1. Diabetes Mellitus Type 2
Dr. Vinod Sanghi MD

2. Slide 4
Overview of Diagnosed and Undiagnosed Diabetes in the United States—2000
Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion and insulin action. This disease affects approximately 17 million people, or 6.2% of the total population (8.6% of the population aged 20 years or older). Of these people, it is estimated that one out of every three has not been medically diagnosed.
Of the nearly 17 million adults with diabetes, 7.8 million are men and 9.1 million are women. Diabetes prevalence rates are 8.3% for men and 8.9% for women aged 20 years or older.
Approximately 1 million individuals are diagnosed each year with diabetes. By the year 2025, it is estimated that nearly 22 million adults in the United States will have diabetes. Similarly, the number of patients with diabetes worldwide is predicted to increase substantially over this period.
The most common form—type 2 diabetes—accounts for more than 90% of all diagnosed cases, whereas type 1 diabetes accounts for less than 10% of all diagnosed cases. Other forms of diabetes may result from specific genetic syndromes, surgery, drugs, malnutrition, infections, or other illnesses; these account for 1% to 5% of all diagnosed cases.
Approximately 150,000 people under the age of 20 years are estimated to have diabetes, predominantly type 1 diabetes.
Five to 10% of women with gestational diabetes are found to have type 2 diabetes after pregnancy. Women who have had gestational diabetes have a 20% to 50% chance of developing type 2 diabetes in the next 5 to 10 years.
NIDDK. National Diabetes Statistics. Accessed September 8, 2003.
King H, et al. Diabetes Care. 1998;21:
ADA. Diabetes Care. 2003;26:S5-S20. 2

3. Diabetes in India People with Diabetes : 40 million
In 2025 : About 70 million people with diabetes
DIABETES CAPITAL OF THE WORLD

4. Diabetes Major impact on Morbidity & Mortality
Diabetes can lead to :
Coronary heart disease
Diabetic retinopathy
Diabetic neuropathy
Diabetic nephropathy

5. Diabetes Prevalence, 1990-2001 Slide 6
Results of a study that used telephone surveys in states that participated in the Behavioral Risk Factor Surveillance System (BRFSS) between the years 1990 and 1998, and for the year 2001 revealed that the prevalence of diabetes increased from 4.9% in 1990 to 6.5% in 1998 (an increase of 33%), with a further increase to 7.9% in 2001, which represents an increase of 61% from 1990.
The BRFSS is an ongoing telephone survey using self-reported answers to survey questions. Questions may vary by year and state, but all states use the same core questions.
With respect to men and women, prevalence of diabetes in 2001 among men was 6.8% and among women it was 8.9%.
The age-sex-race standardized prevalence of diabetes was reported to be 4.9% in 1990, and it increased by 20%, to 5.9%, in Weight also increased in both sexes during the study period.
Other findings for the period 1990 to 1998 included a 70% increase in the prevalence of diabetes in people aged 30 to 39 years; a 63% increase in people with some college education; a 52% increase in former smokers; and a 47% increase in people with at least a college degree. In addition, increases in prevalence were observed in 35 of the 43 participating states.
Finally, there was an approximately 9% increase in diabetes for every self-reported kilogram of weight gained. The investigators speculate that “this large difference in added risk [for diabetes] imparted by an increase in weight of 1 kg may be explained by the rapid increase in obesity prevalence in the United States.”
Mokdad AH, et al. Diabetes Care. 2000;23:
Mokdad AH, et al. JAMA. 2003;289:76-79.
CDC. Health Risks in the United States: Behavioral Risk Factor Surveillance System. Accessed September 8, 2003. 5

6. Diabetes is increasing in India
Diabetes in India
Fast food
Lack of exercise
Diabetes is increasing in India

7. Estimated Costs of Diabetes in the United States—2002
Slide 10
Estimated Costs of Diabetes in the United States—2002
According to the American Diabetes Association (ADA), diabetes cost the US an estimated $132 billion in excess medical costs and lost productivity in 2002.
Of the $132 billion, $92 billion is direct medical expenditures, including $23 billion for diabetes care, $25 billion for chronic diabetes-related complications, and $44 billion for excess prevalence of general medical conditions due to diabetes. The remaining $40 billion is indirect expenditures attributable to lost workdays ($4.5 billion), restricted activity ($6.3 billion), permanent disability ($7.5 billion), and mortality ($21.6 billion).
Diabetes causes an estimated 88 million disability days and 176,475 person-years of permanent disability annually.
Controlling for age, men with diabetes average 3.1 more lost workdays and 7.9 more bed days per year than men without diabetes.
Women with diabetes average 0.6 more lost workdays and 8.1 more bed days than women without diabetes.
On average, people with diabetes incurred $13,243 in healthcare expenditures in 2002, compared with costs of $2,560 for people without diabetes, a ratio of approximately 5:1. When adjusted to reflect the demographic composition of the population with diabetes, the costs for the population without diabetes was $5,642.
Cost estimates are based on ADA criteria used in earlier ADA cost estimates, comparing healthcare use of patients with and without diabetes, calculated using an etiological fraction. Estimates are based on 12.1 million people with diabetes in 2002.
Study authors caution that costs are likely underestimated, owing to the exclusion of people with undiagnosed diabetes and not calculating for aspects of medical care, such as dental and optometry care, that are used at higher rates by people with diabetes, as well as omission of intangibles such as unpaid caregivers and pain and suffering.
American Diabetes Association. Diabetes Care. 2003;26: Accessed July 2003. 7

