1-h OGTT e rischio cardio-metabolico. Lo studio CAtanzaro ... - SID … OGTT Studio Catameris...

1-h OGTT e rischio cardio-metabolico.

Lo studio CAtanzaro MEtabolic RIsk factors

(CATAMERI)

Giorgio Sesti

Università “Magna Graecia” di CatanzaroDiapositiva preparata da Giorgio Sesti e

ceduta alla Società Italiana di D

iabetologia.

Per avere una versione originale si prega di scrivere a [email protected]

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Adapted from: American Diabetes Association. Diabetes Care.37 Suppl 1:S81-90., 2014

Normal

Diabetes Mellitus

PrediabetesImpaired Glucose

Tolerance

Fasting PlasmaGlucose

126 mg/dL

2-hour Plasma Glucose On OGTT

200 mg/dL

140 mg/dL

Any abnormality must be repeated and confirmed on a separate day

The diagnosis of diabetes can also be made based on unequivocal symptoms and a random glucose >200 mg/dL

100 mg/dL

PrediabetesImpaired Fasting

Glucose

What is Prediabetes?

Normal

Diabetes Mellitus

Hemoglobin A1C

6.5%

5.7%

Prediabetes

Normal

Diabetes Mellitus

Diapositiva preparata da Giorgio Sesti e


iabetologia.


Classification of glucose tolerance states - ADA

State FPG

(mg/dl)

2-h PG OGTT

(mg/dl)

HbA1c

(%)

NGT <100 <140 <5.7

Isolated IFG 100-125 <140 <5.7

Isolated IGT <100 140-199 <5.7

Isolated A1c <100 <140 5.7-6.4

Combined IFG/IGT

100-125 140-199 <5.7

CombinedIFG/A1c

100-125 <140 5.7-6.4

Combined

IGT/A1c

<100 140-199 5.7-6.4

Combined

IFG/IGT/A1c

100-125 140-199 5.7-6.4Diapositiva preparata da Giorgio Sesti e


iabetologia.


Venn diagram representing the percentage of elevated A1c, IGT, and IFG in an Italian cohort with dysglycemia (n=420)

19.0%

11.4%

10.2%

9.5%

IGT19.0%

IFG13.3%

A1c17.4%

Marini MA et al. Diabetes Care 35:1144–1149, 2012



iabetologia.




50

70

90

110

130

150

170

190

210

230

250

0 30 60 90 120

NGT 1h-low

NGT 1h-high

Isolated IFG

IGT

Time (min)

Pla

sm

a g

luco

se

co

nce

ntr

ati

on

(mg

/d

l)

x

Fiorentino TV et al. J Clin Endocrinol Metab 2015

Plasma glucose levels during OGTT in subjects with NGT 1h-low, NGT 1h-high, isolated IFG and IGT



iabetologia.




Abdul-Ghani MA et al. Diabetes Care 31:1650–1655, 2008

Incidence of type 2 diabetes according to 1-hour post-load plasma glucose

(>155 mg/dl) in the San Antonio Heart Study (n=1610)

Incidence of type 2 diabetes according to 1-hour post-load plasma glucose (>155 mg/dl) in the Botnia Study

(n=2442)


NGT1-h PG<155

NGT1-h PG>155

NGT1-h PG<155

NGT1-h PG>155Diapositiv

a preparata da Giorgio Sesti e ceduta alla Società Ita

liana di Diabetologia.



Area under the ROC curve for various predictive parameters for future development of T2DM

Parameter ROC Cutoff Sensitivity Specificity

Fasting plasma glucose 0.75

Plasma glucose at 30 min 0.77

Plasma glucose at 60 min 0.84 155 0.75 0.79

Plasma glucose at 120 min 0.79 140 0.51 0.92



iabetologia.




iabetologia.


Cox regression analyses adjusted for age, gender and BMI at baseline comparing the risk of NGT 1h-high, isolated IFG and IGT to develop T2DM

HR

NGT1-h PG<155

(n=174)

NGT1-h PG>155

(n=60)

IGT(n=86)

Isolated IFG(n=72)

1.06-15.26

2.09-21.24

0.44-8.29

Fiorentino TV et al. J Clin Endocrinol Metab100:3744-3751, 2015



iabetologia.




