PATOFISIOLOGI DM TIPE 2

DM tipe 2 dikarakteritikan dengan tiga patofisiologi : ketidak mampuan sekresi inuslin,

resistensi insulin perifer dan produksi glukosa hepatik yang berlebihan, dan metabolisme

lemak yang abnormal. Obesitas sangat umum pada DM tipe 2. Sel adiposa mensekresi

banyak produk biologi seperti leptin, TNF, asam lemak bebas, resistin dan adinopectin yang

memodulasi sekresi insulin dan berkontribusi pada terjadinya resistensi insulin. Pada fase

awal kelainan, toleransi glukosa masih memperlihatkan keadaan mendekati normal begitu

juga dengan resistensi insulin. Hal ini dikarenakan Sel Beta Pankreas mengkompensasinya

dengan peningkatan sekresi insulin. Ketika terjadi resistensi insulin dan dikompensasi dengan

hiperinsulinemia dalam waktu lama, pankreas pada kebanyakan individu tidak dapat

mempertahankan keadaan hiperinsulinemia sehinga membuat seseorang jatuh kedaam

kondisi Toleransi Glukosa Terganggu (TGT).11 Progresifitas perjalanan penyakit dari

toleransi glukosa yang normal ke toleransi glukosa terganggu pada awalnya akan ditandai

dengan peningkatan level gukosa postprandial.9 Lebih jauh lagi, menurunan sekresi insulin

dan peningkatan produksi glukosa hepatik akan mengakibatkan kondisi diabetes dengan

hiperglikemia puasa. Pada akhirnya kegagalan sel beta pankreas pun terjadi.1 Penanda

inflamasi seperti IL-6 dan C-reactive protein sering meningkat pada DM tipe 2.

Resistensi Insulin

Resistensi insulin adalah penurunan kemampuan insulin untuk berkerja efektif pada

jaringan target, terutama otot, hati dan lemak, ini adalah gambaran penting DM tipe 2. Dan

hal ini merupakan hasil kombinasi keterlibatan genetik dengan obesitas.10) Resistensi insulin

tidak hanya terjadi pada DM tipe 2, pada obesitas dan kehamilan, sensitifitas jaringan

terhadap insulin juga menurun (bahkan ketika tidak ada penyakit DM), dan kadar insulin

dalam serum dapat meningkat untuk mengkompensasi resistensi insulin.10,11 Resistensi insulin

mengganggu penggunaan glukosa oleh jaringan sensitif terhadap insulin dan meningkatkan

pengeluaran glukosa hati; kedua efek tersebut menyebabkan terjadinya hyperglycemia.

Peningkatan pengeluaran glukosa hepatik utamanya akan menyebabkan peningkatan kadar

glukosa puasa. Sedangkan penurunan penggunaan glukosa di perifer akan menyebabkan

hiperglikemia postprandial. Pada otot rangka ada terjadi penurunan lebih besar dalam

penggunaan glukosa nonoxidativ (formasi glikogen) dibandingkan gangguan metabolisme

glukosa oksidativ melalui glikolisis. Metabolisme glukosa pada jaringan tidak tergantung

insulin tidak terganggu pada DM tipe 2.

Dasar-dasar molekuler untuk resistensi insulin masih belum jelas. Penurunan jumlah

reseptor insulin dan aktivitas tyrosine kinase pada otot rangka berkurang , 11 Akan tetapi

perubahan ini akibat sekunder dari hiperinsulinemia bukan merupakan kerusakan primer.

Yang diyakini sebagai penyebab utama dari resistensi insulin adalah adanya gangguan pada

sinyal post reseptor yang diberikan insulin.Patogenesis resistensi insulin difokuskan pada

defek sinyal Proinsulin-3-kinase, yang akan mengurangi translokasi GLUT4 ke membran

plasma.10 Seperti diketahui, ikatan insulin dan reseptornya menyebabkan translokasi GLUTs

terhadap sel membrane yang akan memfasilitasi pengambilan glukosa oleh sel. Diduga

pengurangan sintesis dan translokasi GLUTs pada otot dan sel-sel lemak menjadi penyebab

dasar dari insulin resisten yang terdapat pada obesitas dan juga pada DM tipe 2.11 .

