Kampala international university

1. Pancreatic hormones and
hypoglycemic drugs
Deparment
of
Pharmacology

2. BIBLIOGRAPHY
 Goodman and Gilman’s. The pharmacological
basis of therapeutics.
 Basic and Clinical Pharmacology. Bertram G.
Katzung.
 Pharmacology. Rang and Dale’s. 6th edition.
 Pharmacology. 3rd edition. Lippincott´s.

3. SUMMARY
1. Glucose
2. Glucagon
3. Insulin
4. Oral hypoglycemic drugs.

4.  The single most important source of energy for almost all
tissues being utilised for both glycolysis and the tricarboxylic
acid (TCA) cycle.
 Most tissues can also utilise fatty acids via the β-oxidation
pathway. The brain is unusual in that, it can only utilise
glucose and ketone bodies but the maintenance of an
adequate plasma glucose concentration is especially
important for the functioning of the CNS.
 Under normal circumstances the blood glucose level is
maintained within a narrow range.
 However, under some circumstances it may fall outside that
range and remain consistently low or high. When this
occurs, the situation becomes potentially dangerous.
Glucose

5. Mechanism of insulin release
 When glucose levels increase there is an entry of glucose to
the pancreatic β cells, glucose is oxidise to G6P with a
release of intracellular ATP.
 The K+-ATP dependant channels located at the cell
membrane of the pancreas get close when the ATP attach
them and the exflux of K+ through these channels stop.
 This provoke a change in the resting membrane potential
(relative depolarization) and the specific voltage value
needed for opening the Ca2+ voltage gated channels at the
pancretatic membranes is reached.
 When these channels open, the Ca2+ flow into the cell and
these is the stimulus for the insulin release from the vesicles
(exocitosis).
 Insulin increases the cell permeability to glucose making its
blood levels lower preventing hyperglicemia.

6.  Following its absorption from the gut into the
bloodstream any glucose that is not immediately
required for energy production is transformed
and stored either as glycogen or triglyceride via
insulin-mediated processes.
 In fasting state, plasma glucose level is
maintained by glycogenolysis and
gluconeogenesis.
 Main regulators of these processes and, of the
plasma glucose level are:
Insulin, Glucagon, Adrenalin, Cortisol & GH
Glucose Regulation

7. EFFECT OF HORMONES ON BLOOD GLUCOSE

8. Pancreatic hormones products
Endocrine: (islets of
Langerhans)
 Glucagon (A or α-Cells)
 Insulin (B or β-Cells)
 Somatostatin (D-Cells):
Inhibits glucagon and
insulin secretion. It is the
major inhibitor of GH
synthesis and release.
Exocrine:
 Digestive enzymes

9.  It is a hormone secreted by the alpha cells of the
islets of Langerhans, when the blood glucose
concentration falls.
 Has several functions that are diametrically opposed
to those of insulin. Most important of these functions
is to increase the blood glucose concentration, an
effect that is exactly the opposite that of insulin.
 It is a large polypeptide, of a chain of 29 amino acids.
 Has a molecular weight of 3485 Da.
 Also called the hyperglycemic hormone.
Glucagon

10.  Its major effects on glucose metabolism:
1. Breakdown of liver glycogen (glycogenolysis).
2. Increased gluconeogenesis in the liver.
- Both of these effects greatly enhance the availability of
glucose to the other organs of the body.
- The most dramatic effect of glucagon is it's ability to cause
glycogenolysis in the liver, which in turn increase the
blood glucose concentration within minutes.
Glucagon

11.  In very high concentration it also:
1. Enhances the strength of the heart.
2. Increases blood flow in some tissues
especially in the kidneys.
3. Enhances bile secretion.
4. Inhibits gastric acid secretion.
All these effects are probably of minimal
importance in the normal function of the body.
Glucagon

12.  It can be given IM or SC as well as IV.
 Treatment of hypoglycemia in unconscious
patients (who cannot drink); unlike IV glucose, it
can be administered by non-medical personnel
(e.g. spouses or ambulance crew). It is useful if
obtaining IV access is difficult.
 Treatment of acute cardiac failure precipitated by
β-adrenoceptor antagonists (to treat the
bradycardia and hypoglycemia).
Glucagon Clinical Uses
Responses of activation of β2-Adrenoceptors: promote
glycogenolysis (breakdown of glycogen to glucose), therefore
β blockers leads to hypoglycemia in diabetic patiens.

