Am ee ‘amine, and the tumor should be removed as soon a the diagnosis ie onimed. The pregnancy need not be terminated, but the operative procedure itself may result in spontaneous abortion. In the third t- ester, treatment with adrenergic blocking agents should be under taken; when the fetus is of suliient size, cesarean section may be {ollowed by extirpation ofthe tumor. Although the safety of adrenergic blocking drugs in pregnancy i not established, these agents have been administered in several case without obvious adverse eft, Ante- partum diagnosis and treatment lowers the maternal deat rate fo that Spoahing sone pheodomocyoms patents; fal ea WRESTLE NO WALIGUAITTOMORS In cages of metastatic o locally in- vasive tumor in patients with intercurrent iiss that precludes sur gery long-term medical management is required. When the manifes- tations eannot be adequately contolled by adrenergic blocking agent, the concomitant administration of metyrosine may be required. This agent inhibits tyrosine hydroxylase, diminishes catecholamine pro- 956, the recurence rates = 10%. After succesful surgery, catecholamine excretion retums to normal in about 2 weeks and should bbe measured to ensure complete tumor removal. Catecholamine ex- ction shouldbe asested a the reappearance of uggestive symptoms or yearly if the patient remains asymptomatic. For malignant pico thromocytoma, the 5-year survival rte is usually Sine t Tine ean) pj a = Phage | So | aoctee | ton ros) i FIGURE 323-1. specram of gcse hamesssis aa dobetes metus (ON). The ‘pectin for noma qucose flee to dabetes ype? OM, tpe 2D aber Specie pes of sabes ne esatonal Mi sown fom eh 0h. mae ups of Me real vests fom oma guar lane ogee gcse tare to oven eae. row ne at ehnges in cv eer Maybe beeen in some pe sf eobete far example, ale nth te 2M may rear tthe nga gzasetleanecteary wth mgt oss gestational OM sees my eer ngage toler or even vom gee tres te er The astg pasa gore (PG) a 7-r plasnn gcse (0), ser 2 Sluee ctlege fr We everest xegones of ues ‘alan, we sown che lowes of te Eure These ves oe appt the Capos of gesatonal DY Some {pes of DM may a ay ot rege ii fx sa, ere the ged ee. (Goel us a tee the gue) lated from keron Diabetes Ae ‘tn 2004) in insulin action and/or secretion give rise to the common phenotype ‘of hyperglycemia in type 2 DM (sce below), Distinct pathogenic pro ‘estes in type 2 DM have important potenil therapeutic implications, as pharmacologic agents that target specifi metabolic derangementsTABLE S251 sien of bts welts 1 Type | dabees (pel desrution, usally leading to abso inslin hee) ‘A Tene edited 3. Wopanse 1. Type 2 abetes (ray range fom predominantly inslin resistance wih relive instin deiieney to a predominant secretory defect ‘oth nin revises) UL Other specie ype of diabetes ‘A. Gente defects of fell incon cacaterized by mutations i 1 Hepatoytemicea anseripion factor HNP) 4a (MODY 1) 2 Ghocokinase QODY 2) 5. HNE-ta (toDy 5) 4 Insulin promoter factor (PE) 1 (MODY 4) 5. HNEAB (MODY 5) NewoD1 (MODY 6) 7. Mitoehondial DNA, 4 Pree orion cone B. Genetic defects in inva ution 1 Type A insulin ressance 2 Lepechatism 5. Rabron Menderll syndrome 4 Lapodyatiophy syndromes C. Diseates of the exoeszepuneeas—pancreatis,pancteatectoy, eoplasia eye Atos emocomatonis, Geocelclous pak= ‘eaiopatiy DD. Endocrnopahion— acromegaly, Cushing's syndrome, pacaton coms, pheorbromocyioma, bypertisriion, somatoatnoma, A owconom 1 Drug. or chemicabindoeed—Vacor, pentane, scone ai ivoconicods, thyroid hormone, dazoxiée, G-adrenerpie ago Sse haar, phenyoin, ainerleron, potas ito apne, bea Blockers Infecions—congenial rubella, ytomegiovius,coxsackic Uncommon forms of inne edited dibees—"¥i-man syndrome, ant nea eeptrantbocier 1. Other ence syndromes tometer atpcaed with dabeles— Down's sjadrone, Klisester's syndrome, Tuer syadome, Woltam’s syndome, Fvdreih's ataxia Huntington's chores Laurence Moa Biel syndrome, myotonic éystophy. porphyrin, Prades Will pyro 1V. Gestational latter melas (GDM) om have become available. Type 2 DM is preceded by a period of abnor- ral glacose homeostasis classified as impaired fasting glucose (FG) or impaired glucose tolerance (IGT). ‘Two feasres ofthe curent classification of DM diverge from pre- vious elasisiations, ist, the terms insulin dependent diabetes mel Litas (DDM) and noninsuln-dependent diabetes mellitus (NIDDM) are obsolete. Since many individuals with type 2 DM eventually quire insulin teatment for conizol of glycemia, the se of the term NIDDM generated considerable confusion. A second difference is that, age is nol a enerion in the classiieation system. Although type 1 DM. most commonly develops before the age of 30, an autoimmune beta cell destructive process can develop at any age. I is estimated that between 5 and 10% of individuals who develop DM ater age 30 have type 1A DM. Likewise, ype 2 DM more typically develops within creasing age, but it also occurs in chien, particularly in obese ado. leseents OTHER TPES OF DM Other etiologies for DM include specific genetic detest in insulin secretion or action, metabolic abnormalities thai pair insulin secretion, mitochondrial abnormalities, and a host of con- ditions that impair glucose tolerance (Table 323-1), Maturity onset diabetes ofthe young (MODY) is a subtype of DM characterized by autosomal dominant inheritance. early onset of hyperglycemia, and Impairment in insulin secretion (discussed below). Mutations in the ‘nln receptor cause a group of rare disorders characterized by severe insulin resistance DM can rel 1 pancreatic exocrine disease when the majority of pancreatic islets (>80%) are destroyed. Hormones that antagonize the action of insulin can lead to DM, Thus, DM is often a feature of ‘endocrinopathies, such as acromegaly and Cushing's disease. Viral infetions have been implicated in pancreatic islet destruction but are an extremely tre cause of DM. Congenital rubella greatly increases the risk for DM: