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Targeting the Underlying
Pathophysiology of Type 2 Diabetes
Aim
Provide practical guidance on improving diabetes
care through highlighting the need to:
• understand that insulin resi...
Type 2 diabetes
• Characterized by chronic hyperglycemia
• Associated with microvascular and macrovascular
complications
•...
What is insulin resistance?
• Major defect in individuals with type 2 diabetes 1
• Reduced biological response to insulin1...
What is β-cell dysfunction?
• Major defect in individuals with type 2 diabetes
• Reduced ability of β-cells to secrete ins...
Insulin resistance and β-cell dysfunction
are core defects of type 2 diabetes
Genetic susceptibility,
obesity, Western
lif...
How do insulin resistance and β-cell
dysfunction combine to cause type 2 diabetes?
Normal

IGT*

Type 2 diabetes

Insulin
...
How is insulin resistance measured?
• Several methods exist, including:
– continuous sampling of insulin/glucose1
• gold s...
More than 80% of patients progressing to
type 2 diabetes are insulin resistant
Insulin sensitive;
low insulin secretion (1...
Insulin resistance – reduced response to
circulating insulin
Insulin
resistance

Liver

IR
Adipose
tissue

Muscle

↑ Gluco...
Overall, 75% of patients with
type 2 diabetes die from
cardiovascular disease

Gray RP & Yudkin JS. Cardiovascular disease...
Insulin resistance is as strong a risk factor
for cardiovascular disease as smoking

Odds ratio for incident CVD

1.8
1.6
...
Insulin resistance is closely linked to
cardiovascular disease
Present in > 80% of
people with type 2 diabetes1
Insulin
re...
Insulin resistance is linked to a range of
cardiovascular risk factors
Hyperglycemia
Dyslipidemia
Insulin
resistance

IR

...
~90% of people with
type 2 diabetes are
overweight or obese

World Health Organization, 2005. http://www.who.int/dietphysi...
How is β-cell function measured?
∀ β-cell function is difficult to measure
and most methods are impractical for
large-scal...
Why does the β-cell fail?
Oversecretion of
insulin to compensate
for insulin resistance1,2

Glucotoxicity2

Chronic
hyperg...
Glycemic control declines over time
Diet
Sulfonylurea or insulin

Median HbA1c (%)

9

8

7
6.2% upper limit of normal ran...
Loss of β-cell function occurs before diagnosis

β-cell function (%)

100
80

Up to
50%
loss

Diagnosis

60
40
20
0
-10 -9...
Oral antidiabetic agents – do they
target insulin resistance and
β-cell dysfunction?
Barriers to achieving good glycemic
control
Inadequate targeting of underlying
pathophysiology
Primary sites of action of oral antidiabetic
agents
α-glucosidase
inhibitors

Sulfonylureas/
meglitinides

↓ Carbohydrate
...
The dual action of thiazolidinediones
reduces HbA1c

Insulin
resistance

IR

+

β

β-cell
function

HbA1c

Lebovitz HE, et...
Potential to prevent progression to type 2
diabetes in at-risk women
Troglitazone reduced progression to type 2 diabetes b...
Can thiazolidinediones delay
progression from IGT to T2DM?
Placebo
100

Rosiglitazone 8 mg/day
T2DM
11%

Subjects (%)

80
...
Does decreasing insulin resistance
decrease macrovascular complications?
Sulfonylureas/insulin

Metformin

Myocardial
infa...
12-month combined event rate (%)

Insulin sensitizers reduce cardiovascular
events in type 2 diabetes
60
50
40
30
20
10
0
...
How can diabetes care and outcomes
be improved?
The Global Partnership recommends:
Address the underlying pathophysiology,...
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Ctg underlying pathophysiology

