Recent advances in Insulin therapy: A comprehensive overview

Dr C Vignesh 1
RECENT ADVANCES IN INSULIN THERAPY
Presenter: Dr. C Vignesh (JR-1)
Dept. of Pharmacology and Therapeutics
King George’s Medical University
Lucknow, Uttar Pradesh, India
vigneshchandrakgmu@gmail.com
10-12-2024

Dr C Vignesh 2
Contents
• Pancreatic islets and its secretions
• Insulin- Secretion, chemical structure, synthesis, MOA, regulation and
types and complications
• DM- Definition, Diagnosis, types and complications
• Timeline of development of insulin
• Recent advances in insulin therapy- Novel insulin analogues and
insulin delivery system
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Specific Learning Objectives
At the end of this teaching learning session the audience will be able to:
• Describe the pancreatic anatomy and physiology
• Describe the insulin structure, mechanism of action, its regulation and types
• Describe DM- Its definition, diagnosis, types and complications
• Describe the timeline of development of insulin
• Describe the recent advances in insulin therapy- Novel insulin analogues and
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Abbreviations
- PYY- Peptide Tyrosine
Tyrosine
- GLP- Glucagon like peptide
- GIP- Glucose dependent
insulinotropic peptide
- PP- Pancreatic
polypeptide cells
(8)
(6)
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Classical and Non-classical Peptides
(5)
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(Peptide YY)
(12)
Islet amyloid polypeptide (IAPP)
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Chemical Structure and Synthesis
Abbreviations
SP- signal peptide
PC- prohormone convertases
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Synthesis of Insulin
• Insulin is initially synthesized as a single polypeptide chain, preproinsulin (110
amino acids), which is processed first to proinsulin and then to insulin and C-
peptide
• Preproinsulin (110 AA) consists of a signal peptide (SP), B chain, C-peptide,
and A chain
• The SP is cleaved and 3 S–S bonds form as the proinsulin folds
• Two prohormone convertases (PC1 and PC2) cleave proinsulin into insulin, C-
peptide and two dipeptides
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• Insulin and C-peptide are stored in granules in equimolar concentration
and secreted
• Insulin has a t1/2 of 5 to 6 min due to extensive hepatic
clearance and renal filtration
• C-peptide- no known physiological function or receptor- t1/2
of 30 min- minimal hepatic clearance- measurement used
for assessment of β cell secretion and to distinguish
endogenous and exogenous hyperinsulinemia
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Mechanism of Insulin Release and its Regulation
ABBREVIATIONS
• G- G protein, with subtype indicated by
subscript
• AC- adenylyl cyclase
• EPAC-exchange protein activated by
cAMP
• GLUT1- glucose transporter 1
• GPCR- G protein-coupled receptor
• PKA- protein kinase A
• PKC- protein kinase C
• PLC- phospholipase C
• SST2/3- somatostatin receptors.
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Regulation of Insulin Secretion
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Pathways of Insulin Signalling
SH- Src Homology (domain)
PI3K- Phosphoinositide 3-Kinase
PKB/Akt- Protein Kinase B/AKT
IRS- Insulin receptor substrate
Src- Proto-oncogene Tyrosine-protein Kinase Src
ShcSrc Homology 2 Domain-containing Transforming
Protein
Cav- Caveolin
APS- Adapter Protein with Pleckstrin Homology and Src
Homology 2 Domains
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Insulin Receptor
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Pathways of Insulin Signaling
• Insulin binding to α subunit of dimer activates the intrinsic tyrosine kinase activity
of the receptor dimer
• Tyrosine phosphorylation of the receptor’s β subunits and a small number of
specific substrates: the IRS proteins and Src-homology-2-containing protein;
within the membrane, a caveolar pool of insulin receptor phosphorylates Cav, APS,
and Cbl
• These tyrosine-phosphorylated proteins interact with signaling cascades via SH2
and SH3 domains to mediate the effects of insulin, with specific effects resulting
from each pathway
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• In skeletal muscle and adipocytes- GLUT4 translocation from intracellular vesicles to the
plasma membrane is stimulated by both caveolar and noncaveolar pathways
• In the noncaveolar pathway, the activation of PI3K is crucial and PKB/Akt
(anchored at the membrane by phosphatidylinositol 3,4,5-trisphosphate) or an
atypical form of PKC is involved
• In the caveolar pathway, caveolar protein flotillin localizes the signaling
complex to the caveola; the signaling pathway involves a series of SH2 domain
interactions that add the adaptor protein CrkII, the guanine nucleotide
exchange protein C3G, and small GTP-binding protein TC10
• The pathways are inactivated by specific phosphoprotein phosphatases (e.g.,
PTB1B)
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• Insulin action on glucose transport depends on the activation of
phosphatidylinositol-3-kinase (PI3K)
• PI3K is activated by interaction with IRS proteins and generates phosphatidylinositol
3,4,5-trisphosphate, which regulates the localization and activity of mTOR
• The isoform Akt2 appears to control the downstream steps that are important for
glucose uptake in skeletal muscle and adipose tissue and to regulate glucose
production in the liver
• Substrates of Akt2 coordinate the translocation of GLUT4 to the plasma membrane
through processes involving actin remodeling and other membrane trafficking
systems
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Fasting and Prandial State
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Effects of Insulin Deficiency
+
Glucagon
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Insulin Dose
• Human insulin, produced by recombinant DNA technology, is soluble in
aqueous solution
• Dose and concentrations is expressed in international units (U)
• One international unit of insulin is defined as the bioequivalent of 34.7 μg of
crystalline insulin; this is equivalent to the older working definition of a U.S.
