1. Doc. Eglė Varanauskienė KMU Endokrinologijos klinika
Riebalų apykaitos sutrikimų įtaka angliavandenių apykaitos sutrikimų išsivystymui
Doc. Eglė Varanauskienė
KMU Endokrinologijos klinika

4. Kodėl didėja kūno svoris?
Mobilūs telefonai ir nuotolinio valdymo prietaisai “apsaugo” mus nuo judėjimo!
20 kartų per dieną x 20 m = 400 m
“Nenueitas” kelias/metus 400x365 = 146,000 m
146 km = 25 h ėjimo
The impact of modern technology on our levels of physical activity is immense, resulting in an increasingly sedentary lifestyle.
Even remote controls and mobile telephones deprive us of physical activity and can lead to the accumulation of almost a kilogram of adipose tissue every year.
Furthermore, just one lump of extra sugar per day also leads to the accumulation of almost a kilogram of additional body fat over a year.
It is this imbalance between energy intake and physical activity over time that results in body fat accumulation.
However, taking a little more activity each day, for example by using the stairs instead of the escalator, would counterbalance this and maintain the balance in body weight.
Per 1 val. einant netenkama = kcal
”Sukaupta” energija = kcal
 kg riebalinio audinio
Rössner, 2002

6. Nutukimo ir cukrinio diabeto paplitimas JAV
Adapted from Mokdad AH, et al. JAMA 2003; 289:76–79.

7. CDC (Department of Health and Human Services Center of Disease Control and Prevention):
30% vyresnių nei 20 metų asmenų (daugiau nei 60 mln žmonių)
JAV yra nutukę;
Nutukimo paplitimas tarp jaunų žmonių
padidėjo 3 kartus nuo 1980 metų;
6-19 metų amžiaus grupėje
daugiau nei 9 mln nutukę (16%).

8. Metabolinis aktyvumas
Energijos balansas
Kaupimas
Išeikvojimas
For each of us, our body weight reflects the balance between our energy intake and our energy expenditure.
The largest part of our energy expenditure comes from our resting energy requirement – the energy we need to keep our bodies alive. We normally refer to that as resting metabolic rate but we know that activity and thermogenesis are also factors involved in dissipating energy.
One of the factors in the increasing prevalence and incidence of obesity seems to be declining activity levels.
At the same time, the availability, palatability and affordability of food has never been greater and it is thus easy for people to over consume.
Sibutramine’s actions favourably affect both sides of the energy balance equation.
Alkis
Sotumas
Maistas
Metabolinis aktyvumas
Termogenezė
Aktyvumas

9. Diabesity (diabetas+nutukimas)20 40 60 80
100
1990
1995
2000
2005
100
200
300
400
1985
1995
2005
2030
Viršsvoris
(įskaitant nutukusius)
Slide 3
Diabesity
Diabetes caused by excessive weight or the condition of having both diabetes and excessive weight is called diabesity.1
The World Health Organization (WHO) has declared that a diabetes epidemic is underway and has recognized that the prevalence of obesity is rapidly rising to epidemic proportions around the world.2
In the United States, results from the National Health and Nutrition Examination Survey (NHANES) conducted in 1999–2000 indicate that about 64.5% of US adults are either overweight or obese. The increasing prevalence of obesity is expected to continue for the foreseeable future.2
In 1985, about 30 million people worldwide had diabetes, and by 1995 this number had increased to about 135 million. By 2005 it was estimated to be about 217 million, and WHO predicts that the number will increase to at least 366 million by the year
JAV populiacija (proc.)
Nutukimas
Metai*
Sergantys CD (mln)**
*Nutukimo paplitimas tarp JAV suaugusių. Duomenys gauti: Centers for Disease Control and Prevention, National Health and Nutrition Examination Survey.
**Pasaulio CD sergančiųjų populiacija (mln). Duomenys gauti: World Health Organization. Adapted from Smyth S et al. Nat Med. 2005;12:75–80.
References:
1. Astrup A, Finer N. Redefining type 2 diabetes: 'diabesity' or 'obesity dependent diabetes mellitus'? Obes Rev. 2000;1:57–59.
2. Smyth S, Heron A. Diabetes and obesity: The twin epidemic. Nat Med. 2005;12:75–80.

10. Metabolinis sindromas
Uždegimas
Protrombotinė būklė
2 tipo diabetas
KVL
In 1998, the World Health Organization identified the components of the metabolic syndrome as hypertension, dyslipidemia (elevated plasma triglycerides [1.7 mmol/L] or reduced high-density lipoprotein cholesterol [HDL-C, <0.9 mmol/L]), obesity, and microalbuminuria. In addition, the metabolic syndrome existed if any two of these components were present in a person with type 2 diabetes.3 Produced by hormonal, genetic, and lifestyle factors, the metabolic syndrome increases risk of cardiovascular disease.4 The metabolic syndrome is also associated with low-grade inflammation, reflected by high levels of C-reactive protein, and a prothrombotic state, indicated by increased fibrinogen levels.5
Dislipidemija
Hipertenzija
Genetika +
gyvenimo būdas
KVL = kardiovaskullinė liga

11. Aterosklerozė, 2 tipo cukrinis diabetas ir metabolinis sindromas
Dislipidemija
Hipertenzija
Aterosklerozė
AKF inhibitoriai
AIIRB
Beta-blokatoriai
Kalcio kanalų blokatoriai
Diuretikai
Statinai
Fibratai
Patients with type 2 diabetes or metabolic syndrome may require therapy targeting these metabolic abnormalities to attenuate atherogenesis and reduce the risk of cardiovascular events.9
Statins and fibrates reduce triglycerides and LDL-C and increase HDL-C. The net result is a lowered risk of CHD-related events.9
Aggressive treatment of hypertension with ACE inhibitors, AIIAs, beta- blockers, calcium-channel blockers, and diuretics significantly decreases the rate of MI and stroke in patients with diabetes.9
Use of antiplatelet agents, such as aspirin or clopidogrel, to counter the heightened thrombotic potential frequently seen in diabetes, may also decrease the incidence of MI and death in these patients.9
Although the impact of strict glycemic control on macrovascular outcomes is unclear, prolonged hyperglycemia clearly increases the incidence of cardiovascular events. Vigorous control of glycemia with insulin, metformin, and sulphonylureas clearly improves microvascular outcomes and may benefit macrovascular outcomes to some degree as well.9
Hiperglikemija Rezistencija insulinui
Trombocitų aktyvacija ir agregacija
Insulinas
Metforminas
Sulfonylkarbamidai
Tiazolidinedionai
Inkretinų mimetikai
DPP-IV inhibitoriai
Aspirinas
Klopidogrelis
Adapted from Beckmann JA et al JAMA 2002;287:2570–2581.

12. Riebaliniai ruoželiai
Aterosklerozė jauname amžiuje susijusi su nutukimu ir “ankstyva” insulino rezistencija
Riebaliniai ruoželiai
Amžius > 24 m.
Iškilūs pažeidimai
Amžius m.
KMI (kg/m2)
< 25
25-30
> 30
Aterosklerozkleroziniai pakitimai aortoje
0-2
10+
Adapted from: McGill Jr. et al. (PDAY) Circulation. 2002;105:

13. Nutukusiems žmonėms būna aktyvi
hipotalamo-hipofizės-antinksčių ašis.
Kartu slopinamas augimo hormono,
Prolaktino, gonadotropinų – lytinių liaukų
ašių aktyvumas.
Gali padidėti kortizolio ir sumažėti augimo
hormono, prolaktino kiekis kraujyje.
Vyrams sumažėja, o moterims padidėja
Testosterono kiekis kraujyje (vystosi
hipogonadizmas)

14. Nutukimas – tai ne paprastas disbalansas tarp gautos ir išeikvotos energijos
Priežastys:
genetinis POMC produkcijos defektas ir MC4 geno mutacija – galima nutukimo priežastis;
Dėl  AKTH produkcijos – centrinis antinksčių nepakankamumas;
Šiam nutukimo tipui būdinga rausvos (raudonos) spalvos plaukai;
POMC ir MC4 geno mutacijos nustatytos 5% nutukusių vaikų.

15. Nutukimo priežastys:
Leptino receptoriaus mutacijos pagumburyje;
PPAR transkripcijos faktoriaus, atsakingo už adipocitų diferenciaciją, receptoriaus mutacijos (susiję su didelio laipsnio nutukimu);
Uždegiminė – infekcinė teorija:
Adenoviruso 36 infekcijos paplitimas tarp normalaus svorio asmenų 5%, tarp nutukusiųjų – 20-30%.
Visuose nutukimo modeliuose, išskyrus POMC produkcijos defektą ir MC4 geno mutacijos modelį – kartu nustatoma rezistencija insulinui
The adipocyte in insulin resistance: key molecules and the impact of the thiazolidinediones. TRENDS in Endocrinology and Metabolism 2003; 14; 3:

16. NUTUKIMO KLASIFIKACIJA
Mitybinis konstitucinis nutukimas
Neuroendokrininis nutukimas:
1) hipotalaminis
2) hiperkorticizmas
3) hipotirozė
4) hipogonadizmas
5) insulinoma
6) hiperinsulinizmas
7) hiposomatotropizmas
8) poliendokrininis
JATROGENINIS NUTUKIMAS
1) vaistai (kortikosteroidai, psichotropiniai ir kt.)
2) pagumburio operacija
DEFORMUOJANTIS NUTUKIMAS:
1) tolygus riebalų pasiskirtymas:
a) dominantinis paveldimumas
b) recesyvinis paveldimumas
c) susijęs su lytine X chromosoma
d) chromosominiai pakitimai
2) vietinis riebalų pasiskirstymas
D.Lašienė, L.Lašas, 1998 m.

