Regulation of Insulin Secretion

Regulation of insulin secretion

Under basal condition ~1U insulin is secreted per hour by human pancreas. Much larger quantity
is secreted after every meal. Secretion of insulin from β cells is regulated by chemical, hormonal
and neural mechanisms.
Chemical The β cells have a glucose sensing mechanism dependent on entry of glucose into the β
cells (through the aegis of a glucose transporter GlUT1) and its phosphorylation by glucokinase.
Glucose entry and metabolism leads to activation of the glucosensor and production of ATP which
inhibits the ATPsensitive K+ channel (K+ATP) resulting in partial depolari zation of the β cells (see
Fig. 19.6). This increases intracellular Ca2+ availability (due to increased influx, decreased efflux
and release from intracellular stores) → exocytotic release of insulin storing granules. Other
nutrients that can evoke insulin release are—amino acids, fatty acids and ketone bodies, but
glucose is the principal regulator and it stimulates the synthesis of insulin as well. Glucose induces
a brief pulse of insulin output within 2 min (first phase) followed by a delayed but more sustained
second phase of insulin release.
Glucose and other nutrients are 2–4 times more effective in invoking insulin release when given
orally than i.v. They generate chemical signals ‘incretins’ from the gut which act on β cells in the
pancreas to cause anticipatory release of insulin. The incretins involved are glucagonlike peptide1
(GlP1), glucosedepen dent insulinotropic polypeptide (GIP), vasoactive intestinal peptide (VIP),
pancreozymincholecys tokinin, etc.; but various incretins may mediate signal from different
nutrients. Glucagon and some of these peptides enhance insulin release by increasing cAMP
formation in the β cells.
Hormonal A number of hormones, e.g. growth hormone, corticosteroids, thyroxine modify insulin
release in response to glucose. More important are the intraislet paracrine interactions between
the hormones produced by different types of islet cells. The β cells constitute the core of the islets
and are the most abundant cell type. The α cells, com prising 25% of the islet cell mass, surround
the core and secrete glucagon. The δ cells (5–10%) elaborating somatostatin are interspersed
between the α cells. There are some PP (pan creatic polypeptide containing) cells as well. •
Somatostatin inhibits release of both insulin
and glucagon.
Fig. 19.2: Paracrine modulation of hormone secretion within the pancreatic islets of Langerhans
• Glucagon evokes release of insulin as well as somatostatin.
• Insulin inhibits glucagon secretion. Amylin, another β cell polypeptide released with insulin,
inhibits glucagon secretion through a central site of action in the brain.
The three hormones released from closely situa ted cells influence each other’s secretion and
appear to provide fine tuning of their output in response to metabolic needs (Fig. 19.2). Neural
The islets are richly supplied by sympathetic and vagal nerves.
• Adrenergic α2 receptor activation decreases insulin release (predominant) by inhibiting β cell
adenylyl cyclase.
• Adrenergic β2 stimulation increases insulin release (less prominent) by stimulating β cell
adenylyl cyclase.
• Cholinergic—muscarinic activation by ACh or vagal stimulation causes insulin secretion through
IP3/DAGincreased intracellular Ca2+ in the β cells.
However, neural influences have only modu latory effect on insulin secretion.
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 Regulation of Insulin Secretion
Basal and Post-Meal Insulin Secretion

Basal Condition: ~1U insulin/hour by the pancreas.

Post-Meal: Much larger quantity secreted.

Mechanisms Regulating Insulin Secretion

Chemical Mechanisms

Glucose Sensing:
β cells sense glucose via GlUT1 transporter.
Glucose phosphorylation by glucokinase.
Glucose metabolism → ATP production.
ATP inhibits ATP-sensitive K+ channel (K+ATP) → partial depolarization of β cells.
Increased intracellular Ca2+ (increased influx, decreased efflux, release from stores) →
exocytosis of insulin granules.
Nutrients: Amino acids, fatty acids, ketone bodies can also evoke insulin release; glucose is the
principal regulator.
Insulin Release Phases:
First Phase: Brief pulse within 2 minutes.
Second Phase: Delayed but sustained release.
Oral vs. IV Administration: Oral intake of glucose and nutrients is 2-4 times more effective due
to incretins.
Incretins: GLP-1, GIP, VIP, pancreozymin-cholecystokinin.
Mechanism: Incretins act on β cells, enhance insulin release by increasing cAMP formation.

Hormonal Mechanisms

Various Hormones: Growth hormone, corticosteroids, thyroxine modify insulin release.

Intra-Islet Paracrine Interactions:
Cell Types:
β cells: Core of islets, most abundant.
α cells: 25%, surround β cells, secrete glucagon.
δ cells: 5-10%, interspersed, secrete somatostatin.
PP cells: Secrete pancreatic polypeptide.
Interactions:
Somatostatin: Inhibits insulin and glucagon release.
Glucagon: Evokes insulin and somatostatin release.
Insulin: Inhibits glucagon secretion.
Amylin: Inhibits glucagon through central action in the brain.

Neural Mechanisms

Sympathetic and Vagal Nerves:

Adrenergic α2 Receptors: Decrease insulin release by inhibiting β cell adenylyl cyclase.
Adrenergic β2 Receptors: Increase insulin release by stimulating β cell adenylyl cyclase.

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 Cholinergic Muscarinic Receptors: Activation by ACh or vagal stimulation increases insulin
secretion through IP3/DAG pathway, increasing intracellular Ca2+ in β cells.
Neural Influence: Primarily modulatory.

Key Points:

1. Chemical Regulation: Glucose is the primary regulator through a complex mechanism involving
ATP and Ca2+.
2. Hormonal Regulation: Multiple hormones, especially intra-islet interactions, play significant
roles.
3. Neural Regulation: Modulates insulin secretion through adrenergic and cholinergic pathways.

This summary provides a comprehensive overview of insulin secretion regulation, incorporating

chemical, hormonal, and neural influences.

ACTIONS OF INSULIN
The overall effects of insulin are to dispose meal derived glucose, amino acids, fatty acids and
favour storage of fuel. It is a major anabolic hormone: promotes synthesis of gylcogen, lipids and
protein. The actions of insulin and the results of its deficiency can be summarized as:

1. Insulin facilitates glucose transport across cell membrane: skeletal muscle and fat are highly
sensitive. The availability of glucose intracellularly is the limiting factor for its utilization. However,
glucose entry in liver, brain, RBC, WBC and renal medullary cells is largely independent of insulin.
Ketoacidosis interferes with glucose utilization by brain and contributes to diabetic coma.
Muscular activity induces glucose entry in muscle cells without the need for insulin. As such,
exercise has insulin sparing effect.
The intracellular pool of vesicles contain ing glucose transporter glycoproteins GlUT4 (insulin
activated) and GlUT1 is in dynamic equilibrium with the GlUT vesicles inserted into the membrane.
This equilibrium is regulated by insulin to favour translocation to the membrane. Moreover, on a
longterm basis, synthesis of GlUT4 is upregulated by insulin.
2. The first step in intracellular utilization of glucose is its phosphorylation to form glucose 6‐
phosphate. This is enhanced by insulin through increased production of glucokinase. Insulin
facilitates glycogen synthesis from glucose in liver, muscle and fat by stimulating the enzyme
glycogen synthase. It also inhibits glycogen degrading enzyme phosphorylase → decreased
glycogenolysis in liver.
3. Insulin inhibits gluconeogenesis (from protein, FFA and glycerol) in liver by gene mediated
decreased synthesis of phosphoenol pyruvate carboxykinase. In insulin deficiency, proteins and
amino acids are funneled from peripheral tissues
to liver where these substances are converted to carbohydrate and urea. Thus, in diabetes there is
underutilization and over production of glucose leading to hyperglycaemia and glycosuria.
4. Insulin inhibits lipolysis in adipose tissue and favours triglyceride synthesis. In diabetes
increased amount of fat is broken down due to unchecked action of lipolytic hormones (gluca‐
gon, Adr, thyroxine, etc.) → increased FFA and glycerol in blood → taken up by liver to produce
acetylCoA. Normally acetylCoA is resynthesized to fatty acids and triglycerides, but this process is
reduced in diabetics and acetyl CoA is diverted to produce ketone bod ies (acetone, acetoacetate,
βhydroxybutyrate). The ketone bodies are released in blood and partly used up by muscle and
heart as energy source, but when their capacity is exceeded, ketonaemia and ketonuria result.
5. Insulin enhances transcription of vascular endothelial lipoprotein lipase, thereby accel erating
clearance of VlDl and chylomicrons.

