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Insulinorezistenta poate fi definita (204) ca starea in care "o cantitate data, cunoscuta, de insulina produce un efect mai mic decat cel normal, asteptat'.
Insulina produce numeroase efecte biologice care pot fi sistematizate in efecte metabolice (efecte asupra metabolismului hidratilor de carbon, al proteinelor si al lipidelor) si efecte mitogenice (efecte asupra cresterii, sintezei ADN, transcriptiei genice). Cu toate ca rezistenta la insulina implica toate aceste efecte, in general termenul de rezistenta la insulina este aplicat doar la efectul insulinei de a promova metabolismul glucozei si de a stimula captarea glucozei in tesuturile -tinta: ficat, muschi, tesut adipos.
Metodele utilizate pentru a determina gradul de rezistenta la actiunea insulinei se bazeaza pe masurarea directa sau indirecta a efectului de crestere a captarii tisulare a glucozei, indus de insulina.
In clinica, la subiectii tratati cu insulina se poate lua in consideratie existenta unei stari de rezistenta la insulina ori de cate ori doza terapeutica de insulina depaseste nivelul normal de secretie al insulinei, apreciat la indivizii normali a fi in jur de 60 U in 24 ore (78), sau este mai mare de 1 U/Kg greutate corporala (4).
Daca conceptul rezistentei la insulina este relativ accesibil este mai dificil a determina cu precizie care persoane sunt sensibile si care au rezistenta la insulina.
Prin consens, Organizatia Mondiala a Sanatatii (1 bis) considera ca indicator al starii de rezistenta la insulina un index SI (determinat in cursul euglycemic clamp) aflat in cuartila inferioara a distributiei acestui index in populatia generala.
Grupul European (35 bis) pentru Studiul Rezistentei la Insulina (EGIR) defineste rezistenta la insulina prin indexul SI aflat in decila inferioara a distributiei acestui index in populatia caucaziana ne-obeza, nediabetica, normotensiva.
Rezistenta la insulina este un fenomen larg raspandit, fiind implicata in patogenia si evolutia clinica a unei diversitati de boli umane importante (125).
Mai jos este redata o lista a bolilor umane caracterizate prin rezistenta la insulina:
1. Rezistenta primara la insulina:
Diabet zaharat tip 2
Sindromul rezistentei la insulina (Sindromul Metabolic)
Diabetul gestational
Rezistenta la insulina severa tip A
Diabetul lipoatrofic
Leprechaunismul
Sindromul Rabson-Mendenhall
Hipertensiunea arteriala
Boala cardiovasculara aterosclerotica
2. Rezistenta secundara la insulina
Obezitatea
Diabetul zaharat tip 1
Rezistenta la insulina severa tip B
Hiperlipidemii
Pubertatea
Sarcina
Boli acute, stres
Tratamente medicamentoase si hormonale (cortizonice, acid nicotinic, hormon de crestere, antipsihotice atipice)
Maladia si Sindromul Cushing
Acromegalia
Feocromocitomul
Hipertiroidismul
Ciroza hepatica
Insuficienta renala
Sindroame lipodistrofice congenitale sau dobandite
3. Rezistenta la insulina asociata la sindroame genetice
Sindroamele Down, Klinefelter, Turner
Ataxia telangiectazia
Distrofii musculare
Ataxia Friedreich
Sindromul Laurence-Moon-Biedl
Sindromul Pseudo-Refsum
Boli neuromusculare ereditare
Studiul rezistentei la insulina a progresat considerabil in urma elaborarii unor metode adecvate de investigatie. Intre acestea, metoda "glucose clamp" reprezinta "standardul de aur". In cursul acestei metode se mentine in platou, prin administrarea insulinei in perfuzie continua, un anumit nivel al insulinemiei. In cursul acestei investigatii se poate realiza, urmand un algoritm anume de administrare a insulinei, orice nivel al insulinemiei cuprins intre 40 si 10.000 mU/ml. Principiul metodei se bazeaza pe determinarea cantitatii de glucoza administrata pentru a mentine constant nivelul bazal normal al glicemiei (de unde si numele "euglycemic hyperinsulinemic clamp") in cursul starii hiperinsulinemice la steady-state. Rata infuziei solutiei de glucoza (20% sau 40%) in timpul perioadei de steady-state, exprimata in mg/Kgcorp/minut ("constanta M") si raportata la nivelul insulinemiei realizat in cursul investigatiei respective este un indicator cantitativ al starii de rezistenta la insulina. Utilizarea acestei metode de investigatie, cu asocierea simultana a calorimetriei indirecte si a investigatiei metabolismului glucozei cu trasori radioactivi, a demonstrat ca majoritatea glucozei administrata in cursul starii de hiperinsulinemie este captata la nivelul muschiului scheletic (foarte putina glucoza este captata in tesutul adipos si in ficat). Rezulta ca rezistenta la insulina se manifesta in special la nivelul captarii glucozei in tesutul muscular.
Prin utilizarea spectroscopiei in RMN (22) a carbonului 13 (1,1% din nucleii de carbon sunt reprezentati de acest izotop natural) in conjunctie cu calorimetria indirecta in cursul "hyperinsulinemic clamp" s-a demonstrat (in vivo) ca pacientii cu diabet zaharat tip 2 au o captare redusa a glucozei in tesutul muscular cu 40% si o scadere cu 60% a sintezei glicogenului muscular in comparatie cu indivizii normali.
Defectul capabil sa produca starea de rezistenta la actiunea insulinei asupra transportului si incorporarii glucozei in glicogenul muscular se afla localizat undeva intre secventele situate dupa legarea insulinei de receptor si incorporarea glucozei in glicogenul muscular.
Glucoza este transportata intracelular prin sistemul transportor GLUT-4 a carei activitate este stimulata de insulina.
Dupa transportul in interiorul celulei musculare, glucoza libera este fosforilata sub actiunea hexokinazei (stimulata de insulina) la glucozo-6-fosfat.
Sub actiunea glicogensintazei, glucozo-6-fosfatul este incorporat in glicogenul muscular.
Se presupune ca instalarea unui blocaj la oricare din nivelele acestei secvente va induce, in urma stimularii cu insulina, o crestere a concentratiei produsilor aflati in amonte de sediul blocajului.
Astfel, un blocaj la nivelul transportului glucozei ar duce la scaderea nivelului intracelular al glucozei libere, a glucozo-6-fosfatului si a glicogenului.
