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RECENT UPDATES ON
INSULINS
Dr Meeta Amit Burande
MBBS, MD (Pharmacology),
D Diabetology (Australia), Fellow in Diabetes (UK)
Professor & Head, Department of Pharmacology,
D Y P Medical College, D Y Patil Deemed to be University,
Kolhapur Consultant Diabetologist, Surya Multispecialty
Hospital, Kolhapur
Webinar conducted by Medical Pharmacologist
Society
DIABETES
 Diabetes is the relative deficiency of the
insulin, which may be either due to absolute
decrease in insulin secretion (Type 1) or due
to increase insulin requirement/ resistance
(Type 2).
Insulin recent updates final
INSULIN
 First treatment discovered and still most effective
and safest therapeutic option
 Insulin in english from insula means island
 By species of origin it is of three types: human,
porcine and bovine. Pork insulin is more
homologous to human insulin.
 Insulin is the polypeptide hormone synthesized in
pancreatic beta cell as per-proinsulin and get
stored in secretary vesicle as proinsulin with the
help of C-peptide. It is secreted in blood along
with C-peptide.
 Insulin was bioassayed in rabbit blood but now it
is assayed by chemical method also.
HISTORY
 Barron noticed endocrine pancreas not affected by bile
duct ligation.
 Banting used the observation for isolation of islets
 Insulin was discovered in 1921 by Banting,Best,
collip and Macleod and awarded noble in1923
 NPH introduced in 1946 by Hagedorn
 Hallas at Novonordisk develop insulin zn i.e. Lente.
 1955- sanger described molecular structure of
insulin and species differences, awarded nobel in
1958
 1970 – purification methods developed and neutral
insulin was produced
 Yalow developed radioimmunoassys, nobel in 1978
 Ulrich cloned the insulin gene in 1997,and first
commercially available human insulin was made in
novonordisk in 1981 and 1984 with saccharomyces
cerevesiae (Baker yeast)
 1982, gentically eingeeneered insulin was made by
el lily in E coli
Insulin productions
 Animal insulin – not available now
 Bovine and porcine – both – monoporcine
 Pancreas- frozen- acid ethanol/water extraction –
neutralization – acidification – evaporation – salting
 Bovine – differs in A8,A10and B30
 Porcine – B30
 Human insulin –
 Semisynthetic – converting porcine to human by enzymatic
replacemnet of B30 alanine to threonine
 Genetically engineered - E coli or saccharomyces
cerevesiae
 Human insulin chain recombinant material (CRB)
 Genetically engineered human insulin (HMge)
 Insulin analogues
Regulation of secretion
 Insulin is secreted continuously under the basal condition at
the rate of 1U/hour. It is interrupted by the pulse of secretion
at meals. It is regulated by different stimuli i.e.
 Chemical – increase blood sugar level, amino acids like
arginine, leucine, guanosine etc. secretion is in 2 phase:
early and delayed
 Hormonal – growth hormone, steroids, thyroids has insulin
resistant action. They inhibits the release of insulin or
increase the resistance in tissue to insulin.
 Neural – alpha 2 receptor decrease the insulin release, beta
2 stimulation decrease the insulin release, cholinergic
muscarinic activation increase insulin release.
 Increased insulin secretion in reactive hypoglycemia,
persistant hyperinsulinomic hypoglycemia of infancy,
insulinoma
Insulin synthesis
 Insulin gene- at p13on short arm of
chromosome 11
 3 exons and 2 introns
 Synthesised in beta cells, yolk sac and fetal
liver
 Other tissues – negative regulatory element
 Insulin gene transplantation !!
Transcription of code:
Chromosome 11 coding for insulin and are transcribed to mRNA in the nucleus.
2. Translation of the code:
Polypeptide synthesis is initiated with the formation of N-terminal signal peptide
(leading sequence)
3. Synthesis of preproinsulin:
Further elongation resulting in the formation of preproinsulin. It is constituted by
109 amino acid residues and mol. wt. is 11.5 kdt.
4. Separation of signal sequence:
N-terminal signal peptide is hydrolysed away by signal peptidase and pro- insulin is
formed Pro-insulin consists of 86 amino acid residues and its mol. wt. is about 9 kd.
5. Transfer of pro-insulin:
Pro-insulin is transported from GER to the Golgi complex.