Pharmacopeia unit as the amount required to reduce the blood glucose
concentration to 45 mg/dL (2.5 mM) in 2.2-kg rabbit fasted for 24 h
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• Most preparations of insulin are supplied in solution
or suspension at a concentration of 100 units/mL,
which is about 3.6 mg insulin per milliliter (0.6 mM)
and termed U-100
• Insulin also is available in more concentrated
preparations (200 [degludec and lispro insulins], 300
[glargine insulin], or 500 [regular insulin] units/mL)
for patients who are resistant to the hormone and
require higher doses
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• In a mixed population of patients with type 1 diabetes, the dose
of insulin is usually 0.4 to 0.7 units/kg body weight per day
• Obese patients, those with type 2 diabetes, and pubertal
adolescents may require more (about 1–2 units/ kg per day)
because of the accompanying insulin resistance
• The basal dose is usually 40% to 50% of the total daily dose,
with the remainder as prandial or premeal insulin
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Insulin Regimen
SPLIT-MIX REGIMEN
BASAL-BOLUS REGIMEN INSULIN INFUSION PUMP
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Insulin Regimen
• In all regimens, long-acting insulins (NPH, glargine, detemir, or degludec)
supply basal insulin, whereas regular, insulin aspart, glulisine, or lispro provide
prandial insulin
• Short-acting insulin analogues should be injected just before (<10 min) and
regular insulin 30–45 min prior to a meal
• Short-acting insulin analogues are sometimes injected just after a meal in
conditions such as- gastroparesis and unpredictable food intake
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• The timing and dose of short-acting, preprandial insulin are altered to
accommodate the SMBG results, anticipated food intake, and physical
activity- offer the patient more flexibility in terms of lifestyle and the
best chance for achieving near normoglycemia
• Meal component of the preprandial insulin dose- insulin-to-
carbohydrate ratio (a common ratio for type 1 DM is 1 unit/10–15 g of
carbohydrate, but this must be determined for each individual) and
also should consider Glycemic index of food taken
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• MDI (multiple daily injection) regimens refer to the combination of basal
insulin and bolus insulin (preprandial short-acting insulin)- consists of-
a) Split-mix Regimen
-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
- Advantage - only two daily injections are required
- Disadvantage- post-lunch glycaemia may not be adequately covered and late
postprandial hypoglycaemia may occur
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b) Basal- Bolus Regimen
Needs 3–4daily injections
- long-acting insulin (glargine) is injected once daily either before breakfast or before
bed-time for basal coverage along with 2–3 meal-time injections of a rapid acting
preparation (insulin lispro or aspart)
- Regimens attempting near normoglycaemia are associated with higher incidence of
severe hypoglycaemic episodes
- Injected insulin fails to reproduce the normal pattern of increased 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 through portal circulation
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Sliding Scale Insulin Regimen (SSI)
• Set of various insulin doses that are administered
based on the patient's glucose reading at the
time
• Short-acting insulin or regular insulin is
subcutaneously administered sliding-scale (RISS)
• Used in ICU and uncontrolled hyperglycaemic
patients
• Prospective and retrospective studies- patients who
received sliding-scale insulin therapy experienced
unsatisfactory glycemic control and other adverse
outcomes, such as hypoglycemia or infection
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Insulin Analogues
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Current Available Insulins and Their Duration of Action
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Adverse Effects of Insulin Therapy
• Hypoglycaemia (m.c)
- Sign and symptoms-
a) Stimulation of the autonomic nervous system – When the blood glucose falls to
around 54 mg/dL (3 mmol/L)- sympathetic (tachycardia, palpitations, sweating,
tremors) and parasympathetic (nausea, hunger)
b) Neuroglycopenia (insufficient glucose for normal CNS function)- <50 mg/dL [2.8
mmol/L]- irritability, confusion, blurred vision, tiredness, headache, and difficulty
speaking, loss of consciousness or even a seizure
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• Hypoglycaemic unawareness
- With repeated episodes of hypoglycemia, there is adaptation, and
autonomic symptoms do not occur until the blood glucose levels are
much lower and so the first symptoms are often due to neuroglycopenia
- Can be reversed by keeping glucose levels high for a period of several
weeks
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• Modest weight gain
• Allergic reactions to recombinant human insulin may occur as a result of
reaction to the small amounts of aggregated or denatured insulin in
preparations, to minor contaminants, or because of sensitivity to a
component added to insulin in its formulation (protamine, Zn2+, etc.)
• Lipoatrophy/dystropy - Atrophy of subcutaneous fat at the site of insulin
injection (rare- in older insulin preparations)
• Lipohypertrophy- enlargement of subcutaneous fat depots- lipogenic action
of high local concentrations of insulin
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Indication of Insulin Therapy
• All type-1 DM patients
• Type-2 DM patients whose target blood sugar levels are not attained despite
three or more OHA
• All Hospitalized Type-2 DM patients due to any infection/ surgical
procedure/other serious illness, etc
• Acute diabetic complications (Diabetic ketoacidosis/ Hyperglycemic hyperosmolar
coma)
• Gestational DM
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Normal and Impaired Blood Glucose Level
• Normal glucose homeostasis: fasting plasma glucose less than 5.6
mmol/L (100 mg/dL)
• Impaired fasting glucose (IFG): 5.6–6.9 mmol/L (100–125 mg/dL)
• Impaired glucose tolerance (IGT): glucose level between 7.8 and 11.1
mmol/L (140 and 199 mg/dL) 120 min after ingestion of 75 g liquid
glucose solution
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Criteria for The Diagnosis of Diabetes (ADA-2022)
• Symptoms of diabetes (Polyuria, polydipsia, polyphagia, fatigue, weight
loss, delayed wound healing, blurred vision, paresthesia, pruritis) plus
random blood glucose concentration ≥11.1 mM (200 mg/dL) OR
• Asymptomatic patients + Fasting plasma glucose ≥7.0 mM (126 mg/dL) OR
• Two-hour plasma glucose ≥11.1 mM (200 mg/dL) during an oral glucose
tolerance test OR
• HbA1c ≥6.5%
• Random is defined as without regard to time since the last meal.