17. Androidinis (centrinis) ir ginoidinis nutukimas:
Normoje:
10% riebalų sudaro poodinį riebalinį sluoksnį;
80% riebalų susikaupę visceraliniuose organuose;
10% riebalų randama retroperitoneume, perirenaliniuose audiniuose ir kt.
Androidinis (centrinis, pilvinis, obuolio tipo) nutukimas:
vyrams: liemens apimtis > 94 cm, liemens/klubų santykis > 0.95,
moterims: liemens apimtis > 80 cm, liemens/klubų santykis > 0.8, reikšmingai didina KVL riziką;
liemens apimtis – vyrams >102 cm, moterims > 88 cm – būtina skubi terapinė pagalba.
2004

18. CENTRINIO TIPO NUTUKIMAS
The characteristic abdominal fat distribution frequently present in the insulin-resistant patient is demonstrated in this cartoon. Fat deposits are present in the liver and muscle as well as the metabolically more active intra-abdominal fat.
DeFronzo RA. Br J Diabetes Vasc Dis. 2003;3(suppl 1):S24-S40.

19. 2 tipo cukrinio diabeto vystymosi eiga
Rezistencija insulinui
Norma
Sutrikusi tolerancija gliukozei
2 tipo diabetas
Mikrovaskulinės komplikacijos
Jautrumas insulinui
Makrovaskulinės
komplikacijos
Hipergli-kemija
Normali insulino sekrecija
Normogli-kemija
Type 2 diabetes is progressive – a continuum
Type 2 diabetes is a progressive disease caused as a result of underlying insulin resistance (leading to loss in glycaemic control and hyperglycaemia).1
Patients can be insulin resistant and have Type 2 diabetes for some years before they are made aware of the problem through the development of complications.1
Until this point, the pancreatic -cells compensate for the insulin resistance by producing increasing amounts of insulin.2
As the -cells become damaged by lipotoxicity and glucotoxicity as a result of insulin resistance, they can no longer compensate, resulting in hyperglycaemia.3,4
Type 2 diabetes is therefore a result of underlying insulin resistance and subsequent -cell dysfunction.5
Link to next slide:
What does this mean for patients?
References
Groop LC. Diabetes Obes Metab 1999; 1: S1–S7.
DeFronzo R. Diabetes 1988; 37: 667–687.
Inzucchi SE. JAMA 2002; 287; 360–372.
Kahn SE. Am J Med 2000; 108: 25–85.
Stumvoll M. Lancet 2005; 365: 1333–1346.
β-ląstelių išsekimas
Gliukozė plazmoje nevalgius
Jautrumas insulinui
Insulino sekrecija
Adapted from DeFronzo R. Diabetes 1988; 37: 667–687.
Groop LC. In: Leslie RDS, Ed. Molecular pathogenesis of diabetes mellitus. Karger; 1997; 22: 131–156.

20. Toksinis gliukozės poveikis
Retinopatija
Nefropatija CH OH 2 H H O
Neuropatija H H OH OH OH
Prolonged exposure to hyperglycemia in diabetes results in a diverse array of pathologic changes. Among these are alterations in the insulin resistance of hepatic and skeletal muscle, pancreatic beta-cell damage, nephropathy, retinopathy, neuropathy, and, in a large proportion of diabetic patients, CVD.3,18,19 OH H
Beta-ląstelių pakenkimas
Kardiovaskulinės ligos
Rezistencija insulinui kepenyse ir skeleto raumenyse

21. Glikemijos po valgio įtaka arterijų sienelės pokyčiams atsirasti
Kraujagyslės-sienelės “stresas”
Hiperglikemija
Hiperlipidemija
The postprandial state has complex and deleterious effects on the vascular wall that are only partly explained by hyperglycemia occurring shortly after a meal. The multiple consequences of postprandial lipemia occurring as hyperglycemia returns to premeal levels include “toxic” effects of remnants and lipolysis products (increased FFAs), activation of coagulation, and endothelial dysfunction. These actions may cause more damage to the vascular wall than that due to hyperglycemia (oxidative stress, glycation) alone.28,31,32 In a study of 30 people with diabetes and 20 nondiabetic individuals who consumed a high-fat meal, 75 g of glucose, or a high-fat meal plus glucose, postprandial hypertriglyceridemia and hyperglycemia had independent effects on the endothelial wall that were partly corrected by simvastatin.33
“Oksidacinis” stresas
Glikolizacija
“Toksiniai” produktai
Lipolizės produktai—LRR
Koaguliacijos suaktyvėjimas
Endotelio disfunkcija
LRR = laisvos riebiosios rūgštys
Adapted from Heine RS, Dekken JM Diabetologia 2002;45:461–475; Ginsberg HN, Illingworth DR Am J Cardiol 2001;88(suppl):9H–15H; Andersen RA et al Atherosclerosis 2001;159:9–15.

22. RIEBALINIO AUDINIO REIKŠMĖ 2 TIPO DIABETO PATOGENEZĖJE
 Laisvosios riebiosios rūgštys
Raumenys Kasa Kepenys
Sumažėja Slopinama  Gliukoneogenezė
gliukozės ß-ląstelių
panaudojimas veikla
2 tipo diabetas

23. Intra-abdominalinis nutukimas skatina rezistencijos insulinui atsiradimą ir b-ląstelių disfunkciją
 Rezistencija insulinui kepenyse
 Kepenų gliukozės produkcija
 Mažos, tankios MTL
Lipolizė
Intra-abdominalinis
nutukimas
 TG-prisot LŽTL-C
Žemas DTL-C
 LRR
CEPB, lipolizė
Portalinė
kraujotaka
Sisteminė krauj.
 Gliukozės pasisav.
 Rezist. insulinui
Intra abdominal adiposity promotes insulin resistance and b-cell dysfunction
Free fatty acids (FFA) are products of lipolysis of triglycerides from adipocytes. According to the portal theory, high concentrations of FFA from intra-abdominal adiposity reach the liver via the portal vein, where they impair metabolic function. Normally, the postprandial insulin rise suppresses lipolysis, but intra-abdominal adipocytes may be more insulin resistant than subcutaneous adipocytes. The excess portal FFA load induces hepatic insulin resistance, leading to increased hepatic glucose production and hyperinsulinaemia.
The hypertriglyceridaemia induces increased secretion of triglyceride-rich VLDL-cholesterol, which is converted to LDL-cholesterol in the circulation, as lipolysis degrades its triglyceride content. The relatively high original triglyceride content results in LDL particles that are smaller and denser than those present in an individual without intra-abdominal adiposity and insulin resistance. Also, cholesteryl ester transfer protein (CETP) exchanges cholesterol from HDL for triglycerides from VLDL and LDL. This results ultimately in small, dense HDL particles that are more rapidly catabolised. The net result is an overall reduction in HDL-cholesterol.
FFA are also toxic to the β-cell at high concentrations, leading to long-term impairment of β-cell function and impaired insulin release.
Lam TK, Carpentier A, Lewis GF et al. Mechanisms of the free fatty acid-induced increase in hepatic glucose production. Am J Physiol Endocrinol Metab 2003;284:E
Carr MC, Brunzell JD. Abdominal obesity and dyslipidemia in the metabolic syndrome: importance of type 2 diabetes and familial combined hyperlipidemia in coronary artery disease risk. J Clin Endocrinol Metab 2004;89:
Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet. 2005;365:
Haber EP, Ximenes HM, Procopio J et al. Pleiotropic effects of fatty acids on pancreatic beta-cells. J Cell Physiol 2003;194:1-12.
Zraika S, Dunlop M, Proietto J, Andrikopoulos S. Effects of free fatty acids on insulin secretion in obesity. Obes Rev 2002;3:
Lėtinis b-ląstelių pažeidimas LRR
 Insulino sekrecija
Vidaus organų & sisteminė krauj.
LRR: laisvos riebiosios rūgštys; CEPB: cholesterino esterių pernašos baltymas.
Lam TK et al. Am J Physiol Endocrinol Metab 2003;284:E863-73; .
Carr MC et al. J Clin Endocrinol Metab 2004;89:2601-7;
Eckel RH et al. Lancet. 2005;365: ; Haber EP et al.
J Cell Physiol 2003;194:1-12; Zraika S et al. Obes Rev 2002;3:

24. Intra-abdominalinio nutukimo sąlygota rezistencija insulinui ir padidėjusi KMR
 Metaboliškai aktyvių medžiagų (adipokinų) sekrecija
 Kepenų LRR sintezė (portalinė hipotezė)
 Intra-abdominalinis nutukimas
 Insulino sąlygota lipolizės supresija
 PAI-1
 Adiponektinas
 IL-6
 TNFa
 LRR
Intra-abdominal adiposity promotes insulin resistance and increased CV risk
Intra-abdominal adiposity can promote insulin resistance and cardiovascular risk indirectly, through increased secretion of free fatty acids into the portal vein in the setting of insulin resistance, leading to increased hepatic triglyceride biosynthesis (the ‘portal hypothesis’). The direct adverse effects of intra-abdominal adiposity occur via the secretion of a range of bioactive substances. These include:
a) Increased secretion of plasminogen activator inhibitor-1 (PAI-1), the endogenous inhibitor of tissue plasminogen activator (tPA). Increased PAI-1 secretion increases the risk of an intravascular thrombus.
b) Adiponectin is a fat-derived hormone that protects the cardiovascular system. Decreased secretion of adiponectin in the setting of intra-abdominal adiposity implies increased cardiovascular risk.
c) Interleukin-6 (IL-6) and tumour necrosis factor alpha (TNFa) are inflammatory mediators. Intravascular inflammation is a key early event in atherogenesis.
Heilbronn L, Smith SR, Ravussin E. Failure of fat cell proliferation, mitochondrial function and fat oxidation results in ectopic fat storage, insulin resistance and type II diabetes mellitus. Int J Obes Relat Metab Disord 2004;28 Suppl 4:S12-21.
Coppack SW. Pro-inflammatory cytokines and adipose tissue. Proc Nutr Soc 2001;60:
Skurk T, Hauner H. Obesity and impaired fibrinolysis: role of adipose production of plasminogen activator inhibitor-1. Int J Obes Relat Metab Disord 2004;28:
 Rezistencija insulinui
 Dislipidemija
Rezultatas:
 Rezistencija insulinui
 Uždegimas
Pro-aterogeninis
Heilbronn L et al. Int J Obes 2004;28 Suppl 4:S12-21;
Coppack SW. Proc Nutr Soc 2001;60:349-56; Skurk T,
Hauner H. Int J Obes 2004;28:

