Etiopatogenia DZ tip 2
INSULINO REZISTENŢA
DEFINITIE SI RELATII GENERALE
STAREA IN CARE NIVELE ALE INSULINEMIEI, EFICIENTE LA SUBIECTII NORMALI, NU PRODUC EFECTELE BIOLOGICE OBISNUITE.
MUSCHI: Stimularea transportului glucozei
FICAT: Suprimarea productiei hepatice de glucoza
TESUT ADIPOS: Inhibitia lipolizei
CELULA BETA PANCREATICA: Functionalitatea si viata celulelor beta pancreatice pot fi afectate de rezistenta la insulina.
IN T2DM, REZISTENTA LA INSULINA ESTE DETERMINATA GENETIC
25% DIN POPULATIA GENERALA PREZINTA REZISTENTA LA INSULINA
RAZISTENTA LA INSULINA ESTE INFLUENTATA DE FACTORI DE MEDIU
- gradul adipozitatii corporale si mai ales distributia ei
- exercitiul fizic si gradul de antrenament
• 25% DIN POPULATIA GENERALA PREZINTA REZISTENTA LA INSULINA
• REZISTENTA LA INSULINA ESTE INFLUENTATA DE FACTORI DE MEDIU:
- gradul adipozitatii corporale si mai ales distributia ei
- exercitiul fizic si gradul de antrenament
• Glucose Clamp
• Insulin Tolerance Test
• Insulin Suppression Test
• Regional Arterio-Venous Balance
• Frequently Samples IV Glucose Tolerance Test (FSIVGTT)
• Homeostatic Model Assessment (HOMA)
• Continuous Infusion of Glucose with Model Assessment
(CIGMA)
• Quantitative Insulin-Sensitivity Check Index (QUICKI)
Metode de masurare a Rezistentei la insulina
Radziuk J. J Clin Endocrinol Metab 2000;85(12):4426-4433. Matsuda M, DeFronzo RA. Diabetes Care 1999;22(9):1462-1470. Welch S, et al. J Clin Endocrinol Metab 1990;71(6):1508-1518. Katz A, et al.J Clin
Endocrinol Metab 2000;85(7):2402-2410. Matthews DR, et al.Diabetologia 1985;28(7):412-419. Fukushima M, et al. Diabetes Care 2000;23(7):1038-9. Taniguchi A, et al.Diabetes Care 2000;23(9):1439-1440.
HOMA (Homeostasis Model Assessment) Estimarile pot fi efectuate utilizand o formula matematica simpla:
Intre sensibilitatea la insulina estimata prin HOMA si cea estimata prin euglycemic clamp a fost gasita o corelatie foarte stransa:
- (r = - 0,820) intr-un studiu recent, pe 115 subiecti europeni obezi si
neobezi, diabetici si nediabetici (Bonora E et al. Diabetes Care 2000,23:67-63
- (r = - 0,613) inainte si (r = -0,734) dupa tratament cu dieta si
exercitiu fizic intr-un studiu asupra 55 subiecti japonezi cu diabet
tip 2 (Katsuki A et al. Diabetes Care, 2001, 24: 362-365).
20 insulin* (U/mL)
glucose* (mmol/L) - 3.5
20 insulin* (U/mL)
glucose* (mmol/L) - 3.5-Cell function (%) =
insulin* (U/mL) glucose* (mg/dl) 405
insulin* (U/mL) glucose* (mg/dl) 405
Insulin resistance =
Glucose clamp
• Metoda se bazeaza pe mentinerea unui nivel fix (de aici si numele derivat din limba engleza : « to clamp » inseamna a fixa) al glicemiei in cursul unei infuzii simultane de insulina si glucoza.
• Nivelul glicemiei care se mentine constant pe parcursul investigatiei poate fi :
1. Nivelul bazal normal (euglycemic clamp).
Aceste metode investigheaza in exclusivitate sensibilitatea tesuturilor (in principal hepatic si muscular) la actiunea insulinei.
3. Nivel crescut al glicemiei, in jur de 180 mg/dl: (hyperglycemic
clamp).
Hyperglycemic clamp este utilizata deobicei pentru masurarea raspunsului
insulinosecretor.
Hyperinsulinemic Euglycemic clamp
1. Administrarea insulinei
Nivelul insulinemiei este crescut si mentinut constant, la un nivel dinainte stabilit, prin administrarea insulinei in infuzie iv.
