Insulin Resistance Diabetic Nephropathy

hyperiltration฀ [282] ,฀a฀phenomenon฀that฀has฀been฀shown฀to฀correlate฀with฀the฀number฀of฀ cigarettes฀ smoked฀ Fig.฀ 7.4 .฀ Nowadays,฀ therefore,฀ alongside฀ the฀ coronary฀ system,฀ the฀ kidneys฀should฀be฀viewed฀as฀the฀second฀organ฀system฀endangered฀by฀the฀harmful฀effects฀ of฀smoking.฀Cigarette฀smoking฀encourages฀the฀progression฀of฀nephropathy฀in฀both฀type฀1฀ and฀type฀2฀diabetes฀ [290] .฀In฀contrast฀–฀although฀a฀subject฀of฀controversy฀in฀the฀past฀–฀asso- ciations฀have฀not฀necessarily฀been฀found฀between฀diabetic฀retinopathy฀and฀cigarette฀smok- ing฀see฀Sect.฀7.2.1.฀In฀a฀1-year฀prospective฀study,฀nephropathy฀progression฀was฀detected฀ in฀53฀of฀smokers฀and฀33฀of฀ex-smokers,฀compared฀with฀only฀11฀of฀non-smokers฀ [291] .฀ Similar฀ results฀ have฀ been฀ obtained฀ in฀ smokers,฀ based฀ on฀ self-reported฀ smoking฀ behaviour฀ [279] .฀An฀investigation฀conducted฀in฀574฀type฀2฀diabetic฀patients,฀aged฀40–60฀ 500 450 400 350 300 250 200 150 100 50 −30 30 60 90 120 150 180 210 240 270 300 −30 1,0 2,0 3,0 30 60 90 120 150 180 210 240 270 300 Time [min] Time [min] p 0,001 p 0,01 Plasma insulin [pmoll] Plasma C-peptide [nmoll] Fig. 7.1 ฀฀฀Plasma฀insulin฀and฀ C-peptide฀concentrations฀in฀ fasting฀NIDDM฀patients฀and฀ effect฀of฀oral฀glucose฀loading฀ with฀75฀g฀ [276] .฀Open฀circle฀ non-smokers;฀illed฀circle฀ smokers 40 30 F-ANOVA = 6,8; P 0,001 20 Insulin-mediated total glucose disposal [µmolmin x kg FFM] 10 0 n=12 Number of cigarettes smoked per day 10 n=5 10–19 n=10 20 n=13 Fig. 7.2 ฀฀฀The฀rate฀of฀total฀ insulin-mediated฀glucose฀ disposal฀in฀relation฀to฀the฀ number฀of฀cigarettes฀smoked฀ per฀day฀ [276] 100 [] 50 Survival rate [] Smoker n = 22 Nonsmoker n = 30 1 2 3 4 Years 5 Fig. 7.3 ฀฀฀Five-year฀survival฀rate฀ of฀diabetic฀non-smokers฀and฀ smokers฀requiring฀dialysis฀ therapy฀for฀advanced฀ ฀nephropathy฀ [293] Fig. 7.4 ฀฀฀Mean฀nocturnal฀ urinary฀albumin฀excretion฀in฀ patients฀with฀type฀1฀diabetes,฀ classiied฀on฀the฀basis฀of฀ smoking฀habit฀ [285] .฀The฀ vertical฀bars฀show฀the฀ standard฀error 6 5 4 3 2 1 Urinary albumin excretion [µgmin] p 0,003 Non-smokers light smokers smokers 100 ng Cml n=166 100–500 ng Cml n=26 500 ng Cml n=46 years,฀identiied฀slightly฀raised฀blood฀pressure,฀slightly฀raised฀total฀cholesterol฀and฀HbA 1c ฀ as฀risk฀factors฀for฀the฀development฀of฀diabetic฀nephropathy฀ [292] . Smoking฀among฀adolescents฀with฀type฀1฀diabetes฀is฀associated฀with฀an฀increase฀in฀mor- tality฀and฀hospital฀admissions,฀including฀number฀of฀treatment฀days,฀and฀these฀patients฀feel฀ “unwell”.฀Since฀details฀on฀smoking฀behaviour฀provided฀by฀diabetic฀patients฀are฀known฀to฀ be฀imprecise฀and฀unreliable,฀urinary฀cotinine฀measurements฀have฀proved฀useful฀for฀moni- toring฀cigarette฀consumption฀ [293] .฀According฀to฀the฀results฀summarised฀in฀Fig.฀ 7.3 ,฀fol- lowing฀assignment฀to฀groups฀on฀the฀basis฀of฀urinary฀cotinine฀excretion฀the฀smoking฀status฀ of฀type฀1฀diabetic฀patients฀correlated฀with฀the฀extent฀of฀renal฀albumin฀excretion฀ [293] . Blood฀pressure฀in฀type฀1฀diabetics฀is฀increased,฀depending฀on฀the฀number฀of฀cigarettes฀ smoked฀ [281,฀294] ;฀however,฀these฀indings฀have฀been฀contested฀ [293] .฀In฀contrast,฀passive฀ smoking฀by฀children฀and฀adults฀has฀been฀shown฀to฀have฀adverse฀implications฀for฀the฀pro- gression฀of฀diabetes฀e.g.฀based฀on฀HbA 1c ฀measurements฀ [295] . Overall,฀the฀medical฀profession฀should฀seriously฀urge฀men฀and฀women฀with฀diabetes฀to฀ give฀up฀smoking,฀particularly฀since฀the฀progression฀of฀the฀disease฀has฀been฀shown฀to฀be฀ accelerated฀by฀smoking,฀as฀conirmed฀by฀major฀national฀studies฀ [259,฀296] .