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 6. Insulin facilitates AA entry into muscles and most other cells. Their synthesis into proteins is
enhanced, and protein breakdown is inhibited. Insulin deficiency leads to protein breakdown →
AAs are released in blood → taken up by liver and converted to pyruvate, glucose and urea. The
excess urea produced is excreted in urine resulting in negative nitrogen balance. Thus, catabolism
takes the upper hand over anabolism in the diabetic state.
Most of the above metabolic actions of insulin are exerted within seconds or minutes and are
called the rapid actions. Others involving DNA mediated synthesis of glucose transporter and
some enzymes of amino acid metabolism have a latency of few hours—the intermediate ac tions.
In addition insulin exerts major long-term effects on multiplication and differentiation of many
types of cells.
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Actions of Insulin
General Effects

Disposal and Storage: Facilitates disposal of meal-derived glucose, amino acids, fatty acids;
promotes storage of fuel.
Anabolic Hormone: Promotes synthesis of glycogen, lipids, and proteins.

Key Actions and Effects of Insulin Deficiency

1. Glucose Transport
Facilitation: Insulin facilitates glucose transport across cell membranes, especially in
skeletal muscle and fat.
Insulin-Independent Tissues: Liver, brain, RBC, WBC, and renal medullary cells.
Ketoacidosis: Interferes with brain glucose utilization, contributing to diabetic coma.
Exercise: Induces glucose entry in muscle cells without insulin.
Glucose Transporters:
GLUT4: Insulin-activated; translocation to membrane regulated by insulin.
GLUT1: In dynamic equilibrium with membrane GLUT vesicles.
Long-term Regulation: Insulin upregulates GLUT4 synthesis.
2. Glucose Utilization and Glycogen Synthesis
Phosphorylation: Insulin enhances phosphorylation of glucose to glucose-6-phosphate via
increased glucokinase production.
Glycogen Synthesis: Stimulates glycogen synthase; inhibits glycogen phosphorylase,
reducing glycogenolysis.
3. Inhibition of Gluconeogenesis
Mechanism: Decreased synthesis of phosphoenol pyruvate carboxykinase.
Insulin Deficiency: Proteins and amino acids converted to glucose and urea in the liver,
leading to hyperglycemia and glycosuria.
4. Lipolysis and Triglyceride Synthesis
Inhibition of Lipolysis: Insulin inhibits lipolysis, favors triglyceride synthesis.
Diabetes: Increased lipolysis, elevated FFA and glycerol, acetyl-CoA diverted to ketone body
production, resulting in ketonemia and ketonuria.
5. Vascular Endothelial Lipoprotein Lipase

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 Transcription Enhancement: Insulin enhances transcription, accelerating clearance of
VLDL and chylomicrons.
6. Amino Acid Entry and Protein Synthesis
Facilitation: Insulin facilitates amino acid entry into cells, enhances protein synthesis,
inhibits protein breakdown.
Insulin Deficiency: Protein breakdown, release of amino acids into the blood, conversion
to pyruvate, glucose, and urea in the liver, resulting in negative nitrogen balance.

Timing of Insulin Actions

Rapid Actions: Metabolic actions exerted within seconds or minutes.

Intermediate Actions: DNA-mediated synthesis of glucose transporters and enzymes, latency of
a few hours.
Long-Term Effects: Multiplication and differentiation of many cell types.

Key Points:

1. Glucose Transport: Insulin facilitates glucose uptake, especially in muscle and fat, regulates
GLUT4.
2. Glycogen Synthesis: Enhances glucose utilization, glycogen synthesis, inhibits glycogenolysis.
3. Gluconeogenesis: Insulin inhibits liver gluconeogenesis, prevents excessive glucose production.
4. Lipolysis and Triglyceride Synthesis: Inhibits lipolysis, promotes triglyceride synthesis, prevents
ketone body overproduction.
5. Lipoprotein Lipase: Enhances transcription, accelerates VLDL and chylomicron clearance.
6. Protein Synthesis: Facilitates amino acid entry, enhances protein synthesis, prevents protein
breakdown.

This summary highlights the multifaceted actions of insulin and the metabolic disruptions caused by
its deficiency.

Mechanism of action Insulin acts on specific receptors located on the cell membrane of practically
every cell, but their density depends on the cell type: liver and fat cells are very rich. The insulin
receptor is a receptor tyrosine kinase (RTK) which is a heterotetrameric glycoprotein consisting of
2 extracellular α and 2 transmembrane β subunits linked together by disulfide bonds. It is
oriented across the cell membrane as a heterodimer (Fig. 19.3). The α subunits carry insulin
binding sites, while the β subunits have tyrosine protein kinase activity.
Binding of insulin to α subunits induces aggregation and internalization of the receptor along
with the bound insulin molecules. This activates tyrosine kinase activity of the β subunits → pairs
of β subunits phosphorylate tyrosine residues on each other → expose the catalytic site to
phosphorylate tyrosine residues of Insulin Receptor Substrate proteins (IRS1, IRS2, etc) and other
caveolar/ noncaveolar proteins. In turn, a cascade of phosphorylation and dephosphorylation
reactions involving phosphatidyl inositol 3 kinase (PI3 kinase) and other kinases is set into motion
which amplifies the signal and results in stimulation or inhibition of enzymes involved in the rapid
metabolic actions of insulin.
Second messengers like phosphatidyl inositol trisphos phate (PIP3) which are generated through
activation of a specific PI3-kinase also mediate the action of insulin on metabolic enzymes.
Insulin stimulates glucose transport across cell membrane by ATP dependent translocation of
glucose transporter GlUT4 to the plasma membrane. The second messenger PIP3 and certain
tyrosine phosphorylated guanine nucleotide exchange proteins play crucial roles in the insulin

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 sensi tive translocation of GlUT4 from cytosol to the plasma membrane, especially in skeletal
muscle and adipose tissue. Over a period of time insulin also promotes expression of the genes
directing synthesis of GlUT4. Genes for a large number of enzymes and carriers are regulated by
insulin through Ras/Raf and MAP-Kinase as well as through the phosphorylation cascade. long‐
term effects of insulin are exerted by generation of transcription factors promoting proliferation
and differentiation of specific cells.
The internalized receptorinsulin complex is either degraded intracellularly or returned back to the
surface from where the insulin is released extracellularly. The relative preponderance of these two
processes differs among diffe rent tissues: maximum degradation occurs in liver, least in vascular
endothelium.
Fate of insulin Insulin is distributed only extracellularly. It is a peptide, and gets degraded in the
g.i.t. if given orally. Injected insulin or that released from pancreas is metabolized primarily in liver
and to a smaller extent in kidney and muscles. Nearly half of the insulin entering portal vein from
pancreas is inacti vated in the first passage through liver. Thus, normally liver is exposed to a
much higher concentration (4–8 fold) of insulin than are
other tissues. As noted above, degradation of insulin after receptor mediated internalization
occurs to variable extents in most target cells. During biotransformation the disulfide bonds are
reduced—A and B chains are separated. These are further broken down to the constituent amino
acids. The plasma t ⁄ of insulin is 5–9 min.
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Mechanism of Action and Fate of Insulin

Mechanism of Action

1. Insulin Receptor
Type: Receptor tyrosine kinase (RTK).
Structure: Heterotetrameric glycoprotein (2 extracellular α and 2 transmembrane β
subunits linked by disulfide bonds).
α Subunits: Insulin binding sites.
β Subunits: Tyrosine protein kinase activity.
2. Activation Process
Binding: Insulin binds to α subunits.
Aggregation/Internalization: Receptor-insulin complex internalizes.
Tyrosine Kinase Activation: β subunits phosphorylate tyrosine residues on each other.
Catalytic Site Exposure: Phosphorylation of Insulin Receptor Substrate proteins (IRS1,
IRS2, etc.) and other proteins.
Phosphorylation Cascade: Involves PI3 kinase and other kinases.
Second Messengers: PIP3 mediates the action on metabolic enzymes.
3. Glucose Transport
Mechanism: ATP-dependent translocation of GLUT4 to the plasma membrane.
Role of PIP3: Crucial in translocation of GLUT4, especially in skeletal muscle and adipose
tissue.
Gene Expression: Insulin promotes expression of genes for GLUT4 synthesis.
4. Regulation of Enzymes and Carriers
Pathways: Ras/Raf and MAP-Kinase pathways.

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 Long-term Effects: Generation of transcription factors promoting cell proliferation and
differentiation.
5. Receptor-Insulin Complex Fate
Degradation vs. Recycling:
Degraded intracellularly or returned to the surface.
Maximum degradation in the liver, least in vascular endothelium.

Fate of Insulin

1. Distribution: Only extracellularly.

Oral Administration: Degraded in the gastrointestinal tract.
Injected/Endogenous: Metabolized primarily in the liver, also in kidneys and muscles.
Portal Vein: Nearly half of insulin inactivated in the first passage through the liver.
2. Degradation Process
Internalization: Insulin receptor complex internalized.
Reduction of Disulfide Bonds: A and B chains separated.
Breakdown: Further degraded to constituent amino acids.
Plasma Half-life: 5–9 minutes.

Key Points:

1. Insulin Receptor: RTK with α and β subunits, insulin binding activates tyrosine kinase activity.
2. Activation Cascade: Phosphorylation of IRS proteins, PI3 kinase involvement, PIP3 as a second
messenger.
3. Glucose Transport: GLUT4 translocation facilitated by insulin, gene expression regulation.
4. Long-term Effects: Cell proliferation and differentiation via transcription factors.
5. Degradation and Fate: Insulin metabolized in the liver, kidneys, and muscles, with variable
degradation in target cells.

