understanding diabetes and insulin resistance syndromes dr. amel arnaout
TRANSCRIPT
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Understanding Diabetes and Insulin Resistance Syndromes
Dr. Amel Arnaout
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Objectives• 3676 Describe the different types of diabetes mellitus and their distinguishing
characteristics (classification). • 3695 Explain insulin resistance.• 3699 Compare and contrast type 1 and type 2 diabetes with respect to
epidemiology, etiology, risk factors, clinical presentation, acute and chronic complications and treatment.
• 3700 Interpret results of an oral glucose tolerance test.• 3701 Discuss the role of, the beta cell, obesity, the liver and the peripheral
cell and genetic factors, in the development of type 2 diabetes.• 3702 Describe the pathological changes in the pancreas for type 2 diabetes.• 3703 Describe the incidence of type 2 with respect to age, gender, race, and
geographical occurrence.• 3704 Describe the following conditions: metabolic syndrome, polycystic
ovarian syndrome and Cushing syndrome. • 3705 Explain the key metabolic abnormalities that lead to insulin resistance.
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Understanding Diabetes• Classification• Epidemiology• Diagnostic Criteria for Diabetes • The Oral Glucose Tolerance Test• Beta Cell Function in Type 2 Diabetes• Can Diabetes Be Prevented?• Insulin resistance• Other syndromes: Metabolic Syndrome, Polycystic
Ovarian Syndrome, Cushing’s syndrome
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Classification of Diabetes
Type Definition
Type 1 Diabetes Diabetes due to pancreatic beta destruction and prone to ketosis
Type 2 diabetes Diabetes that ranges from insulin resistance with relative insulin deficiency to a predominant secretory defect with insulin resistance
Gestational DiabetesMellitus
Glucose intolerance with onset or first recognition in pregnancy
Other types Variety of uncommon diseases, genetic forms, or diabetes associated with drug use.
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TYPE 1 Diabetes TYPE 2 DiabetesProportion of diabetes cases
10% 90%
Pathogenesis Beta cell destruction (usually autoimmune)
Insulin resistance, relative insulin deficiency
Endogenous insulin secretion
Low or absent Variable
Need for insulin therapyRequired for survival
Required in <50%, to improve control rather than for survival
Age of onsetOften <30 (but can occur at any age) Often >40 but even in kids
Body habitus Usually lean Often obese
Genetic component Smaller Very large
Symptoms at onset Acute, severe Often mild, slow onset
Ketoacidosis Yes Rare
Long-term complications present at dx?
No Retinopathy ~20%, CVD relatively common
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Understanding Diabetes• Classification• Epidemiology• Diagnostic Criteria for Diabetes • The Oral Glucose Tolerance Test• Beta Cell Function in Type 2 Diabetes• Can Diabetes Be Prevented?• Insulin resistance• Other syndromes: Metabolic Syndrome, Polycystic
Ovarian Syndrome, Cushing’s syndrome
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Diabetes in Canada
• 2.4 million Canadians living with diabetes– 1.9 million formally diagnosed in 2007
• 570,000 Canadians have undiagnosed type 2 diabetes
– Nearly 1 million Ontarians living with diabetes
• 6 million Canadians with pre-diabetes or at high risk of type 2 diabetes– Fastest growing population segments at highest risk!
• Aboriginal• Asian, Southeast Asian, Latin American and African• “Boomers”
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The Epidemic: Ethnic Groups at High Risk for DM
Aboriginal Latino
South AsianAsian
African Descent
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Public Health Agency of Canada. Diabetes in Canada: Facts and figures from a public health perspective. Ottawa, 2011.
Prevalence of diagnosed diabetes among individuals aged ≥ 1 year, by age group and sex, 2008/09
Diabetes in Canada: Prevalence of Diagnosed Diabetes by age and sex
Prevalence increased with age. The sharpest increase occurred after age 40 years. The highest prevalence was in the 75-79 year age group.
