PATOFISIOLOGI DM TIPE 2DM 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.10Pada 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).10Keadaan 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.10Peningkatan 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.8Pengeluaran 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 type

2 diabetes mellitus appears to be polygenic in origin. Type 2 diabetes is also an example of a disease in

which 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 for

the development and growth of the pancreas. Targeted disruption of the PDX-1 gene in mice resulted in a

phenotype of pancreatic agenesis.[67] A child born without a pancreas was shown to be homozygous for

inactivating mutations in the IPF-1 gene (IPF-1 in the human nomenclature).[68] Notably, the parents and

their 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 development

of diabetes. The possibility that a mutated IPF-1 allele may be one of several diabetes genes is supported

by the observation that PDX-1/IPF-1 and the helix-loop-helix transcription factors E47 and -2 appear to be

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

PATHOGENESIS

The pathogenesis of T2DM is complex and involves the interaction of genetic and environmental factors. A

number 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 is

also heterogeneous, with a wide range in age of onset, severity of associated hyperglycemia, and degree of

obesity. From a pathophysiologic standpoint, persons with T2DM consistently demonstrate three cardinal

abnormalities: resistance to the action of insulin in peripheral tissues, particularly muscle and fat but also

liver; defective insulin secretion, particularly in response to a glucose stimulus; and increased glucose

production by the liver.

Although the precise way these genetic, environmental, and pathophysiologic factors interact to lead to the

clinical onset of T2DM is not known, our understanding of these processes has increased substantially. With

the exception of specific monogenic forms of the disease that might result from defects largely confined to

the pathways that regulate insulin action in muscle, liver, and fat or defects in insulin secretory function in the

pancreatic beta cell, there is an emerging consensus that the common forms of T2DM are polygenic in

nature and are due to a combination of insulin resistance and abnormal insulin secretion. From a

pathophysiologic standpoint, it is the inability of the pancreatic beta cell to adapt to the reductions in insulin

sensitivity that occur over the lifetime of human subjects that precipitates the onset of T2DM. The most

common factors that place an increased secretory burden on the beta cell are puberty, pregnancy, a

sedentary lifestyle, and overeating leading to weight gain. An underlying genetic predisposition appears to

be a critical factor in determining the frequency with which beta cell failure occurs.

Genetic Factors in the Development of Type 2 Diabetes

Genetically, T2DM consists of monogenic and polygenic forms. [23] [24] The monogenic forms, although

relatively uncommon, are nevertheless important, and a number of the genes involved have been identified

and characterized. The genes involved in the common polygenic form or forms of the disorder have been far

more difficult to identify and characterize.

Monogenic Forms of Diabetes

In the monogenic forms of diabetes, the gene involved is both necessary and sufficient to cause disease. In

other words, environmental factors play little or no role in determining whether or not a genetically

predisposed person develops clinical diabetes. The monogenic forms of diabetes generally occur in young

patients, often in the first two to three decades of life, although if only mild asymptomatic elevations in blood

glucose 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 the

mechanism is a defect in insulin secretion and those that involve defective responses to insulin or insulin

resistance.

TABLE 30-5 -- MONOGENIC FORMS OF DIABETES

ASSOCIATED WITH INSULIN RESISTANCE

Mutations in the insulin receptor gene

Type A insulin resistance

Leprechaunism

Rabson-Mendenhall

syndrome

Lipoatrophic diabetes

Mutations in the PPAR gene

ASSOCIATED WITH DEFECTIVE INSULIN SECRETION

Mutations in the insulin or proinsulin genes

Mitochondrial gene mutations

Maturity-onset Diabetes of the Young

(MODY)

HNF-4a (MODY 1)

Glucokinase (MODY 2)

HNF-1a (MODY 3)

IPF-1 (MODY 4)

HNF-1 (MODY 5)

NeuroD1/Beta2 (MODY 6)

HNF, hepatocyte nuclear factor; IPF, insulin promoter factor; NeuroD1/Beta2, neurogenic differentiation

1/beta cell E-box trans-activator 2; PPAR, peroxisome proliferator-activated receptor.

Monogenic Forms of Diabetes Associated with Insulin Resistance

Mutations in the Insulin Receptor

More than 70 mutations have been identified in the insulin receptor gene in various insulin-resistant

patients.[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, and

hyperandrogenism.[26] Patients with leprechaunism have multiple abnormalities, including intrauterine

growth retardation, fasting hypoglycemia, and death within the first 1 to 2 years of life. [27] [28] [29] The

Rabson-Mendenhall syndrome is associated with short stature, protuberant abdomen, and abnormalities of

teeth 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 decreasing

the number of receptors expressed on the cell surface, for example, by decreasing the rate of receptor

biosynthesis (class 1), accelerating the rate of receptor degradation (class 5), or inhibiting the transport of

receptors to the plasma membrane (class 2). The intrinsic function of the receptor may be abnormal if the

affinity of insulin binding is reduced (class 3) or if receptor tyrosine kinase is inactivated (class 4). The insulin

resistance that is associated with insulin receptor mutations may be severe and present in the neonatal

period, as with leprechaunism and the Rabson-Mendenhall syndrome, or it can occur in a milder form in

adulthood, leading to insulin-resistant diabetes with marked hyperinsulinemia, acanthosis nigricans, and

hyperandrogenism.