7.5 Gastrointestinal Tract

According฀to฀one฀older฀study฀in฀456฀patients,฀associations฀were฀found฀between฀gastroin- testinal฀disease฀and฀ingestion฀of฀aspirin฀or฀non-steroidal฀anti-inlammatory฀drugs฀NSAIDs,฀ but฀no฀correlations฀were฀detected฀with฀smoking฀or฀alcohol฀ [297] .฀Smoking฀is฀known฀to฀ modify฀the฀blood฀glucose฀response฀to฀an฀oral฀glucose฀load,฀possibly฀by฀altering฀gastroin- testinal฀tract฀motility:฀this฀is฀relected฀in฀higher฀serum฀motilin฀a฀hormone฀secreted฀by฀the฀ stomach฀in฀smokers฀than฀in฀non-smokers฀ [298] .

7.5.1 Oesophageal Cancer

After฀lung฀cancer,฀cancers฀of฀the฀oesophagus฀are฀the฀commonest฀smoking-related฀tumours฀ [299,฀ 300] .฀ One฀ possible฀ cause฀ is฀ thought฀ to฀ be฀ the฀ UDP-glucuronyltransferase฀ 1A7฀ UGT1A7฀system฀which฀detoxiies฀tobacco฀carcinogens;฀this฀is฀genetically฀altered฀in฀vari- ous฀individuals,฀and฀the฀risk฀for฀orolaryngeal฀cancers฀is฀increased฀in฀subjects฀with฀low- activity฀UGT1A7฀genotypes฀who฀are฀heavy฀smokers฀OR฀=฀6.1;฀CI:฀1.5–25฀or฀light฀smokers฀ OR฀=฀3.7;฀CI:฀1.1–12฀ [301] .฀In฀addition,฀tobacco฀smoke฀is฀regarded฀as฀the฀target฀for฀the฀ p53฀gene฀ [302] .฀These฀tumours฀are฀caused฀by฀contact฀carcinogens,฀particularly฀since฀these฀ are฀condensed฀in฀the฀pharynx,฀then฀cleared฀by฀the฀lungs฀and฀transported฀to฀the฀oesophageal฀ mucosa฀where฀they฀produce฀neoplasia฀ [303] . The฀risk฀of฀oesophageal฀cancer฀increases฀with฀duration฀of฀smoking฀and฀falls฀following฀ smoking฀cessation,฀as฀has฀been฀conirmed฀in฀a฀US฀study฀OR฀=฀2.1,฀and฀the฀risk฀is฀some- what฀reduced฀by฀ilter฀cigarettes฀compared฀with฀non-ilter฀cigarettes฀ [304] .฀In฀a฀multi-ethnic฀ study,฀current฀cigarette฀smoking฀was฀a฀signiicant฀risk฀factor฀for฀oesophageal฀cancers:฀the฀ association฀ was฀ strongest฀ for฀ oesophageal฀ adenocarcinomas฀ OR฀ =฀ 2.80;฀ CI:฀ 1.8–4.3,฀ intermediate฀for฀gastric฀cardia฀adenocarcinomas฀OR฀=฀2.12;฀CI:฀1.5–3.1,฀and฀weaker฀for฀ distal฀gastric฀adenocarcinomas฀OR฀=฀1.50;฀CI:฀1.1–2.1฀ [305] .฀In฀the฀USA,฀80฀of฀cases฀ of฀ oesophageal฀ cancer฀ observed฀ in฀ the฀ 1990s฀ were฀ related฀ to฀ smoking.฀ Alcohol฀ intake฀ potentiates฀the฀carcinogenic฀effect฀of฀smoking฀ [306,฀307] .฀The฀odds฀ratio฀for฀adenocarci- noma฀of฀the฀distal฀oesophagus฀for฀current฀smokers฀has฀been฀reported฀at฀2.3฀CI:฀1.4–3.9฀ compared฀with฀1.9฀for฀ex-smokers฀CI:฀1.2–3.0.฀Drinkers฀four฀or฀more฀glasses฀of฀whisky day฀also฀have฀an฀odds฀ratio฀of฀2.3฀CI:฀1.3–4.3,฀and฀an฀additive฀effect฀of฀alcohol฀and฀ smoking฀is฀likely฀ [308] .