8. Slide 8
Prevalence of Diabetes* in the United States According to Age and Sex—2000
An estimated 16.9 million adults aged 20 years or older and 151,000 children and adolescents in the United States have diagnosed or undiagnosed diabetes. The prevalence of diabetes in these two age groups is 8.6% and 0.2%, respectively.
The total adult population with diabetes has increased from 1997 figures of million and 8.2%.
Diabetes is most prevalent in adults older than 65 years; it has increased from 6.3 million cases (18.4%) in 1997 to 7 million and 20.1% of that population.
Diabetes prevalence in men has risen from 7.5 million (8.2%) to 7.8 million (8.3%).
The increase is more dramatic in women, with total cases rising from 8.1 million to 9.1 million, an increase from 8.2% to 8.9%.
Type 2 diabetes is increasingly prevalent among adolescents particularly in minority populations. It is estimated that approximately 30% of newly diagnosed cases of diabetes among Native North American adolescents are type 2 diabetes.
NIDDK. National Diabetes Statistics. Accessed September 8, 2003.
NIDDK. National Diabetes Statistics. Accessed July 19, 2000.
Rosenbloom AL, et al. Diabetes Care. 1999;22: 8

9. Estimated Prevalence of Diabetes in Global Adult Population—1995-2025
Slide 17
Estimated Prevalence of Diabetes in Global Adult Population—
In 1995, an estimated 135 million adults worldwide had diabetes; 51 million in developed countries and 84 million in developing countries. (According to United Nations definitions, “developed” countries comprise Europe, North America, Australia, New Zealand, and Japan. All other countries are termed “developing” countries.)
By 2025, diabetes prevalence will more than double to 300 million adults, 228 million of them in developing countries—a 170% increase in 30 years. Developed countries will see an increase of 42%, to 72 million adults with diabetes.
Diabetes prevalence in developing countries comprised 62% of the total in 1995; that percentage will rise to more than 75% by 2025.
In developing countries, the majority of people with diabetes are aged 45 to 64 years; it is projected that that age group will remain the majority in 2025.
The majority of people in developed nations with diabetes are aged 65 years or older, a trend that is expected to grow by 2025.
The study’s authors caution that some of the data from developing nations is based on surveys from the 1980s; hence, the diabetes prevalence in the developing world may be underestimated.
King H, et al. Diabetes Care. 1998;21: 9

10. DCCT: Effects of Intensive vs Conventional Glycemic Control
Slide 102
DCCT: Effects of Intensive vs Conventional Glycemic Control
The Diabetes Control and Complications Trial (DCCT) asked the question, “Do efforts to control blood glucose impact the development or progression of the long-term complications of diabetes?”
In this prospective, randomized, multicenter study involving 1,441 patients with type 1 diabetes followed for 6½ years, the effects of intensive insulin therapy vs conventional insulin therapy on early microvascular and neurologic complications were compared. Intensively treated patients received either insulin pump therapy or three or more injections of insulin daily. Adjustments in treatment were determined by the results of frequent home blood glucose monitoring.
A1C levels reached a nadir in the intensively treated group in 6 months. The difference in the average A1C between the two groups was statistically significant (P<0.001) and was maintained after baseline (average, 9.1% and 7.2% for the conventional and intensive therapy groups, respectively).
This slide summarizes the effects of improved blood glucose control on retinopathy, nephropathy, and neuropathy. Intensive therapy reduced the risk for:
development of retinopathy by 63% (P<=0.002; 95% confidence interval [CI], 52% to 71%)
nephropathy, determined by albuminuria (excretion rate >=300 mg/24 hr), by 54% (P<0.04; 95% CI, 19% to 74%)
clinical neuropathy by 60% (P<=0.002; 95% CI, 38% to 74%).
Diabetes Control and Complications Trial Research Group. N Engl J Med ;329:
Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. N Engl J Med. 2000;342: 10