however, most of theee individual also have im- ‘munologie markers indicative of autoimmune beta ell destruction, GESTATOKAL DIABETES MELLTUS (GDM) Glucose intolerance may de- velop during pregnancy. Insulin resistance related to the metabolic ‘changes of late pregnancy increases insulin requirements and may lead 1oIGT. GDM occurs in approximately 4% of pregnancies inthe United States; most women revert to normal glucose tolerance post-parcum but have a substantial risk (30 to 60%) of developing DM later in lite EPIDEMIOLOGY “The workdwide prevalence of DM has risen dramatically over the past too decades. Likewise, prevalence rates of IFG are also increasing Although the prevalence of both type I and type 2 DM is ineeasing worldwide, the prevalence of type 2 DM is expected to rise more "apidly inthe future because of increasing obesity and reduced activity levels. DM increases with aging. In 2000, the prevalence of DM was ‘estimated to be 0.19% in people <20 years old and 8.6% in people 20 years old, In individ 65 years the prevalence of DM was 20.18. The prevalence ie similar in men and women throughout most age ranges bul is slightly greater in men >60 years, ‘Thete i considerable geographic variation in the incidence of both \ype I and type 2 DM. Scandinavia has the highest incidence of type DM (, in Finland, the incidence is 35/100,000 per yea). The Pacific Rim has a much ower rate (in Japan and China, the incidence is 1 to 3/100,000 per yeas) of type 1 DM: Norther Europe and the United States share an intermediate rate (8 to 17/100,000 per year ‘Much of the increased risk of type 1 DM is believed to reflect the Frequency of high-risk HLA alleles among ethnie groups in different geographic locations. The prevalence of type 2 DM and its harbinger, IGT is higher in certain Pacific islands, intermediate in countrce sich ts India andthe United States, and relatively low in Russia and China This variability is likely due to genetic, behavioral, and envionment, factors. DM prevalence also varies among different ethnic populations ‘within a given country. In 2000, the prevalence of DM in the United States was 139 in African Americans, 102% in Hispanie Americans 5.5% in Native Americans (American Indians and Alaska natives) and 7.8% in non-Hispanic whites. The onset of type 2 DM occurs, on average, at an easter age in ethnie groups other than non Hispanic whites. DIAGNOSIS ‘The National Diabetes Data Group and World Health Organization hhave issued diagnostic criteria for DM (Table 323-2) based on the following premises: (1) the spectrum of fasting plasma glucose (FPG) tnd the response to an orl glucose load varies among normal indi- TABLE 325-2 Cite forte Digi of Dies Mei Symptoms of dibetes plas andom bod gcos concentration =11.1 mmol (200 mello + Fading plasma grove 270 mmol. (126 mei)? or + Twotbou plana glucose =111 mmol (200 mpl) daring an oral gleose toetanee tsFr ee vidusls, and (2) DM is defined asthe level of glycemia al which dia- Ietesspeciic complications occur rather than on deviations from a population-based mean. For example, the prevalence of retinopathy in [Native Americans (Pima Indian population) begins to increase at 2 FPG > 6.4 mmolf. (116 mg/dl) (Fg. 323-2) Glucose tolerance is classified into three categories aed on the FPG: (1) FPG < 5.6 mmol. (100 mg/dL.) is considered normal (2) FPG = 5.6 mmol/L. (100 mg/dL) but <7.0 mmo. (126 mgldL) is, 80% (Canenton ns lend aoe sewed te Tae) (pga 202 dean Diatetes fesacn Fam Dele Car 25S) 85-80, 202) DM may be present for up to a decade before diagnosis, (3) as many a8 505% of individuals with type 2 DM have one ot more diabetes specific complications atthe me of their diagnosis, and (4) ueatment of type 2 DM may favorably alter the natural history of DM. The ‘American Diabetes Association (ADA) recommends srcening alli dividuals 45 years every 3 years and sereening individuals with ad ional tsk factors (Table 325-3) atan eater age. Th contrast to type 2 DM, along asymptomatic period of hyperglycemia is rare prior to the diagnosis of type 1 DM, A number of immunologie markers for type 1 DM are becoming available (discussed below), bat their rousine use is discouraged pending the identification of clinically beneficial {interventions for individuals at high vsk for developing type DML INSULIN BIOSYNTHESIS, SECRETION, AND. ACTION BIOSYNTHESIS insulin is produced in the beta cells ofthe pancreatic islets, Ite inilly synthesized as a single chain 86-amino acid pre curtor polypeptide, preproinulin, Subsequent proteolytic processing removes the aminoterminal signal peptide. giving ise to proinsulin, Proinsulin is suerually elated to insti like growth factors Tana T, ‘which bind weakly tothe insulin receptor (Chap. 317), Cleavage of an internal 3T-eside fragment from prosulin generates the C pep- tide and the A 21 amino acids) and B (30 amino acids) chains of insulin, which are connected by disulide bonds. The mature insulin molecule and C peptide are stored together and coseceted from se creiory granule inthe beta cll. Because the C peptide i lest #as- ceptible than insulin to hepatic degradation, i s a useful marker of, insulin secretion and allows discrimination of endogenous end exog: ‘enous souree® of insulin in the evaluation of hypoglycemia (Chap 5324), Human insulin is now produced by recombinant DNA technol ogy; structural alterations atone or more residues ae useful for mod: ifying its physical and pharmacologiecharacterisis (see below) SECRETION Glucose is the key regulator of insulin secretion by the pancreatic beta cel. although amino acids, ketones, various tren {asroinestinal peptides, and neurotransmites also influence insulin fecreson, Glucose levels >3.9 mmoV/. (70 mg/dL) simulate insulin synthesis, primarily by enhancing protein translation and processing Glucose stimulation of insulin seertion begins with ts teanspor into the beta cell by the GLUT2 glucose transporter (Fig. 