KARYA TULIS AKHIR
PENGARUH PEMBERIAN KOPI TERHADAP PENURUNAN KADAR GLUKOSA DARAH PADA TIKUS PUTIH STRAIN WISTAR DIABETES MELLITUS TIPE 2
Oleh : ALIFANETA YUSTISIANI 08020114
UNIVERSITAS MUHAMMADIYAH MALANG FAKULTAS KEDOKTERAN 2012
PENGARUH PEMBERIAN KOPI TERHADAP PENURUNAN KADAR GLUKOSA DARAH PADA TIKUS PUTIH STRAIN WISTAR DIABETES MELLITUS TIPE 2
KARYA TULIS AKHIR Diajukan kepada Universitas Muhammadiyah Malang untuk Memenuhi Salah Satu Persyaratan dalam Menyelesaikan Program Sarjana Fakultas Kedokteran
Oleh: ALIFANETA YUSTISIANI 08020114
UNIVERSITAS MUHAMMADIYAH MALANG FAKULTAS KEDOKTERAN 2012
LEMBAR PENGESAHAAN LAPORAN HASIL PENELITIAN Telah disetujui sebagai hasil penelitian untuk memenuhi persyaratan Pendidikan Sarjana Fakultas Kedokteran Universitas Muhammadiyah Malang
Tanggal : 21 Maret 2012 Pembimbing I
dr. Isbandiyah, Sp.PD.
Pembimbing II
dr. Thontowi Djauhari, M.Kes Mengetahui, Fakultas Kedokteran Dekan,
dr. Irma Suswati, M.Kes.
LEMBAR PENGUJIAN Karya Tulis Akhir oleh Alifaneta Yustisiani telah diuji dan dipertahankan di depan Tim Penguji Pada tanggal : 21 Maret 2012 Tim Penguji
dr. Isbandiyah, Sp.PD.
, Ketua
dr. Thontowi Djauhari, M.Kes.
, Anggota
dr. Hawin Nurdiana, M.Kes.
, Anggota
KATA PENGANTAR Alhamdulillahirrabil’alamin, puji syukur kehadirat Allah SWT yang telah melimpahkan karunianya sehingga penulis dapat menyelesaikan karya tulis akhir yang berjudul “Pengaruh Pemberian Kopi Terhadap Penurunan Kadar Glukosa Darah Pada Tikus Putih Strain Wistar Diabetes Mellitus Tipe 2”. Penulisan penelitian ini dilakukan dalam rangka memenuhi salah satu syarat untuk mencapai gelar Sarjana Kedokteran Jurusan Pendidikan Dokter pada Fakultas Kedokteran Universitas Muhammadiyah Malang. Dalam menyelesaikan usulan penelitian ini, penulis banyak mendapatkan bimbingan dan bantuan dari berbagai pihak. Oleh kerena itu dalam kesempatan ini penulis mengucapkan terima kasih kepada : 1. dr. Irma Suswati, M.Kes, selaku Dekan Fakultas Kedokteran. 2. dr. Meddy Setiawan, Sp.PD, selaku Pembantu Dekan I Fakultas Kedokteran. 3. dr. Fathiyah Safitri, M.Kes, selaku Pembantu Dekan II Fakultas Kedokteran. 4. dr. Iwan Sis Indrawanto, Sp.KJ, selaku Pembantu Dekan III Fakultas Kedokteran. 5. dr. Isbandiyah, Sp.PD, selaku pembimbing I yang telah meluangkan waktunya untuk membimbing dan mengoreksi demi kesempurnaan penelitian ini. 6. dr. Thontowi Djauhari, M.Kes, selaku pembimbing II yang telah meluangkan waktunya untuk memberi informasi dalam berbagai hal serta memberi semangat dalam menyelesaikan penelitian ini. 7. dr. Hawin Nurdiana, M.Kes, selaku penguji yang telah memberi tambahan ilmu dan kritik demi kesempurnaan penelitian ini. 8. Mas Aris Sandi beserta staf Lab. Kimia UMM, terima kasih banyak atas segala bantuan, dukungan dan ilmu yang telah diberikan. 9. Orang tua dan keluarga saya yang telah memberikan bantuan dukungan material dan moral. 10. Ega Astari, mbak Sisca Desi Prastyaningtias dan Irna Farah Nadiansyah yang telah menjadi teman diskusi yang baik dan memberi banyak masukan serta dukungan dalam menyelesaikan penelitian ini. 11. Sahabat-sahabat yang telah banyak membantu dan memberikan semangat dalam menyelesaikan penelitian ini Dewi, Mega, Utari, Annisa, Fajar, Afif, Dicky, Rezky. 12. Teman-teman angkatan 2008 Fakultas Kedokteran UMM, terima kasih atas dukungan dan do’a sehingga dapat menyelesaikan tugas akhir ini. 13. Seluruh staf Tata Usaha FK UMM (Pak Yono, Bu Rom, Mas Didit, dan Mas Faisal). Terima kasih atas bantuannya selama ini.
