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Diabetes Mellitus DM
Criteria for the Diagnosis of Diabetes: 2003 ADA Guidelines
Plasma Glucose level mg/dL Stage of Glycemic Control Normal IFG or IGT Diabetes Fasting Plasma Glucose 100 100 - 125 140 - 199 126 200 OGTT 2-hr Postload Glucose 140
Third criterion: 200 mg/dL casual plasma glucose regardless of the time since last meal plus symptoms of diabetes polyuria, polydipsia, unexplained weight loss ADA, Diabetes Care 26:2003
Classification of Various Hyperglycemias
DIABETES MELLITUS DM
Type 1 diabetes:
Immune Mediated Idiopathic
Type 2 diabetes: individuals with insulin resistance who
usually have relative rather than absolute insulin deficiency obese or non-obese Pancreatic disease Endocrinopathies Drug-induced
Other types of diabetes:
Gestational Diabetes GDM
IMPAIRED GLUCOSE TOLERANCE IGT
Major Characteristics of Types 1 and 2 Diabetes
Features
Age at onset Proportion of all diabetes Seasonal trend Appearance of symptoms Metabolic Ketoacidosis Obesity at onset ß-Cells Insulin
Type 1 DM
Usually 40 About 10 Fall and Winter Acute or subacute Frequent Uncommon Decreased Decreased or absent
Type 2 DM
Usually 40 About 90 None Slow or subacute Rare Common
Variable Variable Absent
Inflammatory cells in islets Present initially
Major Characteristics of Types 1 and 2 Diabetes cont
Features cont
Family history of diabetes Concordance in identical twins HLA Association Antibody to islet cells ICA Insulin autoantibodies IAA 64K GAD antibodies Treatment
Type 1 DM
Uncommon 30-50 Yes Yes Yes in younger age Yes Insulin, diet, Pancreas and Islet Transplant
Type 2 DM
Common 90-95 No Uncommon No No Diet, weight reduction, exercise, OHA, Insulin
Glutamic acid decarboxylase GAD; Oral hypoglycemic agents; Except in African-Americans
Widespread Impact Of Diabetes In The United States
2002
Approximately 18 million Americans have diabetes 90 - 95 are type 2 13 million diagnosed; 52 million undiagnosed
Available at: http://wwwdiabetesorg/diabetes-statistics/national-diabetes-fact-sheetjsp Accessed 1/30/04
Diabetes Statistics
21 Million IGT, 18 Million Diabetes
Type GDM DMI IGT DM2
- Diagnosed - Undiagnosed
Prevalence 3 04 11 8
5 3
Total Direct and Indirect Cost of Diabetes in 2003 was 132 Billion Dollars
Number of People in the United States With Diagnosed Diabetes
Number of persons in millions The prevalence of diabetes has increased by
six-fold during the past four decades
Increasing Prevalence of Obesity in US Adults
Increasing Prevalence of Diagnosed Diabetes in US Adults
FATTEST CITIES:
1 2 3 4 5 6 7 8 9 10 11 12 13 14 Detroit Houston Dallas San Antonio Chicago Fort Worth Philadelphia Arlington Cleveland Columbus Atlanta Mesa Oklahoma City Kansas City 15 16 17 18 19 20 Miami Las Vegas Indianapolis Phoenix Tulsa Memphis
FITTEST CITIES:
1 2 3 4 5 6 7 8 9 10 11 12 13 14 Honolulu San Francisco Virginia Beach Denver Colorado Springs Seattle Boston Portland Tucson Sacramento Omaha Albuquerque Jacksonville San Diego 15 16 17 18 19 20 Fresno Wichita Oakland Minneapolis Austin San Jose
Source: Mens Fitness
Impact of Diabetes: Mortality in US
Mortality: 57,000 deaths directly attributable to diabetes — 7 cause Mortality: 193,000 deaths linked to diabetes — 3 cause Leading cause of blindness, chronic renal failure, need for dialysis and nontraumatic amputations
Source: CDC Diabetes Surveillance 1997; CDC Web Site 2000
American Diabetes Association Diabetes Facts and Figures March 2000