Pre
va
len
ce
(%
)
0
10
15
25
30
1-19
5
20
20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 ≥85 CanadaAge group (years)
Females
Males
Total
Overall Prevalence
6.4%
7.2%
6.8%
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Diabetes in Canada: Prevalence of Diagnosed Diabetes 1998/99 to 2008/09Age-standardized prevalence and number of cases of diagnosed diabetes among
individuals aged ≥ 1 year, 1998/99 to 2008/09
3.3%
5.6%
Public Health Agency of Canada. Diabetes in Canada: Facts and figures from a public health perspective. Ottawa, 2011.
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Canada: Diabetes Projection
1998 2010 2020
Canadian Diabetes Association, Economic Report 2009, www.diabetes.ca.
1998: 4.8% of population
2010: 7.4% of population
2020: 9.9% of population
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Prevalence of Diabetes among Individuals aged 20-79 years, Europe, North America, Oceania, 2010
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Diabetes in Canada: Prevalence by Province and Territory
Public Health Agency of Canada. Diabetes in Canada: Facts and figures from a public health perspective. Ottawa, 2011.
NL6.5%
ON 6.0%
QC 5.1%
PE5.6%
NB5.9%
NS 6.1%
MB 5.9%
SK 5.4%
AB 4.9%
BC 5.4%
NT 5.5%
YT 5.4%
NU 4.4%
† Age-standardized to the 1991 Canadian population.
Age-standardized† prevalence of diagnosed DM among individuals ≥ 1 year, 2008/09
NL, NS and ON had the highest prevalence, while NU, AB and QC had the lowest.
< 5.0
5.0 < 5.5
5.5 < 6.0
6.0 < 6.5
≥ 6.5
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Diabetes: prevalence in Canadian Aboriginal peoples
Diabetes in Canada, National Statistics and Opportunities for Improved Surveillance, Prevention, and Control. Minister of Public Works and Government Services Canada, 1999.
% w
ith
dia
bet
es
Age group
1 2 35
10
18
23
0
5
10
15
20
25
15-19 20-24 25-29 30-39 40-49 50-64 65+
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The Causes of Type 2 Diabetes• Genetics Aspects
– High concordance in identical twins– Family History of Diabetes/Insulin resistance– Ethnicity– Many candidate genes (polygenic is the most
common although there are monogenic forms)• Lifestyle Factors
– Diet– Physical inactivity
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Understanding Diabetes• Classification• Epidemiology• Diagnostic Criteria for Diabetes • The Oral Glucose Tolerance Test• Beta Cell Function in Type 2 Diabetes• Can Diabetes Be Prevented?• Insulin resistance• Other syndromes: Metabolic Syndrome, Polycystic
Ovarian Syndrome, Cushing’s syndrome
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FPG ≥7.0 mmol/LFasting = no caloric intake for at least 8 hours
or
A1C ≥6.5% (in adults)Using a standardized, validated assay, in the absence of factors that affect the
accuracy of the A1C and not for suspected type 1 diabetes
or
2hPG in a 75-g OGTT ≥11.1 mmol/Lor
Random PG ≥11.1 mmol/L Random= any time of the day, without regard to the interval since the last meal
Diagnosis of Diabetes
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In the absence of symptomatic hyperglycemia, if a single laboratory test is in the diabetes range, a repeat confirmatory laboratory test (FPG, A1C, 2hPG in a 75-g OGTT) must be done on another day. It is preferable that the same test be repeated (in a timely fashion) for confirmation. If results of two different tests are available and both are above the diagnostic cutpoints, the diagnosis of diabetes is confirmed.
Confirmatory Laboratory Test
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Diagnostic Testing With 3 Different Tests
Dealing with Discordance
•Many people identified as
having diabetes using A1C will
not be identified as having
diabetes by traditional glucose
criteria, and vice versa.
• When results of more than one test are available (amongst FPG,
A1C, 2hPG in a 75-g OGTT) and the results are discordant, the test
whose result is above diagnostic cut-point should be repeated, and
the diagnosis made on basis of the repeat test.