14. Mas Joko, mbak Tia, mbak Fat, mas Miftah, mbak Emi, mbak Dila dan seluruh staf Lab. Terpadu FK UMM, terima kasih banyak atas bantuan dan dukungannya. Penulis menyadari bahwa penelitian ini masih belum sempurna, untuk itu kritik dan saran kami harapkan demi kesempurnaan, serta kami mengharapkan agar usulan penelitian ini dapat berguna bagi kita semua, serta bermanfaat untuk bidang kedokteran.
Malang, Maret 2012
Penulis
ABSTRAK Yustisiani, Alifaneta. 2012. Pengaruh Pemberian Kopi Terhadap Penurunan Kadar Glukosa Darah Pada Tikus Putih Strain Wistar Diabetes Mellitus Tipe 2. Tugas Akhir, Fakultas Kedokteran, Universitas Muhammadiyah Malang. Pembimbing: (1) Isbandiyah (2) Thontowi Djauhari Pendahuluan : Kopi merupakan salah satu minuman kegemaran masyarakat dunia yang mengandung banyak senyawa antioksidan. Berbagai penelitian membuktikan bahwa kopi dapat menurunkan risiko diabetes mellitus tipe 2. Penelitian mengenai kopi sebagai terapi alternatif diabetes tipe 2 dengan melihat kadar glukosa darah pada tikus putih strain wistar diabetes mellitus tipe 2 belum pernah dilakukan di Indonesia. Tujuan : Membuktikan pengaruh kopi terhadap penurunan kadar glukosa darah pada tikus putih strain wistar diabetes mellitus tipe 2. Metode : Eksperimen laboratoris rancangan the post test only control group desain. Sampel tikus putih strain wistar dibagi 4 kelompok. Sampel I : kontrol negatif, II: kontrol positif, dua kelompok lainnya diberikan kopi Robusta berbagai dosis (5,4 mL/200 gr BB/ hari, 10,8 mL/200 gr BB/hari). Analisis data menggunakan One Way Anova, uji Tukey 5%, uji korelasi dan uji regresi linier. Hasil : Hasil uji One Way Anova terdapat pengaruh perlakuan dengan perbedaan yang bermakna terhadap penurunan kadar glukosa darah. Dari uji korelasi terdapat korelasi yang berbanding lurus dan sangat bermakna antara dosis kopi dan jumlah penurunan kadar glukosa darah tikus putih diabetes mellitus tipe 2 dengan nilai Pearson Correlation -0,978 pada glukosa darah puasa dan -0,932 pada glukosa darah 2 jam post pandrial, sedangkan hasil uji regresi didapatkan nilai R2 = 0,956 pada glukosa darah puasa dan 0,869 pada glukosa darah 2 jam post pandrial. Kesimpulan : Pemberian kopi berbagai dosis dapat menurunkan kadar glukosa darah tikus diabetes mellitus tipe 2. Kata kunci : diabetes mellitus tipe 2, kadar glukosa darah, kopi Robusta
ABSTRACT Yustisiani, Alifaneta. 2012. The Influence of Coffee to Decrease the Blood Glucose Level of Diabetes Type 2 Wistar Strain White Mice Models. Final Assignment, Medical Faculty, University of Muhammadiyah Malang, Adviser: (1) Isbandiyah (2) Thontowi Djauhari Introduction : Coffee is one of several favorite drink in the world that contains many antioxidant compounds. Various experiments prove that coffee can reduce the risk of diabetes type 2. Study about coffee as the alternative therapies in diabetes type 2 by observing the number of blood glucose level of of diabetes type 2 wistar strain white mice models is not yet been conducted in Indonesia.. Objective : Understanding the effect of coffee to decrease the blood glucose level in diabetes mellitus type 2 wistar strain white mice models. Method : Laboratory experiment the post test only control group design. Wistar white mice groups were divided into 4 groups. Sample I : negative control, II: positive control, the other two groups were treated with Robusta coffee in various doses (5,4 mL/200 grBW/day, 10,8 mL/200 gr BW/day). Data analysis used One Way Anova, Tukey test 5%, correlation test, and linear regression test. Result : One way Anova test result’s that there were an influence of treatments with the obviously different to decrease the blood glucose level. From the correlation test result that there were an inversely and meaningful correlation between coffee doses and the increasing of decrease of blood glucose level in diabetes mellitus type 2 white mice models with the value of Pearson Correlation -0,978 fasting glucose blood and -0,932 2 hours post pandrial, while regression test result was R2 = 0,956 fasting glucose blood and R2= 0,869 2 hours post pandrial. Conclusion : Coffee administration in various doses can reduce the number of blood glucose level in diabetes type 2 mice models. Keywords : diabetes type 2, the number of blood glucose level, Robusta coffee