Diabetes Mellitus in the US: Health Impact of the Disease
Renal failure Blindness 6th leasing cause of death Life expectancy
5 to 10 yrs
Diabetes
Cardiovascular disease 2X to 4X Nerve damage in 60 to 70 of patients
Amputation
Diabetes is the no 1 cause of renal failure, new cases of blindness, and non-traumatic amputations Diabetes Statistics October 1995 updated 1997 NIDDK publication NIH 96-3926 Harris MI In Diabetes in America, 2nd ed 1995: 1-13
Diabetic Epidemics
Causes
MODIFIABLES Weight/BMI Central obesity Sedentary lifestyle NON-MODIFIABLES Age Ethnicity Genetics
GENETIC SUSCEPTIBILITY
INEFFECTIVE DEFENSE BARRIERS Insulting Agent eg, Pancreotropic Virus Autoimmune Process Begins T-Lymphocytes
INEFFECTIVE IMMUNE RESPONSE
Macrophages Ag presenting cell Ag Peptide
CD 4
TNF-
INF-
-Cell Destruction 90 Destruction TYPE 1 Diabetes Mellitus
Interleukin 1
Precipitating factors or Stressors
Estimated Lifetime Risks of Type 1 DM
Classification
GENERAL POPULATION Background risk DR Susceptible DR?DQ alleles FAMILY MEMBERS Parents Offspring Sibling Identical twins HLA identical haploidentical nonindentical 10 16 2 9 01 3 5 68 30 50 02 03 24 6 85
Risk
Pathogenesis of Type 2 Diabetes
Impaired Insulin Secretion and Insulin Resistance
Genes Lifestyle Insulin Resistance IGT
Impaired
Insulin Secretion
Type 2 Diabetes Progressive Hyperglycemia and High FFA
Progressive Nature of Type 2 Diabetes
Insulin Deficiency Due to -Cell Failure
IGT
Endogenous Insulin
Diabetes
Normal InsulinInsulinInsulin Resistance
Insulin Resistance
Postprandial BG
FBG FBG
Normal BG
Years
Avg Dx 912 yr
Bergenstal RM et al In: DeGroot LJ et al, eds Endocrinology 4th ed Philadelphia: WB Saunders; 2001:821 Originally in Type 2 Diabetes BASICS Minneapolis, International Diabetes Center, 2000 Adapted with permission from International Diabetes Center
Factors That May Drive The Progressive Decline Of -Cell Function
Hyperglycemia glucose toxicity
Insulin Resistance
-cell -cell
Lipotoxicity
elevated FFA, TG
FFA free fatty acids; TGtriglycerides Adapted from: Kahn SE J Clin Endocrinol Metab 2001;86:4047-4058 Adapted from: Ludwig DS JAMA 2002;287:2414-2423
THREE FORMS OF TYPE 2 DIABETES
Adult Onset Diabetes Multifactorial Maturity Onset Diabetes of the Young MODY Obese Type 2 Diabetes with DKA Minority Group
Pathophysiology of Type 2 Diabetes
Peripheral Tissues Muscle
Insulin resistance
Receptor postreceptor defects
Glucose Liver
Increased glucose production
Pancreas
Impaired
insulin secretion
Saltiel AR, Olefsky JM Diabetes 1996;45:1661-1669 Diabetes 1996;45:1661-
Role of T-cells and E-cells in T2DM CVD
Environmental Genetic Factors
Insulin Resistance Dyslipidemia Dysglycemia
T-cell activation TNF- IL-6
Fibrinogen PAI-1 CRP
Diabetes Mellitus
Inflammation stress Endothelial Dysfunction
ROS NO SAM ICAM
Metabolic Syndrome
Vasoconstriction
Cardiovascular Diseases
Microvascular Macrovascular Cerebrovascular
Kitabchi, IAMA Bulletin, 2006
Figure 13 above Relation of Hepatic glucose production to fasting plasma glucose in normal weight diabetic subjects o vs age, weight matched control subjects Figure 14 right Glucose metabolism during euglycemic hyperinsulinemic clamp studies 38 normal weight DM 2 NIDD and 33 age weight matched controls From: DeFronzo 1991
Figure 15 above Insulinmedicated rates euglycemic insulin-clamp technique of whole-body glucose intake total height of bar, glucose oxidation, and nonoxidative glucose disposal in control, normal-weight diabetic, obese nondiabetic, obese glucoseintolerant, and obese diabetic subjects