11. Slide 104
UKPDS: Design
This multicenter, randomized, controlled trial sought to determine whether:
intensive glycemic control (study goal: fasting plasma glucose [FPG] <108 mg/dL) reduces the risk of microvascular and macrovascular complications of type 2 diabetes
sulfonylurea, metformin (in obese patients), or insulin has specific advantages or disadvantages
tight blood pressure control (<150/85 mm Hg) reduces the risk of complications
tight blood pressure control with an ACE inhibitor or a beta-blocker has specific advantages in preventing the microvascular and macrovascular complications of diabetes.
Of the 7,616 patients referred to the UKPDS, 5,102 were enrolled in a 3-month dietary run-in phase during which they followed a diet that was low in saturated fats, was of moderately high fiber, and that derived 50% of calories from carbohydrates. The other 2,514 patients were excluded from the study.
After completion of the dietary phase, 744 patients were excluded because their FPG was >270 mg/dL and an additional 149 were excluded because of FPG levels that were <=108 mg/dL. The remaining patients (4,209) were stratified by ideal body weight and randomized to conventional or intensive treatment.
Conventional treatment consisted of initial dietary therapy only, with a goal FPG of <270 mg/dL. If the goal was not met, subjects were randomized to receive a sulfonylurea, insulin, or metformin. The FPG goal remained the same.
Intensive treatment consisted of a sulfonylurea (either chlorpropamide, glibenclamide, or glipizide) or insulin, with a goal of maintaining FPG <108 mg/dL. Intensive metformin therapy was an additional treatment option for overweight patients.
In the intensive treatment group, combination therapy was initiated when glycemic goals were not achieved with monotherapy. For those patients who had been receiving a sulfonylurea, metformin or insulin was added; metformin-treated patients had a sulfonylurea added if the glycemic goal was not met; and insulin was substituted for a sulfonylurea if necessary to achieve the glycemic goal.
Aggregate endpoints included:
any diabetes-related clinical endpoint (sudden death, death from hyperglycemia or hypoglycemia, fatal or nonfatal MI, angina, heart failure, stroke, renal failure, amputation of at least one digit, vitreous hemorrhage, retinal photocoagulation, blindness in an eye, or cataract extraction)
diabetes-related death (death from an MI, stroke, peripheral vascular disease (PVD), renal disease, hyperglycemia or hypoglycemia, or sudden death)
all-cause mortality.
UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352: 11

12. UKPDS: Effects of Intensive (Sulfonylurea/Insulin) Treatment
Slide 105
UKPDS: Effects of Intensive (Sulfonylurea/Insulin) Treatment
Patients were followed for 10 years and median A1C levels were 7% in the intensively treated patients vs 7.9% in those who received conventional treatment. No differences in A1C levels were observed in individual therapies.
Significant reductions were observed in diabetes complications in the intensively treated groups compared with the conventionally treated group.
There was a reduction of 16% in MI in the intensive treatment group, which approached statistical significance (P=0.052).
Analysis of the data revealed that any reduction in A1C level is predictive of benefit to patients with type 2 diabetes.
American Diabetes Association. Diabetes Care. 1999;22(suppl 1):S27-S31.
UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352: 12

13. UKPDS: Effects of Intensive (Metformin) Treatment*
Slide 106
UKPDS: Effects of Intensive (Metformin) Treatment*
Of the 1,704 overweight patients in the study, 342 were randomized to intensive therapy with metformin.
Patients in whom glycemic goals were not met with intensive monotherapy received combination therapy. In sulfonylurea-treated patients either metformin or insulin was added and in metformin-treated patients a sulfonylurea was added; if the glycemic goal was still not met, insulin was substituted for the sulfonylurea.
The aggregate endpoints for metformin-treated patients were:
any diabetes-related clinical endpoint (sudden death, death from hyperglycemia or hypoglycemia, fatal or nonfatal MI, angina, heart failure, stroke, renal failure, amputation of at least one digit, vitreous hemorrhage, retinopathy requiring photocoagulation, blindness in an eye, or cataract extraction)
diabetes-related mortality (death from MI, stroke, PVD, renal disease, hyperglycemia or hypoglycemia, or sudden death)
all-cause mortality.
To determine the effect of intensive treatment on vascular disease, secondary outcomes analysis included:
MI (both fatal and nonfatal and sudden death)
stroke (both fatal and nonfatal)
amputation of at least one digit or death from PVD
microvascular complications (retinopathy necessitating photocoagulation, vitreous hemorrhage, fatal and nonfatal renal failure).
Intensive metformin therapy significantly reduced any diabetes-related endpoint by 32% (P=0.0023); diabetes-related mortality by 42% (P=0.017); all-cause mortality by 36% (P=0.011); and MI by 39% (P=0.01).
UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:
American Diabetes Association. Diabetes Care. 1999;22(suppl 1):S27-S31. 13

