Diabetes:  The Burden of Disease Fall, 2007 NUR464
Prevalence of Diabetes Is Escalating  2001 (Includes Gestational Diabetes) Source: Mokdad A, et al.  Diabetes Care . 2000;...
Diabetes Mortality Continues Unabated  Year Freid VM, et al.  National Center for Health Statistics, 2003. Age ­ Adjusted ...
Type 2 Accounts for the Vast Majority of Diabetes Mellitus Cases <ul><li>Type 2 diabetes </li></ul><ul><ul><li>About 90% o...
Link Between Obesity and  Type 2 Diabetes:  Harvard Nurses’ Health Study Colditz GA, et al.  Ann Intern Med . 1995;122:481...
2002 — Total Per Capita Health Care Expenditures ADA.  Diabetes Care . Mar. 2003;26(3):917-932.
Physiologic Blood Insulin Secretion Profile Plasma  Insulin  ( µ U/mL)  4:00 25 50 75 8:00 12:00 16:00 20:00  24:00 4:00 B...
Normal Physiologic Insulin  Sensitivity and   ­ Cell Function  Produce Euglycemia Pancreas Normal Insulin Sensitivity Liv...
 ­ Cell Dysfunction and Insulin Resistance Produce Hyperglycemia in Type 2 Diabetes Pancreas Insulin Resistance Liver Hyp...
Frequent Symptoms of Type 2 Diabetes <ul><li>Usually slow onset </li></ul><ul><li>May be  asymptomatic </li></ul><ul><li>3...
Stages of Type 2 Diabetes Related to Beta-Cell Function Adapted from Lebovitz HE.  Diabetes Reviews.  1999;7(3). 2 ­ 12 ­ ...
Significant Loss of Beta ­ Cell Function at Diagnosis <ul><li>UKPDS </li></ul><ul><ul><li>At the time diabetes was diagnos...
Glucose Excursions in Type 2 Diabetes Time of Day 400 300 200 100 0 0600 0600 1000 1400 1800 2200 0200 Glucose (mg/dL) Dia...
Insulin Secretion in Type 2 Diabetes Polonsky KS, et al.   N Engl J Med . 1996 Mar 21;334(12):777-783.  Normal Type 2 diab...
Normal A1C < 6.0% A1C PPG FPG + = CDC.  National Diabetes Fact Sheet . 2003; Atlanta, GA. US Dept. HHS, Center for  Diseas...
Relative Risk for Death Increases with 2 ­ hour Blood Glucose Regardless of the FPG Level 2.4 2.0 1.6 1.2 1.0 Relative  Ri...
As Patients Get Closer to A1C Goal, the Need to Manage PPG Significantly Increases Adapted from Monnier L, Lapinski H, Col...
Blood Glucose Control Guidelines American Diabetes Association.  Diabetes Care.  2003;26(suppl 1):S33-S50. American Colleg...
UKPDS 57: Over Time Increasing Numbers of Patients Require Insulin Patients  Requiring Additional  Insulin (%) Adapted fro...
Insulin is Associated with the Most Profound Effects on A1C Nathan DM.  NEJM . Oct 24, 2002;347(17):1342-1349. None 16 ­ 4...
Human Insulins <ul><li>Regular </li></ul><ul><li>Neutral Protamine Hagedorn (NPH) </li></ul><ul><li>Premix 70/30 (70% NPH ...
Human Insulin Time-Action Patterns  Time (hours)   SC injection Normal insulin secretion at mealtime Change in serum insul...
Human Insulin Time-Action Patterns  Time (hours)   SC injection Regular insulin (human) Baseline Level Theoretical represe...
Human Insulin Time-Action Patterns  Time (hours)   SC injection NPH insulin (human) Baseline Level Theoretical representat...
Human Insulin Time-Action Patterns  Time (hours)   SC injection Baseline Level Theoretical representation of  profile asso...
Analog Insulins <ul><li>Rapid-acting  </li></ul><ul><li>Basal  </li></ul><ul><li>Premix </li></ul>
Analog Insulin Time-Action Patterns  Time (hours)   SC injection Baseline Level Theoretical representation of  expected in...
Analog Insulin Time-Action Patterns  Time (hours)   SC injection Baseline Level Theoretical representation of  profile ass...
