Lipid and Cholesterol Metabolism

studies฀ [229–232] .฀Smoking฀increases฀circulating฀levels฀of฀atherogenic฀LDL฀cholesterol฀by฀ accelerating฀the฀lipid฀conversion฀of฀HDL฀cholesterol฀and฀delaying฀the฀clearance฀of฀LDL฀ cholesterol฀from฀the฀plasma฀compartment฀ [233] . According฀to฀a฀more฀recent฀study฀in฀which฀energy฀intake฀and฀basal฀metabolic฀rate฀were฀ calculated฀in฀205฀women฀and฀141฀men,฀cigarette฀smokers฀had฀a฀higher฀energy฀intake฀from฀ fat฀than฀non-smokers฀29฀vs.฀26,฀a฀lower฀intake฀from฀carbohydrates฀50฀vs.฀54฀and฀a฀ lower฀intake฀of฀vitamin฀C฀11฀vs.฀16฀mg฀ [234] . An฀epidemiological฀study฀conducted฀in฀Westphalia฀in฀several฀thousand฀men฀and฀women฀ showed฀that฀the฀frequency฀of฀subjects฀with฀low฀plasma฀HDL฀cholesterol฀values฀0.907฀ mmolel฀in฀men,฀1.166฀mmolel฀in฀women฀was฀about฀10฀higher฀in฀smokers฀than฀in฀ex- smokers฀ or฀ non-smokers฀ [235] .฀ A฀ study฀ of฀ cardiovascular฀ risk฀ factors฀ in฀ 166฀ cigarette฀ smokers฀revealed฀lower฀serum฀HDL฀cholesterol฀0.76฀vs.฀0.81฀mmolel฀and฀higher฀serum฀ triglycerides฀1.92฀vs.฀1.71฀mmolel฀in฀comparison฀with฀values฀measured฀in฀312฀non- smokers฀ [236] .฀Higher฀triglyceride฀and฀total฀cholesterol฀levels฀have฀also฀been฀reported฀in฀ other฀studies฀of฀smokers฀compared฀with฀non-smokers฀and฀ex-smokers฀ [237–245] .฀A฀meta- analysis฀of฀data฀obtained฀in฀children฀and฀adolescents฀aged฀8–19฀years฀revealed฀associa- tions฀between฀smoking฀or฀non-smoking฀status,฀and฀blood฀lipids฀and฀cholesterol฀fractions;฀ the฀indings฀were฀analogous฀to฀those฀obtained฀in฀adults฀ [228] .฀Plasma฀thiocyanate฀levels,฀ measured฀as฀an฀indicator฀of฀the฀extent฀of฀tobacco฀exposure฀during฀a฀smoking฀reduction฀ programme,฀ correlated฀ signiicantly฀ and฀ inversely฀ with฀ HDL฀ cholesterol฀ and฀ skinfold฀ thickness,฀ but฀ not฀ with฀ LDL฀ cholesterol฀ or฀ triglycerides฀ [230] .฀ The฀ less฀ an฀ individual฀ smoked,฀the฀greater฀was฀the฀increase฀in฀HDL฀cholesterol. Smoking฀during฀pregnancy฀has฀been฀found฀to฀produce฀signiicant฀differences฀in฀various฀ lipid฀parameters฀in฀the฀newborns฀of฀smoker฀mothers฀compared฀with฀the฀newborns฀of฀non- smoker฀mothers: Lower฀HDL฀cholesterol฀21฀vs.฀26฀mgdl •฀ Higher฀total฀cholesterolHDL฀cholesterol฀ratio฀4.7฀vs.฀3.7 •฀ Lower฀apolipoprotein฀A-1฀105฀vs.฀129฀mgdl •฀ Higher฀apolipoprotein฀B฀apolipoprotein฀A-1฀ratio฀0.44฀vs.฀0.3 •฀ Similar฀differences฀were฀also฀detected฀in฀the฀smoker฀and฀non-smoker฀mothers฀ [246] .฀In฀ adult฀ smokers,฀ the฀ deleterious฀ consequences฀ for฀ the฀ coronaries฀ are฀ attributable฀ to฀ the฀ changes฀in฀HDL฀cholesterol฀and฀apolipoprotein฀A-1฀levels฀ [226] . Attempts฀to฀use฀antioxidants฀vitamin฀C,฀a-tocopherol฀to฀reduce฀LDL฀oxidisability฀due฀ to฀ smoking฀ or฀ to฀ block฀ superoxide฀ anion฀ production฀ by฀ leucocytes฀ have฀ been฀ largely฀ unsuccessful฀in฀various฀studies฀ [247] ,฀as฀have฀been฀the฀efforts฀to฀reduce฀raised฀plasma฀ levels฀of฀soluble฀intercellular฀adhesion฀molecule-1฀sICAM-1฀or฀antibodies฀against฀oxi- dised฀LDL฀ [248] . During฀smoking฀cessation฀therapy฀with฀nicotine฀products฀in฀smokers฀attempting฀to฀quit,฀ triglycerides฀ and฀ HDL฀ cholesterol฀ are฀ increased฀ whereas฀ LDL฀ cholesterol฀ is฀ lowered฀ [249–251] .฀ Plasma฀ triglyceride฀ levels฀ after฀ smoking฀ cessation฀ have฀ shown฀ varying฀ responses:฀unchanged฀values฀have฀been฀found฀in฀some฀studies฀ [229,฀232,฀252,฀253] ฀whereas฀ a฀17.2฀reduction฀has฀been฀reported฀after฀6฀weeks฀of฀smoking฀cessation฀ [231] .฀Total฀cho- lesterol฀ rises฀ minimally฀ 2.2฀ [254] ,฀ and฀ HDL฀ cholesterol฀ more฀ markedly฀ 20–30฀ [231,฀254] .฀The฀extent฀of฀the฀rise฀in฀HDL฀cholesterol฀correlated฀with฀the฀type฀of฀diet,฀with฀ HDL฀cholesterol฀being฀increased฀more฀rapidly฀by฀a฀high-fat฀than฀a฀low-fat฀diet฀ [254] .

