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Diabetes mellitus
Sapra A, Bhandari Fr.

Kegiatan Pendidikan Berkelanjutan

Diabetes Mellitus (DM) merupakan penyakit yang disebabkan oleh tidak adekuatnya pengendalian kadar glukosa darah. Ini memiliki banyak
subklasifikasi, termasuk tipe 1, tipe 2, diabetes onset dewasa muda (MODY), diabetes gestasional, diabetes neonatal, dan diabetes yang diinduksi
steroid. DM tipe 1 dan 2 merupakan subtipe utama, masing-masing dengan patofisiologi, presentasi, dan manajemen yang berbeda, namun
keduanya berpotensi untuk hiperglikemia. Kegiatan ini menguraikan patofisiologi, evaluasi, dan manajemen DM dan menyoroti peran tim
interprofessional dalam mengelola pasien dengan kondisi ini.

Tujuan:

Menjelaskan patofisiologi penyakit diabetes melitus.

Menjelaskan epidemiologi dan faktor risiko diabetes mellitus.
Tinjau pertimbangan pengobatan dan komplikasi umum diabetes mellitus.
Mengidentifikasi pentingnya meningkatkan kolaborasi dan koordinasi perawatan di antara tim interprofesional untuk meningkatkan
pemberian perawatan bagi pasien yang terkena diabetes mellitus.

Akses pertanyaan pilihan ganda gratis tentang topik ini.

pengantar
Diabetes mellitus diambil dari kata Yunani diabetes , yang berarti menyedot - melewati dan kata Latin  mellitus artinya manis. Tinjauan sejarah
menunjukkan bahwa istilah "diabetes" pertama kali digunakan oleh Apollonius dari Memphis sekitar 250 hingga 300 SM. Peradaban Yunani,
India, dan Mesir kuno menemukan sifat manis urin dalam kondisi ini, dan karenanya penyebaran kata Diabetes Mellitus muncul. Mering dan
Minkowski, pada tahun 1889, menemukan peran pankreas dalam patogenesis diabetes. Pada tahun 1922 Banting, Best, dan Collip memurnikan
hormon insulin dari pankreas sapi di Universitas Toronto, yang mengarah pada ketersediaan pengobatan yang efektif untuk diabetes pada tahun
1922. Selama bertahun-tahun, pekerjaan luar biasa telah dilakukan, dan banyak penemuan, serta strategi manajemen, telah diciptakan untuk
mengatasi masalah yang berkembang ini. Sayangnya, bahkan hari ini, diabetes adalah salah satu penyakit kronis yang paling umum di negara ini
dan di seluruh dunia. Di AS, itu tetap sebagai penyebab kematian ketujuh.

Diabetes mellitus (DM) adalah penyakit metabolik, yang melibatkan peningkatan kadar glukosa darah yang tidak tepat. DM memiliki beberapa
kategori, termasuk tipe 1, tipe 2, diabetes onset dewasa muda (MODY), diabetes gestasional, diabetes neonatal, dan penyebab sekunder karena
endokrinopati, penggunaan steroid, dll. Subtipe utama DM adalah diabetes tipe 1 mellitus (T1DM) dan diabetes mellitus tipe 2 (T2DM), yang
secara klasik disebabkan oleh gangguan sekresi insulin (T1DM) dan/atau tindakan (T2DM). T1DM muncul pada anak-anak atau remaja,
sedangkan T2DM diperkirakan mempengaruhi orang dewasa paruh baya dan lebih tua yang mengalami hiperglikemia berkepanjangan karena
gaya hidup dan pilihan diet yang buruk. Patogenesis DMT1 dan DMT2 sangat berbeda, oleh karena itu setiap jenis memiliki etiologi, presentasi,
dan pengobatan yang berbeda.

Etiologi
Di pulau Langerhans di pankreas, ada dua subkelas utama sel endokrin: sel beta yang memproduksi insulin dan sel alfa yang mensekresi
glukagon. Sel beta dan alfa terus-menerus mengubah kadar sekresi hormonnya berdasarkan lingkungan glukosa. Tanpa keseimbangan antara
insulin dan glukagon, kadar glukosa menjadi tidak seimbang. Dalam kasus DM, insulin tidak ada dan/atau memiliki gangguan kerja (resistensi
insulin), dan dengan demikian menyebabkan hiperglikemia.

