AVC/MTP/05/22270/1

Dr C RajeswaranConsultant Physician, Diabetes ,Obesity& Endocrinology

Director, simplyweight Ltd

www.simplyweight.co.uk

www.thelondonobesityclinic.com

Diabetes and Insulin resistance

AVC/MTP/05/22270/1

AVC/MTP/05/22270/1

Israeli sand rat

AVC/MTP/05/22270/1

AVC/MTP/05/22270/1

AVC/MTP/05/22270/1

Insulin resistance

Insulin secretion

Beta cell function

Beta cell dysfunction in type2 diabetes

Therapeutic implications

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Insulin secretion

Insulin secretion can be divided into basal (postabsorptive) and stimulated (postprandial) states.

Basal state prevails during the interprandial phases and plays a major role during the overnight fast.

Postprandial states regulates glucose metabolism when carbohydrate is abundant and must be disposed of.

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A Constellation of Complications

GastropathGastropathyy

Autonomic Autonomic NeuropathyNeuropathy

Renal Renal DiseaseDisease

Peripheral Peripheral NeuropathyNeuropathy

Retinopathy/ Retinopathy/ Macular Macular

EdemaEdema

HypertensionHypertensionCardiovascular Cardiovascular

DiseaseDisease

DyslipidemiaDyslipidemia

Peripheral Peripheral

Vascular Vascular DiseaseDisease

Erectile Erectile DysfunctionDysfunction

DiabetesDiabetes

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Who develops complications?

Risk of developing complications is variable

Nephropathy-Genetic influence

Macrovascular disease-Duration of DM, glycaemic control, hypertension

Microvascular disease- Smoking, hypertension, lipids and microalbuminuria

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Pathophysiology

Glucotoxicity: Intracellular hyperglycaemia develops in cells that cannot down regulate the uptake of glucose

This stimulates metabolic and haemodynamic abnormalities

Signalling molecules and growth factor are activated with consequent tissue damage

Lipotoxicity

Genetic factors

External accelerators : overproduction of superoxide by the mitochondrial electron transport chain

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Increased Visceral Fat

InsulinResistance

Endothelial Dysfunction

Modified from Caballero AE. Current Diabetes Reports 2004; 4: 237- 246

Visceral Fat, Insulin Resistance and Endothelial Dysfunction

Cytokines, SubstratesHormones

HyperglycemiaHypertensionDyslipidemia

IL1, IL6, TNF- , FFA,, PAI-1, RAS,

leptin, resistin Adiponectin

GenesGenesGenesGenes

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How do I prevent - complications?

Glucose control

DCCT in type 1 diabetes and UKPDS in type 2 diabetes showed that

lower the HbA1C achieved , lower the risk of microvascular

complications

Period of good glycaemic control reduces the risk of complications

for longer than the duration of tight control, a phenomenon known

as METABOLIC MEMORY

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The association between glucose control and cardiovascular disease is less strong but is still important???

UKPDS found a 14% reduction in the risk of MI for each 1% reduction in HbA1C

EDIC( long term follow up of DCCT) CV event risk reduction was 42% lower in the intensively managed group.

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Most patients will not achieve glycaemic control with lifestyle changes alone

Turner RC et al. JAMA 1999; 281: 2005–2012.

0

25

50

75

100

% p

atie

nts

with

HbA

1c >

7%

Years from diagnosis3 6 9

Patients failing with diet alone

75%

91%88%

Normal weight and overweight patients studied

AVC/MTP/05/22270/1Nathan et al. Diabetologia 2006; DOI: 10.1007/s00125-006-0316-2 Ref

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ADA-EASD Hyperglycemia Algorithm

• Metformin therapy should be initiated along with lifestyle modification at diagnosis

• Titrate metformin dosage to maximum effective dose over 1-2 months

• Check A1c every 3 months until <7%; every 6 months thereafter

Step 1: Lifestyle and Metformin

Nathan et al. Diabetologia 2006; DOI: 10.1007/s00125-006-0316-2 Ref

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ADA-EASD Hyperglycemia Algorithm

• Additional medications within 2-3 months if A1c target not achieved:

• Insulin

• Sulfonylureas

• Glitazones

• Choice of agent depends on A1c level (e.g., insulin when A1c >8.5%)

Step 2: Additional Medications

Nathan et al. Diabetologia 2006; DOI: 10.1007/s00125-006-0316-2 Ref

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ADA-EASD Hyperglycemia Algorithm

• Intensify insulin therapy if steps 1 and 2 not efficacious

• Addition of a third oral agent may be considered when A1c close to goal (i.e., <8%)

Step 3: Further Adjustments

Nathan et al. Diabetologia 2006; DOI: 10.1007/s00125-006-0316-2 Ref

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Unmet needs in T2 Diabetes Treatment

Progressive loss of beta-cell function and mass

Inappropriate glucagon secretion

Uncontrolled postprandial hyperglycemia

Possible impaired satiety signals resulting in weight gain

Accelerated gastric emptying

Deficient incretin effect

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Newer insulins

Glitazars

GLP-1

DPP IV inhibitor

Amylin

Rimonobant

Drugs for complications for diabetes

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Lipids

Statins should be prescribed for patient

Over 40

Under 40(who have micro/ macrovascular complications,

hypertension, metabolic syndrome,

or a strong Family History of CVS disease)

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Total cholesterol should be < 4.5 mmol/l

LDL-cholesterol should be < 2.5 mmol/l

Fibrates should be prescribed if triglycerides > 2.3 mmol/l and LDL-C < 2.5 mmol/l

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Limitations in Efficacy of LDL-C–Lowering Therapy

• For every doubling of the statin dose, LDL-C is lowered only by another 6%

Adapted from Grundy SM et al J Am Coll Cardiol 2004;43:2142–2146; Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults Circulation 2002;106:3143–3421; Knopp RH N Engl J Med 1999;341:498–509; Stein E Eur Heart J Suppl 2001;3(Suppl E):E11–E16.

10 20 30 40 50 60

% Reduction in LDL-C

0

–6% –6%

Statin 10 mg 20 mg

40 mg

80 mg

–6%

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Dual Inhibition for Greater Efficacy

Adapted from Shepherd J Eur Heart J Supple 2001;3(Suppl E):E2–E5; Bay H Expert Opin Invest Drugs 2002;11:1587–1604.

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JBS 2 guideline on prevention of CV disease

TC< 4.0 mmol/l and LDL-C < 2.0 mmol/l, or a 25% reduction in TC anda 30% reduction in LDL-C

whichever gets the person to the lowest absolute value.

HDL-C and triglyceride values should also be considered in overall lipid management.

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Blood pressure

BP should be as low as possible (avoiding symptoms of postural hypotension)

Aim for <130/80

OR

<125/75mmHg if

proteinuria present

eGFR< 60ml/min/1.73m2

Presence of CVS disease

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Screening for diabetic nephropathy

Annually, if blood glucose control is stable

Serum creatinine and eGFR

Dipstick early morning urine sample for proteinuria

≥ 2++ <2++

MCR- ♂= ♀Ur Protien:Creat

Yes, repeat twice in 3/12 No, repeat annually

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Indications for referring patients to nephrology

GFR < 45ml/min/1.73m2 (if possible <60ml) or serum 150 micromol/l

eGFR falls > 20% each year.

Presence of nephrotic syndrome

Diagnosis is unclear

BP is uncontrolled

Haemoglobin <10gm/dl

Abnormalities in bone chemistry

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