• Fasting is defined as no caloric intake for at least 8 h.
• The test should be performed using a glucose load containing the equivalent of 75 g
anhydrous glucose dissolved in water; this test is not recommended for routine
clinical use
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Types of Diabetes Mellitus
Nuclear DNA
mutation
(HNF- Hepatic Nuclear Factor)
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MODY (Maturity Onset Diabetes in Young)
• The most common form of monogenic diabetes- accounts for 1–2.5% of all diabetes
cases
• Characterized by autosomal dominant inheritance, early onset of diabetes under 25
years of age, and impaired insulin secretion due to mutations in transcription factors
involved in beta cell differentiation and function
• To date, 14 MODY subtypes have been reported, including MODY1 (HNF4A), MODY2
(GK), MODY3 (HNF1A), MODY4 (PDX1), MODY5 (HNF1B), and MODY6 (NeuroD1).
(HNF- Hepatic Nuclear Factor)
• HNF1A gene mutations are the most common cause of MODY
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• Patients younger than 30 years with endogenous insulin production (urinary C-
peptide/creatinine ratio of 0.2 nmol/mmol or higher) and negative
autoantibodies are candidates for genetic screening for MODY
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Complications of DM
• Acute complications- Diabetic ketoacidosis, Hyperglycemic hyperosmolar coma
• Chronic Complications-
i. Microvascular (Reversible)- Diabetic retinopathy, neuropathy
(mononeuropathy/polyneuropathy/autonomic neuropathy), nephropathy.
ii. Musculoskeletal- Charcot arthropathy- complication of peripheral neuropathy
iii. Macrovascular (Irreversible)- ACS and Stroke (ischemic)
iv. Ocular- Cataract, Retinopathy (proliferative- due to VEGF/ non-proliferative)
• Obstetric complication- Polyhydramnios, Macrosomia, preeclamsia/ eclampsia,
unexplained fetal loss
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Charcot arthropathy
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Aim of Diabetic Management
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Its Important to Know History to Appreciate How Far
We Have Reached
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The History of Insulin Discovery and Its Mechanism of
Action
• Before the discovery of insulin, evidence on the cause of diabetes started
to accumulate in the late 19th century
• 1889- von Mering and Minkowski - reported that pancreatectomized dogs
developed severe diabetes
• 1893- Laguesse -Conceptualized that internal secretion by the ‘islets of
Langerhans’ of the pancreas control carbohydrate metabolism
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• 1920- Banting’s idea of ligating the pancreatic duct to induce selective degeneration
of acini leaving islets and isolating internal secretion came up after reading an article
by Barron
• Frederick G. Banting, John J. R. Macleod and Charles H. Best
• January 11, 1922: First human insulin recipient (Leonard Thompson: 14-year-old
T1DM patient, 30 kg)- Initial injection: Slight blood glucose reduction, developed an
abscess, became more ill
• January 23: Received refined insulin extract from James Collip
- Normalized blood glucose levels and eliminated glycosuria and ketonuria
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• March 1922 - The effect of insulin in several patients was reported in the issue of
the Canadian Medical Association Journal and partnership with pharmaceutical
companies, Eli Lilly (Indianapolis, IN, USA) and Nordisk (Bagsværd, Denmark), soon
made insulin widely available
• October 1923 - The Nobel Prize in Physiology or Medicine was awarded to Banting
and Macleod
• 1955 - Frederik Sanger (British chemist)- Elucidated complete amino acid sequence
of Insulin (first protein whose amino acid sequence was elucidated)- by using acids
to breakdown the molecule and incorporating electrophoresis and chromatography
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• 1958 - Sanger - Nobel Prize in Chemistry- principle that every
protein had a unique sequence
• 1959- Yalow and Berson- developed radioimmunoassays (RIA)
using radiotracers and antibodies to measure hormones with
extremely low circulating levels- following the measurement of
animal insulins, they succeeded in measuring human plasma
insulin
- First to propose the concept that peptides such as insulin could
stimulate an immunologic response
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• 1964- Dorothy C. Hodgkin (British chemist )- Nobel Prize in Chemistry-
determinations of the structures of important biomolecules, such as vitamin
B12 by X-ray techniques
• 1969- C. Hodgkin – 3-D structure of insulin was elucidated.