This summary encapsulates the detailed mechanism of insulin action and its metabolic fate, providing
a clear overview of its biological role.

Preparations of insulin
The older commercial insulin preparations were produced from beef and pork pancreas. They
contained ~1% (10,000 ppm) of other proteins (proinsulin, other polypeptides, pancreatic proteins,
insulin derivatives, etc.) which were potentially antigenic. Such insulins are no longer produced
and have been totally replaced by highly purified pork/beef insulins, recombinant human insulins
and insulin analogues.
Highly purified insulin preparations
In the 1970s improved purification techniques like gel filtration and ion-exchange
chromatography were applied to produce ‘single peak’ and ‘monocomponent (MC)’ insulins which
contain <10 ppm proinsulin. The MC insulins are more stable and cause less insulin resistance or
injection site lipodystrophy. The immunogenicity of pork MC insulin is similar to that of
recombinant human insulin. Types of insulin preparations
Regular (soluble) insulin It is a buffered neu tral pH solution of unmodified insulin stabilized by a
small amount of zinc. At the concentration of the injectable solution, the insulin molecules self
aggregate to form hexamers around the zinc ions. After s.c. injection, insulin monomers are
released gradually by dilution, so that absorption occurs slowly. Peak action is produced only after
2–3 hours and action continues upto 6–8 hours. The absorption pattern is also affected by dose;

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 higher doses act longer. When injected s.c. just before a meal, this pattern often creates a
mismatch between the need and the availability of insulin to result in early postprandial hyper‐
glycaemia and late postprandial hypoglycaemia. Regular insulin is optimally injected 1 hour
before a meal. Regular insulin injected s.c. is also not suitable for providing a low constant basal
level of action in the interdigestive pe riod. However, the slow onset of action is not applicable to
i.v. injection, because the insulin hexamer dissociates rapidly to produce prompt action. Regular
insulin is the only insulin used for i.v. injection.
To overcome the above problems, some long-acting ‘modified’ or ‘retard’ preparations of insulin
were soon developed. Recently, both rapidly acting as well as peakless and long acting insulin
analogues have become available.
For obtaining retard preparations, insulin is rendered insoluble either by complexing it with
protamine (a small molecular basic protein) or by precipitating it with excess zinc and increasing
the particle size.
Lente insulin (Insulin-zinc suspension): Two types of insulinzinc suspensions have been pro duced.
The one with large particles is crystalline and practically insoluble in water (ultralente). It is long‐
acting. The other has smaller particles and is amorphous (semilente), is shortacting. Their 7:3 ratio
mixture is called ‘lente insulin’ and is intermediateacting.
Isophane (Neutral Protamine Hagedorn or NPH) insulin: Protamine is added in a quantity
just sufficient to complex all insulin molecules; neither insulin nor protamine is present in free
form and pH is neutral. On s.c. injection, the complex dissociates slowly to yield an inter mediate
duration of action. However, the time course of absorption and intensity of action of NPH insulin
is relatively inconsistent. It is mostly combined with regular insulin (70:30 or 50:50) and injected
s.c. twice daily before
breakfast and before dinner (splitmixed regimen). 1. Highly purified (monocomponent) pork
regular insulin:
ACTRAPID MC, RAPIDICA 40 U/ml inj.
2. Highly purified (MC) pork lente insulin: LEnTARD, MonoTARD MC, LEnTInSuLIn-HPI, zInuLIn 40
U/ml
3. Highly purified (MC) pork isophane (nPH) insulin:
InSuLATARD 40 U/ml inj.
4. Mixture of highly purified pork regular insulin (30%) and isophane insulin (70%): RAPIMIx,
MIxTARD 40 U/ml inj.
Human insulins In the 1980s, the hu man insulins (having the same amino acid sequence as
human insulin) were produced by recombinant DNA technology in Escherichia coli—‘proinsulin
recombinant bacterial’ (prb) and in yeast—‘precursor yeast recombinant’ (pyr), or by ‘enzymatic
modification of porcine
insulin’ (emp).

In the USA pork and beef insulins are no longer manufactured, but they are still available in U.K.,
India and some European countries. In Britain now > 90% diabetics who use insulin are taking
human insulins or insulin analogues. In India also human insulins and analogues are commonly
used, except for considerations of cost. Human insulin is more water soluble as well as
hydrophobic than porcine or bovine insulin. It has a slightly more rapid s.c. absorption, earlier and
more defined peak concentration and slightly shorter duration of action. Human insulin is also
modified similarly to produce isophane (NPH) and lente preparations. lente human insulin is no
longer prepared in the USA.
The allegation that human insulin produces more hypoglycae- mic unawareness has not been
substantiated. However, after prolonged treatment, irrespective of the type of insulin used, many
diabetics develop relative hypoglycaemic unawareness/ change in hypoglycaemic symptoms,
because of autonomic neuropathy, changes in perception/attitude and other factors.
Clinical superiority of human insulin over pork MC insulin has not been demonstrated. Though
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 new patients may be started on human insulins, the only indication for transfer from purified pork
to human insulin is allergy to pork insulin. It is unwise to transfer stabilized patients from one to
another species insulin without good reason.
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Preparations of Insulin
Historical Overview

Older Preparations: Derived from beef and pork pancreas; contained ~1% other proteins, which
were antigenic.
Current Preparations: Highly purified pork/beef insulins, recombinant human insulins, and
insulin analogues.

Highly Purified Insulin Preparations

Development: 1970s, using gel filtration and ion-exchange chromatography.

Monocomponent (MC) Insulins: Contain <10 ppm proinsulin; more stable, less immunogenic,
and cause less injection site lipodystrophy.
I
Types of Insulin Preparations

Regular (Soluble) Insulin

I Tur -
I

II
Composition: Buffered neutral pH solution with zinc; forms hexamers.
Absorption: Slow absorption after subcutaneous (s.c.) injection, with peak action at 2-3 hours,
-
lasting 6-8 hours.
-

Administration: Ideally injected 1 hour before a meal; not suitable for constant basal levels.
Intravenous (i.v.) Use: Rapid action due to hexamer dissociation.
Disadvantage -
Postprandial hyperglepemiaa late postprandial hypoglycemia.
Long-Acting and Modified Insulin Preparations
(taken before meal)

Development: To address issues of regular insulin.

Composition: Insulin complexed with protamine or precipitated with excess zinc to increase
particle size.
-
Lente Insulin (Insulin-Zinc Suspension):
Ultralente: Large, crystalline, long-acting.
Semilente: Small, amorphous, short-acting.
Lente Insulin: 7:3 mixture, intermediate-acting. (neither is free)
Neutral Isophane (NPH) Insulin: Insulin-Protamine
Protamine Composition: Complexed with protamine; neutral pH.
Hugedron -
Action: Intermediate duration; absorption and action can be inconsistent.
Administration: Often combined with regular insulin (70:30 or 50:50), injected s.c.
twice daily before meals.

Specific Highly Purified Pork Insulin Preparations

1. Regular Insulin: ACTRAPID MC, RAPIDICA.

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 2. Lente Insulin: LEnTARD, MonoTARD MC, LEnTInSuLIn-HPI, zInuLIn.
3. Isophane (NPH) Insulin: InSuLATARD.
4. Mixture of Regular and Isophane Insulin: RAPIMIx, MIxTARD.

Human Insulins

Production: 1980s, via recombinant DNA technology in E. coli (proinsulin recombinant bacterial,
prb) and yeast (precursor yeast recombinant, pyr), or by enzymatic modification of porcine
insulin (emp).
Availability: Dominant in the USA, U.K., India, and Europe.
Properties: More water-soluble and hydrophobic, slightly faster s.c. absorption, earlier peak, and
shorter duration of action compared to porcine or bovine insulin.

Clinical Considerations

Hypoglycemic Unawareness: Not substantiated to be higher with human insulin; related to

autonomic neuropathy and other factors.
Clinical Superiority: No proven superiority of human insulin over pork MC insulin.
Indications for Switching: Allergy to pork insulin; otherwise, stabilized patients should not
switch without a good reason.

Key Points:

1. Highly Purified Insulin: Modern insulins are highly purified to reduce immunogenicity.
2. Regular Insulin: Slow absorption, ideal for pre-meal injection; only insulin used for i.v. injection.
3. Modified Insulins: Long-acting and intermediate-acting preparations developed to address
regular insulin's limitations.
4. Human Insulins: Produced via recombinant DNA technology; more water-soluble with faster
absorption.
5. Clinical Use: No significant clinical advantage of human insulin over pork MC insulin; switching
insulins should be done cautiously.

This summary captures the evolution, types, and clinical considerations of various insulin
preparations, providing a clear overview of their development and use.