14. UKPDS: Risk Reduction in Diabetes- Related Complications (A1C)
Slide 109
UKPDS: Risk Reduction in Diabetes- Related Complications (A1C)
Glycemic exposure over time for each individual was determined from the updated mean of measurements of A1C made each year during follow-up. For each 1% decline in updated A1C, the reduction in risk for microvascular complications and amputation or death from peripheral vascular disease was the greatest. Risk for microvascular disease declined by 37% (95% CI, 33% to 41%; P<0.0001), and risk for amputation or death from peripheral vascular disease decreased by 43% (95% CI, 31% to 53%; P<0.0001).
In comparison, risk for MI declined by 14% (95% CI, 8% to 21%; P<0.0001); risk for stroke decreased by 12% (95% CI, 1% to 21%; P=0.035); and risk for heart failure decreased by 16% (95% CI, 3% to 26%; P=0.016). In addition, risk for cataract extraction decreased by 19% (95% CI, 11% to 26%; P<0.0001) for each 1% reduction in updated A1C. Notably, there was no indication of an updated A1C threshold for any complication below which risk no longer decreased or a level above which risk no longer increased.
This prospective observational study demonstrates that risk for diabetic complications is strongly associated with previous hyperglycemia. Moreover, the results show that any reduction in A1C is likely to reduce the risk for both microvascular and macrovascular complications. The lowest risk is associated with A1C values in the normal range (<6%).
Stratton IM, et al. BMJ. 2000;321: 14

15. UKPDS: Effects of Tight vs Less-Tight Blood Pressure Control
Slide 117
UKPDS: Effects of Tight vs Less-Tight Blood Pressure Control
The UKPDS also investigated the effects of blood pressure control on the prevention of complications of diabetes. One thousand one hundred forty-eight (1,148) of the randomized (4,297) patients had hypertension (mean BP160/94 mm Hg).
Patients were randomized to either an ACE inhibitor or a beta-blocker to achieve either tight BP control (<150/85 mm Hg) or less tight control (180/105 mm Hg), with avoidance of treatment with ACE inhibitors or beta-blockers. However, medications were permitted in each group if required to achieve or maintain goals.
Mean BP was reduced significantly during the follow-up period (median 8.4 years) in the tight control group compared with the less tight control group, with mean BP of 144/82 mm Hg and 154/87 mm Hg, respectively. However, after 9 years of follow-up, three or more medications were required in the tight control group to sustain goal BP.
Statistically significant reductions in both microvascular and macrovascular complications were observed in the tight control group vs the less tight control group. These reductions are illustrated on this slide. It should be noted that a reduction (not shown here) in all-cause mortality did not reach statistical significance.
The investigators also found that the studied ACE inhibitor and beta-blocker were equally safe and effective.
UK Prospective Diabetes Study Group. BMJ. 1998;317:
UK Prospective Diabetes Study Group. BMJ. 1998;317: 15

16. The 4S Diabetes Substudy
Slide 111
This multicenter, double-blind, controlled study included 4,444 patients with CHD who were randomized to simvastatin treatment or placebo and followed for a median of 5.4 years.
Two hundred two (202) of the 4,444 patients had diabetes.
The primary endpoint of this study was mortality from all causes and the secondary endpoint was major CHD events.
Simvastatin reduced risk of mortality from all causes by 43% (relative risk=0.57; P=0.087) in patients with diabetes; the reduction in risk did not achieve statistical significance because of the small sample size.
In patients with diabetes, simvastatin significantly reduced the risk of a major CHD event by 55% (relative risk=0.45; P=0.002) and significantly reduced the risk of any atherosclerotic event by 37% (relative risk=0.63; P=0.018).
The risk reduction by treatment with simvastatin was not dependent on baseline level of total cholesterol, LDL-C, HDL-C, or TGs. However, there was a trend for a greater treatment effect among patients with diabetes who were either in the lower half of the HDL-C distribution (<42.54 mg/dL) or in the upper half of the TG distribution (>= mg/dL).
Pyörälä K, et al. Diabetes Care. 1997;20: 16