7.4.2 Diabetes and Smoking

People฀with฀diabetes฀have฀a฀tendency฀to฀develop฀complications฀simply฀because฀of฀their฀ underlying฀disease.฀The฀extensive฀body฀of฀smoking-related฀indings฀published฀during฀the฀ past฀two฀decades฀should฀make฀diabetic฀patients฀and฀the฀physicians฀who฀treat฀them฀ponder฀ seriously฀the฀implications฀of฀failing฀to฀quit฀smoking.฀Speciic฀complications฀said฀to฀be฀ “supported”฀by฀smoking฀include: Increasing฀insulin฀resistance •฀ Renal฀microangiopathy฀with฀increasing฀albuminuria •฀ Progression฀of฀atherosclerosis฀in฀the฀coronary฀arteries฀coronary฀heart฀disease,฀myocar- •฀ dial฀infarction,฀stroke฀ [255] ฀and฀the฀peripheral฀blood฀vessels฀peripheral฀arterial฀occlu- sive฀disease฀ [256] Research฀conducted฀in฀the฀Netherlands,฀USA฀and฀Japan฀suggests฀that฀cigarette฀smoking฀ should฀also฀be฀regarded฀as฀a฀risk฀factor฀in฀its฀own฀right฀for฀the฀development฀of฀type฀2฀dia- betes฀ [257–261] ;฀however,฀a฀cohort฀study฀in฀Great฀Britain฀has฀not฀corroborated฀this฀theory฀ [262] .฀It฀remains฀open฀to฀speculation฀whether฀ethnic฀or฀methodological฀differences฀in฀ characterising฀a฀person฀with฀diabetes฀might฀be฀responsible฀for฀these฀discrepant฀indings.฀ As฀demonstrated฀by฀the฀results฀from฀a฀large฀Japanese฀patient฀population฀Table฀ 7.5 ,฀a฀ statistically฀signiicant฀association฀exists฀between฀pack-years฀of฀cigarette฀smoking฀and฀the฀ risk฀for฀acquiring฀type฀2฀diabetes. The฀association฀between฀diabetic฀neuropathy฀and฀cigarette฀smoking฀has฀not฀been฀stud- ied฀extensively.฀However,฀diabetic฀patients฀with฀autonomic฀neuropathy฀have฀been฀shown฀to฀ have฀more฀profound฀vasoconstrictor฀responses฀to฀cigarette฀smoking฀than฀diabetic฀patients฀ without฀neuropathy฀or฀healthy฀controls฀ [263] ,฀assuming฀that฀the฀measured฀reductions฀in฀ skin฀temperature฀are฀acceptable฀correlates฀of฀blood฀low. Table 7.5 ฀฀฀Data฀on฀the฀relative฀risk฀for฀the฀development฀of฀non-insulin-dependent฀diabetes฀mellitus฀ as฀function฀of฀pack-years฀of฀smoking฀ [261] Pack-years Total฀ person-years Cases฀of฀type฀ 2฀diabetes Age-adjusted฀ relative฀risk฀฀ 95฀CI Relative฀risk,฀ multi-variate a ฀ 95฀CI 13,266 79 1.00 1.00 0.1–20.0 15,132 93 1.12฀0.82–1.69 1.22฀0.89–1.67 20.1–30.0 12,980 120 1.56฀1.17–1.81 1.57฀1.16–2.11 30.1–40.0 5,332 47 1.44฀1.00–2.64 1.55฀1.06–2.26 40.0 3,854 42 1.69฀1.15–2.49 1.73฀1.15–2.60 p฀for฀trend ฀ ฀ 0.0007 0.001 a Covariates:฀age,฀body฀mass฀index,฀alcohol฀consumption,฀physical฀activity,฀family฀history฀of฀diabe- tes,฀fasting฀glucose฀level,฀total฀cholesterol,฀triglycerides,฀HDL฀cholesterol฀and฀haematocrit Arteriosclerotic฀changes฀in฀the฀major฀vessels฀occur฀at฀an฀early฀stage฀in฀type฀1฀diabetic฀ patients฀ who฀ die฀ early฀ from฀ smoking฀ [264] .฀ Levels฀ of฀ circulating฀ adhesion฀ molecules฀ cAM฀are฀increased,฀and฀these฀ultimately฀inluence฀endothelial฀function฀and฀hence฀pro- mote฀the฀risk฀of฀cardiovascular฀disease฀ [265–267] .฀A฀study฀of฀the฀levels฀of฀circulating฀ intercellular฀adhesion฀molecule฀cICAM฀in฀type฀1฀diabetic฀patients฀without฀clinical฀mac- roangiopathy,฀in฀comparison฀with฀healthy฀controls,฀revealed฀raised฀plasma฀cICAM฀con- centrations฀ in฀ type฀ 1฀ diabetic฀ smokers,฀ with฀ the฀ highest฀ plasma฀ levels฀ +25฀ being฀ recorded฀in฀individuals฀smoking฀more฀than฀10฀cigarettesday฀ [268] .