13. Insulin
 It is a small protein with molecular weight of
5808 Da.
 It is a polypeptide hormone with 2 amino acid
chains linked by disulfide (-S-S-) bridges.
 To initiate it’s effects on target cells, insulin
first binds with and activates a membrane
receptors protein.
 It is the activates receptor, not the insulin,
that causes the subsequent effects of insulin.

14. Insulin cont.
 Within seconds after insulin binds with it’s
membrane receptors, the membrane of about
80% of the body’s cells markedly increase their
uptake of glucose and amino acids and regulate
glycogen metabolism and triglycerides in the
cells. This is especially true of muscle cells and
adipose cells but not true of most neurons in the
brain.
 The cell membrane becomes more permeable to
many amino acids, potassium ions, and
phosphate ions, causing increased transport of
these substances into cells.

15. Insulin cont.
 When insulin is secreted into the blood, it’s
circulated almost entirely in an unbound form; it
has plasma half life averages only about 6 min,
so that it is mainly cleared from the circulation
within 10-15 min.
 Except for the portion of the insulin that
combines with receptors in the target cells, the
remained is degraded by the enzyme insulinase
mainly in the liver, to a lesser extent in the
kidneys and muscles.

16. Actions of Insulin (anabolic hormone)
Tyr kinase
Insulin reduces blood glucose
Insulin Insulin
α
β
P
P
P
P
Glucose
Recruits additional
glucose transporter
Increased formation
of glycogen, protein
and fat
Increased
glucose
uptake
Increased
glucose
utilisation
Decreased formation
of glucose from
glycogen, fat and protein
Promote cell division
and
growth
Cell wall

17. In summary insulin:
• Increases glucose uptake into the muscle and fat
via Glut-4 enhancing glucose metabolism.
• Increase glycogen, protein and fat synthesis.
• Decreases gluconeogenesis (synthesis of glucose
from non-carbohydrate sources).
• Decreases glycogenolysis (glycogen breakdown).
• Increase glycolysis (glucose utilisation).
• Increases glycogenesis (glycogen synthesis).
• Increases lipogenesis.
• Decreases lipolysis.
• Decreases protein breakdown.

18. Comparison between Insulin
& Glucagon
Insulin
 Is released by β-cells in the
Islets of Langerhans in the
pancreas.
 Responds to high levels of
blood sugar; is released
when someone has a meal
and needs to store extra
energy.
 Lack of insulin or response to
insulin leads to diabetes.
Glucagon
 Is released by α-cells in
the Islets of Langerhans
in the pancreas.
 Responds to low levels of
blood sugar; is released
when someone hasn’t
eaten or requires extra
energy.
 Basically, glucagon is the
opposite of insulin.

19. Diabetes mellitus
 Elevation of blood glucose.
 Relative or absolute insulin deficiency.
 It is aggravated by an excess of glucagon.
 Polydipsia, polyphagia, polyuria and weight
loss.
 Can be classified in:
a) DM Type 1 (Insulin dependant).
b) DM Type 2 (Non-insulin dependant).
c) DM Type 3 (It is due to mutations of genes).
d) DM Type 4 (Gestational diabetes).

21. Absolute or
relative lack
of insulin
(Diabetes
Mellitus)
Retinophaty Nephropathy Neurophaty
Cardiovascular
Complications
Hyperglycemia
- Hypertension is 2 to 3 times
more common in diabetes.
- Both hypertension and diabetes
are risk factors for CVS and
other complications.

