The Continuum of PreD: Guiding Diagnosis & Treatment of Progression to Diabetes Andrea M Girman, MD, MPH VOMA 27 April 2012 © 2010
Download ReportTranscript The Continuum of PreD: Guiding Diagnosis & Treatment of Progression to Diabetes Andrea M Girman, MD, MPH VOMA 27 April 2012 © 2010
Slide 1
The Continuum of PreD:
Guiding Diagnosis & Treatment of
Progression to Diabetes
Andrea M Girman, MD, MPH
VOMA
27 April 2012
© 2010
2008
Slide 2
The Continuum of PreD: Guiding
Diagnosis & Treatment of Progression to
Diabetes
Andrea M. Girman, MD, MPH
The following potential conflict of interest relationships are germane
to my presentation:
Equipment: None
Speakers Bureau: None
Stock Shareholder: None
Grant/Research Support: None
Consultant: None
Employment: Genova Diagnostics
Status of FDA devices used for the material being presented:
NA/Non-Clinical
Status of off-label use of devices, drugs or other materials
that constitute the subject of this presentation:
NA/Non-Clinical
Slide 3
Continuum of PreD:
Conversation Goals
• Examine the focus on obesity as major
identifier of people at risk for Type 2 DM
• Identify an underlying driver of progression
to Type 2 Diabetes: Inflammation
• Define the Stages of Pre-Diabetes
progression
• Consider Stage-specific Therapeutic
Interventions ~ Lifestyle +/- Meds
3
© 2010
Slide 4
Obesity:
Challenging Assumptions
• Many clinicians assume that they can
accurately predict patient risk for diabetes
based on obesity.
• If this is true, are tests designed to assess
risk of diabetes really needed?
4
© 2010
Slide 5
Defining Overweight/Obesity
5
© 2010
Slide 6
Overweight/Obesity Worldwide
% Population (2007)
New Zealand
62.6%
United Kingdom
61.0%
Iceland
60.2%
Luxembourg
54.8%
Ireland
51%
Finland
48.9%
Canada
46.8%
Slovak Republic
46.2%
Italy
45.5%
Netherlands
45.5%
Sweden
44.0%
Switzerland
37.3%
6
© 2010
Slide 7
Obesity Trends* Among U.S. Adults
BRFSS, 1990, 2000, 2010
2000
1990
2010
No Data
<10%
10%–14%
15%–19%
7
20%–24%
25%–29%
≥30%
© 2010
Slide 8
BMI < 25
BMI 25-30
BMI >30
MEN
30%
51%
71%
WOMEN
21%
43%
65%
26%
46%
68%
TOTAL
Rates of CardioMetabolic Syndrome
8
© 2010
Slide 9
CDC: Only 40% of the risk of
developing diabetes occurs in
people who are obese.
How do we find
the 60% of
people at risk
for developing
diabetes who
are NOT obese?
9
© 2010
Slide 10
PreD Assessment &
Clinical Utility
• Identify patients who are at risk for diabetes
& who are not obese
• Define that individual’s stage of
progression to Type 2 Diabetes (i.e.
Insulin Resistance/Cardio-Metabolic
Syndrome)
• Provide stage-specific therapeutic
interventions.
10
© 2010
Slide 11
The Significance of
Type 2 Diabetes Mellitus
• According to the CDC, 10% of the US
population has diabetes today.
• By the year 2050, the CDC projects that
21-33 % will be diagnosed with diabetes.
• This will lead to a 2-4x increase in health
care costs, or approximately $171 billion
per year.
11
© 2010
Slide 12
Slide 13
Type 2 DM Pathophysiology
• Initial compensation of IR by increased
pancreatic β-cell insulin secretion
– Lifestyle considerations leading to IR
• Insulin drives differentiation of
mesenchymal stem cells into preadipocytes and adipose tissue
• Concomitant qualitative β-cell dysfunction
as cellular cleavage capacity of proinsulin
to insulin exhausted
– Added adipogenic effect of proinsulin
13
© 2010
Slide 14
Type 2 DM Pathophysiology
• Increased hormonal secretion & increased
caloric intake = increased production of
visceral adipose tissue
• Visceral adipose tissue is metabolically
active
– Cytokines (adipokines) which negatively
influence IR
– Supression of adiponectin secretion by mature
adipose tissue = increased visceral adipose
production, increased IR, decreased
vasoprotective and anti-atherosclerotic effects
14
© 2010
Slide 15
Pfutzner A, et al A Biomarker Concept for Assessment of Insulin Resistance , β-Cell
Function and Chronic Systemic Inflammation in Type 2 Diabetes Mellitus. Clin Lab 2008;
54:486-490.
15
© 2010
Slide 16
.
16
© 2010
Slide 17
PreD Guide
Slide 18
Inflammation is an underlying driver of
the progression to diabetes.
1.
2.
3.
4.