Insulin analogues
Using recombinant DNA technology, analogues of insulin have been produced which have
modified pharmacokinetics on s.c. injection, but similar pharmacodynamic effects and
immunogenicity. Greater stability and consistency of the preparations are the other advantages.
Insulin lispro: Produced by reversing proline and lysine at the carboxy terminus B 28 and B 29
positions, it forms very weak hexamers that dissociate rapidly after s.c. injection resulting in a
quick and more defined peak as well as shorter duration of action. Individual variability in
absorption is minimized. Unlike regular in sulin, it is best injected s.c. 0–20 min before a meal. A
better control of mealtime glycaemia and a lower incidence of late postprandial hypoglycaemia
have been obtained. Using a regimen of 2–3 daily mealtime insulin lispro injections, a slightly
greater reduction in HbA compared to regular insulin has been reported.
Fewer hypoglycaemic episodes occurred.
HUMAlOG 100 U/ml, 3 ml cartridge, 10 ml vial.
Insulin aspart: The proline at B 28 of human insulin is replaced by aspartic acid. This change

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 reduces the tendency for selfaggregation, and a time-action profile similar to insulin lispro is
obtained. It more closely mimics the physi ological insulin release pattern after a meal, with the
same advantages as above. novoLog, novoRAPID 100 U/ml inj.
Biphasic insulin aspart: The 70:30 mixture of isophane complex of insulin aspart with
uncomplexed insulin aspart has the advantage of rapid and predictable onset along with inter‐
mediate duration of action. It is called ‘biphasic insulin aspart’, and can be injected twice daily just
before each major meal.
novoMIx 30 FLExPEn 100 U/ml in 3 ml inj., also
as PENFIl injection.
Insulin glulisine: Another rapidly acting insulin analogue with lysine replacing asparagine at B 23
and glutamic acid replacing lysine at B 29. Properties and advantages are similar to insulin lispro.
It has been particularly used for continuous subcutaneous insulin infusion (CSII) by a pump.
Insulin glargine: This longacting biosynthetic insulin has 2 additional arginine residues at the
carboxy terminus of B chain and glycine replaces asparagine at A 21. This analogue remains
soluble at pH4 of the formulation, but precipitates at neutral pH encountered on s.c. injection. A
depot is created from which monomeric insulin dissociates slowly to enter the circulation. Onset
of action is delayed, but relatively low blood levels of insulin are maintained for upto 24 hours. A
smooth ‘peakless’ effect is obtained. Thus, it is suitable for once daily injection to provide
background insulin action. Fasting and interdigestive blood glucose levels are effec tively lowered
irrespective of time of the day when injected or the site of s.c. injection. It is mostly injected at bed
time. lower incidence of nighttime hypoglycaemic episodes compared to isophane insulin has
been reported. However, it does not control mealtime glycaemia, for which a rapid acting insulin
or an oral hypoglycaemic is used concurrently. Because of acidic pH, it cannot be mixed with any
other insulin prepara
tion; must be injected separately. Insulin detemir Myristoyl (a fatty acid) radical is attached to the
amino group of lysine at B29 of insulin chain. As a result, it binds to albumin after s.c. injection
from which the free form becomes available slowly. A pattern of insulin action almost similar to
that of insulin glargine is
obtained, but twice daily dosing may be needed.
LEvEMIR FLExPEn 100 u/mL in 3 mL prefilled pen injector.
Insulin degludec It is a new ultra longacting insulin analogue with a flat plasma glucose lowering
effect lasting for ~ 40 hours, suitable for meeting basal insulin require- ment in type 1 and type 2
diabetic patients. After single daily injection the daytoday variability in response and risk of
nocturnal hypoglycaemia are less than with insulin glargine. An alternate day regimen has also
been tried, but may not be satisfactory. It has also been coformulated with rapidacting insulin
aspart.
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Insulin Analogues
Overview

Production: Using recombinant DNA technology.

Advantages: Modified pharmacokinetics, similar pharmacodynamics and immunogenicity,
greater stability, and consistency.

Rapid-Acting Insulin Analogues

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 1. Insulin Lispro
Modification: Reverses proline and lysine at B28 and B29 positions.
Action: Forms weak hexamers, dissociates rapidly after subcutaneous (s.c.) injection.
Administration: Best injected 0-20 min before a meal.
Benefits: Better control of meal-time glycemia, lower incidence of late post-prandial
hypoglycemia, slightly greater reduction in HbA1c, fewer hypoglycemic episodes.
Product: HUMALOG 100 U/ml.
2. Insulin Aspart
Modification: Proline at B28 replaced by aspartic acid.
Action: Reduces self-aggregation, similar time-action profile to insulin lispro.
Benefits: Mimics physiological insulin release pattern after a meal.
Product: NOVOLOG, NOVORAPID 100 U/ml.
3. Biphasic Insulin Aspart
Composition: 70:30 mixture of isophane complexed insulin aspart with uncomplexed
insulin aspart.
Action: Rapid and predictable onset, intermediate duration.
Administration: Injected twice daily before major meals.
Product: NOVOMIX 30 FLEXPEN 100 U/ml.
4. Insulin Glulisine
Modification: Lysine replaces asparagine at B23, glutamic acid replaces lysine at B29.
Action: Similar properties and advantages to insulin lispro.
Use: Particularly used for continuous subcutaneous insulin infusion (CSII) by a pump.

Long-Acting
↑
Insulin Analogues

1. Insulin Glargine
-

Modification: Two additional arginine residues at the carboxy terminus of B chain, glycine
-

replaces asparagine at A21.

-

Action: Soluble at pH4, precipitates at neutral pH, creating a depot for slow dissociation.
Administration: Once daily injection, mostly at bedtime.
Benefits: Smooth 'peakless' effect, effective fasting and interdigestive blood glucose
control, lower incidence of night-time hypoglycemic episodes.
Limitation: Does not control meal-time glycemia; cannot be mixed with other insulin
preparations.
Product: LANTUS.
2. Insulin Detemir
Modification: Myristoyl (fatty acid) radical attached to the amino group of lysine at B29.
Action: Binds to albumin after s.c. injection, free form becomes available slowly.
Administration: May need twice daily dosing.
Product: LEVEMIR FLEXPEN 100 U/ml.
3. Insulin Degludec
Action: Ultra long-acting, flat plasma glucose-lowering effect lasting ~40 hours.
Benefits: Suitable for basal insulin requirement, less day-to-day variability, lower risk of
nocturnal hypoglycemia.
Administration: Single daily injection; alternate day regimen may not be satisfactory.
Product: TRESIBA, coformulated with rapid-acting insulin aspart.

Key Points:

Insulin Lispro: Rapid action, best before meals, reduces post-prandial hypoglycemia.

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 Insulin Aspart: Similar benefits to lispro, mimics physiological insulin release.
Biphasic Insulin Aspart: Combines rapid and intermediate actions, suitable for twice daily use.
Insulin Glulisine: Rapid-acting, ideal for insulin pumps.
Insulin Glargine: Long-acting, provides steady insulin levels, used once daily.
Insulin Detemir: Similar to glargine but may need twice daily dosing.
Insulin Degludec: Ultra long-acting, stable effect, lower hypoglycemia risk.

These notes provide a clear and concise overview of various insulin analogues, their modifications,
actions, benefits, and clinical uses.

REACTIONS TO INSULIN
1. Hypoglycaemia This is the most frequent and potentially the most serious reaction. Hypo‐
glycaemic episodes are more common in patients of ‘labile’ diabetes in whom insulin requirement
fluctuates unpredictably. Hypoglycaemia can occur in any diabetic following inadvertent injection
of large dose, by missing a meal after injec tion or by performing vigorous exercise. The
symptoms can be divided into those due to counterregulatory sympathetic stimulation, viz.
sweating, anxiety, palpitation, tremor; and those due to deprivation of the brain of its essential
nutrient glucose (neuroglucopenic symptoms)— dizziness, headache, behavioural changes, visual
disturbances, hunger, fatigue, weakness, muscular incoordination and sometimes fall in BP. Gen‐
erally, the reflex sympathetic symptoms occur, before the neuroglucopenic, but the warning
symptoms of hypoglycaemia differ from patient to patient and also depend on the rate of fall in
blood glucose level. Diabetic neuropathy can abolish the autonomic symptoms. Hypoglycaemic
unawareness (loss of warning symptoms) tends to develop in patients who experience frequent
episodes of hypoglycaemia.
Finally, when blood glucose falls further (to < 40 mg/dl) mental confusion, abnormal behaviour,
seizures and coma occur. Irrevers ible neurological deficits are the sequelae of prolonged
hypoglycaemia.
Treatment Glucose (or glucose yielding car bohydrate, e.g. sugar) 15–20 g orally reverses the
symptoms rapidly in most cases. If no improvement occurs, the same amount may be repeated
after 15–20 min. In severe cases 30–50 ml of 50% glucose may be injected i.v. over 10 min.
Glucagon 0.5–1 mg i.v. or Adr 0.2 mg s.c. (less desirable) may be given as an expedient measure in
patients who are not able to take sugar orally and injectable
glucose is not available.
2. Local reactions Swelling, erythema and stinging sometimes occur at the injected site, especially
in the beginning. Lipodystrophy of the subcutaneous fat around the injection site occurred
occasionally with the older pork/beef insulin preparations. This is rare with the newer
preparations.
3. Allergy This is due to contaminating proteins, and is very rare with human/highly purified
insulins.
Urticaria, angioedema and anaphylaxis are the mani festations.
4. Edema Some patients develop shortlived dependent edema (due to Na+ retention) when insulin
therapy is started.
Drug interactions
1. β adrenergic blockers prolong hypoglycaemia by inhibiting compensatory mechanisms
operating through β2 receptors (β1 selective blockers are less liable). Warning signs of
hypoglycaemia like palpitation, tremor and anxiety are masked.
2. Thiazides, furosemide, corticosteroids, oral contraceptives, salbutamol, nifedipine tend to raise
blood sugar and reduce effectiveness of insulin.
3. Acute ingestion of alcohol can precipitate hypoglycaemia by depleting hepatic glycogen.