22. Dehydration

23. Chronic neuropathy:
Trophic ulceration

24. Gangrene

25. Gangrene with infection

26. Insulin
Preparations
Oral
Hypoglycemic
Agents
Can prevent morbidity
Reduce mortality

27. Insulin preparations
 As drug, insulin is destroyed enzymatically in the GIT and
must be given parenterally.
 Usually is given SC but the absorption into the circulation is
variable and depends on local blood flow.
 Consequently it is used IV or IM in emergencies.
 Once it has entered the blood flow it is bound by specialized
receptors that are found on the membranes of most tissues.
 The dose of insulin is adjusted on an individual basis.
 Insulin therapy in diabetic patients should be instituted
temporarily during intercurrent illness such as myocardial
infarction, infection, trauma and coma.
 Hypoglycaemic effect of insulin is enhanced by β-blockers.
(β2-Adrenoceptors Promote glycogenolysis)

28. Administration of Insulin in Diabetes
 The normal daily insulin requirement depends
on body mass, sugar intake and energy
expenditure. In most individuals it varies
between 60 and 75 units per day.
 Insulin is used in Type 1 diabetes (a
deficiency of insulin), and in a minority of
patients with Type 2 diabetes (insensitivity to
insulin).

29. Administration of Insulin in Diabetes
cont.
 Injections are usually given on the anterior
abdominal wall or thigh, but other sites may
also be used.
 Patients should not use the same injection
site continuously. The injection through scar
tissue is less painful but the problem is erratic
absorption & side effect of insulin lipodystrophy.
 Children and elderly patients requiring insulin
should be taught to inject themselves.

30. Insulin
Lipodystrophy
(Loss of local fat deposits
in patients as a
complication of repeated
insulin injections into the
same subcutaneous
tissue)

31. Insulin Preparations
 Insulin for clinical use was once either porcine or
bovine but is now almost entirely human (made by
recombinant DNA technology).
Short/Rapid acting insulins
 Examples include:
 Soluble insulin
 Insulin lispro – a synthetic insulin, in which a lysine
and a proline are switched. It is even shorter acting
than soluble insulin.
 Short acting insulins are injected at the start of a meal
and mediate their effect for 30-60 min.
 They permit a patient to match closely insulin
requirement (blood glucose) with the dose of insulin.

32. Insulin Preparations cont.
Medium or Intermediate acting insulins
 Isophane insulin: Insulin may be complexed with
protamine. This renders the insulin molecule less
soluble, and it is distributed from the injection site
more slowly than soluble insulin. Its effect lasts for
several hours.
Isophane insulin may be given in a combined
preparation with soluble insulin (Mixtard).
Mixtard insulin is convenient and easy to manage.
The control of blood glucose is often sub-optimal
however.

33. Medium or Intermediate acting insulins
 Insulin zinc suspension: Insulin may be prepared
in a suspension with zinc salts. Again, the
consequence is reduced solubility of insulin, and
delayed distribution of insulin from the injection site.
The duration of action is similar to, or a little longer
than, isophane insulin.
Insulin-zinc suspensions cannot be given in a
combined injection with soluble insulin. The zinc salts
are in excess in insulin-zinc suspension, and in
combination with soluble insulin, all the insulin
becomes bound to zinc.
Insulin Preparations cont.

34. Insulin Preparations cont.
Long or Slow acting Insulins
 Protamine zinc insulin: In this preparation, insulin is
complexed to both protamine and zinc. Its effect is long
lasting.
 Glarg-insulin: This is another chemically modified
recombinant insulin, containing the amino acid glargine.
The structure forms a micro-precipitate at the neutral pH
of an injection site, and is very slowly absorbed.
Glarg-insulin is a new and relatively expensive preparation,
and it is used to provide the background low level insulin
requirement, which can be supplemented at meal times by
soluble insulin or insulin lispro.
 The latter regime is now considered to provide the best
cover for patients with Type 1 diabetes.

36. Insulin ADR
 Risk of hypoglycemia (is common and, if very
severe, can cause brain damage). The treatment is
to take a sweet drink or snack or, if the patient is
unconscious, to give IV glucose or IM glucagon.
 Insulin Lypodystrophy.
 Rebound hyperglycaemia ('Somogyi effect') can
follow insulin-induced hypoglycaemia, because of
the release of counter-regulatory hormones
(glucagon, epinephrine, cortisol, GH).
 Allergy to human insulin is unusual but can occur.
 Insulin resistance as a consequence of antibody
formation is rare.