Analog Insulin Time-Action Patterns  Time (hours)   SC injection QD (basal) Analog Insulin Baseline Level Theoretical repr...
Analog Insulin Time-Action Patterns  Time (hours)   SC injection Baseline Level Theoretical representation of  profile ass...
<ul><li>“ Although insulin therapy has not traditionally been implemented early  in the course of Type 2 diabetes,  there ...
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  • Diabetes: The Burden of Disease
  • Prevalence of Diabetes Is Escalating 6.3% of the U.S. Population 8.7% of Americans &gt; 20 years of age 18.3% of US population &gt; 60 years of age As of 2002, 18.2 million Americans 13 million diagnosed; 5.2 million undiagnosed 1.3 million new cases per year in individuals aged 20 or older Key words: Prevalence Burden Sources: Mokdad A, et al. Diabetes trends in the US: 1990-1998. Diabetes Care . 2000;23:1278-1283. Mokdad A, et al. The continuing epidemics of obesity and diabetes in the US. J Am Med Assoc. 2001;286:10. Mokdad A, et al. Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA. 2003;289:76-79. CDC. National Diabetes Fact Sheet . 2003; Atlanta, GA. US Dept. HHS, Center for Disease Control and Prevention 2003. http://www.cdc.gov/diabetes/statistics/maps/1
  • Diabetes Mortality Continues Unabated Mortality due to heart disease and cerebrovascular disease have declined dramatically since 1980. Cancer mortality has remained relatively flat for the past decade. However diabetes mortality continues its steady escalation despite efforts by diabetes experts (ADA and AACE) to increase early diagnosis and more intensive therapy. Key words: Burden Mortality Freid VM, et al. Chartbook on trends in the health of Americans. Health, US 2003. Hyattsville, MD: National Center for Health Statistics, 2003.
  • Type 2 Accounts for the Vast Majority of Diabetes Mellitus Cases About 90% of the diabetes population has Type 2 diabetes. It is characterized by relative insulin deficiency caused by β cell failure and insulin resistance. Treatment focuses on improving or correcting impairments in glucose metabolism and restoring glycemic control. The prevalence of Type 2 diabetes increases with age, is related to obesity, and has demonstrated a strong familial link. Key words: Prevalence Burden
  • Link Between Obesity and Type 2 Diabetes: Harvard Nurses’ Health Study Conclusion: The excess risk for diabetes with even modest and typical adult weight gain is substantial. These findings support the importance of maintaining a constant body weight throughout adult life and suggest that the 1990 U.S. Department of Agriculture guidelines that allow a substantial weight gain after 35 years of age are misleading. Key words: Prevalence Obesity Colditz GA, et al. Ann Intern Med . 1995;122:481-486.
  • 2002 — Total Per Capita Health Care Expenditures Inpatient days (43.9%), nursing home care (15.1%), and office visits (10.9%) constituted the major expenditure groups by service settings. The ratio of expenditures for patients with diabetes compared to nondiabetics is approximately 5.1 in this analysis. (Not Shown) Previous estimates have estimated a ratio of approximately 2.5. The authors derived an age-adjusted annual per-capita expenditure of $5,642 for patients with diabetes to control for differences in demographic characteristics. This value approximates the previous estimated ratios in the range of 2.5. Key words: Economic Burden ADA. Economic Costs of Diabetes in the U.S. in 2002. Diabetes Care . Mar. 2003;26(3):917-932.
  • Physiologic Blood Insulin Secretion Profile Physiologic insulin secretion has two components: basal insulin + bolus insulin to cover PPG excursions. Basal or bolus insulin alone is not physiologic therapy. There is a basal level of insulin secretion, and then a surge of insulin secretion (bolus) to cover mealtime needs. This is what occurs in people without diabetes. Ideally, every patient with diabetes would be managed with a therapy that would mimic the normal physiologic profile as closely as possible. This typically requires what we call “intensive insulin therapy” or MDI (multiple daily injections). The goals are to: Maintain near-normal glycemia Minimize long-term complications, both microvascular and macrovascular Improve quality of life Key words: Physiologic Insulin profile White JR, Campbell RK, Hirsch I. Postgraduate Medicine. June 2003;113(6):30-36.
