For nothing is secret, that shall not be made manifest; neither any thing hid, that shall not

be known and come abroad.

(Luke 8:17, KJV)

Diabetes Mellitus & Metabolic Syndrome

Mangatas SMM
Endocrinology, Metabolism & Diabetes Division Internal Medicine Department Faculty of Medicine, Udayana University / Sanglah Hospital Denpasar - Bali

Definition
* Diabetes (also known as diabetes mellitus) has several forms, but each is characterized by excessively high blood glucose (hyperglycaemia). The hyperglycaemia is caused by either defects in insulin production or insensitivity to insulin, or both (IDF, 2005). * a group of chronic metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both (ADA, 2007).
The chronic hyperglycemia of diabetes is associated with longterm damage, dysfunction, and failure of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels

Diabetes Fact Sheet (CDC 2003)

6th Leading Cause of Death 2000 Total Population Diagnosed Undiagnosed
older)

18.2 million (6.3% of population) 13 million 5.2 million

New cases diagnosed q year (20 years and 1.3 million Prevalence by Race Native Americans Whites African-Americans Hispanic/Latino Americans Direct medical costs Indirect costs 14.9% 12.5% 11.4% 8.2% Cost of Diabetes 2002 92 billion 40 billion Increase in Children not Breast-fed Northern European Countries Asian Population 40 per 100,000 Japan 1 2 per 100,000

Global Projections for the Diabetes Epidemic: 2003-2025

NA EUR

23.0 M 36.2 M 57.0%

48.4 M 58.6 M 21%

EMME

WP SEA

19.2 M 39.4 M 105%

AFR

39.3 M 81.6 M 108%

43.0 M 75.8 M 79%

World
2003 = 194 M 2025 = 333 M 72%

SACA

14.2 M 26.2 M 85%

7.1M 15.0 M 111%

2003 2025
M = million, AFR = Africa, NA = North America, EUR = Europe, SACA = South and Central America, EMME = Eastern Mediterranean and Middle East, SEA = South-East Asia, WP = Western Pacific Diabetes Atlas Committee. Diabetes Atlas 2nd Edition: IDF 2003. 2005. American College of Physicians.

Countries with highest Numbers of estimated Diabetes Mellitus (WHO, 2003)

Ranking Country 1 2 3 4 5 6 7 8 9 10 India China U.S. Indonesia Japan Pakistan Russian Federation Brazil Italy Bangladesh 2000 People w/DM (millions) 31.7 20.8 17.7 8.4 6.8 5.2 4.6 4.6 4.3 3.2 Country India China U.S. Indonesia Japan Pakistan Russian Federation Brazil Italy Bangladesh 2030 People w/DM (millions) 79.4 42.3 30.3 21.3 13.9 11.3 11.1 8.9 7.8 6.7

1 in every 8 New Yorkers (1,000,000) has diabetes (2006)

Etiologic Classification of DM
Type 1 Type 2 Other specific types b-cell destruction with lack of insulin Insulin resistance with insulin deficiency Genetic defects in b-cell function, exocrine pancreatic diseases, endo crinopathies, drug- or chemicalinduced, and other rare forms Insulin resistance with b-cell dysfunction

Gestational

Adapted from The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 1997;20:1183 - 1 1 97.

4 tipe DM
DM Tipe 1 : usia < 30 thn; tergantung insulin; 5-12 % dari seluruh kasus DM; kadar insulin tubuh rendah DM Tipe 2 : usia > 40 thn; tdk tergantung insulin (awalnya, pada tahap lanjut atau jika tidak ditangani dgn baik akan tergantung insulin ); 85-90 % dari seluruh kasus DM, faktor keturunan & diet + life style; kadar insulin tubuh tinggi DM Tipe 3 : terutama pada usia pertengahan; akibat penyakit pada pankreas atau pemakaian obat2an tertentu, misalnya kortikosteroid (prednison, deksametason) yang lama, eg pada asma bronkial & terapi kanker atau peny rematik; tergantung atau tidak tergantung insulin DM Tipe 4 : DM pada ibu hamil; tergantung insulin Yang jadi masalah kesehatan utama buat kita : DM Tipe 2

Physiology
Normal glucose range: 60 -150 mg/dL Normal plasma glucose levels are critical to survival, because glucose is main fuel for CNS CNS does not synthesize glucose and only stores a few minutes supply of glucose. Brief hypoglycemia can cause profound brain dysfunction Prolonged severe hypoglycemia can cause cellular death

Glucose
Derived from 3 sources:
1. intestinal absorption 2. glycogenolysis glycogen breakdown 3. gluconeogenesis glucose formed from precursors such as lactate, pyruvate, amino acids, glycerol

After glucose ingestion, plasma levels rise and endogenous production is suppressed.

