This presentation gives you an insight to Diabetes and Insulin resitance
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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.
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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
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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
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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
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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.
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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.
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16. Nathan et al. Diabetologia 2006; DOI: 10.1007/s00125-006-0316-2
Ref
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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
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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
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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
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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
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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)
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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
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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.
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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.
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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.
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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
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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
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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
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Leading cause of adult blindness
Results in 2- to 4-fold increase in cardiovascular risk
Nearly double the rates of diagnosed depression
The more fat cells present the greater risk of developing diabetes and cardiovascular disease. Modulating obesity helps with reducing the risk of developing diabetes and cardiovascular disease.
IL-1 – interleukin 1, IL-6 – interleukin 6, TNF – tumor necrosis factor, FFA – free fatty acids, PAI-1 – plasminogen activator inhibitor, RAS – renin angiontensin system.
Even though lifestyle modifications are always beneficial due to their insulin-sensitising properties, the UKPDS demonstrated that adhering to dietary changes alone is rarely sufficient in the long term – almost all patients will eventually require pharmacotherapy to control their glucose levels.1
Even when pharmacotherapy is initiated, it is nonetheless important to continue encouraging lifestyle modifications.
Reference
1. Turner RC et al. JAMA 1999; 281: 2005–2012.
ATP III established an LDL-C goal of <100 mg/dl (2.5 mmol/L) because that goal was as low as could be supported by the clinical trials conducted up to that time. A goal of <100 mg/dl (2.5 mmol/L) was also considered the practical limit that could be achieved with standard statin therapy.8 For example, the ATP III report referred to the limitation of statin therapy recognized in the Rule of 6: each time the dose of a statin is doubled, LDL-C is reduced by only another 6%.21-23
In view of the need for better lipid-lowering therapy to achieve the lower goals now recommended, it has been suggested that combination therapy with agents such as ezetimibe plus a statin is an effective approach to reach goals.9 Ezetimibe coadministered with a statin provides innovative dual inhibition of cholesterol absorption from the intestine (ezetimibe) and cholesterol synthesis in the liver (statin).24 The result is greater lipid lowering versus the statin alone.24
There are two main sources of cholesterol: biosynthesis of cholesterol from the liver and extrahepatic tissues, and absorption of cholesterol in the intestines. The cholesterol pool in the intestines is composed of both dietary and biliary cholesterol, with the biliary cholesterol source being the major contributor.25 Approximately 50% of this intestinal cholesterol pool is absorbed by the intestines and recirculated through the body, whereas the remainder is excreted through the feces.26
Coadministration of ezetimibe with a statin achieves dual inhibition of two sources of cholesterol.19,24 On the one hand, ezetimibe inhibits intestinal absorption of dietary and biliary cholesterol, resulting in decreased delivery of cholesterol to the liver.27 On the other hand, statins inhibit cholesterol biosynthesis.28