Study NGT 1-hPG<155

NGT 1-h PG>155

OddsRatio

95% CI

San Antonio

Heart Study

33/250 32/1117 5,15 3,10 to 8,56

Botnia Study 15/191 12/946 6,63 3,05 to 14,41

Asian Indians 98/502 50/677 3,04 2,11 to 4,37

CATAMERI 10/60 5/170 6,60 2,15 to 20,21

Total (random effects)

156/1003 99/2910 4,51 2,97 to 6,85

Test for Heterogeneity for 4 studies:P= 0,1313, I2= 46,67%

Meta-analysis of four prospective studies

Meta-analysis

1 10 100

Odds ratio

San Antonio Heart Study

Botnia Study

Asian Indians

CATAMERI

Total (fixed effects)


Meta-analysis

1 10 100

Odds ratio

San Antonio Heart Study

Botnia Study

Asian Indians

CATAMERI

Total (fixed effects)


OR: 4.5195% CI 2.97-6.85;

P <0.001



iabetologia.


Fiorentino TV et al. Nutr Metab Cardiovasc Dis 2016

NGT(n=1658)

IFG/IGT combo

(n=302)

Isolated IFG

(n=401)

Isolated IGT

(n=397)

New T2DM(n=242)

%

Proportion of subjects with 1-h PG >155mg/dl across dysglycemic conditions.The CATAMERI study (n=3020)

1-h PG >155mg/dl



iabetologia.




AGENDA

Clinical characteristics of NGT 1h-high individuals:

insulin sensitivity and β-cell function,

classical and non classical CV risk factors,

hepatic steatosis,

CV organ damage, and risk of CVD.



iabetologia.


Insulin sensitivity is reduced in NGT subjects with 1-h PG >155mg/dl as compared with individuals with 1-h PG<155 mg/dl or IFG

P<0.05P=0.02

Le

an

glu

co

se

dis

po

sa

l (m

g x

Kg

-1 F

FM

x m

in-1

)

P values refer to results after analyses with adjustment for age, gender, and BMI

NGT1-h PG<155

(n=344)

NGT1-h PG>155

(n=101)

IGT(n=80)

Isolated IFG

(n=70)




iabetologia.




Insulin secretion is reduced in NGT subjects with 1-h PG >155mg/dl as compared with individuals with 1-h PG<155 mg/dl or IFG

P<0.05P<0.0001

Insu

lin

og

en

ic i

nd

ex

(

Ins

30/

Glu

c3

0)


NGT1-h PG<155

(n=344)

NGT1-h PG>155

(n=101)

IGT(n=80)

Isolated IFG

(n=70)




iabetologia.




Disposition index is reduced in NGT subjects with 1-h PG >155mg/dl as compared with individuals with 1-h PG<155 mg/dl or IFG

P<0.001P<0.0001


NGT1-h PG<155

(n=344)

NGT1-h PG>155

(n=101)

IGT(n=80)

Isolated IFG

(n=70)

Dis

po

sit

ion

ind

ex

(In

s3

0/

Glu

c3

0x

M

FFM

)




iabetologia.




P<0.0001 P<0.05

Insulin sensitivity is reduced in NGT subjects with 1-h PG >155mg/dl as compared with individuals with 1-h PG<155 mg/dl stratified by HbA1c

HbA1c <5.7% 1-h PG<155

(n=198)

HbA1c <5.7% 1-h PG>155

(n=95)

HbA1c 5.7–6.4%1-h PG>155

(n=41)

HbA1c 5.7–6.4%1-h PG<155

(n=32)


Le

an

glu

co

se

dis

po

sa

l (m

g x

Kg

-1 F

FM

x m

in-1

)

Sesti et al.unplublished



iabetologia.