FPG 2hPG
A1C
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Pros and Cons of Diagnostic TestsTest Advantages Disadvantages
FPG Established standardFast and easySingle Sample
Sample not stableDay-to-day variabilityInconvenient to fastGlucose homeostasis in single time point
2hPG in 75 g OGTT
Established standard Sample not stableDay-to-day variabilityInconvenient, UnpalatableCost
A1C ConvenientSingle sampleLow day-to-day variabilityReflects long term [glucose]
$$$Affected by medical conditions, aging, ethnicityStandardized, validated assay requiredNot used for age <18, pregnant women or suspected T1DM
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Considerations when using A1C for Diagnosis
• Need validated standardized assay
• Repeat confirmatory test on another day
• Recognize conditions leading to misleading A1C
• A1C is not used for diagnosis in children,
adolescents, pregnancy or suspected type 1 diabetes
• Ethnicity and age can affect A1C results
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Recognize pitfalls of A1C: conditions that can affect
valueFactors affecting A1C
Increased A1C Decreased A1C Variable Change in A1C
Erythropoiesis B12/Fe deficiency Decreased erythropoiesis
Use of EPO, Fe, or B12Reticulocytosis Chronic liver Dx
Altered hemoglobin
Fetal hemoglobin Hemoglobinopathies Methemoglobin
Altered glycation Chronic renal failure (use of EPO decreases A1C)
ASA, vitamin C/E Hemoglobinopathies ↑ erythrocyte pH
Erythrocyte destruction
Splenectomy HemoglobinopathiesChronic renal failureSplenomegalyRheumatoid arthritisHAART meds, RibavirinDapsone
Assays HyperbilirubinemiaCarbamylated HbETOHChronic opiates
Hypertriglyceridemia
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Diagnosis of Prediabetes*Test Result Prediabetes Category
Fasting Plasma Glucose(mmol/L)
6.1 - 6.9
Impaired fasting glucose (IFG)
2-hr Plasma Glucose in a 75-g Oral Glucose Tolerance Test (mmol/L)
7.8 – 11.0 Impaired glucose tolerance (IGT)
GlycatedHemoglobin(A1C) (%)
6.0 - 6.4 Prediabetes
* Prediabetes = IFG, IGT or A1C 6.0 - 6.4% high risk of developing T2DM
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A1C Level and Future Risk of Diabetes: Systematic Review
A1C Category (%)5-year incidence of
diabetes
5.0-5.5 <5 to 9%
5.5-6.0 9 to 25%
6.0-6.5 25 to 50%
Zhang X et al. Diabetes Care. 2010;33:1665-1673.
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Understanding Diabetes• Classification• Epidemiology• The Metabolic Syndrome• Diagnostic Criteria for Diabetes • The Oral Glucose Tolerance Test• Beta Cell Function in Type 2 Diabetes• Can Diabetes Be Prevented?
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IFG
6060 9090 120120 150150 180180300-30MinutesFasting
Plasma glucose (mmol/l)
8.3
11.1
IGT
DiabetesFPG 7NormalFPG <6
Diabetes
11.1
Normal<7.8
OGTT
Impaired Fasting Glucose, Impaired Glucose Tolerance, and Type 2 Diabetes
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Definitions of Impaired Fasting Glucose (IFG) and Impaired Glucose Tolerance
(IGT) and Diabetes
Fas
ting
Glu
cose
(mm
ol/
L)
3.5
4.5
5.5
6.5
7.5
8.5
3 4 6 8 10 12 14
2-h Post-load Glucose (mmol/L)
Diabetes
IFG + IGT
NormalGlucose
IGT
IFG6.1
6.9
7.8 11.1
* 1. ADA Diabetes Care 2006;29(Suppl 1):S47,2. CDA Can J Diabetes 2003;27(Suppl 2):S7, 3.WHO 1999 NDC/NCS.99.2 accessed Mar 2 2006 from www.who.int
5.6*
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Understanding Diabetes• Classification• Epidemiology• Diagnostic Criteria for Diabetes • The Oral Glucose Tolerance Test• Beta Cell Function in Type 2 Diabetes• Can Diabetes Be Prevented?• Insulin resistance• Other syndromes: Metabolic Syndrome, Polycystic
Ovarian Syndrome, Cushing’s syndrome
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Understanding Diabetes• Classification• Epidemiology• The Metabolic Syndrome• Diagnostic Criteria for Diabetes • The Oral Glucose Tolerance Test• Beta Cell Function in Type 2 Diabetes• Can Diabetes Be Prevented?