  • Normal Physiologic Insulin Sensitivity and  -Cell Function Produce Euglycemia The important metabolic sites that are sensitive to insulin include the liver, where glycogen is synthesized, stored, and broken down; skeletal muscle, where glucose oxidation produces energy; and adipose tissue, where glucose can be converted to fatty acids, glyceryl phosphate, and triglycerides. Insulin affects carbohydrate, protein, and lipid metabolism. Ingestion of a carbohydrate load results in a prompt increase in the amount of insulin release and a concomitant decrease in plasma glucagon. The presence of insulin favors the uptake and use of glucose by insulin-sensitive sites. In skeletal muscle, glucose uptake and subsequent energy production increase. In the liver, glucose uptake and the formation of glycogen increase in the presence of insulin (decreasing glucose production) The presence of insulin also favors the production of tryglycerides from free fatty acids (FFAs), effectively decreasing plasma FFA. When insulin deficiency causes an energy deficit, FFAs are oxidized to β-hydroxybutyric acid, acetoacetic acid, and acetone. Key words: Beta cell function Physiology Setter S, et al. In: Herfindal T, Courley D eds. Textbook of therapeutics: drug and disease management. 7th ed. Philadelphia: Lipincott, Williams and Wilkins 2000:377-406.
  •  -Cell Dysfunction and Insulin Resistance Produce Hyperglycemia in Type 2 Diabetes Dual Impairment Impaired insulin action (Insulin Resistance) Impaired insulin secretion (Impaired  -cell function) In adipose tissue resistant to the effects of insulin, there is increased lipolysis resulting in elevated level of plasma free fatty acids (FFA). Elevated FFA lead to an increase in hepatic glucose production and decrease in glucose uptake in the muscle. Impaired  -cell function and  -cell degranulation lead to a reduction in circulating insulin. This reduction in circulating insulin leads to hyperglycemia. Impaired insulin action or insulin resistance results in a decreased response to insulin in insulin sensitive tissues. In the liver, insulin resistance results in an increase in hepatic glucose production. Whether the impairment is to insulin secretion or action, the resulting hyperglycemia has a negative effect on muscle and adipose tissue by decreasing expression of GLUT4 which, in turn, limits glucose transport into insulin-sensitive tissues. Key words: Type 2 Defects Beta cell Insulin resistance
  • Frequent Symptoms of Type 2 Diabetes Onset is usually slow May be asymptomatic Some of the signs and symptoms of Type 2 diabetes are: polyuria, polydipsia or polyphagia weakness/fatigue glycosuria dry, itchy skin visual changes skin and mucous membrane infections While the 3 P’s are identical to Type 1 diabetes, Type 2 does not manifest itself as rapidly; the onset is slow and insidious. Unlike Type 1 diabetes in which insulin secretion is precipitously lost due to beta cell destruction, Type 2 diabetes is caused by a slow and progressive loss of beta cell function overlaid on a background of insulin resistance at the level of peripheral tissues. Key words: Type 2 Symptoms
  • Stages of Type 2 Diabetes Related to Beta-Cell Function Beta-cell Function from 0 to 6 years post-diagnosis appear as data points extracted from UKPDS data Hyperglycemia in Type 2 diabetes is associated with a decline in Beta-cell function. Insulin deficiency ultimately causes reduced insulin-mediated glucose uptake from muscle, exaggerated glucose production from the liver, and increased free fatty acid mobilization from adipose tissue. The result initially is postprandial hyperglycemia, which later is followed by fasting hyperglycemia. Insulin resistance, whether genetic or acquired, can contribute to the development of Type 2 diabetes by increasing the requirements for insulin, thus leading to insulin insufficiency in those individuals whose ß cells have limited secretory reserve. Key words: Type 2 Beta cell UKPDS 16. Overview of 6 years’ therapy of type 2 diabetes: a progressive disease. UKPDS. Diabetes . 1995;44:1249-1258. Adapted from Lebovitz HE. Insulin secretagogues: old and new. Diabetes Reviews. 1999;7(3).