T1DM ditandai dengan penghancuran sel beta di pankreas, biasanya sekunder akibat proses autoimun. Hasilnya adalah penghancuran mutlak sel
beta, dan akibatnya, insulin tidak ada atau sangat rendah.

T2DM melibatkan onset yang lebih berbahaya di mana ketidakseimbangan antara kadar insulin dan sensitivitas insulin menyebabkan defisit
fungsional insulin. Resistensi insulin adalah multifaktorial tetapi umumnya berkembang dari obesitas dan penuaan.

Latar belakang genetik untuk kedua jenis sangat penting sebagai faktor risiko. Ketika genom manusia dieksplorasi lebih lanjut, ada lokus berbeda
yang ditemukan yang memberi risiko DM. Polimorfisme telah diketahui mempengaruhi risiko T1DM, termasuk kompleks histokompatibilitas
utama (MHC) dan antigen leukosit manusia (HLA). [1]

T2DM melibatkan interaksi yang lebih kompleks antara genetika dan gaya hidup. Ada bukti jelas yang menunjukkan bahwa DMT2 memiliki
profil herediter yang lebih kuat dibandingkan dengan DMT1. Mayoritas pasien dengan penyakit ini memiliki setidaknya satu orang tua dengan

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DMT2. [2]

Kembar monozigot dengan salah satu kembar yang terkena memiliki kemungkinan 90% dari kembar lainnya mengembangkan DMT2 dalam
hidupnya. [3]  Sekitar 50 polimorfisme sampai saat ini telah dijelaskan untuk berkontribusi pada risiko atau perlindungan untuk T2DM. Gen-gen
ini mengkode protein yang terlibat dalam berbagai jalur yang mengarah ke DM, termasuk perkembangan pankreas, sintesis insulin, sekresi, dan
pengembangan, deposisi amiloid dalam sel beta, resistensi insulin, dan gangguan regulasi glukoneogenesis. Sebuah studi asosiasi genome-wide
(GWAS) menemukan lokus genetik untuk faktor transkripsi 7-seperti 2 gen (TCF7L2), yang meningkatkan risiko T2DM. [4] [5]  Lokus lain yang
berimplikasi pada perkembangan DMT2 termasuk NOTCH2, JAZF1, KCNQ1, dan WFS1. [6] [7]

MODY adalah kelainan heterogen yang diidentifikasi oleh diabetes non-insulin-dependent yang didiagnosis pada usia muda (biasanya di bawah
25 tahun). Ini membawa transmisi dominan autosomal dan tidak melibatkan autoantibodi seperti pada T1DM. Beberapa gen memiliki implikasi
pada penyakit ini, termasuk mutasi pada hepatosit nuclear factor-1-alpha (HNF1A) dan gen glukokinase (GCK), yang terjadi pada 52 hingga 65
dan 15 hingga 32 persen kasus MODY. [8] [9]  Genetika penyakit ini masih belum jelas karena beberapa pasien memiliki mutasi tetapi tidak
pernah mengembangkan penyakit, dan yang lain akan mengembangkan gejala klinis MODY tetapi tidak memiliki mutasi yang dapat
diidentifikasi.

Diabetes gestasional pada dasarnya adalah diabetes yang bermanifestasi selama kehamilan. Masih belum diketahui mengapa itu berkembang;
namun, beberapa berspekulasi bahwa antigen HLA mungkin berperan, khususnya HLA DR2, 3, dan 4. Proinsulin yang berlebihan juga dianggap
berperan dalam diabetes gestasional, dan beberapa menyarankan bahwa proinsulin dapat menginduksi stres sel beta. Yang lain percaya bahwa
konsentrasi tinggi hormon seperti progesteron, kortisol, prolaktin, laktogen plasenta manusia, dan estrogen dapat mempengaruhi fungsi sel beta
dan sensitivitas insulin perifer. [10]

Beberapa endokrinopati, termasuk akromegali, sindrom Cushing, glukagonoma, hipertiroidisme, hiperaldosteronisme, dan somatostatinoma, telah
dikaitkan dengan intoleransi glukosa dan diabetes mellitus, karena aksi glukogenik yang melekat dari hormon endogen yang disekresikan secara
berlebihan dalam kondisi ini. Kondisi seperti hemokromatosis idiopatik berhubungan dengan diabetes mellitus karena deposisi besi yang
berlebihan di pankreas dan penghancuran sel beta.

