A. Ferrara

A. Monticelli

COCOZZA, SERGIO

L. Pianese

PORCELLINI, ANTONIO

RICCARDI, GABRIELE

S. Varrone

English

Archivio della ricerca - Università degli studi di Napoli Federico II

IjetterAcknowledgments—This research was sup-ported in part by Grant RR-30 from the Gen-eral Clinical Research Center Program of theDivision of Research Resources, National In-stitutes of Health (N1H), NIH Research Sci-entist Development Award K01-MH00303 toR.S.S., and by funds from the Research Net-work on the Consequences and Determinantsof Health Promoting and Health DamagingBehaviors of the John D. and Catherine T.MacArthur Foundation.Data was managed and analyzed with theClinfo Data Analysis System of the ClinicalResearch Unit of Duke University MedicalCenter (General Clinical Research CentersRR-30).References1. Feldberg W, Pike DA, Stubbs WA: On theorigin of non-insulin-dependent diabetes.Lancet 1:1263-64, 19852. Surwit RS, Feinglos MN: Stress and auto-nomic nervous system in type II diabetes:a hypothesis. Diabetes Care 11:83-85,19883. Giugliano D: Morphine, opioid peptides,and pancreatic islet function. DiabetesCare 7:92-98, 19844. Feldman M, Kiser RS, Unger RH, Li CH:Beta-endorphin and the endocrine pan-creas. N EnglJ Med 308:349-53, 19835. Surwit RS, McCubbin JA, Kuhn CM, Co-chrane C, Feinglos MN: Differential glyce-mic effects of morphine in diabetic andnormal mice. Metabolism 38:282-85,19896. Vermes 1, Steinmetz E, SchoorlJ, van dcrVeen EA, Tilders FJH: Increased plasma lev-els of immunoreactive p-endorphin andcorticotropin in non-insulin-dependent di-abetes (Letter). Lancet 2:725-26, 19857. Saad MF, Pettitt DJ, Mott DM, KnowlerWC, Nelson RG, Bennett PH: Sequentialchanges in serum insulin concentrationduring development of non-insulin-de-pendent diabetes. Lancet 1:1356-58,19898. Banerji MA, Lebovitz HE: Insulin-sensi-tive and insulin-resistant variants inNIDDM. Diabetes 38:784-92, 1989Mutations in Insulin-ReceptorGeneVal996 Allele in White NIDDM PatientsANTONIO PORCELUNI, MDSERGIO COCOZZA, MDANTONELLA MONTICELU, MDLUIGI PlANESE, BSGABRIELE RlCCARDI, MDASSIAMIRA F E R R A R A , MDSTEUO VARRONE, MDThe insulin-receptor (IR) gene playsa critical role in allowing cells torespond to insulin (1), and insulinresistance is a prominent feature of non-insulin-dependent diabetes mellitus(NIDDM; 2). The involvement of the IRdefects in the etiology of diabetes melli-tus has been suggested by the findings ofFROM THE DEPARTMENT OF CELLULAR AND MOLECULAR BIOLOGY AND PATHOLOGY "L. CALIFANO" ANDCENTRO DI ENDOCRINOLOGIA ED ONCOLOGIA SPERIMENTALE, NATIONAL RESEARCH COUNCIL, NAPLES;AND THE INSTITUTE OF INTERNAL MEDICINE AND METABOLIC DISEASE, 2ND MEDICAL SCHOOL, UNIVERSITYOF NAPLES, ITALY.ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO SERGIO COCOZZA, MD, DIPARTIMENTO DIBIOLOGIA E PATOLOGIA, CELLULARE E MOLECOLARE "L. CALIFANO," VIA S. PANSINI 5, 80131 NAPLES,ITALY.mutations in the IR gene in rare patientswith genetic syndromes of severe insulinresistance (3-12). Odawara et al. (7)have described a case of young Japanesemale with insulin resistance and acan-thosis nigricans in which valine is sub-stituted for glycine at position 996 (GTCinstead of GGC) in the tyrosine kinasedomain of the IR gene. Whether thismutation also contributes to the etiologyof the common forms of NIDDM is un-known. Therefore, we determined theprevalence of the Valg96 allele of the IRgene in a population of white NIDDMpatients.We studied a population of 103NIDDM patients referred to the DiabeticClinic of our Medical School. Diagnosisof NIDDM was made according to Na-tional Diabetes Data Group criteria. Allsubjects gave their informed consent toparticipate in the study. Subjects had amean ± SE age of 56.9 ± 1.06 yr and abody mass index of 28.12 ± 0.45 kg/m2.Their diabetes duration was 12.97 ±0.85 yr. Forty-three were men and 60were women. We used a modification ofthe polymerase chain reaction (PCR)procedure that permits the rapid identi-DIABETES CARE, VOLUME 15, NUMBER 4, APRIL 1992 591Letterfication of mutations at sites not recog-nized by restriction endonucleases (13).We altered the sequence of the senseprimer such that amplification of DNAcontaining a G, but not any other nucle-otide, at position 