6. Splitting of pro-insulin:
In Golgi cisternae pro-insulin is hydrolysed by trypsin like peptidase to yield a 53
amino acid insulin precursor and pro-c-peptide has 33 amino acids.
7. Formation of insulin:
In the Golgi complex about 95% of the pro-insulin is converted to active insulin.
Insulin synthesis
Insulin recent updates final
Release of insulin
Actions of insulin
 Increase glucose transport from blood to tissue
 Formation of muscle proteins
 Lipid synthesis (Lipogenesis)
 Increased activity of lipoprotein lipase in blood
vessels so decrease serum VLDL and
chylomicrons
 Reduction in hepatic glucose output
 Mitogenic action i.e. proliferation of endothelial
cells in blood vessels.
Mechanism of action
 Insulin act on membrane bound heteroreceptor
with tyrosine kinase enzymatic activity.
Pharmacokinetics
 Orally given destructed in GIT so given
parenterally. It is distributed extracellularly and
metabolized in liver and kidney. Normally
secreted insulin is highly metabolized in liver
with plasma half life of 5 minutes.
Preparations of insulin
 Ultra short acting – Insulin lispro, Insulin
Aspart, insulin glusiline
 Short acting – Regular insulin
 Intermediate acting – NPH & Lente Insulin
 Long acting - PZI, Glargine & Detemir
 Premixed insulins – NPH & Regular, Lispro &
LPL, NPA & Aspart etc.
 Lispro protamine/lispro – 50/50, 75/35
 Protamine /aspart – 70/30
Highly purified insulins
 Conventional preparations contain impurities
and are more antigenic. So they are purified by
different methods like
 Gel filtration – single peak insulin
 Ion exchange chromatography – highly
purified and monocomponent insulin
Human insulins
 Produced by recombinant DNA technology i.e.
proinsulin recombinant bacterial, precurasor yeast
recombinant, enzymatic modification of porcine
insulin. Human insulin are specially indicated in –
 insulin resistance
 allergy to conventional preparations
 lipodystrophy at injection site
 short term use like surgery, trauma, infection,
ketoacidosis
 preganacy
Insulin analogues
 Insulin lispro: reversing praline and lysine at 28 and 29
for beta chain. Form hexamers that dissociate very
rapidly
 Insulin aspart: praline of B 28 is replaced by aspart. So it
reduces the aggregation
 Insulin glulisine: replace aspargine at B23 by lysine and
lysine at B29 by glutamic acid
 Insulin glargine: long acting with 2 additional arginine at
B chain. It is soluble at acidic pH but precipitates at
neutral pH so depot in subcutaneous tissue on injection.
It releases slowly and give peakless profile in blood.
Given once a day to control fasting blood sugar level
 Insulin detemir: it is highly protein bound long acting
insulin that dissociate from the binding site slowely.
Significantly less weight gain as compared to NPH
Insulin degludec: slow release
following injection
Insulin degludec
multi-hexamers
Zinc diffuses slowly causing individual
hexamers to disassemble, releasing
monomers
Subcutaneous depot Zn2+
Monomers are absorbed from
the depot into the circulation
20
Basal Insulin
Prandial Boluses
0hr 24hr
BGmg/dl
Physiologic Insulin Therapy
21
Time Activity of
Human Insulins
Pharmacodyn
amics of NPH
versus
Glargine
Insulin
Lepore, et al. Diabetes 1999; 48 (suppl 1): A97
Bolli et al. The Lancet • Vol 356 • August 5 2000
Plasma glucose
Glucose infusion rate
Biologic activity over 24-
hours more consistent for
basal insulin analogs
GIR = Glucose Infusion Rate
Heise et al. Diabetes 2004; 53 (6): 1614-1620
Insulin detemir
24
Insulin Bolus Dosage
 Amount to “cover” food eaten
- Usually calculated as 1 unit per x number gms of carbohydrate
- For example: 6 units needed to cover 60 gms CHO if using 1 unit per 10
gms CHO (60/10 = 6)
 Amount to lower blood sugar to target range
- Usually calculated according to sliding scale or correction factor
- Sliding scale: give units of insulin for each range of BG
- Correction factor: Blood glucose level – target blood glucose/correction
factor = units insulin to be given
- Ex: BG=150 (actual) minus Target BG (100) = 50 divided by Correction
factor (50) = 1 unit insulin needed
 Add together to get Insulin Bolus Dosage
www.diabetesclinic.ca 25
Two injections/day
Blood Glucose (mmols)
8am noon 6pm 2am 4am 8am
