INSULIN, ORAL

HYPOGLYCEMIC AGENTS
AND GLUCAGON

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• DM is a metabolic disorder characterized by hyperglycaemia
• Two major types of diabetes mellitus are:
a) Type I Insulin-dependent diabetes mellitus (IDDM)/juvenile onset
diabetes mellitus: characterized by the immune system attacking and destroying the
insulin-producing cells in the pancreas. As a result, the body produces little to no insulin.
Without insulin, cells cannot take in glucose, and it remains in the bloodstream, leading to high
blood sugar levels.

b) Noninsulin-dependent diabetes mellitus (NIDDM)/maturity onset

diabetes mellitus: the body either doesn't produce enough insulin or the cells become
resistant to the effects of insulin. As a result, glucose cannot enter the cells efficiently, again
leading to elevated blood sugar levels.

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Causes of type 2 DM may be:
a) Abnormality in gluco-receptor of β cells or relative β cell deficiency
b) Reduced sensitivity (relative resistance); of peripheral tissues to
insulin
c) Excess of hyperglycaemic hormones (glucagon, etc.)

1.Fasting Blood Sugar:

1. Normal: Less than 100 mg/dL (5.6 mmol/L)
2. Diabetes: 126 mg/dL (7.0 mmol/L) or higher
2.Postprandial (After Meals) Blood Sugar:
1. Normal: Less than 140 mg/dL (7.8 mmol/L)
2. Diabetes: 200 mg/dL (11.1 mmol/L) or higher

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INSULIN
• Insulin is a two chain polypeptide having 51 amino acids and MW
about 6000.
• A-chain has 21 while B-chain has 30 amino acids.
• The A and B chains are held together by two disulfide bonds.
• Insulin is synthesized in the β cells of pancreatic islets as a single chain
peptide Preproinsulin (110 AA) from which 24 AAs are first removed
to produce Proinsulin
• The connecting or ‘C’ peptide (35 AA) is split off by proteolysis in Golgi
apparatus
• Both insulin and C peptide are stored in granules within the cell. The C
peptide is secreted in the blood along with insulin

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Actions of insulin
1. Facilitates glucose uptake: promotes the movement of glucose from
the bloodstream into cells (in muscle, adipose (fat), and liver
cells) helps lower blood glucose levels.
2. Promotes glycogen synthesis: Glycogen is a stored form of
glucose. Insulin stimulates the conversion of excess glucose into
glycogen in the liver and muscle cells
3. Inhibits gluconeogenesis
4. Promotes protein synthesis: by enhancing the uptake of amino
acids into the cells
5. Inhibits lipolysis (breakdown of stored fats )
6. Stimulates lipogenesis: (synthesis of fats in adipose tissues)
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• Insulin is a peptide that is degraded in g.i.t if given orally
• Metabolized primarily in liver and to smaller extent in kidney and
muscles
• During biotransformation, the disulfide bonds are reduced- A & B
chains are separated
• Further broken down to the constituent amino acid
• Plasma t ½ of insulin is 5-9 min.
• Older commercial insulin preparations were produced from beef and
pork pancreas
• Such insulins are no longer produced and have been totally replaced
by highly purified pork/ beef insulins, recombinant human and insulin
analogues

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Types of insulin preparations
Regular insulin Lente insulin (insulin-Zinc Isophane insulin
suspension) (neutral protamine
Hagedorn)

• Buffered neutral pH • 2 types of insulin-zinc • Intermediate acting

solution of unmodified suspensions ultralente (with insulin
insulin stabilized by a large particles, crystalline, • suspension with
small amount of zinc insoluble in water, long acting) protamine which
• Short acting (3 to 6 • Other is semilente ( smaller slows absorption
hours) particles, amorphous, short • Injected twice a day to
• Injected 30 minutes acting) provide basal insulin
before meals to control • 7:3 ratio mixture is called Lente coverage
postprandial glucose insulin and is intermediate acting
levels • Injected twice a day to provide
• Ex: Humulin R, Novolin basal insulin coverage
R • Ex: Humulin L, Novolin L

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Human insulin
• Produced by recombinant DNA technology in Escherichia coli-
proinsulin recombinant bacterial and in yeast – precursor yeast
recombinant or by enzymatic modification of porcine insulin
• Regular human insulin, when injected subcutaneously, has a relatively
slower onset of action compared to rapid-acting insulin analogs.
• It typically starts working within 30 minutes to an hour after injection.

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Insulin analogues
• Analogues of insulin produced using recombinant DNA technology
have modified pharmacokinetics on s.c. injection but similar
pharmacodynamic effects.
1. Insulin lispro (rapid acting, shorter duration)
2. Insulin aspart (rapid acting, shorter duration)
3. Insulin glargine (intermediate acting insulin analogues)
4. Insulin detemir (intermediate acting insulin analogues)
5. Insulin degludec (intermediate acting insulin analogues)
•Can be injected using syringes, insulin pens, or insulin pumps.
•Reduced risk of hypoglycemia, and improved postprandial glucose control.
•Limitations: Generally more expensive than human insulins.
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Reactions to insulin
1. Hypoglycemia: (common reaction to insulin) It occurs when dose of insulin is
too high in relation to the person's food intake or physical activity.
• Symptoms include: shakiness, sweating, confusion, dizziness, loss of
consciousness
2. Allergic reactions: rare
• Symptoms include: redness, swelling, itching at the injection site, skin rash
3. Lipodystrophy: is fat atrophy or fat accumulation due to prolonged use of same
injection site
4. Insulin resistance: where body’s cell become less responsive to the effects of
insulin
5. Edema: fluid retention may occur as a side effect of insulin therapy leading to
swelling in the hands, feet or other parts of the body