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 4. lithium, high dose aspirin and theophylline may also accentuate hypoglycaemia by enhanc ing
insulin secretion, as well as peripheral glucose utilization.
Create conceptual and revisable notes on the above paragraphs

*Mnemonic

WALL-E
Reactions to Insulin HAL-E

1. Hypoglycemia

Frequency: Most common and serious reaction.

Risk Factors:
Labile diabetes with fluctuating insulin requirements.
Large dose injections.
Missing meals post-injection.
Vigorous exercise.
Symptoms:
Sympathetic Stimulation: Sweating, anxiety, palpitation, tremor.
Neuroglucopenic Symptoms: Dizziness, headache, behavioral changes, visual
disturbances, hunger, fatigue, weakness, muscular incoordination, fall in BP.
Severe Symptoms: Mental confusion, abnormal behavior, seizures, coma, irreversible
neurological deficits (when blood glucose < 40 mg/dl).
Treatment:
Mild Cases: 15-20 g glucose orally; repeat after 15-20 min if no improvement.
Severe Cases: 30-50 ml of 50% glucose i.v. over 10 min.
Alternative: Glucagon 0.5-1 mg i.v. or adrenaline 0.2 mg s.c.

2. Local Reactions

Symptoms: Swelling, erythema, stinging at injection site.

Occurrence: Common in the beginning; rare with newer insulin preparations.
Complication: Lipodystrophy with older pork/beef insulin.

3. Allergy

Cause: Contaminating proteins.

Incidence: Very rare with human/highly purified insulins.
Symptoms: Urticaria, angioedema, anaphylaxis.

4. Edema

Occurrence: Short-lived dependent edema due to Na+ retention when starting insulin therapy.

Drug Interactions

1. β-Adrenergic Blockers
Effect: Prolong hypoglycemia by inhibiting compensatory β2 receptor mechanisms.
Symptom Masking: Palpitation, tremor, and anxiety.
2. Hyperglycemic Agents

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 Examples: Thiazides, furosemide, corticosteroids, oral contraceptives, salbutamol,
nifedipine.
Effect: Raise blood sugar, reduce insulin effectiveness.
3. Alcohol
Effect: Can precipitate hypoglycemia by depleting hepatic glycogen.
4. Other Drugs
Examples: Lithium, high dose aspirin, theophylline.
Effect: Accentuate hypoglycemia by enhancing insulin secretion and peripheral glucose
utilization.

Key Points:

Hypoglycemia: Most serious reaction, requires prompt treatment with glucose.

Local Reactions: Swelling and erythema at injection site, rare lipodystrophy with modern
insulins.
Allergy: Rare with purified insulins, can cause severe reactions.
Edema: Short-lived, due to Na+ retention.
Drug Interactions: Beta-blockers, certain diuretics, steroids, contraceptives, and alcohol can
influence insulin's effectiveness and hypoglycemia risk.

These notes summarize the key points regarding insulin reactions, making it easier to study and revise
the important concepts.

REACTIONS TO INSULIN
1. Hypoglycaemia This is the most frequent and potentially the most serious reaction. Hypo‐
glycaemic episodes are more common in patients of ‘labile’ diabetes in whom insulin requirement
fluctuates unpredictably. Hypoglycaemia can occur in any diabetic following inadvertent injection
of large dose, by missing a meal after injec tion or by performing vigorous exercise. The
symptoms can be divided into those due to counterregulatory sympathetic stimulation, viz.
sweating, anxiety, palpitation, tremor; and those due to deprivation of the brain of its essential
nutrient glucose (neuroglucopenic symptoms)— dizziness, headache, behavioural changes, visual
disturbances, hunger, fatigue, weakness, muscular incoordination and sometimes fall in BP. Gen‐
erally, the reflex sympathetic symptoms occur, before the neuroglucopenic, but the warning
symptoms of hypoglycaemia differ from patient to patient and also depend on the rate of fall in
blood glucose level. Diabetic neuropathy can abolish the autonomic symptoms. Hypoglycaemic
unawareness (loss of warning symptoms) tends to develop in patients who experience frequent
episodes of hypoglycaemia.
Finally, when blood glucose falls further (to < 40 mg/dl) mental confusion, abnormal behaviour,
seizures and coma occur. Irrevers ible neurological deficits are the sequelae of prolonged
hypoglycaemia.
Treatment Glucose (or glucose yielding car bohydrate, e.g. sugar) 15–20 g orally reverses the
symptoms rapidly in most cases. If no improvement occurs, the same amount may be repeated
after 15–20 min. In severe cases 30–50 ml of 50% glucose may be injected i.v. over 10 min.
Glucagon 0.5–1 mg i.v. or Adr 0.2 mg s.c. (less desirable) may be given as an expedient measure in
patients who are not able to take sugar orally and injectable
glucose is not available.
2. Local reactions Swelling, erythema and stinging sometimes occur at the injected site, especially
in the beginning. Lipodystrophy of the subcutaneous fat around the injection site occurred
occasionally with the older pork/beef insulin preparations. This is rare with the newer
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 preparations.
3. Allergy This is due to contaminating proteins, and is very rare with human/highly purified
insulins.
Urticaria, angioedema and anaphylaxis are the mani festations.
4. Edema Some patients develop shortlived dependent edema (due to Na+ retention) when insulin
therapy is started.
Drug interactions
1. β adrenergic blockers prolong hypoglycaemia by inhibiting compensatory mechanisms
operating through β2 receptors (β1 selective blockers are less liable). Warning signs of
hypoglycaemia like palpitation, tremor and anxiety are masked.
2. Thiazides, furosemide, corticosteroids, oral contraceptives, salbutamol, nifedipine tend to raise
blood sugar and reduce effectiveness of insulin.
3. Acute ingestion of alcohol can precipitate hypoglycaemia by depleting hepatic glycogen.
4. lithium, high dose aspirin and theophylline may also accentuate hypoglycaemia by enhanc ing
insulin secretion, as well as peripheral glucose utilization.
Create conceptual and revisable notes on the above paragraphs

Reactions to Insulin
1. Hypoglycemia

Frequency: Most common and potentially serious reaction.

Risk Factors:
Labile diabetes with unpredictable insulin requirements.
Large dose injections.
Missing meals after injection.
Vigorous exercise.
Symptoms:
Sympathetic Stimulation: Sweating, anxiety, palpitation, tremor.
Neuroglucopenic Symptoms: Dizziness, headache, behavioral changes, visual
disturbances, hunger, fatigue, weakness, muscular incoordination, fall in BP.
Severe Symptoms: Mental confusion, abnormal behavior, seizures, coma, irreversible
neurological deficits (when blood glucose < 40 mg/dl).
Warning Signs: Vary among patients; depend on the rate of blood glucose drop. Diabetic
neuropathy can abolish autonomic symptoms.
Hypoglycemic Unawareness: Develops with frequent hypoglycemic episodes.
Treatment:
Mild Cases: 15-20 g glucose orally; repeat after 15-20 min if no improvement.
Severe Cases: 30-50 ml of 50% glucose i.v. over 10 min.
Alternative: Glucagon 0.5-1 mg i.v. or adrenaline 0.2 mg s.c. (less desirable).

2. Local Reactions

Symptoms: Swelling, erythema, stinging at injection site, especially initially.

Complication: Lipodystrophy with older pork/beef insulin, rare with newer preparations.

3. Allergy

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 Cause: Contaminating proteins.
Incidence: Very rare with human/highly purified insulins.
Symptoms: Urticaria, angioedema, anaphylaxis.

4. Edema

Occurrence: Short-lived dependent edema due to Na+ retention when starting insulin therapy.