  • Significant Loss of Beta-Cell Function at Diagnosis Each therapeutic agent, as monotherapy, increased 2- to 3-fold the proportion of patients who attained A1C below 7% compared with diet alone. However, the progressive deterioration of diabetes control was such that after 3 years only 50% of patients could attain this goal with monotherapy, and by 9 years this declined to approximately 25%. The majority of patients need combination therapy or insulin to attain these glycemic target levels in the longer term. Key words: Type 2 Beta cell Dysfunction UKPDS 16. Overview of 6 years’ therapy of type 2 diabetes: a progressive disease. UKPDS. Diabetes . 1995;44:1249-1258. Turner RC, et al. Glycemic control with diet, sulfonylurea, metfornin, or insulin in patients with type 2 diabetes: progressive requirement for multiple therapies (UKPDS 49). UKPDS. JAMA . 1999 Jun 2;281(21):2005-2012.
  • Glucose Excursions in Type 2 Diabetes As expected, plasma glucose levels were considerably higher in the diabetic patients both under fasting conditions and in response to meals. Although diabetic patients and the controls secreted, on the average, similar amounts of insulin under fasting conditions and during the 24-hour study, significant differences in insulin secretion in response to meals were found. Indeed, meal-related increases were clearly smaller in the diabetic patients. During the four-hour period after each meal, the increases in insulin secretion above the pre-meal levels were significantly lower ( P &lt; 0.005) in the diabetic patients than in the controls. Key words: Type 2 Glucose Excursions Polonsky KS, et al. Abnormal patterns of insulin secretion in non-insulin-dependent diabetes mellitus. NEJM . 1988;21;318(19):1237-1239.
  • Insulin Secretion in Type 2 Diabetes The insulin response in Type 2 diabetes is delayed and blunted reflecting the progressive dysfunction of the pancreatic beta cells Key words: Type 2 Beta cell Dysfunction Polonsky KS, et al. N Engl J Med . 1996 Mar 21;334(12):777-783.
  • Normal A1C &lt; 6.0% In the past, it was thought that A1C level was primarily dependent on FPG. However, postprandial hyperglycemia is also an important component of generating A1C. The A1C reflects both the FPG and the PPG excursions. In the patient with diabetes, postprandial hyperglycemia may be disproportionately increased. Several recent studies show that there is better correlation between PPG and A1C rather than between FPG and A1C. 1-4 Of these, the Bastyr study is most interesting because it is interventional. It showed that lispro therapy, which targeted postprandial glucose, reduced A1C more than either glyburide plus metformin or glyburide plus NPH at bedtime, which targeted preprandial and fasting glucose. A recent publication has shown that when A1C levels are &lt; 8.5%, postprandial glucose is the major contributor to A1C. 5 However, one study indicates a closer correlation with preprandial glucose. 6 Achieving target A1C levels in patients with Type 2 diabetes requires adequate treatment of both fasting and postprandial plasma glucose. Studies showing correlation of PPG and CV risk: Whitehall Study Helsinki Policemen Study Paris Prospective Survey Tecumseh Study Honolulu Heart Program Studies showing PPG more predictive than FPG or A1C for CV risk: Diabetes Intervention Study (DIS) Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe (DECODE) Key words: A1C FPG PPG Rohlfing CL, et al. Diabetes Care . 2002;25:275. Bastyr EJ, et al. Diabetes Care . 2000;23:1236. Avignon A, et al. Diabetes Care . 1997;20:1822. De Veciana M, et al. N Engl J Med . 1995;333:1237. Monnier L, et al. Diabetes Care . 2003;26:881-885.). Bonora E, et al. Diabetes Care . 2001;24:2023.
  • Relative Risk for Death Increases with 2-hour Blood Glucose Regardless of the FPG Level Results from the DECODE study show that the relative risk for death increases with 2-hour postprandial blood glucose irrespective of fasting plasma glucose (FPG) levels. It can clearly be seen that within each FPG category, the hazard ratio for death increased with increasing 2-hour blood glucose. In contrast, increasing FPG levels appear to have a minimal effect on the relative risk of death. This indicates that increases in 2-hour blood glucose levels are closely associated with the relative risk of mortality, irrespective of the FPG level. Fasting plasma glucose categories were defined as: normal &lt; 110 mg/dl, impaired fasting glucose (IFG) 110–125 mg/dl, new fasting diabetes  126 -139 mg/dL, and old fasting diabetes &gt;140 mg/dL. Two-hour plasma glucose categories were defined as: normal &lt; 7.8 mmol/l (&lt; 140 mg/dl), impaired glucose tolerance (IGT) 7.8–11 mmol/l (140–198 mg/dl) and diabetes  11.1mmol/l (  200 mg/dl). Key words: Postprandial PPG Diagnosis Cardiovascular Risk DECODE Study Group. Lancet. 1999;354:617-621.