Epidemiologi
Secara global, 1 dari 11 orang dewasa menderita DM (90% menderita DMT2). Onset DMT1 secara bertahap meningkat sejak lahir dan mencapai
puncaknya pada usia 4 sampai 6 tahun dan kemudian meningkat lagi dari 10 sampai 14 tahun. [11]  Sekitar 45% dari anak-anak hadir sebelum
usia sepuluh tahun. [12]  Prevalensi pada orang di bawah usia 20 adalah sekitar 2,3 per 1000. Sementara sebagian besar penyakit autoimun lebih
sering terjadi pada wanita, tidak ada perbedaan gender yang jelas dalam kejadian DMT1 masa kanak-kanak. Pada beberapa populasi, seperti pada
pria tua asal Eropa (lebih dari 13 tahun), mereka mungkin lebih mungkin mengembangkan DMT1 dibandingkan dengan wanita (rasio 3:2 pria
dan wanita). [13]  Insiden DMT1 telah meningkat di seluruh dunia. Di Eropa, Australia, dan Timur Tengah, tarif meningkat sebesar 2% hingga
5% setiap tahun. [14][15] [16]  Di Amerika Serikat, tingkat T1DM meningkat di sebagian besar kelompok usia dan etnis sekitar 2% setiap tahun,
dan tingkat lebih tinggi pada remaja Hispanik. [17]  Alasan pasti untuk pola ini masih belum diketahui. Namun, beberapa metrik, seperti gudang
data Sistem Kesehatan Militer Amerika Serikat, ditemukan stabil selama 2007 hingga 2012 dengan prevalensi 1,5 per 1000 dan insiden 20,7
hingga 21,3 per 1000. [18]

Timbulnya DMT2 biasanya di kemudian hari, meskipun obesitas pada remaja telah menyebabkan peningkatan DMT2 pada populasi yang lebih
muda. T2DM memiliki prevalensi sekitar 9% pada total populasi Amerika Serikat, tetapi sekitar 25% pada mereka yang berusia di atas 65 tahun.
Federasi Diabetes Internasional memperkirakan bahwa 1 dari 11 orang dewasa antara 20 dan 79 tahun menderita DM secara global pada tahun
2015. Para ahli memperkirakan prevalensi DM meningkat dari 415 menjadi 642 juta pada tahun 2040, dengan peningkatan paling signifikan pada
transisi populasi dari rendah ke menengah. tingkat pendapatan. [19]  DMT2 bervariasi di antara kelompok etnis dan 2 hingga 6 kali lebih umum
pada orang kulit hitam, penduduk asli Amerika, orang Indian Pima, dan orang Amerika Hispanik dibandingkan dengan orang kulit putih di
Amerika Serikat. [20] [21] Sementara etnis saja memainkan peran penting dalam T2DM, faktor lingkungan juga sangat memberikan risiko
penyakit. Misalnya, orang Indian Pima di Meksiko lebih kecil kemungkinannya untuk mengembangkan DMT2 dibandingkan dengan orang
Indian Pima di Amerika Serikat (6,9% vs. 38%). [22]

Patofisiologi
Seorang penderita DM berpotensi mengalami hiperglikemia. Patologi DM dapat tidak jelas karena beberapa faktor sering dapat berkontribusi
pada penyakit ini. Hiperglikemia saja dapat mengganggu fungsi sel beta pankreas dan berkontribusi terhadap gangguan sekresi insulin.
Akibatnya, ada lingkaran setan hiperglikemia yang mengarah ke keadaan metabolisme yang terganggu. Kadar glukosa darah di atas 180 mg/dL
sering dianggap hiperglikemik dalam konteks ini, meskipun karena berbagai mekanisme, tidak ada titik batas yang jelas. Pasien mengalami
diuresis osmotik karena kejenuhan transporter glukosa di nefron pada kadar glukosa darah yang lebih tinggi. Meskipun efeknya bervariasi, kadar
glukosa serum di atas 250 mg/dL cenderung menyebabkan gejala poliuria dan polidipsia.

