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Diabetes and Insulin resistance
Dr C Rajeswaran
Consultant Physician, Diabetes ,Obesity& Endocrinology
Director, simplywei...
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 implicati...
Insulin secretion

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

Bas...
A Constellation of Complications

Erectile
Dysfunction

Renal
Disease

Peripheral
Vascular
Diabetes

Disease
Gastropathy
D...
AVC/MTP/05/22270/1
Who develops complications?
Risk of developing complications is variable
Nephropathy-Genetic influence

Macrovascular di...
Pathophysiology
Glucotoxicity: Intracellular hyperglycaemia develops in
cells that cannot down regulate the uptake of gluc...
Visceral Fat, Insulin Resistance and Endothelial Dysfunction
IL1, IL6, TNF- α,
FFA,, PAI-1, RAS,
leptin, resistin
Adiponec...
How do I prevent - complications?
Glucose control
DCCT in type 1 diabetes and UKPDS in type 2 diabetes showed that
lower t...
The association between glucose control and
cardiovascular disease is less strong but is still
important???

UKPDS found a...
Most patients will not achieve glycaemic control with lifestyle changes alone

% patients with HbA1c > 7%

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

Ref

AVC/MTP/05/22270/1
ADA-EASD Hyperglycemia Algorithm

Step 1: Lifestyle and Metformin
•

Metformin therapy should be initiated along with life...
ADA-EASD Hyperglycemia Algorithm

Step 2: Additional Medications
•

Additional medications within 2-3 months if A1c target...
ADA-EASD Hyperglycemia Algorithm

Step 3: Further Adjustments
•

Intensify insulin therapy if steps 1 and 2 not efficaciou...
Unmet needs in T2 Diabetes Treatment
Progressive loss of beta-cell function and mass
Inappropriate glucagon secretion
Unco...
Newer insulins
Glitazars
GLP-1
DPP IV inhibitor
Amylin
Rimonobant
Drugs for complications for diabetes
AVC/MTP/05/2...
Lipids
Statins should be prescribed for patient
Over 40
Under 40
(who have micro/ macrovascular complications,
hypertensio...
Total cholesterol should be < 4.5 mmol/l
LDL-cholesterol should be < 2.5 mmol/l
Fibrates should be prescribed if
triglycer...
Limitations in Efficacy of LDL-C–Lowering
Therapy
• For every doubling of the statin dose, LDL-C is
lowered
only by anothe...
Dual Inhibition for Greater Efficacy

Adapted from Shepherd J Eur Heart J Supple 2001;3(Suppl E):E2–E5; Bay H Expert Opin ...
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 and
a 30% redu...
Blood pressure
BP should be as low as possible (avoiding
symptoms of postural hypotension)
Aim for <130/80
OR
<125/75mmHg ...
Screening for diabetic nephropathy
Annually, if blood glucose control is
stable
Serum creatinine and eGFR
Dipstick early m...
Indications for referring patients to nephrology
GFR < 45ml/min/1.73m2 (if possible <60ml) or serum 150 micromol/l
eGFR ...
Thank you!
Visit http://www.simplyweight.co.uk for more information

AVC/MTP/05/22270/1
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Diabetes and Insulin resistance

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Diabetes and Insulin resistance

  1. 1. Diabetes and Insulin resistance Dr C Rajeswaran Consultant Physician, Diabetes ,Obesity& Endocrinology Director, simplyweight Ltd www.simplyweight.co.uk www.thelondonobesityclinic.com AVC/MTP/05/22270/1
  2. 2. AVC/MTP/05/22270/1
  3. 3. Israeli sand rat AVC/MTP/05/22270/1
  4. 4. AVC/MTP/05/22270/1
  5. 5. AVC/MTP/05/22270/1
  6. 6. Insulin resistance Insulin secretion Beta cell function Beta cell dysfunction in type2 diabetes Therapeutic implications AVC/MTP/05/22270/1
  7. 7. 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
  8. 8. A Constellation of Complications Erectile Dysfunction Renal Disease Peripheral Vascular Diabetes Disease Gastropathy Dyslipidemia Cardiovascular Disease Peripheral Neuropathy Retinopathy/ Macular Edema Autonomic Neuropathy Hypertension AVC/MTP/05/22270/1
  9. 9. AVC/MTP/05/22270/1
  10. 10. 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
  11. 11. 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
  12. 12. Visceral Fat, Insulin Resistance and Endothelial Dysfunction IL1, IL6, TNF- α, FFA,, PAI-1, RAS, leptin, resistin Adiponectin Increased Visceral Fat Genes Cytokines, Substrates Hormones Insulin Resistance Hyperglycemia Hypertension Dyslipidemia Genes Endothelial Dysfunction Modified from Caballero AE. Current Diabetes Reports 2004; 4: 237- 246 AVC/MTP/05/22270/1
  13. 13. 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 AVC/MTP/05/22270/1
  14. 14. 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
  15. 15. Most patients will not achieve glycaemic control with lifestyle changes alone % patients with HbA1c > 7% Patients failing with diet alone 100 75 88% 91% 75% 50 25 0 3 6 Years from diagnosis 9 Normal weight and overweight patients studied Turner RC et al. JAMA 1999; 281: 2005–2012. AVC/MTP/05/22270/1
  16. 16. Nathan et al. Diabetologia 2006; DOI: 10.1007/s00125-006-0316-2 Ref AVC/MTP/05/22270/1
  17. 17. ADA-EASD Hyperglycemia Algorithm Step 1: Lifestyle and Metformin • 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 Nathan et al. Diabetologia 2006; DOI: 10.1007/s00125-006-0316-2 Ref AVC/MTP/05/22270/1
  18. 18. ADA-EASD Hyperglycemia Algorithm Step 2: Additional Medications • 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%) Nathan et al. Diabetologia 2006; DOI: 10.1007/s00125-006-0316-2 Ref AVC/MTP/05/22270/1
  19. 19. ADA-EASD Hyperglycemia Algorithm Step 3: Further Adjustments • 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%) Nathan et al. Diabetologia 2006; DOI: 10.1007/s00125-006-0316-2 Ref AVC/MTP/05/22270/1
  20. 20. 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 AVC/MTP/05/22270/1
  21. 21. Newer insulins Glitazars GLP-1 DPP IV inhibitor Amylin Rimonobant Drugs for complications for diabetes AVC/MTP/05/22270/1
  22. 22. 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) AVC/MTP/05/22270/1
  23. 23. 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
  24. 24. Limitations in Efficacy of LDL-C–Lowering Therapy • For every doubling of the statin dose, LDL-C is lowered only by another 6% –6% Statin 10 mg 0 10 20 –6% 20 mg 30 40 40 mg –6% 80 mg 50 60 % Reduction in LDL-C 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. AVC/MTP/05/22270/1
  25. 25. 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. AVC/MTP/05/22270/1
  26. 26. 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 and a 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. AVC/MTP/05/22270/1
  27. 27. 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 AVC/MTP/05/22270/1
  28. 28. Screening for diabetic nephropathy Annually, if blood glucose control is stable Serum creatinine and eGFR Dipstick early morning urine sample for proteinuria ≥ 2++ Ur Protien:Creat Yes, repeat twice in 3/12 <2++ MCR- ♂= ♀ No, repeat annually AVC/MTP/05/22270/1
  29. 29. 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
  30. 30. Thank you! Visit http://www.simplyweight.co.uk for more information AVC/MTP/05/22270/1

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