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Bruce H.R. Wolffenbuttel, MD PhDDept of Endocrinology, UMC Groningenwebsite: www.umcg.net & www.gmed.nl
Twitter: @bhrw
Insulin therapy in various type 1 diabetes patients ‐ workshop
Case no. 1
• Male of 35 years of age• T1DM for over 20 years• Relatively limited microvascular complications
• Uses multiple insulin regimen consisting of insulin glargine and insulin aspart before the main meals
• For his glycaemic control: see the recording made with an iPro (blinded continuous glucose sensor)
• What would be your strategy, and what would be your advice to the patient ?
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Insulin treatment in type 1 diabetes
• Mimic normal physiology
• Normal physiology = 3 main meals Fast‐acting or ultra‐fast‐acting insulin Basal = longacting insulin at bedtime (NPH or analogue)
• Treatment needs to be adjusted the local or country nutritional habits, exercise, etc.
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Goals of treatment
Blood glucose Good Acceptable Poor
Fasting (mmol/l) 4 – 7 7 – 8 > 8
Before the main meals (mmol/l)
4 – 7 7 – 8 > 8
Postprandial (mmol/l) < 9 9 – 10 > 10
At bedtime 7 – 9 9 – 10 > 10
Action profile of current day insulin preparations
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Fast‐acting (normal/regular) insulin
0
10
20
30
40
50
60
70
80
90
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14uren
Actrapid
Humulin regular
Isuhuman Rapid
hours
Ultrafast‐acting insulin
0
10
20
30
40
50
60
70
80
90
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15uren
Insulin aspart
Insulin lispro
Insulin glulisine
hours
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Ultrafast‐acting insulin
• ‘Reconstructed / modified’ insulin: • Insulin lispro, insulin aspart, insulin glulisin
• Faster resorption from the subcutaneous tissue
• But also shorter‐acting, around 4‐5 hours• May be too short when long period between lunch and dinner• Patients may need additional injection with basal insulin,
eventually taking 2 x daily a basal insulin, 3 x fast‐acting insulin before meals
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Insulin profiles
0 60 120 180 240 300 360 420 480Meal Minutes
Endogenous insulinFast‐acting insulinUltrafast‐acting insulin
Insulin (mU/L)
60
50
40
30
20
10
0
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Hypoglycaemic events during treatment with insulin aspart and human insulin
Insulin aspart Human insulin RR (95% CI) P‐valueN /pt‐year N /pt‐year
Minor 1590 35.8 1752 38.2 0.93 (0.87‐1.00) 0.048Major all 38 0.85 51 1.12 0.72 (0.47‐1.09) 0.12night 9 0.80 31 2.70 0.28 (0.13‐0.59) 0.001daytime 29 0.86 20 0.58 1.38 (0.78‐2.45) 0.27
Heller et al. Diab Med 2004;21:769‐75
Self‐monitored blood glucose profiles obtained during the last week of treatment periods
human insulin (■, solid line), insulin aspart (∆, dashed line)
Heller et al. Diab Med 2004;21:769‐75
HbA1c
7.7
7.7
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Longacting insulin (NPH, Neutral Protamine Hagedorn)
0
10
20
30
40
50
60
70
0 2 4 6 8 10 12 14 16 18 20
Humulin NPH
Insulatard
Isuhuman Basal
hours
Twice daily insulin mix
Breakfast Lunch Dinner Bedtime
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Multiple insulin injection regimen
Breakfast Lunch Dinner Bedtime
Long‐acting insulin analogues
• ‘Modified’ insulin: • Insulin glargine, insulin detemir
• Slow and gradual resorption from the subcutaneous tissue
• More comparable action from day to day, less variation, hence less variation of the fasting blood glucose
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Phe Val Asn Gln His
Gly Ile Val Glu Gln Ile
His
Glu
Leu
Cys Asn
Gly Phe Pro Lys
Gly
Arg Arg
Replacement
Added
Insulin glargine (LantusR)
21A‐Gly‐30Ba‐L‐Arg‐30Bb‐L‐Arg humaan insuline(di‐arginyl insuline)
Acid insulin (pH 4.5), will after injection ……..Subsequently gradual uptake into the blood stream
Insulin glargine (LantusR)
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Insulin detemirLysB29(N‐tetradecanoyl)des(B30) human insulin
A-chain S
S
Gly
Val Asn Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Pro LysPhe
Ile Val Glu Gln Cys Cys Thr Ser Ile Leu Tyr Gln Leu Asn Cys AsnTyrGluSerCys
S
1 2 3 4 5 96 7 8 10 11 12 13 14 15 16 17 18 19 2 0 21
B-chain
S
1 2 3 4 5 96 7 8 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29
Mode of action of insulin detemir
resorption
distribution
binding tocells in the body
Insulin pen device
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Where to inject insulin ?
NPH/Long‐acting
(U)short‐acting
• Long‐insuline the upper leg (slower resorption of insulin)
• Mix‐insulines: Morning: in the abdomen Evening: in the leg
• Rotate injection sites• Resorption of insulin is influenced
by temperature, sports/exercise, massage
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Modern insulin treatment with pumps
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Continuous subcutaneous insulin infusion (CSII)
• Advantages• More natural mode of administration of insulin (but still
by subcutaneous route !)
• More predictable resorption of insulin into the blood• Better glycaemic control with less hypoglycaemia
(especially with ultrafast‐acting analogue in pump)
• Smaller chance of severe hypoglycaemia (coma)• More normal living
• Disadvantages• Slightly faster glycaemic derangements / keto‐acidosis• Skin infections
Reasons to start insulin pump treatment
• Achieve better glycaemic control• Repeated and /or severe hypoglycaemia• Pregnancy or desire to become pregnant• Improve insulin sensitivity• The “Dawn” phenomena • Diabetic complications despite reasonable glycaemic control• Variable work / daily activities
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CSII in the DCCT study
• 34% of the patients was using an insulin pump• HbA1c was 0.2 ‐ 0.4% lower in the pump patients
• Comparable number / severity of hypoglycaemia• (remember: this was still in the period before ultrafast‐acting analogues)
• Severe hypo’s: 1 episode per 5.6 patient‐years• Infections: 1 episode per 8.3 patient‐years
Dawn phenomena
• Early morning hyperglycaemia caused by rise of cortisol and other BG‐increasing hormones
• Difficult to correct with long‐acting insulin, pump is perfect as a treatment for this
Somogyi effect
• Reactive hyperglycaemia as a reaction on a nocturnal hypoglycaemia
• Its relevance is still under debate
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Causes of fasting hyperglycaemia
Innovations: the artificial pancreas …
De Vries H. 2014
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Innovations: developments in insulin therapy
Innovations: faster acting insulin analogues
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To pump or not to pump …..Learn to critically review the literature ….
To pump or not to pump ….. Learn to critically review the literature ….
Insulin pen users:were older
were less well educatedhad longer duration of diabetes
had higher bloodpressurehad more cardiovascular disease
but similar HbA1c levels
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