Blocarea la nivelul hexokinazei ar duce la scaderea concentratiei intracelulare a glucozo-6-fosfatului si a glicogenului, insotite de o crestere a glucozei libere intracelulare; blocarea in aval de hexokinaza ar duce la scaderea nivelului glicogenului muscular si la cresterea nivelului glucozo-6-fosfatului intracelular.
Folosind metoda spectroscopiei in rezonanta magnetica nucleara (RMN) cu C-13 si P-31 Cline si colab. (22) au putut masura la subiecti umani (6 pacienti cu DZ tip 2 si 7 subiecti normali) concentratiile intramusculare ale glucozei libere, glucozo-6-fosfatului si glicogenului in conditiile unui hyperinsulinemic (57 µU/ml), hyperglycemic (180 mg/dl) clamp mimand nivelele postprandiale obisnuite, la nivelul muschiului gastrocnemian.
In aceste conditii, nivelul mediu al sintezei glicogenului muscular si al cresterii glucozo-6-fosfatului au fost reduse cu 80% (comparativ) la subiectii diabetici in timp ce nivelul glucozei libere intracelulare nu a crescut semnificativ.
Aceste date sprijina ipoteza conform careia afectarea transportului glucozei joaca un rol important in producerea rezistentei la insulina a pacientilor cu diabet tip 2.
Deoarece concentratiile GLUT-4 sunt normale la nivelul tesutului muscular scheletic al subiectilor cu diabet zaharat tip 2 probabil ca insulinorezistenta se datoreaza unui defect localizat pe caile care regleaza translocarea GLUT-4.
La nivelul ficatului, rezistenta la insulina determina cresterea (relativa sau absoluta) a productiei hepatice de glucoza, iar la nivelul tesutului adipos o insuficienta supresie a lipolizei cu cresterea nivelului circulant al acizilor grasi liberi.
Dintre factorii de mediu, obezitatea joaca rolul cel mai important in patogeneza diabetului zaharat tip 2. Obezitatea este asociata cu rezistenta la insulina.
Studii epidemiologice au aratat ca riscul pentru diabet zaharat tip 2 creste (aproape exponential) cu cresterea greutatii corporale. Comparativ cu un individ al carui index al masei corporale (BMI) este mai mic de 22 Kg/m2, riscul este de 80 ori mai mare la un individ cu BMI > 40 Kg/m2 (5).
Distributia tesutului gras este cel putin la fel de importanta. Obezitatea centrala (abdominala) este in mod deosebit asociata cu diabetul zaharat tip 2. Riscul de diabet zaharat tip 2 este de 12 ori mai mare la barbatii cu o circumferinta a taliei (ca indicator al cantitatii de grasime intra-abdominala) ce depaseste 102 cm comparativ cu cei la care aceasta este mai mica de 88 cm (19).
Circumferinta taliei este asociata cu rezistenta la insulina, intre cele doua variabile fiind o corelatie directa (1) astfel incat masurarea circumferintei abdominale, la nivelul taliei, ar putea reprezenta un indicator al starii de rezistenta la insulina.
Obezitatea poate majora rezistenta la insulina prin cresterea eliberarii AGL in circulatie si eliberarea, din adipocite, a TNF-a (111) si a leptinei (23) local (la nivelul depozitelor de trigliceride tisulare in muschi) putand sa induca, printr-un efect paracrin, o stare de disfunctionalitate la nivelul receptorului insulinei.
Rezistenta la insulina este parte componenta a unui sindrom denumit "sindromul metabolic" sau "sindromul X" care asociaza, la rezistenta la insulina, o "panoplie" de factori de risc cardiovascular: hipertrigliceridemie, HDL-colesterol scazut, obezitate abdominala, hipertensiune arteriala, nivel crescut al PAI-1 (plasminogen-activator inhibitor 1), microalbuminurie s.a. Sindromul metabolic implica obligatoriu rezistenta la insulina cu sau fara tulburari de glicoreglare. Prezenta lui inca din fazele precoce ale istoriei naturale ale diabetului zaharat tip 2 explica de ce cauza majora a morbiditatii si mortalitatii in diabetul zaharat tip 2 o constituie bolile cardiovasculare.
In faza manifesta clinic a diabetului zaharat tip 2 ambele defecte metabolice (deficienta beta-celulara si rezistenta la insulina) sunt bine exprimate. In aceasta faza este imposibil a preciza care din cele doua defecte este prezenta primar (genetic) si determina, cu timpul, aparitia celuilalt sau daca ambele defecte sunt de origine genetica dar se manifesta la timpi diferiti.
Studiile transversale si longitudinale, efectuate asupra indivizilor cu risc crescut pentru diabet zaharat tip 2, au sugerat ca rezistenta la insulina este depistata mai intai in cursul istoriei naturale a bolii. Daca unul din defecte este primar si poate induce cu timpul aparitia celuilalt sau ambele sunt determinate genetic dar se manifesta la timpi diferiti ramane inca un subiect de controversa. Este posibil ca aceasta controversa sa fie alimentata si de "zgomotul" produs de imperfectiunea (49) mijloacelor de investigatie folosite in culegerea "semnalului".
Indiferent de aceste consideratii, exista numeroase argumente (50, 91, 92, 159) ca rezistenta la insulina este determinata genetic. Rezistenta la insulina nu este insa apanajul exclusiv al diabetului zaharat. Ea se intalneste deopotriva la subiecti fara diabet zaharat: rude de gradul 1 (neafectate) ale unor pacienti cu diabet zaharat tip 2, la indivizii obezi fara diabet (55, 67) si la 25% din indivizii normali (60, 61) din populatia generala. Se intelege de aici ca rezistenta la insulina, singura, nu este suficienta pentru a determina aparitia diabetului zaharat.
Initial, la indivizii prediabetici cu rezistenta la insulina, toleranta la glucoza este mentinuta in limite normale printr-un efort insulinosecretor aparent compensator. In aceasta faza, caracterizata prin hiperinsulinism (ca un corolar al starii de rezistenta la insulina) si toleranta normala la glucoza, mijloacele de investigatie actuale pot evidentia un raspuns insulinosecretor crescut in valoare absoluta, dar inadecvat (scazut) pentru nivelul rezistentei la insulina.
Functia beta-celulara diminua progresiv, in paralel cu deteriorarea continua a tolerantei la glucoza si in cele din urma se ajunge in faza clinic manifesta a diabetului zaharat. Daca exista rezistenta la insulina fara diabet zaharat, deocamdata nu se concepe diabet zaharat tip 2 fara deficienta beta-celulara.
Deficienta beta-celulara este defectul metabolic ce caracterizeaza diabetul zaharat.
