Enzo Bonora
Endocrinologia, Diabete e Malattie del Metabolismo Università e Azienda Ospedaliera Universitaria
Integrata di Verona
Il diabete tipo 2 è
tutto uguale?
Disclosures (last 15 years)
Advisory Boards
Abbott, Astrazeneca, Becton Dickinson, Boehringer Ingelheim, Bristol-Myers Squibb, Bruno Farmaceutici, Janssen, Daiichi-Sankyo, Johnson&Johnson, Lilly, MSD, Mundipharma, Novartis, Novo Nordisk, Roche, Sanofi, Servier, Takeda
Research Grants
Astrazeneca, Genzyme, Menarini Diagnostics, Novo
Nordisk, Roche Diagnostics, Takeda
Esprimo massima gratitudine alla Società Italiana di Diabetologia per avermi formato, guidato, stimolato, sostenuto e gratificato in 40 anni di professione (1980-2020).
SID è la mia casa e SID è nel mio cuore.
Ringraziamento
Diabete: non una sola malattia
Secondario
Altri monogenici
MODY
LADA
Tipo 2
Tipo 1
Gestazionale
• LADA (~150.000-200.000 casi in Italia)
• MODY (~30.000-40.000 casi in Italia)
• Diabete pancreatogenico (~50.000-100.000 casi in Italia)
• Diabete secondario a varie patologie (???)
Sembra diabete tipo 2 ma non lo è!!!
Circa 1 su 10-15 casi non lo è. La diagnosi va ripensata
N=1922 admitted to hospital
Origine del diabete associato a malattia pancreatica (T3c DM)
Hardt PD et al – Diabetes Care 2008; 31 (suppl 2): S165
Il T2DM e i suoi satelliti più o meno visibili
MODY
LADA T3c DM
GDM T2DM
Cushing subclinico Diabete
epatogeno
Forme Genetiche
rare
Malattie endocrine
T1DM
Diabete iatrogeno
Il diabete tipo 2 non è una sola malattia
Rilevante o apparentemente irrilevante carico di geni predisponenti
Inizio precoce o tardivo nella vita
Obesità, sovrappeso o normopeso (o quasi normopeso)
Carenza insulinica importante o limitata
Notevole o modesta insulino-resistenza
Rapida o lenta progressione verso il severo deficit insulinico
Controllo metabolico agevole o difficile
Glicemia elevata a digiuno e/o picchi post-prandiali
Tendenza più o meno marcata a sviluppare danno d’organo
Complicanze microvascolari, macrovascolari o entrambe
Hyperglycemia
Liver
Increased endogenous glucose
production
Skeletal muscle
Impaired glucose utilization (transport, storage, oxidation)
Endocrine pancreas
Impaired insulin secretion Exaggerated glucagon secretion
The complex pathogenesis of hyperglycemia in T2DM
Gut
Impaired incretin effect
Kidney
Increased glucose reabsorption
Brain
Abnormal metabolic control
Adipose tissue
Release of
diabetogenic molecules (FFA, adipocytokines)
Adapted from DeFronzo
0
15 45 60
Isolated IR
% 30
Isolated DC defect
Isolated PC defect
IR &
PC defect IR &
DC defect
IR, DC &
PC defect 59.8
15.0
2.0 4.4 0.8
8.6 N= 808
IR=insulin resistance (insulin clamp)
DC=derivative control of beta-cell function (OGTT & minimal model) PC=proportional control of beta-cell function (OGTT & minimal model)
Proportion of drug-naive newly diagnosed subjects with T2DM who have insulin resistance and/or a defect of
derivative and/or proportional control of beta-cell function
Bonora E, Trombetta M, Bonadonna RC et al - submitted
DC &
PC defect
8.0
HbA1c Fasting PG
2-h OGTT PG
Pre- prandial
BG
Post- prandial
BG
Prandial increase in
BG
Age -0.029
(NS)
0.087 (0.004)
0.102 (<0.001)
0.038 (NS)
0.065 (NS)
0.058 (NS) Gender
(male)
0.058 (NS)