- Solving the crystal structure of insulin led to an understanding of its chemical
reactions, cellular functions, and receptor binding
- Enabled mass production of insulin for medical use and modified the
structure to create insulin with different profiles
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• 1977 - Yalow received the Nobel Prize in Physiology or Medicine (Berson died
before the award was given)
• 1971 - The presence of insulin receptors in the cell membrane and their relation to
insulin bioactivity were suggested
• 1972 -Receptor proteins were isolated
• 1977 and 1980 - by Ullrich et al. and Bell et al.’s group - The sequences of rat and
human insulin genes were reported
• 1980s - The human insulin receptor gene was sequenced, and its relation to
transmembrane signaling was unveiled and thereafter tremendous amount of
research on insulin signaling and insulin resistance carried on
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The Evolution of Insulins
• Early insulin- poorly defined, inconsistent, and extracted from animal
pancreas
• Animal insulins- anti-insulin antibodies, insulin resistance, and lipoatrophy
• Recombinant human insulin and insulin analogs with known PK and PD
profiles mimic endogenous insulin
• Initial insulin required multiple daily injections with large volumes and had
a high hypoglycemia risk
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• 1936 - Hans C. Hagedorn: Introduced the first extended-action
insulin by adding protamine
- Hagedorn applied the principle that proteins are least soluble at
isoelectric pH and chose a highly basic protein protamine because
the isoelectric point of insulin was below physiological pH
(approximately 5.2)
- Protamine crystalizes with insulin hexamers and is dissolved
slowly after injection- dissociation of insulin hexamers and the
absorption of monomers into circulation are delayed
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• 1946 - Nordisk - Neutral Protamine Hagedorn (NPH) insulin, or
Isophane insulin, was developed by adding zinc to protamine insulin
• With a longer duration of action and ability to be mixed with regular
insulin in the same syringe, NPH improved glycemic control and patient
acceptability with twice daily administration
• 1950s - Lente and Ultralente insulin with a longer duration than NPH
was developed- use was limited due to high day-to-day variability in
absorption, inconsistent peak patterns, and incompatibility with
regular insulin
• 1970s- Method for cloning and expressing genes in Escherichia coli was
developed
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• 1978 and 1979 – successful gene expression of somatostatin and insulin
• The gene sequence of human insulin was not known at that time, the genes for the A
and B chains of insulin were designed using the amino acid sequence
• The collaboration of scientists working on chemical DNA synthesis, bacterial and
mammalian gene regulation, restriction enzyme-based recombinant DNA technology,
and cloning vectors and industry support (Genentech, San Francisco, CA, USA; and Eli
Lilly) led to the birth of the first human insulin Humulin, which is still widely used
• 1982 - Insulin was the first therapeutic protein to be produced by recombinant
deoxyribonucleic acid (DNA) technology and approved for use in humans by the U.S.
Food and Drug Administration (FDA)
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• 1980-1990- The understanding that action profile of insulin depends on the
formulation (monomer or hexamer) and the stability of hexamers, which
determine the time to onset
• To bridge the gap between early insulin profiles and physiological insulin
secretion, recombinant DNA technology engineered insulin analogs with
modified amino acid structures to alter PK and PD properties
• 1996 - The first insulin analog- rapid-acting insulin Lispro approved by the FDA.
• 1998-2000- Aspart and Glulisine - Rapid-acting insulins- better mealtime
insulins with comparable efficacy and reduced hypoglycemia compared with
regular insulin
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• 2000- Glargine was approved, till then NPH insulin was used as basal insulin
• 2015 –Approval of insulin glargine U-300 (3-fold concentrated) and insulin
Degludec- longest-acting (duration of action-42 hours) insulin analog to date
• Newer long-acting analogs- more physiological basal profile and provide
comparable efficacy and a lower risk of hypoglycemia than first-generation
long-acting analogs
• Premixed insulins- advantages of fewer injections, convenience, and
preventing mixing errors- disadvantages-ratio of individual components cannot
be adjusted freely- more suitable for patients with regular lifestyle patterns
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Innovation in Insulin
Aim:
i. Different noninvasive route of administration for better patient
compliance and outcome
ii. New insulin preparation (eg: long acting- to extend the duration of
action so as to decrease the frequency of administration- better
patient compliance and outcome).
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Novel Insulin Analogues
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The Future of Insulin Therapy: Shorter- and Longer-acting
Insulins
Why do we need alternative ultra short acting insulin?
• To more closely mimic normal physiologic insulin secretion in response to a meal
Why do we need more longer acting basal insulin?
• Reduced dosing frequency may improve adherence to insulin treatment and enhance
convenience
• Easier to use for individuals who need assistance in insulin injection and would reduce
treatment burden
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Faster Asparts- FIASP (Novo Nordisk)
• Fiasp (Novo Nordisk) was approved by the FDA in 2017
• Formulation consisting of niacinamide (for faster absorption) and L-arginine (for
stabilization of the molecule) added to insulin aspart
• Niacinamide acts as a hydrotrope to further shift the balance from hexamers toward
monomers that are more readily available for absorption and also serves as a
vasodilator to increase blood flow to the injection site
• Exhibits faster on and off effects when administered via insulin pump
• In both T1DM and T2DM patients, postprandial glucose control was superior with
similar hypoglycemia and tolerability compared to insulin aspart
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• Meta-analysis of pharmacokinetic/pharmacodynamic studies in adults with
T1D demonstrated faster appearance in venous blood (4 vs. 9min), with
greater concentration, and greater insulin action in the first 30 min compared
with insulin aspart
• In a phase 3 study of people with T2D only on basal insulin at baseline, the
addition of Fiasp was noninferior with regard to change A1c compared with
aspart
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• A 26-week phase 3 study in people with T1D was randomized to premeal