Nu este pe deplin lamurit daca acest proces "de epuizare" afecteaza celulele betapancreatice normale sau numai pe acelea care, avand un defect "ocult" (146) sunt susceptibile sa se epuizeze. Aceasta vulnerabilitate a celulelor betapancreatice, ca si susceptibilitatea de a fi influentata de factori de mediu, ar putea fi determinata genetic. Faptul ca diabetul zaharat tip 2 este de 10 ori mai frecvent la obezii care au un parinte diabetic, in comparatie cu indivizii obezi fara istoric familial de diabet, pledeaza in favoarea unui defect betacelular "ocult", determinat genetic.
Este probabil ca in viitor sa se descopere ca, in baza interactiunii cu mediul, combinatii complexe ale unor defecte genice realizand un profil genetic particular determina aparitia diabetului zaharat tip 2.
1. ABATE N, GARG A, PESHOK RM SI COL.: Relationship of generalized regional adiposity to insulin sensitivity in men with NIDDM. Diabetes 1996; 45: 1684-1693
1 bis. ALBERTI KG, ZIMMET PZ: Definition, diagnosis and classification of diabetes mellitus and its complications. Diabet Med 1998; 15: 539-553
2. ANDREWS WJ, VASQUEZ B, NAGULESPARAN M SI COL.: Insulin therapy in obese, noninsulindependent diabetes induces improvements in insulin action that are maintained for two weeks after insulin withdrawal. Diabetes 1984; 33: 634-642
3. BARNETT AH, EFF C, LESLIE RDG AND PYKE DA: Diabetes in Identical Twins. A Study of 200 Pairs, Diabetologia 1981; 20: 87-93
4. BECK-NIELSEN H, Clinical Disorders of Insulin Resistance, In Alberti KGMM, DeFronzo R, Keen H, Zimmet P (eds): International Textbook of Diabetes Mellitus, John Wiley & Sons Ltd, 1992: 532-550
5. BENNETT PH., Epidemiology of diabetes mellitus. Rifkin H, Porte DJr (eds), Ellenberg and Rifkin's diabetes mellitus. New York, Elsevier, 1990: 363
6. BINGLEY PJ, MATTHEWS DR, WILLIAMS AJK SI COL.: Loss of regular oscillatory insulin secretion in islet cell antibody positive non-diabetic subjects. Diabetologia 1992; 35: 32-38
7. BONNER-WEIR S: Islet growth and development in the adult. J Mol Endocr 2000; 24: 297- 304
8. BONNER-WEIR S, DEERY D, LEAHY JL AND WEIR CG: Compensatory growth of pancreatic B-cells in adult rats after short-term glucose infusion Diabetes, 1989; 38: 49-53
9. BONNER-WEIR S, TRENT DF, HONEY RN, WEIR GC: Responses of neonatal islets to streptozotocin: limited B-cell regeneration and hyperglycemia. Diabetes, 1981; 30: 64-69
10. BONNER-WEIR S, TRENT DF, WEIR GC: Partial pancreatectomy in the rat and subsequent defect in glucose-induced insulin release. J. Clin. Invest. 1983; 71: 1544-1553
11. BONNER-WEIR S: Islet growth and development in the adult. J Mol Endocrinol 2000; 24: 297-302
12. BRATUSCH-MARRAIN P, KOMJATI M AND WALDHAUSL WK: Efficacy of pulsatile vs continuous insulin administration on hepatic glucose production and glucose utilization in Type I diabetic humans. Diabetes, 1986; 35: 922-926
13. BRUCE DG, CHISHOLM DJ, STORLIEN LH AND KRAEGEN EW: Physiological importance of deficiency in early pradial insulin secretion in non-insulin-dependent diabetes. Diabetes, 1988; 37: 736-744.
14. BRUNZELL JD, ROBERTSON RP, LARNERRL SI COL.: Relationship between plasma glucose levels and insulin secretion during intravenous glucose tolerance tests, J. Clin. Endocrinol. Metab. 1976; 42: 222-229
15. BUTEAU J, RODUIT R, SUSINI S, PRENTKI M: Glucagon-like peptide-1 promotes DNA synthesis, activates phosphatidylinositol 3-kinase and increases transcription factor pancreatic and duodenal homeobox gene (PDX-1) DNA binding activity in beta (INS-1)-cells. Diabetoloia 1999;42 : 856- 864
16. CALLES-ESCANDON J, ROBBINS DC: Loss of early phase of insulin release in humans impairs glucose tolerance and blunts termic effect of glucose. Diabetes, 1987; 36: 1167-1172
17. CERASI E, LUFT R: The plasma insulin response to glucose infusion in healthy subjects and in diabetes mellitus, Acta Endocrinol 1967; 55: 278-304
18. CERASI E, NESHER R, GADOT M SI COL.: Insulin secretion in obese and non-obese NIDDM, Diabetes Res. Clin. Prat. 1995; 28[Suppl]: S27-S37
19. CHAN JM, RIMM GA, COLDITZ GA SI COL. : Obesity, fat distribution and weight gain as risk factors for clinical diabetes in men. Diabetes Care 1994; 17: 961-969
20. CLARK A, WELLS CA, BULEY ID SI COL.: Islet amyloid, increased A-cells, reduced B-cells and exocrine fibrosis: quantitative changes in the pancreas in type 2 diabetes, Diabetes res. 1988; 9: 151-159
21. CLARK A, JONES LC, deKONIG E SI COL.: decreased Insulin Secretion in Type 2 Diabetes: A Problem of Celluler Mass or Function? Diabetes 2001, 50 Suppl 1: S169-S171
22. CLINE GW, PETERSEN KF, KRSSAK M SI COL., Impaired glucose transport as a cause of decreased insulin stimulated muscle glycogen synthesis in type 2 diabetes, N. Engl. J. Med. 1999; 341:240-246
23. COHEN B, NOVICK D, RUBINSTEIN M: Modulation of insulin activities by leptin. Science 1996; 274: 1185-1188
24. COLWELL JA, LEIN A: Diminished insulin response to hyperglycemia in prediabetes and diabetes, Diabetes, 1967; 16: 560-565
25. CORBETT J, SERUP P, BONNER-WEIR S, NIELSEN JP: Beta-cell ontogeny: growth and death. Diabetologia 1997;40 (Suppl 3): B27-B32
26. COCKBURN BN, OSTREGA DM, STURIS J SI COL.: Changes in pancreatic islet glucokinase and hexokinase activities with increasing age, obesity and the onset of diabetes. Diabetes 1997; 46: 1434-1439