Strongly Agree
Agree
Disagree
Strongly Disagree
0%
0%
4
1
2
Countdown
Slide 19
Inflammation:
Driving the
Progression 2 Diabetes
© 2010
2008
Slide 20
Inflammation & Chronic Disease
20
© 2010
Slide 21
Diabetes Mellitus
Heart Disease
Abdominal
Obesity
Dysglycemia
Dyslipidemia
Hypertension
© 2010
2008
Slide 22
Diabetes Mellitus
Heart Disease
Abdominal
Obesity
Insulin
Resistance
Dysglycemia
Dyslipidemia
Hypertension
© 2010
2008
Slide 23
Diabetes Mellitus
Heart Disease
Abdominal
Obesity
Inflammation
Insulin
Resistance
Dysglycemia
Dyslipidemia
Hypertension
© 2010
2008
Slide 24
Causes of Inflammation
• Diet
– Sugar
– Trans & saturated fats
– Polyunsaturated omega 6 oils (except GLA)
•
•
•
•
•
•
Allergens (food & environmental)
Stress
Lack of exercise
Toxins (metals, petrochemicals)
Infections (especially dental/gingivitis)
Obesity & Insulin Resistance
24
© 2010
Slide 25
Inflammation:
A Critical Underlying Driver
• Inflammation is a major driver of the
progression to diabetes through each
stage.
• “Inflammation causes insulin resistance . . .”
– Jerrald M. Olefsky, MD
• The use of multiple inflammatory markers
provides greater insight into the effects of
inflammation -> one marker for
inflammation may not provide a full clinical
picture.
25
© 2010
Slide 26
Markers of Inflammation
• hs-CRP
– Acute phase response protein/IR
• Interleukin IL-6
– Inflammatory cytokine/abdominal obesity
• Interleukin IL-8
– Inflammatory cytokine/abdominal obesity
• Tumor Necrosis Factor Alpha (TNFα)
– Inflammatory cytokine/abdominal obesity
• Plasminogen Activator Inhibitor 1 (PAI-1)
– Acute phase response protein/visceral obesity
26
© 2010
Slide 27
hs-CRP: Risk Factor for CVD
Kuller MRFIT1996
Ridker PHS 1997
Ridker PHS1997
Tracy CHS/RHPP1997
Ridker PHS1998,2001
Ridker WHS 1998,2000,2002
Koenig MONICA1999
Roivainen HELSINKI 2000
Mendall CAERPHILLY 2000
Danesh BRITAIN 2000
Gussekloo LEIDEN 2001
Lowe SPEEDWELL 2001
Packard WOSCOPS 2001
Ridker AFCAPS 2001
Rost FHS 2001
Pradhan WHI 2002
Albert PHS 2002
CHD death
MI
Stroke
CHD
PAD
CVD
CHD
CHD
CHD
CHD
Fatal Stroke
CHD
CV Events
CV Events
Stroke
MI, CVD death
Sudden Death
0
1.0
2.0
3.0
4.0
5.0
Relative Risk (upper versus lower quartile)
Ridker PM. Circulation
27 2003;107:363-369
6.0
© 2010
Slide 28
C-Reactive Protein
• Marker of inflammation, infection and injury
– Aspirin’s reduction of MI risk appears to be
related to CRP levels
– CRP activates complement which injures the
inner layer of blood vessels constriction of
vessels, arrhythmia
• Strong predictor of the risk of future MI
JUPITER Study – November, 2008
• 49% decrease in CAD end-points
• 20% decrease in ‘all cause’ mortality
• ‘40% of participants had insulin resistance’
28
© 2010
Slide 29
Inflammation & Risk of T2DM
29
© 2010
Slide 30
Slide 31
Stages of
Progression 2 Diabetes
© 2010
2008
Slide 32
Progression of Pre-Diabetes
32
© 2010
Slide 33
Optimal Function
Intervention = Maintenance of healthy diet & lifestyle
33
© 2010
Slide 34
Stage 1: Early Insulin Resistance
34
© 2010
Slide 35
Adiponectin
•
•
Protective adipose-derived protein
Plays an important role in regulating glucose
and lipid metabolism
– Moderates fat tissue
– Promotes insulin sensitivity
– Is inversely related to glucose & insulin
– Decreases hepatic glucose & lipid
production
– Protects against atherosclerosis by
suppressing vascular inflammation (antiinflammatory)
35
© 2010
Slide 36
Low Adiponectin associated with:
•
Insulin resistance
•
Glucose intolerance
•
Dyslipidemia
•
Increased risk of vascular injury &
atherosclerosis
•
Increased risk of diabetes mellitus
•
Inflammation
36
© 2010
Slide 37
Stage 1: Early Insulin Resistance
•
Pattern recognition:
– LOW Adiponectin
– ‘Normal’ Glucose, HbA1C, Insulin, and Proinsulin
– Normal or slightly high HOMA-IR
• “Normal” fasting blood sugar = < 100 mg/dL
• Blood sugar >87 mg/dL = progressive increase of
type 2 DM.
• Blood sugar < 81 mg/dL = low risk of DM
NEJM 2005;353:1454-62.
•
Treat with diet, lifestyle, supplementation.
37
© 2010
Slide 38
Stage 1 – Early Insulin Resistance
Stage 1 of metabolic dysglycemia represents
early insulin resistance, with adequate pancreatic beta
cell compensation to maintain normal glucose. Insulin
level may be normal or high. Adiponectin, which
provides protection against insulin resistance, diabetes
and cardiovascular disease, is typically low.