12 jam

Fisiologi
Glukosa plasma Insulin plasma (after
meal)

Makan

usus

Glukosa masuk sel Glukosa plasma

insulin basal

ATP/Energi

Deposit : - hati (2/3) - otot (1/3)

5-7 jam

Glikogenesis

Glikogenolisis

Glukosa darah normal

Liver and Kidney

Liver and kidney contain glucose-6-phosphatase enzyme necessary for the release of glucose into the circulation The liver is the sole source of endogenous glucose production in normal conditions Hepatocytes do not require insulin for glucose transport across cell membrane But, insulin augments hepatocyte glucose uptake and storage for energy Insulin inhibits hepatic gluconeogenesis and glycogenolysisThe renald treshold level of glucose is about 180 mg/dl & if the blood glucose exceeds 300 mg/dl, the tubules cannot absorb anything The kidney undergoes gluconeogenesis under prolonged starvation.

Muscle cells
Can store and use glucose via glycolysis In muscle: glucose pyruvate Pyruvate lactate or alanine transported to liver precursor for gluconeogenesis Fasting conditions: L glucose uptake use fatty acids as energy, mobilize amino acids to liver for energy.

Counterregulatory hormones
Glucagon
The major catabolic agent that increases blood glucose cells of pancreas Released in response to hypoglycemia, stress, trauma, infection, starvation. Decreases glycolysis, increases gluconeogenesis Increases ketone production in liver

Epinephrine K hepatic glucose production and limits

glucose use through a and b adrenergic mechanisms acts directly: glycogenolysis, gluconeogenesis

Norepinephrine similar to epinephrine Growth hormone and cortisol initially L glucose,

but long-term will K glucose

Endogenous Insulin
Protein Hormone Secreted by Beta Cells-Pancreas 1-2 Units per hour 4-6 Units per meal
1 units x 24hrs + 4 units x 3 meals

Total 36 Units per day

Insulin actions
Increase cell membrane permeability for glucose to enter it. Increase glucose phosphorylation Increase glycogenesis Increase fat synthesis (glycerol) Suppress glucagon and epinephrine release

Falling blood glucose levels

Glucagon released: glycogenolysis Epinephrine/norepi released: fat metabolism enhanced > glycogenolysis Cortisol : enhanced fat metabolism Growth hormone : enhanced Insulin production and release inhibited

Patogenesis DM
DMT1 : destruksi sel B pankreas karena proses autoimun, faktor genetik berperan penting DMT2 : resistensi insulin + disfungsi sel B faktor lingkungan sangat berperan disamping faktor genetik

Type 1 Diabetes Mellitus

Demonstrates pancreatic atrophy and specific loss of beta cells Macrophages, T and B lymphocytes, and natural killer cells are present Two types
Immune Nonimmune

Type 1 Diabetes Mellitus

Pathogenesis of type 1 Diabetes

MA Atkinson and GS Eisenbarth (2001) Lancet 358:221

Islets of Langerhans Stress Adipocytes

-cell destruction
tisol r o C , i p E GH

Insulin Deficiency

Decreased Glucose Utilization & Increased Production Muscle Increased Protein Catabolism FattyAcids Liver Increased Ketogenesis Gluconeogenesis, Glycogenolysis Glucagon

Amino Acids

IncreasedLipolysis

Polyuria Volume Depletion Ketonuria

Threshold 180 mg/dl

Hyperglycemia Ketoacidosis HyperTG

 Type I: IDDM
Clinical Presentation
Polydipsia - BGL = intracellular dehydration and hypothalamus thirst response Polyuria - BGL = Glycosuria and osmotic diuresis Polyphagia - cellular carbohydrate, fat, and protein = cellular starvation Weight loss Due to loss of body fluid and tissue Fatigue Poor use of food products

Type 2 diabetes
Characterized by chronic hyperglycemia Associated with microvascular and macrovascular complications Generally arises from a combination of insulin resistance and -cell dysfunction

Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Department of Noncommunicable Disease Surveillance, World Health Organization, Geneva 1999. Available at: http://www.diabetes.org.uk/infocentre/carerec/diagnosi.doc

Risk Factors of T2DM

Family History Obesity (BMI > 25) Race/Ethnicity (AfricanAmerican, HispanicAmerican, Native Americans, Asian Americans, Pacific Islanders) Age > 45 Hypertension (> 140/90) Smoking Family History HDL Cholesterol < 45 Triglycerides > 150 History of GDM History of Macrosomia Polycystic Ovarian Disease Previous Abnormal Screening Physically Inactive Vascular Disease

Pathogenesis of Type 2 Diabetes

Progression to Type 2 Diabetes

Genetics Insulin resistance Hyperinsulinemia Compensated insulin resistance Normal glucose tolerance Impaired glucose tolerance Genetics -cell "failure" Type 2 diabetes Insulin resistance Hepatic glucose output Insulin secretion
FFA = free fatty acid. Kruszynska Y, Olefsky JM. J Invest Med. 1996;44:413-428. 2005. American College of Physicians. All Rights Reserved.

