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FREQUENCY OF DYSLIPIDAEMIA IN TYPE 2 DIABETES MELLITUS IN PATIENTS OF HAZARA DIVISION Nasir Ahmed !

aha"#ir $ha" Tahir Saeed Siddi%&i' De(ar)me") *+ Medi,i"e U"i) -B- 'De(ar)me") *+ Paedia)ri,s A.&/ Medi,a0 C*00e#e A//*))a/ad Ba,1#r*&"d : Diabetesmellitusincreases therisk ofatherosclerotic vascular disease because ofassociated dyslipidaemia. Many studies advocate aggressive management of lipid disorders in Type 2 Diabetes to decrease these complications. This study was carried out to know the frequency of dyslipidaemia in our patients and also to determine that whether patients with good glycaemic control ( b!"c#$%& are having better lipid profile than poorly controlled group. 'ross(sectional survey was conducted in Medical )*D and Medical +,+ -ard of !yub Teaching ospital. !bbottabad between March 2//0 to March 2//1. Me)h*ds2 *atients with Type 2 Diabetes mellitus coming to Medical )*D as well as among those admitted in Medical +,+ -ard fulfilling the inclusion criteria were selected. ,lood was taken in the fasting state for lipid profile. fasting blood glucose and glycosylated haemoglobin determination. Res&0)s2 !mong "// patients with Type 2 Diabetes. 1$ were found to have hypertriglyceridaemia. while. 22 had 3D3('holesterol in borderline cardiovascular risk status. )ut of 1$ patients with hypertriglyceridaemia 40 (52%& were poorly controlled diabetics ( b!"c6$%& emphasi7ing the importance of good glycaemic control. owever none of our patients had a low D3('holesterol as found in some other studies. C*",0&si*"2 ypertriglyceridaemia along with impaired 3D3('holesterol is present in ma8ority of our patients. 9ood glycaemic control does affect the lipid profile in Type 2 Diabetes mellitus. owever to provide the benefits of lipid lowering therapyto our patients. as confirmed in manystudies. we need more awarenessand placebo controlled double blind studies. $e.3*rds : Dyslipidaemia. 9lycosylated haemoglobin. Type 2 Diabetes mellitus INTRODUCTION Type 2 Diabetes Mellitus is a heterogeneous condition characteri7ed by the presence of both impaired insulin secretion and insulin resistance. " ;t has. unfortunately. reached epidemic proportions

now(a(days. 2 Diabetes care is comple< and requires that many issues. beyond glycaemic control. be addressed. = ;t is a chronic disease and usually irreversible. 4 Therefore the patients with diabetes often have to consult health(care providers for the remainder of their lives. They are prone to certain complications and evidence emerged in the "22/s supporting the benefits of glycaemic control as well as control of blood pressure and lipid levels in the prevention or delay in onset > severity of diabetes complications. 5?1 Diabetes mellitus is a common secondary cause of hyperlipidaemia. particularly. if glycaemic control is poor $?"" . which in(turn is an important risk factor for atherosclerosis and coronary heart disease. -hile the management of hyperglycaemia.the hallmark metabolic abnormality associated with diabetes. has historically had centre stage in the treatment of diabetes. therapies directed at other coincident features such asdyslipidaemia. hypertension. hypercoagulability. obesity and insulin resistance have also been a ma8or focus of research and therapy. = ;ntensive treatment strategies have been demonstrated to reduce complications in diabetics. 5? 1."2 *atients with diabetes can have a reasonably normal life(style if they are well educated and motivated concerning the disease. owever. most of our patients belong to low or middle socioeconomic

class and are less educated. !s a result. dietary control and compliance with treatment is not up to standards. This study was conducted to see whether they are having dyslipidaemia consistent with other studies and at increased risk of coronary artery disease > other diabetes related complications. $? "/."=."4.24.25 The study also aims to compare lipid levels of patients with good glycaemic control to those with poor glycaemic status. MATERIALS AND METHODS Type 2 Diabetic patients coming to Medical )*D as well as those admitted in Medical +,+ -ard during March. 2//0 to March. 2//1 fulfilling the inclusion criteria were selected. undred patients were enrolled in the study who were@4/ years and no clinicalAelectrocardiographic evidence of coronary artery disease and not suffering from other causes of secondary hyperlipidaemia. ;ncidentally. 5/% of the patients were females. ,lood samples were taken from the patients in the fasting state for lipid estimation. ;n addition. patients+ B,9 (fasting blood glucose& and b!"c (9lycosylated haemoglobin& were also estimated to know about the glycaemic control of patients. !ny previous records of blood sugars with the patients were also noted. C'9 (electrocardiogram& of all patients was taken and routine investigations done. 3ipid levels of patients were compared against the recommendations for adults with diabetes. "5."0 ;n addition a comparison Pa#e 2 ! A.&/ Med C*00 A//*))a/ad 2445624728 http:AAwww.ayubmed.edu.pkAD!M'A*astA2/(2AEasir.pdf 52 was also made of the lipid levels in patients with good control of diabetes ( b!"c#$% & "1 with those having poor glycaemic control ( b!"c6$%&.The data was collected on a questionnaire and entered into computer using F*FF("/. 'ontinuous variables were described in terms of MeanGFD and categorical variables in terms of frequencies and percentages.

RESULTS The results of our study are given in Table(" to 5 and Bigure(". b !"c #$% b !"c 6$% Fi#&re9:2 Per,e")a#e *+ (a)ie")s 3i)h h.(er9 )ri#0.,eridaemia a,,*rdi"# )* )heir #0.,aemi, s)a)&s Ta/0e9:2 Li(id 0e;e0s *+ Pa)ie")s 3ipids Hecommended levelfor adults withDiabetes ofpatientsas per recommendations 3D3('holesterol I2.0 mmolAl(I"// mgAdl& Eone Triglycerides I".1 mmolAl(I"5/ mgAdl& 22 D3('holesterol 6"./ mmolAl(64/ mgAdl& "// Ta/0e922 Cardi*;as,&0ar ris1 s)a)&s *+ Pa)ie")s a,,*rdi"# )* )heir 0i(id 0e;e0s 3ipids *lasma 'oncentration 'ardiovascular Hisk Ftatus Eo. of *atients 3D3('holesterol 6=.4 mmolAl 2.0?=.4 mmolAl I2.0 mmolAl igh ,orderline 3ow 0 24 / Triglycerides 64.5 mmolAl 2.2?4.5 mmolAl I2.2 mmolAl igh

,orderline 3ow / "0 $4 D3('holesterol I/.2 mmolAl ".2?/.2 mmolAl 6".2 mmolAl igh ,orderline 3ow / "/ 2/ Ta/0e9<2 =0.,aemi, s)a)&s *+ Pa)ie")s b!"c 9lycaemic Ftatus Eo. )f *atients # $%J 9ood 5/ 6 $% *oor 5/ JHeferencedtoanon(diabeticrangeof4.4(0.1using,io(Fystemsbasedassay Ta/0e9>2 Li(id 0e;e0s *+ (a)ie")s a,,*rdi"# )* )heir #0.,aemi, s)a)&s b!"c 3ipids Hecommended level for adults with Diabetes Eo. of *atients # $% 3D3('holesterol Triglycerides D3('holesterol I2.0 mmolAl I".1 mmolAl 6"./ mmolAl / "$ 5/ 6 $% 3D3('holesterol

Triglycerides D3('holesterol I2.0 mmolAl I".1 mmolAl 6"./ mmolAl / 4 5/ Ta/0e9?2 Cardi*;as,&0ar ris1 s)a)&s a,,*rdi"# )* )he 0i(id 0e;e0s @ #0.,aemi, s)a)&s b!"c 3ipids *lasma 'oncentration 'ardiovascular Hisk Ftatus Eo. of *atients 3D3( 'holesterol 6=.4 mmolAl 2.0?=.4 mmolAl I2.0 mmolAl igh ,orderline 3ow / 5/ / Triglycerides 64.5 mmolAl 2.2?4.5 mmolAl I2.2 mmolAl igh ,orderline 3ow / / 5/ A5B D3( 'holesterol I/.2 mmolAl ".2?/.2 mmolAl 6".2 mmolAl igh

,orderline 3ow / 4 40 3D3( 'holesterol 6=.4 mmolAl 2.0?=.4 mmolAl I2.0 mmolAl igh ,orderline 3ow 0 44 / Triglycerides 64.5 mmolAl 2.2?4.5 mmolAl I2.2 mmolAl igh ,orderline 3ow / "0 =4 C5B D3( 'holesterol I/.2 mmolAl ".2?/.2 mmolAl 6".2 mmolAl igh ,orderline 3ow / 0 44 DISCUSSION Diabetes mellitus increases the risk for atherosclerotic vascular disease. The risk is greatest in people who have other known risk factors. such as. dyslipidaemia. hypertension. smoking and obesity. There is a twofold to fourfold e<cess risk of coronary artery disease in type 2 diabetes mellitus compared with non(diabetic patients.