27. DAVIES M, RAYMAN G, GRAY IP SI COL.: Insulin deficiency and increased plasma concentrations of intact and 32/33 split proinsulin in subjects with impaired glucose tolerance, Diab. Med. 1993; 10: 313-320
28. DAVIS BM, BERNSTEIN R, KOLTERMAN O. SI COL.: Defect in glucose removal in nonketotic diabetic patients with fasting hyperglycemia. Diabetes, 1979; 28: 32-41
29. DEFRONZO RA: The triumvirate: B-cell, Muscle, Liver. A Collusion Responsible for NIDDM. Diabetes, 1988; 37: 667-687
30. DOWSE GK, ZIMMET PZ: The prevalence and incidence of non-insulin-dependent diabetes mellitus. In Frontiers of diabetes research: Current trends in non-insulin-dependent diabetes mellitus. Alberti KGMM and Mazze R (eds) Elsevier Science Publishers B. V. 1989: 37-59
31. EDLUND H: Factors controlling pancreatic cell differentiation and function. Diabetologia 2001; 44: 1071-1079
32. ELBEIN SC, HASSTEDT SJ, WEGNER K, KAHN SE: Heritability of Pancreatic β-Cell Function among Nondiabetic Members of Caucasian Familial Ttype 2 Diabetic Kindreds. J Clin Endocr Metab 1999; 84: 1398-1403
33. ELLIS BA, POYNTEN A, LOWY AJ SI COL. : Long-chain acyl-CoA esters as indicators of lipid metabolism and insulin sensitivity in rat and human muscle. Am J Physiol 2000; 279: E554-E560
34. FAJANS S , CONN J: An approach to the prediction of diabetes mellitus by modification of the glucose tolerance test with cortisone. Diabetes 1954; 3: 296-304
35. FELBER JP, JALLUT D, GOLAY A SI COL.: Obesity to diabetes. A longitudinal study of glucose metabolism in man. Diabetes, 1989; 38 [Suppl 2]: 221 A(Abstract)
35 bis FERRANNINI E, NATALI A, BELL P SI COL.: Insulin resistance and hypersecretion in obesity. European Group for the Study of Insulin Resiatance (EGIR). J Clin Invest 1997; 100: 1166-1173
36. FERY F, BALASSE EO: Glucose metabolism during the starved-to-fed transition in obese patients with NIDDM. Diabetes 1994;43: 1418-1423
37. FLIER SN, KULKARNI RN, KAHN RC: Evidence for a circulating islet cell growth factor in insulinresistant states. Proc Nat Acad Sci USA 2001; 98: 7475-7480
38. FRITSCHE A, MADAUS A, ATEFAN N SI COL.: Relationship Among Age, Proinsulin Conversion, and β-Cell Function in Nondiabetic Humans. Diabetes 2002;51 Suppl 1 s234-S239
39. GANDA OP, SRIKANTA S, BRINK SJ SI COL.: Differential sensitivity to B-cell secretagogues in 'early' type I diabetes mellitus. Diabetes, 1984; 33: 516-521
40. GARDNER LI, STERN MP, HAFFNER SM: Prevalence of diabetes in Mexican Americans: relationship to percent of gene pool derived from native American sources. Diabetes, 1984; 33: 86-92
41. GERICH J: Is Reduced First-Phase Insulin Release the Earliest Detectable Abnornmality in Individuals Destined to Develop Type 2 Diabetes? Diabetes 2002; 51 (Suppl 1): S117-S121
42. GILON P, SHEPHERD RM, HENQUIN JC: Oscillations of secretion driven by oscillations of cytoplasmic Ca 2+ as evidence in single pancreatic islets. J. Biol. Chem. 1993; 268: 22265-22268
43. GOODNER CJ, KOERKER DJ, WEIGLE DS, MCCULLOCH DK: Decreased insulin and glucagon pulse amplitude accompanying B-cell deficiency induced by streptozotocin in baboons. Diabetes, 1989; 38: 925-931
44. GORDEN P, HENDRICKS CM, ROTH J: Circulating proinsulin-like component in man: increased proportion in hypoinsulinemic states. Diabetologia 1974; 10: 469-474
45. GRAPENGIESSER E, GYLFE E, HELLMAN B: Glucose-induced oscillations of cytoplasmic Ca2+ in the pancreatic beta-cell. Biochem Biophys Res Commun 1991; 12: 229-240
46. GRENWOOD R, MAHLER F, HALES C: Improvement of insulin secretion in diabetes after diazoxide. Lancet 1976, I: 444-447
47. GRILL V, BJORKLUND A: Overstimulation and β-Cell Function. Diabetes 2001; 50 (Suppl 1): S122-S124
48. GRILL V, WESTBERG M, OSTENSON C-G: B cell insensivity in a rat model of non-insulin-dependent diabetes: evidence for a rapidly reversible effect of previous hyperglycemia. J. Clin. Invest. 1987; 80: 664-669
49. GROOP LC, WIDEN E, FERRANNINI E: Insulin resistance and insulin deficiency in the pathogenesis of type 2 (non-insulin-dependent) diabetes mellitus: errors of metabolism or of methods ? Diabetologia 1993; 36: 1326-1331
50. GULLI G, HAFFNER S, FERRANNINI E, DEFRONZO RA: What is inherited in NIDDM ? Diabetes, 1990; 39 [Suppl 1]: 116 A(Abstract)
51. HAFFNER SM, GONZALEZ C, MYKKANEN L, STERN M: Total immunoreactive proinsulin, immunoreactive insulin and specific insulin in relation to conversion to NIDDM: The Mexico City Diabetes Study. Diabetologia 1997; 40: 830-837
52. HAFFNER SM, MYKKANEN L, STERN M SI COL. : Relationship of proinsulin and insulin to cardiovasscular risk factors in nondiabetic subjects. Diabetes, 1993; 42: 1297-1302
53. HALES CN: The pathogenesis of NIDDM, Diabetologia 1994; 37 [Suppl 2]: S162-S168
54. HALTER JB, GRAF RI, PORTE DJR: Potentiation of insulin secretory responses by plasma glucose levels in man: evidence that hyperglycemia in diabetes compensates for impaired glucose potentiation. J. Clin. Endocrinol. Metab. 1979; 48: 946-954
55. HANSEN BC AND BODKIN NL: Heterogeneity of insulin responses: phases leading to Type 2 (non-insulin-dependent) diabetes mellitus in the rhesus monkey. Diabetologia 1986; 29: 713-719