25. “Tiksinčio laikrodžio” hipotezė
Komplikacijos “Laikrodis pradeda tiksėti”
Makrovaskulinės Prieš diagnozuojant
komplikacijos hiperglikemiją
Mikrovaskulinės Nustačius hiperglikemiją
komplikacijos
Microvascular complications occur as a result of hyperglycemia.17,18 Therefore, “the clock starts ticking” for these complications at the onset of hyperglycemia.18
Conversely, “the clock may start ticking” for macrovascular complications long before the diagnosis of diabetes.15 This is because many risk factors for the metabolic abnormalities leading to macrovascular disease precede by many years the clinical manifestations of diabetes.18
Adapted from WHO Diabetologia 1985;28:615–640; Haffner SM et al JAMA 1990;263:2893–2898.

26. Visceralinis nutukimas didina 2 tipo cukrinio diabeto riziką24 20 16
Santykinė rizika 12 8
These data are from the Nurses’ Health Study (Carey VJ et al, 1997), an observational study that followed a cohort of 43,581 women between 1986 and 1994 in the USA. The analysis presented here was designed to define the association between waist circumference and the risk of developing type 2 diabetes.
The risk of developing type 2 diabetes increased linearly with an increasing waist circumference. The relative risk for women at the 90th percentile of waist circumference (equivalent to a waist measurement of 92 cm [36 in]) was 5.1 (95% CI 2.98.9) compared with women at the 10th percentile (waist measurement of 67 cm [26.2 in]). High waist circumference is a powerful predictor of an increased risk of developing type 2 diabetes (Wang Y et al, 2005). 4
< 71
> 96.3
Liemens apimtis (cm)
Carey VJ, et al. Am J Epidemiol. 1997;145:
Carey VJ, Walters EE, Colditz GA, et al. Body fat distribution and risk of non-insulin-dependent diabetes mellitus in women. The Nurses' Health Study. Am J Epidemiol 1997;145:
Wang Y, et al. Comparison of abdominal adiposity and overall obesity in predicting risk of type 2 diabetes among men. Am J Clin Nutr. 2005;81:

27. Liemens apimties (cm) kvintilės
Visceralinis nutukimas susijęs su padidėjusia koronarinės širdies rizika
Liemens apimtis reikšmingai susijusi su padidėjusia, standartizuota pagal amžių KŠL rizika, nepriklausomai nuo KMI ir kitų kardiovaskulinės rizikos veiksnių
0.0
0.5
1.0
1.5
2.0
2.5
3.0
< < < < <139.7
1.27
2.06
2.31
2.44
p = 0.007
Reliatyvi rizika
Liemens apimties (cm) kvintilės
The prospective Nurses Health Study set out to assess the impact of factors such as waist circumference in determining risk of CHD in a cohort of 44,702 US female registered nurses, aged 40 to 65 years, recruited between 1986 and Study subjects were free of prior CHD at baseline.
During 8 years of follow-up, there was a direct, independent and continuous relationship between waist circumference and age-adjusted risk of CHD.
CHD: coronary heart disease; BMI: body mass index
Rexrode KM et al, 1998
Rexrode KM, Carey VJ, Hennekens CH et al. Abdominal adiposity and coronary heart disease in women. J Am Med Assoc 1998;280:1843–8.

28. The MRC/BHF Heart Protection Study Rizikos sumažėjimas =24%
Reikšminga liekamoji kardiovaskulinė rizika pacientams, gydytiems statinais
The MRC/BHF Heart Protection Study 30
Placebas
Statinai 20
Rizikos sumažėjimas =24%
(p<0.0001)
19.8% statinais gydytų pacientų buvo reikšmingų KV įvykių per 5 metus
% Pacientai 10
Substantial residual cardiovascular risk in statin-treated patients
The MRC/BHF Heart Protection Study was one of the landmark trials that have established the place of statins in the management of hypercholesterolaemia. A population of 20,536 patients at high cardiovascular risk through the presence of coronary disease, other arterial disease or diabetes were randomly assigned to treatment with simvastatin or placebo for an average of 5 years.
The intervention was highly effective, with a significant reduction in the risk of cardiovascular events of 24%. However, a majority of cardiovascular risk remains unaffected after statin treatment, and almost 20% of patients in the statin group had a major cardiovascular event during the 5-year follow-up period.
Total cholesterol and LDL-C were markedly reduced by treatment with the statin (mean changes from baseline of –1.2 mmol/L [–46 mg/dL] and –1.0 mmol/L [–39 mg/dL], respectively). However, other lipid components, such as triglycerides of HDL-C impact importantly on cardiovascular risk and were changed only slightly in the study (mean changes from baseline of –0.3 mmol/L [–27 mg/dL] and 0.03 mmol/L [1 mg/dL], respectively).
We may need to look beyond effects on LDL-C to achieve greater results in the management of overall cardiovascular risk. 1 2 3 4 5 6
Stebėjimo metai
Heart Protection Study Collaborative Group, 2002
Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:7-22.

29. IAN = intra-abdominalinis nutukimas
Intra-abdominalinis nutukimas – vienas iš pagrindinių padidėjusios kardiometabolinės rizikos veiksnių
IAN = intra-abdominalinis nutukimas
Susijęs su uždegiminiais
markeriais
(C-reaktyvinis baltymas) 
Dislipidemija
Padidėjusi
kardiometabolinė
rizika
LRR 
Rezistencija
insulinui
This slide summarises the relationships between intra-abdominal adiposity (IAA) and increased cardiometabolic risk. Intra-abdominal adiposity drives the progression of multiple risk factors directly, through the secretion of excess free fatty acids and inflammatory adipokines, and decreased secretion of adiponectin. The important contributions of IAA to dyslipidaemia and insulin resistance provide an indirect, though clinically important, link to the genesis and progression of atherosclerosis and cardiovascular disease.
The location of excess IAA is an important determinant of cardiometabolic risk. IAA is associated with insulin resistance, hyperglycaemia, dyslipidaemia, hypertension, and prothrombotic/proinflammatory states. Excess IAA typically is accompanied by elevated levels of C-reactive protein (CRP) and free fatty acids (FFAs), as well as decreased levels of adiponectin. Elevated CRP is an indicator of inflammation. Abdominal obesity has been shown to be associated with the inflammation cascade, with adipose tissue expressing a number of inflammatory cytokines. Inflammation is now believed to play a role in the development of atherosclerosis and type 2 diabetes. Elevated levels of CRP are considered to be predictive of cardiovascular disease and insulin resistance.
Elevated FFA levels appear to play a significant role in the cause of insulin resistance. It has been suggested that elevated FFAs and intracellular lipids inhibit the insulin signaling mechanism, leading to decreased glucose transport to muscle. FFAs also play a mediating role between insulin resistance and β-cell dysfunction, indicating that a reduction in FFA level could be a desirable therapeutic target.
Adiponectin is an adipose tissue-specific circulating protein which is involved in the regulation of lipid and glucose metabolism. Adiponectin has been shown to be reduced in adults with obesity and type 2 diabetes. In non-diabetics, hypertriglyceridaemia and low HDL-cholesterol have been shown to be associated with low plasma adiponectin concentrations.
All of these components help to explain why excess abdominal adiposity is considered to be a great threat to cardiovascular and metabolic health.
Adipokinų
sekrecija
(↓ adiponektino) 
Uždegimas
IAA: intra-abdominal adiposity
Kershaw EE et al, 2004; Lee YH et al, 2005; Boden G et al, 2002
Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab 2004;89:2548–2556.
Lee YH, Pratley RE. The evolving role of inflammation in obesity and the metabolic syndrome. Curr Diab Rep 2005;5:70–75.
Boden G, Shulman GI. Free fatty acids in obesity and type 2 diabetes: defining their role in the development of insulin resistance and beta-cell dysfunction. Eur J Clin Invest 2002;32:14–23.