Population at Risk for Type 2 DM
younger than 45 years old
1 2 3 5 6 7 8 9 Persons with classic signs and
symptoms of diabetes ie, polyuria, polydipsia, polyphagia, and loss of weight Obesity particularly upper body adiposity with BMI 27 Kg/m2 or 120 of ideal body weight Strong family history of Type 2 DM History of delivering infant weighing greater than nine pounds Having a HDL 35 mg/dl or TG 250 mg/dl History of impaired glucose tolerance or impaired fasting glucose History of gestational diabetes History of coronary artery disease and/or hypertension 140/90
4 Ethnic groups ie, Blacks, Hispanics, Native Americans, and Asians
10 Persons ingesting high doses of corticosteroids
Patterns of Glucose, Insulin, and Glucagon After Oral Glucose in Type 2 Diabetes
400
Postprandial hyperglycemia Type 2 Diabetes Normal
Glucose mg/dL
300 200 100 60 0 60 120 180 240 300 60 45 30 60
Delayed and reduced
240 120 0
Glucagon fmol/L
360
Minutes
Insulin pmol/L
High and not suppressed
60
0
60
120
180
240
300
0
60
120
180
240
300
Minutes
Minutes
Mitrakou A et al Diabetes 1990;39:1381-1390
Insulin Response During OGTT in Obese Non-diabetic and Diabetic Individuals
Plasma Insulin U/ml
Time minutes
GLP-1 Effects Are Glucose Dependent in Type 2 Diabetes
Placebo GLP-1
180 90 0
-30 0
200 100 0 -30 0
Glucagon pmol/L
270 Glucose mg/dL
PBO GLP-1 Insulin pmol/L
300
PBO GLP-1 20
PBO GLP-1
10
60 120 180 240 Time min
60 120 180 240 Time min
0 -30 0
60 120 180 240 Time min
N 10; Mean SE; P005 Data from Nauck MA, et al Diabetologia 1993;36:741-744
Deficient Insulin: Hypersecreted Glucagon
TYPE 2 DIABETES
Without Diabetes n14 Type 2 Diabetes n12 120
Insulin U/mL
60 0 140
Defects in diabetes:
Deficient insulin release Glucagon not suppressed postprandially Hyperglycemia
Glucagon 120 pg/mL
100 360
Glucose mg/dL
300 240 110 80 -60 0 60 120 180 240
Data from Muller WA, et al N Engl J Med 1970; 283:109-115
Amylin Is Deficient in Diabetes
Meal 20
Plasma Amylin pM
Meal
Time min
15
Without Diabetes
10
Late Stage Type 2
5 Type 1 0 30 60 90 120 150 180
0 -30
Time After
Sustacal
Meal min
Without diabetes; n 27 Late-stage type 2; n 12 Type 1; n 190 Data from Kruger D, et al Diabetes Educ 1999; 25:389-398
GENES AND TYPE 2 DIABETES MELLITUS
Prime suspect: the TCF7L2 gene and type 2 diabetes risk
Andrew T Hattersley
Institute of Biomedical and Clinical Sciences, Peninsula Medical School, Exeter, United
Kingdom
Transcription factor-7like 2 TCF7L2 is the most important type 2 diabetes susceptibility gene identified to date, with common intronic variants strongly associated with diabetes in all major racial groups This ubiquitous transcription factor in the Wnt signaling pathway was not previously known to be involved in glucose homeostasis, so defining the underlying mechanisms will provide new insights into diabetes In this issue of the JCI, Lyssenko and colleagues report on their human and isolated islet studies and suggest that the risk allele increases TCF7L2 expression in the pancreatic cell, reducing insulin secretion and hence predisposing the individual to diabetes
Hattersley, JCI 2007
Figure 1 From genetic association to pathophysiology in TCF7L2 genotypes predisposing to type 2 diabetes Diagram of proposed pathophysiological pathway explaining how TCF7L2 risk genotypes predispose to type 2 diabetes The risk genotype results in overexpression of TCF7L2 in pancreatic cells, which in turn results in reduced insulin secretion Reduced insulin secretion results in a predisposition to type 2 diabetes directly and also indirectly by increasing hepatic glucose output Dotted