  1. 1. Targeting the Underlying Pathophysiology of Type 2 Diabetes
  2. 2. Aim Provide practical guidance on improving diabetes care through highlighting the need to: • understand that insulin resistance and β-cell dysfunction are core defects of type 2 diabetes • address the underlying pathophysiology
  3. 3. Type 2 diabetes • Characterized by chronic hyperglycemia • Associated with microvascular and macrovascular complications • Generally arises from a combination of insulin resistance and β-cell dysfunction Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Department of Noncommunicable Disease Surveillance, World Health Organization, Geneva 1999. Available at: http://www.diabetes.org.uk/infocentre/carerec/diagnosi.doc
  4. 4. What is insulin resistance? • Major defect in individuals with type 2 diabetes 1 • Reduced biological response to insulin1–3 • Strong predictor of type 2 diabetes4 • Closely associated with obesity5 IR 1 2 American Diabetes Association. Diabetes Care 1998; 21:310–314. Beck-Nielsen H & Groop LC. J Clin Invest 1994; 94:1714–1721. 3Bloomgarden ZT. Clin Ther 1998; 20:216–231. 4 Haffner SM, et al. Circulation 2000; 101:975–980. 5Boden G. Diabetes 1997; 46:3–10.
  5. 5. What is β-cell dysfunction? • Major defect in individuals with type 2 diabetes • Reduced ability of β-cells to secrete insulin in response to hyperglycemia β β β β DeFronzo RA, et al. Diabetes Care 1992; 15:318–354.
  6. 6. Insulin resistance and β-cell dysfunction are core defects of type 2 diabetes Genetic susceptibility, obesity, Western lifestyle Insulin resistance β IR β-cell dysfunction Type 2 diabetes Rhodes CJ & White MF. Eur J Clin Invest 2002; 32 (Suppl. 3):3–13.
  7. 7. How do insulin resistance and β-cell dysfunction combine to cause type 2 diabetes? Normal IGT* Type 2 diabetes Insulin resistance Increased insulin resistance Insulin secretion Hyperinsulinemia, then β-cell failure Postprandial glucose Abnormal glucose tolerance Fasting glucose Hyperglycemia *IGT = impaired glucose tolerance Adapted from Type 2 Diabetes BASICS. International Diabetes Center (IDC), Minneapolis, 2000.
  8. 8. How is insulin resistance measured? • Several methods exist, including: – continuous sampling of insulin/glucose1 • gold standard, but impractical for large-scale use – single measure of insulin/glucose2 • simple estimate from fasting insulin and glucose • useful for assessment on a larger scale 1 Bergman RN, et al. Eur J Clin Invest 2002; 32 (Suppl. 3):35–45. 2 Matthews DR, et al. Diabetologia 1985; 28:412–419.
  9. 9. More than 80% of patients progressing to type 2 diabetes are insulin resistant Insulin sensitive; low insulin secretion (16%) Insulin sensitive; good insulin secretion (1%) Insulin resistant; low insulin secretion (54%) 83% Insulin resistant; good insulin secretion (29%) Haffner SM, et al. Circulation 2000; 101:975–980.
  10. 10. Insulin resistance – reduced response to circulating insulin Insulin resistance Liver IR Adipose tissue Muscle ↑ Glucose output ↓ Glucose uptake ↓ Glucose uptake Hyperglycemia
  11. 11. Overall, 75% of patients with type 2 diabetes die from cardiovascular disease Gray RP & Yudkin JS. Cardiovascular disease in diabetes mellitus. In Textbook of Diabetes 2nd Edition, 1997. Blackwell Sciences.
  12. 12. Insulin resistance is as strong a risk factor for cardiovascular disease as smoking Odds ratio for incident CVD 1.8 1.6 1.4 1.2 1.0 0.8 0.6 Age Smoking Insulin Total cholesterol: HDL cholesterol resistance Bonora E, et al. Diabetes Care 2002; 25:1135–1141.
  13. 13. Insulin resistance is closely linked to cardiovascular disease Present in > 80% of people with type 2 diabetes1 Insulin resistance IR Approximately doubles the risk of a cardiac event2 Implicated in almost half of CHD events in individuals with type 2 diabetes2 1 2 Haffner SM, et al. Circulation 2000; 101:975–980. Strutton D, et al. Am J Man Care 2001; 7:765–773.