Drug Interactions
1. β-Adrenergic Blockers
Effect: Prolong hypoglycemia by inhibiting compensatory β2 receptor mechanisms.
Symptom Masking: Palpitation, tremor, and anxiety.
2. Hyperglycemic Agents
Examples: Thiazides, furosemide, corticosteroids, oral contraceptives, salbutamol,
nifedipine.
Effect: Raise blood sugar, reduce insulin effectiveness.
3. Alcohol
Effect: Can precipitate hypoglycemia by depleting hepatic glycogen.
4. Other Drugs
Examples: Lithium, high dose aspirin, theophylline.
Effect: Accentuate hypoglycemia by enhancing insulin secretion and peripheral glucose
utilization.

Key Points:

Hypoglycemia: Most serious reaction, requires prompt treatment with glucose.

Local Reactions: Swelling and erythema at injection site, rare lipodystrophy with modern
insulins.
Allergy: Rare with purified insulins, can cause severe reactions.
Edema: Short-lived, due to Na+ retention.
Drug Interactions: Beta-blockers, certain diuretics, steroids, contraceptives, and alcohol can
influence insulin's effectiveness and hypoglycemia risk.

USES OF INSULIN
Diabetes mellitus The purpose of therapy in diabetes mellitus is to restore metabolism to normal,
avoid symptoms due to hyperglycaemia and glucosuria, prevent shortterm complications
(infection, ketoacidosis, etc.) and longterm sequelae (cardiovascular, retinal, neurological, renal,
etc.). The generally accepted criteria for adequate glycaemia control in an adult diabetic treated
with insulin or oral antidiabetics are:
• Fasting (morning) blood glucose levels
90–130 mg/dl
• Blood glucose levels <150 mg/dl 2 hours
after meals
• HbAIC levels < 7%.
Insulin is effective in all forms of diabetes mellitus and is a must for type 1 cases, as well as for
post pancreatectomy diabetes and gestational diabetes. Many type 2 cases can be controlled by
lifestyle measures like diet, reduc tion in body weight and appropriate exercise supplemented, if

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 required, by oral antidiabetics. Insulin is needed by such patients when:
• Not controlled by diet and exercise or when these are not practicable.
• Primary or secondary failure of oral antidia betics or when these drugs are not tolerated.
• Under weight patients.
• Temporarily to tide over infections, trauma,
surgery, pregnancy. In the perioperative period and during labour, monitored i.v. insulin infusion
is preferable.
• Any complication of diabetes, e.g. keto acidosis, nonketotic hyperosmolar coma, gangrene of
extremities.
When instituted, insulin therapy has to
be tailored according to the requirement and convenience of each patient. A tentative regi men is
instituted and the insulin requirement is assessed by testing blood glucose levels (portable
glucometers are available). Most type 1 patients require 0.4–0.8 U/kg/day. In type 2 patients,
insulin dose varies (0.2–1.6 U/kg/day) with the severity of diabetes and body weight: obese
patients require higher per kg doses due to relative insulin resistance.
Any satisfactory insulin regimen should pro vide basal control by inhibiting hepatic glucose
output, lipolysis and protein breakdown, as well as supply extra amount to meet postprandial
needs for disposal of absorbed glucose and amino acids. A single daily injection of any longacting
or intermediateacting or shortacting insulin or a mixture of these cannot fulfil both
these requirements. Either multiple (2–4) injec tions daily of long and short acting insulins or a
single injection daily of longacting insulin supplemented by oral hypoglycaemics for meal time
glycaemia is used.
Split-mixed regimen: A frequently selected regimen utilizes mixture of regular with lente or
isophane insulin. The total daily dose of a 30:70 or 50:50 mixture of regular and NPH insulin is
usually split into two and injected s.c. before breakfast and before dinner. Several variables, viz.
site and depth of s.c. injection, posture, regional muscular activity, injected volume and type of
insulin alter the rate of absorption of s.c. injected insulin, so that vari ability in timecourse of
insulin action within the same patient is large. The advantage is that only two daily injections are
required, but the postlunch glycaemia may not be adequately covered (see Fig. 19.4 A), and late
postprandial hypoglycaemia may occur. Basal-bolus regimen: This is a more intensive regimen
that is now advised. It needs 3–4 daily injections (see Fig. 19.4B). A longacting insulin (glargine) is
injected once daily either before breakfast or before bedtime for basal coverage along with 2–3
mealtime injections of a rapid acting preparation (insulin lispro or aspart). The dose of basal
insulin is usually kept constant for a patient, while that of meal time rapid acting insulin is varied
according to carbohydrate content of food consumed. Such intensive regimens more completely
meet the objective of achieving roundtheclock euglycae mia, but are more demanding and
expensive.
The large multicentric Diabetes Control and Complications Trial (DCCT) among type 1 patients has
established that intensive insulin therapy markedly reduces the occurrence of primary diabetic
retinopathy, neuropathy, nephropathy and slows progression of these complications in those who
already have them, in comparison to conventional regimens which attain only intermit tent
euglycaemia. Thus, the risk of microvascular disease appears to be related to the glycaemia
control. The ‘UK Prospective Diabetes Study’ (UK PDS, 1998) has extended these observa tions to
type 2 DM patients as well. Since the basis of pathological changes in both type 1 and type 2 DM is
accumulation of glycosylated proteins and sorbitol in tissues as a result of exposure to high
glucose concentrations, tight glycaemia control can delay endorgan damage in all diabetic
subjects.
However, regimens attempting near normo glycaemia are associated with higher incidence of
severe hypoglycaemic episodes. Moreover, injected insulin fails to reproduce the normal pattern
of enhanced insulin secretion in response to each meal, and liver is exposed to the same
concentration of insulin as other tissues, while normally it receives much higher concentration
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 through portal circulation. As such, the overall desirability and practicability of intensive insulin
therapy has to be determined in individual pa tients. Intensive insulin therapy is best avoided in
young children (risk of hypoglycaemic brain damage) and in the elderly (more prone to
hypoglycaemia and its serious consequences).
Create conceptual and revisable notes on the above paragraphs

Uses of Insulin
Diabetes Mellitus

Therapy Goals:
Restore metabolism to normal.
Avoid symptoms of hyperglycemia and glucosuria.
Prevent short-term complications (e.g., infection, ketoacidosis).
Prevent long-term complications (e.g., cardiovascular, retinal, neurological, renal).
Criteria for Adequate Glycemic Control:
Fasting blood glucose: 90–130 mg/dl.
Blood glucose <150 mg/dl, 2 hours after meals.
HbA1c levels < 7%.
Indications for Insulin Use:
Type 1 Diabetes: Essential.
Post-Pancreatectomy Diabetes: Essential.
* Gestational Diabetes: Essential.
Type 2 Diabetes:
Not controlled by diet, exercise, or oral antidiabetics.
Primary or secondary failure of oral antidiabetics.
Underweight patients.
Temporary need during infections, trauma, surgery, pregnancy.
Y Complications of diabetes (e.g., ketoacidosis, hyperosmolar coma, gangrene).
Insulin Requirements:
Type 1 Patients: 0.4–0.8 U/kg/day.
Type 2 Patients: 0.2–1.6 U/kg/day, higher doses for obese patients due to insulin
resistance.
Satisfactory Insulin Regimen:
Basal Control: Inhibits hepatic glucose output, lipolysis, and protein breakdown.
Postprandial Needs: Disposes of absorbed glucose and amino acids.
Typical Regimens:

Y Multiple daily injections of long and short-acting insulins.

Single injection of long-acting insulin with oral hypoglycemics for mealtime glycemia.

Regimens

Split-Mixed Regimen

Description: Mixture of regular with lente or isophane insulin.

Dosage: 30:70 or 50:50 mixture split into two injections before breakfast and dinner.
Pros: Only two daily injections.

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 Cons: Inadequate post-lunch glycemia control, late postprandial hypoglycemia.

Basal-Bolus Regimen

Description: Intensive regimen with 3-4 daily injections.

Dosage: Long-acting insulin (e.g., glargine) once daily, with 2-3 meal-time injections of rapid-
acting insulin (e.g., lispro, aspart).
Pros: Achieves round-the-clock euglycemia.
Cons: More demanding and expensive.

Key Studies and Findings

Diabetes Control and Complications Trial (DCCT):

Intensive insulin therapy reduces primary diabetic complications in type 1 patients.
Slows progression of retinopathy, neuropathy, nephropathy.
Tight glycemic control correlates with reduced microvascular disease risk.
UK Prospective Diabetes Study (UK PDS, 1998):
Extends DCCT findings to type 2 diabetes.
Tight glycemic control delays end-organ damage in all diabetic subjects.

Considerations

Risks of Intensive Therapy:

Higher incidence of severe hypoglycemic episodes.
Fails to mimic normal insulin secretion patterns in response to meals.
Exposes the liver to similar insulin concentrations as other tissues (unlike normal portal
circulation).
Suitability:
Intensive therapy may not be suitable for young children (risk of hypoglycemic brain
damage) and the elderly (prone to hypoglycemia and its consequences).
Desirability and practicality of intensive therapy should be individualized.