7.5.2 Gastrointestinal Ulcers

Peptic฀ulcers฀show฀a฀particular฀association฀with฀smoking,฀as฀demonstrated฀by฀a฀wealth฀of฀ publications฀in฀the฀literature฀from฀the฀1950s฀to฀the฀1980s.฀According฀to฀one฀meta-analysis,฀ 24฀of฀all฀peptic฀ulcers฀are฀attributable฀to฀NSAIDs,฀48฀to฀Helicobacter฀pylori฀and฀23฀ to฀ cigarette฀ smoking฀ [309] .฀ Women฀ who฀ smoke฀ are฀ twice฀ as฀ likely฀ as฀ non-smokers฀ to฀ develop฀peptic฀ulcers,฀and฀it฀is฀estimated฀that฀approximately฀20฀of฀incident฀peptic฀ulcer฀ cases฀among฀US฀women฀are฀attributable฀to฀cigarette฀smoking฀ [310] .฀A฀larger฀Polish฀study฀ conducted฀in฀eight฀different฀regions฀underlines฀these฀indings฀ [311] ,฀although฀other฀authors฀ consider฀smoking฀unlike฀Helicobacter฀pylori฀infection฀not฀to฀be฀an฀independent฀factor฀ for฀ulcer฀development฀ [312] . On฀the฀basis฀of฀endoscopy฀indings,฀an฀association฀has฀been฀reported฀between฀cigarette฀ smoking฀and฀Helicobacter฀pylori฀infection฀ [313] ,฀with฀the฀result฀that฀increased฀susceptibility฀ to฀Helicobacter฀pylori฀may฀be฀assumed.฀Gastritis฀caused฀by฀Helicobacter฀pylori฀or฀by฀smok- ing฀is฀associated฀with฀reduced฀concentrations฀of฀the฀intragastric฀epidermal฀growth฀factor฀ EGF,฀a฀substance฀found฀in฀the฀mucosa฀and฀produced฀in฀increased฀quantities฀when฀ulcers฀ develop;฀however,฀this฀growth฀factor฀did฀not฀play฀a฀role฀in฀the฀pathogenesis฀of฀duodenal฀ulcer฀ [314] .฀Experimental฀animal฀work฀indicates฀that฀smoking฀reduces฀EGF-induced฀angiogenesis฀ and฀delays฀ulcer฀healing฀ [315] .฀In฀addition,฀smoking฀depresses฀gastric฀mucosal฀blood฀low฀as฀ well฀as฀the฀production฀of฀NO฀by฀inhibiting฀NO฀synthase฀ [316] . One฀study฀from฀Spain฀in฀Helicobacter฀pylori-positive฀patients฀did฀not฀reveal฀any฀asso- ciation฀between฀Helicobacter฀pylori฀infection฀and฀alcohol฀consumption฀or฀smoking฀ [317] .฀ Smoking฀was฀also฀not฀an฀additional฀risk฀factor฀for฀dyspepsia฀ [318] .฀Where฀smokers฀had฀ successfully฀undergone฀therapy฀to฀eradicate฀Helicobacter฀pylori,฀cigarette฀smoking฀did฀not฀ increase฀the฀recurrence฀of฀peptic฀ulcers฀ [319] . Duodenal฀ulcers฀are฀also฀provoked฀by฀smoking,฀and฀smokers฀have฀been฀reported฀to฀ have฀more฀relapses฀and฀bleeding฀episodes฀than฀ex-smokers฀or฀non-smokers฀63.3฀vs.฀31.2฀ vs.฀34.5฀for฀relapses.฀Ulcer฀bleeding฀occurred฀in฀smokers,฀but฀not฀in฀response฀to฀nicotine฀ intake฀ [320] .฀It฀has฀been฀established฀that฀smoking฀encourages฀the฀development฀of฀duode- nal฀ ulcers฀ by฀ inhibiting฀ duodenal฀ mucosal฀ bicarbonate฀ secretion,฀ an฀ important฀ defence฀ mechanism฀against฀acid฀and฀peptic฀damage฀ [321] .฀Moreover,฀serum฀pepsinogen฀I฀levels฀ are฀elevated฀in฀smokers฀because฀of฀augmented฀pepsin฀secretory฀capacity฀ [322] .