30. Riebalinis audinys – endokrininis organas
Senas požiūris: energijos depo
Naujas požiūris: sekrecinis/endokrininis
organas
Riebiosios rūgštys Gliukozė
Po valgio
Nevalgius Tg
Įvairios sekretuojamos
medžiagos Tg Tg
Raumenys
The evolving view of adipose tissue: an endocrine organ
Previously, adipocytes were considered to be little more than inert storage depots, storing fat as triglyceride in the fed state, and releasing fuel as fatty acids and glycerol in times of fasting.
It is now clear that adipocytes are highly active endocrine glands that secrete important hormones, cytokines, vasoactive substances, and other peptides. These exert marked influences on metabolic function and cardiovascular risk in a number of organ systems throughout the body. The following slides describe some of the principal adipocyte-derived agents, and summarise their metabolic and cardiovascular effects.
Lyon CJ, Law RE, Hsueh WA. Minireview: adiposity, inflammation, and atherogenesis. Endocrinology 2003;144:
Riebiosios rūgštys Glicerolis
Kraujagyslės
Kepenys
Kasa
Lyon CJ et al 2003

31. Kardiometabolinis adipocitų išskiriamų medžiagų poveikis
↑ Lipoproteinlipazė
Hipertenzija
↑ IL-6
↑ Angiotenzinogenas
Uždegimas
↑ Insulinas
Aterogeninė
dislipidemija
↑ LRR
Adipose tissue
↑ TNFα
↑ Rezistinas
↑ Leptinas
↑ Adipsinas (Komplementas D)
Adverse cardiometabolic effects of products of adipocytes
This slide shows a more complete list of the bioactive substances secreted by adipocytes, that modulate insulin resistance and cardiovascular risk.
Lyon CJ, Law RE, Hsueh WA. Minireview: adiposity, inflammation, and atherogenesis. Endocrinology 2003;144:
Trayhurn P, Wood IS. Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr 2004;92:
Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet. 2005;365:
↑ Laktatas
2 tipo CD
↓ Adiponektinas
↑ Plazminogeno aktyvatoriaus inhibitorius-1 (PAI-1)
Aterosklerozė
Trombozė
Lyon 2003; Trayhurn et al 2004; Eckel et al 2005

32. Laisvos riebiosios rūgštys:
TNF  stimuliuoja adipocitų lipolizę;
Daugėja LRR;
Vystosi rezistencija insulinui
periferiniuose audiniuose
ir kepenyse;
Kepenyse LRR padidėjimas skatina
gliukoneogenezę ir trigliceridų sintezę;
LRR padidėjimas lipotoksiškai veikia kasą ir  ląsteles – sutrikdoma insulino sekrecija;
Skeleto raumenyse LRR konkuruoja su gliukoze –
kai LRR, raumenyse oksiduojamos LRR
(Randlio ciklas)

35. Riebalinis audinys – endokrininis organas
Nutukusiems asmenims stebima:
neigiama koreliacija tarp plazmos adiponektino koncentracijos ir riebalinio audinio kiekio, centrinio riebalų pasiskirstymo, insulino koncentracijos nevalgius, TG ir rezistencijos insulinui
CB1
Adipose tissue as an endocrine organ
Adiponectin levels are inversely correlated with percent body fat, central fat distribution, fasting plasma insulin and oral glucose tolerance.1 Plasma concentrations of adiponectin are high in lean individuals, and lower in obese subjects and in subjects with type 2 diabetes.2 Administration of adiponectin to mice significantly reduced levels of free fatty acids.3
Adiponectin has been shown to activate the peroxisome PPARα pathway, thus enhancing insulin sensitivity, increasing fatty acid oxidation and glucose uptake, and decreasing gluconeogenesis.4,5
1. Goldstein B et al. Adiponectin: a novel adipokine linking adipocytes and vascular function. J Clin Endocrinol Metab 2004;89:2563–8
2. Arita Y et al. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 1999;257:79–83
3. Berg AH et al. The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med 2001;7:947–53
4. Yu S et al. Adipocyte-specific gene expression and adipogenic steatosis in the mouse liver due to peroxisome proliferator-activated receptor-γ1 (PPAR-γ1) overexpression. J Biol Chem 2003;278:498–505
5. Gil-Campos M et al. Adiponectin, the missing link between insulin resistance and obesity. Clin Nutr. 2004;23:963–74

36. Adiponektinas Specifinis cirkuliuojantis riebalinio audinio baltymas.
Dalyvauja riebalų1 ir gliukozės apykaitoje2
Nustatytas sumažėjęs adiponektino kiekis nutukusiems ir 2 tipo CD sergantiems asmenims
Žemas adiponektino kiekis yra susijęs su DTL-chol sumažėjimu, hipertrigliceridemija ir MTL-chol padidėjimu.
Padidėjęs adiponektino kiekis susijęs su kūno svorio mažėjimu ir mažesniu insulino kiekiu, lemiančiu geresnį jautrumą insulinui
Adipose
tissue
Adiponectin
Adiponectin is an adipocyte-derived hormone and plays a key role in the regulation of lipid and glucose metabolism.1,2 Adiponectin levels have been shown to be reduced in adults with obesity and type 2 diabetes.3,4 For example, hypertriglyceridaemia and low HDL-C were associated with low plasma adiponectin concentrations in In 352 non-diabetic women,5 and increased adiponectin levels are associated with improved insulin sensitivity.6
Experimental studies have established a mechanistic link between adiponectin and energy/body weight homeostasis. For example, administration of adiponectin to mice consuming a high-fat/high-sucrose diet resulted in weight loss and a decrease in plasma glucose, free fatty-acids and triglycerides.7
1. Yamauchi T et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med 2002;8:1288–95
2. Berg AH et al. The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med 2001;7:947–53
3. Weyer C et al. Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab 2001;86:1930–5
4. Lindsay RS et al. Adiponectin and development of type 2 diabetes in the Pima Indian population. Lancet 2002;360:57–8
5. Matsubara M et al. Decreased plasma adiponectin concentrations in women with dyslipidemia. J Clin Endocrinol Metab 2002;87:2764–9
6. Chandran M et al. Adiponectin: more than just another fat cell hormone? Diabetes Care 2003;26:2442–50
7. Fruebis J et al. Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice. Proc Natl Acad Sci USA 2001;98:2005–10
Yamauchi et al 2002; Berg et al 2001; Weyer et al 2001; Lindsay et al 2002; Matsubara et al 2002; Fruebis et al 2001; Chandran et al 2003

37. Hormonai, veikiantys
smegenyse ir reguliuojantys trumpalaikį bei ilgalaikį
apetitą, medžiagų
apykaitą.

38. GHRELIN didina apetitą, veikdamas pagumburio apetito centrus; stimuliuoja skrandžio motoriką, turi teigiamą poveikį kardiovaskulinei sistemai (didina minutinį širdies tūrį ir kt.).

40. GHRELIN GHRELIN stimuliuoja apetitą ir slopina leptino sintezę
Mažai miegant, didėja apetitas ir
nutukimo pavojus –
GHRELIN
stimuliuoja apetitą ir slopina leptino
sintezę

41. Nutukimas ir 2 tipo diabetas didina endokanabinoidinės sistemos aktyvumą
Endokanabinoidų konc. tarp nutukusių moterų didesnė nei tarp normalaus svorio
Endokanabinoidų konc. didesnė esant visceraliniam nutukimui
Endokanabinoidų konc. didesnė sergant 2 tipo diabetu
Liesi (n=20)
Poodin. nutukimas (n=20)
Visceralinis nutuk. (n=20) 12 * 30 **
Kontrolė 3 *
2 tipo diabetes 10 ** 4 * 20 8 * 2 3
2-AG pmol/ml
2-AG pmol/ml 6
Anandamidas pmol/ml
pmol/ml blood 2 10 1 4
Elevated blood anandamide levels in obese women
A study was conducted in 20 lean and 20 obese post-menopausal women. Circulating levels of ECS transmitters were significantly higher in obese women, relative to non-obese women showing that increased activity of the ECS is associated with aberrant energy homeostasis (such as obesity).
Engeli S, Bohnke J, Feldpausch M et al. Activation of the peripheral endocannabinoid system in human obesity. Diabetes 2005;54:
The endocannabinoid system is overactive in abdominal obesity
The relationships between the level of activity of the ECS and adiposity were studied in 62 untreated, apparently healthy men with BMI ranging between 18.7 kg/m2 and 35.2 kg/m2. Here, anthropometric parameters are presented in patients stratified for circulating levels of ECS transmitters.
Neither anandamide nor 2-AG levels varied significantly with increasing BMI (left-hand panels). In contrast, levels of both transmitters varied significantly with the extent of intra-abdominal adiposity. Subjects with the highest levels of 2-AG had the greatest intra-abdominal adiposity, on average, while subjects with the highest anandamide levels had the lowest intra-abdominal adiposity.
Elevated 2-AG levels were found only in subjects with intra-abdominal adiposity, measured using CT scanning, and were not elevated in subjects without intra-abdominal adiposity who had similar BMI. Thus, an overactive ECS is primarily associated with abdominal obesity (intra-abdominal adiposity) rather than generalised obesity (high BMI).
The study also showed that 2-AG levels correlated with a number of cardiometabolic risk parameters, including positive correlations with waist circumference, triglycerides and insulin, and negatively with HDL-C and the cardioprotective hormone, adiponectin. Thus the overactive ECS was associated with intra-abdominal adiposity and multiple markers of increased cardiometabolic risk.
Côté M, Matias I, Lemieux I et al. Circulating endocannabinoid levels, abdominal adiposity and related cardiometabolic risk factors in obese men. Int J Obes (Lond) 2007;31:692-9.
Elevated 2-arachidonoylglycerol levels in visceral fat of obese patients
In this study, visceral and/or subcutaneous fat from 24 obese patients and from 10 normal-weight patients was studied (fat was removed during surgery). The level of 2-AG was similar in subcutaneous fat from obese patients and in visceral fat from normal-weight patients. However, the level of 2-AG in visceral fat from obese patients was markedly and significantly higher. A larger difference was observed in men vs. women, although differences between genders did not achieve statistical significance. Levels of anandamide did not differ between groups.
These data are consistent with those from the previous slide an demonstrate increased activity of the ECS in visceral fat in obese patients.
Matias I, Gonthier MP, Orlando P et al. Regulation, function, and dysregulation of endocannabinoids in models of adipose and beta-pancreatic cells and in obesity and hyperglycemia. J Clin Endocrinol Metab 2006;91: 1 2
Liesi
Nutukę
Liesi
Nutukę
Anandamidas 2-AG
Liesi
Poodin.
Visceralinis
Nutukimas
Engeli S, et al. Diabetes 2005; 54:2838–2843
Bluher M, et al. Diabetes. 2006;55:
Matias I, et al. JCE&M.
2006;91:3171–3180
2-AG =2-Arachidonoylglycerol