56. HARRIS MI, HADDEN WC, KNOWLER WC: Prevalence of diabetes and impaired glucose levels in US population aged 20-74 yr. Diabetes, 1987; 36: 523-534
57. HATTERSLEY AT, CLARK PM, COOK JTE SI COL.: Maturity onset diabetes of the young is a beta-cell disorder with normal proinsulin levels. Diabetologia 1993; 36[Suppl 1]: 67 A (Abstract)
58. HEINE RJ, NIJPELS J, MOOY JM: New data on the rate of progression of impaired glucose tolerance to NIDDM and predicting factors. Diabetic med. 1996; 13 [Suppl 2]: S12-S14
59. HENRIKSEN JE, ALFORD F, WARD GM, BECK-NIELSEN H: Risk and mechanism of dexamethasone-induced deterioration of glucose tolerance in non-diabetic first-degree relatives of NIDDM patients. Diabetologia 1997; 40: 1439-1448
60. HOLLENBECK CB, CHEN N, CHEN Y-D, REAVEN GM: Relationship between the plasma insulin response to oral glucose and insulin stimulated glucose utilization in normal subjects. Diabetes, 1984; 33: 460-468
61. HOLLENBECK CB, REAVEN G: Variations in insulin stimulated glucose uptake in healthy individuals with normal glucose tolerance. J. Clin. Endocrinol. Metab. 1987; 64: 1169-1173
62. HUTTON JC: Insulin secretory granule biogenesis and the proinsulin-processing endopeptidases. Diabetologia 1994; 37[Suppl 2]: S48-S56
63. JACOB S, MACHANN J, RETT K SI COL.: Association of Increased Intramyocellular Lipid Content with Insulin Resistance in Lean Nondiabetic Offspring of Type 2 Diabetic Subjects. Diabetes 1999; 48: 1113-1119
64. JASPAN JB, LEVER E, POLONSKY KS, VAN CAUTER E: In vivo pulsatility of pancreatic islet peptides, Am. J. Physiol. 1986; 251: E215-E226
65. JONES CNO, PEI D, STARIS P SI COL.: Alterations in the Glucose-Stimulated Insulin Secretory Dose-Response and in Insulin Clearance in Nondiabetic Insulin-Resistant Individuals. J Clin Endocr Metab 1997; 82: 1834-1838
66. KAHN SE: The Importance of β-Cell Failure in the Development and Progression of Type 2 Diabetes. J Clin Endocr Metab 2001; 86: 4047-4058
67. KAHN SE, LEONETTI DL, PRIGEON RL SI COL.: Proinsulin as a Marker for the Development of NIDDM in Japanese-American Men. Diabetes, 1995; 44: 173-179
68. KAHN SE, PRIGEON RL, MC CULLOCH DK SI COL.: Quantification of the relationship between insulin sensitivity and B-cell function in human subjects: evidence for a hyperbolic function. Diabetes, 1993; 42: 1663-1672
69. KARAM JH, GRODSKY GM, FORSHAM PH Excessive insulin response to glucose in obese subjects as measured by immunochemical assay Diabetes, 1963; 12: 197-209
70. KAWATE R, NISHIMOTO Y, YAMAKIDO M: Migrant studies among the Japanese in Hiroshima and Hawaii. Waldhausl wk (ed). Excerpta Medica, Amsterdam, 1980: 526-531
71. KERN H, LOGOTHETOPOULOS J: Steroid diabetes in the guinea pig: studies on islet cell ultrastructure and regeneration. Diabetes 1970; 19: 145-154
72. KING H, ZIMMET P, BENNETT P SI COL.: Glucose tolerance and ancestral genetic admixture in six semitraditional Pacific populations. Genet. Epidemiol. 1984; 1: 315-328
73. KLOPPEL G, LOHR M, HABICH K SI COL.: Islet pathology and the pathogenesis of type 1 and type 2 diabetes mellitus revisited. Surv. Synth. Pathol. Res. 1985; 4: 110-125
74. KNOWLER WC, BENNETT PH, HAMMAN RF, MILLER M: Diabetes incidence and prevalence in Pima Indians: A 19 fold greater incidence than in Rochester, Minnesota. Am. J. Epidemiol. 1978; 108: 479-504
75. KOITER TR, WIJKSTRA S, VAN DER SCHAAF-VERDONK GCJ SI COL.: Pancreatic β-cell function and islet proliferation: effect of hyperinsulinemia. Physiol Behav 1995; 57:717-721
76. KOSAKA K, HAGURA R, KUZUYA T: Insulin responses in equivocal and definite diabetes, with special reference to subjects who had mild glucose intolerance but later developed definitive diabetes. Diabetes, 1977; 26: 944-952
77. KOSAKA K, KUZUYA T, AKANUMA Y, HAGURA R: Increase in insulin response after treatment of overt maturity-onset diabetes is independent of the mode of treatment Diabetologia 1980; 18: 23-28
78. KRUSZYNSKA YT, HOME PD, HANNING I, ALBERTI KGMM: Basal and 24-h C-Peptide and insulin secretion rate in normal man. Diabetologia, 1987; 30: 16-21
79. KULKARNI R, BRUNNING J WINNAY J SI COL. : Tissue-speccific knockout of the insulin receptor in pancreatic β-cells creates an insulin secretory defect similar to that in type 2 diabetes. Cell 1999; 96: 329-339
80. LAEDTKE T, SCHMITZ O, PORKSEN N SI COL.: Mechanism of impaired pulsatile insulin secretion in NIDDM. Diabetes 1996, 45 (Suppl 2): 40 A (abstract)
81. LANG DA, MATTHEWS DR, BURNETT M SI COL.: Pulsatile, synchronous basal insulin and glucagon secretion in man. Diabetes, 1982; 31: 22-26
82. LANG DA, MATTHEWS DR, PETO J AND TURNER RC: Cyclic oscillations of basal plasma glucose and insulin concentrations in human beings. N. Engl. J. Med. 1979; 301: 1023-1027
83. LARSON H, AHREN B: Relative Hyperiproinsulinemia as a Sign of Islet Dysfunction in Women With Impaired Glucose Tolerance. J Clin Endocr Metab, 1999; 84: 2068-2077
84. LEAHY JL, BONNER WEIR S, AND WEIR C: Abnormal glucose regulation of insulin secretion in models of reduced B-cell mass. Diabetes, 1984; 33: 667-673
85. LEAHY JL, COOPER HE, DEAL DA, WEIR GC: Chronic hyperglicemia is associated with impaired glucose influence on insulin secretion: a study in normal rats using chronic in vivo glucose infusions. J. Clin. Ivest. 1986; 77: 908-915