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Resistensi insulin disebabkan oleh kelebihan asam lemak dan sitokin proinflamasi, yang menyebabkan gangguan transportasi glukosa dan
meningkatkan pemecahan lemak. Karena ada respons atau produksi insulin yang tidak memadai, tubuh merespons dengan meningkatkan
glukagon secara tidak tepat, sehingga selanjutnya berkontribusi pada hiperglikemia. Sementara resistensi insulin adalah komponen dari DMT2,
tingkat penuh penyakit terjadi ketika pasien memiliki produksi insulin yang tidak memadai untuk mengkompensasi resistensi insulin mereka. 

Hiperglikemia kronis juga menyebabkan glikasi nonenzimatik protein dan lipid. Tingkat ini dapat diukur melalui tes glikasi hemoglobin (HbA1c).
Glikasi menyebabkan kerusakan pada pembuluh darah kecil di retina, ginjal, dan saraf perifer. Kadar glukosa yang lebih tinggi mempercepat
proses. Kerusakan ini menyebabkan komplikasi diabetes klasik retinopati diabetik, nefropati, dan neuropati dan hasil yang dapat dicegah dari
kebutaan, dialisis, dan amputasi, masing-masing. [23]

Sejarah dan Fisik

During patient history, questions about family history, autoimmune diseases, and insulin-resistant are critical to making the diagnosis of DM. It
often presents asymptomatically, but when symptoms develop, patients usually present with polyuria, polydipsia, and weight loss. On physical
examination of someone with hyperglycemia, poor skin turgor (from dehydration) and a distinctive fruity odor of their breath (in patients with
ketosis) may be present. In the setting of diabetic ketoacidosis (DKA), clinicians may note Kussmaul respirations, fatigue, nausea, and vomiting.
Funduscopic examination in a patient with DM may show hemorrhages or exudates on the macula. In frank diabetic retinopathy, retinal venules
may appear dilated or occluded. The proliferation of new blood vessels is also a concern for ophthalmologists and can hasten retinal hemorrhages
and macular edema, ultimately resulting in blindness. While T1DM and T2DM can present similarly, they can be distinguished based on clinical
history and examination. T2DM patients are typically overweight/obese and present with signs of insulin resistance, including acanthosis
nigricans, which are hyperpigmented, velvety patches on the skin of the neck, axillary, or inguinal folds. Patients with a longer course of
hyperglycemia may have blurry vision, frequent yeast infections, numbness, or neuropathic pain. The clinicians must ask the patient bout any
recent skin changes in their feet during each visit. The diabetic foot exam, including the monofilament test, should be a part of the routine
physical exam.

Evaluation
The diagnosis of T1DM is usually through a characteristic history supported by elevated serum glucose levels (fasting glucose greater than 126
mg/dL, random glucose over 200 mg/dL, or hemoglobin A1C (HbA1c exceeding 6.5%) with or without antibodies to glutamic acid
decarboxylase (GAD) and insulin.

Fasting glucose levels and HbA1c testing are useful for the early identification of T2DM. If borderline, a glucose tolerance test is an option to
evaluate both fasting glucose levels and serum response to an oral glucose tolerance test (OGTT). Prediabetes, which often precedes T2DM,
presents with a fasting blood glucose level of 100 to 125 mg/dL or a 2-hour post-oral glucose tolerance test (post-OGTT) glucose level of 140 to
200 mg/dL.[24][25]

According to the American Diabetes Association (ADA), a diagnosis of diabetes is through any of the following: An HbA1c level of 6.5% or
higher; A fasting plasma glucose level of 126 mg/dL (7.0 mmol/L) or higher (no caloric intake for at least 8 hours); A two-hour plasma glucose
level of 11.1 mmol/L or 200 mg/dL or higher during a 75-g OGTT; A random plasma glucose of 11.1 mmol/L or 200 mg/dL or higher in a patient
with symptoms of hyperglycemia (polyuria, polydipsia, polyphagia, weight loss) or hyperglycemic crisis.[24] The ADA recommends screening
adults aged 45 years and older regardless of risk, while the United States Preventative Service Task Force suggests screening individuals between
40 to 70 years who are overweight.[26].