42. Endokanabinoidinė sistema (EKS)
EK sistema – tai endogeninė fiziologinė sistema, ypač svarbi organizmo energijos homeostazei, lipidų bei gliukozės apykaitai – veiksniams, turintiems įtaką kardiometabolinei rizikai
Canabis sativa – pasaulyje naudojama apie metų (marihuana, hašišas ir kt. narkotiniai preparatai)
Pagrindinis aktyvus alkaloidas –delta-9-tetrahydrocannabinol (THC), izoliuotas 1964 m., randama > nei 60 kitų kanabinoidų
The Endocannabinoid System
The endocannabinoid system (EC system), acting through the CB1 receptor, is closely involved in the central and peripheral regulation energy homeostasis, fat accumulation and metabolic unbalance.1
Recent experimental data has shown that over activation of the EC system, associated with excessive food intake and fat accumulation, leads to increased levels of EC transmitter in the Lorain and the periphery this leads to disruption of the feedback mechanisms regulating energy homeostasis, characterized by hyperphagia, excessive fat accumulation and disturbance of glucose and lipid balance. Selective CB1 receptor blockage regulates the over activation of the EC system and has been shown to improve these adverse metabolic consequences, improving multiple cardiometabolic risk factors .2,3
Selective CB1 receptor blockade thus provides a key therapeutic target for intervention in the management of the multiple cardiovascular risk factors that lead to adverse cardiovascular outcomes.
1. Cota D et al. The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. J Clin Invest 2003;112:423–31
2. Ravinet-Trillou C et al. Anti-obesity effect of SR141716, a CB1 receptor antagonist, in diet-induced obese mice. Am J Physiol Regul Integr Comp Physiol. 2003;284:R345–53
3. Arnone M et al. Selective inhibition of sucrose and ethanol intake by SR141716, an antagonist of central cannabinoid (CB1) receptors. Psychopharmacology 1997;132:104–6
4. Hayashi T et al. Visceral adiposity and the risk of impaired glucose tolerance. Diabetes Care 2003;26:650–5
5. Nguyen-Duy T et al. Visceral fat and liver fat are independent predictors of metabolic risk factors in men. Am J Physiol Endocrinol Metab 2003;284:E1065–71

43. EKS sudaro:
2 tipų kanabinoidiniai receptoriai – CB1 ir CB2, pirmą kartą aprašyti 1990
CB1 receptoriai randami smegenyse (CNS) ir periferiniuose organuose – riebaliniame audinyje, kepenyse, raumenyse, virškinimo trakte, miokarde, kraujagyslių endotelyje ir simpatinių nervų galūnėse;
CB2 receptoriai pagrinde randami limfoidiniame audinyje ir periferiniuose makrofaguose (imuninė sistema)
Endokanabinoidiniai ligandai (Endokanabinoidai) - N-arachidonyl ethanolamine anandamide (Sanskrito kalba – “vidinė palaima”) ir 2-arachidonyl glycerol 2-AG; abu endokanabinoidai jungiasi ir aktyvuoja CB1 receptorius
Fermentai, dalyvaujantys endokanabinoidų biosintezėje ir degradacijoje

44. Kanabinoidiniai receptoriai
1964
1992
D9-Tetrahydrocannabinol
Anandamide E L M
472 1
360
CB1 , CB2
Hipocampus
Bazaliniai ganglijai
Žievė
Smegenėlės
Pagumburis
Limbinės struktūros
Smegenų kamienas
Virškinimo sistema
Imuninės ląstelės ir audiniai

45. ENDOKANABINOIDAI sintezuojami pagal poreikį iš ląstelių membranos
Phospholipid remodeling
Fosfolipidiniai
pirmtakai R 1 O O O O - R 2 O O - R O P O 3 N O C H H O - O H N A P E - P L D D A G L i p a s e O
Endokanabinoidai O O H O H N H O C H O H
Anandamide
2-Arachidonoylglycerol F a t t y A c i d A m i d e H y d r o l a s e M A G L i p a s e
Degradacijos produktai O O H O H O H H O C H H 2 N O H
veikia vietiškai
yra iš karto suardomi pasibaigus veikimui

46. Svarbios endokanabinoidų savybės
Kilę iš lipidų pirmtakų
Sintezuojami pagal poreikį
Veikia vietiškai (parakrininiu arba autokrininiu būdu )
Greitai suyra atlikę savo funkciją
Nervų sistemoje veikia kaip retrogradiniai neurotransmiteriai
Slopina kitų neurotransmiterių atsipalaidavimą
Important Features of Endocannabinoids
This slide summarises the key properties of cannabinoid ligands. They are produced on demand, and act locally and transiently, as described above.1–5
Activation of CB1 receptors in the brain is involved in retrograde neurotransmission.6 This means that release of cannabinoid ligands from a neurone is able to inhibit neurotransmitter release from nerve terminals connecting with that neurone. In this way, the ECS modulates the activity of other neuronal pathways.
1. Devane WA et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 1992;258:1946–9
2. Sugiura T et al. 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem Biophys Commun 1995;215:89–97
3. Schmid HHO. Pathways and mechanisms of N-acylethanolamine biosynthesis: can anandamide be generated selectively? Chem Phys Lipids 2000;108:71–87
4. Howlett AC et al. Cannabinoid physiology and pharmacology: 30 years of progress. Neuropharmacology 2004;47:345–58
5. Hillard CJ et al. The movement of N-arachidonoylethanolamine (anandamide) across cellular membranes. Chem Phys Lipids. 2000;108:123–34
6. Alger BE. Retrograde signaling in the regulation of synaptic transmission: focus on endocannabinoids. Prog Neurobiol 2002;68(4):247–86
Devane et al 1992; Sugiura et al 1995; Schmid 2000; Howlett et al 2004;
Hillard et al 2000; Alger 2002

47. Centrinis ir periferinis veikimo mechanizmai
EK sistema
Centrinis ir periferinis veikimo mechanizmai
Mezolimbinė sistema
mitybos stimulą paverčia motyvacija valgyti/rūkyti
Sumažėjęs adipocitų sintetinamo leptino kiekis – signalas apie energijos deficitą pagumburiui, kuris paverčia šį signalą apetitu.
Kanabinoidiniai (CB1) receptoriai ir juos aktyvuojantys endokanabinoidai (ECBs), yra visuose šiuose audiniuose
Energijos perteklius kaupiamas riebalų pavidalu adipocituose, kurie pradeda sintetinti daugiau leptino ir siunčia signalus i pagumburį.

48. Centriniai ir periferiniai EKS taikiniai bei jos hiperaktyvumo poveikis
Riebalinis
audinys
Raumenys
Kepenys
Virškinimo
traktas
Gausiau valgoma
Didėja riebalų atsargos
Rezistencija insulinui
DTL-C TG
Gliukosės įsisavinimas
Adiponektinas
Hypothalamus:
alkis
Nucleus accumbens:
motyvacija valgyti ^
Smegenys
Periferiniai audiniai
Central and peripheral targets of ECS and effects of overactivity
CB1 receptors have been shown to play an important role in energy balance and are directly implicated in lipid and glucose metabolism. CB1 receptors are located centrally in the brain, and peripherally in adipose tissue, liver, skeletal muscle and the gastrointestinal tract.
In the brain, the hypothalamus plays a principal role in the control of feeding and regulation of body weight, and CB1 receptor stimulation leads to dopamine release in the nucleus accumbens shell, which increases motivation to eat. These effects result in increased food intake and fat accumulation.
Peripherally, ECS promotes lipogenesis at the level of adipose tissue and the liver. ECS activity in the gastrointestinal tract interferes with feelings of satiety, and CB1 receptor stimulation of skeletal muscle decreases glucose uptake. All of these central and peripheral effects indicate that an overactivated ECS could contribute to the increased risk of atherogenic dyslipidaemia (low HDL-C, high triglycerides), insulin resistance, glucose intolerance and increased cardiometabolic risk.
Bensaid M et al, 2003; Pagotto U et al, 2005;
Osei-Hyiaman D et al, 2005;
Di Marzo V et al, 2005; Liu YL et al, 2005
Bensaid M, Gary-Bobo M, Esclangon A, et al. The cannabinoid CB1 receptor antagonist SR increases Acrp30 mRNA expression in adipose tissue of obese fa/fa rats and in cultured adipocyte cells. Mol Pharmacol 2003;63:908–14.
Pagotto U, Vicennati V, Pasquali R. The endocannabinoid system and the treatment of obesity. Ann Med 2005;37:270–275.
Osei-Hyiaman D, DePetrillo M, Pacher P, et al. Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest 2005;115:1298–1305.
Di Marzo V, Matias I. Endocannabinoid control of food intake and energy balance. Nature Neurosci 2005;8:585–589.
Liu YL, Connoley IP, Wilson CA, Stock MJ. Effects of the cannabinoid CB1 receptor antagonist SR on oxygen consumption and soleus muscle glucose uptake in Lep(ob)/Lep(ob) mice. Int J Obes Relat Metab Disord 2005;29:183–187.