17. Slide 112
The CARE Trial: Reduction of Coronary Events in Subjects With and Without Diabetes
The Cholesterol and Recurrent Events (CARE) trial was a 5-year study that compared the effects of pravastatin and placebo in 4,159 patients with known CHD and average cholesterol levels. Five hundred eighty-six (586) of the patients had diabetes.
The primary endpoint of the trial was the combination of death from CHD plus nonfatal MI. Average duration of follow-up was 5 years. An expanded endpoint was defined as the primary endpoint, bypass surgery (CABG), or angioplasty (PTCA), and it was used for subgroup analysis.
The mean baseline lipid concentrations in the group with diabetes (LDL-C 136 mg/dL; HDL-C 38 mg/dL; and triglycerides 164 mg/dL) were similar to those in the group without diabetes.
Patients with diabetes who received pravastatin had a 25% reduction in risk of coronary events, including CHD death, nonfatal MI, CABG, and PTCA, compared with patients who received placebo (P=0.05). A similar reduction in risk was seen in the group without diabetes. Adjustment for age and sex did not affect the magnitude of the risk reduction.
Goldberg RB, et al. Circulation. 1998;98: 17

18. Evidence Supporting Multiple Risk Factor Reduction
Slide 121
Evidence Supporting Multiple Risk Factor Reduction 18

19. Slide 122
Multifactorial Intervention in Patients With Type 2 Diabetes: Steno-2 Study—Design
Danish researchers conducted a randomized, open, parallel study comparing the effect of a targeted, intensified, multifactorial intervention versus conventional intervention on modifiable risk factors for cardiovascular disease in patients with type 2 diabetes and microalbuminuria.
Mean follow-up: 7.8 years.
Primary endpoint was a composite of death from cardiovascular causes, nonfatal stroke, nonfatal myocardial infarction, revascularization, and amputation as a result of ischemia.
Secondary endpoints consisted of indicators of microvascular disease, including incidence of diabetic nephropathy and/or the development or progression of diabetic retinopathy or neuropathy.
Gæde P, et al. N Engl J Med. 2003;348: 19

20. Slide 126
Multifactorial Intervention in Patients With Type 2 Diabetes: Steno-2 Study—Treatment Goals
In the Steno-2 Study, significantly more patients who received intensive, target-driven treatment aimed at multiple risk factors achieved the intensive-treatment goals than did patients who received conventional treatment. Intensive-treatment goals included A1C <6.5%, fasting total cholesterol <175 mg/dL, fasting triglycerides <150 mg/dL, and blood pressure <130/80 mm Hg.
Conventional treatment was completed by 63 patients, while 67 patients completed intensive treatment, which consisted of stepped administration of behavior modification (diet, exercise) and pharmacologic treatment that targeted hyperglycemia (oral hypoglycemic agents, insulin), hypertension (angiotensin-converting enzyme [ACE] inhibitors, angiotensin II-receptor blockers [ARBs], diuretics, calcium-channel blockers, beta-blockers), dyslipidemia (statins, fibrates), microalbuminuria, and cardiovascular risk (aspirin). All intensive-treatment patients were treated with an ACE inhibitor or ARB irrespective of blood pressure and aspirin. Mean age of all patients in the study was 55 years and mean follow-up was 7.8 years.
In addition to the outcomes shown on this slide, fasting plasma glucose levels and urinary albumin excretion rates were significantly better in the intensively treated group than in the conventionally treated group (P<0.001 and P=0.007, respectively). Changes in diet and exercise were moderate in both groups—only intake of carbohydrate and fat was significantly improved in the intensively treated group.
Gæde P, et al. N Engl J Med. 2003;348: 20

21. Slide 125
Multifactorial Intervention in Patients With Type 2 Diabetes: Steno-2 Study—CV Events
In the Steno-2 Study, an intensive, target-driven treatment aimed at multiple risk factors reduced the risk of cardiovascular (CV) events by 47% in patients with type 2 diabetes and microalbuminuria.
This slide shows Kaplan-Meier estimates of the composite study endpoint, which consisted of nonfatal myocardial infarction, death from CV causes, coronary artery bypass grafting, percutaneous coronary intervention, nonfatal stroke, amputation, and surgery for peripheral atherosclerotic artery disease. There were 118 CV events during follow-up: 85 events in 35 conventionally treated patients and 33 events in 19 intensively treated patients, for a risk reduction of 47%. The divergence of the curves suggests that continued intensive therapy may have resulted in an even better prognosis.
A course of conventional treatment was completed by 63 patients while 67 patients completed intensive treatment, which consisted of stepped administration of behavior modification (diet, exercise) and pharmacologic therapy that targeted hyperglycemia (oral hypoglycemic agents, insulin), hypertension (angiotensin-converting enzyme inhibitors, angiotensin II-receptor blockers, diuretics, calcium-channel blockers, beta-blockers), dyslipidemia (statins, fibrates), microalbuminuria, and CV risk (aspirin). Mean age of all patients in the study was 55 years and mean follow-up was 7.8 years.
Gæde P, et al. N Engl J Med. 2003;348: 21

22. Pathophysiology of Type 2 Diabetes and Insulin Resistance
Slide 20
Pathophysiology of Type 2 Diabetes and Insulin Resistance 22