De obicei rata infuziei de insulina este raportata la suprafata corporala.
Suprafata corporala ( S ) se calculeaza dupa urmatoarea formula:
S (m2) = G 0,425 (kg) x I 0,725 (cm) x 71,84 x 10-4
Rata de infuzie cel mai des folosita este de 40 mU·min-1·m2 si corespunde cu
aproximatie la 1 mU/Kgcorp/min.
Rata de infuzie
(mU/Kg/min)
0.4 0.5 1.0 2.0 5.0 10 30
Nivelul
insulinemiei
(U/ml)
364 575 102 14 18215 65362 1718850 10277577
Hyperinsulinemic Euglycemic Clamp
2. Administrarea glucozei
Pentru a mentine constant nivelul glicemiei pe durata probei, este necesara administrarea unei infuzii (variabile) de ser glucozat (deobicei ser glucozat hiperton, solutie 20%) cu ajutorul unei pompe de infuzie automata.
In cursul investigatiei se tinde la obtinerea perioadei de steady-state.
In acesta conditii, daca emisia hepatica de glucoza este complet suprimata, rata de infuzie a glucozei este egala cu rata de captare a glucozei in tesuturile periferice (in principal tesutul muscular) sub actiunea insulinei.
Rata de infuzie a glucozei reprezinta astfel un indicator al sensibilitatii tesuturilor la insulina.
Cu cat subiectul este mai rezistent la insulina cu atat rata de infuzie a glucozei, la steady-state, va fi mai mica.
Euglycemic ClampEuglycemic Hyperinsulinemic Clamp
Ferrannini E. Atlas of Diabetes (R. Kahn editor) Current Medicine,Philadelphia, 2000: 95
Avantaje:
Posibilitatea de a asocia EC cu alte investigatii :
- calorimetria indirecta - biopsia musculara- cateterism regional (pentru a masura schimburile regionale, la nivelul unui membru sau organ). - rezonanta magnetica nucleara (NMR)- tomografia in emisie de pozitroni (PET).
Muschiul striat scheletic sediul major al rezistentei la insulina
1. In cursul Euglycemic clamp (E clamp), majoritatea glucozei este captata in tesuturile periferice:
- muschi (in principal)
- tesut adipos (1%)
- splanhne (o cantitate neglijabila)
2. Glucoza captata in muschi poate fi utilizata pe una din cele doua cai:
- oxidativa : CO2 + H2O
- neoxidativa: lactat sau glicogen
Spectroscopia in RMN a nucleelor de C13 din
glicogenul muscularA permis masurarea directa, in vivo (la niv m. gastrocnemian) a cantitatii de glicogen sintetizat in cursul E Clamp:
-Captarea glucozei redusa la diabetici : 30 fata de 51 mol/Kg/min la normali
-Rata medie a metab neoxidativ al glucozei redusa la diabetici: 22 fata de 42 mol/Kg/min la normali
-Rata medie a sintezei glicogenului redusa la diabetici: 78 fata de 183 mol unitati glicosil/Kg/min
CONCLUZIE: Rezistenta la insulina este rezultatul unui defect al caii metabolice a sintezei glicogenului muscular
Shulman, 1990
CAILE METABOLICE ALE GLUCOZEI IN MUSCHIUL
STRIAT
Metoda spectroscopiei in RMN folosind C13 si P 31
S-a masurat concentratiile intramiocelulare (6 T2DM si 7 N) in cursul Hyperglycemic Clamp (180 mg/dl) pentru:
glucoza libera
glucozo 6-fosfat
glicogen
Rezultate:
Nivelele sintezei glicogenului si ale glucozo 6-fosfatului reduse cu 80% la diabetici
Concluzie: Afectarea transportului glucozei joaca un rol important in producerea rezistentei la insulina
Cline et al. 1999
Actiunea insulinei asupra transportului glucozei
Cellular mechanisms in the insulin resistance associated to
obesity and type 2 diabetes mellitus
Nauru seen from the air
Melanesian and Polynesian in its descent, the population had a traditional way of life till the beginning of the 20th century.
Extensive phosphate mining let the money to flow in …
In 1970, Nauruans were among the richest people and this changed their way of life: become sedentary and consuming a high fat hypercaloric diet.