DAFTAR ISI
Halaman HALAMAN JUDUL. ....................................................................................... i LEMBAR PENGESAHAN ............................................................................. iii LEMBAR PENGUJIAN .................................................................................. iv KATA PENGANTAR ..................................................................................... v ABSTRAK..... .................................................................................................. vii ABSTRACT... .................................................................................................. viii DAFTAR ISI .................................................................................................... ix DAFTAR TABEL ............................................................................................ xiii DAFTAR GAMBAR ....................................................................................... xiv DAFTAR SINGKATAN ................................................................................. xv DAFTAR LAMPIRAN .................................................................................... xvi BAB 1 PENDAHULUAN .............................................................................. 1 1.1 Latar Belakang ............................................................................ 1 1.2 Rumusan Masalah ....................................................................... 3 1.3 Tujuan Penelitian ........................................................................ 4 1.3.1 Tujuan umum ..................................................................... 4 1.3.2 Tujuan khusus .................................................................... 4 1.4 Manfaat Penelitian ...................................................................... 4 1.4.1 Manfaat Akademik ............................................................ 4 1.4.2 Manfaat Klinis ................................................................... 4 1.4.3 Manfaat Masarakat ........................................................... 4
BAB 2 TINJAUAN PUSTAKA ..................................................................... 5 2.1 Kopi ............................................................................................. 5 2.1.1
Kopi Robusta................................................................... 5
2.1.1.1 Definisi Kopi Robusta ..................................................... 5 2.1.1.2 Kandungan Kopi Robusta ............................................... 6 2.1.1.3 Manfaat Kopi Robusta. ................................................... 6 2.2 Diabetes Mellitus ......................................................................... 11 2.2.1 Definisi Diabetes Mellitus ................................................. 11 2.2.2 Diabetes Mellitus Tipe II ................................................... 11 2.2.3 Patogenesis Diabetes Mellitus Tipe II................................ 13 2.2.4 Manifestasi klinis ............................................................... 14 2.2.5 Diagnosis Diabetes Mellitus .............................................. 15 2.2.6 Pengaturan Glukosa Darah ................................................. 16 2.2.6.1 Glikolisis. ........................................................................ 17 2.2.6.2 Glukoneogenesis. ............................................................ 18 2.2.7 Mekanisme Homeostasis Glukosa Darah .......................... 19 2.3 Kopi dan Diabetes Mellitus Tipe 2 .............................................. 22 2.3.1 Kafein................................................................................. 22 2.3.2 Chlorogenic Acid. .............................................................. 23 2.4 Bahan Penginduksi Diabetes Mellitus ......................................... 25 2.4.1 Streptozotocin .................................................................... 25 2.4.2 Nicotinamide ...................................................................... 29 BAB 3 KERANGKA KONSEP DAN HIPOTESIS....................................... 22 3.1 Kerangka Konsep ........................................................................ 32