Dyslipidemia may or may not be present, including
elevated triglycerides and LDL-C, and/or low HDL-C.
At this stage, dietary and lifestyle measures are
usually adequate for improving insulin sensitivity
and preventing progression to Stage 2.
Treatment recommendations for Stage 1:
Lifestyle considerations
Reduce excess weight;
Increase physical
activity;
Reduce stress ;
Treat inflammatory
disorders (TNF-α
inhibits adiponectin)
Dietary considerations
Supplement considerations
Minimize sugar and refined
carbohydrates, fructose, soft drinks,
and saturated fats. Avoid trans fats.
Nutritional: B vitamins,
vitamin D, biotin,
magnesium, zinc, chromium,
alpha-lipoic acid & other
antioxidants, fish oils;
Emphasize a low-saturated fat,
Mediterranean-type diet (complex
carbohydrates, fresh fruits and
vegetables, nuts & other
monounsaturates, foods rich in
omega-3 fats, such as cold water
fish).
Herbal: Green tea,
cinnamon, fenugreek;
Hormonal: DHEA (if low)
Medication
considerations
Meds are not
usually needed
at this stage if
dietary and
lifestyle
measures are
followed.
Slide 39
Stage 2: Elevated Fasting Insulin
39
© 2010
Slide 40
Stage 2: Elevated Fasting Insulin
• Pattern recognition:
– LOW Adiponectin
– HIGH or high-normal HOMA-IR
– HIGH Insulin, but normal Proinsulin
– Mildly elevated glucose and/or HbA1C
• Fasting glucose 100-126 mg/dl and/or 2-hr pp glucose 140200 mg/dl and/or HbA1C 5.5-6.0%
• Usually due to a combination of insulin resistance & early beta-cell
impairment
• 24 million cases of type 2 DM in the U.S., but 57 million cases of
‘pre-diabetes’
• Treat with diet, lifestyle, supplementation, possible
pharmacotherapy.
40
© 2010
Slide 41
Stage 2 – Elevated Fasting Insulin
Stage 2 represents impaired glucose tolerance, usually
due to combination of insulin resistance and early pancreatic
beta-cell impairment. In most cases of insulin resistance,
compensatory increased insulin secretion is sufficient to
prevent hyperglycemia. However, in combination with betacell dysfunction, hyperglycemia can develop.1
Adiponectin is usually low, and glucose and/or HbA1C are
elevated, although not yet to a diabetic level. Insulin is usually
elevated. Dyslipidemia may or may not be present, including
elevated triglycerides and LDL-C, and/or low HDL-C.
At this stage, diet and lifestyle measures, along with
supplementation can help improve insulin sensitivity,
restore proper glucose regulation, and prevent
progression to diabetes (Stage 3).
Treatment recommendations for Stage 2
Lifestyle considerations
Reduce weight;
Increase physical
activity (esp. aerobic);
Reduce stress;
Treat any inflammatory
disorders
Dietary considerations
Avoid sugar and refined
carbohydrates, fructose, soft
drinks, alcohol, and trans fats.
Minimize saturated fats.
Emphasize a high-fiber, lowsaturated fat, Mediterranean-type
diet (e.g., legumes and whole
grains, fresh fruits and vegetables,
nuts & other monounsaturates,
foods rich in omega-3 fats, such
as cold water fish).
Supplement
considerations
Nutritional: B vitamins,
vitamin D, biotin, Mg, Zn,
Cr, α-lipoic acid & other
antioxidants, flavonoids
(e.g., grape seed extract),
fish oils, fiber supplement;
Herbal: Gymnema
sylvestre, green tea,
cinnamon, fenugreek;
Hormonal: DHEA (if low)
Medication considerations
Insulin sensitizers:
Biguanides (e.g.,
metformin); Dual PPAR
agonists (e.g., aleglitazar);
Inhibitors of starch
digestion: α-Glucosidase
inhibitors (e.g., acarbose);
Improvement of HbA1C:
DPP-4 Inhibitors (e.g.,
sitagliptin) or Pramlintide
Slide 42
Stage 3: Elevated Proinsulin
42
© 2010
Slide 43
Proinsulin
• Produced by pancreatic β-cells
• Precursor to insulin
• Serves as a marker of later stage β-cell
dysfunction & insulin resistance
• Has been used in trials (proinsulin/insulin
ratio) to describe improved β-cell function
resulting from β-cell sensitizing meds (ie,
biguanides/Metformin, TZDs/Actose)
43
© 2010
Slide 44
Proinsulin
• β-cell dysfunction impaired cleavage of
proinsulin to insulin levels of proinsulin increase
• Higher circulating levels of circulating proinsulin
(compared to insulin) indicate advancing β-cell
dysfunction & increased risk or presence of
diabetes.
• With advancing pre-diabetes, levels of both insulin
& proinsulin decline.