Polimorfisme pada IRS-1 (Insuline Reseptor Substrat) dapat berhubungan dengan intoleransi

glukosa, peningkatan kemungkinan polimorfisme pada molekul post reseptor merupakan

kombinasi untuk menciptakan keadaan resistensi insulin.

Sebagian besar penderita diabetes melitus tipe 2 memiliki berat badan berlebih.

Obesitas terjadi dengan penyebab yang multifaktorial, beberapa dari hal tersebut adalah

faktor genetik, asupan makanan yang berlebihan, dan aktifitas fisik yang kurang.

Ketidakseimbangan antara asupan dan pengeluaran energi akan menyebabkan peningkatan

konsentrasi asam lemak (FFA) di dalam darah.7 Hal ini selanjutnya akan menurunkan

penggunaan glukosa di otot dan jaringan lemak. Akibatnya, terjadi resistensi insulin di otot

skelet dan hati yang merangsang terjadinya hiperinsulinemia, peningkatan produksi glukosa

dari hati, dan gangguan fungsi sel beta pankreas. Karena adanya penurunan regulasi insulin,

resistensi insulin akan semakin meningkat.7,10 Pada keadaan obesitas, terjadi suatu mekanisme

perubahan metabolik yang belum jelas dimengerti, yang mana terjadi perubahan sesitivitas

jaringan adiposa terhadap insulin untuk menyesuaikan berat badan, selera makan, dan

pengeluaran energi.10

Pada DM tipe 2, resistensi insulin di hati mencerminkan kegagalan hiperinsulinemia

untuk menekan glukoneogenesis, yang berakibat pada hiperglikemik puasa dan penurunan

penyimpanan glikogen oleh hati pada keadaan pos prandial. Peningkatan produksi glukosa

hepatik biasanya terjadi pada fase awal rangkaian perkembangan diabetes, namun demikian

mungkin juga terjadi setelah kondisi sekresi insulin abnormal dan resistensi insulin di otot

skelet. Sebagai akibat dari resistensi insulin di jaringan adiposa dan pada obesitas, FFA dari

jaringan adiposa meningkat, yang berakibat pada peningkatan sintesis lipid (VLDL dan

Trigliserid) dalam hepatosit. Penumpukkan lipid dalam hati tersebut akhirnya dapat berakhir

pada penyakit perlemakan hati non-alkoholik (NAFL) dan tes fungsi hati yang abnormal. Hal

ini juga yang menyebabkan terjadinya dislipidemia pada DM tipe 2 (peningkatan TG,

penurunan HDL, peningkatan LDL).10

Keadaan resistensi insulin secara fisiologik akan menyebabkan ketidakmampuan

insulin untuk menetralisir glukosa, sehingga terjadi hiperglikemia persisten, dan stimulasi

terus-menerus tehadap sel beta pankreas sebagai tindakan kompensasi tubuh.10

Peningkatan produksi glukosa hepatik

Pada DM tipe 2, resistensi insulin pada hati menggambarkan kegagalan

hiperinsulinemia untuk menekan glukoneogenesis, yang akan menyebabkan kenaikan gula

darah puasa dan penurunan penyimpanan glikogen oleh hati saat keadaan postprandial.

Peningkatan produksi glukosa terjadi pada awal diabetes, meskipun setelah terjadi

abnormalitas sekresi insulin dan resistensi insulin pada otot rangka.