"$."2 ;ndeed. 15?$/% of adult diabetic patients die of coronary artery disease. cerebrovascular disease. peripheral vascular disease or a combination of these conditions. 2/.2" *atients with type 2 diabetes can have many lipid abnormalities. including hyper( chylomicronaemia. elevated levels of very low(density lipoprotein cholesterol (K3D3('&.low(density lipoprotein cholesterol (3D3('& and triglycerides: and low levels of high(density lipoprotein cholesterol ( D3('&. 22 3ipid abnormalities may be the result of the unbalanced metabolic state of diabetes (ie. hyperglycaemia and insulin resistance& and improved control of hyperglycaemia does moderate diabetes(associated dyslipidaemia. 2=.24 ;n type 2 diabetes the ma8or disturbances in lipoprotein metabolism are reflected by an increase in plasma triglyceride and a low D3( 'holesterol with normal or near normal 3D3( 'holesterol levels. owever in diabetics this 3D3 fraction contains a greater proportion of small. dense 3D3 particles which are believed to be more atherogenic. 25.20 ;n our patients none was found to have 3D3('holesterol meeting the recommended level while Triglycerides were as per recommendations in only22% of patients (Table("&. D3('holesterol level was. however. meeting the recommendations in all of our patients (Table("&. ;n patients with good glycaemic control ( b!"c#$%& 04%

of patients had triglycerides above the recommended level compared with 22% of patients with poor E o . (% & o f * a t i e n t s w i t h y p e rt ri g l y c e ri d a e m i a / "/ 2/ =/ 4/ 5/ 0/

1/ $/ 2/ "// " 2 = 4 Pa#e < ! A.&/ Med C*00 A//*))a/ad 2445624728 http:AAwww.ayubmed.edu.pkAD!M'A*astA2/(2AEasir.pdf 5= glycaemic control ( b!"c6$%& (Table(4 and 0&. Moreover as far as cardiovascular risk status is concerned. all the patients with b!"c#$% were in low risk category while among patients with b!"c6$%. "0 (=2%& were having borderline cardiovascular risk status (Table(5&. 3D3('holesterol levels did not meet the recommendations in both groups of patients while D3('holesterol was above required levels in all patients (Table(4&. 3ongitudinal epidemiology has pointed to the importance of raised plasma triglycerides and low D3( 'holesterol as a risk factor for coronary disease in diabetic sub8ects 24.20 and there is supportive evidence for aggressive management of lipid disorders in type 2 diabetes. 21?=/ Ma8ority of our patients have hypertriglyceridaemia. ie. 1$% of patients (Table("& and 3D3('holesterol in borderline cardiovascular status. ie. 24% of patients (Table(2& which is consistent with other studies. 2."/.24.25.22 owever none of our patients had a low D3('holesterol compared with other studies "=."4.24 . which. is also a modifiable risk factor for coronary vascular disease. !lthough evidence has been provided for new treatment guidelines regarding dyslipidaemia in diabetes "5."0

and one local study has shown that one out of every three patients with !cute Myocardial ;nfarction was found to have Diabetes Mellitus. emphasi7ing its deleterious effects on the body. =" owever to apply these guidelines to our patients we need more controlled studies. !s far as glycaemic status and lipid disorders are concerned hypertriglyceridaemia was found in 04% of patients with good glycaemic control compared with 22% of patients in poorly controlled group. ie. p I/./5 (Table(4 and Bigure("&. This is statistically quite significant and needs to be evaluated on a larger scale as there are studies showing that improved control of hyperglycaemia do modify diabetes associated dyslipidaemia. 2=.24 3D3('holesterol and D3( 'holesterol.on the other hand. revealed the same pattern in both groups of patients (Table(4&. AC$NODLED=EMENT The study was partially funded by *9M; *eshawar. for which we are grateful to the ;nstitute. ;n addition we wish to e<press our thanks to Mr. !rshad. who carried out the tests in ,io('hemistry Department of !yub Medical 'ollege. !bbottabad. REFERENCES ". Davidson M,. Fchriger D3. *eters !3. !n alternative approach to the diagnosis of diabetes with a review of the literature. Diabetes 'are "225:"$:"/05?1". 2. C<pert 'ommittee on the Diagnosis and 'lassification of Diabetes Mellitus: Heport of the C<pert 'ommittee on the Diagnosis and 'lassification of Diabetes Mellitus. Diabetes 'are.2//":24(Fuppl "&:F5?F2/.

=. !merican Diabetes !ssociation. *osition Ftatement: Ftandards of Medical 'are in Diabetes(2//1.Diabetes 'are 2//1:=/:F4?F4". 4. Kinicor B. -hen is diabetesL D!M!."222:2$":"222?4. 5. MN *rospective diabetes study (MN*DF& 9roup. ;ntensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with Type 2 Diabetes(MN*DF ==&. 3ancet"22$:=52:$=1?5=. 0. MN *rospective Diabetes Ftudy (MN*DF& 9roup.Cffect of intensive blood glucose control with Metformin on complications in overweight patients with Type 2 Diabetes (MN*DF =4&. 3ancet."22$:=52:$54?05. 1. Ftratton ;M. !dler !;. Eeil !. Matthews DH. Manley FC. 'ull '!. et al . !ssociation of glycaemia with macrovascular and microvascular complications of Type 2 Diabetes (MN*DF =5&:*rospective )bservational Ftudy. ,MD.2///:=2":4/5?"2. $. oward ,K. ;nsulin resistance and lipid metabolism. !m D 'ardiol."222:$4: 2$8?=28. 2. Marwat M!. -a7ir OM. ypertriglyceridaemia in Diabetes Mellitus. D !yub Med 'oll. !bbottabad 2///:"2(4&:24?5. "/. Eaheed T. Nhan !. Masood 9. Dyslipidaemias in Type 2 Diabetes Mellitus *atients in a Teaching ospital of 3ahore.*akistan. *ak D Med Fci 2//=:"2(4&:2$=?$0. "". Eathen DM. ,use D,. Davidson M,. eine HD. olman HH. Fherwin H et al . Management of yperglycaemia in Type 2 Diabetes:! 'onsensus !lgorithm for the ;nitiation and !d8ustment of Therapy: ! consensus statement from the !merican Diabetes !ssociation and the Curopean !ssociation for the Ftudy of Diabetes. Diabetes 'are. 2//0:22:"20=?12. "2. )hkubo P. Nishikawa . !raki C. Takao M. ;sami F. Motoyoshi F et al . ;ntensive insulin therapy prevents the progression of diabetic microvascular complications in Dapanese patients with E;DDM: ! randomi7ed prospective 0(year study. Diabetes Hes 'lin *ract "225:2$:"/=?"1. "=. Hukhsana !F. !hmad F. ussain F. ;rtia7 Hi7vi FM. Damal !ra. Brequency of 3ipid abnormalities in Cssential ypertension. D Furg *ak 2//2:1(4&:2?4. "4. Nhan D!. Nhan F*. !hmed O. Fhah F . Nhaliq M!. 3evel of hyper(cholesterolemia in patients admitted for heart diseases: a

pilot study. *ak D Med Hes 2//":4/("&:"$?2. "5. !merican Diabetes !ssociation. Management of dyslipidaemia in adults with diabetes. Diabetes 'are "222:22 (suppl "&:F50?2. "0. -atts 9B. 'oronary disease. dyslipidaemia and clinical trials in Type 2 Diabetes Mellitus: Heview !rticle *rac Diab ;ntern. 2///:"1(2&:54?2. "1. Nilpatrick CF. 9lycated haemoglobin in the year 2///. D 'lin *athol. 2///:5=:==5?=2. "$. *yorala N. 3aakso F. Musitupa M. Diabetes and atherosclerosis: an epidemiologic view. Diabetes Metab Hev "2$1:=(2&:40=?524. "2. affner FM. 3ehto F. Honnemaa T. *yorala N. 3aakso M. Mortality from coronary heart disease in sub8ects with type 2 diabetes and in nondiabetic sub8ects with and without prior myocardial infarction. E Cngl D Med "22$:==2:222?=4. 2/. 3aakso M. Dyslipidaemia. morbidity and mortality in non(insulin dependant diabetes mellitus. 3ipoproteins and coronary heart disease in non(insulin dependant diabetes mellitus. D Diabetes 'omplications. "221:""(2&:"=1?4". 2". affner FM. Management of dyslipidaemia in adults with diabetes. Diabetes 'are."22$:2"("&:"0/?1$. 22. !merican Diabetes !ssociation. Management of dyslipidaemia in adults with diabetes. Diabetes 'are "22$:2"("&:"12?$2. 2=. Marcus !). 3ipid disorders in patients with type 2 diabetes: Meeting the challenges of early. aggressive treatment. *ostgrad Med. 2//":""/("&:"""?2=. 24. 3ehto F. Honneman T. affner FM. *yorala N. Nallio K. 3aakso M. Dyslipidaemia and hyperglycaemia predict coronary heart disease events in middle(aged patients with E;DDM. Diabetes "221:40:"254?=52. 25. Fyvanne M.Taskinen MH. 3ipids and lipoproteins as coronary risk factors in non(insulin dependant diabetes mellitus. 3ancet "221:=5/(suppl "&:2/?=. 20. okanson DC. !ustin M!. *lasma triglyceride level as a risk factor for cardiovascular disease independe

