© 2013 Eli Lilly and Company Managing insulin therapy in Insulin resistance Speaker name and affiliation Prescribing information is available on the last

© 2013 Eli Lilly and Company

Managing insulin therapy in Insulin resistance

Speaker name and affiliation

Prescribing information is available on the last slide.

© 2013 Eli Lilly and Company

UKDBT01534 September 2013

Company Confidential © 2012 Eli Lilly and Company© 2013 Eli Lilly and Company

Back to Basics

What are the clinical indications for insulin therapy in Type 2 diabetes?

Types of insulin at initiation

– What are the clinical characteristics of a basal pt – What are the clinical characteristics of a mixture patient– How do you determine regime at initiation– Does one size fit all ??– Initial regime is vital .... Wrong insulin wrong time and place..... May

contribute to insulin resistance.

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Back to BasicsWhat does insulin do??

Released 1st acute phase lasts a few minutes followed by a sustained second phrase1

Increases glucose uptake at cell level by transporting glucose across cell membrane1

Decreases Glycogenolysis (Glycogen breakdown)

Decreases gluconeogenisis (production of new glucose)

Decreases lipolysis (fat breakdown)

Insulin binds to cell surface receptor

Insulin has many functions primary function is to lower blood glucose level

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1. Bilous R & Donnelly R 2010, 28:Handbook of diabetes


What is insulin resistance

Defined as early as 19301

Effect on glucose uptake and utilisation that defines insulin resistance1

The development of insulin resistance is seen as the core defect for the development of type 2 diabetes2

Insulin resistance + deficient beta cell function = Type 2 diabetes1

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1. Lebovitz H.E Insulin resistance :definition and consequences: Endocrinology and diabetes 2001 S135 -148 2. Schofield & Sutherland 2012 Disordered insulin secretion in the development of insulin resistance and Type 2 diabetes: Diabetic medicine 2012: 1464


The underlying defects: Insulin resistance and -cell dysfunction

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5. Ramlo-Halsted BA, et al. Prim Care 1999;26:771–789.

Impaired Insulin Production & Secretion

Insulin Resistance (IR)

- Hyperinsulinaemia - Normal Glucose Tolerance

IR + Declining Insulin Levels + Impaired Glucose Tolerance

- Failure of β-Cell to Adapt to IR

Impaired Responsivenessto Insulin

↑FFA Levels

Sedentary Lifestyle

Diet Obesity

Type 2 Diabetes

Glucotoxicity

-Cell Dysfunction

Genetic Predispositions


Pathophysiology of type 2 diabetes involves three core defects and multiple organ systems

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Inzucchi SE. JAMA 2002; 287: 360–372

HYPERGLYCAEMIA

Insulinresistance

1. Peripheral tissues1. Peripheral tissuesDecreased

glucose uptakeIncreased lipolysis

2. LiverIncreased

glucose production

2. LiverIncreased

glucose production

Combined islet cell dysfunction and insulin resistance

3. Pancreatic beta cells

Decreased insulin secretion

Pancreatic alpha cellsExcessive

glucagon secretion

3. Pancreatic beta cells

Decreased insulin secretion

Pancreatic alpha cellsExcessive

glucagon secretion

Islet cell dysfunction


Insulin resistance and insulinhypersecretion precede type 2 diabetes

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Adapted from: Beck-Nielsen H, Groop LC. J Clin Invest 1994; 94: 1714–1721.

Insulin Insulin Macrovascularsecretion resistance disease

- - ++ ++

- +(+) +

+ - + -

+ +

IGT

Impaired glucose

metabolism

Normal glucose metabolism

Type 2 diabetes


What are the clinical characteristics of an insulin resistant patient?

Central obesity1

Insulin dose >1 unit /kg in weight1

Continued hyperglycaemia despite increasing insulin doses1

Weight gain on insulin therapy1

Hypertension2

Hyperlipidaemia (especially triglycerides) 2

Increased cvd risk2

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1. W Crasto et al Insulin U-500 in severe insulin resistance in type 2diabetes mellitus2. G Reaven; Role of Insulin resistance in human disease (syndrome x): An expanded definition.


Potential causes of Insulin resistance

Central obesity/ visceral adiposity1

Genetic abnormalities in insulin action cascade1

Decreased physical activity1

Foetal malnutrition1

Exogenous causes1

– Pregnancy– Cushings – Acromegaly– Polycystic ovaries – Smoking2

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1. Lebovitz H.E Insulin resistance :definition and consequences: Endocrinology and diabetes 2001 S135 -1482. Evans & Krentz: 2000:Insulin resistance and beta cell dysfunction as therapeutic targets in Type 2 diabetes Diabetes. Obesity and Metabolism, 3, 2001 , 219-229 2

leading to increase in counter regulatory hormones


Measuring insulin resistance

HOMA ir All techniques used to measure IR use the relationship between

insulin and glucose uptake and utilisation Homa assessment1

– Steady state beta cell function (expressed % Bcf)– Insulin sensitivity (expressed % sensitvity)

Fasting plasma glucose and fasting plasma insulin

PTS MUST BE OFF EXOGENOUS INSULIN FOR 2 WEEKS

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1. http://www.dtu.ox.ac.uk/homacalculator/


Monitoring Insulin Resistance

• Record progression of doses, weight gain and HbA1C

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Consider concordance with insulin– Check number of pens or cartridges used

Use of discovery sheets– pre and post prandial monitoring

Date Insulin Type and dose

Units/kg HbA1C weight


Treatment of Insulin Resistance in Type 2 diabetes

Lifestyle– Exercise

Insulin sensitivity can be improved by exercise independently from weight reduction and changes in body composition1

– Weight Loss– Consider low carb/low GI diet

to reduce post prandial glucose excursions

– Stop smoking

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Pharmacology

– Metformin2

– Reduces effect of insulin resistance

– Acarbose2

– Acts mainly to reduce post prandial glucose excursion

– Thiazolidinediones2

– Increase insulin sensitivity

– GLP1’S2

– Potential for weight loss

– Optimise insulin, ensure current regime targets problem blood glucose areas

– Pump therapy3

1. Matthaei S et al 2000 21: 585-618 2. Bailey C J Treating insulin resistance in type 2 diabetes with metformin and thiazolidinediones 7:675-691; 2005 3. W Crasto et al Insulin U-500 in severe insulin resistance in type 2diabetes mellitus 2009;85: 219-22


Treatment of Insulin Resistance in Type 2 diabetes cont

Optimise insulin therapy, ensure current regimen targets problem blood glucose areas

Assess pre and post prandial blood glucose levels

Simply increasing current insulin regime may not address poor control or insulin resistance

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Conclusion

The development of insulin resistance is seen as the core defect for the development of type 2 diabetes

Treatment strategies need to address- Carbohydrate intake and load

- Obesity, lack of physical activity, smoking cessation

- Pharmacological interventions to improve insulin sensitivity

- Optimising insulin therapy

- A consideration of pump therapy

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UKDBT01534 September 2013

Documents

© 2013 Eli Lilly and Company Managing insulin therapy in Insulin resistance Speaker name and affiliation Prescribing information is available on the last