Patofisiologi gejala DM

Pada keadaan defisiensi insulin relatif, masalah yang akan ditemui terutama adalah

hiperglikemia dan hiperosmolaritas yang terjadi akibat efek insulin yang tidak adekuat.8, 6

Hiperglikemia pada diabetes melitus terjadi akibat penurunan pengambilan glukosa

darah ke dalam sel target, dengan akibat peningkatan konsentrasi glukosa darah setinggi 300

sampai 1200 mg per 100ml.6,7 Hal ini juga diperberat oleh adanya peningkatan produksi

glukosa dari glikogen hati sebagai respon tubuh terhadap kelaparan intrasel.6 Keadaan

defisiensi glukosa intrasel ini juga akan menimbulkan rangsangan terhadap rasa lapar

sehingga frekuensi rasa lapar meningkat (polifagi). Penimbunan glukosa di ekstrasel akan

menyebabkan hiperosmolaritas.8

Kadar glukosa plasma yang tinggi (di atas 180 mg%) yang melewati batas ambang

bersihan glukosa pada filtrasi ginjal, yaitu jika jumlah glukosa yang masuk tubulus ginjal

dalam filtrat meningkat kira-kira diatas 225mg/menit, maka glukosa dalam jumlah bermakna

mulai dibuang atau terekskresi ke dalam urin yang disebut glukosuria.4,6 Keberadaan glukosa

dalam urin menyebabkan keadaan diuresis osmotik yang menarik air dan mencegah

reabsorbsi cairan oleh tubulus sehingga volume urin meningkat dan terjadilah poliuria.8,4,6

Karena itu juga terjadi kehilangan Na dan K berlebih pada ginjal.8

Pengeluaran cairan tubuh berlebih akibat poliuria disertai dengan adanya

hiperosmolaritas ekstrasel yang menyebabkan penarikan air dari intrasel ke ekstrasel akan

menyebabkan terjadinya dehidrasi, sehingga timbul rasa haus terus-menerus dan membuat

penderita sering minum (polidipsi).6,8 Dehidrasi dapat berkelanjutan pada hipovolemia dan

syok, serta AKI akibat kurangnya tekanan filtrasi glomerulus.6 Jadi, salah satu gambaran

diabetes yang penting adalah kecenderungan dehidrasi ekstra sel dan intra sel, dan ini sering

juga disertai dengan kolapsnya sirkulasi.6

Dan perubahan volume sel akibat keadaan hiperosmotik ekstrasel yang menarik air

dari intrasel dapat mengganggu fungsi sel-sel dalam tubuh.6,8

The insulin resistance in muscle and liver central to the etiology of type2 diabetes mellitus appears to be polygenic in origin. Type 2 diabetes is also an example of a disease inwhich end organ insensitivity is worsened by signals from other organs, in this case by signals originating in

fat cells.

The homeodomain protein pancreas duodenum homeobox 1 or PDX-1 (somatostatin transcription factor 1[STF-1], islet duodenum homeobox 1 [IDX-1], insulin promoter factor 1 [IPF-1]) appears to be responsible forthe development and growth of the pancreas. Targeted disruption of the PDX-1 gene in mice resulted in aphenotype of pancreatic agenesis.[67] A child born without a pancreas was shown to be homozygous forinactivating mutations in the IPF-1 gene (IPF-1 in the human nomenclature).[68] Notably, the parents andtheir ancestors who are heterozygous for the affected allele have a high incidence of maturity-onset (type 2)diabetes mellitus, suggesting that a decrease in gene dosage of IPF-1 may predispose to the developmentof diabetes. The possibility that a mutated IPF-1 allele may be one of several “diabetes genes” is supportedby the observation that PDX-1/IPF-1 and the helix-loop-helix transcription factors E47 and ß-2 appear to be

key up-regulators of the transcription of the insulin gene.[69]

PATHOGENESISThe pathogenesis of T2DM is complex and involves the interaction of genetic and environmental factors. Anumber of environmental factors have been shown to play a critical role in the development of the disease,