0.058 (NS)
0.060 (0.016)
0.042 (NS)
0.073 (0.035)
0.073 (NS) Insulin
sensitivity
-0.162 (<0.001)
-0.233 (<0.001)
-0.272 (<0.001)
-0.226 (<0.001)
-0.258 (<0.001)
-0.172 (<0.001) Beta-cell
function
-0.496 (<0.001)
-0.556 (<0.001)
-0.687 (<0.001)
-0.498 (<0.001)
-0.530 (<0.001)
-0.314 (<0.001)
Predictors of HbA1c, fasting plasma and blood glucose levels during the day (mean of 5 days) in in drug-naive
newly diagnosed subjects with T2DM
Bonora E, Trombetta M, Bonadonna RC et al - submitted
M -cl am p In su lin se cr et io n -P C
Deciles
Deciles
Insulin resistance and deficit of proportional control of beta-cell function in drug-naive newly diagnosed subjects
with T2DM
Bonora E, Trombetta M, Bonadonna RC et al - submitted
Subtypes of diabetes: precision medicine
Prasad RB and Groop L – J Intern Med 2019; 285:40
SIDD = severe insulin-deficient diabetes (17.5%)
SIRD = severe insulin-resistant diabetes (15.3%)
MOD = mild obesity-related diabetes (21.6%)
MARD = mild age-related diabetes (39.1%)
Clinical features in subgroups (cluster) of patients with T2DM
N = 8980 newly diagnosed
Cluster 1 = SAID = severe autoimmune diabetes (6.4%) = early-onset, relatively low BMI, poor control, insulin deficiency, GADA + Cluster 2 = SIDD = severe insulin-deficient diabetes (17.5%) = early-onset, relatively low BMI, poor control, insulin deficiency, GADA - Cluster 3 = SIRD = severe insulin-resistant diabetes (15.3%) = high BMI, insulin resistance
Cluster 4 = MOD = mild obesity-related diabetes (21.6%) = high BMI, no insulin resistance
Cluster 5 = MARD = mild age-related diabetes (39.1%) = older age, lower BMI, no insulin resistance
Ahlqvist E et al – Lancet Diabetes Endocrinol 2018; 6:361
Incidence of complications in subgroups (cluster) of patients with T2DM
Ahlqvist E et al – Lancet Diabetes Endocrinol 2018; 6:361
Nephropathy Retinopathy CVD
N = 8980 newly diagnosed
Cluster 1 = SAID = severe autoimmune diabetes (6.4%) = early-onset, relatively low BMI, poor control, insulin deficiency, GADA + Cluster 2 = SIDD = severe insulin-deficient diabetes (17.5%) = early-onset, relatively low BMI, poor control, insulin deficiency, GADA - Cluster 3 = SIRD = severe insulin-resistant diabetes (15.3%) = high BMI, insulin resistance
Cluster 4 = MOD = mild obesity-related diabetes (21.6%) = high BMI, no insulin resistance
Cluster 5 = MARD = mild age-related diabetes (39.1%) = older age, lower BMI, no insulin resistance
SIRD
MOD
MOD SIDD
SIRD SIRD
MARD
MARD
Glucose control (HbA1c) and time to insulin therapy in subgroups (cluster) of patients with T2DM
Ahlqvist E et al – Lancet Diabetes Endocrinol 2018; 6:361
SAID
SIDD
N = 8980 newly diagnosed
Cluster 1 = SAID = severe autoimmune diabetes (6.4%) = early-onset, relatively low BMI, poor control, insulin deficiency, GADA + Cluster 2 = SIDD = severe insulin-deficient diabetes (17.5%) = early-onset, relatively low BMI, poor control, insulin deficiency, GADA - Cluster 3 = SIRD = severe insulin-resistant diabetes (15.3%) = high BMI, insulin resistance
Cluster 4 = MOD = mild obesity-related diabetes (21.6%) = high BMI, no insulin resistance
Cluster 5 = MARD = mild age-related diabetes (39.1%) = older age, lower BMI, no insulin resistance
MARD
Time (years)