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Natural History of Type 2 Diabetes
Henry. Am J Med 1998;105(1A):20S-6S.
Normal Impaired glucosetolerance
Type 2 diabetes
Time
Insulinresistance
Insulinproduction
Glucoselevel
b-celldysfunction
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Normal Insulin Secretion
Insulin secretio
n
early peak
late phase
minutesGlucose stimulus
Release of pre-formed insulin
Synthesis and release of newly formed insulin
5 10 15 20 25 30
Hosker J. Metabolism 1989;38(8):767-772
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Diminishedinsulin
Hyperglycemia
Liver
1. Insulin deficiency
2. Excess glucose output
3. Insulin resistance
Pancreas
Muscle and fat
Excess glucagon
Islet
Diminishedinsulin
α-cell produces excess glucagon
β-cell produces less insulin
The pathophysiology of T2DM includes three main defects
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Understanding Diabetes• Classification• Epidemiology• Diagnostic Criteria for Diabetes • The Oral Glucose Tolerance Test• Beta Cell Function in Type 2 Diabetes• Can Diabetes Be Prevented?• Insulin resistance• Other syndromes: Metabolic Syndrome, Polycystic
Ovarian Syndrome, Cushing’s syndrome
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Understanding Diabetes• Classification• Epidemiology• The Metabolic Syndrome• Diagnostic Criteria for Diabetes • The Oral Glucose Tolerance Test• Beta Cell Function in Type 2 Diabetes• Can Diabetes Be Prevented?• The Case for Glycemic Control
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Prevention of Type 1 Diabetes
• T1DM is a chronic autoimmune condition with destruction of pancreatic beta cells
• Ongoing or completed trials– ENDIT: High-dose nicotinamide – Not effective – DPT-1: Low-dose insulin in high risk relatives – Not effective overall– TRIGR: Exclusion of cow’s milk protein to infants until 6-8 months of
age – Trial ongoing
• Alternate strategy to use immunosuppression / modulation at the time of diagnosis but significant side effects and ethical considerations
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Prevention of Type 2 Diabetes
Diabetes Prevention Program (DPP) Research Group. N Engl J Med 2002;346:393-403.
Years
• Benefit of diet and exercise or Metformin on diabetes prevention in at-risk patients
• N = 3234 with IFG and IGT, without diabetes
00
10
20
30
40
1.0 2.0 3.0 4.0
Placebo
Metformin
Lifestyle
Cumulativeincidence of diabetes(%)
31%
58%
P*< 0.001
< 0.001
*vs placeboIFG = impaired fasting glucose, IGT = impaired glucose tolerance
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STOP-NIDDM Study
Chiasson JL, et al. Lancet 2002;359:2072-77.