3.2 Hipotesis ...................................................................................... 35 BAB 4 METODE PENELITIAN ................................................................... 36 4.1 Rancangan Penelitian ................................................................. 36 4.2 Lokasi .......................................................................................... 36 4.3 Populasi dan Sample 4.3.1 Populasi .............................................................................. 36 4.3.2 Sampel Penelitian ............................................................... 36 4.3.3 Estimasi Besar Sampel ....................................................... 36 4.3.4 Karakteristik Sampel Penelitian . ....................................... 37 4.4 Variabel Penelitian ...................................................................... 38 4.4.1 Variabel Bebas ................................................................... 38 4.4.2 Variabel Terkait ................................................................. 38 4.4.3 Variabel Kontrol................................................................. 38 4.4.4 Definisi Operasional........................................................... 38 4.5 Alat dan Bahan. ........................................................................... 39 4.5.1 Alat ..................................................................................... 39 4.5.2 Bahan.................................................................................. 40 4.6 Alur Penelitian ............................................................................ 41 4.7 Prosedur Penelitian...................................................................... 42 4.7.1 Adaptasi Hewan Uji ........................................................... 42 4.7.2 Penentuan Dosis ................................................................. 42 4.7.3 Penyiapan Larutan Uji........................................................ 43 4.7.4 Pengambilan Darah Tikus. ................................................. 44 4.7.5 Percobaan ........................................................................... .44
4.8 Analisis Data ............................................................................... 48 BAB 5 HASIL PENELITIAN DAN ANALISIS DATA. .............................. 49 5.1 Hasil Penelitian. ........................................................................... 49 5.2 Analisis Data ............................................................................... 52 5.2.1 Uji One Way ANOVA ...................................................... 52 5.2.2 Hasil Uji Tukey 5% ........................................................... 53 5.2.3 Uji Korelasi ........................................................................ 54 5.2.4 Uji Regresi ......................................................................... 55 BAB 6 PEMBAHASAN ................................................................................. 58 BAB 7 KESIMPULAN DAN SARAN .......................................................... 63 7.1 Kesimpulan .................................................................................. 63 7.2 Saran ............................................................................................ 63 DAFTAR PUSTAKA ...................................................................................... 64 LAMPIRAN .................................................................................................... 69
DAFTAR TABEL
Tabel 2.1 Komposisi Kimia Biji Kopi Robusta yang Disangrai ..................... 6 Tabel 2.2 Kadar Glukosa Darah Sewaktu dan Puasa Sebagai Patokan Penyaring dan Diagnosis Diabetes Mellitus ..................................... 15 Tabel 2.3 Glucose Transporters ....................................................................... 21 Tabel 4.1 Konversi Dosis Antar Spesies .......................................................... 43 Tabel 5.1 Hasil Rerata Kadar Glukosa Darah Tikus ........................................ 50 Tabel 5.2.1 Resume Uji Tukey ........................................................................ 54 Tabel 5.2.2 Uji Korelasi Kadar Glukosa Darah Puasa Tikus Setelah Pemberian Kopi...................................................................................54 Tabel 5.2.3 Uji Korelasi Kadar Glukosa Darah 2 Jam PP Tikus Setelah Pemberian Kopi....................................................................55