49. Dėl centrinės bei periferinės EKS disreguliacijos vyksta tiesioginis nuo svorio priklausantis jungimasis prie CB1
Valgymas
EKS
Nepriklauso nuo svorio
Priklauso nuo svorio
EKS
Endokanabinoidinė sistema
Visceraliniai reibalai
Svoris
CB-1 blockade
CB-1 blokada
2 tipo diabetas
Dislipidemija
TG-sotieji LMTL-C
Mažo tankio MTL-C
Sumažėja DTL-C
Lipolizė
CETP, lipolizė
Hepatinis rezistentiškumas insulinui
Gliukozės išmetimas iš kepenų
Periferinis rezistentiškumas insulinui
Adiponektinas
ECS dysregulation and weight-dependent and direct effects of CB1 blockade on peripheral tissues
This slide summarises the central and peripheral actions that contribute to the beneficial cardiometabolic profile of rimonabant.
Normally, the central nervous ECS activates to promote feeding behaviour as required, and then becomes quiescent. However, the continued intake of highly palatable, high-energy food common in developed nations sets up a vicious cycle where a chronically overactive ECS in key areas of the brain helps to maintain a high level of energy intake. This inevitably leads to the development of excess intra-abdominal adiposity which increases the risk of dyslipidaemia and type 2 diabetes.
The peripheral ECS is also involved in the regulation of metabolism in the periphery. Overactivity of the ECS in intra-abdominal adipocytes promotes the secretion of a range of bioactive substances, including:
Decreased secretion of the cardio-protective hormone, adiponectin, which increases insulin resistance and cardiovascular risk
Increased free fatty acid delivery to the liver which promotes hepatic insulin resistance, hyperglycaemia and atherogenic dyslipidaemia
Large and well-designed clinical trials in patients with multiple cardiometabolic risk factors (the RIO program) have shown that selective blockade of central and peripheral CB1 receptors by rimonabant improves multiple cardiometabolic risk factors by countering the adverse effects of the overactive ECS. Moreover, the therapeutic efficacy of rimonabant on indices of cardiometabolic risk arises through a direct effect on peripheral tissues including adipocytes and liver, in addition to effects secondary to weight loss. Indeed, about half of the beneficial effects of rimonabant on levels of adiponectin, HbA1c, HDL-C, triglycerides, insulin and other cardiometabolic risk factors were not attributable to weight loss alone in the RIO programme, suggesting a direct metabolic effect of the drug.
Portnė cirkuliacija
Kepenys
FFA
ECS
EKS
Modified from: Lam TKT, 2003; Carr DB, 2004; Eckel R, 2005; Pagotto U, 2005; Di Marzo V et al, 2005
FFA=free fatty acids
CETP=cholesterol
ester transfer protein
Lam TKT et al. Mechanisms of free fatty acid-induced increase in hepatic glucose production. Am J Physiol Endocrinol Metab 2003;284:E863–73.
Carr DB, Utzschneider KM, Hull RL et al. Intra-abdominal fat is a major determinant of the National Cholesterol Education Program Adult Treatment Panel III criteria for the metabolic syndrome. Diabetes 2004 Aug;53(8):2087–94.
Eckel R, Grundy S, Zimmet P. The metabolic syndrome. Lancet 2005;365(9468):1415–28.
Pagotto U, Pasquali R. Fighting obesity and associated risk factors by antagonising cannabinoid type 1 receptors. Lancet 2005;365:1363–4.
Di Marzo V, Matias I. Endocannabinoid control of food intake and energy balance. Nature Neuroscience 2005;8:585–9

50.  Trigliceridų pasisavinimas  Rezistencija insulinui
Hepatinės EKS disreguliacija skatina lipogenezę ir rezistenciją insulinui kepenyse esant nutukimui
*anandamide
AEA*
 CB1R
Gausi riebalų dieta
 SREBP1c
 RR sintetazė
 AcCoA cbxlase
 RR sintezė
 RR oksidacija
 Kepenų lipidų kiekis
High fat feeding increases expression of the CB1-receptor and hepatic anandamide levels. Activation of CB1-receptor increases the hepatic gene expression of the lipogenic transcription factor SREBP-1c. Through induction of hepatic acetyl-CoA carboxylase and fatty acid synthase, this shifts the balance of fatty acid oxidation and synthesis, leading to an increased hepatic accumulation of fat, which would be expected to increase VLDL production and triglyceride flux, and to increase hepatic insulin resistance.
However, this shift in hepatic fatty acid metabolism occurs early in the course of high fat feeding, prior to any significant difference in body weight, and thus represents direct effects of ECS up regulation on hepatic metabolism, rather than a secondary consequence of body weight change.
CB1-receptor blockade by rimonabant represses the expression of sterol response element binding protein-1c (SREBP-1c), which is critically involved in coordinating hepatic pathways of fatty acid synthesis and oxidation, thus ameliorating the accumulation of liver fat.
 Trigliceridų pasisavinimas
 LMTL gamyba
 Rezistencija insulinui
CB1 blokada
Osei-Hyiaman D et al, 2005
Osei-Hyiaman D et al. Endocannabinoid activation at hepatic CB1 receptors stimulates fatty synthesis and contributes to diet-induced obesity. J Clin Invest 2005:115:1298–1305.

51. CB1 receptorių lokalizacija ir CB1 blokados poveikis
Dauginės veikimo vietos
Mechanizmas
Poveikis
Hypothalamus /
Nucleus accumbens 1,2,3,4,5
 Maisto suvartojimas
Kūno svoris
Intraabdominalinis nutukimas
Riebalinis audinys 1,2,3,4,5
 Adiponektinas  Lipogenezė
Dislipidemija
Rezistentiškumas insulinui
Raumenys 6
 Gliukozės sunaudojimas
Kepenys 7
 Lipogenezė
Rezistencija insulinui
Virškinimo traktas 8
 Sotumo jausmas
Kūno svoris Intraabdominalinis nutukimas
CB1 receptor expression is widespread centrally and peripherally in brain, adipose tissue, muscle, liver and the gastrointestinal tract (Di Marzo V, 2001; Ravinet Trillou C, 2003; Cota D, 2003; Pagotto U, 2005; Van Gaal L, 2005; Liu Y, 2005; Osei-Hyiaman D, 2005; Massa F, 2005). The ECS acts centrally in the hypothalamus to influence orexigenic drive and has been shown to interact with other hypothalamic neuropeptides known to be involved in the regulation of energy balance and lipid and glucose metabolism (Di Marzo V, 2001; Cota D, 2003).
The ECS also acts peripherally to enhance lipoprotein lipase activity in adipose tissue (Osei-Hyiaman D, 2005), increasing glucose uptake in skeletal muscle (Liu Y, 2005). Emerging evidence that CB1 receptors are also present in liver and skeletal muscle and contribute to the peripheral metabolic activity of the ECS.
Clinical trials have demonstrated the potential of selective CB1 blockade* to address the unmet clinical needs of the next decade in addressing multiple cardiometabolic risk factors. (*in vitro and animal data may not necessarily correlate with clinical results).
1. Di Marzo V 2001; 2. Ravinet Trillou C, 2003; 3. Cota D, 2003; 4. Pagotto U, 2005; 5. Van Gaal L, 2005;6.Liu Y 2005; 7. Osei-Hyiaman D 2005; 8. Massa F, 2005
Di Marzo M et al. Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature 2001;410:822–5.
Ravinet Trillou C, Arnone M, Delgorge C et al. Anti-obesity effect of SR141716, a CB1 receptor antagonist, in diet-induced obese mice. Am J Physiol Regul Integr Comp Physiol 2003;284:R345–53.
Cota D, Marsicano G, Lutz B et al. Endogenous cannabinoid system as a modulator of food intake. Int J Obes Relat Metab Disord 2003;27:289–301.
Pagotto U, Pasquali R. Fighting obesity and associated risk factors by antagonising cannabinoid type 1 receptors. Lancet 2005;365:1363–4.
Van Gaal L et al. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet 2005; 365:1389–97.
Liu YL et al. Effects of the cannabinoid CB1 receptor antagonist SR on oxygen consumption and soleus muscle glucose uptake in Lepob/Lepob mice. Int J Obes Relat Metab Disord. 2005;29:183–187.
Osei-Hyiaman D, DePetrillo M, Pacher P et al. Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest 2005;115:1298–1305.
Massa F et al. The endocannabinoid system in the physiology and pathophysiology of the gastrointestinal tract. J Mol Med 2005;83:944–54.

52. CB1 blokada mažina daugybinių kardiometabolinių veiksnių riziką
Centrinis nutukimas
( LA)*
Aterogeninė dislipidemija
 Mažai DTL-Chol
 Daug TG
 Daug MTL - chol
Gliukozės netoleravimas
Insulino rezistencija
 Hiperinsulinemija
2 tipo diabetas
Intra-abdominalinis
nutukimas
CB1 blockade reduces multiple cardiometabolic risk factors
Clinical and experimental evidence supports a role for selective CB1 receptor blockade in the management of multiple cardiovascular risk factors associated with the metabolic syndrome. These include classical cardiometabolic risk factors, such as abdominal obesity, atherogenic dyslipidaemia, insulin resistance and glucose intolerance, and also emerging risk factors such as vascular inflammation.
Selective CB1 receptor blockade can meet the unmet clinical need beyond available treatments and has the potential to address multiple cardiometabolic risk factors..
Ravinet Trillou C et al. Am J Physiol Regul Integr Comp Physiol 2003;284:R345–53.
Bensaid M et al. Mol Pharmacol 2003; 63: 908–914.
Pagotto U, Pasquali R. Fighting obesity and associated risk factors by antagonising cannabinoid type 1 receptors. Lancet 2005;365:
Van Gaal L et al. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet 2005; 365:
Carr MC, Brunzell JD. Abdominal obesity and dyslipidemia in the metabolic syndrome: importance of type 2 diabetes and familial combined hyperlipidemia in coronary artery disease risk. J Clin Endocrinol Metab 2004;89:
Caballero AE. Endothelial dysfunction in obesity and insulin resistance: a road to diabetes and heart disease. Obes Res 2003;11:
Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet. 2005;365:
Lėtinis uždegimas
Metabolinis sindromas
*LA = liemens apimtis
Ravinet Trillou et al 2003; Bensaid et al 2003; Pagotto et al 2005; Van Gaal et al 2005; Carr & Brunzell 2004; Caballero 2003; Eckel et al 2005