23. Insulin Resistance Slide 21
Insulin resistance is a primary defect in type 2 diabetes. As reported in a recent study by Haffner and colleagues, 92% of patients with type 2 diabetes have insulin resistance. It can be defined as an impaired response to the physiological effects of insulin, including those on glucose, lipid, and protein metabolism, and the effects on vascular endothelial function.
Haffner SM, et al. Diabetes Care. 1999;22:
Consensus Development Conference of the American Diabetes Association. Diabetes Care. 1998;21: 23

24. Natural History of Type 2 Diabetes
Slide 22
Natural History of Type 2 Diabetes
Before the manifestation of the metabolic defects that lead to type 2 diabetes, fasting and postprandial insulin levels are similar and constant. In the majority of patients in whom type 2 diabetes develops, increasing insulin resistance leads to compensatory increases in circulating insulin, which prevents an increase in glucose levels.
As time progresses, the insulin resistance reaches a peak and stabilizes, while the compensatory increase in insulin continues to prevent fasting glucose levels from becoming abnormal.
However, at some point, either because of early beta-cell dysfunction or because of a natural limit of beta-cell capacity, challenge of this delicate balance with a glucose load may demonstrate that, although fasting glucose levels remain normal, postprandial glucose levels become abnormal as a limitation in insulin response is reached.
Following the onset of beta-cell dysfunction, insulin levels can no longer keep up in overcoming the insulin resistance, and fasting and postprandial glucose levels increase progressively over time. 24

25. Development of Type 2 Diabetes
Slide 23
Development of Type 2 Diabetes
Insulin resistance and impaired beta-cell function are primary defects that occur early in the course of development of type 2 diabetes. Insulin resistance leads to an obligatory hyperinsulinemia in order to maintain normal glucose tolerance.
In most cases of type 2 diabetes, beta-cell dysfunction develops subsequent to the development of insulin resistance, and it is not until such beta-cell dysfunction develops that any abnormality in glucose tolerance is seen.
The condition that results is termed impaired glucose tolerance (IGT). In some cases beta-cell dysfunction may develop in the absence of early insulin resistance. However, exposure of tissues to hyperglycemia in the face of beta-cell dysfunction increases resistance to the effects of insulin whether or not insulin resistance was present to begin with.
Ultimately, type 2 diabetes is the result of worsening beta-cell function, either in the most common situation of chronic pre-existing insulin resistance or, in the less common scenario of decreased beta-cell function without pre-existing insulin resistance.
Saltiel A, Olefsky JM. Diabetes. 1996;45: 25

26. Slide 26
Hyperglycemia in Type 2 Diabetes Results From Three Major Metabolic Defects
Three major metabolic defects contribute to hyperglycemia in patients with type 2 diabetes: increased hepatic glucose production, impaired pancreatic insulin secretion, and peripheral tissue insulin resistance.
After eating a meal or ingesting glucose, insulin is secreted, hepatic glucose output is suppressed, and insulin-dependent glucose uptake by peripheral tissues is stimulated. In type 2 diabetes, insulin resistance and impaired insulin secretion inhibit normal suppression of hepatic glucose output. As a consequence, the liver continues to release glucose into the circulation. Moreover, peripheral insulin resistance coupled with insufficient insulin results in decreased uptake of glucose by insulin-dependent target tissues, notably skeletal muscle and adipose tissue. These mechanisms contribute to postprandial hyperglycemia in type 2 diabetes.
In type 2 diabetes, increased hepatic glucose production is the primary factor responsible for the fasting hyperglycemia. Moreover, in patients with type 2 diabetes, fasting blood glucose levels correlate strongly with rates of hepatic glucose output. In the setting of peripheral insulin resistance, insulin-mediated glucose uptake cannot accommodate the increased hepatic glucose output and rise in fasting glucose levels.
Kruszynska YT, et al. J Invest Med. 1996;44:
Henry RR. Ann Intern Med. 1996;124: 26

27. Insulin Resistance: Associated Conditions
Slide 32
Insulin Resistance: Associated Conditions
In addition to type 2 diabetes, insulin resistance is associated with the development of a broad spectrum of clinical conditions. These include hypertension, atherosclerosis, dyslipidemia, decreased fibrinolytic activity, impaired glucose tolerance, acanthosis nigricans, hyperuricemia, polycystic ovary disease, and obesity.
Adapted from Consensus Development Conference of the
American Diabetes Association. Diabetes Care. 1998;21: 27

28. Standards of Care for Glycemia, Lipids, and Hypertension
Slide 66
Standards of Care for Glycemia, Lipids, and Hypertension
The following series of slides is based on the Clinical Practice Recommendations of the American Diabetes Association (ADA). 28