3116 of the 1R gene,would generate a recognition site for theenzyme Msp I. This region was amplifiedas follows: 200 ng of genomic DNA fromeach patient were amplified in 50 |xl ofPCR buffer (10 mM Tris-HCl [pH 8.3],1.5 mM MgCl2, 50 mM KC1, 0.001%gelatin) containing 20 pmol of each oli-gonucleotide primer (nucleotides 3089to 3115, sense strand; nucleotides 3191to 3217, antisense strand) and 10 nmolof each deoxyribonucleotide triphos-phate; one unit of thermus aquaticusDNA polymerase (Perkin Elmer Cetus,Norwalk, CT) was added and 100 p-l ofmineral oil was layered over the samples.The samples were incubated at 95, 55,and 72°C, respectively, for 45, 50, and50 s; this cycle was performed 36 timesin a DNA-RNA amplifier (Biostar Violet,Rome, Italy). The amplified DNAs wererestricted with Msp I and analyzed byelectrophoresis in 2.5% agarose.Because all the DNAs were di-gested by Msp I showing the presence ofa G at position 3116 of the IR gene, wenever detected Val996 allele in our dia-betic patients.Our data are consistent with avery low prevalence of the Val996 allele ofthe IR gene (< 1/206 alleles) in theNIDDM population. Further studies areneeded to establish the prevalence ofother IR gene mutations among diabeticindividuals.References1. Rosen OM: After insulin binds. Science237:1452-58, 19882. Reaven GM: Banting Lecture: role of in-sulin resistance in human disease. Diabe-tes 37:1595-1607, 19883. Kadowaki T, Bevins CL, Cama A, OjamaaK, Marcus-Samuels B, Kadowaki H, BeitzL, McKeon C, Taylor SI: Two mutantalleles of insulin receptor gene in a pa-tient with extreme insulin resistance. Sci-ence 240:787-90, 19884. Yoshimasa Y, Seino S, Wihttaker J,Kakehi T, Kosaki A, Kuzuya H, Imura H,Bell GI, Steiner DF: Insulin-resistant di-abetes due to a point mutation that pre-vents insulin proreceptor processing. Sci-ence 240:784-87, 19885. Kobayashi M, Sasaoka T, Takata Y,Ishibashi O, Sugibayashi M, Shigeta Y,Hisatomi A, Nakamura E, Tamaki M,Teraoka H: Insulin resistance by unproc-essed insulin proreceptors point muta-tion at the cleavage site. Biochem BiophysRes Commun 153:657-63, 19886. Moller DE, Flier JS: Detection of an al-teration in the insulin-receptor gene in apatient with insulin resistance, acantho-sis nigricans, and the polycystic ovarysyndrome (type A insulin resistance). NEnglJ Med 319:1526-1529, 19887. Odawara M, Kadowaki T, Yamamoto R,Shibasaki Y, Tobe K, Accili D, Bevins C,Mikami Y, Matsuura M, Akanuma Y,Takaku F, Taylor SI, Kasuga M: Humandiabetes associated with a mutation inthe tyrosine kinase domain of the insulinreceptor. Science 245:66-68, 19898. Taira M, Taira M, Hashimoto N, ShimadaF, Suzuki Y, Kanatsuka A, Nakamura F,Ebina Y, Tatibana M, Makino H, YoshidaS: Human diabetes associated with a de-letion of the tyrosine kinase domain ofthe insulin receptor. Science 245:63-66,19899. Accili D, Frapier C, Mosthaf L, McKeonC, Elbein S, Permutt MA, Ramos E,Lander E, Ullrich A, Taylor SI: A muta-tion in the insulin receptor gene thatimpairs transport of the receptor to theplasma membrane and causes insulin re-sistant diabetes. EMBO J 8:2509-17,198910. Klinkhamer MP, Groen NA, van der ZonGCM, Lindhout D, Sandkuyl LA, KransHMJ, Moller W, MaassenJA: A leucine-to-proline mutation in the insulin recep-tor in a family with insulin resistance.EMBO J 8:2503-07, 198911. Magre J, Goldstein BJ, Kriauciunas KM,Kahn CR: Mutation of the insulin recep-tor at tyrosine-1146 associated with anovel tyrosine kinase defect in a patientwith leprechaunism (Abstract). Diabetes39:113A, 199012. Kadowaki T, Kadowaki H, Rechler MM,Serrano-Rios M, RothJ, Gorden P, Tay-lor SI: Five mutants alleles of the insulinreceptor gene in patients with geneticforms of insulin resistance. J Clin Invest86:254-64, 199013. Embury SH, Scharf SJ, Saiki RK, GholsonMA, Golbus M, Arnheim N, Erlich HA:Rapid prenatal diagnosis of sickle cellanemia by a new method of DNA anal-ysis. N EnglJ Med 12:656-61, 1987592 DIABETES CARE, VOLUME 15, NUMBER 4, APRIL 1992

Mutations in insulin-receptor gene. Val996 allele in white NIDDM patients

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Mutations in insulin-receptor gene. Val996 allele in white NIDDM patients

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