53. Endokanabinoidinės sistemos padidinto aktyvumo poveikis
Per didelis maisto suvartojimas
Labai skanus maistas
Nutukimas
Išorinis stimulas
(pvz. nikotinas)
Hiperaktyvuota EC sistema
SMEGENYS
PERIFERINIAI audiniai
Hypothalamus
 apetitas
Nucleus accumbens
 motyvacija valgyti / rūkyti
Adipocitai
 riebalų kaupimasis
 Insulino rezistencija
 Gliukozės netoleravimas
 Adiponektinas
 DTL-Ch
 Trigliceridai
Padidėjęs maisto suvartojimas
Ilgalaikė rūkymo priklausomybė

54. Pamažu progresuodama aterosklerozė yra dažniausia KVL priežastis
Insultas
TIA MI KA
Aukštas AKS
IFN
PAL
Putotos ląstelės
Riebalinės juostelės
Tarpiniai pokyčiai
Ateroma
Fibrozinė plokštelė
Komplikuoti pakenkimai/ plyšimas
Endothelial dysfunction underlies much of the progression of atherosclerosis from its early stages.1
Fatty streaks initially consist lipid-laden macrophages and monocytes, followed by the migration of smooth muscle cells.2
Fatty streaks develop into intermediate and advanced lesions and the lipid-laden core is covered by a fibrous plaque.2
Rupture of the plaque may result in thrombus formation and the occlusion of the artery.2
Endotelio disfunkcija
Nuo pirmo dešimtmečio
Nuo trečio dešimtmečio
Nuo ketvirto dešimtmečio
Didėjanti lipidų akumuliacija
Lygieji raumenys ir kolagenas
Trombozė Hematoma
Pepine CJ. Am J Cardiol. 1998;82:23S-27S.
References
1. Pepine CJ. The effects of angiotensin-converting enzyme inhibition on endothelial dysfunction: potential role in myocardial ischemia. Am J Cardiol. 1998;82:23S-27S.
2. Ross R. Atherosclerosis - an inflammatory disease. N Engl J Med. 1999;340:

55. Lipoproteinų struktūra
Laisvas cholesterolis
Fosfolipidai
Trigliceridai
Lipids can be divided into two main groups, simple and complex. The two most important simple lipids are cholesterol and fatty acids. Lipids become complex lipids when fatty acids undergo esterification to produce esters.1-3
Simple lipids Cholesterol is a soft waxy substance present in all cells of the body. Most tissues can produce cholesterol, but it is synthesised primarily in the liver and small intestine. Approximately 50% of the cholesterol requirement is synthesised, whilst the rest is obtained from animal produce in the diet. Cholesterol is important in the repair of cell membranes and in the synthesis of steroid hormones, vitamin D and bile acids. Fatty acids are the simplest form of lipid found in the body and are an important energy source. They exist as saturated, monounsaturated and polyunsaturated forms, distinguished by the number of bonds between the hydrocarbon chain and carbon atoms. The most common fatty acids in the body are stearic and palmitic (saturated), and oleic (monounsaturated). Fatty acids exist freely in the plasma mostly bound to albumin, but are stored in adipose tissue as triglycerides.1-3
Complex lipids Triglycerides are mainly stored in adipose tissue and are the main lipid currency of the body. Phospholipids are glycerol esters containing two fatty acids. They have a water-soluble and a lipid-soluble surface and are an important component of the cell membrane. Cholesterol esters, oleate and linoleate, are the storage molecules of cholesterol in cells.1-3
Lipoproteins In order for these insoluble lipids to be transported around the body in the blood they are incorporated into lipoproteins. These multimolecular packages consist of a hydrophobic core containing cholesteryl esters and triglyceride, surrounded by a hydrophilic surface layer of phospholipids, proteins and some free cholesterol. While structurally similar, lipoproteins vary in their proportions of component molecules and the type of proteins present.1-3
References
1. In: Fast Facts - Hyperlipidaemia. Eds Durrington P, Sniderman A. Health Press Ltd, Oxford,
2. In: Manual of Lipid Disorders, 2nd Edition. Eds Gotto A, Pownall H. Williams & Wilkins, US,
3. In: Statins - The HMG-CoA Reductase Inhibitors in Perspective. Eds Gaw A, Packard CJ, Shepherd J. Martin Dunitz 2000, 1-19.
Cholesterolio esteriai
Apolipoproteinai

56. Lipoproteinų tipai Lipoproteinai, kuriuose daug trigliceridų
Chilomikronai
Labai mažo-tankio lipoproteinai (LMTL)
Lipoproteinai, kuriuose daug cholesterolio
Mažo-tankio lipoproteinai (MTL)
Didelio-tankio lipoproteinai (DTL)
There are four types of lipoprotein particle. Chylomicrons and very low-density lipoproteins (VLDL) are the two triglyceride-rich lipoproteins whereas low-density lipoprotein (LDL) and high-density lipoprotein (HDL) are the two cholesterol-rich lipoproteins.
Chylomicrons are the largest in size, lowest in density and are not associated with atherosclerosis. They are synthesised in the intestinal mucosal cells after a fatty meal. They transport dietary triglyceride from the intestine to the sites of use and storage, and are cleared rapidly from the bloodstream.1,2 Each chylomicron also contains many different apolipoproteins including one molecule of ApoB45 and other such as ApoE and ApoC-II.
VLDL particles are similar in structure to chylomicrons but are smaller. They are produced in the liver and are the main carriers of endogenous (synthesised in the liver rather then dietary) triglycerides and cholesterol to sites for use or storage. As the triglycerides are removed, the VLDL remnants continue to circulate as LDL particles. Thus, VLDL are implicated in atherosclerosis development.1,2
LDL particles are the principal lipoproteins involved in atherosclerosis. Oxidised LDL is the most atherogenic form of LDL. They are the main carriers of cholesterol – as cholesteryl ester or free cholesterol - accounting for 60–70% of plasma cholesterol. Thus, the concentration of LDL-C provides a good estimate of the total concentration of serum cholesterol. LDL particles are remnants of VLDL particles, but they contain only a single apolipoprotein, ApoB100. 1,2
HDL particles are the smallest, but most abundant of the lipoproteins, and contain almost one quarter of serum cholesterol. They do not cause atherosclerosis, but actually protect against its development. This is because they return about 20-30% of cholesterol in the blood to the liver from peripheral tissue for excretion (reverse cholesterol transport). They also inhibit the oxidation of LDL and they decrease the attraction of macrophages to the artery wall. HDL particles also contain apolipoproteins, including ApoA-I.1,2
References
1. In: Fast Facts - Hyperlipidaemia. Eds Durrington P, Sniderman A. Health Press Ltd, Oxford, Second Edition –12.
2. In: Manual of Lipid Disorders, 2nd Edition. Eds Gotto A, Pownall H. Williams & Wilkins, US, –10.

57. MTL-C: svarbus vaidmuo vystantis aterosklerozei
The role of LDL and inflammation in the process of atherosclerosis is becoming better understood. We now know how LDL triggers atherosclerosis and leads to plaque formation. And inflammation has been implicated in all phases of the process from initiation through progression and complication.
(Build) At normal levels, LDLs easily pass in and out of the intima. At excessive levels, however, they become stuck in the matrix where they undergo oxidation and trigger a defensive inflammatory response
(Build) The most widely studied marker of inflammation is C-reactive protein (CRP). Elevated CRP has been associated with increased risk of cardiovascular disease. Some studies suggest that it may also play an active and direct role in atherogenesis
(Build) One of the earliest clinical manifestations of atherosclerosis is endothelial dysfunction. LDL, and especially oxidized LDL, inhibits endothelial function by stimulating the expression of harmful chemoattractants on its surface. CRP may add to the dysfunction by reducing the bioavailability of protective nitric oxide. With endothelial defenses down, monocytes are induced to attach to the vessel wall, and squeeze into the intima
(Build) Once inside, monocytes multiply, mature into macrophages, and begin scavenging oxidized LDL particles. Once packed with fat droplets they become known as foam cells because they look foamy under the microscope. They form a fatty streak, the earliest stage of plaque. Macrophages and dysfunctional endothelial cells prod smooth muscles to migrate to the top of the intima and synthesize into a fibrous cap that wallsoff the plaque from the bloodstream
(Build) Over time, however, foam cells can secrete inflammatory substances and enzymes that destabilize the cap and prevent its repair. If the weakened plaque ruptures a thrombus will form. If the clot is large enough, it will completely block blood flow and lead to a heart attack.

58. Oksiduotas MTL-C: labai padidina uždegimą ir vazokonstrikciją
The role of LDL and inflammation in the process of atherosclerosis is becoming better understood. We now know how LDL triggers atherosclerosis and leads to plaque formation. And inflammation has been implicated in all phases of the process from initiation through progression and complication.
(Build) At normal levels, LDLs easily pass in and out of the intima. At excessive levels, however, they become stuck in the matrix where they undergo oxidation and trigger a defensive inflammatory response
(Build) The most widely studied marker of inflammation is C-reactive protein (CRP). Elevated CRP has been associated with increased risk of cardiovascular disease. Some studies suggest that it may also play an active and direct role in atherogenesis
(Build) One of the earliest clinical manifestations of atherosclerosis is endothelial dysfunction. LDL, and especially oxidized LDL, inhibits endothelial function by stimulating the expression of harmful chemoattractants on its surface. CRP may add to the dysfunction by reducing the bioavailability of protective nitric oxide. With endothelial defenses down, monocytes are induced to attach to the vessel wall, and squeeze into the intima
(Build) Once inside, monocytes multiply, mature into macrophages, and begin scavenging oxidized LDL particles. Once packed with fat droplets they become known as foam cells because they look foamy under the microscope. They form a fatty streak, the earliest stage of plaque. Macrophages and dysfunctional endothelial cells prod smooth muscles to migrate to the top of the intima and synthesize into a fibrous cap that walls off the plaque from the bloodstream
(Build) Over time, however, foam cells can secrete inflammatory substances and enzymes that destabilize the cap and prevent its repair. If the weakened plaque ruptures a thrombus will form. If the clot is large enough, it will completely block blood flow and lead to a heart attack.
Oksiduotas MTL-C
MTL-C
CRB