'ompo7itia lipidelor plasmatice: 3ipide totale : 4//(1// mgA"// ml Trigliceride (T9&: 1/("1" mgA"// ml Q "/(2/% 'olesterol total ('&: "$5 mgA"// ml 'olesterol liber Q =5 (2/ mgA"// ml 'olesterol esterificat Q ""5 ? "1/ mgA"// ml

Bosfolipide (*3&Q "5/ ? 25/ mgA"// ml

Kalori normale diferite pe grupe de varsta 'ompo7itia lipidelor plasmatice pe electrofore7a T9. *3 si ' se asocia7a cu proteinele din ribo7omi la nivel hepaticsi formea7a lipoproteine ;dentificarea si do7area lor se face prin electrofore7a pe hartie. ef in gel de agaro7a. flocularea lipoproteinelor cu poli7aharide

Holul lipoproteinelor in transportul lipidelor 3ipoproteinele (3*& ? particule globulare cu 9M mare ce transporta T9si colesterol esterificat ('C& in plasma Biecare 3* contine un mie7 (T9 R 'C in variate proportii& ;n 8urul lui ? fosfolipide ce stabili7ea7a continutul Q Spicaturi degrasimeT Biecare particula contine proteine specifice Q !*)*H)TC;EC ? e<pusela suprafata ? se leaga la en7ime specifice sau proteine de transportcatre locurile de metaboli7are

Transport lipide: cale e<ogena:

T9 si ' din dieta sunt incorporate in chilomicroni care traversea7a barieraintestinala si a8ung in plasma U2/% din T9 sunt preluate la nivel fb musculare si adipocite sub actiuneen7imatica U!ci7ii grasi a8ung in adipocite sau celule musculare si o<idate la T9 Udupa e<tragerea continutului de T9. ce a ramas din chilomicron se intoarcein circulatie si preluat de ficat care e<trage continutul de colesterol

calea endogena: 'arbohidratii din dieta sunt transformati de ficat in T9 care suntsecretate in circulatie sub forma particulelorK3D3(low densitylipoprotein& ? particule relativ mari cu continut ridicat in T9 caretransporta grasimile spre periferie 3a nivelul capilarelor tisulare. sub actiune en7imatica particuleleK3D3 sunt hidroli7ate. particula restanta;D3(intermediate densitylipoprotein& este cataboli7ata la nivel hepatic prin legarea la H pt3D3. o parte sunt metaboli7ate in plasma ? sunt transformate inparticule3D3bogate in colesterol K3D3 este asadar principala sursa de 3D3 U3D3 se leaga la H pt 3D3. endocitate sidigerate de de li7o7omii celulariUcolesterolul neesterificat re7ultat dinturnoverul celular este eliberat in plasma siinglobat in D3(high density lipoprotein&. seleaga la un acid gras si este esterificat:Uesterii de colesterol ce se formea7a lasuprafata D3 sunt transferati catreK3D3

Cf separa fractiunile lipoproteice: V" ? D3 (25(=5% *reW( K3D3 ? "/("2% W( 3D3 ? 52(0/% 'hilomicroni ? apar numai dupa un pran7 bogat in lipide. au origine alimentarasi sunt constituiti din: T9Q$5%. prot Q2%. ' Q 5%. *3Q$% 3D3 ? sinteti7ati in ficat. contin45% '.""% T9. 2"% prot. 22%*3 K3D3 ? sinteti7ati in ficat.5/% T9."2% '. $% prot. "$% *3 D3 ? sinteti7ati in ficat.5/% prot."1% '. $% T9. 22% *3

Dislipoproteinemii 'restere separata sau mi<ta a diverselor fractiuni U Tulburarea sinte7ei sau secretiei prin membrana hepatocitului 'lasificare:

D3* primare? familiale ? un defect genetic interesea7a fiesinte7a de proteine. fie diversele etape ale metabolismuluiducand la sinte7a crescuta de '. T9. etc D3* secundare? nonfamiliale ? datorate de7echilibrului ratiealimentare sau de7echilibrului reglarii hormonale (insulina& MCT)DC DC;EKCFT;9!HC statice dinamice

Metode statice ? metode screening. rapide.orientative b.Do7area lipidelor totale Fer R fenol R Ea'lR 2) E Q 5// ? 1// mg A"// ml c.Do7area colesterolului total Fer R acid sulfosalicilic R anhidrida acetica E Q "$5 mg A"// ml d.!spectul serului racit la 4 grade ?'lar ( ser normal A D3* tip ;; XT9 (n& . 'YY ?)palescent U'u stratificare UBara stratificare

d. Teste de dislipoproteinemie UHeactia Nunkel ? precipitare 3* de catre Ea'l in pre7enta fenol Xcitire fotometrica UHeactia ,urstein ? precipitare selectiva a 3* in pre7entaheparinei. sulfatului de de<tran sau polivinilpirolidonei

?Ferurile n raman clare. cele patologice se tulbura 5.Heactia cu 3ugol precipitare 3* anormale de catre iod Xcitirefotometrica 0.Do7area 3D3 si K3D3. T91.Clectrofore7a lipoproteinelor in ca7 de dislipidemii formefamiliale

Dupa met orientative se face electrofore7a pt incadrarea D3*: U D3* ;Qhiperchilomicronemie ( f. Hara ' ( n sauY T9 ( f multY 'A9 Q /.2 ? /." ? 'hilomicroni mult crescuti. D3 sca7ut U D3* ;; aQ hiper betaQhiper 3D3 ? frecventa ' ( multY . 3D3 crescut T9 ? n 'AT9 Q 2 U QD3* ;;bQ hiper betaR pre beta Qhiper 3D3 R K3D3 ? frecventa ? '( f mult YT9 ( Y'AT9 Q variabi

*robe dinamice? se urmareste influentarea e<ercitata asuprametabolismului lipidic de catre: Uo ratie alimentara hipercalorica globala UC<ces de lipide UC<ces de glucide U!lcool D3* ; si K ? sunt dependente de ratia alimentaraD3* ;;;. ;K si ;; b ? dependente de aportul de glucide

Modificari lipidice in DO. alcool. contraceptive orale UDO: *re7ente dislipidemii (D3*& cu doua particularitati: ?*re7ente la 5/ ? 05% din DO necontrolat . 25 % dinpacientii cu DO echilibrat Fpre desebire de marea ma8oritate a D3* din populatiagenerala in care este crescut colesterolul. in DO cresc inprincipal trigliceridele U*rincipalele tulburari lipidice sunt: DO tip ; : sinte7aY K3D3.Ychilomicroni.hipertrigliceridemie 6 "/ gAl . Deoarece este secundaradeficitului de lipoproteinlipa7a. direct dependenta dedeficitul de insulina. poate sa dispara complet in "/("5 7iledupa instituirea tratamentului cu insulina ? DO tip ;;: YK3D3.Z D3 U!lcool: crestere nivel T9. K3D3 (alcoolul inhibaesterificarea !9 si creste sinte7a !9 la nivel ficat& U')? creste cant K3D3. in special la cele care aupredispo7itie catre un tip de dislipidemie http:AAwww.scribd.comAdocA"=$22=/0AMetabolismul(9lucidic(Fi(3ipidic

igure "4.4(": Derailment of fat metabolism in diabetes. a: Disinhibition of hormone( sensitive lipase in fat tissue triggers breakdown of triacylglycerol. b: ;ncreased levels of

fatty acids and of glucose lead to increased formation of ketone bodies. cholesterol. and triacylglycerol.

'onte<tual setting !lthough abnormal glucose metabolism defines type 2 diabetes and accounts for many of its symptoms and complications. efforts to understand the pathogenesis of type 2 diabetes are increasingly focussed on disordered lipid metabolism. ere we review recent human studies e<ploring the mechanistic links between disorders of fatty acid(A lipid metabolism and insulin resistance. !s SMouse Models of ;nsulin HesistanceT were comprehensively reviewed in *hysiological Heviews by Eandi et al in 2//4 ( 01 &. we will concentrate on human studies involving the use of isotopes andA or magnetic resonance spectroscopy. occasionally drawing on mouse models which provide additional mechanistic insight.

;ntroduction ;nsulin resistance is a key element in the pathogenesis of the metabolic syndrome and type 2 diabetes. both of which have reached epidemic proportions worldwide ( "=/ &.