44
© 2010
Slide 45
Stage 3: Elevated Proinsulin
•
Pattern recognition:
– LOW Adiponectin
– HIGH Insulin & Elevated Proinsulin
– HIGH HOMA-IR
– HIGH Glucose & HbA1C
May or may not meet ADA definition for Type 2
Diabetes Mellitus
– Fasting Glucose > 125 mg/dL
– HgbA1c > 6.5%
•
Treat with diet, lifestyle, supplementation, and
pharmacotherapy.
45
© 2010
Slide 46
Stage 3 – Elevated Pro-Insulin
Stage 3 represents the development of diabetes, with insulin
Treatment recommendations for Stage 3
Lifestyle
considerations
Reduce
weight;
Increase
physical
activity (esp.
aerobic);
Reduce
stress;
Treat any
inflammatory
disorders
Dietary considerations
Avoid sugar and refined
carbohydrates, fructose, soft
drinks, alcohol, and trans fats.
Minimize saturated fats.
Emphasize a high-fiber, lowsaturated fat, Mediterranean-type
diet (e.g., legumes and whole
grains, fresh fruits and veggies,
nuts & other monounsaturates,
foods rich in omega-3 fats, such
as cold water fish).
resistance and progressive pancreatic beta-cell impairment. Betacell dysfunction can result from glucose toxicity, inflammatory
cytokines, oxidative stress, and/or lipotoxicity in the presence of
excess glucose.1,2
Glucose and HbA1C are significantly elevated, and insulin may
or may not be elevated, depending on beta-cell capacity to produce
adequate insulin. Sequential measurements can help reveal the
degree of beta-cell dysfunction; declining insulin along with
increasing proinsulin signifies late-stage impairment. The most
important therapeutic goal at this stage is to normalize and
maintain normal blood glucose levels.3
At this stage, a comprehensive approach is essential,
including diet and lifestyle measures, supplementation, and
targeted pharmaceuticals, based on the degree of beta-cell
impairment.
Supplement considerations
Nutritional: B vitamins (esp.
niacinamide, B6, B12, folate),
vitamin D, biotin, Mg, Zn, Cr, V,
antioxidants (e.g., NAC,
vitamins C, E, α-lipoic acid,
Se), flavonoids (e.g., grape
seed, bilberry), fish oils, fiber
supplement, carnosine;
Herbal: Gymnema, green tea,
cinnamon, fenugreek, maitake,
American or Panax ginseng,
rehmannia, scutellaria
Medication considerations
Insulin sensitizers: Thiazolidinediones
(e.g., pioglitazone); Biguanides (e.g.,
metformin); Dual PPAR agonists (e.g.,
aleglitazar); Inhibitors of starch
digestion: α-Glucosidase inhibitors
(e.g., acarbose); Improvement of
HbA1C: DPP-4 Inhibitors (e.g.,
sitagliptin) or Pramlintide; AGE
Inhibitor: Aminoguanidine; Insulin
secretagogues: Sulfonylureas (e.g.,
glipizide); Meglitinides; exanatide;
Insulin & K channel openers
Slide 47
Metabolic Markers
© 2010
2008
Slide 48
PreD Guide
48
© 2010
Slide 49
Hemoglobin A1c (HbA1c)
• Measures the amount of hemoglobin in a
red blood cell (RBC) that has been glycated
by excess glucose.
• Reflects average glucose concentration
during the previous 3 month period ~ the
life cycle of the RBC.
49
© 2010
Slide 50
HOMA-IR
• Homeostatic Model AssessmentInsulin Resistance
• Calculation based on plasma levels of:
– Fasting Glucose & Insulin
– Non-invasive, mathematical estimate insulin
resistance
50
© 2010
Slide 51
C-Peptide
• C-peptide is produced when proinsulin is
cleaved to form insulin and C-peptide.
• Increased levels of C-peptide reflect insulin
resistance.
51
© 2010
Slide 52
Conversion of Proinsulin to Insulin
(cleavag
e)
(cleavag
e)
©2007 by National Academy of Sciences
52
© 2010
Slide 53
Leptin
• Leptin is an adipocyte-derived hormone that
regulates appetite.
• In a healthy body, overeating induces leptin
production which suppresses appetite and
controls weight gain.
• Leptin is protective against obesity.
53
© 2010
Slide 54
Elevation of Leptin
• Indicates leptin resistance (interference with
leptin signaling)
• Associated with:
– High BMI & abdominal obesity
– Pancreatic beta-cell damage
– High triglycerides & Low HDL-C
54
© 2010
Slide 55
Case Study
© 2010
2008
Slide 56
56
© 2010
Slide 57
Slide 58
Key Points on Progression to Diabetes
• Can be prevented
• Can be reversed
• Can be treated effectively
• Metabolic processes may be present when
the patient is not yet symptomatic.
58
© 2010
Slide 59
Obesity: Final Considerations
• Obesity remains a major clinical concern. Insulin
resistance is a major cause of obesity (at least 70%).
• Diabetes Prevention Program trial showed 58%
reduction in incidence of T2DM with lifestyle
modifications.
• 5-10% reduction in body weight improves insulin
sensitivity, lipid profiles, endothelial function, reduces
thrombosis and inflammatory markers.
• There is a 3-fold increase in the odds that a patient
will attempt weight loss if it is recommended by a
trusted health care professional.