59. Oksiduotas MTL-C sąlygoja greitą aterosklerozės progresavimą
Modifi-kuotas MTL-C
Aterogeninis poveikis
Putliųjų ląstelių susidarymas
Monocitų judrumas
Endotelio adhezija
Laisvų-radikalų susidarymas
Negy-dant
Įprastas MTL-C
Oksida-cinis
stresas
Based on Witztum JL et al. Trends Cardiovasc Med. 2001;11:

60. DTL cholesterolis
DTL-C mažina aterosklerozės ir IŠL išsivystymo riziką
Epidemiologiniai tyrimai įrodė, jog kuo mažesnis DTL-C kiekis, tuo didesnė aterosklerozės ir IŠL rizika
mažas kiekis (<40 mg/dL, 1 mmol/L) didina riziką
DTL-C turi polinkį mažėti didėjant trigliceridams
DTL-C mažina rūkymas, nutukimas ir sumažėjęs fizinis aktyvumas
ApoA-I yra pagrindinis DTL-C apolipoproteinas; ApoA-I didėjimas mažina KVL riziką
There is a strong inverse association between plasma HDL-C and the risk of CHD; therefore, HDL-C has a protective effect. This has been shown in both patients with CHD and asymptomatic subjects, in men and women, and is independent of LDL-C and other risk factors. The lower the HDL-C level the higher the risk for CHD; a low level (<40 mg/dL, 1.0 mmol/L) increases risk and a higher level (60 mg/dL, 1.6 mmol/L) can be considered a negative risk factor.1 Concentrations of HDL-C tend to be low when triglycerides are high. It is thought that HDL-C goal should be higher for women than that for men.
Low concentrations of HDL-C are also associated with an atherogenic lifestyle, as HDL-C is lowered by smoking, obesity and physical inactivity.2
A combination of plasma triglycerides >2 mmol/L (180 mg/dL) and HDL-C <1 mmol/L (40 mg/dL) predicts a high risk of CHD, in particular if the total cholesterol to HDL-C ratio is greater than 5.2
ApoA-I is the major apolipoprotein in HDL and an elevated ApoA-I is linked to reduced CVD risk.3
References
1. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001:285;2486–2497.
2. Wood D et al, for the Joint European Committee, Second Task Force of European and other Societies. Atherosclerosis 1998;140:199–270.
3. In: Fast Facts - Hyperlipidaemia. Eds Durrington P, Sniderman A. Health Press Ltd, Oxford, Second Edition, –12.

61. Trigliceridai Gali būti susiję su padidėjusia IŠL rizika
Padidėjusią IŠL riziką skatina keletas veiksnių:
tiesioginis mažų TG-turtingų lipoproteinų poveikis ir/ar
kartu esantys:
mažas DTL lygis
labai aterogeninės MTL-C formos
hiperinsulinemija/atsparumas insulinui
prokoaguliacinė būklė
hipertenzija
pilvinis nutukimas
Controversy exists as to whether hypertriglyceridaemia is associated with increased risk of CVD events. However, the association is not as strong as that of LDL-C, and becomes much weaker when other risk factors are taken into account. The link between triglycerides and increased CVD risk is complex. It may reflect the atherogenic effects of the triglyceride-rich lipoproteins themselves, particularly the smaller particles. It may also mark the presence of other atherogenic risks such as low levels of HDL, the presence of small dense LDL particles and the presence of the metabolic syndrome.1 In fasting plasma, triglycerides are transported in VLDL synthesised in the liver, and after meals are also found in chylomicrons. Catabolism of these triglyceride-rich lipoproteins produces remnant lipoproteins that have atherogenic potential.
According to NCEP ATP III guidelines, average triglyceride levels are <150 mg/dL (1.7 mmol/L), borderline-high 150–199 mg/dL ( mmol/L), high mg/dL ( mmol/L) and very high 500 mg/dL (5.6 mmol/L).1
Patients with elevated triglycerides may have accompanying dyslipidaemias that increase the risk for CHD (e.g. familial combined hyperlipidaemia or diabetic dyslipidaemia). Severe hypertriglyceridaemia (>1000 mg/dL, 11.3 mmol/L), possibly due to chylomicrons and large forms of VLDL, increases the risk of pancreatitis but not CHD, as chylomicrons and VLDL are too large to enter the arterial wall.
Reference
1. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001:285;2486–2497.

62. Apolipoproteinai Lipoproteinų baltyminė dalis
ApoB kiekis nurodo MTL dalelių kiekį ir ↑ KVL riziką
ApoA-I – pagrindinis DTL-C apolipoproteinas, nurodo ↓ KVL riziką
Apolipoproteinų funkcijos:
skatina lipidų transportą
aktyvuoja tris lipidų metabolizmo fermentus
lecithin cholesterol acyltransferase (LCAT)
lipoprotein lipase (LPL)
hepatic triglyceride lipase (HTGL)
Jungiasi prie ląstelės paviršiaus receptorių
Apolipoproteins are the protein constituents of lipoproteins and they have three main functions:1
1. They facilitate lipid transport by stabilising the water soluble lipids, cholesterol esters and triglycerides in aqueous plasma.
2. They regulate the interaction of these lipids with the enzymes lecithin cholesterol acyltransferase (LCAT), lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL).
3. They bind to cell surface receptors.
There are eight broad groups of apolipoproteins that have currently been identified. These are designated ApoA to F, ApoH and ApoJ.
Each VLDL and LDL particle contains one molecule of ApoB100 whereas each chylomicron particle contains one molecule of ApoB40. Because there is one ApoB molecule per particle, the level of ApoB gives a good estimate of LDL particle number and is an important marker for atherosclerosis. ApoA-I is the major apolipoprotein in HDL and is linked to reduced CVD risk.2
References
1. In: Statins - The HMG-CoA Reductase Inhibitors in Perspective. Eds Gaw A, Packard CJ, Shepherd J. Martin Dunitz 2000, 1–19.
2. In: Fast Facts - Hyperlipidaemia. Eds Durrington P, Sniderman A. Health Press Ltd, Oxford, Second Edition, –12.  

63. MTL-C ir DTL-C pokyčių įtaka IŠL rizikai
1% MTL-C ↓ IŠL riziką sumažina 1%
1% DTL-C ↑ sumažina IŠL riziką 3%
In the USA, the NCEP Expert Panel have estimated, based on data from epidemiology studies as well as intervention studies, that each 1% decrease in LDL-C equates to a 1% reduction in CHD risk.
In addition, every 1% increase in HDL-C equates to a 3% reduction in CHD risk.
Reference
1. Third Report of the NCEP Expert Panel. NIH Publication No
Third Report of the NCEP Expert Panel. NIH Publication No

64. CRB: reikšmingas uždegimo markeris vystantis aterosklerozei
The role of LDL and inflammation in the process of atherosclerosis is becoming better understood. We now know how LDL triggers atherosclerosis and leads to plaque formation. And inflammation has been implicated in all phases of the process from initiation through progression and complication.
(Build) At normal levels, LDLs easily pass in and out of the intima. At excessive levels, however, they become stuck in the matrix where they undergo oxidation and trigger a defensive inflammatory response
(Build) The most widely studied marker of inflammation is C-reactive protein (CRP). Elevated CRP has been associated with increased risk of cardiovascular disease. Some studies suggest that it may also play an active and direct role in atherogenesis
(Build) One of the earliest clinical manifestations of atherosclerosis is endothelial dysfunction. LDL, and especially oxidized LDL, inhibits endothelial function by stimulating the expression of harmful chemoattractants on its surface. CRP may add to the dysfunction by reducing the bioavailability of protective nitric oxide. With endothelial defenses down, monocytes are induced to attach to the vessel wall, and squeeze into the intima
(Build) Once inside, monocytes multiply, mature into macrophages, and begin scavenging oxidized LDL particles. Once packed with fat droplets they become known as foam cells because they look foamy under the microscope. They form a fatty streak, the earliest stage of plaque. Macrophages and dysfunctional endothelial cells prod smooth muscles to migrate to the top of the intima and synthesize into a fibrous cap that the plaque from the bloodstream
(Build) Over time, however, foam cells can secrete inflammatory substances and enzymes that destabilize the cap and prevent its repair. If the weakened plaque ruptures a thrombus will form. If the clot is large enough, it will completely block blood flow and lead to a heart attack.
CRB
MTL-C

65. 2 tipo cukrinio diabeto gydymo rekomendacijos (Lietuva)
Aktyviai gydyti dislipidemiją:
Skirti statiną įprastine doze > 40 metų amžiaus asmenims, kuriems diagnozuota ŠKL
Skirti statiną įprastine doze visiems > 20 metų amžiaus asmenims, kuriems nustatyta mikroalbuminurija ar jie priklauso padidėjusios ŠKL išsivystymo rizikos grupei pagal JKPDS skalę
Jei Tg > 2.3 mmol/l, prie statino pridėti fenofibratą, kai mažo tankio lipoproteinas cholesterolis (MTL-Ch) kontroliuojamas optimaliai
Skirti kitus lipidus mažinančius vaistus (nikotininę rūgštį, omega 3 riebiąsias rūgštis, ezetimibą), jei nepadeda įprastiniai vaistai ar įprastinio gydymo netoleruoja
Kiekvieno vizito metu būtina tikrinti lipidų pokyčius ir koreguoti gydymą, siekiant tikslinių reikšmių:
MTL-Ch < 2,5 mmol/l, Tg < 2.3 mmol/l ir DTL-Ch > 1.0 mmol/l.
Ruošta pagal: Global Guideline for Type 2 Diabetes. International Diabetes
Federation, 2005

67. AČIŪ UŽ DĖMESĮ