!lthough the pathogenesis of type 2 diabetes remains poorly understood. most investigators agree on the following:

;nsulin resistance. which can be defined as a state of reduced responsiveness to normal circulating levels of insulin. plays a ma8or role in the development of type 2 diabetes. This conclusion is based upon the following observations: i& cross sectional studies demonstrating the consistent presence of insulin resistance in patients with type 2 diabetes ( =1 . 50 &: ii& the presence of insulin resistance in non(diabetic offspring of patients with type 2 diabetes ( ""$ &: iii& prospective studies demonstrating the usefulness of insulin resistance as a predictive marker of the future development of type 2 diabetes ( 50 . ""$ &: and iv& prevention of diabetes by insulin sensiti7ing agents ( "0 &. Carly in the disease. W(cells secrete sufficient insulin to compensate for insulin resistance and maintain euglycemia. Mltimately however. relative or absolute insulin deficiency supervenes precipitating hyperglycemia and overt diabetes. W(cell dysfunction is therefore a sine qua non of the diabetic state but need not be the primary abnormality ( $ &. Type 2 diabetes is a heterogeneous cluster of conditions rather than a uniform entity. The spectrum includes individuals with maturity(onset diabetes of the young or M)DP. manifesting predominantly W(cell dysfunction caused by mutations in genes involved in W(cell function ( 22 &. and people with Donohue+s syndrome due to insulin receptor mutations. whose phenotype is dominated by insulin resistance ( 52 &. The current rise in prevalence of type 2 diabetes and the metabolic syndrome is believed to be a result of increasingly sedentary lifestyles combined with ready access to energy rich food sources in genetically susceptible individuals. ealthy humans respond to positive energy balance primarily by storing e<cess energy as triglyceride in adipose tissue. -hile this response enables humans to cope efficiently with fluctuating energy supplies. it predisposes persistently over(nourished individuals to weight gain and ultimately obesity. ;t also appears to induce lipid accumulation in Sectopic sitesT such as the liver and skeletal muscle. and even in pancreatic W(cells and possibly the kidney ( ""5 &. The simple e<planation being that in obese states. energy intake e<ceeds the storage capacity of adipose tissue leading to energy SoverflowT to ectopic sites. This notion is supported by the almost universal finding of ectopic lipid accumulation in mice and humans with generali7ed lipodystrophy " . an e<treme e<ample of limited adipose tissue storage capacity in the face of e<cess calorie ingestion (food intake tends to be increased in sub8ects with generalised lipodystrophy secondary to hypoleptinemia&. )ne way to reduce ectopic lipid deposition in lipodystrophic mice is to transplant adipose tissue from wild type mice. a procedure which dramatically improved insulin sensitivity ( =5 . 4$ &. !nother way in which ectopic lipid deposits can be reduced in lipodystrophic mice and humans is by replacing leptin. an anore<ogenic adipocyte(derived hormone ( 1" . "/" &. This leads to a significant reduction in energy intake and dramatic improvements in insulin(stimulated liver and muscle carbohydrate metabolism ( $/ &. The notion of energy intake e<ceeding adipose tissue storage capacity is further supported by the finding that weight loss induced by large scale liposuction fails to improve the metabolic status of obese humans ( 42 & ? in effect this procedure simply reduces adipose tissue storage

capacity in the face of unchanged energy intake and could potentially e<acerbate lipid accumulation in liver and skeletal muscle. )n the other hand. relatively small reductions in weight due to dieting and or e<ercise can substantially improve insulin sensitivity ( 11 . 1$ . ""/ &. These observations. together with a growing awareness of the molecular interplay between lipid and carbohydrate metabolism have led to what might be termed a SlipocentricT view of the pathogenesis of insulin resistance and type 2 diabetes.

ere. after briefly describing the use of magnetic resonance spectroscopy in humans. we begin by reviewing human studies utilising this technique in combination with stable isotope measurements to determine the key rate(controlling steps in insulin(stimulated glucose disposal in muscle and the effects of insulin on hepatic glucose production in normal volunteers. -e then consider abnormalities in these processes observed in insulin resistant type 2 diabetics and in insulin resistant offspring of type 2 diabetics. before going on to consider the notion that SectopicT lipid accumulation and disorders of fatty acid(lipid metabolism might cause insulin resistance. -e also review recent insights into the mechanisms of ectopic lipid accumulation and briefly allude to mechanistic insights into the pathogenesis of type 2 diabetes obtained from studies using thia7olidinediones. Binally we consider the potential impact of inflammatory pathways on the insulin signaling cascade and the notion that inflammation in adipose tissue may be involved in inducing systemic insulin resistance in obese states (a topic recently reviewed by -ellen and otamisligil ( "2/ &&.

,asic principles of magnetic resonance spectroscopy The basic principles of magnetic resonance spectroscopy (MHF& have been described in detail in a number of reviews ( $2 . 24 . "/0 &. ;n short. some nuclei possess magnetic properties (referred to as the magnetic moment or SspinT&. -ithin a strong. static magnetic field generated by a nuclear magnetic resonance (EMH& spectrometer. the nuclei spin around their own a<is with a characteristic frequency in order to align with or against the magnetic field. Ftimulation of nuclei by an additional oscillating magnetic field at their frequency of precession transiently swings these nuclei out of alignment. Heturn to the low energy(state within the static magnetic field is associated with emission of energy in the form of radiowaves which are detected by a receiver coil. Mnder standard e<perimental conditions. resonant waves from various nuclei are superimposed. generating a picture of oscillating amplitudes in an intensity vs. time display (free induction decay. B;D&. Bourier transformation is used to convert the B;D into a display of signal intensities vs. frequencies. thereby enabling one to distinguish compounds with characteristic peak frequencies. The area under the particular peak corresponds to its tissue concentration. This result can be converted into molar terms by comparison with data obtained from a phantom containing a known amount of that compound. ;t can also be compared with the area under the peak of an intrinsic compound with a known concentration eg water peak in muscle.

Despite a low natural abundance of "."%. "= ' can be used to measure hepatic glycogen and muscle glycogen. "= ' spectroscopy can also be used to trace "= ' incorporation into glycogen during infusion or ingestion of ["( "= '\(enriched glucose. which can increase the sensitivity of the method by up to "//(fold. Fequential infusions of "= '(enriched and unlabelled glucose ( "= ' pulse( "2 ' chase e<periments& have facilitated measurements of rates of glycogen synthesis and simultaneous glycogenolysis in humans. ;n these e<periments. the increment in total hepatic glycogen over time during infusion of ["( "= '\ glucose gives the flu< through glycogen synthase. The ["( "= '\ glucose infusate is then switched to an unenriched glucose infusate. ;n order to obtain an estimate of glycogenolysis. the change in ["( "= '\ glycogen concentration is compared with the predicted increment. assuming constant flu< through glycogen synthase and no glycogen breakdown. 9lycogenolysis can then be estimated from the difference between predicted and observed glycogen concentrations. The ratio of glycogen breakdown to glycogen synthesis provides relative rates of glycogen turnover ( 12 . $0 . $1 . "/4 &.

*roton ( " & MHF is now widely used to measure hepatic and muscle triglycerides. )ne of the ma8or problems with direct measurements of T9 in muscle biopsies is the need to carefully dissect off fat surrounding the myotubules. Bortunately in vivo MHF can identify two sets of resonances from methylene and methyl protons of T9 acyl chains within muscle. shifted in frequency from each other by /.2 ppm. ;t turns out that these signals originate from two distinct compartments. namely an e<tramyocellular adipocyte pool and intramyocellular T9. Magnetic susceptibility differences between compartments and the geometric arrangement of the tissue in musculature might cause the observed frequency shift. This technique has been well validated against biochemical T9 measurements ( "/2 &.

*hosphorus ( =" *& MHF can be used to measure the rate of !T* synthesis by direct observation of =" *(magnetisation transfer between inorganic phosphate (* i & and !T*. The steady state intramyocellular * i magneti7ation is measured in the presence of selective irradiation of the ] resonance of !T* and then compared to the equilibrium * i magneti7ation in a control spectrum (without irradiation of ] !T*& ( 55 . 15 &. To date. this technique has been used to measure the rate of !T* synthesis in skeletal muscle and brain in humans.

