Diabetes is a metabolic disorder caused by a partial or absolute insulin deficiency.
We will discuss the process of insulin production in a cell.


Pancreatic β-cell production of insulin is regulated by

a.    Plasma glucose concentration

b.    Neural inputs,

c.    Other hormones by paracrine and endocrine actions.

Proinsulin consists of an amino-terminal β-chain, a carboxy-terminal α-chain, and a connecting peptide (C-peptide) in the middle.

C-peptide functions by allowing folding of the molecule and the formation of disulfi de bonds between the α- and β-chains.

C-peptide is cleaved from proinsulin by endopeptidases in the β-cell endoplasmic reticulum (ER) to form insulin.

Insulin and C-peptide are packaged into secretory granules in the Golgi apparatus. The secretory granules are released into the portal circulation by exocytosis.

Insulin is degraded in the liver, kidney, and target tissues; it has a circulating half-life of 3 to 8 minutes.

C-peptide does not act at the insulin receptor and is not degraded by the liver; it has a circulating half-life of 35 minutes. Thus, measurement of serum C-peptide concentration serves as a measure of β-cell secretory capacity.

Defects in the synthesis and cleavage of insulin can lead to rare forms of diabetes mellitus (e.g., Wakayama syndrome, proinsulin syndromes).

Insulin is released in a pulsatile and rhythmic background pattern throughout the day and serves to suppress hepatic glucose production and mediates glucose disposal by adipose tissue.

Superimposed on the background secretion of insulin is the meal-induced insulin release.

There are two phases of caloric intake–induced insulin secretion.

In the first phase, prestored insulin is released over 4 to 6 minutes. The second phase is a slower onset and longer sustained release because of the production of new insulin

The regulators of insulin release include nutrients (e.g., glucose and amino acids), hormones (e.g., glucagon-like peptide 1 [GLP-1], somatostatin, insulin, and epinephrine), and neurotransmitters (e.g., acetyl[1]choline, norepinephrine).

The β-cells are exquisitely sensitive to small changes in glucose concentration; maximal stimulation of insulin secretion occurs at plasma glucose concentrations more than 400 mg/dL.

Glucose enters the β-cells by a membrane-bound glucose transporter (GLUT 2). Glucose is then phosphorylated by glucokinase as the first step in glycolysis (leading to the generation of acetyl-coenzyme A and adenosine triphosphate (ATP) through the Krebs cycle.

The rise in intracellular ATP closes (inhibits) the ATP sensitive potassium (K+ ) channels and reduces the efflux of K+ , which causes membrane depolarization and opening (activation) of the voltage-dependent calcium (Ca2+ ) channels. The resultant Ca2+ influx increases the concentration of intracellular Ca2+, which triggers the exocytosis of insulin secretory granules into the circulation. The β-cell Ca2+ concentrations can also be increased by the ATP generated from amino acid metabolism

Insulin release from β-cells can be amplified by cholecystokinin, acetylcholine, gastric inhibitory polypeptide (GIP), glucagon, and GLP-1. Orally administered glucose stimulates a greater insulin response than an equivalent amount of glucose administered intravenously because of the release of enteric hormones (e.g., GLP-1, GIP) that potentiate insulin secretion. This phenomenon is referred to as the incretin effect, a finding that has led to new pharmacotherapeutic options in the treatment of patients with type 2 diabetes mellitus.

Acetylcholine and cholecystokinin bind to cell surface receptors and activate adenylate cyclase and phospholipase C, which leads to inositol triphosphate (IP3) breakdown and mobilization of Ca2+ from intracellular stores; activation of protein kinase C also triggers insulin secretion.

GLP-1 receptor activation leads to increased cyclic adenosine monophosphate (cAMP) and activation of the cAMP-dependent protein kinase A; the Ca2+ signal is amplified by decreasing Ca2+ uptake by cellular stores and by activation of proteins that trigger exocytosis of insulin.

Somatostatin and catecholamines inhibit insulin secretion through G-protein–coupled receptors and inhibition of adenylate cyclase.

Normal insulin secretion is dependent on the maintenance of an adequate number of functional β-cells (referred to as β-cell mass).

The β-cells must be able to sense the key regulators of insulin secretion (e.g., blood glucose concentration).

In addition, the rates of proinsulin synthesis and processing must be sufficient to maintain adequate insulin secretion.


Defects in any of these steps in insulin secretion can lead to hyperglycemia and diabetes mellitus.