37. Oral hypoglycemic drugs

38. Insulin secretagogues
Sulfonylureas Meglitinide analogs
Promote insulin release

39. Sulfonylureas
 Mechanism of action: Stimulate β-islet cells to
release insulin, by blocking KATP channels, which
leads to depolarisation of the cell membrane,
Ca2+ influx and insulin secretion.
PANCREATIC ISLET
Insulin
–
β-Cell
Glibenclamide blocks KATP channel
Ca2+

40. Sulfonylureas
 They can lower blood sugar in non-diabetic patients.
 First-generation: Chlorpropamide, tolbutamide.
 Second-generation: They are more potent than first
generation- Glyburide, glipizide, glimepiride,
glibenclamide, gliclazide, gliquidone. They are
effective only when some residual pancreatic β-cell
activity is present.
 Tolbutamide: short acting, t½ = 4 h, very weak
action.
 Glipizide, gliclazide: t½ = 7 h
 Glibenclamide: t½ = 10 h
 Chlorpropamide: t½ > 15 h (should no longer be
used).

41.  ADR: Weight gain, Hyperinsulinemia, Hypoglicemia
which is most frequently seen with longer acting
agents (chlorpropamide and glibenclamide), Allergic
skin rashes, Bone marrow suppression (rare).
 Sulfonylureas (or their active metabolites) are excreted
in the urine.
 The risk of hypoglycaemia is therefore greater in
patients with renal failure and in the elderly.
 Contraindications: Hepatic or renal failure. Pregnant
women with DM2 should be treated with insulin.
(Sulfonylureas traverse the placenta, can deplete
insulin from the fetal pancreas).
Sulfonylureas

42. Meglitinide analogs
They include: Repaglinide, Nateglinide
 Similar action to sulfonylureas, inhibitors of KATP channels,
but have a short duration of action, and cause less
hypoglycaemia.
 Their action is dependent on functioning pancreatic β-cells.
 They bind to a distinct site on the sulfonylurea receptor of
KATP channels, initiating a series of reactions culminating in
the release of insulin.
 They are given shortly before meals, and there is evidence
that they stimulate appetite less than sulfonylureas.
 They are categorized as postprandial glucose regulators.
 Combined therapy with metformin or glitazones is better
than the monotherapy.
 Contraindications: Pregnant women with DM2.

43. Insulin sensitizers
Biguanides Thiazolidinediones
or glitazones
Impruve insulin action.
Lower blood sugar
by improving target-cell response to insulin
without increasing pancreatic insulin secretion.

44. Biguanides
Only drug of this class: Metformin.
 Lowers blood glucose by accelerating the
metabolism of glucose 6-phosphate to
pyruvate, thus increases glucose uptake
and conversion to G-6-P by hexokinase. It
reduces hepatic gluconeogenesis.
 It requires insulin for its action but does
not promote insulin secretion.
 It also reduces low-density and very low-
density lipoproteins.

45.  ADR:
 While preventing hyperglycaemia, does not cause
hypoglycaemia.
 Commonly nausea – dose related. Also appetite is
suppressed.
 Biguanides may (rarely) cause lactic acidosis.
 Clinical uses: Are widely used in type 2 diabetes
(especially among obese patients) and are
recommended in combination with sulfonylureas,
glitazones or insulin in type 2 diabetes – there is a
reduced incidence of diabetic retinopathy and other
complications.
 Excretion: Unchanged in the urine.
Biguanides

46. They include: Ciglitazone, troglitazone,
rosiglitazone, pioglitazone.
 The drugs increase sensitivity to insulin, but their effects are
not seen maximally for several weeks (4-6) after the drugs is
started.
 They are used as adjunctive therapy (sulfonylurea or
biguanide in type 2 diabetic patients).
 They reduce hepatic gluconeogenesis, and increase uptake of
glucose into muscle.
 Their effect is mediated by activation of a nuclear receptor
called peroxisome proliferator-activated receptor- γ (PPARγ).
 ADR: The principle adverse effect is hepatotoxicity, but also
GI disturbances, headache, weight gain and fatigue and
occasionally anaemia.
 Contraindications: Pregnant and nursing mothers.
Glitazones

47.  Acarbose, miglitol and voglibosa
inhibit GI α-glucosidase.
 It delays carbohydrate absorption, and
delivers more undigested carbohydrate to
the colon. This leads to flatulence,
diarrhoea, abdominal discomfort and
bloating.
 The drug is most use in obese type 2
diabetics.
 Contraindications: Patients with chronic
or inflammatory bowel disease. Pregnancy
Alpha-glucosidase inhibitors

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