DAFTAR GAMBAR
Gambar 2.1 Struktir Kimia Streptozotocin ..................................................... 26 Gambar 2.2 Struktir Kimia Nicotinamide ....................................................... 29 Gambar 2.3 Skema Mekanisme Streptozotocin dan Nicotinamide ................. 31 Gambar 3.1 Kerangka Konseptual .................................................................. 32 Gambar 4.1 Alur Penelitian............................................................................. 41 Gambar 5.1 Diagram Batang Rerata Hasil Pengukuran Kadar Glukosa Darah Pasca Perlakuan 1 ........................................................................ 51 Gambar 5.2 Diagram Batang Rerata Hasil Pengukuran Kadar Glukosa Darah Pasca Perlakuan 2 ........................................................................ 52 Gambar 5.3 Uji Regresi Penurunan Kadar Glukosa Darah Puasa Tikus Setelah Pemberian Kopi ........................................................................... 56 Gambar 5.4 Uji Regresi Penurunan Kadar Glukosa Darah 2 Jam PP Tikus Setelah Pemberian Kopi .............................................................. 57
DAFTAR SINGKATAN
ADP
: Adenosine Diphosphate
AMP
: Adenosine Monophosphate
ANOVA
: Analysis of Variance
ATP
: Adenosine Triphosphate
cAMP
: cyclic Adenosine Monophosphate
CGA
: Chlorogenic acid
DM
: Diabetes Melitus
DNA
: Deoxyribose Nucleic Acid
eNOS
: endothelial Nitric Oxide Synthase
GDM
: Gestational Diabetes Mellitus
GLUT
: Glucose Transporter
IDDM
: Insulin Dependent Diabetes Mellitus
NAD
: Nicotinamide Adenine Dinucleotide
NADH
: Nicotinamide Adenine Dinucleotide Hydrogenase
NADP
: Nicotinamide Adenine Dinucleotide Phosphate
NADPH
:Nicotinamide Adenine Dinucleotide Phosphate Hydrogenase
NO
: Nitric Oxide
NOD
: Non-Obese Diabetes
PBS
: Phosphate Buffered Saline
PJK
: Penyakit Jantung Koroner
PP
: Post Prandial
RNA
: Ribo Nucleic Acid
ROS
: Reactive Oxygen Species
SHBG
: Sex Hormone Binding Globulin
STZ
: Streptozotocin
WHO
: World Healthy Organization
DAFTAR LAMPIRAN
Lampiran 1 Data Pengamatan Glukosa Darah ................................................ 69 Lampiran 2 Analisis Data Kadar Glukosa Darah ............................................ 73
DAFTAR PUSTAKA AAK, 2009, Budidaya Tanaman Kopi, Yogyakarta, Kanisius American Association of Clinical Endocrinologists, 2007, Medical Giudelines for Clinical Practice for The Management of Diabetes Mellitus, Endocrine Practice 13 (Suppl 1) American Diabetes Association, 2011, Diagnosis and Classification of Diabetes Mellitus, Diabetes Care 32 (S): 62-7 American Diabetes Association, 2011, Definition and Description of Diabetes Mellitus, Diabetes Care 32 (S): 62 Anonim, 2004, Migraines, Headaches, and Caffeine, WebMD, viewed 5 August 2011,
. Arendash G.W, 2006, Caffeine Protects Alzheimer’s Mice Against Cognitive Impairment and Reduces Brain Beta-Amyloid Production, Neuroscience. Barik R, Jain S, Qwarta D, et al., 2008, Antidiabetic Activity of Aqueous Root Extract of Ichnocarpus frutecens in STZ-Nicotinamide Induced Type II Diabetic in Rats, Research article India. Benedetti MD, 2000, Smoking, alcohol, and coffee consumption preceding Parkinson’s disease, Neurology, 55, pp. 1350–1358. Choi HK, Willett W, Curhan G, 2007, Coffee Consumption and Risk of Incident Gout in Men: A Prospective Study, Arthritis Rheum, 56, pp. 2049–55. Chu YF, Brown, Peter H, et al., 2009, Roasted Coffees High in Lipophilic Antioxidants and Chlorogenic Acid Lactones are More Neuroprotective Than Green Coffees, Journal of Agricultural and Food Chemistry, 57(20), pp. 9801–9808. Clifford MN 2003 The Analysis and Characterization of Chlorogenic Acids and Other Cinnamates, In : C. Santos-Buelga & G. Williamson (eds.). Methods in Polyphenol Analysis, Royal Society of Chemistry, Cambridge, pp. 314–337. Edward O, Terry E, Lorraine A, et al., 2002, Regulation of GLUT4 Biogenesis in Muscle : Evidence for Involvement of AMPK and Ca2+, Am J Physiol Endocrinol Metab 282, pp. 1008-1013. Egawa T, Hamada T, Kameda N, et al., 2009, Caffeine Acutely Actives 5’Adenosine Monophosphate Actived Protein Kinase and Increase Insulin Independent Glucose Transport in Rat Skeletak Muscle, Metabolism, 58(11), pp. 1609-17.