They sow no need to work for a living while other Pacific Islander were doing the work in the mines. The future looked bright…
… “in a short time, Nauru get one of the world fattest populations.
While diabetes was not known before 1950, now around 50% of Nauruans suffer from the disease and it stems from their sedentary lifestyle and fatty diet coupled with genes more suited to protect them from starvation”.
The Economist 2001 20th December
Obesity is an important risk for type 2 diabetes mellitus
Insulin resistance states (such as obe- Insulin resistance states (such as obe- sity and type 2 diabetes) are sity and type 2 diabetes) are characterized by lipid accumulation as characterized by lipid accumulation as triglyceride stores in non-adipose tissue: triglyceride stores in non-adipose tissue: liver, skeletal and cardiac muscle, and in liver, skeletal and cardiac muscle, and in pancreatic pancreatic ββ-cells.-cells.
Electron micrograph of tibialis anterior muscle
mi: mithocondria; IMCL droplets in close contact to mitochondria; mf:myofibrils
IMCL
Howald H et al: J Appl Physiol 2002;92:2264-2272
Electron micrograph of a longitudinal section of skeletal muscle tissue
Hoppeler H et al 2002
li: lipid droplet; mc: central mitocondria; mf:myofilaments
1H magnetic resonance spectroscopy can quantitate the intracellular (liver and muscle)
triglyceride stores
Szczepaniak LS et al. Am J Physiol Endocrinol Metab 1999;276:E977-E989
The FFA levels are an important link connecting obesity and type 2 diabetes
to insulin resistance.
An increased FFA level accounts for 50% ot the insulin resistance in people with
obesity and/or type 2 diabetes
Boden G et al.Best Pract Res Clin Endocrinol Metab 2003;17:399-410
Relationship between IMCL-triglycerides and plasma FFA levels
Boden G et al. Diabetes 2001;50:1612-1617
Skeletal muscle glucose transport/fosforilation and glycogen synthesis at high FFA levels ( triglyceride emulsion+heparin infusion)
during hyperinsulinemic euglycemic clamp (healthy subjects)
Roden M et al. J Clin Invest 1966;97:2859-2865Open symbols: TG + heparin infusion
Closed symbols: no TG/heparin infusion
Insulin resistance is manifest after a 4-6 hours from increase in FFA levels and is accompanied by:
Increase in cellular levels of
- Triglycerides
- DAG (di-acyl-glycerol)
- Increased PKC activity
Decreased levels of Iκβ
Boden G et al. Diabetes 2001;50:1612-1617
Itani S et al. Diabetes 2002;51:2005-2011
Potential mechanisms of FFA on insulin resistance and atherogenesis in human muscle
IRS1- serine/threonine phosph.IRS1- serine/threonine phosph.
IRS1- tirosine phosphorilationIRS1- tirosine phosphorilation
PI 3 – Kinase/Akt-PKB PI 3 – Kinase/Akt-PKB
GLUT 4 – translocation at cellular GLUT 4 – translocation at cellular membranemembrane
Glucose Glucose uptake/transportuptake/transport
Fatty Acil- CoAFatty Acil- CoA
DAGDAG
CeramideCeramide
PKCPKC
NFNFκβκβ Activation Activation
IIκβκβ Degradation Degradation
ROSROS
ROSROS
plasma plasma FFA FFA
Proinflammatory andProinflammatory and
Proatherogenic ProteinsProatherogenic Proteins
Boden G, Laakso M. Diabetes Care 2004;27:2253-2259Boden G, Laakso M. Diabetes Care 2004;27:2253-2259
In the (A-ZIP/F-1) lipoatrophic mice the lack of fat is associated with insulin resistance and
hyperglycemia
Gavrilova O et al. J Clin Invest 2000;105:271-278
The phenotype of lipoatrophic mice is similar to that of human lipoatrophic diabetes :
-lack of fat, insulinresistance with hyperinsuline- mia , hiperphagia, hiperlipidemia, fatty liver and organomegaly.
Transplantation of wild-type fat reversed completely or partially the lipoatrophic phenotype.
The beneficial effects of fat transplantation were dose dependent.
In this figure, lipoatrophic sham operated mice (left) and lipoatrophic mice after 3 weeks of fat (seven graft) transplantation.