Fiasp, postmeal Fiasp (20 min postmeal) and premeal standard aspart-
demonstrated noninferiority of Fiasp for both mealtime and postmeal
dosing with slightly more frequent early postprandial hypoglycemia than
the comparison group, whereas postprandial hypoglycemia rates 2–4 h
after meals were lower, leading to similar overall rates of hypoglycemia-
superiority for 1 and 2 h postprandial glucose control on a meal test
compared with aspart (estimated treatment difference of -21.21 mg/dL
at 1 h [95% CI -29.65 to -12.77]; P < 0.0001)
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• Superior postprandial glucose control and
noninferior HbA1c lowering effects
compared to insulin lispro in patients
with both T1DM and T2DM
• Advantage of ultrarapid insulin analogs is
flexibility in meal scheduling
• Postmeal administration of faster aspart
was similarly effective as mealtime insulin
aspart
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Biochaperone Insulin Lispro- (BCLIS; Adocia)
• Developed by Adocia, Lyon, France - ultrarapid-acting insulin under development-
currently in phase 3 trials
• It contains a novel modified oligosaccharide excipient BioChaperone BC222 and
citrate to promote insulin lispro hexamer dissociation and accelerate absorption
• It better mimicked prandial insulin secretion and significantly improved postprandial
glucose compared to rapid acting insulins
• This technique is also being tested for various combinations, including insulin glargine
plus lispro or insulin lispro plus pramlintide
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Superfast insulin ASPART- AT247 (Arecor Limited)
• AT247 (Arecor Limited) is a formulation of aspart using excipients with metal ion binding capacity
• Data presented in abstract form for swine studies showed modestly faster glucose lowering than
RAI.53
• As of December 2019, announced completion of a phase 1 clinical study comparing AT247 with
aspart and Fiasp
• Results from Phase I clinical - when delivered by continuous subcutaneous infusion via an insulin
pump over a period of three days, announced in October 2022, showed that AT247 delivered
significantly accelerated insulin absorption and early exposure (PK profile) when compared to
currently available gold standard rapid acting insulins, NovoRapid®
and Fiasp®
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ICODEC
• ICODEC - A novel once-weekly basal insulin analog- showed favorable results
in phase 2 clinical trials
- It was designed by three amino acid substitutions (A14 glutamic acid, B16
histidine, and B25 histidine) for molecular stability and reducing enzymatic
degradation, removal of B30 threonine, and addition of a C20 eicosane fatty
diacid side chain at B29 lysine attached via a hydrophilic spacer for strong
albumin binding and reduced receptor-mediated clearance
- Preclinical studies showed half-life of 196 hours
- After injection, hexamers are slowly dissociated and bind to albumin to form an
inactive depot
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• Steady state is achieved after 3 to 4 weekly doses
• At steady state, variations in dosing time and amount cause minimal
changes in the immediate glucose-lowering effect, enhancing its
flexibility
• In a pivotal phase 2 trial of a once-weekly insulin icodec compared
with once-daily insulin glargine U100 in insulin-naïve patients with
T2DM taking metformin with or without a dipeptidyl peptidase 4
inhibitor, a similar glucose-lowering effect was observed (estimated
mean change in HbA1c from baseline: –1.33% in the icodec group
and –1.15% in the glargine group)
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• Another phase 2 study investigated the efficacy and safety of insulin icodec when
switching from once or twice daily basal insulin versus insulin glargine U100 . The
icodec group with a 100% loading dose at the first injection showed a significantly
longer time-in-range (70 to 180 mg/dL) and numerically larger changes in HbA1c
from baseline compared to the glargine U100 group without increasing the risk of
hypoglycemia. This study showed that adding an initial loading dose is safe and
effective when switching from daily basal insulin to weekly icodec
• Several phase 3 trials with different patient populations, different treatment
combinations, long-term efficacy and safety, and patient-reported outcomes are
ongoing
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Basal Insulin Fc (BIF)
• Another once-weekly insulin under development
• It is a fusion protein of the human IgG2Fc domain and a novel single-chain variant of
insulin
• Recently introduced first in-human data showed a half-life of approximately 17 days and
peakless PK profile over a 1-week dosing interval in subjects with T2DM
• A 32-week phase 2 study demonstrated noninferior efficacy of BIF compared with insulin
degludec
• The data presented to date suggest the feasibility of once-weekly insulin, although more
clinical trials and the issue of the difficulty of short-term adaptation need to be addressed
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Hepato-preferential Insulins
• What is the purpose for its development?
- Conventional subcutaneous insulin administration results in much greater
exposure of insulin to muscle and lower exposure to liver, resulting in different
degrees of action in these organs compared to physiologic endogenous insulin
- Hepato-preferential insulin has been suggested as an alternative to restore the
physiologic portal-to-peripheral insulin ratio and reduce the risk of
hypoglycemia, weight gain, and insulin resistance
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I. Insulin Peglispro (Diasome Pharmaceuticals, Inc.)
• Molecule consisting of a polyethylene glycol chain covalently bound to B28 lysine of
insulin lispro and has hepatopreferential effects due to its large hydrodynamic size
• IMAGINE phase 3 clinical trial program- 6000 patients with T2DM and T1DM- insulin
peglispro consistently showed a greater HbA1c reduction, less glycemic variability, reduced
nocturnal hypoglycemia, and tendency to gain less weight compared to glargine and NPH
• Adverse effects- associated with higher liver fat and triglycerides and a higher frequency of
elevation of aminotransferase levels
• Although it was not due to severe liver injury, the manufacturer decided to stop the
development program in 2015
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Dr C Vignesh 79
II. Hepatic-directed Vesicle (HDV) Insulin
• An insulin delivery system that contains biotin-phosphatidylethanolamine as a
hepatocyte-targeting molecule in phospholipid bilayer vesicles
• In a phase 2b study of T1DM, HDV insulin lispro showed noninferior HbA1c
lowering and no significant differences in hypoglycemia or insulin dosing compared
with insulin lispro
• Further delineation of its efficacy and safety is awaited.