  • As Patients Get Closer to A1C Goal, the Need to Successfully Manage PPG Significantly Increases Postprandial glycemic excursions become more predominant in patients with good control of fasting plasma glucose. Therefore, treatment should focus on both FPG and PPG excursions in order to reach and maintain A1C targets. Key words: Diagnosis Total glucose control A1C FPG PPG Postprandial glucose Adapted from Monnier L, Lapinski H, Collette C. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of Type 2 diabetic patients: variations with increasing levels of HBA(1c). Diabetes Care . 2003;26:881-885.
  • Blood Glucose Control Guidelines The American Diabetes Association (ADA) and the American College of Endocrinology (ACE) have made recommendations to optimize glycemic control Both of these associations have acknowledged that high PPG levels are associated with increased CVD risk independent of FPG The average A1C for patients with Type 2 diabetes is 8.5% to 9.0%. Blood glucose guidelines established by the ACE and the ADA for patients with diabetes are considerably lower than the average A1C currently achieved. The ACE Diabetes Mellitus Consensus Conference held in August 2001 established blood glucose targets for patients with diabetes including A1C of &lt; 6.5%, preprandial glucose of &lt; 110 mg/dL, and postprandial glucose of &lt; 140 mg/dL. The ADA guidelines for adequate blood glucose levels in patients with diabetes include A1C of &lt; 7.0%, preprandial glucose of 90-130 mg/dL, and postprandial glucose of &lt; 180 mg/dL. Key words: Guidelines A1C FPG PPG American Diabetes Association. Standards of Medical Care for Patients with Diabetes Mellitus. Diabetes Care . 2003;26(suppl 1):S37-S50. American College of Endocrinology. Endocr Pract . 2002;8(suppl 1):40-82.
  • UKPDS 57: Over Time Increasing Numbers of Patients Require Insulin As the study period progressed, a greater number of patients required insulin to be added to their treatment: At year 3, the proportion of patients requiring insulin was 35% in the chlorpropamide group, and 38% in the glipizide group. At year 6, 53% required additional insulin therapy, with no significant difference between those allocated to chlorpropamide and glipizide (49 vs. 56%, p = 0.28) Key words: UKPDS Type 2 Progressive Insulin Adapted from Wright A, Burden AC, Passey RB, et al for the UKPDS group. Sulfonylurea inadequacy: efficacy of addition of insulin over 6 years in patients with type 2 diabetes on the UKPDS (UKPDS 57). Diabetes Care. 2002;25:330-336.
  • Insulin is Associated with the Most Profound Effects on A1C In all cases, dosing is obviously limited by toxicity in individual patients. “ Maximal Dosing” defined in reference source: Sulfonylureas Glyburide, 20 mg/day Glipizide, 40 mg/day Glitinides Nateglinide, 120 mg before meals Repaglinide, 4 mg before meals Metformin, 2550 mg/day (850 mg with each meal) Alpha glycosidase Inhibitors Acarbose, 100 mg with meals Miglitol, 100 mg with meals TZDs (Thiazolidinediones) Rosiglitazone, 8 mg in 1 or 2 daily doses Pioglitazone, 45 mg/day Insulin can be titrated until an effective dose is reached Key words: A1C Insulin Nathan DM. Initial management of glycemia in type 2 diabetes. NEJM . Oct 24, 2002;347(17):1342-1349.