86. LEAHY JL, HALBAN PA, WEIR GC: Increased pancreatic proinsulin: insulin ratio in diabetic rats. Diabetes, 1989; 38 [Suppl 2]: 206 A (Abstract)
87. LEAHY JL: Increased proinsulin/insulin ratio in pancreas extracts of hyperglycaemic rats. Diabetes 1993; 42: 22-27
88. LEAHY JL, WEIR GC: Unresponsiveness to glucose in a streptozocin model of diabetes: inappropriate insulin and glucagon responses to a reduction of glucose concentration. Diabetes, 1985; 34: 653-659
89. LEE Y, HIROSE H, OHNEDA M SI COL. : β-cell lipotoxicity in the pathogenesis of noninsulin-dependent diabetes mellitus of obese rats: impairment in adipcite β-cell relationships. Proc Natl Acad Sci USA 1994; 91: 10878-10882
90. LICHIARDOPOL R, DUMITRESCU C: Impaired glucose tolerance is associated with decreased insulin response Diabetologia 1991; 34 [Suppl 2]: 109 A (Abstract)
91. LILLIOJA S, MOTT DM, RAVUSSIN E SI COL.: Insulin resistance and insulin secretory disfunction as a precursor of non-insulin-dependent diabetes mellitus N. Endl. J. Med. 1993; 329: 1988-1992
92. LILLIOJA S, MOTT DM, ZAWADZKI JK SI COL.: In vivo Insulin Action is familial characteristic in nondiabetic Pima Indians, Diabetes, 1987; 36: 1329-1335
93. LUZI L, DEFRONZO RA: Effect of loss of first-phase insulin secretion on hepatic glucose production and tissue glucose disposal in humans. Am. J. Physiol 1989; 257: E241-E246
94. MACLEAN N, OGILVIE RF: Quantitative estimation of the pancreatic islet tissue in diabetic subjects. Diabetes, 1955; 4: 367-376
95. MAKO ME, STARR JI, RUBENSTEIN AH: Circulating proinsulin in patiens with maturity onset diabetes. Am. J. Med. 1977; 63: 865-869
96. MANDRUP-POULSEN T: β-Cell Apoptosis. Stimuli and Signalling. Diabetes 2001; 50 (Suppl 1): S58-S63
97. MARSHALL S : The hexosamine signaling pathway: a new road to drug discovery. Curr Opin Endocr Diab 2002; 9: 160-167
98. MATHER HM, KEEN H: The Southall diabetes survey: prevalence of known diabetes in Asians and Europeans, Br. Med. J. 1985; 291: 1081-1084
99. MATTHEWS DR, NAYLOR BA, JONES RG AND AL: Pulsatile insulin has greater hypoglycemic effect than continuous delivery. Diabetes, 1983; 32: 617-621
100. MATTHEWS DR, TURNER RC: Brief, irregular oscillations of basal plasma insulin and glucose concentration in diabetic man. Diabetes, 1981; 30: 435-439
101. McGARRY D: Banting Lecture 2001: Dysregulation of Fatty Acid Metabolism in the Etiology of Type 2 Diabetes. Diabetes, 2002; 51: 7-18
102. MILBURN JL, HIROSE H, LEE Y SI COL.: Pancreatic β-cells in obesity: evidence for induction of functional, morphologic and metabolic abnormalities by increased long-chain fatty acids. J Biol Chem 1995; 270: 1295-1299
103. MØLDRUP A, PETERSEN ED, NIELSEN JH: Effects of sex and pregnancy hormones on growth hormone and prolactin receptor gene exxpression in insulin-producing cells. Endoctinology 1993; 133: 1165-1172
104. MITRAKOU A, KELLEY D, MOKAN M SI COL.: Role of reduced suppression of glucose production and diminished early insulin release in impaired glucose tolerance. N. Engl. J. Med. 1992; 326: 22-29
105. MYKKANEN L, HAFFNER SM, KUUSISTO J SI COL.: Serum proinsulin levels are disproportionately increased in elderly prediabetic subjects. Diabetologia 1995; 38: 1176-1182
106. O'MEARA NM, STURIS J, VAN CAUTER E, POLONSKY KS: Lack of control by glucose of ultradian insulin secretory oscillations in impaired glucose tolerance and in non-insulin-dependent diabetes mellitus. J. Clin. Invest. 1993; 92: 262-271
107. NIE Y, NAKASHIMA M, BRUBAKER PL SI COL.: Regulation of pancreatic PC1 and PC2 associated withy increased glucagon-like peptide 1 in diabetic rats. J Clin Invest 2000;105: 955-965
108. NIELSEN JH, GALSGAARD ED, MØLDRUP A SI COL.: regulation of β-Cell Mass by Hormones and Growth Factors. Diabetes 2001; (Suppl 1): S25-S29
109. O 'MEARA NM, STURIS J, BLACKMAN JD SI COL. : Oscillatory insulin secretion after pancreas transplant. Diabetes 1993;42: 855-861
110. ØLSON LK, SHARMA A, PESHAVARIA M: Reduction of insulin gene transcription in HIT-T15 β-cells chronically exposed to supraphysiologic glucose concentration is associated with loss of STF-1 transcription factor expression. Proc Natl Acad Sci USA 1995; 92: 9127-9132
111. PERALDI P, SPIEGELMAN B: TNF-alpha and insulin resistance: summary and future prospects. Moll Cell Biochem 1998; 182: 169-173
112. PERFETTI R, MERKEL P: Glucagon-like peptide-1: a major regulator of pancreatic β-cell function. Europ J Endocrinol 2000; 143: 717-725
113. PERSEGHIN G, SCIFO P, DeCOBELLI F SI COL. : Intramyocellular triglyceride content is a determinant of in vivo insulin resistance in humans: a 1H-13C nuclear magnetic resonance spectroscopy assessment in offspring of type 2 diabetic parents. Diabetes 1999; 48: 1600-1606
114. PETTITT DJ, ALECK KA, BAIRD HR SI COL.: Congenital susceptibility to NIDDM. Role of intrauterineenvironment. Diabetes 1988; 37: 622-628
115. PICK A, CLARK J, KUBSTRUP C SI COL.: Role of apoptosis in failure of β-cell mass compensation for insulin resistance and β-cell defects in male Zucker diabetic fatty (ZDF) rat. Diabetes, 1998; 47: 358-362