7.4.2.1 Insulin Resistance

According฀to฀recently฀published฀indings,฀smoking฀may฀have฀a฀deleterious฀effect฀on฀insulin฀ activity฀both฀in฀healthy฀subjects฀ [269,฀270] ฀and฀in฀non-insulin-dependent฀diabetic฀NIDDM฀ patients฀ [271] .฀In฀addition,฀compared฀with฀non-smokers,฀non-diabetic฀smokers฀are฀insulin- resistant฀and฀exhibit฀hyperinsulinaemia฀ [272–275] .฀Furthermore,฀smokers฀display฀typical฀ signs฀ of฀ an฀ insulin฀ resistance฀ syndrome.฀ The฀ deviations฀ from฀ normal฀ metabolism฀ are฀ related฀to฀smoking฀habits฀ [272] .฀The฀progression฀of฀arteriosclerosis฀is฀directly฀and฀indi- rectly฀ fostered฀ by฀ compensatory฀ hyperinsulinaemia฀ [276] .฀ In฀ a฀ study฀ of฀ 28฀ non-obese฀ NIDDM฀smokers฀compared฀with฀12฀otherwise฀similar฀non-smokers,฀plasma฀insulin฀and฀ C-peptide฀responses฀to฀oral฀glucose฀load฀after฀fasting฀were฀signiicantly฀higher฀in฀smokers฀ than฀non-smokers,฀whereas฀glucose฀levels฀were฀not฀substantially฀different฀see฀Fig.฀ 7.1 .฀In฀ addition,฀the฀rate฀of฀total฀insulin-mediated฀glucose฀disposal฀depends฀on฀the฀number฀of฀ cigarettes฀smoked฀Fig.฀ 7.2 .฀Fasting฀glucose฀levels฀and฀HbA 1c ฀were฀also฀higher฀in฀smokers฀ than฀in฀non-smokers฀ [276] ,฀as฀relected฀in฀the฀propensity฀of฀these฀patients฀to฀develop฀dia- betic฀complications฀more฀often฀ [277] .

7.4.2.2 Diabetic Nephropathy

The฀effect฀of฀smoking฀in฀accelerating฀the฀progression฀of฀diabetic฀nephropathy฀has฀been฀ demonstrated฀ in฀ numerous฀ studies฀ [278–284] .฀ As฀ illustrated฀ by฀ the฀ data฀ presented฀ in฀ Fig.฀ 7.3 ,฀the฀effect฀on฀shortening฀survival฀is฀particularly฀evident฀in฀diabetic฀patients฀in฀ ฀end-stage฀nephropathy฀where฀the฀patient฀requires฀haemodialysis฀ [285] . Diabetic฀ nephropathy฀ is฀ characterised฀ primarily฀ by฀ a฀ decline฀ in฀ excretory฀ function฀ because฀of฀vascular฀damage฀caused฀by฀diabetes.฀In฀patients฀with฀type฀2฀diabetes,฀renal฀ damage฀additionally฀accelerates฀the฀progression฀of฀arteriosclerosis,฀as฀assessed฀in฀terms฀of฀ carotid฀artery฀intima-media฀thickness฀IMT฀ [286] .฀Whereas฀age฀and฀impaired฀creatinine฀ clearance฀lead฀to฀thickening฀of฀the฀carotid฀artery฀wall฀p฀£฀0.001,฀the฀duration฀of฀diabetes฀ and฀smoking฀status฀were฀found฀to฀affect฀the฀femoral฀artery฀p฀฀0.0001฀ [286] . An฀early฀sign฀of฀nephropathy฀is฀the฀onset฀of฀microalbuminuria฀ [287–289] ,฀accompa- nied฀in฀addition฀by฀increased฀numbers฀of฀free฀radicals฀in฀plasma.฀In฀insulin-treated฀dia- betic฀ patients,฀ albumin฀ excretion฀ is฀ already฀ triggered฀ by฀ smoking-related฀ glomerular฀