;nsulin resistance and muscle glucose metabolism ow do healthy individuals dispose of glucose loadsL

;ngested glucose can either be o<idi7ed or stored as glycogen. or to a lesser e<tent as fat (via de novo lipogenesis&. Carly studies using indirect calorimetry in combination with femoral vein catheterisation and the euglycemic(insulin clamp suggested that non(

o<idative glucose metabolism was the ma8or pathway for glucose disposal in healthy sub8ects ( 25 &. C< vivo glycogen measurements in sequential muscle biopsy studies taken in the presence of high plasma glucose concentrations (peak 2/ mmolAl& suggested that over half of an infused glucose load was stored as muscle glycogen ( 0 . 02 &. "= ' MHF provided the first opportunity to directly assess small sequential changes in muscle glycogen concentration during hyperglycemic(hyperinsulinemic clamps ( "/5 &. ;ndirect calorimetry was used concurrently to calculate whole body non(o<idative glucose disposal. These data suggested that during a hyperglycemic(hyperinsulinemic clamp skeletal muscle accounts for the vast ma8ority of glucose uptake in normal humans and that over $/% of this glucose is then stored as muscle glycogen ( "/5 &. Direct "= ' MHF measurements of muscle glycogen have also been undertaken in healthy sub8ects following standard meals. ;n this situation. muscle glycogen synthesis accounts for ^=/% of the ingested glucose ( "22 &. 9lycogen concentrations peak at ^"// mmolA3 around 5 hours after a meal. declining thereafter ( "$ . ""= &.

ow is this altered in insulin resistant type 2 diabetics and in insulin resistant diabetic offspringL

,aseline muscle glycogen concentrations were significantly lower in type 2 diabetics than in matched controls ( "$ . "/5 & and the rate of glycogen synthesis in skeletal muscle was appro<imately 5/% lower in diabetic sub8ects than in normal volunteers during hyperglycemic(hyperinsulinemic clamps ( "/5 &. *ostprandial increments in muscle glycogen were also significantly lower than those in normal volunteers ( "$ &. Birst( degree relatives of type 2 diabetics have a ^4/% lifetime risk of developing diabetes ( 5" &. ;nsulin resistance is the best predictor of the development of diabetes in these offspring ( 50 . ""$ & and probably plays an important role in its pathogenesis. ,aseline muscle glycogen concentrations (^1/ mmolA3& were similar to those of healthy controls. but insulin(stimulated rates of muscle glycogen synthesis were reduced by 0=% in these individuals ( 14 &.

-hat are the rate(controlling steps in glucose disposalL

Mnder the influence of insulin. glucose is transported into myocytes via 93MT 4 (glucose transporter 4&. where it is phosphorylated by he<okinase. 9lucose 0(phosphate is then either utili7ed in the glycolytic pathway or incorporated into glycogen by glycogen synthase.

'lick on image to 7oom

"= ' and =" * MHF were used together to monitor both intracellular glucose(0(phosphate concentration and intramuscular glycogen synthesis during hyperinsulinemic( hyperglycemic clamps ( 2= &. 9lucose(0(phophate is an intermediate between glucose transport into the cell and its subsequent phosphorylation by he<okinase. and glycogen synthesis. The fact that the increment in glucose(0(phosphate concentration was significantly reduced in type 2 diabetics suggested that glucose transport andAor phosphorylation was the rate(controlling step in insulin(stimulated glucose disposal in skeletal muscle rather than glycogen synthase ( 2= &. Fimilar observations were also made in lean insulin resistant offspring of type 2 diabetics ( 2" & and in non(diabetic obese women (,M; == G " kgAm 2 & ( 1$ &. suggesting that this defect precedes the development of type 2 diabetes and is common to insulin resistant offspring of type 2 diabetics and obese sub8ects: both states significantly increase the risk of developing type 2 diabetes. 9lucose transport in skeletal muscle is largely mediated by a specific insulin responsive transporter. known as 93MT4. whereas glucose phosphorylation is catalysed by he<okinase. ;n order to determine which of these two steps was defective. a novel "= ' MHF method was used to assess intracellular free glucose in muscle ( "2 &. the idea being that if he<okinase were rate(controlling in insulin resistant type 2 diabetics intracellular glucose concentrations should increase substantially (62mM&. The fact that intracellular glucose concentrations in skeletal muscle from type 2 diabetics (during a hyperinsulinemic(hyperglycemic clamp& were "A25 what they would have been if he<okinase were the primary rate(controlling en7yme suggested that glucose transport was rate(controlling as opposed to he<okinase ( "2 &. Taken together these data indicate that glucose transport into muscle is the rate(controlling step for insulin(stimulated muscle glycogen synthesis in patients with insulin resistant type 2 diabetes. They also suggest that this defect precedes the development of type 2 diabetes in lean offspring of type 2 diabetics and in obese adults.

;nsulin resistance and liver glucose metabolism The liver plays a pivotal role in maintaining energy homeostasis during fed(fasting transitions. -hilst peripheral tissues (predominantly skeletal muscle& account for the ma8ority of postprandial insulin(stimulated glucose disposal. the liver also plays a key role in buffering ingested carbohydrate by suppressing hepatic glucose output and stimulating glucose deposition as liver glycogen. ;n the fasting state. hepatic glycogen stores are rapidly mobilised in order to maintain circulating glucose concentrations. ;n addition. the liver. aided to some e<tent by the kidney. converts lactate. glycerol and amino acids to glucose by gluconeogenesis.

Carly human studies of hepatic glucose metabolism required invasive procedures such as liver biopsy andA or indirect measurements of hepatic gluconeogenesis based on sampling from arterial and hepatic vein catheters. "= ' MHF has made non(invasive. real(time and repetitive measurements of hepatic glycogen concentrations possible. enabling

investigators to monitor net rates of hepatic glycogen synthesis and glycogenolysis in vivo .

Basting state ( Big. " &

Hothman et al ( 22 & combined "= ' MHF measurements of liver glycogen with magnetic resonance imaging of liver volume and infusion of [=( = \glucose which was used to determine net hepatic glucose production. to trace the relative contributions of hepatic gluconeogenesis and hepatic glycogenolysis during a prolonged fast (0$ hours&. ;n the first 22 hours after a modest 05/ kcal meal. liver glycogen decreased in an almost linear fashion from =20 G 22 mmolAl at 4 hours to 25" G =/ mmolAl at "5 hours [the latter concentration is in agreement with that of appro<imately 21/ mmolAl obtained by needle biopsy following a similar fasting period ( 1/ & and findings in a subsequent MHF study ( == &\. Eet rates of glycogenolysis were calculated to be 4.= G /.0 _molAkgAmin. which only accounted for =0% of whole body glucose production. suggesting that gluconeogenesis must be the dominant contributor to whole body glucose production even in the early period of fasting. !s this observation contrasted with earlier studies suggesting that the contribution of gluconeogenesis to whole body glucose production was less than =$% after an overnight ("2?"4 hour& fast ( 22 . 1/ . ""1 &. net glycogenolysis was followed between 5 and "2 hours after a large "/// kcal evening meal. which was designed to fully replete liver glycogen content ( $" &. ;n that study [0.0( 2 \ glucose was used to determine whole body glucose production. ere again. net hepatic glycogenolysis (5.$ G /.$ _molAkgAmin& contributed only 45% of whole body glucose production. These data imply that gluconeogenesis contributes as much as 5/% of whole body glucose production in the early hours following a mi<ed meal. These findings were later confirmed by 3andau et al ( 54 & who used a novel D 2 ) method to directly assess the contribution of gluconeogenesis to whole body glucose production in healthy volunteers following an overnight fast. ealthy sub8ects drank D 2 ) and after "4. 22 and 42 hours of fasting the enrichments of deuterium in the hydrogens bound to carbons 2. 5 and 0 of blood glucose and in body water were determined. Cnrichment of the deuterium bound to carbon 5 of glucose relative to that of water or to that of carbon 2 of glucose directly equals the fraction of glucose formed by gluconeogenesis. ,etween 22 and 40 hours of fasting. net glycogenolysis decreased to ".1 G /.5 _molAkgAmin. indicating that even at this early stage gluconeogenesis accounts for as much as 04% of endogenous glucose production. ,etween 40 and 04 hours the rate of net hepatic glycogenolysis fell to /.= G /.0 _molAkgAmin ( 22 &. !fter 04 hours. liver glycogen content had fallen by $=% and gluconeogenesis was almost solely responsible (20%& for endogenous glucose production ( 22 &. ,y this point. fat o<idation and ketone bodies make a substantial contribution towards meeting whole body energy requirements.

Bigure "

Helative contribution of gluconeogenesis and glycogenolysis to glucose production during fasting Bed (postprandial& state

epatic glucose output is suppressed within =/ minutes after an oral glucose load and the liver takes up glucose to replenish glycogen stores. Taylor et al ( ""2 & observed that liver glycogen concentrations increased from 2/1 G 22 mmolA3 after an overnight fast to a peak of ="0 G "2 mmolAl 5 hours after a liquid mi<ed meal giving a net rate of glycogen synthesis of /.=4 _molAlAmin (representing appro<imately "2% of the carbohydrate content of the meal&. The data are consistent with estimates of 25% obtained after an oral glucose load by double tracer studies ( $2 &. splanchnic balance techniques ( 4= & and an independent MHF study ( 4 &. wang et al ( 4" & monitored liver glycogen concentrations in normal sub8ects during the course of a day in which three mi<ed meals were ingested. 3iver glycogen stores increased from 214 G "" mmolAl. peaked 8ust before the ne<t meal and were ma<imal 4 hours after dinner (42/ G "2 mmolAl&. These data suggest that net hepatic glycogenolysis is negligible in resting healthy sub8ects consuming three meals a day. and therefore glucose absorption from meals and possibly gluconeogenesis account for the ma8ority of glucose production during the day. whereas net hepatic glycogenolysis only contributes to whole body glucose production during the night.