116. PIMENTA W, KORYTKOWSKI M, MITRAKOU A SI COL.: Pancreatic Beta-Cell Dysfunction as the Primary Genetic Lesion in NIDDM. Evidence From Studies in Normal Glucose-Tolerant Individuals with a First-Degree NIDDM Relative. JAMA 1995; 273: 1855-1861
117. POLONSKI KS, GIVEN BD, HIRSCH LJ SI COL.: Abnormal patterns of insulin secretion in non-insulin-dependent diabetes mellitus, N. Engl. J. Med. 1988; 318: 1231-1239
118. PORKSEN N, HOLLINGDAL M, JUHL C SI COL.: Pulsatile Insulin Secretion: Detection, Regulation and Role in Diabetes. Diabetes, 2002; 51 (Suppl 1): S245-S254
119. PORKSEN N, MUNN S, FERGUSON D SI COL.: Coordinate pulsatile insulin secretion by chronic intraportally transplanted islets in the isolated perfused rat liver. J Clin Invest 1994; 94: 219-227
120. PORKSEN N, NYHOLM B, VELDHUIS JD SI COL. : Pulsatile insulin secretion accounts for seventy-five percent of total insulin secretion during fasting. Am J Physiol 1995; 269: E478-E488
121. PRATLEY RE, WEYER C: The role of impaired early insulin secretion in the pathogenesis of type II diabetes mellitus. Diabetologia 2001; 44: 929-945
122. PRENTKI M, JOLY E, EL-ASSAD W, RODUIT R: Malonyl-CoA Signaling, Lipid Partitioning and Glucolipotoxicity: Role in beta-Cell Adaptation and Failure in the Etiology of Diabetes. Diabetes 2002; 51 (Suppl 3): S405-S413
123. O'RAHILLY S, TURNER RC AND MATTHEWS DR: Impaired pulsatile secretion of insulin in relatives of patients with non-insulin-dependent diabetes. N. Engl. J. Med. 1988; 318: 1225-1230
124. RAMIYA VK, MARAIST M, ARFORS KE SI COL.: reversal of insulin-dependent diabetes using islets generated in vitro from pancreatic stem cells. Nature Med 2000; 6: 278-282
125. REAVEN GM Role of Insulin Resistance in Human Disease, Diabetes, 1988; 37: 1595-1607
126. ROBERTSON RP: Type II diabetes, glucose 'non-sense' and islet desensitization, Diabetes, 1989; 38: 1501-1505
127. ROBERTSON RP, HARMON J, TRAN POSI COL.: Glucose Toxicity in beta-Cells: Type 2 Diabetes, Good Radicals Gone Bad, and the Glutatione Connection. Diabetes 2003; 52: 581-587
128. RODEN M, PRICE TB, PERSEGHIN G SI COL. : Mechanism of free fatty acid-induced insulin resistance in humans. J Clin Invest 1996; 97: 2859- 2865
129. RODER ME, PORTE DJR, SCHWARTZ RS, KAHN SE: Disproportionately elevated proinsulin levels reflect the degree of impaired B cell secretory capacity in patients with noninsulin-dependent diabetes mellitus. J Clin Endocrin Metab 1998; 83: 604-608
130. SAAD MF, KAHN SE, NELSON RG SI COL.: Disproportionately elevated proinsulin in Pima Indians with noninsulin dependent diabetes mellitus, J. Clin. Endocrinol. Metab. 1990; 70: 1247-1253
131. SAITO K, YAGIMURA N, TAKAHASHI T: Differential volumetry of A-, B-, and D-cells in the pancreatic islets of diabetic and non diabetic subjects. Tokohu J. Exp. Med. 1979; 129: 273-283
132. SAKO Y, GRILL V: Coupling of B-cell desensitisation by hyperglycemia to excessive stimulation and circulating insulin in glucose-infused rats. Diabetes 1990; 39: 1580-1583
133. SCAGLIA L, SMITH FE, BONNER-WEIR Sl Apoptosis contributes to the involution of β-cell mass in the post partum rat pancreas. Endocrinology 1995; 136: 5461-5468
134. SEINO Y, KURAHACHI H, GOTO Y SI COL.: Comparative insulinogenic effects of glucose, arginine and glucagon in patients with diabetes mellitus, endocrine disorders and liver disease. Acta Diabetol. Lat. 1975; 12: 89-94
135. SELTZER HS, ALLEN EW, HERRON AL, BRENNAN MT: Insulin secretion in response to glycemic stimulus: relation of delayed initial release to carbohydrate intolerance in mild diabetes. J. Clin. Invest. 1967; 46: 323-335
136. SERJEANTSON SW, OWERBACH D, ZIMMET P, NERUP J, THOMA K: Genetics of diabetes in Nauru: effects of foreign admixture, HLA antigens and the insulin-gene-linked polymorfism. Diabetologia 1983; 25: 13-17
137. SHIMABUKURO M, ZHOU Y-T, LEVI M, UNGER RH: Fatty acid-induced β-cell apoptosis: A link between obesity and diabetes. Proc Natl Acad Sci USA 1998; 95: 2498-2502
138. SHIRAISHI I, IWAMOTO Y, KUZUYA T SI COL.: Hyperinsulinemia in obesity is not accompanoed by an increase in serum proinsulin/insulin ratio in groups of human subjects with and without glucose intolerance Diabetologia 1991; 34: 737-741
139. SHULMAN G: Cellular mechanisms of insulin resistance. J Clin Invest 2000; 106: 171-176
140. SIMON C, BRANDENBERGER G, FOLLENIUS M: Ultradian oscillations of plasma glucose, insulin and C-peptide in man during continuous enteral nutrition. J. Clin. Endocrinol. Metab. 1987; 64: 669-674
141. SIMON C, FOLLENIUS M, BRANDENBERGER G: Postprandial oscillations of plasma glucose, insulin and C-peptide in man. Diabetologia 1987; 30: 769-773
142. SONNENBERG G, HOFFMAN R, JOHNSON CP SI COL.: Low- and high- frequency insulin secretion pulses in normal subjects and pancreas transplant recipients: role of extrinsec innervation. J Clin Invest 1992; 90 : 545-553
143. SONNENBERG G, HOFFMAN R, MUELLER R, KISSEBACH A: Splanchnic insulin dynamics secretion pulsatilities in abdominal obesity, Diabetes 1994; 43: 468-477
144. STEFAN Y, ORCI L, MALAISSE-LAGAE F SI COL.: Quantitation of endocrine cell content in the pancreas of non diabetic and diabetic humans. Diabetes 1982; 31: 694-700
145. STEIN DT, DOBBINS R, SZCZEPANIAK L SI COL.: Skeletal muscle triglyceride stores are increased in insulin resistance. Diabetes 1997;46: 23 A (Abstract)