59
© 2010
Slide 60
The Continuum of PreD:
Guiding Diagnosis & Treatment of
Progression to Diabetes
Andrea M Girman, MD, MPH
PAFP
9 March 2012
© 2010
2008
The Continuum of PreD:
Guiding Diagnosis & Treatment of
Progression to Diabetes
Andrea M Girman, MD, MPH
VOMA
27 April 2012
© 2010
2008
Slide 2
The Continuum of PreD: Guiding
Diagnosis & Treatment of Progression to
Diabetes
Andrea M. Girman, MD, MPH
The following potential conflict of interest relationships are germane
to my presentation:
Equipment: None
Speakers Bureau: None
Stock Shareholder: None
Grant/Research Support: None
Consultant: None
Employment: Genova Diagnostics
Status of FDA devices used for the material being presented:
NA/Non-Clinical
Status of off-label use of devices, drugs or other materials
that constitute the subject of this presentation:
NA/Non-Clinical
Slide 3
Continuum of PreD:
Conversation Goals
• Examine the focus on obesity as major
identifier of people at risk for Type 2 DM
• Identify an underlying driver of progression
to Type 2 Diabetes: Inflammation
• Define the Stages of Pre-Diabetes
progression
• Consider Stage-specific Therapeutic
Interventions ~ Lifestyle +/- Meds
3
© 2010
Slide 4
Obesity:
Challenging Assumptions
• Many clinicians assume that they can
accurately predict patient risk for diabetes
based on obesity.
• If this is true, are tests designed to assess
risk of diabetes really needed?
4
© 2010
Slide 5
Defining Overweight/Obesity
5
© 2010
Slide 6
Overweight/Obesity Worldwide
% Population (2007)
New Zealand
62.6%
United Kingdom
61.0%
Iceland
60.2%
Luxembourg
54.8%
Ireland
51%
Finland
48.9%
Canada
46.8%
Slovak Republic
46.2%
Italy
45.5%
Netherlands
45.5%
Sweden
44.0%
Switzerland
37.3%
6
© 2010
Slide 7
Obesity Trends* Among U.S. Adults
BRFSS, 1990, 2000, 2010
2000
1990
2010
No Data
<10%
10%–14%
15%–19%
7
20%–24%
25%–29%
≥30%
© 2010
Slide 8
BMI < 25
BMI 25-30
BMI >30
MEN
30%
51%
71%
WOMEN
21%
43%
65%
26%
46%
68%
TOTAL
Rates of CardioMetabolic Syndrome
8
© 2010
Slide 9
CDC: Only 40% of the risk of
developing diabetes occurs in
people who are obese.
How do we find
the 60% of
people at risk
for developing
diabetes who
are NOT obese?
9
© 2010
Slide 10
PreD Assessment &
Clinical Utility
• Identify patients who are at risk for diabetes
& who are not obese
• Define that individual’s stage of
progression to Type 2 Diabetes (i.e.
Insulin Resistance/Cardio-Metabolic
Syndrome)
• Provide stage-specific therapeutic
interventions.
10
© 2010
Slide 11
The Significance of
Type 2 Diabetes Mellitus
• According to the CDC, 10% of the US
population has diabetes today.
• By the year 2050, the CDC projects that
21-33 % will be diagnosed with diabetes.
• This will lead to a 2-4x increase in health
care costs, or approximately $171 billion
per year.
11
© 2010
Slide 12
Slide 13
Type 2 DM Pathophysiology
• Initial compensation of IR by increased
pancreatic β-cell insulin secretion
– Lifestyle considerations leading to IR
• Insulin drives differentiation of
mesenchymal stem cells into preadipocytes and adipose tissue
• Concomitant qualitative β-cell dysfunction
as cellular cleavage capacity of proinsulin
to insulin exhausted
– Added adipogenic effect of proinsulin
13
© 2010
Slide 14
Type 2 DM Pathophysiology
• Increased hormonal secretion & increased
caloric intake = increased production of
visceral adipose tissue
• Visceral adipose tissue is metabolically
active
– Cytokines (adipokines) which negatively
influence IR
– Supression of adiponectin secretion by mature
adipose tissue = increased visceral adipose
production, increased IR, decreased
vasoprotective and anti-atherosclerotic effects
14
© 2010
Slide 15
Pfutzner A, et al A Biomarker Concept for Assessment of Insulin Resistance , β-Cell
Function and Chronic Systemic Inflammation in Type 2 Diabetes Mellitus. Clin Lab 2008;
54:486-490.
15
© 2010
Slide 16
.
16
© 2010
Slide 17
PreD Guide
Slide 18
Inflammation is an underlying driver of
the progression to diabetes.
1.
2.
3.
4.
