TY - JOUR
T1 - Insulin biosynthesis and diabetes mellitus
AU - Permutt, Alan
AU - Chirgwin, John
AU - Giddings, Steve
AU - Kakita, Keiji
AU - Rotwein, Peter
N1 - Funding Information:
STUDY OF THE POLYPEPTIDE HORMONE INSULIN has played an important role in the fields of biochemistry and molecular biology. In the early 1950's, insulin was the first polypeptide whose primary sequence was determined (1). During the 1960's, joining of the Band A-chain of insulin was shown to occur by synthesis of a single chain precursor, proinsulin, followed by posttranslational removal of the connecting peptide (2). In the last few years, isolation of proinsulin mRNA and insulin genes yielded a considerable amount of information about the structure and the regulation of expression of genes in man and experimental animals. This knowledge has come about through the use of recombinant DNA techniques. The present review will focus on these new developments as they relate to diabetes. These methods have allowed us to study in non-diabetic and diabetic individuals the structure of the insulin gene, and the regulation of its expression at the level of proinsulin mRNA. On the basis of these findings, an * This work was supported by NIH grant AM-16724. °Recipient of a National Research Service Award AM-07120 from the National Institutes of Arthritis, Metabolism and Digestive Diseases. ** Recipient of a U.S. Public Health Service Career Development Award AM-00033 and to whom correspondence should be sent.
PY - 1981/10
Y1 - 1981/10
N2 - This review reports the use of recombinant DNA techniques in the study of the structure and regulation of expression of insulin genes in man and experimental animals. Insulin biosynthesis by pancreatic islet cells is predominantly regulated by change in plasma glucose concentration. Using a cell-free protein synthesizing system as an assay of functional proinsulin messenger RNA (mRNA), and hybridization analysis with a cloned DNA complementary to proinsulin mRNA, it has been determined that at least part of glucose regulation of insulin hiosynthesis occurs through changes in proinsulin mRNA levels. Insulin genes of the rat, chicken and human have been isolated and sequenced. The 5′ ends of the genes have similar sequences suggesting areas important for regulation of transcription. There are two non-allelic insulin genes in the rat, but only one in chickens and humans. Intervening sequences, areas of DNA transcribed into precursor mRNA but which do not appear in mature mRNA, have been described within insulin genes. The insulin gene resides on chromosome 11 of humans as determined by DNA hybridization analysis of mouse human hybrid cells. The structure of the insulin gene in genomic DNA of humans has been analyzed in diabetics and non-diabetics. Insertions of DNA between 1500 and 3400 base pairs have been detected near the transcription initiation site in 65% of type II diabetics, and 25-30% of non-diabetics (this difference is significant at the p <0.001 level). Limitation of these insertions to this potential promoter region of the insulin gene suggests that they may alter gene expression in type [] diabetes. These insertions of DNA may prove to be useful genetic markers for diabetes.
AB - This review reports the use of recombinant DNA techniques in the study of the structure and regulation of expression of insulin genes in man and experimental animals. Insulin biosynthesis by pancreatic islet cells is predominantly regulated by change in plasma glucose concentration. Using a cell-free protein synthesizing system as an assay of functional proinsulin messenger RNA (mRNA), and hybridization analysis with a cloned DNA complementary to proinsulin mRNA, it has been determined that at least part of glucose regulation of insulin hiosynthesis occurs through changes in proinsulin mRNA levels. Insulin genes of the rat, chicken and human have been isolated and sequenced. The 5′ ends of the genes have similar sequences suggesting areas important for regulation of transcription. There are two non-allelic insulin genes in the rat, but only one in chickens and humans. Intervening sequences, areas of DNA transcribed into precursor mRNA but which do not appear in mature mRNA, have been described within insulin genes. The insulin gene resides on chromosome 11 of humans as determined by DNA hybridization analysis of mouse human hybrid cells. The structure of the insulin gene in genomic DNA of humans has been analyzed in diabetics and non-diabetics. Insertions of DNA between 1500 and 3400 base pairs have been detected near the transcription initiation site in 65% of type II diabetics, and 25-30% of non-diabetics (this difference is significant at the p <0.001 level). Limitation of these insertions to this potential promoter region of the insulin gene suggests that they may alter gene expression in type [] diabetes. These insertions of DNA may prove to be useful genetic markers for diabetes.
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U2 - 10.1016/S0009-9120(81)90940-1
DO - 10.1016/S0009-9120(81)90940-1
M3 - Article
C2 - 7037227
AN - SCOPUS:0019768997
SN - 0009-9120
VL - 14
SP - 230
EP - 236
JO - Clinical Biochemistry
JF - Clinical Biochemistry
IS - 5
ER -