  • Human Insulins Typical Treatment Modalities with Regular Insulins Key words: Human Insulin
  • Human Insulin Time-Action Patterns Key Words: Insulin profile
  • Human Insulin Time-Action Patterns Characteristics of regular insulin (mealtime) Should inject 30 minutes before meals Risk of early postprandial hyperglycemia Risk of late postprandial hypoglycemia Key words: Insulin profile Regular Human Insulin
  • Human Insulin Time-Action Patterns Characteristics of NPH insulin (basal) No control of early hyperglycemia Increased risk of late hypoglycemia Key words: Insulin profile NPH
  • Human Insulin Time-Action Patterns Characteristics of Human Premix 70/30 are the same as NPH and Regular Human Insulin because it contains 70% NPH and 30% Regular Human Insulin. Because it is a mix of these 2 insulins, there is an additive effect which creates a broader peak. Characteristics of NPH insulin (basal) No control of early hyperglycemia Increased risk of late hypoglycemia Characteristics of regular insulin (mealtime) Should inject 30 minutes before meals Risk of early postprandial hyperglycemia Risk of late postprandial hypoglycemia Key words: Insulin profile Human Premix 70/30 Regular Human Insulin NPH Human
  • Analog Insulins Current Treatment Modalities with Analog Insulins Key words: Insulin Analogs
  • Analog Insulin Time-Action Patterns Key words: Insulin profiles
  • Analog Insulin Time-Action Patterns Key words: Insulin profiles
  • Analog Insulin Time-Action Patterns QD (basal) analog insulin alone provides limited coverage against early hyperglycemia Basal analog insulin alone does not cover postprandial glucose excursions Key Words: Insulin profile Basal Analog
  • Analog Insulin Time-Action Patterns Key words: Insulin profiles
  • Key Words: Insulin Type 2
  • Diabetes slideshow

    1. 1. Diabetes: The Burden of Disease Fall, 2007 NUR464
    2. 2. Prevalence of Diabetes Is Escalating 2001 (Includes Gestational Diabetes) Source: Mokdad A, et al. Diabetes Care . 2000;23:1278-1283; Mokdad A, et al. J Am Med Assoc. 2001;286:10; Mokdad A, et al. JAMA. 2003;289:76-79. 1990 1995 No Data < 4% 4%-6% 6%-8% 8%-10% > 10%
    3. 3. Diabetes Mortality Continues Unabated Year Freid VM, et al. National Center for Health Statistics, 2003. Age ­ Adjusted Death Rate Relative to 1980
    4. 4. Type 2 Accounts for the Vast Majority of Diabetes Mellitus Cases <ul><li>Type 2 diabetes </li></ul><ul><ul><li>About 90% of the diabetes population </li></ul></ul><ul><ul><li>Dual impairment: Insulin deficiency & Insulin resistance </li></ul></ul><ul><ul><li>No longer a disease of adults only </li></ul></ul><ul><ul><li>Obesity </li></ul></ul><ul><ul><li>Genetic link </li></ul></ul><ul><li>Type 1 diabetes </li></ul><ul><ul><li>Approximately 10% of diabetes population </li></ul></ul><ul><ul><li>Absolute insulin requirement </li></ul></ul><ul><ul><li>Autoimmune mediated </li></ul></ul>CDC. National Diabetes Fact Sheet . 2003; Atlanta, GA. US Dept. HHS, Center for Disease Control and Prevention 2003.
    5. 5. Link Between Obesity and Type 2 Diabetes: Harvard Nurses’ Health Study Colditz GA, et al. Ann Intern Med . 1995;122:481-486. 0 20 40 60 80 100 120 < 22 22 ­ 22.9 23 ­ 23.8 24 ­ 24.9 25 ­ 26.9 27 ­ 28.9 29 ­ 30.9 31 ­ 32.9 33 ­ 34.9 > 35 BMI (kg/m 2 ) Age ­ Adjusted Relative Risk for Diabetes Mellitus
    6. 6. 2002 — Total Per Capita Health Care Expenditures ADA. Diabetes Care . Mar. 2003;26(3):917-932.
    7. 7. Physiologic Blood Insulin Secretion Profile Plasma Insulin ( µ U/mL) 4:00 25 50 75 8:00 12:00 16:00 20:00 24:00 4:00 Breakfast Lunch Dinner Time 8:00 Adapted from White JR, Campbell RK, Hirsch I. Postgraduate Medicine. June 2003;113(6):30-36.