Acquired Obesity Sedentary lifestyle Aging

Acquired Glucotoxicity FFA levels Other

Causes of Hyperglycemia in Type 2 Diabetes

1 Intestine: glucose absorption Insulin resistance

2 Muscle and adipose tissue: decreased glucose uptake

Blood glucose
4 Liver: increased hepatic glucose output

Insulin resistance
3 Pancreas: impaired insulin secretion
DeFronzo RA. Diabetes. 1988;37:667-687. Lebovitz HE. In Joslin's Diabetes Mellitus. 1994:508-529.

Gejala klinis
* Poliuria & Polakisuria (banyak b.a.k, > 10 x / hari, jumlah total urin > 4
L/24 jam, dgn vol urine/tiap b.a.k > 500 cc), nocturia (b.a.k malam > 4 x) * Polidipsia (haus terus meskipun sudah banyak minum) Dehidrasi & gangguan keseimbangan elektrolit * Unexplained weight loss (banyak makan tapi BB terus) Badan lemah, cepat capai, lesu * Polifagia (lapar terus meskipun sdh banyak makan, porsi makan besar) * Kesemutan, terutama pada ujung-ujung jari kaki & tangan, dapat disertai sensibilitas yang menurun (baal, kebas) Keputihan yg lama & terinfeksi * Disfungsi ereksi (DE) pada pria * Bisul yang banyak, luka yang lama sembuhnya, kulit kering Gangguan ketajaman penglihatan, dengan / tanpa katarak Libido yg menurun Peningkatan tek darah, gangguan kadar lemak darah, asam urat darah Depresi

* Gejala yg sangat penting

Diagnosis
Symptoms of DM (eg, polyuria, polydipsia*, unexplained weight loss) + random plasma/blood glucose 200 mg/dL OR FPG 126 mg/dL (Fasting Plasma Glucose) AND / OR 2-h Post Meal Plasma Glucose 200 mg/dL OR

200 mg/dL during an OGTT (Oral Glucose Tolerance Test) Each method must be confirmed on a subsequent day unless unequivocal symptoms of hyperglycemia are present FPG is the preferred method of diagnosis

Diabetes merupakan penyebab penyakit jantung koroner, hipertensi, stroke, penyakit ginjal, katarak & retinopati, peny arteri perifer, luka (kaki diabetes), perlemakan hati, dll Faktor risiko dari penyakit jantung koroner & stroke ada 2 golongan : tradisional & faktor-faktor risiko baru

F.risiko tradisional peny jantung koroner & stroke :

1. Hipertensi (TD 140/90 mmHg) 2. Diabetes Melitus 3. Umur > 40 tahun (P) & > 50 tahun / pasca menopause (W) 4. Merokok 5. Gangguan profil lipid : kolesterol total/TC > 200 mg/dL kolesterol LDL / LDL-C >160 mg, kolesterol HDL / HDL-C < 40 mg/dL & trigliserida > 200 mg/dL 6. Gemuk / obesitas (lihat definisi obesitas berdasarkan IMT)

Faktor risiko tradisional (lanjutan)

7. Riwayat keluarga dengan penyakit jantung koroner & / stroke 8. Sedentary life style 9. Stress psikis, cemas (& stress fisik berat), kepribadian tipe A (ambisius, pekerja keras, keras kepala) 10.Albuminuria (mikro & makro) - Jika terdapat > 2 faktor risiko maka kemungkinan terkena serangan jantung & stroke akan meningkat > 30 % - Jika terdapat > 3 faktor risiko, kemungkinan meningkat > 50 % - Jika terdapat > 4 faktor risiko, kemungkinan meningkat > 80 % Faktor risiko baru terdiri dari > 40 faktor & tidak dibahas disini, contohnya ialah hiperhomosisteinemia, peningkatan PAI-1, dsb.

Screening Recommendations
Patients at high-risk for diabetes (2-3 risk factors) screened every 3 years
IGT/IFG Screen every 1-2 years

Screening Tests
Fasting Plasma Glucose - Preferred - accuracy, ease, low-cost. 2 hour OGTT (75 gm glucose load) Random Plasma Glucose - very inaccurate, discourage use. HgA1C - NOT a screening test. Repeat and Confirm all Screening Tests in 24 Hours!

Screening Tests
Normal FPG < 109 2hPG < 139 IFG or IGT FPG 110-125 2hPG 140-199 Diabetes FPG > 126 2hPG > 200 Random > 200

Parameter
*Usia (tahun) *F Keluarga Patogenesis Kadar insulin tubuh Insulin Dependency *Habitus Komplikasi utama Pengendalian GD Marker lab Kromosom

DMT1

DMT2

<30 >40 (-) / ? + Autoimun Resistensi Insulin << s/d (-) >> + (-) kurus gemuk/obesitas sentral KAD HHS/HONK Sulit (brittle) relatif lbh mudah IcA, C-peptide HOMA & Clamp
6 1q21-q24,2,3,6,7,8,10p,11,16p,20p