P<0.0001 P<0.0001

Insulin secretion is reduced in NGT subjects with 1-h PG >155mg/dl as compared with individuals with 1-h PG<155 mg/dl stratified by HbA1c

HbA1c <5.7% 1-h PG<155

(n=602)

HbA1c <5.7% 1-h PG>155

(n=418)

HbA1c 5.7–6.4%1-h PG>155

(n=292)

HbA1c 5.7–6.4%1-h PG<155

(n=119)


Insu

lin

og

en

ic i

nd

ex

(

Ins

30/

Glu

c3

0)




iabetologia.




P<0.0001

P<0.0001

Disposition index is reduced in NGT subjects with 1-h PG >155mg/dl as compared with individuals with 1-h PG<155 mg/dl stratified by HbA1c

HbA1c <5.7% 1-h PG<155

(n=602)

HbA1c <5.7% 1-h PG>155

(n=418)

HbA1c 5.7–6.4%1-h PG>155

(n=292)

HbA1c 5.7–6.4%1-h PG<155

(n=119)


Dis

po

sit

ion

in

de

x(

Ins

30/

Glu

c3

0x

M

ats

ud

a i

nd

ex

)




iabetologia.




Insulin clearance is reduced in NGT subjects with 1-h PG >155mg/dl as compared with individuals with 1-h PG<155 mg/dl

NGT1-h PG<155

(n=278)

P=0.006

P=0.01

NGT1-h PG>155

(n=96)

IGT(n=64)

Marini MA. et al. PLoS One 8: e77440, 2013

Insu

lin

cle

ara

nce

(m

l/m

in x

m2)




iabetologia.




2h-Insulin levels are increased in NGT subjects with 1-h PG >155mg/dl as compared with individuals with 1-h PG<155 mg/dl

NGT1-h PG<155

(n=278)

P<0.001

P<0.0001

NGT1-h PG>155

(n=96)

IGT(n=64)

Marini M.A. et al. PLoS One 8: e77440, 2013

2-h

in

su

lin

(p

mo

l/l)




iabetologia.




Insulin clearance correlates with 2h insulin levels

Marini M.A. et al. PLoS One 8: e77440, 2013

Insulin clearance (ml/min x m2)

r = -26; P<0.0001



iabetologia.




Correlation between minutes spent in hypoglycemia and 2-h post-load insulin levels

Min

ute

s p

er

da

y i

n h

yp

og

lyce

mia

2-h Insulin levels (µU/ml)

r =0.27P=0.02

Castaldo E. et al. PLoS ONE 6 (12): e28312, 2011



iabetologia.




SGLT1

β-actin

SG

LT

1 p

rote

in l

eve

ls(%

ove

r N

GT

1h

-lo

w)

NGT1-h PG<155

(n=12)

NGT1-h PG>155

(n=12)

IGT(n=11)

DM2(n=9)

Intestinal SGLT1 protein levels are increased in subjects with post-load hyperglycemia

P=0.003




iabetologia.


L’espressione di SGTL1 non correla con la glicemia a digiuno




iabetologia.


L’espressione di SGTL1 correla con la glicemia a 1 ora post-carico




iabetologia.


L’espressione di SGTL1 non correla con la glicemia a 2 ore post-carico




iabetologia.


GLU

T2

pro

tein

le

ve

ls

(% o

ve

r N

GT

1h

-lo

w)

GLUT2

β-actin

IGT(n=11)

DM2(n=9)

Intestinal GLUT2 expression is increased in subjects with type 2 diabetes

NGT1-h PG<155

(n=12)

NGT1-h PG>155

(n=12)

P=0.007




iabetologia.


AGENDA




hepatic steatosis,




iabetologia.