Time
R or H + N in AM R or H + N at Supper
10-
8-
6-
4-
2-
0
www.diabetesclinic.ca 26
Three injections/day
Blood Glucose (mmols)
8am noon 6pm 2am 4am 8am
Time
R or H + N in
AM
R or H at
Supper
N before bed
10-
8-
6-
4-
2-
0
www.diabetesclinic.ca 27
Four injections/day
Blood Glucose (mmols)
8am noon 6pm 2am 4am 8am
Time
R or H at every meal N or U once or twice/day
10-
8-
6-
4-
2-
0
www.diabetesclinic.ca28
Continuous Infusion
Blood Glucose (mmols)
8am noon 6pm 2am 4am 8am
Time
10-
8-
6-
4-
2-
0
New insulin delivery devices
 insulin syringes, pen devices, inhaled insulin,
insulin pumps, implantable pumps, external
artificial pancreas, liposomal delivery
30
Insulin Syringes
 Sizes – 30, 50,
100 units
 Disposable-
31
Insulin Pen: Devices
Prefilled pens
Reusable (cartridge) pens
Auto injectors
Dual chamber catridge
32
Insulin Pump Therapy
 Based on what body does
naturally
- Small amounts of insulin all the
time
(basal insulin)
- Extra doses to cover each meal or
snack
(bolus insulin)
 Rapid or Short-Acting Insulin-
analogues preferred due to less
crystalization in plastic tubes
 Precision, and Flexibility
33
What is an Insulin Pump?
 Battery operated device about the size of a pager
 Reservoir filled with insulin
 Computer chip with user control of insulin delivery
 Worn 24 hours per day
 Delivers one type of insulin
 Temporarily disconnected from cannula in place at time of bathing
etc.
What Pumps Do
 Bolus for food intake and to correct high blood glucose levels.
 Many pumps will calculate bolus dosages.
 Delivers pre-determined amount of basal insulin throughout the day.
 Some blood glucose meters communicate with pump.
Uses
Diabetes mellitus
 Indication for insulin therapy are –
 OHA failure – it may be primary or secondary
 OHA contraindications i.e. pregnancy, hepatic
failure, renal failure, stress, allergy to OHA etc.
 Metabolic emergencies i.e. DKA, HONK etc.
 Overt hyperglycemia i.e. fasting BSL is more
than 300 mg % at diagnosis
 Underweight patients
Insulin requirement of
diabetes in children
 Stages -
 Stage of metabolic recovery -1.5 to 3 u/kg/day –
occurs at the time of diagnosis. Very high requirement
due to high bsl, high stress hormones and
compensatory hyperphagia.
 Partial remission or honeymoon phase - drops to 0.3
to 0.5 U/kg/day due to decreased stress, inflammation
and glucotoxicity, 1 to 2 unit per day !
 Intensification – after 3 to 12 months due to continued
beta cell destruction
 Total diabetes – usually after 2 years of initial
diagnosis
 After 8 yrs of age – should inject themselves
Insulin in patients doing
ramdan fasting
paradoxical risk of food excess after the hours of
fasting.
individualized education improved safety during
Ramadan in terms of decreasing hypoglycemic
events, improved diabetes control, and prompted
weight loss.
premixed insulin can be given with the sunset meal
and half the usual evening dose to be used with
the predawn meal (suhoor)
Long-acting insulin-like glargine can be given as a
single injection and this can be administered with
short-acting insulin or metformin.
Before ramadan Fasting 100 to 180 no change in
total dose per day
Special cases
 Diabetes in elderly – many complications,
reduced vision and financial constraints, prefer
simple regimens, less dose due to ckd and risk
of hypo and cognitive dysfunction
 Diabetes and pregnancy – requirement
increases gradually from 0.7 to 1 unit/ kg till
last trimester, split bbf in two portions, start
premix at bbf, Regular nph npl, lispro aspart
 Quantity for insulin initiation –
 0.6 – 0.7 U/ Kg – average dose
 1-2 U/kg – obese patients
 Fasting BSL/ 10
Insulin resistance
 When requirement is increased more than 200
U per day insulin resistance is developed. It
may be
 Acute –
 Infection, trauma, surgery, emotional stress,
corticosteroids
 Ketoacidosis
 Chronic –
 Chronic diabetics treated for years with animal insulin
 IRS1 PC1 K121Q region gene polymorphism
Combined therapy approach to type 2 DM
Side effects –
 Hypoglycemia: most frequent and commonly seen in labile
diabetes although can occur in any diabetic. The symptoms
are secondary to sympathetic stimulation and
neuroglucopenic symptoms in CNS. It is treated by i.v./oral
glucose.