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Uses of insulin
1. Diabetes management: Insulin is essential part of managing type 1
& 2 diabetes
2. Diabetic ketoacidosis: characterized by high blood sugar levels,
dehydration and the presence of ketones (breakdown of fatty acids in liver) in the
blood
3. Hyperkalemia: (elevated levels of potassium in the blood). Insulin
works by promoting the uptake of potassium into the cells, reducing
its concentration in the bloodstream
4. Hyperosmolar coma: characterized by extremely high blood
glucose levels, profound dehydration, and a state of
hyperosmolarity in the blood leads to altered mental status
( confusion, lethargy, seizures)
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Glucagon-like peptide-1 (GLP-1) receptor agonists
• GLP-1 is an important incretin released from the gut in response to
ingested glucose
• It induces insulin release from pancreatic β cells only at high glucose
concentration
• Inhibits glucagon release from α cells
• Suppresses appetite by activating specific GLP-1 receptors (surface
GPCRs) expressed on α and β cells, central and peripheral neurons,
gastrointestinal mucosa etc.
• The incretin system appears to promote β cell health as well by
decreasing islet cells apoptosis

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• GLP-1 based therapy appears to be the most effective measure to
preserve β cell function in type 2 DM
• GLP-1 itself is not suitable for clinical use because of rapid
degradation by the enzyme dipeptidyl peptidase-4 (DPP-4)

• Exenatide: it is a synthetic DPP-4 resistant analogue which activates

GLP-1 receptors.
• Inactive orally, given s.c
• Plasma t1/2 is 3 hrs
• Duration of action 6-10 hrs
• Side effect is nausea and vomiting

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Oral antidiabetic drugs
• These drugs lower blood glucose levels in diabetics and are effective
orally

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Sulfonylureas (KATP Channel blockers)
Classified as insulin secretagogues
promote insulin release from β cells
Example: tolbutamide, glibenclamide,
glipizide
MOA: bind to sulfonylurea receptor
(subunit of ATP-sensitive potassium
channels) located on cell membrane of β
cells drug in the presence of high glucose
levels promotes closure of KATP channels
membrane depolarization in turn activates
voltage gated calcium channels Ca2+
influx insulin exocytosis from the
vesicles insulin released into blood stream

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Glinides
• Example: repaglinide, nateglinide
• MOA:
 stimulate insulin secretion
Like sulfonylureas close ATP-sensitive potassium
channels release of insulin
Glinides not used in combination with sulfonylureas due to
overlapping mechanisms of action risk of hypoglycemia

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Dipeptidyl peptidase-4 inhibitors
• Exmaple: Alogliptin, sitagliptin
• Orally active DPP-4 inhibitors
MOA:
• Inhibit the enzyme DPP-4 (responsible for the inactivation of incretin
hormones such as GLP-1)
• Prolonged activity of GLP-1 increased insulin release in response to
meals
• May be used as monotherapy or in combination with SU,
Thiazolidinedione or insulin

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Biguanides
• Example: Metformin
• Decreases insulin resistance by increasing glucose uptake by target
tissues
• Does not promote insulin secretion hyperinsulinemia not a problem
• MOA:
Reduction of hepatic gluconeogenesis by inhibiting key enzymes involved
such as glucose-6-phosphatase and phospho-enol-pyruvate
carboxykinase (as excess glucose produced by the liver is a major source
of high blood glucose in type 2 diabetes)
Improves peripheral glucose uptake and utilization
• Contraindicated in renal dysfunction due to risk of lactic acidosis

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Thiazolidinediones
• Insulin sensitizers
• Example: pioglitazone
MOA:
• Act as agonists for peroxisome proliferator-activated receptor γ (PPAR γ) (nuclear
receptor) found in adipose tissue, liver and skeletal muscle
• Activation of PPAR γ regulates the transcription of genes involved in glucose and
lipid metabolism
• Activation of receptors increased insulin sensitivity by enhanced glucose
uptake in peripheral tissues
• TZDs can be used as monotherapy or in combination with other glucose-lowering
agents or insulin
• AE: Weight gain may occur because they may increase subcutaneous fat and
cause fluid retention avoided in patients with severe heart failure
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α glucosidase inhibitors
• Inhibit the activity of enzyme α-glucosidase slow down the
digestion and absorption of carbohydrates reduction in post-
prandial glucose levels
• The enzyme is responsible for breaking down complex carbohydrates
into simpler sugar like glucose present on the brush border of the
small intestine
• 2 main types of enzymes: maltase and sucrase
• Examples: Acarbose and miglitol competitively inhibit enzymes

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Sodium-glucose co-transport-2 (SGLT-2) inhibitor
• All the glucose filtered at the glomerulus is reabsorbed in the
proximal tubules.
• The major transporter for this is SGLT-2
• The inhibition of this transporter induces glucosuria and lowers blood
glucose levels in type 2 DM
• Example: Dapagliflozin, canagliflozin

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GLUCAGON
• Single chain polypeptide containing 29 amino acids, MW 3500
• It is secreted by α cells of the pancreas
• Now produced by recombinant DNA technology
• High glucose levels inhibit glucagon secretion
• Incretin GLP-1, insulin also inhibit glucagon release
• Glucagon causes hyperglycemia primarily by enhancing glycogenolysis
and gluconeogenesis in liver
• It acts through its Gs protein coupled receptor present in liver, fat
cells, heart and other tissues

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