323-3), Glucose phosphorylation by glucokinase i the rate-limiting step that contols licoze-egulatedinrulin secretion, Farther metabolism of glucose-S- phosphate vis glycolysis generates ATP, which inhibits the activity of an ATP-sensitive K’ channel. This channel consists of two separate proteins: one isthe receptor for certain oral hypoglycemic (eg. sl fonyluseas, meghtinides; the oter isan inwardly rectifying K~ has nel protein. Inhibition ofthis K~ channel induces beta cell membrane Aepolasization, which pent vollage-dependent caeiam channels (eading to an influx of calcium), and stiulates insulin seeretion. In sulin secretory profiles reveal a pulsatile pattem of hormone release, ‘with small secretory bursts occuring about every 10 min, superim posed upon greater amplitude oscillations of about $0 to 150 min Meals or other major stimuli of insulin secretion induce large (four TABLE 3 ik eters fo Tpe 2 Dihtes Melis + amily history of diabetes (Le. parent sibling with type 2 diabetes) + Obesity (BM = 25 kg) {+ Habito pyielinasvcy + Racefetety (eg. Afean American, Hispanic American, Naive ‘Ameriean, Asian Americ, Pai alan) + Previously identied IEG or IGT History of GDM or delivery of baby > kg (29 1) + Hypertension (lod pressure = 140/90 malig) + HDL cholestrol level = 35 mga. (090 mmol) andor a eglyeeide level =250 gil (2.82 mmol) 1+ eljeysteovaysyndcome or aeuabons nsgrcans History of vase dense ‘Note BOL ody ats ed IF, npc tng gc: IGT. epee ie: earn es ly HD ih riATP-tanetive iM channe! Depolanzaion cose FIGURE 323-3. asetes an snomaiies i gcose-stinuned inn see, Guease and tar rates repute sun Seen by the sues bets cl (see waegoned byte SLs gee spore, sanegune ue ebm by he beta el ates en chanel att, dng tal secen. The SUR receptor ‘ne Binding at or rane et 3 sn serge. Mins eve e prees unaeines are hse arty ose abe fhe young (MODY) 2 ihr far fabs 0 safle ee AP, aes esha: AP drone dnaspite(Acapced fom ML Love, i Jmeson (ed). Pacles of HeleclrWeatine, Tetoue, W, Humane, 188) to fivefold inezease versus basline) busts of insulin secretion that ‘usually las for 2 10 3h before retuming to baseline. Derangementsin these normal teeetory pater ae one ofthe earliest signs of beta cell FHGune 323-4 cise balance between hepatic glucose production and peripheral glucose up- {ake and uilization, Insulin i the most important regulator of this metabolic equilibrium, bat neural input, metabolic sinnals, and hormones (eg, elucagen) result in integrated contol of glocose supply and utilization (Chap. 324; see Fig. 324-1), Inthe fasting sate low i sulin levels inrease glucose production by promoting hepatic gluconeogenesis Cela pres adie wl wey ke tension guthay ia slat mae. The sue apa Bas ise ose Kase ety an eras wie rece sustres (RS an She) eA rabef "cokg e's dt hast mete acs of sun (GO-2, 505, SAP? 65, 0, ad pospaiynastl= Kase @-3-rase). nln eases uss ase ugh -)-tnse an he Cl pathy, ahi poets trolcatin of Itaclr vesies cating LUT gst rrspoer to te pasma membrane. (Aged fom ML ue, in Piles of Molec Weae, ome felts, My Hunan, 198; A Pana ea) hn vest 10952 1988 For cesar ee Sate and Kb, 2601)ra ee Immunologie ‘nage Immune abrormattos canstic sreispcsion' _Prgreseve inpament 100 ‘linen raze 5 a 7 2 "Honeymoon ie reas i i ese ob ; ny rey te 35 eg lt eto ge es at 2 genet pespeston ae esse to ar mutloge nger litte an Tetnmure proces, resign gral deci n ea cel ms. The deena Spe tthe betel mss ees moe rai The props npimer fn fees vests datees ween “HD of Ge Bea eel mash estes. & "Senymosr ae maybe seni te fet or yes er thee of eaoees ‘rds wescsas three nan recoremes. get rem led! Maree Ime of Te 1 Diabetes, 36 ed 18 Siler (eq). Alena, VA, Amerie Dube: Sissel, 1988) 4s the autoimmune process destroys the remaining beta ces, and the individual becomes completely insulin deficient, ‘GEVETIC CONSIDERATIONS Genetic suscep to type 1A DM involves muliple genes. The concordance of type 1A DM in identieal twins ranges between 30 and 70%, indiatng that additional rodiying faciore mist be involved in determining whether diabetes 75%) diagnosed with nev-onset type 1A DM, in& significant minority of individuals with newly diagnosed type 2 DM (5 to 10%), and occasionally in individ: tals with GDM (5%). ICAs are present in 3 to 4% of first-degree fclatives of individuals with type 1A DM. In combination with in paired insulin secretion alter intravenous ghicose tolerance testing, they predict a 2508 risk of developing type 1A DM within 5 years, ‘Without thie impairment in ineulin secretion, the presence of ICA: predits «5-year risk of <25%, Based on these dat, the risk of is. fegree relative developing type 1A DM is relatively low, At presen, the measurement of ICA‘ in nondiabetic individuals isa resezch ool because no teatments have been approved to prevent the occurrence or progression of type 1A DM. Enviromental Factors Numerous environmental events have been pro: poted to tigger the autoimmune process in genetically sutcepsble individuals; however, none have been conclusively linked to diabetes, entiication of an environmental trigger has been diffielt because the event may precede the onset of DM by several years (Fig. 323-5), Putative environmental riggers include viruses (coxsackie and rubella ‘ott prominently), bovine milk proteins, and nitosourea compounds Preven of Type 1A DM A numberof interventions have successfully delayed or prevented diabetes in animal models. Some interventions have targeted the iamune system dteetly (munosuppression, sleetive coll subset deletion, induction of imminologic tolerance to islet proteins), whereas others have prevented islet cell death by blocking cytotoxic eytokines or increasing islet resistance othe destructive pro- cess, Though resulis in animal models ae promising, these interven- tons ave not heen successful in preventing type 1A DM in humans ‘The Diabetes Prevention Trial—type 1 recently concluded that ad ministering insulin to individuals