particularly excessive caloric intake leading to obesity and a sedentary lifestyle. The clinical presentation isalso heterogeneous, with a wide range in age of onset, severity of associated hyperglycemia, and degree ofobesity. From a pathophysiologic standpoint, persons with T2DM consistently demonstrate three cardinalabnormalities: resistance to the action of insulin in peripheral tissues, particularly muscle and fat but alsoliver; defective insulin secretion, particularly in response to a glucose stimulus; and increased glucoseproduction by the liver.Although the precise way these genetic, environmental, and pathophysiologic factors interact to lead to theclinical onset of T2DM is not known, our understanding of these processes has increased substantially. Withthe exception of specific monogenic forms of the disease that might result from defects largely confined tothe pathways that regulate insulin action in muscle, liver, and fat or defects in insulin secretory function in thepancreatic beta cell, there is an emerging consensus that the common forms of T2DM are polygenic innature and are due to a combination of insulin resistance and abnormal insulin secretion. From apathophysiologic standpoint, it is the inability of the pancreatic beta cell to adapt to the reductions in insulinsensitivity that occur over the lifetime of human subjects that precipitates the onset of T2DM. The mostcommon factors that place an increased secretory burden on the beta cell are puberty, pregnancy, asedentary lifestyle, and overeating leading to weight gain. An underlying genetic predisposition appears tobe a critical factor in determining the frequency with which beta cell failure occurs.Genetic Factors in the Development of Type 2 DiabetesGenetically, T2DM consists of monogenic and polygenic forms. [23] [24] The monogenic forms, althoughrelatively uncommon, are nevertheless important, and a number of the genes involved have been identifiedand characterized. The genes involved in the common polygenic form or forms of the disorder have been farmore difficult to identify and characterize.Monogenic Forms of DiabetesIn the monogenic forms of diabetes, the gene involved is both necessary and sufficient to cause disease. Inother words, environmental factors play little or no role in determining whether or not a geneticallypredisposed person develops clinical diabetes. The monogenic forms of diabetes generally occur in youngpatients, often in the first two to three decades of life, although if only mild asymptomatic elevations in bloodglucose occur the diagnosis may be missed until later in life.The monogenic forms of diabetes are summarized in Table 30-5 and can be divided into those in which themechanism is a defect in insulin secretion and those that involve defective responses to insulin or insulinresistance.

TABLE 30-5 -- MONOGENIC FORMS OF DIABETESASSOCIATED WITH INSULIN RESISTANCEMutations in the insulin receptor gene• Type A insulin resistance• Leprechaunism• Rabson-MendenhallsyndromeLipoatrophic diabetesMutations in the PPAR geneASSOCIATED WITH DEFECTIVE INSULIN SECRETIONMutations in the insulin or proinsulin genesMitochondrial gene mutationsMaturity-onset Diabetes of the Young(MODY)HNF-4a (MODY 1)Glucokinase (MODY 2)HNF-1a (MODY 3)IPF-1 (MODY 4)HNF-1ß (MODY 5)NeuroD1/Beta2 (MODY 6)HNF, hepatocyte nuclear factor; IPF, insulin promoter factor; NeuroD1/Beta2, neurogenic differentiation1/beta cell E-box trans-activator 2; PPAR, peroxisome proliferator-activated receptor.Monogenic Forms of Diabetes Associated with Insulin ResistanceMutations in the Insulin ReceptorMore than 70 mutations have been identified in the insulin receptor gene in various insulin-resistantpatients.[25] There are at least three clinical syndromes caused by mutations in the insulin receptor gene.Type A insulin resistance is defined by the presence of insulin resistance, acanthosis nigricans, andhyperandrogenism.[26] Patients with leprechaunism have multiple abnormalities, including intrauterinegrowth retardation, fasting hypoglycemia, and death within the first 1 to 2 years of life. [27] [28]

[29] TheRabson-Mendenhall syndrome is associated with short stature, protuberant abdomen, and abnormalities ofteeth and nails; pineal hyperplasia was a characteristic in the original description of this syndrome.[30]