Emily Updegraff, C. Wilborn, 2003, What’s GLUT 4?, viewed 9 March 2012, < http://www.wisegeek.com/what-is-glut4.htm>. Firdous MR, Koneri CH, Sarvaradu, et al., 2009, NIDDM Antidiabetic Activity of saponins of Momordica cymbalaria in Streptozotocin-Nicotinamide Departement of Pharmacology, RR College of Pharmacy, Bangalore, India, (3), pp. 1460-1465 Foster DW, 2000, Diabetes Melitus, Prinsip-Prinsip Ilmu Penyakit Dalam Horrison, Jakarta, EGC. Gustaviani, Reno, 2006, Buku Ajar Ilmu Penyakit Dalam Jilid III, Pusat Penerbitan Departemen Ilmu Penyakit Dalam Fakultas Kedokteran Universitas Indonesia, Jakarta. Gustavo D Pimintel, Juliane CS Zemdegs, Joyce A Theodoro, et al., 2009, Does Long-Term Coffee Intake Reduce Type 2 Diabetes Mellitus Risk?, Diabetology & Metabolic Syndrome, 1, pp. 9-16. Guyton AC, 2007, Textbook of Medical Physiology, 11th edn, EGC, Jakarta Harvey S, David Zieve, 2009, Gallstones and gallbladder disease – Prevention, University of Maryland Medical Center, viewed 17 august 2011 Hery Winarsi MS, 2007, Antioksidan Alami dan Radikal Bebas, Kanisius, Jakarta.
Penerbit
Jarvis MJ, 2005, Does Caffeine Intake Enhance Absolute Levels of Cognitive Performance?, Psychopharmacology, 110, pp. 1–2, 45–52. J. Margot de Koning Gans, Cuno SPM Uiterwaal, Yvonne T. van der Schouw, et al., 2010, Tea and Coffee Consumption and Cardiovascular Morbidity and Mortality, Journal Arteriosclerosis, Thrombosis, and Vascular Biology. Johnson-Kozlow M, et al., 2002, Coffee Consumption and Cognitive Function among Older Adults, Am J Epidemiol, 156, pp. 842–850. Johnston KL, Clifford MN, Morgan LM, 2003, Coffee Acutely Modifies Gastrointestinal Hormone Secretion and Glucose Tolerance in Humans: Glycemic Effects of Chlorogenic Acid and Caffeine, Am J Clin Nutr, 79 (4), pp. 728–733. Kati H, Riitta T, Isabel B, et al., 2010, Impact of Dietary Polyphenols on Carbohydrate Metabolism, International Journal of Molecular Science 11, pp. 1365-1402. Kallow W, Tang BK, 1993, The Use of Caffeine for Enzyme Assays: A Critical Appraisal, Clin Pharmacol Ther, 53(5), pp.503–514. Klatsky AL, Morton C, Udaltsova N, et al., 2006, Coffee, Cirrhosis, and Transaminase Enzymes, Arch. Intern. Med, 166 (11), pp. 1190–1195.
Knip M, Douek IF, Moore WP, et al., 2000, Safety of high-dose nicotinamide: a review, Diabetologia, 43 (11), pp. 1337–45. Koizumi A, Mineharu Y, Wada Y, et al., 2011, Coffee, Green Tea, Black Tea and Oolong Tea Consumption and Risk of Mortality from Cardiovascular Disease in Japanese Men and Women, Journal of Epidemiology and Community Health, 65, pp. 230–240. Koolman J, 1995, Atlas Berwarna & Teks Biokimia, Hipokrates, Jakarta. Kumalaningsih S, 2007, Antioksidan Alami Penangkal Radikal Bebas, PT. Trubus Swadaya, Depok. Liu S, et al, 2009, Sex Hormone-Binding Globulin and Risk of Type 2 Diabetes in Women and Men, The New England Journal of Medicine, 361 (11) pp. 52-63 Lopez-Grazia E, van Dam RM, Li TY, et al., 2008, The Relationship of Coffee Consumption with Mortality, Annals of Internal Medicine, 148(12), pp. 904-914. Maclean PS, Zheng D, Jones JP, et al., 2002, Exercise-induced transcription of the muscle glucose transporter (GLUT 4) gene, Biochemical and biophysical research communications, 292 (2), pp. 409–414. Morton, Lincoln W, Rima ACC, et al., 2007, Chemistry And Biological Effects of Dietary Phenolic Compounds: Relevance To Cardiovascular Disease, Clin Exp Pharmacol and Physiol, 27(3): 152-59 Muljana W, 2006, Bercocok Tanam Kopi, Semarang: CV Aneka Ilmu, p: 12 Murray RK, Granner DK, Mayes PA, et al. 1999, Biokimia