thigh risk for developing type 1A. DM did not prevent ype 1A DM. PE 2 DM Inslin sesistance and abnormal ntlin secretion ate ce teal tothe developmeatof pe 2 DM. Although controversy remains regaring the primary defcl, mos susie support the Wiew that nsulin resistance precedes insulin sceetory defect and that diabetes develops ny it inslin secretion becomes inadequate § GENETIC CONSIDERATIONS Type 2 DM has a strong genetic com onent, Major genes that predispose to this disorder have yet be identi, bot ti clea tha the disease ve polygense and ma torial Various genetic loci conte to sucepsibility, and enviton mental factors (suchas nition and physical activity) farther mod~ Inte phenotypic expression of the diease The concordance of type 2 Min identical twine i Between 70 and 90%. Individoals wih a parent with type 2 DM have an inereased risk of diabetes: if both patents ave type 2 DM, the risk approaches 40%, Insulin resistance, 35 demonstrated by redveed glucose ubiizaton in skeletal muscle, i present in many nondiabetic, frs-degre relatives of individuals with {ype 2 DM. However, defnition ofthe genetic susceptibility remains a challenge because the genetie defect im insulin seeretion of action ‘hay not manifest elf unless an environmental event or another ge- ete defect, such as obesity, is superimposed. Mutations im various rmolecules involved in insulin action (eg the insulin receptor and enzymes involved in glucose homeostasis) account for avery small fraction of type 2 DM, Likewise genetic defects in proteins involved in inslin seeetion have ot been found in mos individcls with ype 2.DM. Genome-wide scanning for mutations or polymerphisms a Soriated with type 2 DM is being wsed in an effort to identify genes ‘stocited with ype 2 DM. The gene forthe protease, alpin 10, i associated with type 2 DM in Hispanie and some other populations. Pathophysiology ‘Type 2 DM is characterized by three pathophysio. loge abnormalities: impaited insulin secretion, perigheta insulin 4e- sistance, and excessive hepatic glucose production. Obesity, particu larly viteral or ented (at evidenced by the hip-wais ratio), i very ‘conimon in type 2 DM. Adipocytes secrete a numberof biologic prod ucts leptin, TNF-a, ftee fatty acids, resistin, and adiponectin) that ‘modulate insulin secretion, insulin ation, and body weight and may Contribute tothe insulin resistance. In the early stages of the disorder, lucoge tolerance remains normal, despite insulin resistance, because the pancreatic beta cells compensate by increasing insulin ouput (Fg. 323-6). As insulin resistance and compensatory hyperinsulinemia pro {ret the pancreatic islets in certain individuals ate unable to sustain the hyperinsulinemie state. IGT, characterized by elevations in post: prandil glucose, then develops. A further decline in insulin seeretion land an increage in hepatic glucore production lead to overt diabetes ‘with fasting hyperglycemia, Ulimately, beta eel faire may ensve “Markers of inflamnation suchas TL-6 and C-reactive protein ae often elevated in type 2 diabetes. Metabeli Abnarmalties a (SUN RESISTANCE The decreased ability ofin- sulin o act effectively on peripheral target tissues (especially muscle tnd Liver) i# 4 prominent feature of type 2 DM and results from a combination of genetic susceptibility and obesity Insulin resistance is relative, however, since supermormal levels of eixculatng insulin will, ‘mule the plasma glucose, Insulin dose-response curves exhibit a rightward shi, indicating reduced sensitivity, and a reduced maximal response, indicating an overall decrease in maximum ghicoseutiliza- tuon (30 to 60% lover than normal individuals). Inulin resistance impairs glucose ulzaton by insulin sensitive atues and increases hepatic glucose output; oth effects contribute to the hyperglycemi 2157 Insuin Senstvy value amatnin perks) FIGURE 323-8 Mette changes dvieg te ceveoper’ type 2 dabtes melts (0M) sin secretin an sn este reat, a 2a al econes tore isin essa (by movg fom oa Ato pa), sn seein ree. Iigive compete by cen he sn econ els aly ged sluasewletace (pa are uma ape? OM an Dated jam ‘SE ta, in Eas ead #6447, 201, Bergman key, Tends Fae a Mee 1.351, 2000) Increased hepatic glucose outpu predominantly account for increased FPG levels, whereas decreased peripheral glucose usage rerlls in postprandial hyperglycemia. In skeletal muscle, there isa greater im pairment in nonoxidatve glucose usage (glycogen formation) than in ‘oxidative glucose metabolism through glycolysis. Glucose metabolism in insulin independent issues isnot altered in type 2 DM. “The precise molecular mechanism of insulin resistance in type 2 DM has not been elucidated, Insulin receptor level and tyrosine kinase activity in skeletal musele are reduced, but these alterations are most likely secondary to hyperinsulinemia and are not a primary defect. ‘Therefore, postreceptr defects ate believed to pla the predominant role in insulin resistance Pig. 323-4), Polymorphisms in IRS-1 may bbe associated with glucose intolerance, raising the possibilty that polymorphisms in various portreceptor molecules may coniine to cre ie an insulin-tesistant state. The pathogenesis of insulin resistance is ‘eurtently focused on a PI-S-kinase signaling defect, which reduces ltanslocation of GLUTS to the plasma membrane, among other ab- ‘normalities. OF note, not all insulin signal transduction pathways are resistant tothe effects of insulin [eg those contolling cell growth an differentiation and using the mitogen-activated protein (MAP) ki- hase pathway; Fig 323-4], Consequently, hyperissulisemia may in- ‘crease the insulin action through these pathways, potentially acceler ing diabetes related conditions such as atherosclerosis, ‘Another emerging theory proposes that elevated levels of te fatty acs, a common feature of obesity, may contribute tothe pathogenesis ‘of type 2 DM. Free fatty acids can impair glucose ulation in skeletal ‘missle, promote glucore production by the liver, and impair beta cell, funtion Iosieo SN SECRETION Thelin secretion and sensitivity ae inter lated (Fig. 323-6). In type 2 DM, insulin secretion isl increases sn response to inulin resistance to maintain normal glucose tolerance, Thitally, the insulin secretory defect is mild and selectively involves lucose-stimulated insulin secretion. The esponse to other nonglicose Seeretagogues, such as arginine, is preserved. Eventually the insulin secretory defect progrestes to a sate of grossly inadequate insulin ‘The reason(s) forthe decline in inulin seeretory eapaity in type 2 DM is unclear. Despite the assumption that a second genetic de- ‘fect— superimposed upon insulin resistance —leads to beta cell fail ‘ue, intense genetic investigation has so far excluded mutations in islet2158 ee ‘candidate genes. Iset amyloid polypeptide or amylin is cosecreted by ‘the beta cell and likely forms the amyloid ilar deposit found in the islets of individuals with long-standing ype 2 DML Whether such islet. amyloid deposits are a primary or secondary event is not known The ‘elabolic envionment of diabetes may also negatively impact islet, function For example, chronic hyperglycemia paradoxically impairs islet funetion glucose toxiity) and leads to a worsening of hyper slycemia. Improvement in glycemic contol is often associated with Jmproved islet fonetion, In addition, elevation of tree faty acid levels (lipotoxieiy”) and dietary fat may also worsen islet function cweseo wept eucosepRUCION Tn type 2 DM, insulin resistance in the liver reflects the failure of hyperinsulinemia o suppress gluconeo- _genest, which results in fasting hyperglyeemia and decreased glyeo- gen storage by the liver in the postprandial stat. Increased hepatic _lucose production oecus early in the course of diabetes, though ikely Mtr the onset of insulin secretory abnormalities and insulin resistance ‘in ekeletal muscle, Insln Resistance Syndromes The insulin resistance condition comprises a specitum of disorders, with hyperglycemia representing one ofthe ioe readily diagnosed features, The metabolic syndrome, the insulin resistance syndrome. or syndrome X are terms used to describe acon- ‘elation of metabolic derangements that includes insulin resistance, hypertension, dyslipidemia (low high-density lipoprotein (HDL) and clevatedtiglyeerides), ceneal or visceral obesity, type 2 diabetes of IGT/IFG, and accelerated cardiovascular diseare. The syndrome is ‘very common. The Centers for Disease Control and Prevention (CDC) cstmats that 208 of US. adults have this syndrome, Epidemiologic evidence supports hyperinsulinemia as a marker for coronary artery ‘ease risk, though an evologe role has not been demonstaied. ‘A numberof relatively rare forms of severe insulin resistance in- clude features of type 2 DM or IGT (Table 325-1), Actos nigr ‘ans and signs of hyperandrogenism (hirsutism, acne, and oligo- ‘nenorthea in women) ae also common physical eatres, Two distinc. syndromes of severe insulin resistance have been described in adults: (Dope A, whieh affects young women and is characterized by severe lhypennsulinemia, obesity, and features of hyperandrogenism: and @2) type B, which affects middle-aged women and is characterized by severe hyperinsulinemia, features of hyperandrogensm, and autoim- tune disorders, Individuals with the pe A insulin resistance syn ‘drome have an undefined defect i the isulin-signaling pathway’ in- viduals with the type B. insulin esistunce syndrome have autoantibodies directed at the insulin receptor. These eeeplor ato- antibodies may block insulin binding or may stimulate the insulin re- «ceptor, leading fo intermittent hypoglycemia, Polycystic ovary syndrome (PCOS) is a common disorder that af- {ecis premenopausal women and is characterized by chronic anova lation and hyperandrogenism (Chap. 326) Insulin resistance is seen in a significant subeet of women with PCOS, and the disorder sub- stantially increases the rik for type 2 DM, independent of the effects, ‘of abesity, Both metformin and the thiavolidinediones attenuate hy- perinsulinemia, ameliorate hyperandrogenism, induce ovulation, and prove plasma lipids, but they are not approved for this indication Prevention Type 2 DM is preceded by a period of IGT, and a numbe of lifestyle modifications and pharmacologic agents prevent or delay the onset of DM, The Diabetes Prevention Program (DP) demon: strated that intensive changes in Ie-tyle (dit and exercize for 30 ‘ninfday five times/week) in individuals with IGT prevented or delayed the development of type 2 diabetes by 58% compared to placcho. Tis effet was seen in individuals regardless of age, sex, or ethnic group. In the same study. metiormin prevented or delayed diabetes by 31% ‘compared to placebo, The life syle intervention group Tost $ to 75 of their body weight during the 3 years ofthe study. Studies in Finnish and Chinese populations noted similar efiacy of dit and exesese in preventing or delaying pe 2 DM; acarbose, metformin, and the thia- 2oliinediones prevent oF delay type 2 DM, but are not approved for this purpose. When administered to nondiabetic individuals for other reason (eardiac, cholesterol lowering, et.) tvo pharmacologic agents (Gamipail, pravastatin) reduced the number of new cases of diabetes Individuals witha song family history, those at igh ris for devel- ‘oping DM, o* those with IEG or IGT should be strongly encouraged to maintain a normal body mass index (BMI) and engage in regular physical activity, GENETICALY DEFINED, MONOGENIC FORMS OF DIABETES MELLITUS Several monogenic forms of DM have been identified, Five different variants of MODY, caused by mutations in genes encoding islet cell, teanscrpton factors ot glucokinase (Fig, 323-3), have een ideniied 0 far and all ae transmitted as autosomal dominant dizordets (Table 528-1). MODY 2 is the reslt of mutations in the glucokinase gene that lead to