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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
AVC/MTP/05/22270/1
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.
AVC/MTP/05/22270/1
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
AVC/MTP/05/22270/1
AVC/MTP/05/22270/1
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
AVC/MTP/05/22270/1
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
AVC/MTP/05/22270/1
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
AVC/MTP/05/22270/1
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.
AVC/MTP/05/22270/1
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
AVC/MTP/05/22270/1
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
AVC/MTP/05/22270/1
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
AVC/MTP/05/22270/1
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
AVC/MTP/05/22270/1
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
AVC/MTP/05/22270/1
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