  14. 14. Insulin resistance is linked to a range of cardiovascular risk factors Hyperglycemia Dyslipidemia Insulin resistance IR Hypertension Damage to blood vessels Clotting abnormalities Atherosclerosis Inflammation Zimmet P. Trends Cardiovasc Med 2002; 12:354–362.
  15. 15. ~90% of people with type 2 diabetes are overweight or obese World Health Organization, 2005. http://www.who.int/dietphysicalactivity/publications/facts/obesity
  16. 16. How is β-cell function measured? ∀ β-cell function is difficult to measure and most methods are impractical for large-scale use1 • Homeostasis model assessment (HOMA) provides a simple estimate of β-cell function2 • Proinsulin:insulin ratio is sometimes used as a marker of β-cell dysfunction1 1 Matthews DR, et al. Diabetologia 1985; 28:412–419.
  17. 17. Why does the β-cell fail? Oversecretion of insulin to compensate for insulin resistance1,2 Glucotoxicity2 Chronic hyperglycemia Lipotoxicity3 High circulating free fatty acids Pancreas β-cell dysfunction 1 3 Boden G & Shulman GI. Eur J Clin Invest 2002; 32:14–23. 2 Kaiser N, et al. J Pediatr Endocrinol Metab 2003; 16:5–22. Finegood DT & Topp B. Diabetes Obes Metab 2001; 3 (Suppl. 1):S20–S27.
  18. 18. Glycemic control declines over time Diet Sulfonylurea or insulin Median HbA1c (%) 9 8 7 6.2% upper limit of normal range 6 0 0 3 6 9 12 15 Years from randomization UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352:837–853.
  19. 19. Loss of β-cell function occurs before diagnosis β-cell function (%) 100 80 Up to 50% loss Diagnosis 60 40 20 0 -10 -9 -8 -7 1 2 -6 -5 -4 -3 -2 -1 Time from diagnosis (years) 3 4 5 6 Holman RR. Diabetes Res Clin Prac 1998; 40 (Suppl.):S21–S25.
  20. 20. Oral antidiabetic agents – do they target insulin resistance and β-cell dysfunction?
  21. 21. Barriers to achieving good glycemic control Inadequate targeting of underlying pathophysiology
  22. 22. Primary sites of action of oral antidiabetic agents α-glucosidase inhibitors Sulfonylureas/ meglitinides ↓ Carbohydrate breakdown/ absorption ↑ Insulin secretion Biguanides Thiazolidinediones ↓ Glucose output ↓ Insulin resistance ↓ Insulin resistance Kobayashi M. Diabetes Obes Metab 1999; 1 (Suppl. 1):S32–S40. Nattrass M & Bailey CJ. Baillieres Best Pract Res Clin Endocrinol Metab 1999; 13:309–329.
  23. 23. The dual action of thiazolidinediones reduces HbA1c Insulin resistance IR + β β-cell function HbA1c Lebovitz HE, et al. J Clin Endocrinol Metab 2001; 86:280–288.
  24. 24. Potential to prevent progression to type 2 diabetes in at-risk women Troglitazone reduced progression to type 2 diabetes by > 50% Troglitazone* 400 mg/day Proportion with diabetes 0.6 Placebo 0.5 0.4 0.3 0.2 0.1 0.0 0 10 20 30 40 50 60 Time on trial (months) *Troglitazone is no longer available Buchanan TA, et al. Diabetes 2002; 51:2796–2803.
  25. 25. Can thiazolidinediones delay progression from IGT to T2DM? Placebo 100 Rosiglitazone 8 mg/day T2DM 11% Subjects (%) 80 IGT 56% 60 IGT 100% 40 IGT 89% IGT 100% NGT 44% 20 0 Screening Week 12 Screening Week 12 Bennett SM, et al. Diabet Med 2004; 21:415–422.
  26. 26. Does decreasing insulin resistance decrease macrovascular complications? Sulfonylureas/insulin Metformin Myocardial infarction All-cause mortality Myocardial infarction All-cause mortality 21% 8% 39% 36% Not significant Not significant Significant Significant UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352:854–865.
  27. 27. 12-month combined event rate (%) Insulin sensitizers reduce cardiovascular events in type 2 diabetes 60 50 40 30 20 10 0 Non-sensitizers Sensitizers Kao JA, et al. J Am Coll Cardiol 2004; 43:37A.
  28. 28. How can diabetes care and outcomes be improved? The Global Partnership recommends: Address the underlying pathophysiology, including treatment of insulin resistance Del Prato S, et al. Int J Clin Pract 2005; 59:1345–1355.

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