mild-to-moderate hyperglycemia, Glucokinase catalyzes the formation of glucose-6 phosphate from glucose 2 reaction that is important for glucose sensing by she beta cells a for glucote wt zation by te liver. As a result of glucokinase mutations, higher gh cose levels are required to elicit insulin secretory response, ths al- tering the setpoint for insulin secretion, Homory ous mutations in glucokinase cause severe, neonatal diabetes. MODY 1, MODY 3, and. ‘MODY 5 are caused by mutations in the hepatocyte nuclear tanserip don factors (HINF) 4, HNF-L, and LINE-1f, respectively. As their names imply, thete anseription factors are expresid in the iver but flso in other tissue, including the pancreatic islets and Kidaey (az a result patients may also have renal absorption abnormalities and renal cysts) The mechanisms by which such mutations lead to DM is not ‘well understood, but itis likely that these factors affect islet devel: ‘opment or the traneription of genes that ae important in stimulating insulin secretion. MODY 1 and 3 begin with mild hyperglycemia, but progressive impairment of inulin seereton requires ieatment with ‘oral agents or insulin. MODY is a rare variant caused by mutations ‘in the insulin promoter factor (IPF) 1, which isa transcription factor that regulates pancreatic development and insulin gene tanscripton, Homozygous inactivating mutations cause pancreatic agenesis, ‘whereas heterozygous mttions result in DM Studies of populations with type 2 DM suggest that mutations in the glucokinase gene and various islet cell wanscription factors are very are in ordinary type 2 DM. ACUTE COMPLICATIONS OF DM. Diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS) are acute complications of diabetes. DKA was formerly con sidered a hallmark o type 1 DM, but it also occurs in individuals who Jack immunologic features of type 1A DM and who can subsequenty be tated with oral glucose-lowering agents (these individuals with type 2 DM are often of Hispanic or Afican-American descent), HHS is primarily seen in individuals with type 2 DM, Both disorders are astocated with absolute or relative insulin deficieney, volume deple won, and acid-bate abnormalities, DKA and HLIS exist along a con- sum of hyperglycemia, with or without ketosis, The metaboli sim- larties and differences in DKA and HHS are highlighted in Table 523-4, Both disorders are associated with potenally serious compli cations if not promptly diagnosed and weated. DIABETIC KETOACIDOSIS m CinalFesturs The symptoms and physical signs of DKA are listed in Table 323-5 and wsvally develop over 24 hours. DKA may be the inital symptom complex that leads to di agnosis of type 1 DM, but more ffequenlly it occurs in individuals ‘with established diabetes, Nausea and vomiting ate often prominent, tnd ther presence in an individual with diabetes warrants laboratory evaluation for DKA. Abdominal pain may be severe and can resemble fscute pancreatitis or ruptured viscous. Hyperglycemia leads to glu cosuria, volume depletion, and tachycardia. Hypotension can occur because of volume depletion in combination with peripheral vasodi- ion, Kussmadl eepirations and a fity odor on the patient's breath (secondaxy to metabolic acidosis and increased acetone) ae classic ign ofthe disorder, Lethargy and central nervous system depressionmay evolve into coma with severe DKA bt should also prompt evaluation for other tea sons for altered mental status (infection, by- poxa. et). Cerebral edema, an extremely se- ous complication of DKA, is seen most Fiequently in chldsen. Signe of infection, ‘which may precipitate DKA, should be sought (on physical examination, even in the absence of fever, Tissue ischemia (heat, hein) ean also be a precipitating factor Pthaphysilegy DKA results from relative or absolute insulin deficiency combined with countemegulatory hormone excess (glucagon. catecholamines, cortisol, and growth hor ‘ione). Both insulin deaciency and glucagon excess, in paticular, ae neceseary Lor DKA to develop, The decreased ratio of ili to els THBLE 325-4 abr aes i Diabetic Rtas (OA) and Ripesueni apesnaer ate (WS) (apse anges et Preset) m7 m5 CGacoee# mmol. (mel) 139-333 250-600) 333-65. (00-1200) Sodium, meg 5-135, 135-185 Potsitm eq. Normal © [ Nenad Magnesium ‘Noval Neal Chloride ‘Nom onal Poompatee 1 Normal Creatinine, mol gil) Sighty f Moderately f (melas) sant) 300-320 0-300 Plasma ketones” are =I Serum bcabonste* mei <1 meg [Nonna sighly | Areal pit ets = ‘arterial Pep me 20-30 Normal ‘Asion gap" Ne ~ (Cl + HCO,). peg 1 Nema aighly ‘eagon promotes gluconeogenesis, glycagenal- ysis, and ketone body formation inthe liver, as well as increases in substrate delivery from fat and muscle (fre fatty acids, amino acids) to the liver “The combination of insulin deficiency and hyperglycemia reduces| the hepatic level of fructose-2.6 phosphate, which alters the activity fof phosphofructokinase and fructose-1,6-isphosphatase, Glucagon, excess decreases the activity of pyruvate kinase, whereas insulin de- ficiency increases the activity of phosphoenolpyruvate carboxykinase, “Those changes shift the handling of pyruvate coward glucose synthesis and away from glycolysis, Te inereated levels of glucagon and ea. ‘cholamtnes inthe face of low insulin levels promote glycogendlysis, Inulin decency also reduces levels of the GLUTS glicose tan porter, which impairs glucose uptake into skeletal muscle and fat and reduces intracellular glucose metabolism (Fig. 323-4) Ketosi results from a marked inereate in tree fatty acid release fom adipocytes, with a resulting shift toward ketone body synthesis ‘in the liver, Reduced insulin levels, in combination with elevations in featecholamines and growth hormone, increase lipolysis and the release of ftee fay acids. Normally, these ftce fay acids are converted (0 Uiglyeerdes or very Tow density lipoproteins (VLDL) in the live, However, in DKA, hyperslucegonemia alters hepatic metabolism