To test for gestational diabetes, all pregnant patients have screening between 24 to 28 weeks of gestation with a 1-hour fasting glucose challenge
test. If blood glucose levels are over 140mg/dL, patients have a 3-hour fasting glucose challenge test to confirm a diagnosis. A positive 3-hours
OGTT test is when there is at least one abnormal value (greater than or equal to 180, 155, and 140 mg/dL for fasting one-hour, two-hour, and 3-
hour plasma glucose concentration, respectively).[27]

Several lab tests are useful in the management of chronic DM. Home glucose testing can show trends of hyper- and hypoglycemia. The HbA1c
test indicates the extent of glycation due to hyperglycemia over three months (the life of the red blood cell). Urine albumin testing can identify the
early stages of diabetic nephropathy. Since patients with diabetes are also prone to cardiovascular disease, serum lipid monitoring is advisable at
the time of diagnosis. Similarly, some recommend monitoring thyroid status by obtaining a blood level of thyroid-stimulating hormone annually
due to a higher incidence of hypothyroidism.[24][25]

Treatment / Management
The physiology and treatment of diabetes are complex and require a multitude of interventions for successful disease management. Diabetic
education and patient engagement are critical in management. Patients have better outcomes if they can manage their diet (carbohydrate and
overall caloric restriction), exercise regularly (more than 150 minutes weekly), and independently monitor glucose.[28] Lifelong treatment is

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often necessary to prevent unwanted complications. Ideally, glucose levels should be maintained at 90 to 130 mg/dL and HbA1c at less than 7%.
While glucose control is critical, excessively aggressive management may lead to hypoglycemia, which can have adverse or fatal outcomes.

Since T1DM is a disease primarily due to the absence of insulin, insulin administration through daily injections, or an insulin pump, is the
mainstay of treatment. In T2DM, diet and exercise may be adequate treatments, especially initially. Other therapies may target insulin sensitivity
or increase insulin secretion by the pancreas. The specific subclasses for drugs include biguanides (metformin), sulfonylureas, meglitinides,
alpha-glucosidase inhibitors, thiazolidinediones, glucagonlike-peptide-1 agonist, dipeptidyl peptidase IV inhibitors (DPP-4), selective,
amylinomimetics, and sodium-glucose transporter-2 (SGLT-2) inhibitors. Metformin is the first line of the prescribed diabetic medications and
works by lowering basal and postprandial plasma glucose. Insulin administration may also be necessary for T2DM patients, especially those with
inadequate glucose management in the advanced stages of the disease. In morbidly obese patients, bariatric surgery is a possible means to
normalize glucose levels. It is recommended for individuals who have been unresponsive to other treatments and who have significant
comorbidities.[29] The GLP-1 agonists liraglutide and semaglutide correlate with improved cardiovascular outcomes. The SGLT-2 inhibitors
empagliflozin and canagliflozin have also shown to improve cardiovascular outcomes along with potential renoprotection as well as prevention
for the development of heart failure.

Regular screenings are necessary since microvascular complications are a feared complication of diabetes. Regular diabetic retinal exams should
be performed by qualified medical personnel to assess for diabetic retinopathy. Neurologic examination with monofilament testing can identify
patients with neuropathy at risk for amputation. Clinicians can also recommend patients perform daily foot inspections to identify foot lesions that
may go unnoticed due to neuropathy. Low-dose tricyclic antidepressants, duloxetine, anticonvulsants, topical capsaicin, and pain medications
may be necessary to manage neuropathic pain in diabetes. Urine microalbumin testing can also assess for early renal changes from diabetes with
albuminuria greater than 30mg/g creatinine along with the estimated GFR. The antiproteinuric effect of the angiotensin-converting enzyme
(ACE) inhibitors and the angiotensin receptor blockers (ARBs) makes them the preferred agents to delay the progression from microalbuminuria
to macroalbuminuria in patients with both Type 1 or Type 2 diabetes mellitus.

The FDA has approved pregabalin and duloxetine for the treatment of diabetic peripheral neuropathy. Tricyclic antidepressants and
anticonvulsants have also seen use in the management of the pain of diabetic neuropathy with variable success. 