N = 1429 people with IGT, BMI 25-40, 40-70 yrs, 3.3 years follow up
Days after randomization
Cum
ulat
ive
prob
abili
ty
P = 0.0022
0
AcarbosePlacebo
100200
300400
500600
700800
9001000
11001200
1300
1.00
0.95
0.90
0.50
0.45
0.40
0.65
0.60
0.55
0.80
0.75
0.70
0.85
Acarbose25%
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Summary of Diabetes Prevention
1. At this time, there are no safe and effective strategies to prevent T1DM
2. Intensive lifestyle modification with weight loss can reduce the risk of progression from pre-diabetes to T2DM by almost 60%
3. Progression from pre-diabetes to T2DM can be reduced by Metformin or Acarbose by approximately 30%
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Understanding Diabetes• Classification• Epidemiology• Diagnostic Criteria for Diabetes • The Oral Glucose Tolerance Test• Beta Cell Function in Type 2 Diabetes• Can Diabetes Be Prevented?• Insulin resistance• Other syndromes: Metabolic Syndrome, Polycystic
Ovarian Syndrome, Cushing’s syndrome
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Definition of Insulin Resistance
• A state in which a given concentration of insulin produces a less-than-expected biological effect
• Disorders associated with insulin resistance:• Obesity• Prediabetes/diabetes• Metabolic syndrome• Polycystic ovarian sundrome• Endocrine disorders – Cushing’s syndrome, acromegaly• Genetic conditions• Use of medications – steroids, cyclosporine, niacin, protease inhibitors
• Insulin resistance also occurs with aging
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Pathophysiology of insulin resistance
• Insulin receptor mediated: • Decreased number (as occurs in obesity)• Postreceptor failure in signalling pathway (mutations in
receptor, signalling proteins, GLUT4)• Autoantibodies to insulin receptor
• Defects in signalling mediators:• Glucose• Free fatty acids• Autonomic nerves• Gut hormones (GLP-1)• Adipokines – high leptin and adiponectin, low ghrelin
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Understanding Diabetes• Classification• Epidemiology• Diagnostic Criteria for Diabetes • The Oral Glucose Tolerance Test• Beta Cell Function in Type 2 Diabetes• Can Diabetes Be Prevented?• Insulin resistance• Other syndromes: Metabolic Syndrome, Polycystic
Ovarian Syndrome, Cushing’s syndrome
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Metabolic Syndrome
A constellation of risk factors • Significantly increased CVD risks• Significantly increased risks for type 2
diabetes
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Clinical Features of the Metabolic Syndrome
• Abdominal obesity• Hyperglycemia• Atherogenic dyslipidemia• Hypertension• Proinflammatory state• Prothrombotic state
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Definition of Metabolic Syndrome
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Metabolic Syndrome –Treatment
• A common condition associated with increased cardiovascular disease risks
• Treatment is aimed at lifestyle modification to achieve desirable body weight and reduce abdominal obesity
• Multiple medical therapy may be required to achieve metabolic targets (lipids, glucose and BP)
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Fat mass : 19.8 kg
VAT : 155 cm2
Fat mass : 19.8 kg
VAT : 96 cm2
Visceral fat is a better marker than weight or general obesity
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300
250
200
150
100
50
060 80 100 120
Waist circumference (cm) V
isce
ral A
T (
cm2 )
r = 0.80Front
Back
Waist
HipSubcutaneous AT
Visceral AT
Waist circumference: a simple measurement thatcorrelates well with visceral obesity
AT= Adipose tissue
The Metabolic Syndrome
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Polycystic Ovarian Syndrome
• Major features:• Menstrual dysfunction (oligomennorhea)• Anovulation• Hyperandrogenism (hirsutism, acne) • Metabolic abnormalities – higher risk of diabetes type 2, dyslipidemia and
hypertension• Obesity
• Abnormal hypothalamic-pituitary-ovarian axis• Although ovarian cysts are commonly present it is not a requirement for
diagnosis (many women have ovarian cysts without the other features of PCOS)
• Insulin resistance: related to postbinding defects in insulin receptor and may have gonodatropin-augmenting effects on ovarian function
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• Diagnostic criteria (Rotterdam Criteria), must have 2 out 3:
• Irregular or absent ovulation• Elevated androgen hormones (clinical or biochemical)• Enlarged ovaries containing at least 12 follicles each
Must exclude other causes of androgen excess
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Cushing’s Syndrome
• Condition characterized by prolonged exposure to elevated levels of endogenous or exogenous glucocorticoids
• Endogenous production may be due to:• ACTH dependent mechanisms (hypothalamic/pituitary
overproduction, paraneoplastic syndrome such as smallc ell lung ca)
• ACTH independent (adrenal tumor)
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Clinical features suggestive of Cushing’s syndrome
• Onset well after menarche• Fat redistribution/weight gain
– Especially supraclavicular area
• Catabolic effects present– Thinning of skin– Easy bruising– Abdominal striae– Poor wound healing– Osteoporosis
• Associated mood/cognitive changes
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Steps in diagnosing
• Does patient have too much glucocorticoid– Screening test– (confirmatory test)
• Etiology– ACTH dependent or independent– Source - imaging
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Screening Tests
24 hr UFC800 and 2200 (not 1600) cortisol (salivary or serum)
1 mg. ON dex suppression