HDL levels are reduced in NGT subjects with 1-h PG >155mg/dl as compared with individuals with 1-h PG<155 mg/dl

HD

L(m

g/d

L)

NGT1-h PG<155

(n=295)

P=0.006

P=0.02

NGT1-h PG>155

(n=109)

IGT(n=202)

Isolated IFG

(n=104)

Sesti et al. BMJ Open Diab Res Care 2:e000016, 2014

P values refer to results after analyses with adjustment for age, gender, and BMIDiapositiv






Triglycerides levels are increased in NGT subjects with 1-h PG >155mg/dl as compared with individuals with 1-h PG<155 mg/dl

Tri

gly

ce

rid

es

(mg

/d

L)

NGT1-h PG<155

(n=295)

P<0.0001

P=0.05

NGT1-h PG>155

(n=109)

IGT(n=202)

Isolated IFG

(n=104)


P=0.02







Apolipoprotein B levels are increased in NGT subjects with 1-h PG >155mg/dl as compared with individuals with 1-h PG<155 mg/dl

Ap

oli

po

pro

tein

B

(mg

/d

L)

NGT1-h PG<155

(n=510)

P=0.02

NGT1-h PG>155

(n=211)

New T2DM(n=58)

IGT(n=233)


P=0.05







Apolipoprotein B/ Apolipoprotein A1 ratio is increased in NGT subjects with 1-h PG >155mg/dl as compared with individuals with 1-h PG<155 mg/dl

Ap

oli

po

pro

tein

B/

Ap

oli

po

pro

tein

A1

NGT1-h PG<155

(n=510)

P=0.02

NGT1-h PG>155

(n=211)

New T2DM(n=58)

IGT(n=233)


P=0.04


P=0.04



iabetologia.




LDL cholesterol/Apolipoprotein B ratio is increased in NGT subjects with 1-h PG >155mg/dl as compared with individuals with 1-h PG<155 mg/dl

LD

L/A

po

lip

op

rote

in B

rati

o

NGT1-h PG<155

(n=510)

P=0.04

NGT1-h PG>155

(n=211)

New T2DM(n=58)

IGT(n=233)


P=0.006


P=0.003



iabetologia.




hsCRP levels are increased in NGT subjects with 1-h PG >155mg/dl as compared with individuals with 1-h PG<155 mg/dl - the CATAMERI study

hsC

RP

(m

g/l)

NGT1-h PG<155

(n=497)

P<0.0001

P<0.0001

NGT1-h PG>155

(n=154)

IGT(n=290)

Sesti et al. Acta Diabetol 51:927-93 , 2014

Isolated IFG

(n=158)







Complement C3 levels are increased in NGT subjects with 1-h PG >155mg/dl as compared with individuals with 1-h PG<155 mg/dl - the CATAMERI study

Co

mp

lem

en

t C

3 (

g/l)

P<0.0001

P<0.001

NGT1-h PG<155

(n=497)

NGT1-h PG>155

(n=154)

IGT(n=290)

Isolated IFG

(n=158)








ESR levels are increased in NGT subjects with 1-h PG >155mg/dl as compared with individuals with 1-h PG<155 mg/dl - the CATAMERI study

ES

R (

mm

/h

)P=0.002

P=0.04

NGT1-h PG<155

(n=497)

NGT1-h PG>155

(n=154)

IGT(n=290)

Isolated IFG

(n=158)








Fibrinogen levels are increased in NGT subjects with 1-h PG >155mg/dl as compared with individuals with 1-h PG<155 mg/dl - the CATAMERI study

Fib

rin

og

en

(m

g/d

l)P=0.02

P=0.01

NGT1-h PG<155

(n=497)

NGT1-h PG>155

(n=154)

IGT(n=290)

Isolated IFG

(n=158)








Uric acid levels are increased in NGT subjects with 1-h PG >155mg/dl as compared with individuals with 1-h PG<155 mg/dl

UA

(m

g/d

L)

NGT1-h PG<155

(n=488)

P<0.0001

NGT1-h PG>155

(n=191)

IGT(n=214)

Perticone F. et al. Diabetes Care 35:153–157, 2012



iabetologia.




Fructose consumption is increased in NGT subjects with 1-h PG >155mg/dl as compared with individuals with 1-h PG<155 mg/dl

Fru

cto

se

(g

)

NGT1-h PG<155

(n=188)

P<0.0001

NGT1-h PG>155

(n=94)

Sciacqua A et al. Nutr Metab Cardiovasc Dis 24, 547-553, 2014

Dietary intake was quantified by a semiquantitative food frequency questionnaire (FEQ) validated in the European Investigation into Cancer and Nutrition (EPIC) study.



iabetologia.