 Oedema: due to sodium retention but short lived.
 Insulin neuritis – osmotic change in nerve fibres, resolve in 1-
2 months
 Transient visual disturbances – due to difference in sugar
lowerin rate in acqous humor and lens. It get corerected
spontaneously with time.
 Local reactions (hypertrophy or atrophy): more common with
impure insulins
 Allergy: more common with impure and animal preparations.
 Neutral on CV risk and Carcinogenesis – evidence by
ORIGIN trial outcome reduction with initial glargine
intervention
Drug interactions
 Beta blockers prolong hypoglycemia as well as
mask the symptoms of hypoglycemia.
 Thiazides, CCBs increase the blood sugar
level
 Acute alcohol decrease the BSL.
 Aspirin and lithium may increase the
hypoglycemia
 Vitamin D improved beta cell function
 Pioglitazone and insulin
 drugs which decrease insulin requirement
 drugs which need increased insulin
Upcoming insulins
 Reverse split insulin – more lispro/aspart and less
NPL
 Ultrafast acting analogues – combination of insulin
lispro with recombinant human hyaluronidase
(rhuPH20)
 Glargine U 300 – flatter pharmacokinetic and
pharmacodynamic profile
 Hepatoselective insulin – LY2605541 –
 Insulin lispro with PEG at B28 lysine
 17 time less binding to IR and 32 times less binding to IGF
as compare to lispro – less mitogenic profile
 Half life 24 hrs, duration of action 36 hrs, unaltered in renal
disease
 Preferential hepatic function-mimic endogenous secretion
– raised liver enzyme !!
 Idegasp/degludecplus/Rhyzodeg – premixed with
Inhalational insulin-Affrezza
 Faster absorption
 Pfizer marketed in 2006
 Mannkind – in 2014 with sanoffi till 2016 than continued alone
– prefilled catrige of 4,8 or 12 unit
 Alkrems with eli lilly and aradygm with Novonordisk
"appears to be as effective, but no better than injected short-
acting insulin. The additional cost is so much more that it is
unlikely to be cost-effective.“
"failed to gain acceptance among patients and physicians“ –
difficult metered dosing, not portable
label restriction for patients having asthma, active lung cancer
or COPD.
May be promoted as add on to oral medications in type 2
Along with basal in type 1
Insulin Transdermal
Patch
H2O2 responsive vesicles integrated
with transcutaneous patches for
glucose mediated insulin delivery
I-port
It includes a built-in inserter, which
gives quick, virtually painless
application. Only a soft flexible
tube, called a cannula stays under
the skin. Once applied, insulin is
injected through the port instead of
skin . It is small and discrete, and
Transpalntation, Gene
therapy, Stem cells
 Pancreatic transplantation along with renal
transplantation
 Islet transplantation – immunosuppressive drugs
are different !
 Mixed bone marrow chimerism
 Costimulatory blockade
 Vaccination to make them more tolerant
 Porcine insulin producing cell line – but no human
 Pancreatic ductal cell to be differentiated as beta cell
 Bone marrow derived stem cell transplanted in type 1
 Genetically developed human pancreatic beta cell is
developed
Practical information
 Vial can be kept in room temperature
 Not to be kept in check in bag – will be ineffective due
to freezing
 Fastest abdomen/gluteal/bracheal/femoral
 Now can be taken without skin pinch due to lesser
length of needle
 Rotate particular injection in particular region
 To reduce pain –inject after spirit is dried and at room
temp, change needle
 After Giving Insulin -Check site for leakage,
Correction doses, Meal/snack doses, Timeliness
in relation to eating, Supervision of food amount
Thank you
Resources
 https://www.pharmacychoice.com/article/the-return-of-
inhaled-insulin.cfm
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC447715
2/
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC562987
2/
 https://www.acs.org/content/acs/en/pressroom/pressp
acs/2017/acs-presspac-january-18-2017/toward-a-
smart-patch-that-automatically-delivers-insulin-when-
needed.html
 https://www.medtronicdiabetes.com/products/i-port-
advance
 G & G, Tripathy, RSSDI text book of Diabetes,
Harrsons etc and journals

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Insulin recent updates final

  • 1. RECENT UPDATES ON INSULINS Dr Meeta Amit Burande MBBS, MD (Pharmacology), D Diabetology (Australia), Fellow in Diabetes (UK) Professor & Head, Department of Pharmacology, D Y P Medical College, D Y Patil Deemed to be University, Kolhapur Consultant Diabetologist, Surya Multispecialty Hospital, Kolhapur Webinar conducted by Medical Pharmacologist Society
  • 2. DIABETES  Diabetes is the relative deficiency of the insulin, which may be either due to absolute decrease in insulin secretion (Type 1) or due to increase insulin requirement/ resistance (Type 2).