29. 2003 ADA Recommendations for Glycemic Control in Type 2 Diabetes
Slide 67
2003 ADA Recommendations for Glycemic Control in Type 2 Diabetes
The ADA recommendations for glycemic control in patients with type 2 diabetes are shown on this slide. These goals are recommended for most patients with type 2 diabetes. Certain populations, such as children, pregnant women, the elderly, and those with comorbid conditions, require special consideration.
For patients who achieve fasting and preprandial glucose but not A1C goals, monitoring of postprandial plasma glucose should be considered 1 to 2 hours after the start of a meal. Treatment to reduce postprandial levels to <180 mg/dL may lower A1C.
American Diabetes Association. Diabetes Care. 2003;26(suppl 1):S33-S50. 29

30. 2003 ADA Lipid Targets in Type 2 Diabetes
Slide 69
2003 ADA Lipid Targets in Type 2 Diabetes
The primary goal of lipid management in adults is to lower LDL-C levels to <100 mg/dL. Lowering LDL-C levels is associated with a reduction in cardiovascular (CV) events.
Triglyceride (TG) levels should be reduced to <150 mg/dL, and HDL-C levels should be increased to >40 mg/dL in men and >50 mg/dL in women. Reducing TG and raising HDL-C levels are associated with a reduction in CV events.
Lipid levels should be measured at least once per year in adult patients. However, values may be measured every 2 years in adults with low-risk lipid values, which include an LDL-C <100 mg/dL, an HDL-C >60 mg/dL, and TG <150 mg/dL.
American Diabetes Association. Diabetes Care. 2003;26(suppl 1):S33-S50. 30

31. 2003 ADA Treatment Recommendations for Hypertension and Nephropathy
Slide 73
2003 ADA Treatment Recommendations for Hypertension and Nephropathy
In addition to being the earliest manifestation of nephropathy, albuminuria is a marker for cardiovascular morbidity and mortality. In order to reduce and/or delay the progression of nephropathy, optimization of glucose and blood pressure control is recommended by the ADA.
Data from the DCCT and UKPDS have definitively shown that intensive therapy for diabetes can significantly reduce the risk of the development of microalbuminuria and overt nephropathy in patients with diabetes.
Use of ACE inhibitors or ARBs is indicated for all patients with microalbuminuria or advanced states of nephropathy.
In hypertensive patients with diabetes and microalbuminuria, ACE inhibitors and ARBs have been shown to delay the progression to macroalbuminuria.
ARBs have been shown to delay the progression of nephropathy in patients with type 2 diabetes, hypertension, macroalbuminuria, and renal insufficiency (serum creatinine >1.5 mg/dL).
In patients unable to tolerate ACE inhibitors or ARBs, consider using a beta-blocker or nondihydropyridine calcium channel blocker.
If ACE inhibitors or ARBs are used, monitor serum potassium levels for the development of hyperkalemia. American Diabetes Association. Diabetes Care. 2003;26(suppl 1):S94-S98. 31

32. NCEP: Diabetes as CHD Risk Equivalent
Slide 76
NCEP: Diabetes as CHD Risk Equivalent
NCEP (ATP III) recognizes that the highest CHD risk is associated with CHD or CHD risk equivalents. These CHD risk equivalents include diabetes and non-CHD vascular disease, including peripheral arterial disease, abdominal aortic aneurysm, and symptomatic carotid artery disease. These carry the same 10-year risk of major CHD events as established CHD (ie, >20%). For example, in more than 20 of 100 people with CHD risk equivalents, CHD will develop or a recurrent CHD event will ensue within 10 years.
People with >=2 CHD risk factors who have a 10-year CHD risk >20% in the CHD risk equivalent category are also included in ATP III.
Diabetes, which is associated with multiple risk factors, is a CHD risk equivalent because it confers a high risk of new CHD within 10 years. Patients with diabetes who experience an MI have an unusually high death rate either immediately or in the long-term. Therefore, a more intensive prevention strategy is warranted in these patients.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285: 32

33. NCEP: Metabolic Syndrome
Slide 79
NCEP: Metabolic Syndrome
The NCEP (ATP III) guidelines designate metabolic syndrome as a secondary target for risk reduction after the primary LDL-C target of <100 mg/dL has been achieved. Of note, the close association between metabolic syndrome and insulin resistance is recognized by ATP III.
People with metabolic syndrome have a constellation of major risk factors, life-habit risk factors, and emerging risk factors. Characteristic of the metabolic syndrome are abdominal obesity, atherogenic dyslipidemia (elevated TG, small, dense LDL particles, and low HDL-C), elevated blood pressure, insulin resistance (with or without glucose intolerance), and prothrombotic and proinflammatory states.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285: 33