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Currently Available and Novel Insulin Delivery Devices
and System
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Insulin Syringes and Needles
• The needles are of 28, 30, and 31 gauges. The 31-gauge needles are almost
painless
• Plastic disposable syringes are available in 1-mL, 0.5-mL, and 0.3-mL sizes
• Three lengths of needles are available: 6 mm, 8 mm, and 12.7 mm
• Long needles are preferable in patients with obesity to reduce variability of
insulin absorption
• “Disposable” syringes may be reused until blunting of the needle occurs
(usually after three to five injections)
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Dr C Vignesh 82
• Cleansing the needle with alcohol may not be desirable since it can
dissolve the silicone coating and can increase the pain of skin puncturing
• Any part of the body covered by loose skin can be used, such as the
abdomen, thighs, upper arms, flanks, and upper buttocks
• Preparation with alcohol is not required prior to injection as long as the
skin is clean
• Rotation of sites is recommended to avoid delayed absorption when
fibrosis or lipohypertrophy occurs from repeated use of a single site
.
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Dr C Vignesh 84
Insulin Pens
• Eliminate the need for carrying insulin vials and syringes
• Smart pens (Companion Medical) that are linked to cell phones can be used to remind
the user to take their insulin before meals, calculate doses, and keep track of timing of
the doses
• Disposable prefilled pens are also available for regular insulin (U100 and U500),
insulin lispro, insulin aspart, insulin glulisine, insulin detemir, insulin glargine, insulin
degludec, NPH, 70% NPH/30% regular, 75% NPL/25% insulin lispro, 50% NPL/50%
insulin lispro, 70% insulin aspart protamine/30% insulin aspart, and 70% insulin
degludec/30% insulin aspart
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Dr C Vignesh 85
• Pen needles are available in 29, 31, and 32
gauges and 4-, 5-, 6-, 8-, and 12.7-mm
lengths
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Dr C Vignesh 86
Insulin Infusion Devices (IID) and Continuous Glucose Monitoring
(CGM)
• Insulin infusion devices provide a constant basal infusion of insulin and have the
option of different infusion rates during the day and night to help avoid the rise in
blood glucose that occurs just prior to awakening from sleep (the DAWN
PHENOMENON) and bolus injections that are programmed according to the size
and nature of a meal.
• In the United States, Medtronic Mini- Med, Insulet, and Tandem make battery
operated continuous subcutaneous insulin infusion (CSII) pumps. SOOIL makes a
pump that is available in Europe and Asia.
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Dr C Vignesh 87
• Features-
1) Ability to set a number of different basal rates throughout the 24 hours
and to adjust the time over which bolus doses are given.
2) Detect pressure build-up if the catheter is kinked.
3) Catheter connecting the insulin reservoir to the subcutaneous cannula
can be disconnected, allowing the patient to remove the pump
temporarily.
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• Advantage-
1) Establishment of a basal profile tailored to the patient allowing for better
overnight and between meals glucose control
2) Deliver a more physiological profile of insulin replacement during exercise
(where insulin production is decreased) and thus less hypoglycemia than
traditional subcutaneous insulin injections provide
3) Take care of Dawn phenomenon and Somoyogi effect
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Dr C Vignesh 89
10-12-2024
Feature Somogyi effect Dawn phenomenon
Definition Rebound hyperglycemia due to
counter-regulatory hormone
response after nocturnal
hypoglycemia
Early morning hyperglycemia due
to increased secretion of counter-
regulatory hormones (growth
hormone, cortisol, epinephrine)
Common
cause
Excessive nighttime insulin dose,
prolonged fasting, or long-acting
sulfonylureas
Normal physiological circadian
hormone variation, particularly in
diabetes mellitus
Management Reduce evening insulin dose or
provide bedtime carbohydrate
snack to prevent hypoglycemia
Adjust insulin regimen (increase
basal insulin at night) and modify
dietary intake (reduce late-night
carbohydrates)

Dr C Vignesh 90
• The integration of an insulin infusion device and CGM (open and closed
loop systems) is rapidly evolving with algorithms and communication that
alter the infusion rate for insulin delivery based on CGM data
• Complications of CSII include ketoacidosis, which can occur when insulin
delivery is interrupted, and skin infections
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Dr C Vignesh 91
• V-go (MannKind) is a mechanical patch pump
designed specifically for patients with type 2
diabetes who use a basal/bolus insulin regimen
• The device is preset to deliver one of three
fixed and flat basal rates (0.83 units/h, 1.25
units/h, or 1.67 units/h) for 24 hours (at which
point it must be replaced), and there is a button
that delivers two units per press to help cover
meals and lower high-glucose excursions
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Dr C Vignesh 92
• CeQur Simplicity (CeQur) is a 3-day mechanical patch device that holds 200 units
of rapid-acting insulin and delivers two units per press of a button to cover meals
and to lower high-glucose excursions
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Dr C Vignesh 95
Noninjecting Insulins
Why do we need to consider developing noninjectable insulin preparations?
