
Strong genetic contribution; Genes still being elucidated but risk variants include:
- TCF7L2 (transcription factor important in pancreatic islet development)
- KCNQ1 (voltage-gated K+ channel involved in glucose-stimulated insulin secretion)
- KCNJ11 (ATP-sensitive K+ channel in pancreatic b cells)
** These gene variants are risk factors for T2DM

Treatment consists of physical activity, weight loss, diet control (limited carbohydrate intake), oral medications to control blood glucose levels

metabolic changes:

1. hyperlgycemia: due to decreased uptake by GLUT 4 in mm and adipose and an increase in gluconeogenesis from loss of PEPCK repression
2. hypertriacylglycerolemia: due to elevated chylomicrons and VLDLs because of decrese in lipoprotein lipase activity

*more mild than type I because insulin signaling restrains ketogenesis