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INSULIN THERAY IN TYPE 1 DIABETES. دکتر رحیم وکیلی استاد غدد ومتابولیسم کودکان دانشگاه علوم پزشکی مشهد. Goals of management. Glycaemic control. BP. Lipids. Lifestyle (e.g. diet & exercise). Patient education. Management. Microalbuminuria & kidneys. Eye care. Foot care.

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Insulin theray in type 1 diabetes

INSULIN THERAYIN TYPE 1 DIABETES

دکتر رحیم وکیلی

استاد غدد ومتابولیسم کودکان

دانشگاه علوم پزشکی مشهد


Goals of management
Goals of management

Glycaemic control

BP

Lipids

Lifestyle (e.g. diet & exercise)

Patient education

Management

Microalbuminuria & kidneys

Eye care

Foot care

  • Manage symptoms

  • Prevent acute and late complications

  • Improve quality of life

  • Avoid premature diabetes-associated death

  • An individualised approach


Diabetes management principles
Diabetes Management Principles

  • An effective insulin regimen

  • Monitoring of glucose

  • As flexible with food and activity as possible

  • Must remember

    • Young children need routine and rules

    • Young children need to develop autonomy

    • Young children need to explore and experience

    • Young children need to begin to make decisions


Question

What are the glycemic targets for young children?


Glycemic targets glucose values are plasma mg ml
Glycemic TargetsGlucose values are plasma (mg/mL)

Diabetes Care 28:186-212, 2005


Ispad guidelines target indicators of glycaemic control for children adolescents
ISPAD guidelines: Target indicators of glycaemic control for children & adolescents

*Levels recommended for adults shown in square brackets; †AM fasting or pre-prandial; DCCT=Diabetes Control and Complications Trial

SMBG=self-monitored blood glucose; BG=blood glucose; PPBG=post-prandial blood glucose

Rewers M, et al. Pediatr Diabetes 2007;8:408–18.


Question

Can Intensive Management Be Done Safely in

Young Children?


The ideal insulin therapy should mimic endogenous insulin secretion

Plasma glucose profiles

Endogenous insulin secretion

Glucose homeostasis

0.08

0.04

0

8

6

4

2

0

Insulin (U/l)

Plasma glucose (mmol/L)

08.00

13.00

16.00

19.00

Time (hours)

The ideal insulin therapy should mimic endogenous insulin secretion

Owens DR, et al. Lancet 2001;358:739−46.


Insulin management
Insulin management

  • Fixed dose regimens:

    • requires scheduled meals and snacks and is not flexible enough for most young children

  • Basal: bolus regimens:

    • MDI

      • useful only if child is willing to take frequent injections

    • Insulin pumps

      • child must be willing to wear the pump


Insulin terminology
Insulin Terminology

  • Basal insulin

    • Long-acting, all Type 1 and most Type 2 DM patients should have basal insulin whether they are eating or not (insulin glargine, insulin detemir, or NPH)

  • Nutritional or pre-meal / prandial insulin

    • Short-acting insulin given with meals in anticipation of carbohydrate load glycemic spike (scheduled insulin aspart, insulin lispro, insulin glulisine, regular insulin)

  • Correction or supplemental insulin

    • Short-acting insulin given to cover high glucose; if substantial use, it should drive adjustment of basal and nutritional insulins


Approximate pharmacokinetic profiles of human insulin and insulin analoguesHirsch IB. N Engl J Med 2005; 352: 174-83

N.B. Duration of action will vary widely between and within people

NPH = neutal protamine hagedorn/isophane insulin


Rationale for basal bolus therapy
Rationale for basal-bolus therapy insulin analogues

  • Basal-bolus should be the regimen of choice for maintaining overall glycaemic control1

  • An ideal basal insulin

    • Peakless profile, prolonged duration of action

    • Flexible dosing

    • Suppresses hepatic glucose production between meals and overnight1

  • An ideal bolus insulin (a bolus with every meal)

    • Rapid onset and short duration of action

    • Limits postmeal hyperglycaemia1

    • Prevents post-prandial hypoglycaemia2

1. Rosenstock J. Clin Cornerstone 2001;4:50–64.

2. Dave JA, Delport SV. S Afr Family Practice 2006;48:30–6.


Commonly used insulin regimens
Commonly used insulin regimens insulin analogues

  • Basal-bolus insulin regimens

    • 1 long-acting basal + mealtime insulin injections or2 intermediate-acting basal + mealtime insulin injections1,2

  • Pre-mixed insulin regimens

    • 2 or more pre-mixed insulin injections2

  • Continuous subcutaneous insulin infusion (CSII)

    • Continuous (rapid-acting) insulin infusion to meet basal insulin needs + 3 or more mealtime doses2

1. DeWitt DE, Hirsch IB. JAMA 2003;289:2254–64. 2. Rosenstock J. Clin Cornerstone 2001;4:50–64.


Action profile of different basal insulins
Action profile of different basal insulin analoguesinsulins

Peak 4–6 hours

4

NPH

s.c. injection0.3 IU/kg or CSII 0.3 IU/kg/24h

Ultralente

3

Glucose infusion rate (mg/kg/min)

2

CSII Insulin lispro

1

Flat action profile lasting for 24 hours

Insulin glargine

0

16

12

0

4

8

24

20

Time (hours)

Rates of glucose infusion needed to maintain plasma glucose at 130 mg/dL (7.2 mmol/L) after s.c. injection in patients with T1DM (n=20)

Lepore M, et al. Diabetes 2000;49:2142−8.