Strongly Agree
Agree
Disagree
Strongly Disagree
0%
0%
4
1
2
Countdown
Slide 19
Inflammation:
Driving the
Progression 2 Diabetes
© 2010
2008
Slide 20
Inflammation & Chronic Disease
20
© 2010
Slide 21
Diabetes Mellitus
Heart Disease
Abdominal
Obesity
Dysglycemia
Dyslipidemia
Hypertension
© 2010
2008
Slide 22
Diabetes Mellitus
Heart Disease
Abdominal
Obesity
Insulin
Resistance
Dysglycemia
Dyslipidemia
Hypertension
© 2010
2008
Slide 23
Diabetes Mellitus
Heart Disease
Abdominal
Obesity
Inflammation
Insulin
Resistance
Dysglycemia
Dyslipidemia
Hypertension
© 2010
2008
Slide 24
Causes of Inflammation
• Diet
– Sugar
– Trans & saturated fats
– Polyunsaturated omega 6 oils (except GLA)
•
•
•
•
•
•
Allergens (food & environmental)
Stress
Lack of exercise
Toxins (metals, petrochemicals)
Infections (especially dental/gingivitis)
Obesity & Insulin Resistance
24
© 2010
Slide 25
Inflammation:
A Critical Underlying Driver
• Inflammation is a major driver of the
progression to diabetes through each
stage.
• “Inflammation causes insulin resistance . . .”
– Jerrald M. Olefsky, MD
• The use of multiple inflammatory markers
provides greater insight into the effects of
inflammation -> one marker for
inflammation may not provide a full clinical
picture.
25
© 2010
Slide 26
Markers of Inflammation
• hs-CRP
– Acute phase response protein/IR
• Interleukin IL-6
– Inflammatory cytokine/abdominal obesity
• Interleukin IL-8
– Inflammatory cytokine/abdominal obesity
• Tumor Necrosis Factor Alpha (TNFα)
– Inflammatory cytokine/abdominal obesity
• Plasminogen Activator Inhibitor 1 (PAI-1)
– Acute phase response protein/visceral obesity
26
© 2010
Slide 27
hs-CRP: Risk Factor for CVD
Kuller MRFIT1996
Ridker PHS 1997
Ridker PHS1997
Tracy CHS/RHPP1997
Ridker PHS1998,2001
Ridker WHS 1998,2000,2002
Koenig MONICA1999
Roivainen HELSINKI 2000
Mendall CAERPHILLY 2000
Danesh BRITAIN 2000
Gussekloo LEIDEN 2001
Lowe SPEEDWELL 2001
Packard WOSCOPS 2001
Ridker AFCAPS 2001
Rost FHS 2001
Pradhan WHI 2002
Albert PHS 2002
CHD death
MI
Stroke
CHD
PAD
CVD
CHD
CHD
CHD
CHD
Fatal Stroke
CHD
CV Events
CV Events
Stroke
MI, CVD death
Sudden Death
0
1.0
2.0
3.0
4.0
5.0
Relative Risk (upper versus lower quartile)
Ridker PM. Circulation
27 2003;107:363-369
6.0
© 2010
Slide 28
C-Reactive Protein
• Marker of inflammation, infection and injury
– Aspirin’s reduction of MI risk appears to be
related to CRP levels
– CRP activates complement which injures the
inner layer of blood vessels constriction of
vessels, arrhythmia
• Strong predictor of the risk of future MI
JUPITER Study – November, 2008
• 49% decrease in CAD end-points
• 20% decrease in ‘all cause’ mortality
• ‘40% of participants had insulin resistance’
28
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Slide 29
Inflammation & Risk of T2DM
29
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Slide 30
Slide 31
Stages of
Progression 2 Diabetes
© 2010
2008
Slide 32
Progression of Pre-Diabetes
32
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Slide 33
Optimal Function
Intervention = Maintenance of healthy diet & lifestyle
33
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Slide 34
Stage 1: Early Insulin Resistance
34
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Slide 35
Adiponectin
•
•
Protective adipose-derived protein
Plays an important role in regulating glucose
and lipid metabolism
– Moderates fat tissue
– Promotes insulin sensitivity
– Is inversely related to glucose & insulin
– Decreases hepatic glucose & lipid
production
– Protects against atherosclerosis by
suppressing vascular inflammation (antiinflammatory)
35
© 2010
Slide 36
Low Adiponectin associated with:
•
Insulin resistance
•
Glucose intolerance
•
Dyslipidemia
•
Increased risk of vascular injury &
atherosclerosis
•
Increased risk of diabetes mellitus
•
Inflammation
36
© 2010
Slide 37
Stage 1: Early Insulin Resistance
•
Pattern recognition:
– LOW Adiponectin
– ‘Normal’ Glucose, HbA1C, Insulin, and Proinsulin
– Normal or slightly high HOMA-IR
• “Normal” fasting blood sugar = < 100 mg/dL
• Blood sugar >87 mg/dL = progressive increase of
type 2 DM.
• Blood sugar < 81 mg/dL = low risk of DM
NEJM 2005;353:1454-62.
•
Treat with diet, lifestyle, supplementation.
37
© 2010
Slide 38
Stage 1 – Early Insulin Resistance
Stage 1 of metabolic dysglycemia represents
early insulin resistance, with adequate pancreatic beta
cell compensation to maintain normal glucose. Insulin
level may be normal or high. Adiponectin, which
provides protection against insulin resistance, diabetes
and cardiovascular disease, is typically low.