  • 4. INSULIN  First treatment discovered and still most effective and safest therapeutic option  Insulin in english from insula means island  By species of origin it is of three types: human, porcine and bovine. Pork insulin is more homologous to human insulin.  Insulin is the polypeptide hormone synthesized in pancreatic beta cell as per-proinsulin and get stored in secretary vesicle as proinsulin with the help of C-peptide. It is secreted in blood along with C-peptide.  Insulin was bioassayed in rabbit blood but now it is assayed by chemical method also.
  • 5. HISTORY  Barron noticed endocrine pancreas not affected by bile duct ligation.  Banting used the observation for isolation of islets  Insulin was discovered in 1921 by Banting,Best, collip and Macleod and awarded noble in1923  NPH introduced in 1946 by Hagedorn  Hallas at Novonordisk develop insulin zn i.e. Lente.  1955- sanger described molecular structure of insulin and species differences, awarded nobel in 1958  1970 – purification methods developed and neutral insulin was produced  Yalow developed radioimmunoassys, nobel in 1978  Ulrich cloned the insulin gene in 1997,and first commercially available human insulin was made in novonordisk in 1981 and 1984 with saccharomyces cerevesiae (Baker yeast)  1982, gentically eingeeneered insulin was made by el lily in E coli
  • 6. Insulin productions  Animal insulin – not available now  Bovine and porcine – both – monoporcine  Pancreas- frozen- acid ethanol/water extraction – neutralization – acidification – evaporation – salting  Bovine – differs in A8,A10and B30  Porcine – B30  Human insulin –  Semisynthetic – converting porcine to human by enzymatic replacemnet of B30 alanine to threonine  Genetically engineered - E coli or saccharomyces cerevesiae  Human insulin chain recombinant material (CRB)  Genetically engineered human insulin (HMge)  Insulin analogues
  • 7. Regulation of secretion  Insulin is secreted continuously under the basal condition at the rate of 1U/hour. It is interrupted by the pulse of secretion at meals. It is regulated by different stimuli i.e.  Chemical – increase blood sugar level, amino acids like arginine, leucine, guanosine etc. secretion is in 2 phase: early and delayed  Hormonal – growth hormone, steroids, thyroids has insulin resistant action. They inhibits the release of insulin or increase the resistance in tissue to insulin.  Neural – alpha 2 receptor decrease the insulin release, beta 2 stimulation decrease the insulin release, cholinergic muscarinic activation increase insulin release.  Increased insulin secretion in reactive hypoglycemia, persistant hyperinsulinomic hypoglycemia of infancy, insulinoma
  • 8. Insulin synthesis  Insulin gene- at p13on short arm of chromosome 11  3 exons and 2 introns  Synthesised in beta cells, yolk sac and fetal liver  Other tissues – negative regulatory element  Insulin gene transplantation !!