Liver histology 13 weeks after fat transplant in lipoatrophic mice
Gavrilova O et al. J Clin Invest 2000;105:271-278
Large vacuolated hepatocytes (due to lipid deposition) in the sham-operated but not transplanted mice
Sham operated (left) and transplanted (right)
But… the fat transplanted from ob/ob mice (leptin-deficient) failed to reverse the metbolic disturbances.
This highlighted the importance of LEPTIN, an adipocyte derived hormone.
Generalized Lipodystrophy
Girl aged 6 yrs, 2 mo.
Height:122 cm Weight:21,5 Kg
Lack of adipose tissue at face, trunk and limbs
The increase in abdomen is due to hepato-splenomegaly. Echography disclosed hepatic steatosis.
Visible ombilical hernia
Acanthosis nigricans, gingival hipertrophy.
Basal values:
Plasma Glucose= 93 mg/dl; serum insulin= 32.3 µU/ml.
HOMA-R index : 7,4
Triglycerides: 193 mg/dl;T-colesterol:126 mg/dl
HDL-colesterol: 21 mg/dl
ALT/AST: 113/64 U/L
Acanthosis Nigricans
The increase in intracellular triglyceride The increase in intracellular triglyceride stores in non-adipose tissues may be the stores in non-adipose tissues may be the consequence of:consequence of:
-Prolonged exposure to increased plasma -Prolonged exposure to increased plasma levels of FFAlevels of FFA
-Defects in mitochondrial (oxidative activity) -Defects in mitochondrial (oxidative activity) fatty acid oxidationfatty acid oxidation
-Both-Both
Intramyocellular lipid content is increased and muscle mitochondrial phosphorylation activity is decreased in healthy young,lean, insulin-resistant offspring of patients with Type 2
DM
Petersen KF et al. N Engl J Med 2004; 350: 664-671
Muscle Mitochondrial oxidative-phosphorylation activity is reduced in lean
offspring of patients with type 2 DM
• 80% increase in intramyocellular triglyceride content• 60% reduction in insulin-stimulated glucose uptake • 30% reduction in mitochondrial phosphorylation
“ Insulin resistance in skeletal muscle of insulin-resistant offspring of patients with type 2 diabetes is associated with dysregulation of intramyocellular fatty acid metabolism, possibly because of an inherited defect in mitochondrial oxidative phosphorylation”.
Petersen KF et al: N engl J Med 2004;350:664-671
Morphological differences in the skeletal muscle mitochondria from volunteers:
a. Lean, healty volunteer
b. Obese volunteer
c. Type 2 diabetes volunteer
Kelley DE et al: Diabetes 2002;51:2944-2950
Relationship between mitochondrial size and insulin sensitivity
Between insulin sensitivity (euglycemic clamp) and muscle mitochondrial size there was a positive correlation.
(r=0,72;n=21;p<0,01)
Kelley DE et al:Diabetes 2002;51:2944-2950
CONCLUSION
• Excessive intake of nutrients and/or mitochondrial dysfunction may lead to increased intracellular content of lipid metabolites.
• Increased intracellular lipid metabolites can activate signal transduction pathways that induce inflammation and impair insulin signalling.
• Future therapeutic strategies may target the decrease in plasma FFA concentration, normalization of mitochondrial function and inhibition of inflammatory pathways in insulin-responsive tissues.
CARDIOVASCULAR RISK FACTORS DURING THE PRELIMINARY PHASES
LEADING TO TYPE 2 DIABETES
- From 135 million in 1995, today 177 million people suffer from diabetes.
-For 2025 it is estimated that at least 300 million people throughout the world will suffer from diabetes.
-The estimated lifetime risk to develop diabetes, for individuals born in year 2000 in USA is: 32.8% for males and 38.5% for females.
-For an individual diagnosed at 40 years, men will lose 11.6 life-years and 18.6 quality-adjusted life-years and women will lose 14.3 life-years and 22.0 quality-adjusted life-years
The Burden of Diabetes
King H et al. Diabetes Care 1998; 21: 1414-1431 Narayan KMV et al. JAMA 2003; 290: 1884-1830
MORTALITY IN PEOPLE WITH DIABETES
Geiss LS et al. In: Diabetes in America 2nd ed. 1995; chap 11
0
10
20
30
40
50
Ischemicheart
disease
Otherheart
disease
Diabetes Cancer Stroke Infection Other
% o
f D
eath
s
Causes of Death
CVD Mortality Decreases in General Population and Diabetes Mortality
Increases
Sobel et al. Circulation. 2003;107:636-642.
