Industrial Production of Insulin Contents 1. Insulin Molecule 2. Effect of Insulin in Body 3. History of Insulin 4. Recent Trends in Insulin Productions and Types 4.1 Animal Insulins 4.2 Long-Acting Insulins 4.3 Human Insulins 4.4 Insulin Analogues 4.5 Biosimilar Insulins 5. Insulin Production (Chain A and Chain B Method) 5.1 Upstream Processing 5.2 Downstream Processing 6. The Proinsulin Process 7. Insulin Available in Market with Different Brand Names 8. References
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Industrial Production of Insulin
Contents
1. Insulin Molecule
2. Effect of Insulin in Body
3. History of Insulin
4. Recent Trends in Insulin Productions and Types
4.1 Animal Insulins
4.2 Long-Acting Insulins
4.3 Human Insulins
4.4 Insulin Analogues
4.5 Biosimilar Insulins
5. Insulin Production (Chain A and Chain B Method)
5.1 Upstream Processing
5.2 Downstream Processing
6. The Proinsulin Process
7. Insulin Available in Market with Different Brand Names
8. References
1. Insulin Molecule
The term “insulin” was derived from the Latin word insula or “island” to describe its origin from
the pancreatic islets of Langerhans. β cells that lie exclusively within these islets produce insulin,
a peptide hormone, which facilitates the entry of glucose into target organs such muscle, fat, and
the liver for further metabolism. The insulin molecule is composed of two polypeptide chains
linked by disulfide bridges: chain A comprising 21 amino acids and chain B comprising 30
amino acids. After it is released, insulin attaches to a glycoprotein receptor on the surface of the
target cell. The α subunit on the glycoprotein receptor binds the insulin hormone, and the β
subunit (a tyrosinasespecific protein kinase) mediates insulin action on metabolism and growth.
Figure 1: Biochemical structure of insulin
2. Effect of Insulin in Body
Insulin is directly released from the pancreatic β cells in a pulsatile fashion into the portal
circulation. Two phases of insulin secretion have been recognized in response to nutrient
(predominantly carbohydrate) ingestion. The first phase is a sharp burst of insulin occurring
within 5–10 min of carbohydrate ingestion; the second phase is a sustained, slow release of
insulin which is directly related to the presence of hyperglycemia. Loss of the insulin pulsatility
factor or loss of the first phase and an attenuated second phase of insulin release contributes to
the development of type 2 diabetes mellitus. Insulin secretion decreases in the presence of
hypoglycemia and increases in response to hyperglycemia, certain amino acids, nonesterified
fatty acids, and sympathetic and parasympathetic stimulation. In brief, insulin facilitates glucose
transport in liver and muscle cells by modulation of GLUT4 glucose receptors, stimulates storage
of glucose in the form of glycogen (glycogenesis), stimulates uptake of fatty acid and
triacylglycerol synthesis in adipose tissue and muscle, inhibits lipolysis resulting in lowering of
plasma fatty acids, stimulates amino acid uptake and protein synthesis in liver, muscle and
adipose tissues, inhibits protein breakdown in muscle.
Figure 2: The role of insulin hormone in human metabolism. GH (growth hormone), FFA (free
fatty acid), T2DM (type 2 diabetes mellitus)
3. History of Insulin
The landmark discovery and development of insulin as a medical therapy can be traced back to
the early nineteenth century. Prior to the discovery of insulin, people with diabetes were
subjected to a starvation diet, with little hope for survival.
In 1922, a series of experiments by Frederick Banting and Charles Best saw the
production of the first pancreatic extract, which later was called “insulin” and
transformed the lives of people with diabetes. In their landmark experiment, Banting and
Best’s rigorous efforts to isolate a purified form of pancreatic extracts from slaughtered
animals saved the life of a young boy, Leonard Thompson, from impending coma and
death due to diabetes.
Although pancreatic extracts remained the main source of insulin for a long time, in 1936
Hans Christian Hagedorn discovered that the action of insulin could be prolonged with
the addition of protamine, a basic protein widely available from fish sperm. Following
this discovery, protamine insulin, with an approximate duration of 12 h, was increasingly
used in people with diabetes to good effect.
The subsequent discovery of adding zinc to protamine insulin by Scott and Fisher paved
the way for the development of neutral protamine Hagedorn (NPH). This longer-acting
and more stable insulin suspension was first marketed by Danish pharmaceutical
company Novo Nordisk in 1946.
The sequencing of insulin by Frederick Sanger then led to the synthesis of human insulin
using DNA recombinant technology, which became widely available through the 1980s
via Eli Lilly pharmaceutical company.
Recognizing the need to improve the physiological profile of insulin to mimic
endogenous insulin secretion and improved knowledge of amino acid sequencing of the
insulin molecule prompted the emergence of synthetic (or analog) insulin. These are now
used extensively in people with diabetes. A summary of key events leading to the
discovery and adoption of insulin for use in diabetes is shown in Table 1.1
Table 1.1 Discovery of insulin timeline
4. Recent Trends in Insulin Productions and Types
Although human insulin has been used for many years, its use does pose a few challenges. For
example, basal (long-acting) neutral protamine Hagedorn (NPH) insulin is associated with an
increased risk of nocturnal hypoglycemia, defensive snacking, and weight gain. Additionally, the
need to carefully time regular human insulin injections with food intake is cumbersome and can
restrict people with busy lifestyles. The need to improve the physiological profile of insulin to
mimic endogenous insulin secretion and improved knowledge of amino acid sequencing of the
insulin molecule has prompted the emergence of bioengineered analog insulin and has heralded
an exciting new era in insulin therapeutics. Analog insulin is similar to human insulin with a
slight variation in amino acid composition and structure but with improved pharmacokinetics.
Table 2: Milestones in the development of insulin
In 1996, analog insulin lispro was first marketed. Subsequently, a host of insulin analogs created
by recombinant DNA technology, including rapid- acting (e.g., aspart), premixed, and long-
acting (e.g., glargine and detemir) analogs, have revolutionized diabetes management. With the