    8. 8. Normal Physiologic Insulin Sensitivity and  ­ Cell Function Produce Euglycemia Pancreas Normal Insulin Sensitivity Liver Euglycemia Islet  ­ Cell Degranulation; Insulin Released in Response to Elevated Plasma Glucose Muscle Adipose Tissue Increased Glucose Transport Decreased Lipolysis ↓ Glucose Production ↑ Glucose Uptake Normal Physiologic Plasma Insulin Decreased Glucose Output Normal  ­ Cell Function Decreased Plasma FFA
    9. 9.  ­ Cell Dysfunction and Insulin Resistance Produce Hyperglycemia in Type 2 Diabetes Pancreas Insulin Resistance Liver Hyperglycemia Islet  ­ Cell Degranulation; Reduced Insulin Content Muscle Adipose Tissue Decreased Glucose Transport & Activity (expression) of GLUT4 Increased Lipolysis ↑ Glucose Production ↓ Glucose Uptake Reduced Plasma Insulin Increased Glucose Output  ­ Cell Dysfunction Elevated Plasma FFA
    10. 10. Frequent Symptoms of Type 2 Diabetes <ul><li>Usually slow onset </li></ul><ul><li>May be asymptomatic </li></ul><ul><li>3 P’s: </li></ul><ul><ul><li>polyuria, </li></ul></ul><ul><ul><li>polydipsia, </li></ul></ul><ul><ul><li>polyphagia </li></ul></ul><ul><li>Weakness/fatigue </li></ul><ul><li>Glycosuria </li></ul><ul><li>Dry, itchy skin </li></ul><ul><li>Visual changes </li></ul><ul><li>Skin and mucous membrane infections </li></ul>
    11. 11. Stages of Type 2 Diabetes Related to Beta-Cell Function Adapted from Lebovitz HE. Diabetes Reviews. 1999;7(3). 2 ­ 12 ­ 2 ­ 10 ­ 6 0 6 10 14 Beta ­ Cell Function (%) 0 50 100 75 25 Type 2 Phase 1 IGT Years from Diagnosis Type 2 Phase 2 Type 2 Phase 3 Postprandial Hyperglycemia
    12. 12. Significant Loss of Beta ­ Cell Function at Diagnosis <ul><li>UKPDS </li></ul><ul><ul><li>At the time diabetes was diagnosed, 50% of beta ­ cell function was lost </li></ul></ul><ul><ul><li>Beta ­ cell function continued to decline over the 10-year course of the study </li></ul></ul><ul><ul><li>Correlated with loss of response to oral therapy </li></ul></ul><ul><li>Secondary failure (progressive loss of beta cell) </li></ul>UKPDS 16. Diabetes . 1995;44:1249-1258 Turner RC, et al. JAMA . 1999 Jun 2;281(21):2005-2012.
    13. 13. Glucose Excursions in Type 2 Diabetes Time of Day 400 300 200 100 0 0600 0600 1000 1400 1800 2200 0200 Glucose (mg/dL) Diabetic Normal Polonsky KS, et al. NEJM . 1988;21;318(19):1237-1239. Meal Meal Meal
    14. 14. Insulin Secretion in Type 2 Diabetes Polonsky KS, et al. N Engl J Med . 1996 Mar 21;334(12):777-783. Normal Type 2 diabetes Time (24 ­ hour clock) 0600 1000 1400 1800 2200 0200 800 600 400 200 0 Insulin Secretion (pmol/min) Meal Meal Meal
    15. 15. Normal A1C < 6.0% A1C PPG FPG + = CDC. National Diabetes Fact Sheet . 2003; Atlanta, GA. US Dept. HHS, Center for Disease Control and Prevention 2003.