% c
han
ge in
age
-ad
just
ed
mor
tali
ty r
ate
sin
ce 1
980
-50
-40
-30
-20
-10
0
10
20
30
40
50
1980 1982 1984 1986 1988 1990 1992 1994 1996 1998
Diabetes
Cancer
All-cause
CVD
All-cause
The vascular complications are already present at the time of diagnosis
Data from UKPDS
- 33% of newly diagnosed type 2 diabetic patients had either an abnormal ECK or retinopathy.
-Arterial Hypertension, defined as systolic pressure>160 mm Hg and diastolic pressure > 90 mm Hg was present in 37% males and 52% females.
-50% from newly diagnosed type 2 diabetic patients had clinical evidence of diabetic tissue damage at diagnosis.
-As compared to age –matched normal subjects, newly diagnosed diabetic patients were more obese, had greater plasma insulin and triglyceride levels, increased urinary albumin excretion and lower levels of HDL-cholesterol.
The vascular complications are associated predominantly with different risk factors
Data from UKPDS
MACROVASCULAR Complications (Strokes, heart attacks,peripheral arterial disease) were predominantly associated with hypertension, hypertrigliceridemia, low HDL-cholesterol, smoking and increased urinary albumin excretion.
MICROVASCULAR Complications: Retinopathy was predominantly associated with hyperglycemia
UK Prospective Diabetes Study 6. Diabetes Res 1990;13:1-11
THE “CLOCK
FOR
CARDIOVASCULAR DISEASE START TICKING
LONG BEFORE THE ONSET
OF CLINICAL DIABETES”
Haffner SM et al: JAMA 1990;263:2893-2898
Elevated risk of cardiovascular disease prior to clinical diagnosis of type 2 diabetes
NURSES HEALTH STUDY
111629 Female nurses 30-35 years, free of diagnosed Diabetes and CVD at baseline
RECRUITED: 1976FOLLOWED: 20 yearsDURING FOLLOW-UP: - 5894 developped T2 DM - 1556 cases of MI - 1405 strokes
Hu FB et al. Diabetes Care 2002; 25: 1129 - 1134
Elevated risk of cardiovascular disease prior to clinical diagnosis of type 2 diabetes
Multivariate RR of MI or stroke before clinical diagnosis of diabetes
Hu FB et al. Diabetes Care 2002;25:1129-1134
Nondiabetic Type 2 Diabetes Difference p
(n=1539) (n=195) (DM – Non-DM)
HDL cholesterol, mmol/L
1.25 ±0.01 1.14±0.02 -0.11 <0.001
LDL cholesterol, mmol/L
3.23±0.02 3.09 ±0.07 -0.14 0.459
Triglyceride, mmol/L 1.53±0.03 2.02±0.07 0.49 <0.001
SBP, mm Hg 117.8±0.35 120.7±1.0 2.9 0.016
DBP, mm Hg 71.5±0.2 73.2±0.7 2.2 0.042
Fasting insulin, pmol/L
74±2 108±6 34.0 <0.001
HOMA IR 2.8±0.1 3.9±0.2 1.1 <0.001
∆I30-I0/∆G30-G0
pmol/mmol227 ±11 119±30 -108 <0.001
San Antonio Heart Study:Clinical characteristics of subjects at baseline according to conversion status at follow-up
Haffner SM et al.Circulation 2000;101:975-980
Insulin Resistance and the Metabolic
Syndrome
IR is associated with the metabolic syndrome, a cluster of risk factors including
Hyperglycemia Abdominal obesity
Low HDL HTN
High TGs Older age
Data from NHANES III demonstrate presence of metabolic syndrome in 23% of the general population
ATP III criteria recognize IR as a CVD risk factor
Park et al. Arch Intern Med. 2003;163:427-436.
