2. Diabetes mellitus (DM)
- a group of metabolic disorders characterized by a high blood sugar level
over a prolonged period of time.
3. • Diabetes is due to either the pancreas not producing enough insulin, or the cells of
the body not responding properly to the insulin produced. There are three main types
of diabetes mellitus:
• Type 1 diabetes results from the pancreas's failure to produce enough insulin due to
loss of beta cells. This form was previously referred to as "insulin-dependent
diabetes mellitus" (IDDM) or "juvenile diabetes“. The loss of beta cells is caused by
an autoimmune response.
• Type 2 diabetes begins with insulin resistance, a condition in which cells fail to
respond to insulin properly. As the disease progresses, a lack of insulin may also
develop. This form was previously referred to as "non insulin-dependent diabetes
mellitus" (NIDDM) or "adult-onset diabetes". The most common cause is a
combination of excessive body weight and insufficient exercise.
• Gestational diabetes is the third main form, and occurs when pregnant women
without a previous history of diabetes develop high blood sugar levels.
5. Insulin
• Insulin is a peptide hormone produced by beta cells of the pancreatic islets.
• Insulin is composed of two peptide chains referred to as the A chain and B
chain.
• The human insulin protein is composed of 51 amino acids in which A chain
consists of 21 amino acids and the B chain of 30 amino acids.
• The chains are connected by two disulfide linkages (A7-B7 and A20-B19) and an
intramolecular disulfide linkage (A6-A11).
• The monomer is the biologically active form.
• Amino acid units cannot be removed from the chain A without significant loss of
activity.
• However, up to the first six and last three amino acid units from chain B can be
removed without significant loss of activity.
• Synthesized by islets β-cells from a 86-amino acid proinsulin.
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7.
8. Function of Insulin
• It regulates the metabolism of carbohydrates, fats and protein by promoting the
absorption of glucose from the blood into liver, fat and skeletal muscle cells.
• In these tissues the absorbed glucose is converted into either glycogen via
glycogenesis or fats (triglycerides) via lipogenesis, or, in the case of the liver,
into both.
9. Production of Insulin
Early commercial insulins were obtained by extraction from bovine or porcine and
purified by crystallization.
Now human insulin id produced by the chemical combination of A and B chains,
which have been obtained from bacteria genetically modified by recombinant
DNA technology.
10. History of Insulin
• Insulin was the first peptide hormone discovered.
• Frederick Banting and Charles Herbert Best were the first to isolate insulin
from dog pancreas in 1921.
• Frederick Sanger sequenced the amino acid structure in 1951, which made insulin
the first protein to be fully sequenced.
• The crystal structure of insulin in the solid state was determined by Dorothy
Hodgkin in 1969.
• Insulin is also the first protein to be chemically synthesized and produced by
DNA recombinant technology.
11. Bovine and Porcine insulins produced allergic reactions in humans due to the
difference in the amino acid sequence.
12. Hormones produced in the pancreatic islets are
secreted directly into the blood flow by different cells.
• Alpha cells producing glucagon
• Beta cells producing insulin and amylin
• Delta cells producing somatostatin
• PP cells (gamma cells or F cells)
producing pancreatic polypeptide
13. The paracrine feedback system of the pancreatic islets has the following
structure:
• Glucose/Insulin: activates beta cells and inhibits alpha cells
• Glycogen/Glucagon: activates alpha cells which activates beta cells and delta
cells
• Somatostatin: inhibits alpha cells and beta cells
14. Since insulin is a polypeptide, it is susceptible to degradation in GIT.
Therefore it is administered by subcutaneous injection.
15. Insulin preparations
Medical preparations of insulin are never just 'insulin in water'. Clinical
insulins are specially prepared mixtures of insulin plus other substances
including preservatives. These delay absorption of the insulin, adjust the pH
of the solution to reduce reactions at the injection site, and so on.
Slight variations of the human insulin molecule are called insulin analogues,
so named because they are not technically insulin, rather they are analogues
which retain the hormone's glucose management functionality.
Most insulins form hexamers, which delay entry into the blood in active
form; these analog insulins do not but have normal insulin activity.
16. The commonly used types of insulin are:
Fast-acting
Insulin aspart, Insulin lispro, and Insulin glulisine (starts within 5 to 15 minutes and are active for 3 to
4 hours)
Short-acting
Regular insulin (starts within 30 minutes and is active about 5 to 8 hours)
Intermediate-acting
NPH insulin (starts 1 to 3 hours and is active for 16 to 24 hours.
Long-acting
Insulin glargine U100 and Insulin detemir (starts within 1 to 2 hours and continues to be active for
about 24 hours)
Ultra-long acting
Insulin glargine U300 and Insulin degludec (starts within 30 to 90 minutes and continues to be active
for greater than 24 hours)
Combination insulin products
Includes a combination of either fast-acting or short-acting insulin with a longer acting insulin, typically
an NPH insulin. The combination products begin to work with the shorter acting insulin (5–15 minutes
for fast-acting, and 30 minutes for short acting), and remain active for 16 to 24 hours. There are
several variations with different proportions of the mixed insulins (e.g. Novolog Mix 70/30 contains
70% aspart protamine, and 30% aspart.)
19. Secretagogues
The insulin secretagogues include the sulfonylureas and meglitinides, and both
increase insulin release from the pancreas by a common mechanism. Sulfonylureas
and meglitinides stimulate insulin secretion by binding to the sulfonylurea receptor
(SUR) of the ATP-sensitive K+ channel on the pancreatic β-cells.
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21. MOA
Sulfonylureas bind to and close ATP-sensitive K+ (KATP) channels on the cell
membrane of pancreatic beta cells, which depolarizes the cell by preventing
potassium from exiting. This depolarization opens voltage-gated Ca2+ channels.
The rise in intracellular calcium leads to increased fusion of insulin granulae with
the cell membrane, and therefore increased secretion of mature insulin.
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Meglitinides act in a similar manner to the sulfonylureas but with a few major
differences. For example, meglitinides bind to the sulfonylurea receptor in beta
cells, but at a different part of the receptor than the sulfonylureas do. The
interaction of the meglitinides with the receptor is not as “tight” as that of the
sulfonylureas, translating to a much shorter duration of action.
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27. MOA
Its pharmacologic mechanisms of action are different from other classes of
oral antihyperglycemic agents.
Metformin decreases:
• hepatic glucose production,
• decreases intestinal absorption of glucose
• improves insulin sensitivity by increasing peripheral glucose uptake and
utilization.
Unlike sulfonylureas, metformin usually does not produce hypoglycemia in
either patients with type 2 diabetes or normal subjects and does not cause
hyperinsulinemia.
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29. MOA
• Thiazolidinediones act by activating PPARγ (peroxisome proliferator-
activated receptor gamma).
• When activated, the receptor binds to DNA increasing transcription of a
number of specific genes and decreasing transcription of others. The main
effect of expression and repression of specific genes is an increase in the
storage of fatty acids in adipocytes, thereby decreasing the amount of fatty
acids present in circulation.
• As a result, cells become more dependent on the oxidation of carbohydrates,
more specifically glucose, in order to yield energy for other cellular
processes, thus lowering the blood glucose level.
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31. MOA
Alpha-glucosidase inhibitors are saccharides that act as competitive inhibitors
of enzymes needed to digest carbohydrates: specifically alpha-glucosidase
enzymes in the brush border of the small intestines.
The membrane-bound intestinal alpha-glucosidases hydrolyze oligosaccharides,
trisaccharides, and disaccharides to glucose and other monosaccharides in the
small intestine.