• Patients are still reluctant to initiate insulin therapy due to the fear of
injection, inconvenience, side effects such as hypoglycemia and weight
gain, and social stigma
A) Inhalational Insulin
B) Oral delivery of Insulin
C) Ingestible Insulin device
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I. EXUBERA
• The first inhalable insulin, Exubera (Pfizer Inc., New York, NY, USA), was
approved and marketed in 2006 but was soon withdrawn from the
market by the manufacturer due to poor sales
• Intrapulmonary delivery of insulin seemed to be an attractive alternative
route but failed to become popular due to cost, inconvenience of the
device and procedure, high demands of instruction and safety concerns
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Dr C Vignesh 97
II. AFREZZA
• Afrezza (MannKind, Westlake Village, CA, USA) is another
ultrarapid-acting inhalable insulin approved by the FDA in 2014
• It’s a dry powder of recombinant human regular insulin
adsorbed onto an excipient of fumaryl diketopiperazine based
on technosphere particle technology
• It has been shown to be as effective as twice daily premixed
biaspart insulin when combined with insulin glargine with
significantly lower weight gain and fewer hypoglycemic
events
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Dr C Vignesh 98
• A pooled data analysis including 5,505 patients in Afrezza trials
showed pulmonary safety except a higher incidence of mild
cough and slight reversible decline in pulmonary function
relative to comparators
• The most common adverse reaction- cough, affecting about 27% of
patients, a small decrease in pulmonary function (FEV1) is seen in
the first 3 months of use, which persists over 2 years of follow-up
• Rapidly absorbed with peak insulin levels reached in 12–15 minutes
and declining to baseline in 3 hours
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Dr C Vignesh 99
• Contraindicated in patients who smokes and/or with pulmonary
diseases such as Bronchial asthma, COPD, Pulmonary carcinoma, etc
• Spirometry should be performed to identify potential lung disease
prior to initiating therapy 6 months after initiation, and then yearly
• Technosphere insulin combined with basal insulin was as effective in
glucose lowering as rapid-acting insulin analogs combined with basal
insulin
• It is formulated as a single-use, color-coded cartridge delivering 4, 8,
or 12 units immediately before the meal
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Dr C Vignesh 105
III. DANCE 501 Inhaled Insulin (Aerami Therapeutics)
• Novel liquid human insulin formulation with a small handheld aerosol device for
inhalation- using Aerami’s smart inhaler technology- generates a gentle mist,
allowing for drug deposition 2-4 times higher than conventional inhalers
• The company’s website indicates this insulin is ready to enter phase 3 trials.
• The relative biopotency compared with subcutaneous RAI is 13%
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Dr C Vignesh 106
• Data presented at the 2019 Diabetes Technology Meeting in people
with T2D showed a linear dose relationship and a more rapid onset of
action (6.5 vs. 20 min, P < 0.02) compared with lispro insulin, with
similar results in adults with T1D presented at the 2019 American
Diabetes Association Scientific Sessions
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Dr C Vignesh 107
Oral Delivery of Insulin
• The most preferable method with a more physiologic portal-to-peripheral insulin
ratio
• Major challenges- interference by meal ingestion, high absorption variability, low
bioavailability, and resulting commercial unviability
• Orally administered therapeutic proteins must navigate extremes of pH,
protease-rich environments, thick mucus layers, and cellular tight junctions
before achieving systemic bioavailability
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I. Prandial Oral Insulins – Phase 2 and 3 studies- failed to show impressive results to date with
no or negligible glucose lowering
A. Insulin Tregopil (IN-105, recombinant insulin conjugated with polyethylene glycol via an acetyl
chain)
B. ORMD-0801 (enteric coated capsule containing insulin and adjuvants to protect the protein and
promote intestinal uptake)
II. Basal Oral Insulin- would be more feasible- it could avoid food effects
• Oral insulin 338 (I338)
Long-acting basal insulin analog coformulated in a gastrointestinal permeation enhancement
technology one (GIPET I) tablet with sodium caprate as an absorption enhancer and shows an
extended half-life of up to 70 hours at a steady state despite relatively fast absorption
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Dr C Vignesh 109
In an 8-week phase 2 trial comparing once-daily I338 with once-daily insulin
glargine in insulin-naïve patients with T2DM, there were no significant
differences in the efficacy measures, including fasting plasma glucose, 10-
point plasma glucose concentrations, HbA1c, fructosamine and fasting C-
peptide concentration, or safety profile, between the two groups
Despite promising results, further development of I338 was discontinued
because the dose required was high due to low bioavailability and therefore
it was not commercially viable for mass production
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Dr C Vignesh 110
Ingestible Insulin Device- (SOMA)
• An ingestible self-orienting millimeter-scale applicator (SOMA) inspired
by a leopard tortoise’s ability to passively reorient can autonomously
position itself to the stomach lining, orient its injection mechanism toward
the tissue wall, and inject a drug through the mucosa
• Using a swine model, this device was shown to successfully deliver insulin
and lower blood glucose levels to a similar degree as those achieved by
subcutaneous injection
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Dr C Vignesh 111
• Recent report by the Langer lab at MIT describes the engineering and in
vivo use of an oral delivery system for biomacromolecules using insulin as a
model protein
• The major problems of biomacromolecule therapeutics revolve around their
inability to be orally administered; their size, stability, and polarity make them
insoluble in solutions, easily metabolized by the gastrointestinal tract, and
poorly permeable through cellular tight junctions
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Dr C Vignesh 112
• The size and material makeup of the SOMAs are similar to those of FDA-approved
ingestible devices such as OROS capsules, ingestible temperature sensors, and capsule
endoscopy systems, supporting likely comparable environmental assessments
• SOMA was tested for self-orientation and persistence of mucosal engagement 300
times ex vivo in swine stomachs and 60 times in vivo in fasted swine. To measure
proper device orientation, endoscopy on and took x-rays of the swine after
administering the devices through an overtube and agitating the abdomen via 180°
rotations and 30° tilts of the animal model. To demonstrate that the mass distribution
affected self-orientation, it showed that the SOMA oriented in 100% of trials, whereas
a device of the same shape made solely of PCL only oriented 50% of the time
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Dr C Vignesh 116
Luminal Unfolding Microneedle Injector (LUMI)
• Orally delivered device bypasses the mucosal barrier by physically inserting insulin-
loaded microneedles into the small intestine
• The LUMI device is a 9mm (diameter) x 30mm (length) coated capsule that dissolves in
the gut and deploys the microneedle device
• Future work will be needed to assess bowel perforation and obstruction risk.