arrows represent previous genetic associations Solid arrows show observations reported by Lyssenko and colleagues in the current issue of the JCI 1
Hattersley, JCI 2007
RISK FACTORS FOR TYPE 2 DIABETES
Gestational diabetes Aging Atherosclerosis Sedentary Life Dyslipidemia Genetic Hypertension Impaired glucose tolerance
Decreased fibrinolytic activity Acanthosis nigricans
Insulin Resistance
Obesity central
Polycystic ovary syndrome
Impaired Fasting Glucose
Mechanism of Apparent Insulin Resistance
Type of Defect
Pre-receptor
Mechanisms
Circulating antinsulin factors: antibodies against insulin; Abnormal insulin synthesis Accelerated insulin degradation
Receptor number of affinity, or both
Primary defects Circulating antireceptor antibodies membrane receptors Physiological regulatory mechanisms ie, down-or up-regulation Absent target site
Post-receptor events
Defective receptorsecond-messenger activity Accelerated destruction of insulin intracellularly Distal steps in insulin action
Adipokines
VISFATIN is a newly-discovered hormone isolated from fat tissue and has insulinlike activity Science 307:366-7, 2005
Body Type and Obesity
Apple shaped
Pear shaped
Obesity and
Insulin Resistance: Importance of Visceral Fat
Adiponectin Properties
1 Lower in:
a b c d e f g Men than in women Obese individuals with metabolic syndrome Obese women with PCOS Patients with type 2 diabetes Patients with CAD Those at risk for type 2 diabetes and first-degree relatives Some adiponectin gene mutations associated with increased type 2 diabetes h Diabetes-susceptibility locus mapped to chromosome 3q27, site of adiponectin gene
2 Higher levels are protective for type 2 diabetes 3 Positively correlates with insulin sensitivity independent of age, BP, adiposity, lipids and HDL-C in patients with and without type 2 diabetes 4 Inversely relates to degree of adiposity BMI, fat mass, glucose, insulin, TG levels, systolic BP, intramuscular fat content, CRP, TNF-, IL-6, and endothelin 5 Increased with weight loss most studies and glitazone therapy 6 Not increased with exercise
How to calculate Ideal Body Weight IBW as well
100 lb for first 5 ft 5 lb for each additional inch
106 lb for first 5 ft 6 lb for each additional inch
How to calculate Body Mass Index BMI
Metric Method: BMI
weight kg height m2
Normal Value 20-25 Overweight 26-29 Obese 30
Non-metric method:
BMI
weight pounds x 703 height inches2
Calorie Requirements and Dietary Composition
Calorie Requirement
Basal requirement Average activity Strenuous activity Weight loss Pregnancy Lactation Ideal body weight x 10 Add 30 to basal requirement Add 100 - 200 to basal requirement Subtract 500 calories/day to lose 1 lb/week Add 300 calories/day Add 500 calories/day
Dietary Composition
Carbohydrate Protein Fat Fiber 50 - 55 of total calories 15 - 20 of total calories 30 of total calories 10 saturated fat 30 gm soluble fiber
Clinical Identification of the Metabolic Syndrome
Risk Factor
Abdominal Obesity Men Women
Defining Level
Waist Circumference 40 inches 35 inches
Fasting Glucose IFG Triglycerides HDL Cholesterol Men Women Blood Pressure
110 mg/dl 150 mg/dl 40 mg/dl 50 mg/dl 130/ 85 mm Hg
Correlation of clinical Conditions and diabetic Syndromes with Various Metabolic Defects
Metabolic Defects Chemical Abnormalities Clinical Abnormalities