Diabetic ketoacidosis (Diabetic coma)

Ketoacidosis of different grades generally occurs in insulin dependent diabetics, and is due to
inadequate/no insulin replacement. It is infrequent in type 2 DM. The most com mon precipitating
cause is infection; others are trauma, stroke, pancreatitis, stressful conditions and inadequate
doses of insulin.
The development of cardinal features of diabetic ketoacidosis is outlined in Fig. 19.5. Patients may
present with varying severity. Typically they are dehydrated, hyperventilating and have impaired
consciousness. The principles of treatment remain the same, irrespective of severity, only the
vigour with which therapy is instituted is varied. Close monitoring of vital signs, plasma glucose,
blood pH, electrolytes, plasma acetone, etc. is needed.
1. Insulin Regular insulin is used to rapidly correct the metabolic abnormalities. A bolus dose of
0.1–0.2 U/kg i.v. is followed by 0.1 U/kg/hr infusion; the rate is doubled if no significant fall in
blood glucose occurs in 2 hr. Fall in blood glucose level by 10% per hour can be considered
adequate response.
Usually, within 4–6 hours blood glucose reaches 300 mg/dl. Then the rate of infusion is reduced to
2–3 U/hr. This is maintained till the patient becomes fully conscious and routine therapy with s.c.
insulin is instituted.

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 2. Intravenous fluids Correction of dehydra tion is vital. Normal saline is infused i.v., initially at the
rate of 1 l/hr, reducing progressively to 0.5 l/4 hours depending on the volume status. Once BP
and heart rate have stabilized and adequate renal perfusion is assured change over to ⁄ N saline.
After the blood sugar has reached 300 mg/dl, 5% glucose in ⁄ N saline is the most appropriate
fluid because blood glucose falls before ketones are fully cleared from the circulation. Also
glucose is needed to restore the depleted hepatic glycogen.
3. KCl Though upto 300 mEq of K+ may be lost in urine during ketoacidosis, serum K+ is usually
normal due to exchange with intracellular stores. When insulin therapy is
instituted ketosis subsides and K+ is driven back intracellularly—dangerous hypokalemia can
occur. After 2–3 hours it is appropriate to add 10–20 mEq/hr KCl to the i.v. fluid.
4. Sodium bicarbonate It is not routine ly needed. Acidosis subsides as ketosis is controlled.
However, if arterial blood pH is < 7.0, acidosis is not corrected spontaneously or hyperventilation
is exhausting, 50 mEq of sod. bicarbonate is added to the i.v. fluid. Bicarbonate infusion is
discontinued when the blood pH rises above 7.1.
5. Phosphate When serum PO4 is in the lownormal range, 3–4 m mol/hr of pot. phos phate
infusion is advocated. Faster phosphate infusion can precipitate tetany, and its routine use is not
required.
6. Antibiotics and other supportive measures as well as treatment of precipitating cause must be
instituted simultaneously.
Hyperosmolar (nonketotic hypergly caemic) coma This is characterized by high blood glucose
(>600 mg/dl) and serum osmo lality (>320 mOsm/l) along with deteriorating mental status. It
generally occurs in elder ly type 2 patients. The cause is obscure, but appears to be precipitated
by the same factors as ketoacidosis, especially those resulting in dehydration. Uncontrolled
glycosuria of DM produces diuresis resulting in dehydration and haemoconcentration over several
days. Urine output is finally reduced and glucose accumulates in blood rapidly raising blood
osmolality leading to coma. Death can occur if not vigorously treated.
The general principles of treatment are the same as for ketoacidotic coma, except that faster fluid
replacement is to be instituted, insulin re quirement is lower, less potassium replacement is
generally needed and alkali is usually not required. These patients are prone to thrombosis (due
to hyperviscosity and sluggish circulation), prophylactic heparin therapy is recommended.
Despite intensive therapy, mortality in hyperosmolar coma remains high. Treatment of
precipitating factor and associated illness is vital.
Create conceptual and revisable notes on the above paragraphs -

Diabetic Ketoacidosis (Diabetic Coma)

Occurrence: Common in insulin-dependent diabetics (Type 1), infrequent in Type 2 DM.
Causes: Inadequate/no insulin replacement, infection, trauma, stroke, pancreatitis, stressful
conditions, inadequate insulin doses.
Symptoms: Dehydration, hyperventilation, impaired consciousness.

Treatment Principles

Close Monitoring: Vital signs, plasma glucose, blood pH, electrolytes, plasma acetone.

↑
1. Insulin:
Regular insulin used to correct metabolic abnormalities.
Bolus dose: 0.1–0.2 U/kg i.v., followed by 0.1 U/kg/hr infusion.

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 Double infusion rate if no significant fall in blood glucose in 2 hours.
Goal: 10% per hour reduction in blood glucose.
After reaching 300 mg/dl glucose, reduce infusion to 2–3 U/hr.
Switch to s.c. insulin once the patient is fully conscious.
2. Intravenous Fluids:
Correct dehydration with normal saline, initially 1 l/hr, reducing to 0.5 l/4 hours.
Switch to 1/2N saline once BP and heart rate stabilize.
After blood sugar reaches 300 mg/dl, use 5% glucose in 1/2N saline.
3. KCl:
Monitor for hypokalemia due to intracellular K+ shift with insulin therapy.
Add 10–20 mEq/hr KCl to i.v. fluid after 2–3 hours.
4. Sodium Bicarbonate:
Not routinely needed.
Use if arterial blood pH < 7.0, or if acidosis persists and hyperventilation is exhausting.
Administer 50 mEq of sodium bicarbonate i.v. and discontinue when pH > 7.1.
5. Phosphate:
Administer 3–4 mmol/hr of potassium phosphate if serum PO4 is low-normal.
Avoid faster infusion to prevent tetany.
6. Supportive Measures:
Antibiotics and treatment of precipitating cause.

Hyperosmolar (Nonketotic Hyperglycemic) Coma

Characteristics: High blood glucose (>600 mg/dl) and serum osmolality (>320 mOsm/l),
deteriorating mental status.
Occurrence: Typically in elderly Type 2 diabetics.
Causes: Similar to ketoacidosis; often results in dehydration and hyperglycemia.

Treatment Principles

Fluid Replacement: Faster fluid replacement than in ketoacidosis.

Insulin: Lower insulin requirement.
Potassium: Less replacement generally needed.
Alkali: Not usually required.
Thrombosis Prevention: Prophylactic heparin therapy due to hyperviscosity and sluggish
circulation.
Mortality: High despite intensive therapy.
Supportive Measures: Treat precipitating factors and associated illnesses.

Insulin resistance
Insulin resistance refers to suboptimal response of body tissues, especially liver, skeletal muscle
and fat to physiological amounts of insulin. As already stated, relative insulin resistance is integral
to type 2 DM. Advanced age, obesity and sedentary lifestyle promote insulin resistance. Women
with polycystic ovarian disease (PCOD) often exhibit insulin resistance.
Insulin sensitivity has been found to decline with age. Obesity is the most important fac tor
causing insulin resistance. Glucose entry into muscle and liver in response to insulin is deficient in
individuals with large stores of body fat. Bigger adipocytes have fewer insulin receptors. However,
in most type 2 diabet ics the transducer mechanism linking insulin receptor to the response