Dyslipidemia may or may not be present, including
elevated triglycerides and LDL-C, and/or low HDL-C.
At this stage, dietary and lifestyle measures are
usually adequate for improving insulin sensitivity
and preventing progression to Stage 2.
Treatment recommendations for Stage 1:
Lifestyle considerations
Reduce excess weight;
Increase physical
activity;
Reduce stress ;
Treat inflammatory
disorders (TNF-α
inhibits adiponectin)
Dietary considerations
Supplement considerations
Minimize sugar and refined
carbohydrates, fructose, soft drinks,
and saturated fats. Avoid trans fats.
Nutritional: B vitamins,
vitamin D, biotin,
magnesium, zinc, chromium,
alpha-lipoic acid & other
antioxidants, fish oils;
Emphasize a low-saturated fat,
Mediterranean-type diet (complex
carbohydrates, fresh fruits and
vegetables, nuts & other
monounsaturates, foods rich in
omega-3 fats, such as cold water
fish).
Herbal: Green tea,
cinnamon, fenugreek;
Hormonal: DHEA (if low)
Medication
considerations
Meds are not
usually needed
at this stage if
dietary and
lifestyle
measures are
followed.
Slide 39
Stage 2: Elevated Fasting Insulin
39
© 2010
Slide 40
Stage 2: Elevated Fasting Insulin
• Pattern recognition:
– LOW Adiponectin
– HIGH or high-normal HOMA-IR
– HIGH Insulin, but normal Proinsulin
– Mildly elevated glucose and/or HbA1C
• Fasting glucose 100-126 mg/dl and/or 2-hr pp glucose 140200 mg/dl and/or HbA1C 5.5-6.0%
• Usually due to a combination of insulin resistance & early beta-cell
impairment
• 24 million cases of type 2 DM in the U.S., but 57 million cases of
‘pre-diabetes’
• Treat with diet, lifestyle, supplementation, possible
pharmacotherapy.
40
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Slide 41
Stage 2 – Elevated Fasting Insulin
Stage 2 represents impaired glucose tolerance, usually
due to combination of insulin resistance and early pancreatic
beta-cell impairment. In most cases of insulin resistance,
compensatory increased insulin secretion is sufficient to
prevent hyperglycemia. However, in combination with betacell dysfunction, hyperglycemia can develop.1
Adiponectin is usually low, and glucose and/or HbA1C are
elevated, although not yet to a diabetic level. Insulin is usually
elevated. Dyslipidemia may or may not be present, including
elevated triglycerides and LDL-C, and/or low HDL-C.
At this stage, diet and lifestyle measures, along with
supplementation can help improve insulin sensitivity,
restore proper glucose regulation, and prevent
progression to diabetes (Stage 3).
Treatment recommendations for Stage 2
Lifestyle considerations
Reduce weight;
Increase physical
activity (esp. aerobic);
Reduce stress;
Treat any inflammatory
disorders
Dietary considerations
Avoid sugar and refined
carbohydrates, fructose, soft
drinks, alcohol, and trans fats.
Minimize saturated fats.
Emphasize a high-fiber, lowsaturated fat, Mediterranean-type
diet (e.g., legumes and whole
grains, fresh fruits and vegetables,
nuts & other monounsaturates,
foods rich in omega-3 fats, such
as cold water fish).
Supplement
considerations
Nutritional: B vitamins,
vitamin D, biotin, Mg, Zn,
Cr, α-lipoic acid & other
antioxidants, flavonoids
(e.g., grape seed extract),
fish oils, fiber supplement;
Herbal: Gymnema
sylvestre, green tea,
cinnamon, fenugreek;
Hormonal: DHEA (if low)
Medication considerations
Insulin sensitizers:
Biguanides (e.g.,
metformin); Dual PPAR
agonists (e.g., aleglitazar);
Inhibitors of starch
digestion: α-Glucosidase
inhibitors (e.g., acarbose);
Improvement of HbA1C:
DPP-4 Inhibitors (e.g.,
sitagliptin) or Pramlintide
Slide 42
Stage 3: Elevated Proinsulin
42
© 2010
Slide 43
Proinsulin
• Produced by pancreatic β-cells
• Precursor to insulin
• Serves as a marker of later stage β-cell
dysfunction & insulin resistance
• Has been used in trials (proinsulin/insulin
ratio) to describe improved β-cell function
resulting from β-cell sensitizing meds (ie,
biguanides/Metformin, TZDs/Actose)
43
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Slide 44
Proinsulin
• β-cell dysfunction impaired cleavage of
proinsulin to insulin levels of proinsulin increase
• Higher circulating levels of circulating proinsulin
(compared to insulin) indicate advancing β-cell
dysfunction & increased risk or presence of
diabetes.
• With advancing pre-diabetes, levels of both insulin
& proinsulin decline.
44
© 2010
Slide 45
Stage 3: Elevated Proinsulin
•
Pattern recognition:
– LOW Adiponectin
– HIGH Insulin & Elevated Proinsulin
– HIGH HOMA-IR
– HIGH Glucose & HbA1C
May or may not meet ADA definition for Type 2
Diabetes Mellitus
– Fasting Glucose > 125 mg/dL
– HgbA1c > 6.5%
•
Treat with diet, lifestyle, supplementation, and
pharmacotherapy.