Polyuria, polydipsia, polyphagia fatigue, muscle weakness, pruritus Carbohydrate Metabolism 1 Diminished uptake of Hyperglycemia glucose by tissues such as muscle, adipose tissue and liver 2 Overproduction of glucose via glycogenolysis
and glyconeogenesis by the liver Protein Metabolism 1 Diminished uptake of amino and diminished synthesis of protein Negative nitrogen Loss of muscle mass balance Weakness Elevated levels of branch-chain amino acids Elevated blood urea nitrogen level Elevated potassium level
Blurred vision Diminished mental alertness
2 Increased proteolysis
Correlation of clinical Conditions and diabetic Syndromes with Various Metabolic Defects Cont
Metabolic Defects
Fat Metabolism 1 Increased lipolysis Elevated plasma fatty acids level Elevated plasma glycerol level Loss of adipose tissue
Chemical Abnormalities
Clinical Abnormalities
2 Decreased ipogenesis 3 Increased production of triglycerides Hypertriglyceridemia
Loss of adipose tissue Exudative xanthoma skin lesions Lipemia retinalis Pancreatitis abdominal pain
4 Decreased removal of ketones and increased ketone production
Elevated plasma and urine ketones
Hyperventilation, metabolic acidosis, abdominal pain
Diabetic Control: Controversies
Whether, or to what extent, complications are related to blood glucose levels? What is the effect of blood glucose control on development of complications? What degree of control is necessary
to prevent, halt, or reverse complications?
Randomization in DCCT
1441 Patients
726 Primary Prevention no retinopathy or microalbuminuria
715 Secondary Intervention minimal retinopathy microalbuminuria
378 Conventional
348 Intensive
352 Conventional
363 Intensive
UKPDS: Main Randomization
5102 patients treated with diet 3 months Metformin Overweight only n342
4209 patients 82
3867 patients Non-overweight and overweight Conventional policy n1138 30 Intensive policy n2729 70 Sulfonylureas n1573 Insulin n1156
UKPDS Group Lancet 1998;352:837-853
Take Home Message from UKPS DCCT Studies
For Every 1 reduction in HbA1c, there is 25-35 reduction in the risk of microangiopathy in DM
Relationship of Glycemic Control to Reduction in Diabetic Complications
Outcome Parameters
SDIS 1 DCCT 2 Type of DM Number of Patients Mean age y Duration of follow-up y Reduction in HbA1c Reduction in risk Retinopathy Nephropathy Neuropathy Myocardial infarctions Any diabetes related endpoint
N Eng J Med 329:977, 1993 Diabetes Res Clin Pract 28:103, 1995
Studies
Kumamoto 3 UKPDS 4 Type 2 102 49 6 - 23 69 70 ——Type 2 4200 53 10 - 09 21 33 –16 25 Type 1 1441 27 65 - 19 63 54 60
—–
Type 1 102 30 75 - 24 52 89 NS —–
N Eng J Med 329:977, 1993 Lancet 352_854-65, 1998
Summary of Landmark Diabetes Prevention Studies
Study N Age yr BMI 45 55 506 26 31 34 Ethnicity Chinese European Multi-ethnic Length 6 yr 32 yr 28 yr Intervention Diet Exercise Diet Exercise Lifestyle Metformin reduction 33-47 58 58 31 Da Qing1 577 Finnish2 DPP3 522 3234
Metabolic Goals in Diabetes ADA
Normal Value
Fasting Blood Glucose Pregnant Postprandial Blood Glucose 2 hr Pregnant 1 hr Glycosylated Hemoglobin A1c Cholesterol HDL Cholesterol Men Women LDL Cholesterol Triglycerides Body Mass Index BMI kg [weight] m2 [height] BMI 27 is defined as obese 35 mg/dl 45 mg/dl 130 mg/dl 150 mg/dl 19 - 25 35mg/dl 45 mg/dl 75 mg/dl 150 mg/dl
19
Goal Value
70 - 120 mg/dl 69 - 90 mg/dl 180 mg/dl 120 mg/dl 7 200 mg/dl
70 - 99 mg/dl 69 - 90 mg/dl 140 mg/dl 140 mg/dl 4 - 6 200 mg/dl
- 25
Some
ethnic groups such as Asians have lower BMI
Source:diabetes.com