-hat determines net hepatic glycogen turnoverL

Eet glycogen synthesis is directly regulated by two en7ymes. glycogen synthase and glycogen phosphorylase. ! combination of "= ' MHF and "= ' glucose pulse( "2 ' glucose chase techniques were used to demonstrate that glycogen synthesis and glycogenolysis occur simultaneously in the liver ie glycogen cycling ( 24 . 5$ . 12 . $0 . "/4 &. This technique was also used to assess the relative impact of glucose and insulin on glycogen turnover under hypoglucagonemic conditions ( 12 &. -hile hyperglycemia primarily inhibits net hepatic glycogenolysis by inhibiting glycogen phosphorylase flu<. hyperinsulinemia primarily stimulates glycogen synthase flu<. The net rate of glycogen synthesis depends on portal vein insulin. requiring concentrations in the "=/?"1/ pmolAl range for half(ma<imal stimulation of glycogen synthesis ( $0 &. Burthermore under basal insulin concentrations. the presence and absence of glucagon was shown to have a profound effect on regulating net hepatic glycogen synthesis ( $0 &.

-hat happens in insulin resistant type 2 diabetesL

;t is well established that fasting hyperglycemia is related to increased rates of endogenous glucose production ( "4 . =" &. This phenomenon could be a consequence of increased gluconeogenesis andAor increased glycogenolysis. Magnussen et al ( 52 & measured rates of net hepatic glycogenolysis in poorly controlled type 2 diabetics (mean hemoglobin !"c "2 G "%&. 9luconeogenesis was simultaneously calculated as the difference between rates of net hepatic glycogenolysis and whole(body glucose production. ,aseline liver glycogen concentration was reduced in the diabetic sub8ects ("=" G 2/ vs. 2$2 G 0/ mmolAl liver&. in keeping with a defect in postprandial hepatic glycogen synthesis and was associated with lower rates of net hepatic glycogenolysis. More importantly the 25% increase in rates of endogenous glucose production observed in these poorly controlled type 2 diabetic sub8ects could entirely be attributed to increased rates of gluconeogenesis.

Batty acidA lipid(induced insulin resistance Muscle

3ipid infusions designed to increase plasma fatty acid (B!& concentrations reduce insulin(stimulated glucose disposal in humans ( 2 . 40 . $$ &. Burthermore. the fall in insulin sensitivity during such clamp procedures only occurs =?5 hours after elevations in B! concentrations. in keeping with the idea that fatty acid metabolite accumulation in skeletal muscle and liver is responsible for this phenomenon ( $ &. Handle et al. originally showed that fatty acids compete with glucose for substrate o<idation in isolated rat heart muscle and rat diaphragm muscle ( $= &. They speculated that an increase in fat o<idation might be responsible for insulin resistance. !ccording to their proposal. increased fatty acid o<idation would cause an increase in the mitochondrial acetyl 'o!:'o! and E!D :E!DR ratios with subsequent inactivation of pyruvate dehydrogenase. This in turn would induce a rise in intracellular citrate levels. leading to inhibition of phosphofructokinase and glucose(0(phosphate accumulation. !s glucose(0(phosphate inhibits he<okinase activity. this would result in intracellular glucose accumulation and decreased glucose uptake. ! series of studies has recently challenged this mechanism ( "" . 2$ . =0 . $$ &. Eon(esterified fatty acid levels in healthy sub8ects were maintained at either high or low levels during hyperinsulinemic(euglycemic clamps. Maintaining high free fatty acid levels for 5 hours caused the e<pected reduction in insulin sensitivity as assessed by glucose uptake. glucose o<idation and glycogen synthesis in skeletal muscle. 8ust as had been observed in type 2 diabetics and their insulin resistant offspring. owever. rather than increasing intracellular glucose(0(phosphate levels. as predicted by the Handle mechanism ( $= &. increasing plasma fatty acid concentrations reduced intracellular glucose(0(phosphate levels ( $$ &. This was consistent with what had been observed in patients with type 2 diabetes ( 2" &.

Batty acid infusion could conceivably have direct effects on 93MT4 activity or it could alter insulin regulated 93MT4 trafficking between intracellular compartments and the cell membrane. To e<plore the latter possibility insulin signalling intermediates were e<amined in skeletal muscle biopsies from sub8ects e<posed to high fatty acid levels for five hours prior to and during hyperinsulinaemic(euglycaemic clamps ( 2$ &. 9lucose o<idation and glycogen synthesis were 5/?0/% lower following the lipid infusion than with the glycerol (control& infusion. and were associated with a ^2/% decrease in the increment in intramuscular glucose(0(phosphate concentration. implying diminished glucose transport or phosphorylation activity. The fact that intracellular glucose concentrations were significantly lower in the lipid infusion studies compared with those during glycerol infusion implied that glucose transport was the rate(controlling step. ;HF( " (insulin receptor substrate "& associated *; =(kinase (phosphoinositol =(kinase& activity was significantly reduced under these conditions ( 2$ &. Fubsequent rodent and human studies suggested that this might be a consequence of serine phosphorylation of ;HF(" ( 2$ . =0 . 00 . "2$ &. !n important and as yet unanswered element in this proposed mechanism for insulin resistance is the precise nature of the lipid moiety responsible for fatty acid induced insulin resistance. !lthough triglyceride accumulation in skeletal muscle and liver clearly correlates with insulin resistance. triglycerides are generally perceived to be metabolically inert associates of more favoured candidates which include long chain acyl(coen7yme ! (3''o!s&. diacylglycerol (D!9& ( 42 . "2$ & and ceramides ( " &. Ftudies by Pu et al have been able to disassociated lipid(induced insulin resistance from any increases in intramuscular triglyceride or ceramide content suggesting that these lipid metabolites are not the trigger in mediating fat(induced insulin resistance in skeletal muscle ( "2$ &. The fact that mt9*!T" (mitochondrial acyl('o!:glycerol(sn(=( phosphate acyltransferase "& knockout mice. which have elevated 3''o!s but reduced D!9 and T9 in liver. have improved hepatic insulin sensitivity suggests D!9 may be a better candidate than 3''o! in mediating fat induced insulin resistance in liver ( 0$ &. *N' is a serineA threonine kinase known to be activated by D!9s and might account for the link between lipid accumulation and serine phosphorylation of ;HF(" in rodents ( =0 . 2$ . 22 &. ;n keeping with these rodent studies. ;tani et al ( 42 & noted that D!9 accumulation in human muscle during lipidA heparin infusions was associated with increased *N' activity. ;f this hypothesis is true. perturbations that result in accumulation of 3''o!s. D!9s or other fatty acid derivatives within muscle and liver. either through increased delivery andAor decreased metabolism. ought to induce insulin resistance.

3iver

The effects of elevated B! concentrations on hepatic glucose metabolism are less clear. ;n the presence of postabsorptive insulin concentrations. plasma B! elevation increased C9* during somatostatin(insulin clamps ( "2 . =/ &. but not after an overnight fast ( "2 . 2/ &. These apparent discrepancies may be caused by B!(induced insulin secretion counterbalancing the stimulatory effect of B!s on C9*. andA or hepatic autoregulation 2 preventing a net increase in hepatic glucose output despite increased gluconeogenesis. Hoden et al ( 2/ & combined measurements of C9* using D([0.0( 2 \glucose with

measurements of gluconeogenesis derived from 2 enrichments in carbons 2 and 5 of blood glucose after D 2 ) ingestion during short term intralipidA heparin infusions. *lasma B! elevation induced insulin secretion sufficiently to prevent any change in plasma glucose concentrations. owever. if plasma insulin concentrations were maintained at fasting peripheral concentrations by a combined somatostatin(insulin infusion. B! e<posure significantly increased plasma glucose primarily by increasing gluconeogenesis. ,oden et al ( "/ & lowered fasting plasma B! concentrations by administering nicotinic acid and then increased B!s by withdrawing nicotinic acid (induces a rebound increase in B!s& whilst measuring 9E9 and 93. They concluded that increased B!s stimulated 9E9 whereas reduced B! concentrations inhibited 9E9.

The mechanisms by which B!s induce 9E9 remain poorly understood. *ostulates have included activation of pyruvate carbo<ylase (secondary to increases in acetyl 'o!& ( 2 & and increased availability of E!D and !T* ( "21 &. Hoden et al ( 2/ & e<cluded the possibility that elevated glycerol. a gluconeogenic substrate which is released with B!s during lipolysis. could have stimulated 9E9 by matching plasma glycerol levels during lipidA heparin infusion with a glycerol infusion in controls.

