Stefan S. Fajans

Mutations in the hepatocyte nuclear factor-1α gene in maturity-onset diabetes of the young (MODY3)

THE disease maturity-onset diabetes of the young (MODY) is a genetically heterogeneous monogenic form of non-insulin-dependent (type 2) diabetes mellitus (NIDDM), characterized by early onset, usually before 25 years of age and often in adolescence or childhood, and by autosomal dominant inheritance1. It has been estimated that 2–5% of patients with NIDDM may have this form of diabetes mellitus2,3. Clinical studies have shown that predia-betic MODY subjects have normal insulin sensitivity but suffer from a defect in glucose-stimulated insulin secretion, suggesting that pancreatic β-cell dysfunction rather than insulin resistance is the primary defect in this disorder4,5. Linkage studies have localized the genes that are mutated in MODY on human chromosomes 20 (MODY1)6, 7 (MODY2)2 and 12 (MODY3}7, with MODY2 and MODY3 being allelic with the genes encoding glucokinase2, a key regulator of insulin secretion, and hepatocyte nuclear factor-1α (HNF-1α)8, a transcription factor involved in tissue-specific regulation of liver genes but also expressed in pancreatic islets, insulinoma cells and other tissues. Here we show that MODY1 is the gene encoding HNF-4α (gene symbol, TCP14), a member of the steroid/thyroid hormone receptor superfamily and an upstream regulator of HNF-1α expression9–11.

Stimulation of insulin secretion by amino acids.

In previous studies we have demonstrated that in healthy subjects the ingestion of protein meals results in large increases in plasma levels of insulin and have concluded that this is an important physiologic phenomenon (1, 3). In those experiments the magnitude of the increases in plasma insulin exceeded that expected from the small increases in plasma leucine measured (3). In addition, chlorpropamide pretreatment failed to accentuate the protein-induced changes in blood glucose and plasma free fatty acids (3), although it greatly augments such leucine-induced changes (4, 5). These findings suggested that amino acids other than leucine or amino acids in combination with leucine stimulate the release of insulin (1, 3, 6). The studies described below were performed to assess in healthy subjects the effects upon plasma levels of insulin of the administration of single amino acids and combinations of amino acids with and without leucine. Essential 1 I-amino acids were administered intravenously individually or as mixtures. Plasma levels of insulin, amino nitrogen, free fatty acids, and blood levels of glu-

A Difference Between the Inheritance of Classical Juvenile-onset and Maturity-onset Type Diabetes of Young People

A difference in the inheritance of diabetes has been shown between the families of twenty-six patients with maturity-onset type diabetes of young people (MODY) and families of thirty-five patients with classical juvenile-onset diabetes (JOD). In the families of MODY: 1) twenty-two of twenty-six (85 per cent) propositi had a diabetic parent; 2) 46 per cent of families showed direct vertical transmission of diabetes through three generations; 3) of forty-seven tested siblings twenty-five (53 per cent) had latent diabetes; 4) the diabetic phenotype in the families was consistent, most affected individuals having a noninsulin requiring type of disease. These findings are compatible with autosomal dominant inheritance of MODY, although they do not exclude multifactorial inheritance. In contrast, in the families of JOD: 1) only four (11 per cent) of propositi had a diabetic parent; 2) three generation inheritance was found in only two (6 per cent) of JOD families, and 3) of seventyfour tested siblings eight (11 per cent) were diabetic. This difference provides further evidence of genetic heterogeneity in diabetes mellitus and indicates that there is a need for careful definition of the phenotype of diabetes in populations in which the genetics of diabetes is to be analyzed.

A Newly Recognized Pancreatic Polypeptide; Plasma Levels in Health and Disease

Publisher Summary Immunohistochemical studies show that aPP is stored in an endocrine-type cell disseminated in the exocrine parenchyma of the chicken pancreas (aPP cells are seldom found in islets of chicken pancreas) and different from islet cell types A, B, and D. Moreover, hPP and several other mammalian pancreatic polypeptides have also been localized to an endocrine-type cell different from islet A, B, and D cells. The PP cells are found both in the peripheral part of the islets and scattered throughout the exocrine parenchyma. In man, hPP cells are found in the periphery of islets and also scattered in the exocrine pancreatic parenchyma and in the epithelium of small and medium-sized ducts. In 1976, Gersell and his associates confirmed that hPP cells are located both within and outside of the islets. This chapter explains distribution of pancreatic polypeptide in tissues, radioimmunoassay of hPP, regulation of secretion of hPP in healthy subjects, and hPP in disease states.