146. STERN MP: Type II diabetes mellitus: interface between clinical and epidemiological investigation. Diabetes Care 1988; 11: 119-126
147. STURIS J, POLONSKY KS, SHAPIRO ET SI COL.: Abnormalities in the ultradian oscillations of the insulin secretion and glucose levels in Type 2 (non-insulin-dependent) diabetic patients. Diabetologia 1992; 35: 681-689
148. SWENNE I, ANDERSSON A: Effect of genetic background on the capacity for islet cell replication in mice. Diabetologia 1984; 27: 464-467
149. SWENNE I, BORG LAH, CRACE CJ SI COL.: Persistent reduction of pancreatic B-cell mass after temporary protein-calorie malnutrition in the rat. Diabetologia 1990; 33: (Suppl. 1): 110 A (Abstract)
150. SWENNE I: Pancreatic Beta-cell growth and diabetes mellitus, Diabetologia 1992; 35: 193-201
152. SWENNE I: Role of the glucose in the in vitro regulation of cell cycle kinetics and proliferation in fetal pancreatic B-cells. Diabetes 1982; 31: 754-750
153. TEMPLE RC, CARRINGTON CA, LUZIO SD SI COL.: Insulin deficiency in non-insulin dependent diabetes. Lancet 1989; 1: 293-295
154. TURNER RC, MCCARTHY ST, HOLMAN RR, HARRIS E: Beta-cell function improved by supplementing basal insulin secretion in mild diabetes. Br. Med. J. 1976; 1: 1252-1254
155. U. K. Prospective Diabetes Study 16. Overview of 6 years' therapy of type II Diabetes: A progressive Disease. Diabetes, 1995; 44: 1249-1258
156. UNGER RH: Lipotoxicity in the Pathogenesis of Obesity-Dependent NIDDM. Diabetes 1995; 44: 863-870
157. UNGER RH, ZHOU YT: Lipotoxicity of β-cells in Obesity and Other Causes of Fatty Acid Spillover. Diabetes 2001; 50 (Suppl 1): S118-S121
158. UNGER RH, ZHOU YT, ORCI L : Regulation of fatty acid homeostasis in cells: Novel role of leptin. Proc Natl Acad Sci USA 1999; 96: 2327-2332
159. UNGER RH, GRUNDY S: Hyperglycemia as an inductor as well as a consequence of impaired islet cell function and insulin resistance: implications for the management of diabetes. Diabetologia 1985; 28: 119-121
160. VAAG A, HENRIKSEN JE, BECK-NIELSEN H: Decreased Insulin Activation of Glycogen Synthase in Skeletal Muscles in Young Nonobese Caucasian First-Degree Relatives of Patients with Non-Insulin-Dependent Diabetes Mellitus. J. Clin. Invest. 1992; 89; 782-788
161. VAGUE P, MOULIN JP: The defective glucose sensitivity of the B cell in non insulin dependent diabetes: improvement after twenty hours normoglycemia. Metabolism 1982; 31: 139-142
162. VAN HAEFTEN TW, DUBBELDAM S, ZONDERLAND ML, ERKELENS DW: Insulin Secretion in Normal Glucose-Tolerant Relatives of Type 2 Diabetic Subjects. Diabetes Care 1998; 21: 278-282
163. WARD WK, LACAVA EC, PAQUETTE TL SI COL.: Disproportionate elevation of immunoreactive proinsulin in type 2 (non-insulin-dependent) diabetes mellitus and in experimental insulin resistance. Diabetologia 1987; 30: 698-702
164. WARRAM JH, MARTIN BC, KROLEWSKI AS SI COL.: Slow glucose removal rate and hyperinsulinemia precede the development of type II diabetes in the ofspring of diabetic parents. Ann. Intern. Med. 1990; 113: 909-915
165. WEIR GC, LEAHY JL, BONNER-WEIR S: Experimental reduction of the B-cell mass implications for the pathogenesis of diabetes. Diab. Metab. Rev. 1986; 2: 125-161
166. WEIR GC, LEAHY JL, WILSON J, MATCHINSKY PM: Defective insulin secretion induced by hyperglycemia is not due to altered glucose transport in B-cell. Diabetes 1988; 37: [Suppl 1] 100A (Abstract)
167. WEYER C, BOGARDUS C, MOTT DM, PRATLEY RE: The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of Type 2 diabetes mellitus. J Clin Invest 1999; 104: 787-794
168. WILLIAMS DRR, BYRNE C, CLARK PMS SI COL.: Raised proinsulin concentration as early indicator of B-cell disfunction Br. Med. J. 1991; 303: 95-96
169. WITHERS D, GUTIEREZ JS, TOWERY H SI COL.: Disruption of IRS-2 causes type 2 diabetes in mice. Nature 1998; 391: 900-904
170. YALOW RS, BERSON SA: Immunoassay of endogenous plasma insulin in man. J. Clin. Invest. 1960; 39: 1157-1175
171. YOSHIOKA N, KUZUYA T, MATSUDA A SI COL.: Serum proinsulin levels at fasting and after oral glucose load in patients with type 2(non-insulin-dependent)diabetes mellitus, Diabetologia 1988; 31: 355-360
172. ZHOU YT, GRAYBURN P, KARIM A SI COL. : Lipotoxic heart disease in obese rats: Implications for human obesity. Proc Natl Acad Sci USA 2000; 97: 1784-1789
173. ZIMMET P, COLLINS VR, DOWSE GK, KNIGHT LT: Hyperinsulinaemia in youth is a predictor of type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 1992; 35: 534-541
174. ZIMMET P, DOWSE G FINCH C: The Epidemiology and Natural History of NIDDM: Lessons from South Pacific, Diabetes/Metab. Rev. 1990; 6: 91-124
175. ZIMMET P, DOWSE G, LAPORTE R SI COL.: Epidemiology-Its Contribution to Understanding of the Etiology, Pathogenesis, and Prevention of Diabetes Mellitus, Creutzfeld W, Lefebvre (eds) Diabetes Mellitus: Pathophysiology and therapy, Springer-Verlag,1988: 5-26
176. ZIMMET P, TAFT P, GUINEA A SI COL.: The high prevalence of diabetes mellitus on a Central Pacific Island, Diabetologia 1977; 13: 111-115
177. ZIMMET P, TAYLOR R, RAM P SI COL.: The prevalence of diabetes and impaired glucose tolerance in the biracial (Melanesian and Indian) population of Fiji-a rural-urban comparison, Am. J. Epidemiol. 1983; 118: 673-688