The ADA also recommends regular blood pressure screening for diabetics, with the goal being 130 mmHg systolic blood pressure and 85 mmHg
diastolic blood pressure.[30] Pharmacologic therapy for hypertensive diabetics typically involves angiotensin-converting enzyme inhibitors,
angiotensin receptor blockers, diuretics, beta-blockers, and/or calcium channel blockers. The ADA recommends lipid monitoring for diabetics
with a goal of low-density lipoprotein cholesterol (LDL-C) being less than 100 mg/dL if no cardiovascular disease (CVD) and less than 70 mg/dl
if atherosclerotic cardiovascular disease (ASCVD) is present. Statins are the first-line treatment for the management of dyslipidemia in diabetics.
The ADA suggests that low dose aspirin may also be beneficial for diabetic patients who are at high risk for cardiovascular events; however, the
role of aspirin in reducing cardiovascular events in patients with diabetes remains unclear.[31][32][33]

Differential Diagnosis
In addition to T1DM, T2DM, and MODY, any disorder that damages the pancreas can result in DM. There are several diseases of the exocrine
pancreas, including:[34] 

Cystic fibrosis
Hereditary hemochromatosis
Pancreatic cancer
Chronic pancreatitis

Hormonal syndromes that can lead to impaired insulin secretion include:

Pheochromocytoma
Acromegaly
Cushing syndrome

Drug-induced insulin resistance is also in the differential of classical diabetes. These drugs include:

Phenytoin
Glucocorticoids
Estrogen

Other diseases in the differential of diabetes mellitus include:

Gestational diabetes[10]
Thyroid disorders

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Pertinent Studies and Ongoing Trials

Various trials have been undertaken to understand the cardiovascular outcomes with antidiabetic medications. The LEADER (Liraglutide Effect
and Action in Diabetes: Evaluation of Cardiovascular Outcome Results), was a double-blinded trial comparing the use of liraglutide, which is a
GLP -1 agonist to placebo in around 10000 patients. After a follow-up period of about four years, liraglutide was shown to reduce mortality from
cardiovascular causes as well as all-cause mortality. It also seemed to reduce the first occurrence of the first nonfatal myocardial infarction (MI)
and stroke.

The EMPA-REG OUTCOME trial ([Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) have shown
considerable reductions in mortality and heart failure hospitalization risks in patients with type 2 diabetes mellitus (T2D), by and cardiovascular
disease with empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor.

The CANVAS trial (Canagliflozin Cardiovascular Assessment Study) subsequently reported a reduction in 3-point major adverse cardiovascular
events and heart failure (HF) hospitalization risk. The proposed mechanism through which SGLT2 inhibitors work helps patients with heart
failure is via the promotion of natriuresis and osmotic diuresis and reduced preload. SGLT2 inhibition is also associated with the preservation of
renal function. Based on data from mechanistic studies and clinical trials, large clinical trials with SGLT2 inhibitors are now investigating the
potential use of SGLT2 inhibition in patients who have HF with and without T2 diabetes mellitus.

Toxicity and Side Effect Management

One of the most common adverse effects of insulin is hypoglycemia. Gastrointestinal upset is the most common side effect of many of the T2DM
medications. Metformin can lead to lactic acidosis and should be used with caution in patients with renal disease and discontinued if the estimated
glomerular filtration rate (e-GFR) is under 30 mL/min. Sulfonylureas can lead to hypoglycemia and may promote cardiovascular death in patients
with diabetes.[35] Thiazolidinediones have fallen out of favor in clinical practice due to their adverse effects, specifically resulting in fluid
retention, worsening heart failure, and fractures.[36][37] DPP-4 may increase the risk for upper respiratory tract infections but may have less
nausea and diarrhea compared to other drugs such as metformin.[38][39] SGLT-2 inhibitors can lead to increased urinary tract infections due to
increased urinary glucose excretion.[40] Both SGLT2 inhibitors and GLP-1 Receptor agonists reduce ASCVD events and are now considered the
second line to metformin in such patients.

Prognosis
Diabetes mellitus was the seventh leading cause of death in the United States in 2015.[41] The prognosis of DM gets significantly influenced by
the degree of glucose management. Chronic hyperglycemia significantly increases the risk of DM complications. The Diabetes Control and
Complications Trial and the United Kingdom Prospective Diabetes Study found that individuals with T1DM and T2DM respectively had
increased microvascular complications with chronic hyperglycemia.[42][43] Patients who can revert to normal glucose during the progression
from pre-diabetes to frank DM had a good prognosis and may be able to slow disease progression.[44]