These mutations might impair receptor function by a number of different mechanisms, including decreasingthe number of receptors expressed on the cell surface, for example, by decreasing the rate of receptorbiosynthesis (class 1), accelerating the rate of receptor degradation (class 5), or inhibiting the transport ofreceptors to the plasma membrane (class 2). The intrinsic function of the receptor may be abnormal if theaffinity of insulin binding is reduced (class 3) or if receptor tyrosine kinase is inactivated (class 4). The insulinresistance that is associated with insulin receptor mutations may be severe and present in the neonatalperiod, as with leprechaunism and the Rabson-Mendenhall syndrome, or it can occur in a milder form inadulthood, leading to insulin-resistant diabetes with marked hyperinsulinemia, acanthosis nigricans, and

hyperandrogenism.Lipoatrophic DiabetesIn another monogenic form of diabetes, lipoatrophic diabetes, severe insulin resistance is associated withlipoatrophy and lipodystrophy. This form of diabetes is characterized by a paucity of fat, insulin resistance,and hypertriglyceridemia.[31] The disease has several genetic forms, including face-sparing partiallipoatrophy (the Dunnigan syndrome or the Koberling-Dunnigan syndrome), an autosomal dominant formcaused by mutations in the lamin A/C gene,[32] and congenital generalized lipoatrophy (the Seip-Berardinellisyndrome), an autosomal recessive form that appears to be due to mutations in either 1-acyl-sn-glycerol-3-phosphate acyltransferase-2 (AGPAT2) or in the Seipin gene product. [33] [34]Mutations in Peroxisome Proliferator-Activated Receptorn–It has been demonstrated that mutations in the transcription factor peroxisome proliferator-activatedreceptor–g (PPARg) can cause T2DM of early onset (familial lipodystrophy type 3).[35] Two differentheterozygous mutations were identified in the ligand-binding domain of PPARg in three subjects with severeinsulin resistance. In the PPARg crystal structure, the mutations destabilize helix 12, which mediates transactivation.Both receptor mutants showed markedly decreased transcriptional activation and inhibited theaction of coexpressed wild-type PPARg in a dominant negative manner. A Dutch kindred with a -14A Gmutation within the promoter of the PPARg4 isoform, which results in decreased expression but noqualitative protein abnormalities, has been described.[36]

A common amino acid polymorphism (Pro12Ala) in PPARg has been associated with T2DM. Peoplehomozygous for the Pro12 allele are more insulin resistant than those having one Ala12 allele and have a1.25-fold increased risk of diabetes. There is also evidence for interaction between this polymorphism andfatty acids, linking this locus with diet. A second polymorphism, C161 T, has been linked to insulinresistance in Hispanic and non-Hispanic white women.[37]Monogenic Forms of Diabetes Associated with Defects in Insulin SecretionMutant Insulin SyndromesThe first syndrome associated with diabetes to be characterized in terms of the clinical picture, geneticmechanisms, and clinical pathophysiology was that associated with mutant insulin or proinsulin.[38] Personswith this disorder present clinically with a mild non–insulin-dependent form of diabetes. Affected personscharacteristically have marked hyperinsulinemia on routine insulin assays. Increases in the concentration ofinsulin in association with diabetes usually indicate insulin resistance, but in this syndrome, insulinresistance can be easily excluded because the patients respond normally to administration of exogenous