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 appears to be faulty, rather than the receptor itself. Exercise increases insulin sensitivity and lack
of it contributes to insulin resistance.
Pregnancy and oral contraceptives often induce relatively low grade and reversible insulin
resistance. Other rare causes are—acromegaly, Cushing’s syndrome, pheochromocytoma, lipo‐
atrophic diabetes mellitus and production of insulin neutralizing antibody. Hypertension
accompanied with relative insulin resistance is a part of metabolic syndrome.
Acute insulin resistance This form of insulin resistance develops rapidly and is usually a short term
problem. Causes are—
(a) Infection, trauma, surgery, emotional stress induce release of corticosteroids and other
hyperglycaemic hormones which oppose insulin action.
(b) Ketoacidosis—ketone bodies and FFA inhibit glucose uptake by brain and muscle. In addition
insulin binding may increase resulting in insulin resistance.
Treatment of acute insulin resistance is to overcome the precipitating cause and to give high
doses of regular insulin. The insulin requirement comes back to normal once the condition has
been controlled.
Newer insulin delivery devices A number of innova tions have been made to improve ease and
accuracy of insulin administration as well as to achieve tight glycaemia control. These are:
1. Insulin syringes Prefilled disposable syringes contain specific types or mixtures of regular and
modified insulins. These are in common use now, and avoid the need for carrying insulin vials and
syringes.
2. Pen devices Fountain pen like; they use insulin cartridges for s.c. injection through a needle.
Preset amounts (in 2 U increments) are propelled by pushing a plunger. They are convenient in
carrying and injecting.
3. Inhaled insulin The early inhaled insulin formulations were found to be unsatisfactory for
clinical use due to risk of pulmonary complications.
A new dry powder formulation (AFREzzA) of recom binant human insulin called ‘Technosphere
insulin’ (TI) has been found satisfactory for use in both type 1 and 2 diabetics. Administered by a
breathpowered inhaler, it is absorbed from the alveoli and acts rapidly within 10–15 min. The
action is terminated by 3 hours. Thus, it is suitable for use just before a meal to control prandial
glycaemia. Combined with basal insulin injection (insulin glargine, etc.), it has been found equi‐
effective in lowering blood glucose and HbA1C levels as prandial insulin aspart injected s.c. (along
with basal insulin). Weight gain and risk of hypoglycaemic episodes is claimed to be lower
compared to rapid acting s.c. insulin. Cough is the most common adverse effect reported by >25%
patients. It is not to be used in smokers and COPD patients.
Another newer inhaled insulin (ExuBERA) has been discontinued by its menufacturer.
4. Insulin pumps Portable infusion devices connected to a subcutaneously placed cannula—
provide ‘continuous subcutaneous insulin infusion’ (CSII). Only regular insulin or a fast acting
insulin analogue is used. The pump can be programmed to deliver insulin at a low basal rate
(approx. 1 U/hr) and premeal boluses (4–15 times the basal rate) to control postprandial
glycaemia. Though, theoreti cally more appealing, no definite advantage of CSII over multidose
s.c. injection has been demonstrated. Moreover, cost, strict adherence to diet, exercise, care of the
device and cannula, risk of pump failure, infusion site infection, are too demanding on the patient.
The CSII may be appropriate for selected type 2 DM cases only.
5. Implantable pumps These consist of an electrome chanical mechanism which regulates insulin
delivery from a percutaneously refillable reservoir. Mechanical pumps, propellant driven and
osmotic pumps have been utilized.
Glucagonlike peptide1 (GLP1) receptor agonists
GlP1 is an important incretin released from the gut in response to ingested glucose. It induces
insulin release from pancreatic β cells, inhibits glucagon release from α cells, slows gastric
emptying and suppresses appetite by activating specific gLP-1 receptors, which are cell surface
gPCRs (see Fig. 19.6) expressed on β and α cells, central and peripheral neurones, gastrointestinal
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 mucosa, etc. Characteristically, GlP1 induces insulin release only at high glucose concentration.
The incretin system appears to promote β cell health as well by decreasing islet cells apoptosis.
Failure of incretins has been implicated in the pathogenesis of β cell dysfunction of type 2 DM,
particularly for progression of the disease. GlP1 based therapy appears to be the most effective
measure to preserve β cell function in type 2 DM.
GlP1 itself is not suitable for clinical use because of rapid degradation by the enzyme dipeptidyl
peptidase-4 (DPP-4) which is expressed on the luminal membrane of capillary endothelial cells,
kidney, liver, gut mucosa and immune cells. Another incretin glucose-depen- dent insulinotropic
peptide (GIP) also induces insulin release, but in humanbeings GlP1 is the more important incretin
and GIP has poor action in type 2 diabetics. The GIP receptor is distinct from GlP1 receptor, but
mediates mostly similar responses. Some metabolically stable analogues of GlP1 have been
produced for clinical use in type2 DM.
Exenatide It is a synthetic DPP4 resistant analogue which activates GlP1 receptors (Fig. 19.6) and
produces the same responses. Being a peptide, it is inactive orally. After s.c. injection its plasma
t ⁄ is ~ 3 hours and duration of action 6–10 hours. Injected s.c. before breakfast and dinner, it is
used as addon drug to metformin/ SU or a combination of these or pioglitazone in poorly
controlled type 2 diabetics. Benefits noted are lowering of postprandial as well as fasting blood
glucose, HbA1C, and body weight. The most important side effect is nausea and vomit ing
occurring in ~ 50% recipients, but tolerance develops later. Many patients develop antibodies to
exenatide, but its response is attenuated only in a few. Acute pancreatitis is a risk.
Dose: Initially 5 μg s.c. before breakfast and dinner; increase to 10 μg BD if needed.
ExAPRIDE 250 μg/vial inj.
Liraglutide This recently developed longeracting GlP1 agonist is closely related to the native
peptide but its tight binding to plasma proteins extends t ⁄ to > 12 hours and duration of action to
> 24 hours. Injected s.c. once daily, alone or added to oral metformin ± SU or pioglitazone, it has
achieved improved glycaemic control in type 2 diabet ics. Nausea and diarrhoea are the frequent
side effects, but decrease in incidence over time. Use of liraglutide is at tended by weight loss and
it is approved for use in obesity.
Hypoglycaemia is rare with exenatide/liraglutide mono therapy, but can occur when combined
with SUs/metfor min. Acute pancreatitis is reported in few patients taking GlP1 agonists.
Albiglutide and dulaglutide are very long acting GlP1 receptor agonists which need to be injected
once weekly.
Amylin analogue
Amylin, also called ‘islet amyloid polypeptide’ (IAP), is produced by pancreatic β cells and is stored
in the same granules as insulin. As such, it is secreted along with insulin, acts in the brain to
reduce glucagon secretion from α cells, delay gastric emptying, retard glucose absorption and
promote satiety.
Pramlintide It is a synthetic amylin analogue which on s.c. injection before meal attenuates
postprandial glycaemia and exerts a centrally mediated anorectic action. The duration of action is
2–3 hours. It is used to supplement meal time insulin injection when insulin alone fails to control
post prandial glycaemic peak, in both type 1 and type 2 diabet ics. Hypoglycaemia is the most
important adverse effect. loss of appetite, nausea and vomiting are the other side effects.
Reduction in body weight is an additional benefit.
Create conceptual and revisable notes on the above paragraphs

Insulin Resistance

Definition and Causes

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 Definition: Suboptimal response of liver, skeletal muscle, and fat to insulin.
Primary Causes: Advanced age, obesity, sedentary lifestyle, PCOD.
Mechanisms:
Larger adipocytes have fewer insulin receptors.
Faulty transducer mechanism linking insulin receptor to response.
Exercise increases insulin sensitivity; lack of exercise contributes to resistance.
Secondary Causes: Pregnancy, oral contraceptives, acromegaly, Cushing’s syndrome,
pheochromocytoma, lipoatrophic diabetes, insulin-neutralizing antibodies.
Associated Conditions: Hypertension (part of metabolic syndrome).

Acute Insulin Resistance

Causes: Infection, trauma, surgery, emotional stress (corticosteroid release); ketoacidosis

(ketone bodies and FFA inhibit glucose uptake).
Treatment: Overcome precipitating cause, high doses of regular insulin.

Newer Insulin Delivery Devices

1. Insulin Syringes:
Prefilled disposable syringes with specific types/mixtures of insulin.
Avoid carrying vials and syringes.
2. Pen Devices:
Use insulin cartridges for s.c. injection.
Convenient and preset amounts.
3. Inhaled Insulin:
AFREZZA: Breath-powered inhaler with rapid action (10–15 min), used before meals,
combined with basal insulin. Common side effect: cough.
Not for smokers and COPD patients.
Exubera: Discontinued by manufacturer.
4. Insulin Pumps:
Portable devices for continuous subcutaneous insulin infusion (CSII).
Regular/fast-acting insulin only, programmed basal and premeal boluses.
No definite advantage over multidose injections; high demands on patient.
5. Implantable Pumps:
Electromechanical mechanism with refillable reservoir.
Types: Mechanical, propellant-driven, osmotic pumps.

GLP-1 Receptor Agonists

GLP-1 (Glucagon-like Peptide-1)

Function: Induces insulin release, inhibits glucagon release, slows gastric emptying, suppresses
appetite.
Characteristics: Insulin release only at high glucose concentration, decreases β cell apoptosis,
promotes β cell health.
Clinical Use: Not suitable due to rapid degradation by DPP-4 enzyme.

GLP-1 Analogues
-Exclatideade Albiglarticle
~ 1. Exenatide: Dulageutide
Synthetic, DPP-4 resistant, activates GLP-1 receptors.
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 s.c. injection before breakfast and dinner.
Benefits: Lowers blood glucose, HbA1C, and body weight.
Side effects: Nausea, vomiting, potential acute pancreatitis.

~ 2. Liraglutide:
Longer-acting GLP-1 agonist, once daily s.c. injection.
Combined with oral antidiabetics, improves glycemic control.
Side effects: Nausea, diarrhea, weight loss.
Approved for obesity.
~ 3. Other Long-acting GLP-1 Agonists:
Albiglutide, Dulaglutide: Once weekly injections.

Amylin Analogue

Pramlintide

Function: Synthetic amylin analogue, reduces glucagon secretion, delays gastric emptying,
promotes satiety.
Use: Supplement meal-time insulin in Type 1 and Type 2 diabetics.
Side Effects: Hypoglycemia, loss of appetite, nausea, vomiting, weight loss.

These conceptual notes provide an overview of insulin resistance, newer insulin delivery devices, GLP-
1 receptor agonists, and amylin analogues, summarizing their definitions, causes, mechanisms,
treatments, and associated clinical use.
ChatGPT can make mistakes. Check important info.

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