  • 9. Transcription of code: Chromosome 11 coding for insulin and are transcribed to mRNA in the nucleus. 2. Translation of the code: Polypeptide synthesis is initiated with the formation of N-terminal signal peptide (leading sequence) 3. Synthesis of preproinsulin: Further elongation resulting in the formation of preproinsulin. It is constituted by 109 amino acid residues and mol. wt. is 11.5 kdt. 4. Separation of signal sequence: N-terminal signal peptide is hydrolysed away by signal peptidase and pro- insulin is formed Pro-insulin consists of 86 amino acid residues and its mol. wt. is about 9 kd. 5. Transfer of pro-insulin: Pro-insulin is transported from GER to the Golgi complex. 6. Splitting of pro-insulin: In Golgi cisternae pro-insulin is hydrolysed by trypsin like peptidase to yield a 53 amino acid insulin precursor and pro-c-peptide has 33 amino acids. 7. Formation of insulin: In the Golgi complex about 95% of the pro-insulin is converted to active insulin. Insulin synthesis
  • 12. Actions of insulin  Increase glucose transport from blood to tissue  Formation of muscle proteins  Lipid synthesis (Lipogenesis)  Increased activity of lipoprotein lipase in blood vessels so decrease serum VLDL and chylomicrons  Reduction in hepatic glucose output  Mitogenic action i.e. proliferation of endothelial cells in blood vessels.
  • 13. Mechanism of action  Insulin act on membrane bound heteroreceptor with tyrosine kinase enzymatic activity.
  • 14. Pharmacokinetics  Orally given destructed in GIT so given parenterally. It is distributed extracellularly and metabolized in liver and kidney. Normally secreted insulin is highly metabolized in liver with plasma half life of 5 minutes.
  • 15. Preparations of insulin  Ultra short acting – Insulin lispro, Insulin Aspart, insulin glusiline  Short acting – Regular insulin  Intermediate acting – NPH & Lente Insulin  Long acting - PZI, Glargine & Detemir  Premixed insulins – NPH & Regular, Lispro & LPL, NPA & Aspart etc.  Lispro protamine/lispro – 50/50, 75/35  Protamine /aspart – 70/30
  • 16. Highly purified insulins  Conventional preparations contain impurities and are more antigenic. So they are purified by different methods like  Gel filtration – single peak insulin  Ion exchange chromatography – highly purified and monocomponent insulin
  • 17. Human insulins  Produced by recombinant DNA technology i.e. proinsulin recombinant bacterial, precurasor yeast recombinant, enzymatic modification of porcine insulin. Human insulin are specially indicated in –  insulin resistance  allergy to conventional preparations  lipodystrophy at injection site  short term use like surgery, trauma, infection, ketoacidosis  preganacy
  • 18. Insulin analogues  Insulin lispro: reversing praline and lysine at 28 and 29 for beta chain. Form hexamers that dissociate very rapidly  Insulin aspart: praline of B 28 is replaced by aspart. So it reduces the aggregation  Insulin glulisine: replace aspargine at B23 by lysine and lysine at B29 by glutamic acid  Insulin glargine: long acting with 2 additional arginine at B chain. It is soluble at acidic pH but precipitates at neutral pH so depot in subcutaneous tissue on injection. It releases slowly and give peakless profile in blood. Given once a day to control fasting blood sugar level  Insulin detemir: it is highly protein bound long acting insulin that dissociate from the binding site slowely. Significantly less weight gain as compared to NPH
  • 19. Insulin degludec: slow release following injection Insulin degludec multi-hexamers Zinc diffuses slowly causing individual hexamers to disassemble, releasing monomers Subcutaneous depot Zn2+ Monomers are absorbed from the depot into the circulation
  • 20. 20 Basal Insulin Prandial Boluses 0hr 24hr BGmg/dl Physiologic Insulin Therapy
  • 22. Pharmacodyn amics of NPH versus Glargine Insulin Lepore, et al. Diabetes 1999; 48 (suppl 1): A97 Bolli et al. The Lancet • Vol 356 • August 5 2000 Plasma glucose Glucose infusion rate
  • 23. Biologic activity over 24- hours more consistent for basal insulin analogs GIR = Glucose Infusion Rate Heise et al. Diabetes 2004; 53 (6): 1614-1620 Insulin detemir
