INSULIN BIOSYNTHESIS

- Produced in the B-cells of the pancreas

Preproinsulin (Single chain 86-Amino Acid Polypeptide)
Endoplasmic Reticulum

Proinsulin (Amino terminal signal peptide removed)

-related to insulin-like GF I & II
-binds weakly to insulin receptors
(Cleavage)
C Peptide
Insulin
-A Chain (21 Amino Acids)
-B Chain (30 Amino Acids)
*Connected by Disulfide bonds

Rough
Golgi Apparatus

Insulin and C Peptide

- Stored together in Beta cells
- Co-secreted from secretory granules
C Peptide
- Cleared more slowly than insulin
- Useful marker of insulin secretion
- Allows discrimination of endogenous and exogenous sources of insulin
Islet of Amyloid Polypeptide (IAPP) or Amylin
- Co-secreted by pancreatic Beta cells
- 37-Amino Acid Polypeptide
- Major component of the amyloid fibrils
- Found in the islets of patients with type 2 DM
- Its analogues are sometimes used in treating patients with Type 1 & 2 DM
INSULIN SECRETION
Glucose
- Key regulator of insulin secretion
Other regulators:
a. Amino acids
b. Ketones
c. Various nutrients
d. Gastrointestinal peptides
e. Neurotransmitters
Glucose Level: >3.9 mmol/L or 70 mg/dL
- Stimulates insulin synthesis by enhancing protein translation and processing

Mechanism of Insulin secretion:

Glucose
(GLUT 2, Facilitative Glucose Transporter)

Glucose Phosphorylation by Glucokinase

(a rate-limiting step that controls glucose-related insulin secretion)

Metabolism of Glucose-6-Phosphate by Glycolysi

Generates ATP

Inhibits activity of an ATP-Sensitive K+ Channel

*Consists of 2 Proteins:
a. Binding site for certain oral hypoglycemics
b. Inwardly rectifying K+ Channel Protein

Beta cell membrane depolarization

Influx of Ca2+ (Repolarization)

Stimulates insulin secretion

Incretins
- Released from neuroendocrine cells of the GI tract following food ingestion.
- Amplify glucose stimulated insulin release.
- Suppress glucagon release.
Glucagon-Like peptide 1 (GLP-1)
- Most potent increti8n
- Released from L cells of small intestines
- Stimulates insulin secretion only when the blood glucose is above fasting
level
- 5.6 mmol/L or 100mg/dL
Dipeptidyl Peptidase IV Inhibitors
- Enhances effects of GLP-1
INSULIN ACTION
- ~50% removed & degraded by the liver
Insulin

Binds to receptors of target cells

a. Myocytes
b. Adipocytes
c. Hepatocytes

Stimulates Intrinsic Kinase Activity

(Tyrosine Kinase)
Receptor Phosphorylation


Recruitment of intracellular signalling molecules
Example: Insulin receptor Substrate (IRS)

Initiation of complex cascade of phosphorylation and dephosphorylation

Example: Translocation of facilitative glucose transporters (GLUT 4)
- For Skeletal Muscles and Fat
Other
a.
b.
c.
d.

Insulin Receptor Signalling Pathway:

Glycogen Synthesis
Protein Synthesis
Fat Synthesis (lipogenesis)
Regulation of various genes in insulin-responsive cells (cell growth)

Glucose Homeostatsis
- Balance between hepatic glucose and [peripheral glucose intake and
utilization
Insulin
- most important regulator of glucose homeostasis
- anaerobic hormone
- promotes storage of carbohydrates and fat and protein synthesis
Fasting State
- low insulin levels
- increase glucose production by glycogenolysis and hepatic gluconeogenesis
- reduce glucose uptake in insulin-sensitive tissues

- Promotes mobilization of stored precursors such as amino acids and free fatty
acids
Other Factors:
a. Neural Input
b. Metabolic Signals
c. Other hormones (Glucagon)
Glucagon
- Secreted by pancreas alpha cells when blood glucose or insulin levels are low
- Stimulates glycogenolysis and gluconeogenesis by the liver and renal
medulla
Criteria for the Diagnosis of Diabetes Mellitus:
1. Classic signs and symptoms of Diabetes Mellitus;
Random Blood Sugar concentration of 11.1 mmol/L (200 mg/dL)
2. Fasting Plasma Glucose of 7.0 mmol/L (126 mg/dL)
3. A1C of >6.5 %
4. Two-hour plasma glucose of 11.1 mmol/L or 200 mg/dL durting an OGTT