Genetics, Physiopathology and Evolution of Type 2 diabetes

Transcription

1 Gruppo di Studio SID - Prevenzione del Diabete di Tipo 2 Genetics, Physiopathology and Evolution of Type 2 diabetes With the unconditionated support by

2 The staff Scientific tutor R. Giorgino Steering commitee S. Del Prato, F. Beguinot, F. R.C. Bonadonna, E. Bonora, A. Consoli, A. Giaccari, F. Giorgino, G. Paolisso Organizing committee R. Miccoli, G. Penno Secretary F. Venditti Central laboratory F. Caricato M.G. Giovannitti Statistical analysis Web consulting R. Miccoli, C. Bianchi, R. Bonadonna Corrado Polentes (

3 GENFIEV centers and local investigators Ancona Bari Bologna Catanzaro Chieti Massa Orbassano Pisa Pistoia Roma 1 Roma 2 Roma 4 Roma 5 Verona E. Faloia F. Giorgino G. Marchesini A. Gnasso A. Consoli M.A. Dolci M. Trovati, F. Cavalot R. Miccoli, G. Penno, C. Bianchi L. Alviggi S. Frontoni G. Cavallo F. Leonetti A. Giaccari R. Bonadonna, E. Bonora

4 Aims To assess the pathophysiologic mechanisms responsible for the Impaired Glucose Regulation (IGR). Phenotypic characterization of IGR and newly diagnosed type 2 diabetes mellitus patients. To explore the biochemical and genetic markers associated with the evolution of IGR to Type 2 diabetes.

5 Flow-chart of the study DM2 DM2 DM2 DM2 OGTT OGTT OGTT OGTT Time (years( years)

6 Products Study protocol (txt, pdf) Operations manual (txt, pdf) Slides kit Data base (web-oriented oriented) Web site: genfiev.itit Riskdiab calculator (FINrisk equation-tuomilheto Tuomilheto) Logistics (information and assistance center, materials, samples storage)

7 Site Map Project People Data-base Doc./News Notepad Protocol Operation manual Flow-chart procedures Participation form Coordinating center Scientific committee Secretary Participating centers Access Screening Clinical data Biochemical and instrumental data Tools & Utilities Scientific informations News & Chat Download

8 Study recruitment Number of cases Screened Recruited Recruitment rate 35% A 2005 B

9 M. M.Trovati, Trovati,Torino Torino M. M.Muggeo, Muggeo,Verona Verona G. G.Marchesini, Marchesini,Bologna Bologna M.A M.ADolci, Dolci,Massa Massa E.E.Faloia, Faloia,Ancona Ancona PISA PISA L.L.Alviggi, Alviggi,Pistoia Pistoia G. G.Cavallo, Cavallo, S.S.Frontoni, Frontoni, A. A.Giaccari, Giaccari, F.F.Leonetti, Leonetti, ROMA ROMA A. A.Consoli, Consoli,Chieti Chieti F.F.Giorgino, Giorgino,Bari Bari A. A.Gnasso, Gnasso,Catanzaro Catanzaro National network

10 General characteristics of study cohort Mean±SD Range N. (M/W) 1017(589/428) - Age (years) 49± BMI (Kg/mq) 29.2± Waist (cm) 102.6± SBP (mmhg) 129± DBP (mmhg) 82± FPG (mg/dl) 98±

11 Categories of Effect of ADA 2004 criteria of glucose tolerance N. of subjects NGT IFG IGT IFG+IGT DM 43% 50% 11% 4% 15% 23% 16% IGR IGR (35% 35% 42%) n=380 8% 15%

12 1st phase of the insulin secretion - dynamic control Norm ifg IFG IGT IFG+IGT DM 2000 Insulin secretion (pmol) * P<0.001 vs Norm * 0 0 0,5 1 1,5 d(glucose)/d(t) (mmol/l)/min

13 2nd phase of the insulin secretion - static control Norm ifg IFG IGT IFG+IGT DM * P< vs Norm Insulin secretion (pmol/min/m 2 ) * * * Glucose (mmol/l)

14 AUC Glucose by glucose tolerance categories NGT IFG IGT IFG+IGT DM AUC-glucose (mg/ml/2 h) ANOVA p<0.0001

15 Insulin sensitivity (HOMA-R) by glucose tolerance categories NGT IFG IGT IFG+IGT DM 8 6 ANOVA p< HOMA-R 4 2 0

16 AUC C-Pep by glucose tolerance categories AUCC peptide (ng/ml/2 h) NGT IFG IGT IFG+IGT DM

17 β-cell function by glucose tolerance categories NGT IFG IGT IFG+IGT DM Insulinogenic index C-pep 30min / Glic 30min 0,10 0,08 0,06 0,04 0,02 0,00 30'C-P/30'G