Lipoatrophic Diabetes

In another monogenic form of diabetes, lipoatrophic diabetes, severe insulin resistance is associated with

lipoatrophy 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 partial

lipoatrophy (the Dunnigan syndrome or the Koberling-Dunnigan syndrome), an autosomal dominant form

caused by mutations in the lamin A/C gene,[32] and congenital generalized lipoatrophy (the Seip-Berardinelli

syndrome), 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-activated

receptorg (PPARg) can cause T2DM of early onset (familial lipodystrophy type 3).[35] Two different

heterozygous mutations were identified in the ligand-binding domain of PPARg in three subjects with severe

insulin resistance. In the PPARg crystal structure, the mutations destabilize helix 12, which mediates transactivation.

Both receptor mutants showed markedly decreased transcriptional activation and inhibited the

action of coexpressed wild-type PPARg in a dominant negative manner. A Dutch kindred with a -14A G

mutation within the promoter of the PPARg4 isoform, which results in decreased expression but no

qualitative protein abnormalities, has been described.[36]

A common amino acid polymorphism (Pro12Ala) in PPARg has been associated with T2DM. People

homozygous for the Pro12 allele are more insulin resistant than those having one Ala12 allele and have a

1.25-fold increased risk of diabetes. There is also evidence for interaction between this polymorphism and

fatty acids, linking this locus with diet. A second polymorphism, C161 T, has been linked to insulin

resistance in Hispanic and non-Hispanic white women.[37]

Monogenic Forms of Diabetes Associated with Defects in Insulin Secretion

Mutant Insulin Syndromes

The first syndrome associated with diabetes to be characterized in terms of the clinical picture, genetic

mechanisms, and clinical pathophysiology was that associated with mutant insulin or proinsulin.[38] Persons

with this disorder present clinically with a mild noninsulin-dependent form of diabetes. Affected persons

characteristically have marked hyperinsulinemia on routine insulin assays. Increases in the concentration of

insulin in association with diabetes usually indicate insulin resistance, but in this syndrome, insulin

resistance 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 the

hyperinsulinemia is due to the presence of the abnormal insulin or proinsulin and related breakdown

products. The increased concentrations of insulin appear to be related to the presence of mutations in

regions of the insulin molecule that are important for receptor binding, particularly the COOH terminus of the

insulin B chain.

Because the liver is the major site of insulin clearance and the first-pass hepatic insulin uptake and

degradation are mediated by the insulin receptor, mutant forms of insulin with diminished insulin receptor

binding ability are cleared more slowly from the circulation, and this reduction in insulin clearance leads to

hyperinsulinemia. 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 circulation

than insulin, proinsulin levels increase. Proinsulin cross-reacts in most commercially available assays, and

this insulin-like immunoreactivity can be characterized as related to the presence of proinsulin rather than

insulin 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 of

proinsulin to insulin, has been described.[41]

Mitochondrial Diabetes

An A-to-G transition in the mitochondrial tRNALeu(UUR) gene at base pair 3243 has been shown to be

associated with maternally transmitted diabetes and sensorineural hearing loss.[42] In other subjects, this

mutation is associated with diabetes and the syndrome of mitochondrial myopathy, encephalopathy, lactic

acidosis, and strokelike episodes (MELAS syndrome). The mitochondrion plays a key role in the regulation

of insulin secretion, particularly in response to glucose. We have documented abnormal insulin secretion on

at least one of a battery of tests in subjects with this mitochondrial mutation, even in subjects with normal or

impaired glucose tolerance who have not developed overt diabetes.[43]

Maturity-Onset Diabetes of the Young

Maturity-onset diabetes of the young (MODY) is a genetically and clinically heterogeneous group of

disorders characterized by nonketotic diabetes mellitus, an autosomal dominant mode of inheritance, onset

usually before 25 years of age and often in childhood or adolescence, and a primary defect in pancreatic

beta cell function. A detailed review of MODY has been published,[44] and the information contained in that

review is summarized.

MODY can result from mutations in any one of at least six different genes. One of these genes encodes the

glycolytic 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-1 (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, and

heterozygous mutations cause diabetes related to beta cell dysfunction. Abnormalities in liver and kidney

function 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 trigger

diabetes onset and affect the severity of hyperglycemia in MODY but do not play a significant role in the

development of MODY.

The most common clinical presentation of MODY is a mild asymptomatic increase in blood glucose in a

child, 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 many

years, whereas others have varying degrees of glucose intolerance for several years before the onset of

persistent hyperglycemia.[44] The diagnosis may be made only in adulthood even though the elevation in

plasma glucose has been present for many years. Prospective testing indicates that in most patients the

disease onset occurs in childhood or adolescence. In some patients, there may be a rapid progression to

overt asymptomatic or symptomatic hyperglycemia, necessitating therapy with an oral hypoglycemic drug or

insulin. The presence of persistently normal plasma glucose levels in subjects with mutations in any of the

known MODY genes is unusual, and the majority eventually experience diabetes (with the exception of

many patients with glucokinase mutations; see later).

Although the exact prevalence of MODY is not known, current estimates suggest that MODY might account

for 1% to 5% of all cases of diabetes in the United States and other industrialized countries.[44] Several

clinical characteristics distinguish patients with MODY from those with T2DM, including a prominent family

history of diabetes in three or more generations, young age at presentation, and absence of obesity.

Functional Effects of MODY Genes

The identification of several genes associated with diabetes has provided a unique opportunity to

characterize the pathophysiologic mechanisms by which genetic mutations can lead to an increase in the

plasma glucose concentration. All the susceptibility genes identified to date cause impaired insulin secretory

responses 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 ).