Ftudies of hepatic insulin signalling have for obvious reasons largely been confined to animals. *N'` translocation to the plasma membrane and activity is increased in rats with isolated hepatic steatosis and hepatic insulin resistance following three days of high fat feeding ( 25 &. suggesting that *N'` may be an important mediator of fat(induced insulin resistance in liver. *N'` has also been shown to be activated in the liver in patients with type 2 diabetes ( 2" &.

Mechanisms of lipid accumulation in skeletal muscle and liver MHF measurements of intra(myocellular lipids (;M'3& correlate more closely with insulin resistance than any other commonly measured indices including body mass inde< (,M;&. waist(hip ratios. or total body fat ( 5= &. Eon(alcoholic steatohepatitis is also increasingly recognised as a component of the insulin resistance or metabolic syndrome ( 0/ . 12 . "// &. 3ipid accumulation in ectopic sites can occur in three ways: increased uptake of fatty acids. increased synthesis within the tissue involved andAor reduced fatty acid o<idationAdisposal ( "/= &. The relative contribution of these factors to ectopic lipid accumulation may well vary in different physiological states and in different tissues. Fimplistically. obesity and lipodystrophy would appear to be associated with ectopic lipid accumulation predominantly due to e<cess lipid influ<Asynthesis in the liver and muscle. whereas in lean elderly sub8ects ( 15 & and lean insulin resistant offspring of type 2 diabetics ( 10 &. impaired mitochondrial fatty acid o<idation may play a ma8or role in this process.

)besity and lipodystrophy

)besity is a very common cause of insulin resistance and a ma8or risk factor for the development of type 2 diabetes. ;nterestingly. lipid accumulation in muscle and liver is characteristic of obesity and what might be considered its opposite e<treme. lipodystrophy ( 11 . $/ &. !s alluded to above. it is clear that lipidAheparin infusions which increase plasma B!s can lead to lipid accumulation in skeletal muscle and short term high fat feeding elevates liver triglycerides in rats ( 25 &: in both cases insulin resistance ensues. ;ncreased fatty acid concentrations are often said to be typical of obesity ( "= &. most likely due to increased B! release from an e<panded fat mass: providing a convenient link between obesity and ectopic lipid accumulation. -hilst suppression of B! levels by insulin is consistently impaired in insulin resistant obese sub8ects and at least in some forms of lipodystrophy ( ""0 &. fasting plasma B! levels are not always elevated in insulin resistant obese sub8ects ( 1$ &. nor are they typically elevated in lipodystrophics ( 20 & (one needs to bear in mind that since triglyceride concentrations are typically increased in lipodystrophy ( =4 &. e< vivo hydrolysis is likely to produce falsely elevated B! measurements if samples are not appropriately collected and stored: one also needs to consider the fact that the normal range for fasting plasma B!s is particularly wide (of the order of 22/?12/ _molA3&&. The notion that obesity and lipodystrophy are associated with persistently elevated plasma B!s. which in turn result in lipid accumulation in muscle and liver is therefore probably overly simplistic. -hat is more likely is that chronic imbalances between energy deliveryA uptake and o<idation ultimately result in e<cess intracellular lipid accumulation. both at the whole body level and in individual organs or tissues. Nelley et al ( 44 . "/$ & have proposed the idea that metabolic infle<ibility ie an impaired capacity to appropriately switch between SfedT (predominantly carbohydrate o<idation& and SfastingT (predominantly lipid o<idation& metabolism. typifies obesity and insulin resistance. This mismatching between energy supply and demand may over time contribute to the accumulation of ectopic lipid. !dipose tissue plays a ma8or role in maintaining metabolic fle<ibility by buffering the postprandial influ< of fatty acids. a function which is disturbed in both obesity and lipodystrophy ( =2 &.

*ero<isome proliferator(activated receptor gamma (**!H]&. a nuclear hormone receptor predominantly e<pressed in adipocytes. appears to be a key player in the ability of adipose tissue to buffer fatty acid influ<. umans with dominant negative loss(of( function mutations in the ligand(binding domain of **!H] manifest a stereotyped form of partial lipodystrophy and impaired postprandial fatty acid trapping ( 21 &. They also have fatty livers and are severely insulin resitant. Thia7olidinediones are commercially available **!H] agonists which substantially improve insulin sensitivity despite promoting weight gain. -hilst their precise mode of action remains unclear. they seem to improve the ability of adipose tissue to buffer fatty acids ( """ &. a phenomenon which is likely to be a key component of their insulin sensitising properties ( 5/ . 0" &. Thia7olidinediones also improve hepatic steatosis ( 02 & and hepatic insulin sensitivity ( = &. ;nterestingly. they do not consistently lower muscle T9 ( 02 &. nor is muscle T9

increased in humans with loss(of(function mutations in **!H] ( 21 &: observations which further suggest that intramyocellular triglyceride is not the trigger for fat induced insulin resistance as previously discussed. owever thia7olidinediones have been shown to lower intramuscular long chain 'o!+s in rodents ( 41 &.

Hecent work employing stable isotopes to track the fate of ingested nutrients suggests that lipid accumulation in the liver is a result of both fatty acid re(esterification and de novo lipogenesis ( 21 &. )ne interesting hypothesis suggests that hyperinsulinaemia could be an important driving force for lipogenesis in the liver (and muscle& by increasing sterol regulatory element(binding protein "c (FHC,*"c& e<pression ( "/2 &. FHC,*"c is a key transcriptional regulator of de novo lipogenesis ( "5 &.

!ging associated insulin resistance and lean diabetic offspring

Together with obesity. aging is a very common cause of insulin resistance: and like obesity it too is characterised by lipid accumulation in muscle and liver ( 2= . 15 &. -hile an increasingly sedentary lifestyle and the associated relative increase in fat mass almost certainly contributes to aging induced insulin resistance. *etersen et al ( 15 & documented insulin resistance in elderly sub8ects matched to young adult controls in terms of fat mass. lean body mass and activity. Burthermore. the ability of insulin to suppress lipolysis as measured by glycerol turnover was similar to that seen in young controls. suggesting that adipose tissue dysfunction was unlikely to be a ma8or determinant of the observed increase in liver and muscle T9 in their study. ;n order to measure mitochondrial o<idative phosphorylation activity in skeletal muscle. MHF was used to monitor "= ' labelling of carbon atoms in glutamate during an intravenous infusion of [2( "= '\acetate providing a direct measure of tricarbo<ylic acid (T'!& cycle flu<. Hates of !T* synthesis were measured using =" * MHF by the direct observation of =" *( magnetisation transfer between inorganic phosphate and !T*. ,oth of these measurements of mitochondrial function in muscle were impaired in the lean elderly insulin resistant sub8ects. Fimilar defects in mitochondrial function in muscle were found in lean insulin resistant offspring of type 2 diabetics. who also have elevated intramyocellular T9s. ;n the case of the elderly. this is likely to be a consequence of acquired mitochondrial mutations. a phenomenon known to occur with aging ( 04 &. whereas in the insulin resistant offspring. it is more likely that the reduction in mitochondrial o<idative phosphorylation is a primary genetic defect. ;nsulin resistant diabetic offspring were also found to have a lower ratio of o<idative type " to glycolytic type 2 muscle fibres in an independent study ( 10 &. Cn7yme defects have also been described in isolated mitochondria derived from human skeletal muscle biopsies from type 2 diabetics ( 45 &. Mitochondria in skeletal muscle appear to be compartmentalised at a subcellular level and one report suggests that there is a disproportionately large reduction of electron transport chain activity in the subsarcolemmal mitochondrial fraction (the other fraction being the intermyofibrillar fraction which generates energy for

muscle contraction& in nondiabetic obese sub8ects and in obese type 2 diabetics ( $5 &. Fubsarcolemmal mitochondria are believed to be crucial for fatty acid o<idation. glucose transport and propogation of insulin signalling as well as several other energy(requiring processes at the cell surface ( =2 . $5 &. ;nterestingly. the reduction in mitochondrial electron transport chain activity did not appear to be entirely attributable to a reduction in mitochondrial mass. suggesting that total cellular mitochondrial activity reflects both mitochondrial mass and the en7yme activity within the mitochondria: in other words some mitochondria may not function optimally ( $5 &. Together. these data suggest that alterations in nuclear(encoded genes that regulate mitochondrial biogenesis such as pero<isome proliferator(activated receptor gamma co(activator "V (*9'("V&. !M* kinase ( 5 . "=" & and '!M ;K kinase ( "24 & may form the genetic basis for inheritance of at least some forms of type 2 diabetes. They also suggest that genes involved in regulating both mitochondrial en7yme activity and mitochondrial mass may be involved in the pathogenesis of type 2 diabetes. This notion is further supported by two microarray studies which revealed a reduction in *9'("V responsive transcripts in patients with type 2 diabetes and their first(degree relatives ( 05 . 1= &. *9'("V is a key regulator of mitochondrial biogenesis ( "25 &. owever. despite demonstrating that the reduction in mitochondrial function seen in insulin resistant diabetic offspring is due to reduced mitochondrial content (assessed by electron microscopy&. Morino et al did not find any differences in *9'(" mHE! or protein e<pression ( 00 &. These data suggest that the previously reported reduction in *9'(" may be a secondary phenomenon. The primary factors responsible for the reduced mitochondrial content in insulin resistant diabetic offspring remain unknown ( 00 &.