The metabolic syndrome
WHOa
Insulin resistance&/or FPG
Plus 2 or more of:
Blood pressure
TG, HDL-C
Microalbuminuria
Central obesity
EGIRb
Insulin resistance(hyperinsulinaemia)
Plus 2 or more of:
Blood pressure
TG, HDL-Cd
Central obesity
NCEPc
FPG
Plus 2 or more of:
Blood pressure
TG
HDL-C
Central obesity
aWorld Health Organisation; bEuropean Group for the study
of Insulin resistance; cNational Cholesterol Education Program; dand/or treatment for dyslipidaemia Eschwege E. Diabetes Metab 2003;29:6S19-27
Definition of Metabolic Syndrome from NCEP ATP III
Metabolic SyndromeThe IDF worldwide consensus definition
Prevalence of metabolic syndrome among NHANES III participants over 50 years of age categorized by glucose
intolerance
Alexander CM et al. Diabetes 2003; 52:1210-1214
Prevalence of CHD among NHANES III participants over 50 years of age categorized by presence of metabolic
syndrome and diabetes
Alexander CM et al. Diabetes 2003; 52:1210-1214
The risk for incidence of type 2 diabetes is greatly increased in persons with the metabolic syndrome
traits
San Antonio Heart Study: more than 60% of the insulin resistant subjects developed diabetes during 7.5 year follow-up
The prevalence of metabolic syndrome increase with deterioration of glucose tolerance
Five-year conversion rates for developing diabetes by the numbers of RFs present at baseline
D’Agostino RB et al. Diabetes Care 2004; 27: 2234 - 2240
Five-year conversion rates for developing diabetes by the presence at baseline of one or more CVD RFs.
The Insulin Resistance Atherosclerosis Study
The metabolic syndrome is a precursor and a significant predictor of CVD and type 2 diabetes
The connections between metabolic abnormalities
and vascular complications.
The risk for microvascular complications such as retinopathy, nephropaty, neuropathy is related to hyperglycemia.
The risk increase with the onset of elevated blood glucose levels.
The risk for macrovascular complications increase much earlier being predominantly associated to metabolic abnormalities that cluster around insulin resistance.
The best time point to start preventive interventions is different for micro and macro-vascular complications.
Is screening and early diagnosis of type 2 diabetes worthwhile?
The length of the preclinical asymptomatic phase during which glucose levels within diabetes range coexist with CVD risk factors may be as long as 12 years
Between UKPDS participants, people with newly diagnosed diabetes and lower initial glycemia had a significantly reduced risk for progression of microvascular complications
Harris MI et al. Diabetes Care 1992; 14: 815-819
Colagiuri S et aliabetes Care 2002;25: 1410-1417
Targeted Screening of high-risk individuals may identify:
-Individuals with prediabetes susceptible to clinical interventions to prevent or delay the progress to clinical diabetes.
- Individuals with diabetes in which multifactorial treatment of risk factors may delay or prevent complications.
Conclusions (1)
Early detecton of T2DM could offer the possibility to implement therapeutic interventions during the preclinical asymptomatic phase:
-Counseling for lifestyle optimisation.
-Tight glycemic control.
-Intensive use and targeted choice of antihypertensive
agents.
-More aggressive use of lipid treatment and aspirin.
However, the magnitude of benefit of earlier therapeutic initiation as compared to initiation after clinical diagnosis is, at present time, not evaluated.
Conclusions (2)
It is presumed, from indirect evidence, that the impact of earlier
interventions that target macrovascular complications (treating
CVD risk factors as hypertension, dyslipidemia, prothrombotic
state) may have a greater favorable effect than earlier initiation
of interventions that target microvascular complications ( as
tight glycemic control).
Current evidence suggests that the benefits of screening for T2DM
are more likely to come from modifications of CVD risk factors
rather than from tight glycemic control.
ADA: Recommendations for evaluation of hig-risk individuals
•Persons aged ≥ 45 years with a BMI ≥ 25 Kg/m2 (Asian Americans at BMI ≥23 Kg/m2 ) should be screened at 3-year intervals.
•Age < 45 years with BMI ≥ 25 Kg/m2 plus additional risk factors for
type 2 diabetes
•FPG is the recommended screening test. The OGTT may
be necessary when FPG is normal.
•Diagnostic testing should be performed in any clinical situation
in which such testing is warranted
•Done as part of health care office visit
ADA: Position statement Diabetes Care 2004; 27 Suppl 1: S11-S14
ADA position statement:Risk factors for T2DM
ADA. Diabetes Care 2004;27 (suppl1):S11-S14
Hypertension
History of gestational diabetes or baby weighing > 4000 g
Polycystic ovary syndrome
High-risk ethnic group
HDL-cholesterol < 35 mg/dl
Triglycerides > 250 mg/dl
First –degree relative with diabetes
History of vascular disease
Habitual inactivity