to favor ketone hody formation, tough activation ofthe enzyme car nine palmitoyluansterase . This enzyme is erucial for regulating fatty aid tanspor into the mitochondria, where beta oxidation and. conversion to ketone bodies aceur. At physiologie pH, ketone bodies exis as ketoacids, which are neutralized by bicarbonate. As bicarbon- ale stores are depleted, metabolic acidosis ensves, Increased lactic acid production aso contributes to the acidosis, The inceased fee fatty facie increase tiglycende and VLDL prodction. VLDL clearance is also reduced becaute the activity of insulin-sensitive lipoprotein lipase in muscle and fat is decreased. Hypenigiyceridemia may be severe ‘enough to cause pancreatitis, DKA is initiated by inadequate levels of plasma insulin (Table 323 5). Most commonly, DKA is precipitated by increased insulin equi rents, as might occur during a concurrent ines. Failure to augment insulin therapy often compounds the problem. Occasionally complete ‘omission of insulin by th patient o health cae team (in ahoepitalized patiat with type 1 DM) precipitates DKA. Patents using insulin in fusion devices with short-acting inslin are at nereased msk of DKA, since even a brief interruption in insulin delivery (e.g, mechanical ‘malfunction) quickly leads to insulin deficiency Labertery Abnormalities and Diagnsis crucal and allows for prompt initation of therapy. DKA is character tized by hyperglycemia, ketosis, and metabolic acidosis (increased a fon gap) along with a number of secondary metabolic derangements (Table 323-4). Occasionally, the serum glucose is only minimally el- vated. Serum biearbonate frequently 10 mmol/L, and arterial pH anges between 6.8 and 7.3, depending onthe severity ofthe acidosis Despite total body potassium dei, the serum potassium at presen tation may be mildly elevated, secondary tothe acidosis, Total-body stores of sodium, chloride, phosphorous, and magnesium are also re- ‘duced in DKA but are not accurately reflected by their levels inthe serum because of dehydration and hyperglycemia. Hevated blood urea riogen (BUN) and serum creatinine levels reflect intravascular vol- ume depletion, Interference from acetoacetate may falsely elevate the serum creatinine measurement. Leukocytosis, hyperuiglyeeridemia, an byperlipoproteinemia are commonly found as well Hyperamyla semia may suggest a diagnosis of pancreatitis, especially when accom- panied by abdominal pain. However, in DKA the amylase is usually of salivary origin and hus is not diagnostic of pancreatitis. Serum lipase should be obtained if pancreatitis is suspected, ‘The measured serum sodium is reduced as a consequence of the hyperglycemia [1.6 mmol. (1.6 meq) reduction in serum sodium for cach 5.6 mmol/L (100 mg/dL) rise inthe serum glucose). A normal frum sodium inthe setting of DKA indicates mote profound water ‘deficit. In “conveational” units, the calculated serum osmolality (2 * {aerum sodium + serum potassium) * plasma glucose (mg/dl. 18 + BUN/2.8] is milay to moderately elevated, though ta lesser degree than that found in IIHS (se below). Th DKA, the Ketone body, B-byroxybutyrate, is synthesized at a threefold greater rate than acctoaceate: however, actoacctate is pret ‘renilly detected by a commonly wed ketosis detection reagent (ai- ltoprusside). Serum ketones are present at significant levels (usually positive at serum dilution of 1:8 or grater). The nitvopruside tablet, brick, often ured to detect urine Ketone; certain medications sich as captopril or penicillamine may cause false positive reactions, Serum for plasma assays for B-hydroxybutyrate more accurately reflect the true Ketone body level ‘The metabolic derangements of DKA exist along spectrum, be inning wih mild acidosis wath moderate hyperglycemia evolving into more severe findings. The degree of acidosis and hyperglycemia do hot necessary correlate closely since a variety of factre determine TLE 33 Mnifestatons of Dik ects —— Piel ang me ren fern Se pen orc are cam apn poesia Tene dupes DKA MEETS enten Taya ae Ecco terme ae ee Sone Ba, Sas ee ce eas ere EeeAo cn the level of hyperglycemia (oral intake, urinary glucose loss). Keto- ‘emia is a consistent finding in DKA and distinguishes it rom simple hyperglycemia. The differential dignosis of DKA includes starvation Ietoss, alcoholic ketoacidosis (bicarbonate 15 meq/L) and other in creased anion gap acidosis (Chap. 42) [&] TREATMENT ‘The management of DKA is outlined i Table 323-6, After initiating ineavenous fluid replacement and insulin therapy, the agen or event that precipitated the episode of DKA should be sought and aggres sively ueated. Ifthe patient i¢ vomiting or hae altered mental statse A natogassie tbe should be intrted to prevent aspiration of gas Contents, Central to successful teatment of DKA ie careful monitoring land frequent reasessment to ensure tha the patient and the metabolic derangements ate improving. A comprehensive flow sheet should record chronologic changes in vital signs, fluid intake and output, and Taboratory values a8 a funetion of insulin administered. ‘After the initial bolue of normal saline, replacement ofthe rodsum and Ince water dei is caried out over the next 2th (uid det often 319 51). When hemodynamic stability and adequate urine out- ut are achieved, intravenous fide shouldbe switched to 0.45% saline rate of 200 10 300 mb, depending on the caleulated volume Aeficit. The change to 0.45% saline help to redace the tend toward Ibyperchloremia later in the course of DKA, Alternatively, inital use ‘of lactated Ringer's intravenous olution may reduce the hyperchlo- emia that commonly occurs with normal saline ‘A bolus of inteavenous (015 una) ot intramuseulas (0.4 units! kg) regular inulin should be administered immediately (Table 423- {5}, and subsequent treatment should provide continuous and adequate THBLE 323-6 Manapenent of ae Rtais 1 Contr dingnoss (7 plas glicre, pniive serum Ketones, meta tale aida 2, Ami to hosp: ivensive-ee sing may be necessary frequent ‘monitoring oi = 700 or aneonscins. 