Binally. one needs to remain cognisant of the fact that. to date. inherited mitochondrial disorders have tended to produce pleiotropic manifestations ( "/1 &. often without diabetes. ;n those cases where diabetes is a feature. W cell dysfunction tends to be the primary abnormality ( 51 . "/1 &. )ne e<ample where insulin resistance also seems to be a feature is Bredreich+s ata<ia although insulin sensitivity has still to be carefully evaluated in this model ( $4 &. ;n our view. the mitochondrial dysfunction seen in the elderly. lean insulin resistant diabetic offspring and insulin resistant type 2 diabetics is probably milder than that observed in disorders where W cell dysfunction predominates. !n important remaining question is whether mitochondrial defects. be they inherited or acquired cause the increases in intramyocellular lipid and insulin resistance. or are they secondary in nature.

;nflammation and insulin resistance -hile lipid accumulation in muscle and liver may be sufficient to e<plain the development of insulin resistance in obese sub8ects. obesity is also associated with a systemic chronic inflammatory response characteri7ed by altered cytokine production and activation of inflammatory signaling pathways ( "2" &: recent reports have linked this inflammatory response to the development of insulin resistance. !lmost all of this data has. to date. come from animal studies and has recently been comprehensively reviewed (

"2/ &. so is not covered in detail here. To summarise. the ma8or findings in humans include:

;ncreased plasma inflammatory markers [eg '(reactive protein ('H*&\ and altered plasma adipokine concentrations have been detected in some ( "2/ &. but not all. insulin resistant states. ;n particular. plasma levels of adiponectin. resistin. ;3(0. TEBV and leptin were unchanged in both lean insulin resistant offspring of type 2 diabetics ( 10 & and in lean insulin resistant elderly sub8ects ( 15 & when compared to insulin sensitive controls. suggesting that inflammatory changes are unlikely to be the primary abnormality in these groups of sub8ects. Moderate weight loss in obese insulin resistant sub8ects also failed to significantly alter adipokine levels despite significant improvements in hepatic insulin sensitivity and normali7ation of fasting plasma glucose concentrations ( 11 &. Fignificantly increased numbers of macrophages accumulate in adipose tissue in obese states ( ""2 . "20 &. Macrophages are found in the stromovascular fraction of adipose tissue in humans and appear to make a substantial contribution to gene e<pression within adipose tissue. These cells are derived from bone marrow precursors and appear to infiltrate adipose tissue in greater numbers in obese states. -hether this inflammatory infiltrate is responsible for the development of insulin resistance is not yet clear. although au et al ( "20 & did suggest that the increase in inflammatory gene e<pression within adipose tissue preceded the dramatic increase in plasma insulin levels noted in high fat fed mice. They also reported down(regulation of these macrophage(derived genes in response to treatment with an insulin(sensiti7ing **!H] agonist (rosiglita7one& ( "20 &. Fubsequent studies in humans have suggested that the inflammatory cell infiltrate (as reflected by mHE! levels of a macrophage marker ('D0$&& correlates with insulin sensitivity more closely than with ,M; and that thia7olidinediones reduce 'D0$ mHE! levels and improve insulin sensitivity ( 20 &. Furgically(induced weight loss (bariatric& also reduces macrophage infiltration in adipose tissue of morbidly obese sub8ects and improves insulin sensitivity ( "1 &. ;n addition to *N'. a number of serineA threonine kinases are activated in inflammatory states. Bor e<ample. Puan et al ( "22 & recently proposed that fatty acid induced serine phosphorylation of ;HF(" might be mediated by ;N, kinase(W (;NN(W&. This hypothesis has been supported by a human study demonstrating that pharmacological inhibition of ;NN(W activity by high dose salicylate therapy (high doses of salicylate are required to inhibit ;NN(W activity& reduced fasting hyperglycaemia and basal hepatic glucose production and. improved peripheral glucose uptake in patients with type 2 diabetes ( 4/ &. otamisligil and co(workers have identified another inflammatory serine kinase potentially involved in inducing serine phosphorylation of ;HF(". namely Dun kinase " (DEN"& ( =$ &. They reported increased DEN activity in obese rodents and human adipose tissue. as well as reduced adiposity and improved insulin sensitivity in DEN" knockout mice. Fuppressor of cytokine signaling = (F)'F=& is another potential contributor to the links among obesity. inflammation and insulin resistance ( ""4 &. )ne particularly intriguing aspect of the F)'F= hypothesis is that increases in F)'F= e<pression have also been observed in the hypothalamus where F)'F= may be involved in inducing leptin resistance ( 1 &. This notion provides a potentially unifying mechanism for both

insulin and leptin resistance. states which frequently co(e<ist in obese humans.

'onclusions The ability to non(invasively monitor biochemical changes in living sub8ects in realtime has yielded a number of significant novel insights into the pathogenesis of insulin resistance and type 2 diabetes. ;nsulin resistance in skeletal muscle manifests primarily as a reduction in insulin(stimulated glycogen synthesis. which is in turn a consequence of reduced glucose transport. ;n the liver. insulin resistance seems to be somewhat parado<ically associated with a reduced ability of insulin signalling to inhibit glucose production whereas insulin stimulated lipogenesis is enhanced. 3ipid accumulation within skeletal muscle is associated with serine phosphorylation on critical sites on ;HF(" and reduced tyrosine phosphorylation of ;HF(" ( Big. 2 &. This in turn inhibits binding and activation of *; =(kinase. ! number of different serine kinases could be responsible for serine phosphorylation of ;HF(". 'andidates include members of the n*N' family. which may be activated by accumulation of lipid intermediates (particularly D!9s&. as well as inflammatory intermediates such as ;NNW. DEN" and TEBV. The latter may be activated within adipose tissue in obese states. 3ipid accumulation in skeletal muscle and liver may be a result of increased deliveryAsynthesis of fatty acids toAin these tissues in states in which energy intake e<ceeds adipose tissue storage capacity (as seen in obesity and lipodystrophy&. or a consequence of either acquired or inherited mitochondrial dysfunction. !s well as re(inforcing the importance of life(style interventions in the management of type 2 diabetes ? dietary restriction to limit the stress on energy stores and e<ercise to increase mitochondrial number and function ( these novel ideas about the molecular pathogenesis of insulin resistance have provided several new therapeutic targets for the treatment and possible prevention of type 2 diabetes.

Bigure 2

Mechanism of fatty acid induced insulin resistance in muscle (!& and liver (,& Ftudies in lean offspring of type 2 diabetics suggest that intramyocellular lipid accumulation and muscle insulin resistance precede the development of hepatic insulin resistance and type 2 diabetes ( 10 &. -e propose that insulin resistance in skeletal muscle is the earliest event in the pathogenesis of type 2 diabetes in most patients. Muscle insulin resistance is in turn associated with peripheral and portal vein hyperinsulinemia which promotes hepatic steatosis. at least in part by inducing FHC,*"c mediated de novo lipogenesis and inhibiting fatty acid o<idation. Hecent work by -olfram et al ( "2= & suggests that hyperinsulinemia induces nuclear e<clusion and inhibition of Bo<a2. a regulator of fatty acid o<idation. ;n time. this leads to lipid accumulation in the liver. hepatic insulin resistance and ultimately type 2 diabetes. !dipocyte dysfunction due to

either obesity or lipodystrophy is associated with e<cessive and untimely delivery of B!s to the liver and skeletal muscle and probably contributes to insulin resistance in both organs. by altering the balance between B! uptakeAsynthesis and disposal leading to increases in intracellular lipid content. Burther human studies will be required to prove or disprove this theory and are also e<pected to continue to unveil novel therapeutic approaches for the treatment and prevention of insulin resistance and type 2 diabetes.

!cknowledgements 9;F is an investigator of the oward ughes Medical ;nstitute. This work was supported by grants from the MF *ublic ealth Fervice: */" DN(0$$22. H/" DN(4/2=0. H/" DN( 422=/. H/" !9(2=0$0. M/" HH(//"25. M24 DN(520=5 and a Distinguished Fcientist !ward from the !merican Diabetes !ssociation. D,F is supported by the -ellcome Trust.

Bootnotes " The lipodystrophic syndromes encompass a rare group of conditions characteri7ed by partial or complete absence of adipose tissue. The disorders may be genetic or acquired. and are further classified according to the anatomical distribution of the lipodystrophy. 2 !utoregulation refers to the tendency of hepatic glycogenolysis to compensate for increased gluconeogenesis. thereby preventing an increase in 9*. www.ncbi.nlm.nih.govApmcAarticlesA*M

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