  • 24. 24 Insulin Bolus Dosage  Amount to “cover” food eaten - Usually calculated as 1 unit per x number gms of carbohydrate - For example: 6 units needed to cover 60 gms CHO if using 1 unit per 10 gms CHO (60/10 = 6)  Amount to lower blood sugar to target range - Usually calculated according to sliding scale or correction factor - Sliding scale: give units of insulin for each range of BG - Correction factor: Blood glucose level – target blood glucose/correction factor = units insulin to be given - Ex: BG=150 (actual) minus Target BG (100) = 50 divided by Correction factor (50) = 1 unit insulin needed  Add together to get Insulin Bolus Dosage
  • 25. www.diabetesclinic.ca 25 Two injections/day Blood Glucose (mmols) 8am noon 6pm 2am 4am 8am Time R or H + N in AM R or H + N at Supper 10- 8- 6- 4- 2- 0
  • 26. www.diabetesclinic.ca 26 Three injections/day Blood Glucose (mmols) 8am noon 6pm 2am 4am 8am Time R or H + N in AM R or H at Supper N before bed 10- 8- 6- 4- 2- 0
  • 27. www.diabetesclinic.ca 27 Four injections/day Blood Glucose (mmols) 8am noon 6pm 2am 4am 8am Time R or H at every meal N or U once or twice/day 10- 8- 6- 4- 2- 0
  • 28. www.diabetesclinic.ca28 Continuous Infusion Blood Glucose (mmols) 8am noon 6pm 2am 4am 8am Time 10- 8- 6- 4- 2- 0
  • 29. New insulin delivery devices  insulin syringes, pen devices, inhaled insulin, insulin pumps, implantable pumps, external artificial pancreas, liposomal delivery
  • 30. 30 Insulin Syringes  Sizes – 30, 50, 100 units  Disposable-
  • 31. 31 Insulin Pen: Devices Prefilled pens Reusable (cartridge) pens Auto injectors Dual chamber catridge
  • 32. 32 Insulin Pump Therapy  Based on what body does naturally - Small amounts of insulin all the time (basal insulin) - Extra doses to cover each meal or snack (bolus insulin)  Rapid or Short-Acting Insulin- analogues preferred due to less crystalization in plastic tubes  Precision, and Flexibility
  • 33. 33 What is an Insulin Pump?  Battery operated device about the size of a pager  Reservoir filled with insulin  Computer chip with user control of insulin delivery  Worn 24 hours per day  Delivers one type of insulin  Temporarily disconnected from cannula in place at time of bathing etc. What Pumps Do  Bolus for food intake and to correct high blood glucose levels.  Many pumps will calculate bolus dosages.  Delivers pre-determined amount of basal insulin throughout the day.  Some blood glucose meters communicate with pump.
  • 34. Uses Diabetes mellitus  Indication for insulin therapy are –  OHA failure – it may be primary or secondary  OHA contraindications i.e. pregnancy, hepatic failure, renal failure, stress, allergy to OHA etc.  Metabolic emergencies i.e. DKA, HONK etc.  Overt hyperglycemia i.e. fasting BSL is more than 300 mg % at diagnosis  Underweight patients
  • 35. Insulin requirement of diabetes in children  Stages -  Stage of metabolic recovery -1.5 to 3 u/kg/day – occurs at the time of diagnosis. Very high requirement due to high bsl, high stress hormones and compensatory hyperphagia.  Partial remission or honeymoon phase - drops to 0.3 to 0.5 U/kg/day due to decreased stress, inflammation and glucotoxicity, 1 to 2 unit per day !  Intensification – after 3 to 12 months due to continued beta cell destruction  Total diabetes – usually after 2 years of initial diagnosis  After 8 yrs of age – should inject themselves
  • 36. Insulin in patients doing ramdan fasting paradoxical risk of food excess after the hours of fasting. individualized education improved safety during Ramadan in terms of decreasing hypoglycemic events, improved diabetes control, and prompted weight loss. premixed insulin can be given with the sunset meal and half the usual evening dose to be used with the predawn meal (suhoor) Long-acting insulin-like glargine can be given as a single injection and this can be administered with short-acting insulin or metformin. Before ramadan Fasting 100 to 180 no change in total dose per day
  • 37. Special cases  Diabetes in elderly – many complications, reduced vision and financial constraints, prefer simple regimens, less dose due to ckd and risk of hypo and cognitive dysfunction  Diabetes and pregnancy – requirement increases gradually from 0.7 to 1 unit/ kg till last trimester, split bbf in two portions, start premix at bbf, Regular nph npl, lispro aspart
  • 38.  Quantity for insulin initiation –  0.6 – 0.7 U/ Kg – average dose  1-2 U/kg – obese patients  Fasting BSL/ 10
  • 39. Insulin resistance  When requirement is increased more than 200 U per day insulin resistance is developed. It may be  Acute –  Infection, trauma, surgery, emotional stress, corticosteroids  Ketoacidosis  Chronic –  Chronic diabetics treated for years with animal insulin  IRS1 PC1 K121Q region gene polymorphism Combined therapy approach to type 2 DM