45
© 2010
Slide 46
Stage 3 – Elevated Pro-Insulin
Stage 3 represents the development of diabetes, with insulin
Treatment recommendations for Stage 3
Lifestyle
considerations
Reduce
weight;
Increase
physical
activity (esp.
aerobic);
Reduce
stress;
Treat any
inflammatory
disorders
Dietary considerations
Avoid sugar and refined
carbohydrates, fructose, soft
drinks, alcohol, and trans fats.
Minimize saturated fats.
Emphasize a high-fiber, lowsaturated fat, Mediterranean-type
diet (e.g., legumes and whole
grains, fresh fruits and veggies,
nuts & other monounsaturates,
foods rich in omega-3 fats, such
as cold water fish).
resistance and progressive pancreatic beta-cell impairment. Betacell dysfunction can result from glucose toxicity, inflammatory
cytokines, oxidative stress, and/or lipotoxicity in the presence of
excess glucose.1,2
Glucose and HbA1C are significantly elevated, and insulin may
or may not be elevated, depending on beta-cell capacity to produce
adequate insulin. Sequential measurements can help reveal the
degree of beta-cell dysfunction; declining insulin along with
increasing proinsulin signifies late-stage impairment. The most
important therapeutic goal at this stage is to normalize and
maintain normal blood glucose levels.3
At this stage, a comprehensive approach is essential,
including diet and lifestyle measures, supplementation, and
targeted pharmaceuticals, based on the degree of beta-cell
impairment.
Supplement considerations
Nutritional: B vitamins (esp.
niacinamide, B6, B12, folate),
vitamin D, biotin, Mg, Zn, Cr, V,
antioxidants (e.g., NAC,
vitamins C, E, α-lipoic acid,
Se), flavonoids (e.g., grape
seed, bilberry), fish oils, fiber
supplement, carnosine;
Herbal: Gymnema, green tea,
cinnamon, fenugreek, maitake,
American or Panax ginseng,
rehmannia, scutellaria
Medication considerations
Insulin sensitizers: Thiazolidinediones
(e.g., pioglitazone); Biguanides (e.g.,
metformin); Dual PPAR agonists (e.g.,
aleglitazar); Inhibitors of starch
digestion: α-Glucosidase inhibitors
(e.g., acarbose); Improvement of
HbA1C: DPP-4 Inhibitors (e.g.,
sitagliptin) or Pramlintide; AGE
Inhibitor: Aminoguanidine; Insulin
secretagogues: Sulfonylureas (e.g.,
glipizide); Meglitinides; exanatide;
Insulin & K channel openers
Slide 47
Metabolic Markers
© 2010
2008
Slide 48
PreD Guide
48
© 2010
Slide 49
Hemoglobin A1c (HbA1c)
• Measures the amount of hemoglobin in a
red blood cell (RBC) that has been glycated
by excess glucose.
• Reflects average glucose concentration
during the previous 3 month period ~ the
life cycle of the RBC.
49
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Slide 50
HOMA-IR
• Homeostatic Model AssessmentInsulin Resistance
• Calculation based on plasma levels of:
– Fasting Glucose & Insulin
– Non-invasive, mathematical estimate insulin
resistance
50
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Slide 51
C-Peptide
• C-peptide is produced when proinsulin is
cleaved to form insulin and C-peptide.
• Increased levels of C-peptide reflect insulin
resistance.
51
© 2010
Slide 52
Conversion of Proinsulin to Insulin
(cleavag
e)
(cleavag
e)
©2007 by National Academy of Sciences
52
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Slide 53
Leptin
• Leptin is an adipocyte-derived hormone that
regulates appetite.
• In a healthy body, overeating induces leptin
production which suppresses appetite and
controls weight gain.
• Leptin is protective against obesity.
53
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Slide 54
Elevation of Leptin
• Indicates leptin resistance (interference with
leptin signaling)
• Associated with:
– High BMI & abdominal obesity
– Pancreatic beta-cell damage
– High triglycerides & Low HDL-C
54
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Slide 55
Case Study
© 2010
2008
Slide 56
56
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Slide 57
Slide 58
Key Points on Progression to Diabetes
• Can be prevented
• Can be reversed
• Can be treated effectively
• Metabolic processes may be present when
the patient is not yet symptomatic.
58
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Slide 59
Obesity: Final Considerations
• Obesity remains a major clinical concern. Insulin
resistance is a major cause of obesity (at least 70%).
• Diabetes Prevention Program trial showed 58%
reduction in incidence of T2DM with lifestyle
modifications.
• 5-10% reduction in body weight improves insulin
sensitivity, lipid profiles, endothelial function, reduces
thrombosis and inflammatory markers.
• There is a 3-fold increase in the odds that a patient
will attempt weight loss if it is recommended by a
trusted health care professional.
59
© 2010
Slide 60
The Continuum of PreD:
Guiding Diagnosis & Treatment of
Progression to Diabetes
Andrea M Girman, MD, MPH
PAFP
9 March 2012
© 2010
2008