5, Races Serum slecolyes(K-, Nar, Mp", Cl, bicarbonate, phos plat) ‘Acid base sts pH, HCO, Peo. BAyeorybunzate ‘Renal faction (renin, ue tp) 4 Replace fide 2-3 L of 09% saline over se 13h (5-10 mag ‘et bus; bnequely, 045% saline a 130-300 lh change oS [Blscove and OSS saline a 100" 200 mo when plume glucose feaches 250 maid (14 mmol). 5: Administer eglar inguin: TV (0. its) or TM (04 tf) ten (tse per hour by contnaous IV infaron increase 21 10-08 if ao eponre by 2-4 Iria tert pasion < 2.3 sh (G3 meg} o sot adsie nlin unl the potasium i corected to> 33 mmol @ Seq 1. Assess patient What prespited the episod (noncompliance, nfe- ‘ton, tama infarction, coeaie) nae appropiate workup fr pre ‘pating event (ules, CXR, ECO), 7. Measure capillary glucose every 1-2 by measure electelyes(espe- lally K' ieatboote, phospiate) and anion gap every 4h for fist aah, |. Monitor blod pes, ple, espiaone, menial sae, dai intake sd utp every a 9. Replace K' 10 megh when plasma K* < 5.5 meq, BCG nonna wine ow and nomal creatinine documented: adminser 40-0 meqi Je when plasm K" <3 5 megiL orf bicarbonate given 10, Comin above unl patent ie sable,gluone goa 150-250 mg! (Ly and acidosis peselved lal infusion aay be deresed to O03 0] nit pe hou 11 Adminis itemmediate or long-eting insulin as soon as pate is ‘ating. Allow fr overlap in inshininfsion and scbevtaneot isin levels of circulating insulin. Intravenous administration is prefered (G41 unitsfkg per hour), because it assures rapid dstebution and allows adjustment of the infusion rate asthe patent responds to therapy. In Teavenous regular insulin should be continued until the acidosis re solves and the patient is metabolically stable. As the acidosis and in sulin resistance associated with DKA resolve, the insulin infusion rate fan be decreased (to 0.05 to 0.1 unitskg pet hous). Intermediate of Jong-acting insulin, m combination with subcutaneous regular insulin, should be administered as soon as the patient resumes eating a this facilitates tansition to an outpatient insulin regimen and reduces length of hospital stay. I is erucial to continue the insulin infusion until adequate inulin levels are achieved by the subcutaneous route [Bven relatively brief periods of inadequate insulin administration in this transition phase may resus in DKA relape, ‘Hyperglycemia urually improves a arate of 4.2 to $6 mmnolL 75 to 100 mi) per hour as a result of insulin mediated glucose dis: otal, reduced hepatic glucose telease, and hydration. The latter se duces catecholamines, increases urinary glucose loss and expands the intravascular volume. The decline in the plasma glucose within the frst Ito 2h may be more rapid and is moslly related to volume expansion, When the plasma glucose reaches 13.9 mmol (250 m@/ AL), glucose shouldbe added tothe 0.45% saline infusion to maintain the plasma glacose in the 111 to 13.9 mmol/L (200 to 250 mg/dL) ‘ange, and the insulin infusion should be continued. Ketoaidosis be {into evolve ae insulin reduces lipolysis, sncreaees peripheral ketone body use, suppreses hepatic ketone body formation, and promotes bicarbonate regeneration. However, the acidosis and ketosis resolve sore slowly than hyperglycemia. As ketoacidosis improves, By ‘roxybutyrate is convered to acetoacetate, Ketone body levels may appear to increase if measured by laboratory assay thal use the nit prussde reaction, which only deteets acetoacetate and acetone. The Improvement in acidosis and anion gap a result of bicarbonate regen tration and decline in ketone bodies, is reflected by a rit in the serum bicarbonate level and the arterial pH. Depending onthe rise of serum, chloride, the anion gap (but not bicarbonate) will normalize. A by: perchloremie acidosis [serum bieathonate of 15 to 18 moll. (15 to 18 mog/L}] often follows successful trexment and gradally resolves athe kidneys regenerate bicarbonate and exeretes chloride Potassium stores are depleted in DKA [estimated deficit 3 to $ rmolikg (to 5 megke)], During teatment with insulin and Aids, varios factors contribute tothe development of hypokalemia, These inclade insulin-medisted potassium transpor into cells, resolution of the acidosis (which alto promotes potassium enty inco cells), ad unary loss of potassium salts of organi acids. Thus, possum re pletion should commence as sn as adequate urine output and anor ‘al serum potassium ate documented, I he intial serum potasium level i elevate, then potasium repletion should be delayed unt the potassium falls into the normal range. Inclusion of 20 to 40 meq of potassium in each itr of intravenous fuidsreasonable, bu additonal potassium supplements may also be required. To reduce the amount Of chloride administered, potassium phosphate or acetate can be sub stituted forthe chloride salt The goal is fo maintain the serum potas: sium >3.5 mmol/L (3.5 meq). I the inital serum potassium i Tess than 3.3 mmol. (1.3 meg/L}, do not administer insulin unl the po tassiu is supplemented to 23.3 mmol (3.3 meg), Despite a bicarbonate deft, biarhonate replacement is not usu ally necessary. In Lact, theoretical arguments suggest that bicarbonate ‘atuinistration and rapid reversl of acidosis may impair cardia fune ton reduce issue oxygenation, and promote hypokalemia. The ests ‘of most elnieal trials do not support the routine ute of bicarbonate replacement, and one study in children found that bicarbonate use Was astoriated with an inereased risk of cecbral edema. However, i the presence of severe acidosis (arterial pH < 7.0 afer initial hydasion), the ADA advises bicarbonate (50 mmol. (meq) of sodium hic bbonate in 200 mi of 0.45% saline over 1 bif PH = 69 %0 7.0; o 100 rumolL. (meajL) of sodium bicarbonate in 400 ml. of 0.48% saline ‘over 2hif pll7 < 69}. Hypophosphatemia may result from increased licoge usage, but randomized clinica tral have not demonstrated