• Despite many years of research into orally delivered insulin, these formulations remain in
early studies
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Dr C Vignesh 118
Glucose-responsive Insulins (GRI)
• Controlled release of insulin triggered by glucose conditions
• Mechanical GRI - Closed-loop insulin delivery system or artificial pancreas that
uses continuous glucose monitoring and an automated pump using an intelligent
algorithm is a form of mechanical GRI, and clinical application has been started
• Two broad classes of molecular GRIs:
(1) Polymer-based systems, which consist of insulin contained within a glucose-
responsive polymeric matrix-based vesicle or hydrogel composed of glucose-
binding proteins, glucose oxidase, or boronate-based chemistries
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Dr C Vignesh 119
• Glucose oxidase catalyzes a reaction of glucose with oxygen and water to generate
gluconic acid and hydrogen peroxide, thus creating a locally acidic environment-
disadvantages of potential immune reaction to a xenogenic enzyme, local toxicity
from the hydrogen peroxide by- product, and inherent degradation of the enzyme
over time
• Con A bind saccharides- Glucose binding proteins-high affinity and specificity-
forms aggregates that can be used as a glucose responsive crosslinking molecule -
immunogenicity and mitogenicity concerns with ConA have diminished
enthusiasm for its clinical utility
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Dr C Vignesh 120
(2) Molecular-based bioconjugation systems, which introduce a glucose-
sensitive motif (phenylboronic acid, glucosamine, or mannose) to the
insulin molecule or its formulation
-Phenylboronic acids (PBA)- nonbiologic small molecules that can
reversibly bind glucose to form glucose responsive hydrogels- pKa of PBA
(8–9) is much higher than physiologic pH requiring addition of moieties to
PBA to shift toward more physiologic pHs
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Dr C Vignesh 123
External Methods for Insulin Release
Mechanism Description
Ultrasound • Low-frequency ultrasound promotes uptake of insulin by inducing air
pockets in the keratinocytes of the stratum corneum and disruption of
lipid layers without effecting barrier properties of the skin.
• Ultrasound-responsive shells and injectable nanonetworks for regulated
release of encapsulated insulin
NIR (near
infrared) light
• Various approaches with photoactivated depot of insulin for light
regulated release
• Gold nanorod complexes with a surfactant are being used to store insulin
• Gold nanorods absorb NIR, which causes the light energy to be converted to
heat to break the stratum corneum
• Gold nanoparticles containing an insulin reservoir, NIR leads to collapse of
the nanoparticle network and insulin release
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Dr C Vignesh 124
Mechanism Description
Temperature Thermal-responsive polymers, beads and microneedle patches for
temperature-dependent insulin release
Site warming
devices
• Warming the site of insulin injection improves local blood flow,
increases insulin absorption
• Infusion site warming devices have been shown to reduce time-to-
peak insulin action in human studies
Microneedle
devices
• Microneedle patches (solid, hollow, or drug loaded) could allow glucose
responsive insulin delivery in combination with biomimetic systems or
external trigger systems
• Consist of micron-sized needles attached to a transdermal patch that
allow for painless subcutaneous delivery of drug delivery
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Dr C Vignesh 125
Specific Learning Objectives Accomplished
At the end of this teaching learning session the audience were be able to:
• Describe the pancreatic anatomy and physiology
• Describe the insulin structure, mechanism of action, its regulation and types
• Describe DM- Its definition, diagnosis, types and complications
• Describe the timeline of development of insulin
• Describe the recent advances in insulin therapy- Novel insulin analogues and
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Dr C Vignesh 126
References
1. English A, Irwin N. Nonclassical Islet Peptides: Pancreatic and Extrapancreatic Actions. Vol. 12,
Clinical Medicine Insights: Endocrinology and Diabetes. SAGE Publications Ltd; 2019.
2. Lee SH, Yoon KH. A century of progress in diabetes care with insulin: A history of innovations
and foundation for the future. Vol. 45, Diabetes and Metabolism Journal. Korean Diabetes
Association; 2021. p. 629–40.
3. Wilson LM, Castle JR. Recent Advances in Insulin Therapy. Vol. 22, Diabetes Technology and
Therapeutics. Mary Ann Liebert Inc.; 2020. p. 929–36.
4. Abramson A, Caffarel-Salvador E, Khang M, Dellal D, Silverstein D, Gao Y, et al. An ingestible self-
orienting system for oral delivery of macromolecules [Internet]. Available from:
https://www.science.org
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Dr C Vignesh 127
5. Abramson A, Caffarel-Salvador E, Khang M, Dellal D, Silverstein D, Gao Y, et al. An ingestible
self-orienting system for oral delivery of macromolecules. Science (1979). 2019 Feb
8;363(6427):611–5.
6. Tripathi KD. Essentials of medical pharmacology. Eighth edition. New Delhi: Jaypee Brothers
Medical Publishers; 2019. p280-305
7. Brunton LL, Knollmann BC, editors. Goodman & Gilman’s the pharmacological basis of
therapeutics. Fourteenth edition. New York: McGraw Hill; 2023. 1 p. 1023-1047
8. Harrison, T. R. and Braunwald, E. (2021) Harrison’s principles of internal medicine. 15th ed. New
York, NY: McGraw-Hill.
9.Papadakis MA, McPhee SJ, Rabow MW, McQuaid KR. Current medical diagnosis & treatment
2023. [New York]: McGraw-Hill; 2023.‌
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Dr C Vignesh 128
THANK YOU
10-12-2024

Recent advances in Insulin therapy: A comprehensive overview

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