  • 40. Side effects –  Hypoglycemia: most frequent and commonly seen in labile diabetes although can occur in any diabetic. The symptoms are secondary to sympathetic stimulation and neuroglucopenic symptoms in CNS. It is treated by i.v./oral glucose.  Oedema: due to sodium retention but short lived.  Insulin neuritis – osmotic change in nerve fibres, resolve in 1- 2 months  Transient visual disturbances – due to difference in sugar lowerin rate in acqous humor and lens. It get corerected spontaneously with time.  Local reactions (hypertrophy or atrophy): more common with impure insulins  Allergy: more common with impure and animal preparations.  Neutral on CV risk and Carcinogenesis – evidence by ORIGIN trial outcome reduction with initial glargine intervention
  • 41. Drug interactions  Beta blockers prolong hypoglycemia as well as mask the symptoms of hypoglycemia.  Thiazides, CCBs increase the blood sugar level  Acute alcohol decrease the BSL.  Aspirin and lithium may increase the hypoglycemia  Vitamin D improved beta cell function  Pioglitazone and insulin  drugs which decrease insulin requirement  drugs which need increased insulin
  • 42. Upcoming insulins  Reverse split insulin – more lispro/aspart and less NPL  Ultrafast acting analogues – combination of insulin lispro with recombinant human hyaluronidase (rhuPH20)  Glargine U 300 – flatter pharmacokinetic and pharmacodynamic profile  Hepatoselective insulin – LY2605541 –  Insulin lispro with PEG at B28 lysine  17 time less binding to IR and 32 times less binding to IGF as compare to lispro – less mitogenic profile  Half life 24 hrs, duration of action 36 hrs, unaltered in renal disease  Preferential hepatic function-mimic endogenous secretion – raised liver enzyme !!  Idegasp/degludecplus/Rhyzodeg – premixed with
  • 43. Inhalational insulin-Affrezza  Faster absorption  Pfizer marketed in 2006  Mannkind – in 2014 with sanoffi till 2016 than continued alone – prefilled catrige of 4,8 or 12 unit  Alkrems with eli lilly and aradygm with Novonordisk "appears to be as effective, but no better than injected short- acting insulin. The additional cost is so much more that it is unlikely to be cost-effective.“ "failed to gain acceptance among patients and physicians“ – difficult metered dosing, not portable label restriction for patients having asthma, active lung cancer or COPD. May be promoted as add on to oral medications in type 2 Along with basal in type 1
  • 44. Insulin Transdermal Patch H2O2 responsive vesicles integrated with transcutaneous patches for glucose mediated insulin delivery I-port It includes a built-in inserter, which gives quick, virtually painless application. Only a soft flexible tube, called a cannula stays under the skin. Once applied, insulin is injected through the port instead of skin . It is small and discrete, and
  • 45. Transpalntation, Gene therapy, Stem cells  Pancreatic transplantation along with renal transplantation  Islet transplantation – immunosuppressive drugs are different !  Mixed bone marrow chimerism  Costimulatory blockade  Vaccination to make them more tolerant  Porcine insulin producing cell line – but no human  Pancreatic ductal cell to be differentiated as beta cell  Bone marrow derived stem cell transplanted in type 1  Genetically developed human pancreatic beta cell is developed
  • 46. Practical information  Vial can be kept in room temperature  Not to be kept in check in bag – will be ineffective due to freezing  Fastest abdomen/gluteal/bracheal/femoral  Now can be taken without skin pinch due to lesser length of needle  Rotate particular injection in particular region  To reduce pain –inject after spirit is dried and at room temp, change needle  After Giving Insulin -Check site for leakage, Correction doses, Meal/snack doses, Timeliness in relation to eating, Supervision of food amount
  • 47. Thank you Resources  https://www.pharmacychoice.com/article/the-return-of- inhaled-insulin.cfm  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC447715 2/  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC562987 2/  https://www.acs.org/content/acs/en/pressroom/pressp acs/2017/acs-presspac-january-18-2017/toward-a- smart-patch-that-automatically-delivers-insulin-when- needed.html  https://www.medtronicdiabetes.com/products/i-port- advance  G & G, Tripathy, RSSDI text book of Diabetes, Harrsons etc and journals