mechanisms of type 2 diabetes

Proportion of patients with cardiovascular disease increases with duration of type 2 diabetes Proportion of patients with cardiovascular disease increases with duration of type 2 diabet

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Mechanisms of Type 2 Diabetes

Adapted from Saltiel et al Diabetes 1996; 45:1661-1669.

Receptor + postreceptor

defects

Insulin resistance

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Natural History of Type 2

17 14 20

0 100

200 50 150

Post-prandial glucose

Fasting glucose

Insulin level Years

At risk for diabetes Beta-cell dysfunction

250

R.M Bergenstal, International Diabetes Center

mmol/L

(%)

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Diabetic complications:

1.Diabetic Nephropathy.

2 Diabetic Neuropathy.

3 Diabetic Retinopathy

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Diabetic Nephropathy

end-stage renal disease (ESRD) are

attributed to diabetes

diabetes began treatment for

end-stage renal disease.

public and private funds to treat

patients with kidney failure.

average rates of nephropathy and

kidney disease

Incidence of ESRD Resulting from Primary Diseases (1998)

Other Causes

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Diabetic Neuropathy

have mild to severe forms of nervous

system damage, including:

 Impaired sensation or pain in the feet or

hands

 Slowed digestion of food in the stomach

 Carpal tunnel syndrome

 Other nerve problems

lower-limb amputations in the United States

occur among people with diabetes

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Diabetic Retinopathy

• Diabetic retinopathy is the most common cause of new cases of blindness among adults 20-74 years

of age.

• Each year, between 12,000 to

24,000 people lose their sight because of diabetes.

• During the first two decades of

disease, nearly all patients with type

1 diabetes and over 60% of patients with type 2 diabetes have

retinopathy

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Proportion of patients with cardiovascular disease

increases with duration of type 2 diabetes

Proportion of patients with cardiovascular disease

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Stratton IM, et al UKPDS 35 BMJ 2000; 321:405–412.

UKPDS: the benefits of improved

 Further improvement in sustained glycemic control

and reduction in the burden of cardiovascular

disease are needed

of diabetes-related complications

would reduce the risk of microvascular complications

by 37%, but have less effect (16%) on

macrovascular complications

and reduction in the burden of cardiovascular

disease are needed

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Adapted from Stratton IM, et al UKPDS 35 BMJ 2000; 321:405–412.

UKPDS: decreased risk of diabetes-related complications

associated with a 1% decrease in A1C

UKPDS: decreased risk of diabetes-related complications

associated with a 1% decrease in A1C

21%

**

related death

Diabetes-21% **

All cause mortality

Micro-37%

**

Cataract extraction

19%

Observational analysis from UKPDS study data

†Lower extremity amputation or fatal peripheral vascular disease

*P = 0.035; **P < 0.0001

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The UKPDS demonstrated progressive

decline of -cell function over time

The UKPDS demonstrated progressive

decline of -cell function over time

HOMA model, diet-treated n = 376

Time from diagnosis (years)

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Years T2DM

Proportion of patients with A1C > 7.0

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• Insulin-independent

glucose uptake by muscles

• Increased muscle mass

improves glycemia

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Lifestyle Intervention

targets using lifestyle intervention alone.

 The first step in treating type 2 diabetes

 Nutrition therapy and exercise can improve glycemic control

 Success of lifestyle intervention related to:

 patient’s initial fasting plasma glucose level

 amount of weight loss achieved by patient

 Only a minority of patients are able to attain treatment

targets using lifestyle intervention alone.

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Blood Glucose

Increased insulin secretion

Decrease in hepatic

glucose production

Increase in glucose uptake

Biguanides Thiazolidinediones

Sulfonylureas and CBAs

Thiazolidinediones Biguanides

Alpha-glucosidase

inhibitors

Decreased digestion of complex sugars

Mechanisms of Action of Diabetes Medications

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Alpha-Glucosidase Inhibitors:

Mechanisms of Action

1 Intestine: glucose absorption

2 Muscle and adipose tissue: glucose uptake

glucose

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Biguanides: Mechanisms of Action

1 Intestine: glucose absorption 2 Muscle and adipose tissue:

Biguanides  glucose utilization

Insulin resistance Blood

glucose

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Mechanisms of Action

Muscle and adipose tissue

Pancreas

 demand for insulin secretion

 beta-cell insulin content

Treatment

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Thiazolidinediones:

Mechanism of Insulin Sensitization

Inzucchi, 1999; Yale University, unpublished

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Thiazolidinediones:

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Thiazolidinediones:

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Insulin Secretagogues: Mechanisms of Action

1 Intestine:

glucose absorption

2 Muscle and adipose tissue: glucose uptake

3 Pancreas:

Insulin secretion Sulfonylureas

 insulin secretion

4 Liver: hepatic glucose

output

Insulin resistance Blood

glucose

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– Can cause low sugars

• Carbamoyl Benzoic Acids:

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– Long-acting agents combined

with decreased oral intake:

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Clinical assessment and initiation of nutrition and physical activity

Mild to moderate hyperglycemia (A1C <9.0%)

Overweight (BMI 25 kg/m 2 )

Non-overweight (BMI 25 kg/m 2 )

Add a drug from a different class

Basal and/or preprandial insulin

Add an oral antihyperglycemic agent from a different class of insulin*

Intensify insulin regimen or add

• biguanide

• insulin secretagogue**

• insulin sensitizer*

• alpha-glucosidase inhibitor

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If not at target

• biguanide

1 or 2 † antihyperglycemic agents from different classes

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• biguanide

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• biguanide

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• biguanide

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or

Use insulin alone or in combination with:

Marked hyperglycemia (A1C 9.0%)

2 antihyperglycemic agents from different classes †

• biguanide

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• biguanide

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or

Use insulin alone or in combination with:

Marked hyperglycemia (A1C 9.0%)

2 antihyperglycemic agents from different classes †

• biguanide

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