Harper Edisi 24, EGC, Jakarta. Nastase A, Ioan S, Braga RI, et al., 2007, Coffee Drinking Enhances The Analgesic Effect of Cigarette Smoking, Neuroreport, 18(9), pp.921-924. Passero K, 2011, NADH Supplements and Information, viewed 30 January 2011, . Pellegrini N, 2003, Total Antioxidant Capacity of Plant Foods, Beverages and Oils Consumed in Italy Assessed by Three Different In Vitro Assays, Journal of Nutrition, 33, pp. 2812-2819. Prabhakar PK, Doble M, 2009, Synergistic effect of phyochemical drugs on glukose uptake myotubes, Departement of Biotechnolog. Indian Institute of Thechnology Madras. Price & Wilson, 2005, Pankreas : Metabolisme Glukosa dan Diabetes Mellitus, Patofisiologi : Konsep Klinis Proses – Proses Penyakit, Jakarta: EGC, 1268-1270
Pimentel D, Zemdegsi CS, Theodoro A, et al., 2009, Diabetology & Metabolic Syndrome : Does long-term coffee intake reduce type 2 diabetes mellitus risk?, BioMed Central, pp: 1-8 Rodriguez T, Altieri A, Chatenoud L, et al., 2004, Risk Factors For Oral and Pharyngeal Cancer in Young Adults. Oral Oncol. 40 (2), pp. 207–13. Rohdiana, Dadan, 2009, Teh Ini Menyehatkan, Alfabeta, Bandung. Robert C, Sandier S, Hellerstrem, 1984, Multiple Low-Dose StreptozotocinInduced Diabetes in Mouse, Departement of Anatomy Pediatrics, Mount Sinai School of Medicine of the City University of New York, NewYork Ruskar AGN, 2010. Kajian Efektivitas Streptozotocin Dalam Induksi Tikus Putih Diabetik, Surabaya, Departemen Biologi, Fakultas Sains dan Teknologi, Universitas Airlangga, Skripsi Schnedl WJ, Ferber S, Johnson JH, et al, 1994, STZ Transport and Cytotoxicity, Specific Enhancement in GLUT2-Expressing Cells, Diabetes 43(11), pp. 1326–33 Schteingart, David E, 2005, Konsep Klinis Proses-Proses Penyakit: Metabolisme Glukosa dan Diabetes Melitus, EGC, Jakarta. Schumm DE, 1993, Intisari Biokimia, Binarupa Aksara Jakarta. Sinclair CJ, Geiger JD, 2000, Caffeine Use in Sports, A Pharmacological Review, Canada. J Sports Med Phys Fitness, 40(1), pp. 71-79. Shafrir E, 2007, Animal Models of Diabetes, Taylor dan Francis Group, United States Soegondo S, 2005, Diagnosis dan Kalsifikasi Diabetes Mellitus Terkini, In : Soegondo S dkk (eds), Penatalaksanaan Diabetes Mellitus Terpadu, Penerbit FKUI, Jakarta. Song YJ, Kristal AR, Wicklund KG, et al., 2008, Coffee, Tea, Colas, And Risk of Epithelial Ovarian Cancer, Cancer Epidemiol, 17(3), pp. 712–716. Svilaas A, 2004, Intakes of Antioxidants in Coffee, Wine, and Vegetablesare Correlated with Plasma Carotenoids in Humans, Journal of Nutritions, 134, pp. 562-567. Szkudelski T, Szkudelska K, 2002, Streptozotocin Induces Lipolysis in Rat Adipocytes in Vitro, Physiol. Res, 51, pp. 255-259. Tondok, A.R, 1999, Kebijakan Pengembangan Kopi di Indonesia, Warta Pusat Penelitian Kopi dan Kakao. Tormo MA, Gil-Exojo L, Romero A, et al, 2006, White bean amylase inhibitor administered orally reduces glycaemia in type 2 diabetic rats, British Journal of Nutrition, 96(3), pp. 539-544
Touger-Decker R, Van LC, 2003, Sugars and Dental Caries, Am J Clin Nutr, 78 (4), pp. 881S-892S. Wang Z, Gleichmann H, 1998, GLUT2 in pancreatic islets: crucial target moleculein diabetes induced with multiple low doses of streptozotocin in mice, Diabetes, 47 (1): 50–6. Webster Ross, G. et al., 2000,Association of Coffee and Caffeine Intake With the Risk of Parkinson Disease, JAMA, 283 (20). World Healthy Organization, 2011, Diabetes Programme, viewed 9 February 2011, . Yusianto, 1999, Kopi : Pengolahan Mutu, Komposisi Kimia, Citarasa. Jember: Pusat Penelitian Kopi dan Kakao
