Diabetes mellitus is a common disease and its complications are responsible for excess morbidity and mortality, loss of independence,
and reduced quality of life (1, 2). Among the major causes of disablement and early death are ischemic heart disease, retinopathy,
nephropathy, peripheral vascular disease, and neuropathy (3). Diabetes mellitus is a serious pathologic condition that is
responsible for major healthcare problems worldwide and costing billions of dollars annually.
The American Diabetes Association recently recommended an etiological classification of diabetes (4). Diabetes resulting from
a deficiency of insulin secretion is classified as type I diabetes. Type I diabetes normally occurs in childhood, has relatively
acute onset, and requires insulin for survival.
Diabetes that results from a resistance to insulin (with or without concomitant insulin secretory defect) is classified as
type II diabetes. Type II diabetes usually occurs later in life, has an insidious onset, and may or may not require exogenous
insulin treatment. Although the majority of diabetes cases falls into one of these two categories, there are several other
forms of diabetes, which cannot be classified as type I or type II diabetes. These other specific types include cases arising
from genetic defects of the β cell (e.g., maturity onset diabetes of the young (MODY] genes, mitochondrial DNA mutations);
genetic defects in insulin action; drug-, chemical-, or disease-induced pancreatic damage; and endocrinopathies. Gestational
diabetes mellitus, defined as any degree of glucose intolerance with onset or first recognition during pregnancy, comprises
the fourth general category in the revised diagnostic criteria for diabetes (4).
The defect in insulin secretion in type I diabetes may result from one of several different mechanisms. The most common is
autoimmune destruction of insulin-producing β cells of the pancreas. Evidence of an immune process occurring in most cases
of type I diabetes is the presence of antibodies to islet cells antigens. Such cases are referred to as autoimmune or type
IA diabetes. In a minority of cases of type 1 diabetes, evidence of such an autoimmune etiology of the insulin secretory defect
is absent. Such cases are referred to as idiopathic or type IB diabetes. This group does not include cases for which a specific
cause of β-cell destruction is known (e.g., neoplasia, cystic fibrosis), which are classified under "other specific types"
Development of insulin
Nearly 100 years have passed since Von Mering and Minkowski first demonstrated that pancreatectomized dogs exhibited signs
and symptoms characteristic of diabetes mellitus (6). Shortly thereafter, Banting and Best used pancreatic extracts to reverse
these symptoms in patients suffering from severe diabetes (7). Insulin replacement therapy has been used in the clinical management
of diabetes mellitus for more than 84 years. It is used as a first-line agent in type I diabetes and sometimes in the treatment
of type II diabetes where oral hypoglycemic agents combined with diet and exercise fail to achieve appropriate metabolic control
Insulin is a small protein with a molecular weight (MW) of 5808 in humans. It contains 51 amino acids arranged in two chains
(A and B) linked by disulfide bridges. There are species differences in amino acids of both chains. Within the β cells, insulin
precursor is produced by DNA and RNA-directed synthesis. Proinsulin, a long single-chain protein molecule, is processed within
the Golgi apparatus and packaged into granules, where it is hydrolysed into insulin and a residual connecting segment called
the C-peptide is formed by removal of four amino acids. Insulin and C-peptides are secreted in equimolar amounts in response
to all insulin secretagogues. A small quantity of unprocessed or partially hydrolyzed proinsulin is released as well. Granules
within the (3 cells store insulin in the form of crystals consisting of two atoms of zinc and six molecules of insulin (7).
For 60 years, animal pancreas was the only source from which insulin could be produced in sufficient quantities to cover therapeutic
needs (9). During the first decade of the "insulin era," only an acid solution of an impure form of hormone was available
for subcutaneous (s.c.) injection (1). The introduction of zinc crystallization in 1934 as well as the development of recrystallization
methods made it possible to crystallize insulin. The introduction of analytical methods such as disk electrophoresis and gel
filtration made it possible to detect the presence of a significant amount of impurities in proteins even in recrystallized
insulin. The use of chromatographic purification reduced the impurities to less than 0.5% and immunologic complications of
insulin treatment were essentially eliminated. During the late 1970s, the advances in recombinant DNA technology made it possible
to biosynthetically produce human insulin. In the 1980s, the first human received injections of human insulin combined from
A and B chains expanded separately in Escherichia coli with chemically prepared genes.