Activity profiles of glargine and detemir diverge after 12 hours in t1dm patients
Activity profiles of glargine and detemir diverge after 12 hours in T1DM patients

Glargine

Detemir

BG (steady state)

GIR (steady state)

12

2.0

10

1.6

8

1.2

BG (mmol/L)

GIR (mg/kg/min)

6

0.8

4

0.4

2

0

0

0

5

10

15

20

25

30

0

5

10

15

20

25

30

Time (h)

Time (h)

Activity profile of insulin glargine allows once-daily dosing, whereas mostpatients require twice-daily dosing with detemir – particularly T1DM patients

Bock G, et al. Diabetologia 2008;51(Suppl. 1):S390.

GIR = glucose infusion rate


3.0 hours in T1DM patients

2.5

2.0

1.5

1.0

0.5

0.0

-60

0

Meal

60

120

180

240

300

360

420

480

Type 1 Diabetes: Serum Insulin Concentrations Following Subcutaneous Injection of Insulin Lisproor Human Regular

Injection

InsulinLispro (n=10)

Human Regular (n=10)

Serum Insulin Conc. (ng/mL)

Mean + SE

0.2 mU/min/kg insulin infusion

Time (minutes)

Heinemann et al. Diabetic Medicine,13:625-629, 1996


Rapid acting insulin analogues reduce risk of pp hyperglycaemia and late hypoglycaemia
Rapid-acting insulin analogues reduce risk of PP hyperglycaemia and late hypoglycaemia

Meal

80

60

40

20

0

Normal post-prandial values

Regular human insulin (RHI)

Better PPBG

control

Insulin lispro, insulin aspart,

or insulin glulisine

Subcutaneous insulin

Plasma-free insulin (µU/mL)

Lower risk of late

post-prandial hypoglycaemia

0 2 4 6 8 10 12

Time after insulin injection or meal ingestion (hours)

PPBG=post-prandial blood glucose

Bolli GB. Av Diabetol 2007;23:326–32.


Basal bolus treatment program with rapid acting and long acting analogs
Basal/Bolus Treatment Program with Rapid-acting and Long-acting Analogs

Breakfast

Lunch

Dinner

Aspart Aspart Aspart

Lispro Lispro Lispro

Glulysene Glulysine Glulysine

Plasma insulin

Glargine

or

Detemir

4:00

8:00

12:00

16:00

20:00

24:00

4:00

8:00

Time


The ideal insulin therapy should mimic endogenous insulin secretion1

Plasma glucose profiles Long-acting Analogs

Endogenous insulin secretion

Glucose homeostasis

0.08

0.04

0

8

6

4

2

0

Insulin (U/l)

Plasma glucose (mmol/L)

08.00

13.00

16.00

19.00

Time (hours)

The ideal insulin therapy should mimic endogenous insulin secretion

Owens DR, et al. Lancet 2001;358:739−46.


Effectiveness of Postprandial Long-acting AnalogsHumalog in Toddlers Rutledge, Chase, Klingensmith et al Pediatrics 100:968,97

Determine if postprandial rapid-acting insulin effective

Subjects < 5 years old

Results: 2-hour glucose excursions lower with postprandial Humalog compared to preprandial regular

Similar to preprandialHumalog


Outcomes of Pump Therapy Long-acting AnalogsKaufman, et al, Diabetes Metabolism and Reviews,2000 6 month data 130 subjects


Results of insulin pump therapy in young children kaufman et al diabetes spectrum 2001
Results of Insulin Pump Long-acting AnalogsTherapy In Young ChildrenKaufman, et al, Diabetes Spectrum, 2001


Question Long-acting Analogs

Why About the Risk of Hypoglycemia

From Intensive Regimens?


Adverse Long-acting AnalogsEvents in Intensively Treated Children and Adolescents with Type 1Nordfeldt, LudvigssonActaPediatr 88:1184,99

  • 139 Subjects, ages 1-18 yrs on MDI

  • Mean HbA1c 6.9%

  • Severe Hypoglycemia - 0.17 events/pt/yr

    • Decreased from 1-2 injections

    • Correlated with previous severe hypoglycemia r=.38,p<0.0001

  • DKA rate 0.015 events/pt/yr

  • MDI effective and safe


Conclusion ultimate goals of diabetes treatment
Conclusion Long-acting AnalogsUltimate Goals Of Diabetes Treatment

Sustained Normal Blood

Glucose Control

Lowest Possible Incidence of Hypoglycemia

No Long-Term Diabetes

Complications

No Acute Diabetes

Complications

=

=

Best Quality of Life with Diabetes

For the child and your family


Summary
Summary Long-acting Analogs

  • Basal-bolus therapy is the treatment of choice

    • Separate FBG and PPBG control

    • Flexible dosing and timing of injections

  • Insulin glargine and insulin glulisine are an effective combination for basal-bolus therapy

    • Glargine: peakless 24 hour coverage

    • Glulisine: fast onset of action and effective PPBG control

    • As effective in children and adolescents as adults

  • Adding glulisine to basal insulin provided more effective glycaemic control than adding lispro in children and adolescents T1DM patients

    • Particularly in adolescents aged 13–17 years

  • The particularities of adolescents need to be considered when treating T1DM


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