Sciacqua A et al. Int J Cardiol 197:271-275, 2015

Uric acid is an independent predictor of cardiovascular events in post-menopausal women (n=645)

*3° tertile vs. 1° tertile

HR=1.903, P=0.021

*Multivariable Cox regression model including age, smoking, LDLcholesterol, pulse pressure, fasting glucose and BMI



iabetologia.




Plasma IGF-1 levels are reduced in NGT subjects with 1-h PG >155mg/dl as compared with individuals with 1-h PG<155 mg/dl

IGF-1

(n

g/m

l)

NGT1-h PG<155

(n=521)

P<0.0001

P<0.0001

NGT1-h PG>155

(n=243)

IGT(n=263)

Perticone F et al. Eur J Clin Invest 42: 1325–1331, 2012



iabetologia.




1st quartile(n=141)

2nd quartile(n=140)

4° quartile(n=139)

3° quartile(n=142)


Risk of developing type-2 diabetes by baseline IGF-I concentrations for 567 nondiabetic individuals, The CATAMERI Study (mean follow-up 5,7 years)

IGF-1

(n

g/m

l)

Sesti G. unpublished



iabetologia.




1st quartile(n=141)

2nd quartile(n=140)

4° quartile(n=139)

3° quartile(n=142)

Ha

za

rd r

ati

o


Risk of developing type-2 diabetes by baseline IGF-I concentrations for 567 nondiabetic individuals, The CATAMERI Study (mean follow-up 5,7 years)

CI95%( 1.6-16.7)

CI95%(1.1-11.4)

CI95%(1.2-12.7)

Sesti G. unpublished



iabetologia.




Svensson,J et al. J Clin Endocrinol Metab 97: 4623–4630, 2012

Kaplan-Meier survival curves for CVD mortality by serum IGF-I concentration

Quintile 1

Quintile 5

Quintile 2-4



iabetologia.


AGENDA




hepatic steatosis,




iabetologia.



NGT1-h PG<155

(n=295)

NGT1-h PG>155

(n=109)

IGT(n=202)

Isolated IFG

(n=104)

ALT

(U

I/l)

Liver enzymes are increased in NGT subjects with 1-h PG >155mg/dl as compared with individuals with 1-h PG<155 mg/dl

P<0.0001

P=0.03








NGT1-h PG<155

(n=295)

NGT1-h PG>155

(n=109)

IGT(n=202)

Isolated IFG

(n=104)

Liver enzymes are increased in NGT subjects with 1-h PG >155mg/dl as compared with individuals with 1-h PG<155 mg/dl

P<0.0001

P=0.03


GG

T (

UI/

l)



iabetologia.




Liver IR index is increased in NGT subjects with 1-h PG >155mg/dl as compared with individuals with 1-h PG<155 mg/dl - the CATAMERI study

Liv

er

IR i

nd

ex

The liver IR index was calculated using the formula: -0.091 + (log insulin AUC 0-120 min × 0.400) + (log fat mass % × 0.346) -(log HDL Cholesterol × 0.408) + (log BMI × 0.435)


NGT1-h PG<155

(n=295)

NGT1-h PG>155

(n=109)

IGT(n=202)

Isolated IFG

(n=104)

P<0.0001

P<0.0001

P=0.01



iabetologia.




Logistic regression analyses adjusted for age, and gender of the association between study group subjects and hepatic steatosis

OR


NGT1-h PG<155

(n=295)

NGT1-h PG>155

(n=109)

IGT(n=202)

Isolated IFG

(n=104)

95% CI 1.55 -3.46

95% CI 1.07 -2.71

95% CI 0.69-1.80



iabetologia.




AGENDA




hepatic steatosis,




iabetologia.