Altered Insulin Secretory Responses to Glucose in Diabetic and Nondiabetic Subjects With Mutations in the Diabetes Susceptibility Gene MODY3 on Chromosome 12

One form of maturity-onset diabetes of the young (MODY) results from mutations in a gene, designated MODY3, located on chromosome 12 in band q24. The present study was undertaken to define the interactions between glucose and insulin secretion rate (ISR) in subjects with mutations in MODY3. Of the 13 MODY3 subjects, six subjects with normal fasting glucose and glycosylated hemoglobin and seven overtly diabetic subjects were studied as were six nondiabetic control subjects. Each subject received graded intravenous glucose infusions on two occasions separated by a 42-h continuous intravenous glucose infusion designed to prime the β-cell to secrete more insulin in response to glucose. ISRs were derived by deconvolution of peripheral C-peptide levels. Basal glucose levels were higher and insulin levels were lower in MODY3 subjects with diabetes compared with nondiabetic subjects or with normal healthy control subjects. In response to the graded glucose infusion, ISRs were significantly lower in the diabetic subjects over a broad range of glucose concentrations. ISRs in the nondiabetic MODY3 subjects were not significantly different from those of the control subjects at plasma glucose levels <8 mmol/l. As glucose rose above this level, however, the increase in insulin secretion in these subjects was significantly reduced. Administration of glucose by intravenous infusion for 42 h resulted in a significant increase in the amount of insulin secreted over the 5–9 mmol/l glucose concentration range in the control subjects and nondiabetic MODY3 subjects (by 38 and 35%, respectively), but no significant change was observed in the diabetic MODY3 subjects. In conclusion, in nondiabetic MODY3 subjects insulin secretion demonstrates a diminished ability to respond when blood glucose exceeds 8 mmol/l. The priming effect of glucose on insulin secretion is preserved. Thus, β-cell dysfunction is present before the onset of overt hyperglycemia in this form of MODY. The defect in insulin secretion in the nondiabetic MODY3 subjects differs from that reported previously in nondiabetic MODY1 or mildly diabetic MODY2 subjects.

An Approach to the Prediction of Diabetes Mellitus by Modification of the Glucose Tolerance Test with Cortisone

A large proportion of presently nondiabetic individuals who have a family history of diabetes mellitus will eventually manifest the disease. If one could separate those who harbor the potentiality for diabetes from those who do not, further study of inciting factors would be possible. It is conceivable that impairment of reserve isletcell function may exist in such individuals even though carbohydrate tolerance can be demonstrated to be normal at the present time. The present study was begun in 1950 with the following objectives: to attempt to unmask the potential diabetic who manifests normal carbohydrate tolerance by present testing methods; and to determine whether or not the established diabetogenic activity of corticotropin and/or cortisone could be used to bring to the surface a subclinical defect in the metabolism of carbohydrate. It became necessary, as the initial step in this investigation, to establish a single testing dose of either corticotropin (ACTH) or cortisone which would not modify significantly carbohydrate tolerance in people with no family history of diabetes, but which would modify significantly carbohydrate tolerance of a considerable number of individuals with known family histories of diabetes mellitus. This has been accomplished and forms the basis of one of our major findings, namely, that 24 per cent of presently nondiabetic relatives of diabetics react to this test in a specific way, while this same response is observed in the control group in but 3 per cent of subjects. As will be detailed below, the total dose of cortisone employed in this test is 100 or 125 mg. of cortisone administered orally as two doses during an eight and one half-hour period prior to the oral glucose tolerance test.

Insulin secretion in response to protein ingestion.