insulin. Characterization of the insulin by high-performance liquid chromatography (HPLC) reveals that thehyperinsulinemia is due to the presence of the abnormal insulin or proinsulin and related breakdownproducts. The increased concentrations of insulin appear to be related to the presence of mutations inregions of the insulin molecule that are important for receptor binding, particularly the COOH terminus of theinsulin B chain.Because the liver is the major site of insulin clearance and the first-pass hepatic insulin uptake anddegradation are mediated by the insulin receptor, mutant forms of insulin with diminished insulin receptorbinding ability are cleared more slowly from the circulation, and this reduction in insulin clearance leads tohyperinsulinemia. Alternatively, mutations in proinsulin can reduce the conversion of proinsulin to insulin,leading to accumulation of proinsulin. [39] [40] Because proinsulin is cleared more slowly from the circulationthan insulin, proinsulin levels increase. Proinsulin cross-reacts in most commercially available assays, andthis insulin-like immunoreactivity can be characterized as related to the presence of proinsulin rather thaninsulin only by HPLC or by the use of assays that are specific for insulin and proinsulin.A patient with a mutation in prohormone convertase 1, one of the enzymes responsible for the conversion ofproinsulin to insulin, has been described.[41]Mitochondrial DiabetesAn A-to-G transition in the mitochondrial tRNALeu(UUR) gene at base pair 3243 has been shown to beassociated with maternally transmitted diabetes and sensorineural hearing loss.[42] In other subjects, thismutation is associated with diabetes and the syndrome of mitochondrial myopathy, encephalopathy, lacticacidosis, and strokelike episodes (MELAS syndrome). The mitochondrion plays a key role in the regulationof insulin secretion, particularly in response to glucose. We have documented abnormal insulin secretion onat least one of a battery of tests in subjects with this mitochondrial mutation, even in subjects with normal orimpaired glucose tolerance who have not developed overt diabetes.[43]Maturity-Onset Diabetes of the YoungMaturity-onset diabetes of the young (MODY) is a genetically and clinically heterogeneous group ofdisorders characterized by nonketotic diabetes mellitus, an autosomal dominant mode of inheritance, onsetusually before 25 years of age and often in childhood or adolescence, and a primary defect in pancreaticbeta cell function. A detailed review of MODY has been published,[44] and the information contained in thatreview is summarized.MODY can result from mutations in any one of at least six different genes. One of these genes encodes theglycolytic enzyme glucokinase (MODY2),[45] and the other five encode transcription factors, hepatocyte

nuclear factor (HNF)-4a (MODY1),[46] HNF-1a (MODY3),[47] insulin promoter factor-1 (IPF-1) (MODY4),[48]

HNF-1ß (MODY5),[49] and neurogenic differentiation 1/beta cell E-box trans-activator 2 (NeuroD1/BETA2)(MODY6).[50] All of these genes are expressed in the insulin-producing pancreatic beta cell, andheterozygous mutations cause diabetes related to beta cell dysfunction. Abnormalities in liver and kidneyfunction occur in some forms of MODY, reflecting expression of the transcription factors in these tissues.Nongenetic factors that affect insulin sensitivity (infection, puberty, pregnancy, and rarely obesity) can triggerdiabetes onset and affect the severity of hyperglycemia in MODY but do not play a significant role in thedevelopment of MODY.The most common clinical presentation of MODY is a mild asymptomatic increase in blood glucose in achild, adolescent, or young adult with a prominent family history of diabetes often in successive generations,suggesting an autosomal dominant mode of inheritance. Some patients have mild hyperglycemia for manyyears, whereas others have varying degrees of glucose intolerance for several years before the onset ofpersistent hyperglycemia.[44] The diagnosis may be made only in adulthood even though the elevation inplasma glucose has been present for many years. Prospective testing indicates that in most patients thedisease onset occurs in childhood or adolescence. In some patients, there may be a rapid progression toovert asymptomatic or symptomatic hyperglycemia, necessitating therapy with an oral hypoglycemic drug orinsulin. The presence of persistently normal plasma glucose levels in subjects with mutations in any of theknown MODY genes is unusual, and the majority eventually experience diabetes (with the exception ofmany patients with glucokinase mutations; see later).Although the exact prevalence of MODY is not known, current estimates suggest that MODY might accountfor 1% to 5% of all cases of diabetes in the United States and other industrialized countries.[44] Severalclinical characteristics distinguish patients with MODY from those with T2DM, including a prominent familyhistory of diabetes in three or more generations, young age at presentation, and absence of obesity.Functional Effects of MODY GenesThe identification of several genes associated with diabetes has provided a unique opportunity tocharacterize the pathophysiologic mechanisms by which genetic mutations can lead to an increase in theplasma glucose concentration. All the susceptibility genes identified to date cause impaired insulin secretoryresponses to glucose, although the mechanisms differ.Glucokinase.Glucokinase is expressed at its highest levels in the pancreatic beta cell and the liver. It catalyzes the

transfer of phosphate from adenosine triphosphate (ATP) to glucose to generate glucose-6-phosphate ( Fig.30-2 ).