Complications
Regardless of the specific type of diabetes, complications involve microvascular, macrovascular, and neuropathic issues. Microvascular and
macrovascular complications vary according to the degree and the duration of poorly control diabetes and include nephropathy, retinopathy,
neuropathy, and ASCVD events, especially if it is associated with other comorbidities like dyslipidemia and hypertension.[45] One of the most
devastating consequences of DM is its effect on cardiovascular disease (ASCVD). Approximately two-thirds of those with DM will die from a
myocardial infarction or stroke.[46] In T2DM, fasting glucose of more than 100 mg/dL significantly contributes to the risk of ASCVD, and
cardiovascular risk can develop before frank hyperglycemia.[47][48]

DM is also a common cause of blindness in adults aged 20 to 74 years in the United States. Diabetic retinopathy contributes to 12000 to 24000
new cases of blindness annually, and treatments generally consist of laser surgery and glucose control.[49]

Renal disease is another significant cause of morbidity and mortality in DM patients. It is the leading contributor to end-stage renal disease
(ESRD) in the United States, and many patients with ESRD will need to start dialysis or receive a kidney transplant.[49] If the albuminuria
persists in the range of 30 to 300 mg/day (microalbuminuria), it seems to be a predictable earliest marker for the onset of diabetic neuropathy.
Once macroalbuminuria (greater than 300 mg/24 hr) sets in, the progression to ESRD hastens up. The random spot urine specimen for
measurement of the albumin-to-creatinine ratio is a quick, easy, predictable method that is the most widely used and preferred method to detect
microalbuminuria. Two of three tests, done over a six month showing a persistent level greater than 30 mcg/mg creatinine, confirms the diagnosis
of microalbuminuria.

DM is also the leading cause of limb amputations in the United States; this is primarily due to vasculopathy and neuropathy associated with DM.
[49] Many patients who develop neuropathy need to have regular foot exams to prevent infection from wounds that go unnoticed.

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The duration of diabetes is the most crucial risk factor for the development of diabetic retinopathy. In people with type 1 diabetes, it typically sets
in about 5 years after disease onset. Hence it is recommended to start the yearly retinal exams in these patients about five years after diagnosis.
Among patients with type 2 diabetes, many patients might already have retinal changes at the time of diagnosis. Approximately 10% at ten years,
40% at 15 years, and 60% at 20 years will have nonproliferative retinal disease. In these patients, the recommendation is to start the yearly retinal
screening at the time of diagnosis. Study after study has shown that reasonable glycemic control favorably affected the onset and progression of
diabetic retinopathy. Uncontrolled blood pressure is an added risk factor for macular edema. Lowering the blood pressure in patients with diabetes
thus also affects the risk of progression of the retinopathy. Injection of antibodies vascular endothelial growth factor (anti-VEGF) agents are
generally in use as the initial therapy in cases of macular edema. In cases of nonproliferative diabetic retinopathy, pan-retinal photocoagulation is
being used. In cases of diabetic proliferative retinopathy, combined modalities of anti-VEGF agents and pan-retinal photocoagulation are now in
use. Sudden loss of vision can occur for several reasons in patients with diabetes mellitus, the most common being vitreous hemorrhage. Less
common causes that merit consideration include vascular occlusion (central retinal vein or branch vein occlusion involving the macula), retinal
detachment, end-stage glaucoma, and ischemic optic neuropathy.

Furthermore, evidence suggests that T2DM may also contribute to cancer development, specifically bladder cancer, in those using pioglitazone.
[50] Patients using metformin had improved cancer-specific survival in those with prostate, pancreatic, breast, and colorectal cancers. However, it
is unclear how metformin plays a role in modulating cancer in patients with diabetes.[51]

Those with gestational diabetes are at a higher risk for cesarean delivery and chronic hypertension. Pregnant patients with T2DM generally have a
better prognosis in terms of neonatal and pregnancy complications compared to those with T1DM. Generally, neonates of DM mothers will
present with hypoglycemia and macrosomia.[52]