18 Glucose tolerance and insulin sensitivity AUC- Gluc (g/*120 ) AUC- C-pep (ng/*120 ) < >280 0 < >280 Glucose 120 OGTT Glucose 120 OGTT

19 AUC C-pep /AUC by glucose Glic ratio tolerance categories 0,6 NGT 0,5 AUCCpep:AUCGluc 0,4 0,3 0,2 0,1 0,0 < >280 Glucose 120 OGTT

20 Glucose tolerance and insulin sensitivity 35 5,0 AUC- Gluc (mg*120 ) HOMA-R 4,5 4,0 3,5 3,0 2,5 2,0 10 1,5 5 1,0 0,5 0 < >280 0,0 < >280 Glucose 120 OGTT Glucose 120 OGTT

21 Glucose tolerance regulation: : interaction among insulin secretion, insulin resistance and glucose levels NGT (DAUCCpep:DAUCGluc)/HOMA-R 0,04 0,03 0,02 0,01 0 < >280 Glucose OGTT 120 min

22 Insulin-resistance vs β-cell secretory defect 60 NoIR/ISec IR/ISec NoIR/NoISec NoISec/IR N. of subjects (%)

23 Distribution of insulin resistance or β-cell secretory defect N. of subjects (%) Secretory defect Insulin-resistance

24 Distribution of insulin resistance and/or β-cell secretory defect N. of subjects (%) Isolated β-cell defect β-cell defect + Insulin resistance Isolated insulin resistance

25 Metabolic characteristics in relationship to insulin resistance and/or β-cell secretory defect β-cell defect No β-cell defect Combined defects Insulin resistance p BMI 29 ± ± ± 5 31 ± Waist 99 ± ± ± ± SBP (mmhg) 134 ± ± ± ± 15 ns DBP (mmhg) 85 ± ± ± ± T-chol. (mg/dl) 215 ± ± ± ± 38 ns LDL-chol (mg/dl) 134 ± ± ± ± 32 ns HDL-chol (mg/dl) 54 ± ± ± ± 9 ns Triglycerides (mg/dl) 149 ± ± ± ±

26 Prevalence of insulin-resistance in subjects with Metabolic Syndrome (ATPIII) N. of subjects (%) 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% No IR 39 % Metabolic Syndrome No MS 40.0% Insulin-Resistance

27 Next step: diabetes conversion Unknown Type 2 Diabetes 152 (15%) Study subjects n IGR n. 355 (35%) 2 yrs follow-up n. 64 (18%) Type 2 Diabetes conversion n. 13 (20%)

28 Summary The screening procedure (based on the nationwide diabetes clinics) allows an high rate of recruitment (42%) of subjects with Impaired Glucose Regulation The phenotype of the study population has been evaluated for: β-cell function Insulin sensitivity Relationship of insulin secretion and sensitivity with glucose tolerance Associated metabolic traits

29 Conclusions (I) Changes in insulin sensitivity and secretion occur in a linear fashion across the different categories of glucose tolerance, and emphasize that major changes in β-cell performance occur even with modest increases in 2-hrPG within the NGT category. Subjects with isolated insulin secretory defect, isolated insulin sensitivity defect or with combined defects may be identified.

30 Conclusions (II) Different metabolic phenotypes characterize the categories of subjects with IGR. The prevalence of metabolic syndrome, as expected, increases with deterioration of glucose tolerance. 61% of subjects with Metabolic Syndrome present insulin-resistance, while 60% of those with insulin resistance satisfy the definition criteria of the Metabolic Syndrome.

31 Scientific publications Comunicazioni orali (a nome del Gruppo di Studio GENFIEV-FoRiSID) Bonadonna R. Declino selettivo della funzione beta-cellulare nell intervallo normale di variazione della glicemia. Del Prato S. Secrezione insulinica e sensibilità insulinica in individui ad elevato rischio di diabete tipo 2. Miccoli R. Relazione fra insulino-resistenza, sindrome metabolica e alterata regolazione glicemica. Poster Presentation (on behalf of the GENFIEV Group) Del Prato S. Insulin secretion and insulin action in individuals at high risk for Type 2 diabetes. Congress Proceedings (on behalf of the GENFIEV Group) Bonadonna R. Selective Decline of Beta Cell Function Within the Normal Range of Glucose Concentration in Humans.

32 Work in progress Papers in preparation: - β-cell function, insulin-resistance and impaired glucose regulation - insulin-resistance, metabolic syndrome and impaired glucose regulation Subject follow-up Genetic studies (DNA-bank) Phenotyping (clinical data-base, biological bank)