A higher proportion of NGT subjects with 1-h PG>155 mg/dl have stage 2 or stage 3 disease as compared with individuals with 1-h PG<155 mg/dl

% P=0.002

1 2 3 1 2 3

Succurro E. et al. Clin J Am Soc Nephrol 5: 1922–1927, 2010

Stages of chronic kidney disease

NGT1-h PG<155

(n=518)

NGT1-h PG>155

(n=250)



iabetologia.




IMT is increased in NGT subjects with 1-h PG >155mg/dl as compared with individuals with 1-h PG<155 mg/dl

IMT

(mm

)

NGT1-h PG<155

(n=231)

P=0.006

NGT1-h PG>155

(n=89)

IGT(n=80)

Succurro E. et al. Atherosclerosis 207 : 245–249, 2009

P=0.03



iabetologia.




Pulse wave velocity is increased in NGT subjects with 1-h PG >155mg/dl as compared with individuals with 1-h PG<155 mg/dl

Pu

lse

wa

ve

ve

locit

y(m

/s)

NGT1-h PG<155

(n=278)

P<0.0001

NGT1-h PG>155

(n=146)

IGT(n=160)

Sciacqua A. et al. Plos ONE 7, e44470, 2012

P<0.0001



iabetologia.




Left ventricular mass is increased in NGT subjects with 1-h PG >155mg/dl as compared with individuals with 1-h PG<155 mg/dl - the CATAMERI study

LV

MI

(g/m

2)

NGT1-h PG<155

(n=356)

P<0.002

P=0.002

NGT1-h PG>155

(n=158)

IGT(n=168)

Sciacqua A. et al. Diabetes Care 34:1406–1411, 2011



iabetologia.




Impairment of left ventricular diastolic function in NGT subjects with 1-h PG >155mg/dl as compared with individuals with 1-h PG<155 mg/dl

E-t

o-A

ra

tio

NGT1-h PG<155

(n=90)

P<0.0001

NGT1-h PG>155

(n=30)

IGT(n=26)

Sciacqua A. et al. Diabetes Care 34:2291–2296, 2011



iabetologia.




Total mortality is increased in subjects with 1-h PG >161 mg/dl as compared with individuals with 1-h PG<161 mg/dl - the Helsinki Businessmen Study

Ha

za

rd R

ati

os

ad

juste

d f

or

ag

e a

nd

sm

ok

ing

1-h Glucose <161mg/dL and BMI <25

P<0.001

P<0.001

1-h Glucose >161mg/dL and BMI <30

1-h Glucose >161mg/dL and BMI >30

Strandberg TE et al. Arch Intern Med 171: 941-3, 2011



iabetologia.


2h PG <140 and 1-h PG<155

(n=1112)

2h PG <140 1-h PG>155

(n=449)

2h PG 140-199 and1-h PG>155

(n=301)

2h PG 140-199 and1-h PG<155

(n=83)

P values refer to results after analyses with adjustment for sex, age, smoking, BMI, systolic and diastolic blood pressure and fasting blood glucose

HR

(9

5%

CI)

Bergman M et al. Diabet. Med. 2016

Total mortality is increased in subjects with 1-h PG >155 mg/dl as compared with individuals with 1-h PG<155 mg/dl - the Israel Study of Glucose

Intolerance, Obesity and Hypertension (n= 1942)

(1.12 to 1.56)

(1.20 to 2.15)

(1.54 to 2.23)



iabetologia.


NGT 1h-high individuals may represent an intermediate state of glucose

intolerance between NGT and type 2 diabetes characterized by insulin

resistance, and reduced β-cell function, the two main pathophysiological

defects responsible for the development of type 2 diabetes.

NGT 1h-high individuals exhibit a worse cardio-metabolic risk profile.

A high level of 1hPG during OGTT may be helpful in the identification of

subjects with normal glucose tolerance, but at increased risk for T2DM

and CVD.

Summary



iabetologia.


THANK YOU !

Now it’s time for discussion.

Sesti lecture



iabetologia.


1-h OGTT e rischio cardio-metabolico. Lo studio CAtanzaro ... - SID … OGTT Studio Catameris...

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