    16. 16. Relative Risk for Death Increases with 2 ­ hour Blood Glucose Regardless of the FPG Level 2.4 2.0 1.6 1.2 1.0 Relative Risk of Death* < 140 > 199 < 110 126- 139 >140 140-198 2-h Postprandial Glucose (mg/dL) Fasting Plasma Glucose (mg/dL) *Adjusted for age, sex, study center Adapted from DECODE Study Group. Lancet. 1999;354:617-621. 110-125
    17. 17. As Patients Get Closer to A1C Goal, the Need to Manage PPG Significantly Increases Adapted from Monnier L, Lapinski H, Collette C. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of Type 2 diabetic patients: variations with increasing levels of HBA(1c). Diabetes Care . 2003;26:881-885. Increasing Contribution of PPG as A1C Improves % Contribution A1C Range (%) 0 20 40 60 80 100
    18. 18. Blood Glucose Control Guidelines American Diabetes Association. Diabetes Care. 2003;26(suppl 1):S33-S50. American College of Endocrinology. Endocr Pract. 2002;8(suppl 1):40-82. American Diabetes Association (ADA) American College of Endocrinology (ACE) ≤ 6.5% < 7% A1C < 140 mg/dL (2 hour) < 180 mg/dL (peak) Postprandial blood glucose < 110 mg/dL 90–130 mg/dL Preprandial blood glucose
    19. 19. UKPDS 57: Over Time Increasing Numbers of Patients Require Insulin Patients Requiring Additional Insulin (%) Adapted from: Wright A, et al. Diabetes Care. 2002;25:330 – 336. 20 40 60 0 1 2 4 5 Years from Randomization 3 6 Chlorpropamide Glipizide
    20. 20. Insulin is Associated with the Most Profound Effects on A1C Nathan DM. NEJM . Oct 24, 2002;347(17):1342-1349. None 16 ­ 45 mg/day 100 mg w/ meals 2550 mg/day SU= 20 ­ 40 mg/day; Glitinides: 4 ­ 120 mg Before meals Max Dose 1.5 ­ 2.5 0.5 ­ 1.0 0.5 ­ 1.0 1.0 ­ 2.0 1.0 ­ 2.0 0.5 ­ 2.0 TypicalChange in A1C Insulin TZDs Alpha ­ glycosidase Inhibitors Metformin SU & Glitinides Diet & Exercise
    21. 21. Human Insulins <ul><li>Regular </li></ul><ul><li>Neutral Protamine Hagedorn (NPH) </li></ul><ul><li>Premix 70/30 (70% NPH / 30% Regular) </li></ul>
    22. 22. Human Insulin Time-Action Patterns Time (hours) SC injection Normal insulin secretion at mealtime Change in serum insulin Baseline Level Theoretical representation of expected insulin release in nondiabetic subjects
    23. 23. Human Insulin Time-Action Patterns Time (hours) SC injection Regular insulin (human) Baseline Level Theoretical representation of profile associated with Regular Insulin (human) Change in serum insulin Normal insulin secretion at mealtime
    24. 24. Human Insulin Time-Action Patterns Time (hours) SC injection NPH insulin (human) Baseline Level Theoretical representation of profile associated with NPH Insulin Change in serum insulin Normal insulin secretion at mealtime
    25. 25. Human Insulin Time-Action Patterns Time (hours) SC injection Baseline Level Theoretical representation of profile associated with Human Premix 70/30 Change in serum insulin Normal insulin secretion at mealtime Human Premix 70/30 (70% NPH & 30% Regular)
    26. 26. Analog Insulins <ul><li>Rapid-acting </li></ul><ul><li>Basal </li></ul><ul><li>Premix </li></ul>
    27. 27. Analog Insulin Time-Action Patterns Time (hours) SC injection Baseline Level Theoretical representation of expected insulin release in nondiabetic subjects Change in serum insulin Normal insulin secretion at mealtime
    28. 28. Analog Insulin Time-Action Patterns Time (hours) SC injection Baseline Level Theoretical representation of profile associated with rapid-acting Insulin Analog Change in serum insulin Rapid-Acting Insulin Analog Normal insulin secretion at mealtime
    29. 29. Analog Insulin Time-Action Patterns Time (hours) SC injection QD (basal) Analog Insulin Baseline Level Theoretical representation of profile associated with Basal Analog Insulin Change in serum insulin Normal insulin secretion at mealtime
    30. 30. Analog Insulin Time-Action Patterns Time (hours) SC injection Baseline Level Theoretical representation of profile associated with Insulin Analog Premix Change in serum insulin Insulin Analog Premix Normal insulin secretion at mealtime
    31. 31. <ul><li>“ Although insulin therapy has not traditionally been implemented early in the course of Type 2 diabetes, there is no reason why it should not be…” </li></ul>Nathan DM. NEJM . Oct 24, 2002;347(17):1342-1349.

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