34. NCEP: Clinical Identification of the Metabolic Syndrome*
Slide 80
NCEP: Clinical Identification of the Metabolic Syndrome*
(Indian : >35in)
(Indian : >30in)
According to NCEP (ATP III), diagnosis of metabolic syndrome can be made in the presence of >=3 risk factors.
The risk factors include abdominal obesity, TG >=150 mg/dL, low HDL-C (<40 mg/dL for men and <50 mg/dL for women), blood pressure >=130/>=85 mm Hg, and fasting glucose >=110 mg/dL. According to ADA recommendations, the target level for blood pressure is <130/80 mm Hg.
ATP III recommends measuring waist circumference, because abdominal obesity is more highly correlated with the metabolic risk factors than is an elevated body mass index. Abdominal obesity is defined by a waist circumference >40 inches in men and a waist circumference >35 inches in women. Multiple metabolic risk factors may develop in men when the waist circumference is only marginally increased, to 37 to 40 inches ( cm). These patients may have a strong genetic contribution to insulin resistance and should benefit from lifestyle changes that control weight and increase physical activity.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285: American Diabetes Association. Diabetes Care. 2001;24(suppl 1):S33-S43. 34

35. Diabetes Prevention Program: Reduction in Diabetes Incidence
Slide 91
Diabetes Prevention Program: Reduction in Diabetes Incidence
Lifestyle reduced the incidence of diabetes by 58% (95% CI, 48%-66%) and metformin reduced the incidence by 31% (95% CI, 17%-43%).
The incidence of diabetes was 39% lower (95% CI, 24%-51%) in the lifestyle group than in the metformin group.
Treatment effects did not differ significantly according to sex or to race or ethnic group.
The lifestyle intervention was highly effective in all subgroups. Its effect was significantly greater among persons with lower baseline glucose concentrations 2 hours after a glucose load than among those with higher baseline glucose values.
The advantage of lifestyle intervention over metformin was greater in older persons and those with a lower body mass index than in younger persons and those with a higher body mass index.
The effect of metformin was less with a lower body mass index or a lower fasting glucose concentration than with higher values for those variables.
The investigators concluded that, compared with placebo, 1 case of diabetes can be prevented for every 7 persons treated with lifestyle changes for 3 years and for every 14 persons treated with metformin for 3 years.
Diabetes Prevention Program Research Group. N Engl J Med. 2002;346: 35

36. Diabetes Prevention Program: Summary
Slide 92
Diabetes Prevention Program: Summary
The study investigators summarized the findings of the Diabetes
Prevention Program as follows:
Metformin and lifestyle modification were highly effective in delaying or preventing type 2 diabetes.
Lifestyle intervention was particularly effective, with 1 case of diabetes prevented for seven patients treated for a period of 3 years.
It should be possible to delay or prevent development of complications and thus reduce the public health burden of diabetes.
Diabetes Prevention Program Research Group. N Engl J Med. 2002;346: 36

37. AACE Guidelines for the Management of Type 2 Diabetes
Slide 94
AACE Guidelines for the Management of Type 2 Diabetes
Updated guidelines published by the American Association of Clinical Endocrinologists (AACE) advocate intensive therapy for diabetes mellitus. Intensive therapy for diabetes involves a comprehensive program designed to achieve physiologic control of blood glucose and associated conditions, such as hypertension, dyslipidemia, and excess weight.
The program includes frequent self-monitoring of blood glucose levels and the use of more sophisticated treatment regimens to achieve and maintain blood glucose at near-normal levels.
Treatment goals are to achieve an A1C of <=6.5%; preprandial glucose of <=110 mg/dL; and postprandial glucose of <=140 mg/dL. AACE guidelines stress that attaining these goals is more important than the actual method used to achieve normoglycemia.
Intensive therapy and maintaining control of blood glucose levels are important factors in improving diabetes-related outcomes. The benefit of intensive therapy is seen at any point in the disease course, but the greatest benefits are generally observed in patients with less advanced disease.
In 2000, AACE issued guidelines for the treatment of dyslipidemia. AACE recommends aggressive intervention to manage dyslipidemia in all patients with diabetes whether or not they also have coronary artery disease. The goals for lipids are as follows: TG <150 mg/dL; TC <170 mg/dL; LDL-C <100 mg/dL; HDL-C >45 mg/dL; and non–HDL-C (total serum cholesterol minus HDL-C) <130 mg/dL.
In addition, AACE agrees with the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure guidelines for blood pressure control to a target of <130/85 mm Hg.
To prevent vascular events, AACE recommends the use of antiplatelet agents (eg, low-dose aspirin).
AACE. Endocr Pract. 2002;8(suppl 1):40-82.
AACE. Endocr Pract. 2000;6(2002 amended version): Accessed October 28, 2002. 37