The most acute complication of DM is diabetic ketoacidosis (DKA), which typically presents in T1DM. This condition is usually either due to
inadequate dosing, missed doses, or ongoing infection.[53] In this condition, the lack of insulin means that tissues are unable to obtain glucose
from the bloodstream. Compensation for this causes the metabolism of lipids into ketones as a substitute energy source, which causes systemic
acidosis, and can be calculated as a high anion-gap metabolic acidosis. The combination of hyperglycemia and ketosis causes diuresis, acidemia,
and vomiting leading to dehydration and electrolyte abnormalities, which can be life-threatening. In T2DM, hyperosmolar hyperglycemic
syndrome (HHS) is an emergent concern. It presents similarly to DKA with excessive thirst, elevated blood glucose, dry mouth, polyuria,
tachypnea, and tachycardia. However, unlike DKA, HHS typically does not present with excessive urinary ketones since insulin still gets
produced by pancreatic beta cells. Treatment for DKA or HHS involves insulin administration and aggressive intravenous hydration. Careful
management of electrolytes, particularly potassium, is critical in the management of these emergent conditions.[54]

Deterrence and Patient Education

Healthcare professionals should take an active approach to educate patients with DM. It is misguided for patients to think that lifestyle changes
for a limited time are appropriate, and instead, lifelong lifestyle changes may be necessary to control their DM adequately. A randomized,
controlled trial identified that individualized education is more effective compared to group education in patients who had poorly controlled DM.
[55] Often, non-clinician healthcare professionals (e.g., nurses, pharmacists) have extensive training in DM education and have more time for
individualized education.

Pearls and Other Issues

Amino acid metabolism may play a critical role in the development of T2DM. Studies have shown that there is a 4-fold increase in isoleucine,
phenylalanine, and tyrosine in individuals with hyperglycemia. Researchers found that these amino acids were elevated up to 12 years before the
onset of the disease.[56] Recent studies have further elucidated the role of these metabolites in the development, screening, and treatment of
metabolic syndrome (MetS), a cardiometabolic cluster that predisposes patients to T2DM and CVD. Studies have shown that choline, L-carnitine,
and trimethylamine-N-oxide were associated with inflammatory pathways and increased the risk of metabolic dysfunction in nascent MetS
patients, who meet classification for MetS but do not have T2DM and cardiovascular disease.[57] Literature has also shown increased levels of
isoleucine and tyrosine and decreased levels of lysine and methionine. These metabolites appear to be early biomarkers of nascent MetS and
significant contributors to the pro-inflammatory burden of MetS.

Low levels of lysine, in particular, were associated with increased inflammation and elevated blood glucose. Thus, increased dietary lysine may
promote anti-inflammatory effects.[58] In a recent investigation, researchers found phosphatidylcholine 34:2, PC (34:2), GABA, and d-
pyroglutamic acid (PGA) were significantly increased in nascent MetS and correlated positively with certain inflammatory parameters.[59]
[60] These findings further support the role of metabolites in the early development of T2DM and suggest that they may have a role in the pro-
inflammatory state associated with diabetes.

Enhancing Healthcare Team Outcomes

https://www.ncbi.nlm.nih.gov/books/NBK551501/ 6/10
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Primary care clinicians are often the first to identify diabetes in their patients. Since DM is a complex disease, it requires an interprofessional
team approach to management. Nurse practitioners and physician assistants can be critical to ensuring proper patient follow-ups and monitoring
the efficacy of treatments. Nutritionists and diabetes educators can also provide consultations to help educate patients on appropriate lifestyle
modifications and at-home glucose management.

Ophthalmologists, neurologists, podiatrists, and nephrologists may also be part of the healthcare team to ensure that patients with DM have
adequate screenings to prevent devastating microvascular complications. Endocrinologists may be consulted when patients have a complex
presentation or are unresponsive to initial treatments. Of course, pharmacists play a crucial role in evaluating proper medication administration
and preventing polypharmacy in DM patients who are often taking multiple medications for the frank disease and its complications; they can
ensure optimal dosing and recommend the most efficient regimens to achieve glycemic control, and also educate the patient on the medications
and disease process.

Sperl-Hillen et al. found that patients with suboptimally controlled diabetes had better glucose control outcomes when given individualized
education compared to group education. These patients also had better psychosocial and behavioral outcomes.[55] Consequentially this
emphasizes the role of an interprofessional team approach, including clinicians, specialists, specialty trained diabetic nurses educators, and
pharmacists who are conversing across disciplines to optimize patient-specific management leading to improved outcomes. [Level 5]

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Publication Details

Author Information

Authors

Amit Sapra1; Priyanka Bhandari2.

Affiliations
1
Southern Illinois University School of Medicine
2
Southern Illinois University School of Medicine

Publication History

Last Update: September 18, 2021.

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