W\e have reported previously that the oral or intravenous administration of the amino acid l-leucine to healthy subjects results in increases in plasma insulin and decreases in blood glucose and plasma free fatty acids (2, 3). After the administration of leucine to healthy subjects pretreated with either chlorpropamide or tolbutamide (2, 3), and also to some patients with functioning islet cell tumors of the pancreas (4), increments in plasma leucine caused increases in plasma insulin and decreases in blood glucose that were significantly greater than those observed in healthy subjects not pretreated with sulfonylurea drugs. Wehave also shown that increased release of insulin from the pancreatic beta cells is the mechanism by which leucine increases peripheral levels of insulin (5). Wesuggested that a rising plasma level of leucine is a physiologic stimulus for the release of insulin, and that the more pronounced sensitivity to leucine hypoglycemia produced experimentally by. administration of sulfonylureas and observed in some patients with idiopathic hypoglycemia or insulin-secreting tumors of the pancreas represents a great exaggeration of a normal physiologic phenomenon (6, 7). In an effort to determine the effect of leucine on insulin release under physiologic circumstances, protein meals rich in leucine were fed to healthy subjects, and the levels of plasma insulin, leucine, amino nitrogen, free fatty acids, and blood glucose

Effect of Amino Acids and Proteins on Insulin Secretion in Man

Following the demonstration that administration of leucine accentuates the hypoglycemia of some patients with “idiopathic hypoglycaemia of childhood” (1956) and of some patients with pancreatic islet cell tumours (1959) we initiated studies to explore the mechanism of leucine-induced hypoglycaemia. Sensitivity to leucine-hypoglycaemia can be induced consistently in healthy subjects after administration of sulfonylurea compounds. Increased release of pancreatic insulin is the primary mechanism by which leucine causes a fall in blood glucose in sulfonylurea-induced as well as in naturally occurring leucine hypoglycaemia. Experimentally-induced sensitivity to leucine hypoglycaemia can be used as a model for the further study of leucine hypoglycaemia. Potentiation of insulin activity has not been demonstrated to play a role in the production of leucine-induced hypoglycaemia in man. Leucine induces release of insulin and lowers blood glucose in healthy subjects without prior administration of hypoglycaemic agents, but to a quantitatively lesser extent than in sulfonylurea-induced leucine hypoglycaemia. The more pronounced sensitivity to leucine hypoglycaemia produced experimentally by administration of sulfonylureas and that observed in some patients with “idiopathic hypoglycaemia” or functioning islet cell tumours represents a great exaggeration of what appears to be a normal physiological phenomenon. To determine the effect of leucine on insulin release under physiologic circumstances, protein meals (cooked beef or chicken liver) rich in leucine were fed to healthy subjects. The increases in plasma insulin which resulted from the ingestion of the protein meals were considerably greater than those which would have been expected to have resulted from the modest increases in plasma leucine which occurred. These findings suggested that amino acids other than leucine or amino acids in combination with leucine stimulated the release of insulin. Essential 1-amino acids, either as mixtures or individually, were administered intravenously to healthy subjects. The various mixtures — whether they contained leucine or not — and most, but not all, of the individual amino acids stimulated the release of insulin. The most effective stimulus for insulin release was either a mixture of 10 essential amino acids or arginine given alone. Histidine was ineffective. Thus, the phenomenon of amino-acid-induced release of insulin does not depend on the presence of leucine in the infusion mixture. A variety of individual amino acids, induce the release of insulin, but there are large differences among these amino acids in their capacities to stimulate its secretion. Increases in blood glucose observed during some of the amino-acid infusions cannot be the major cause of the increases in plasma insulin. Rising plasma levels of certain amino acids after protein feeding can be considered to be physiologic stimuli for the secretion of insulin. It is speculated that the purpose of the insulinogenic response to protein ingestion is to aid in the utilization of absorbed amino acids and in their synthesis to protein. Leucine and arginine themselves, rather than one of their metabolites, are the potens stimuli to insulin release when these amino acids are administered. The mechanism by which leucine induces insulin release differs from that by which the other essential amino acids induce release of insulin. The magnitude of insulin secretion induced by the administration of mixtures of amino acids or ingested proteins depends not only upon the amount administered but also on the synergism between particular amino acids and in the case of mixed meals of protein and carbohydrate upon synergism between amino acids and glucose as well. Administration of human growth hormone and adrenalcortical steroids increases the sensitivity of the pancreatic islet cells to the insulin-releasing stimulus of amino acids. In non-obese, mildly diabetic subjects, increases in plasma insulin after administration of the 10-amino-acid mixture and of arginine were smaller than in healthy subjects. The history of the study of “leucine hypoglycaemia” and related phenomena is an example of how the exploration of a seemingly uncommon metabolic aberration observed in pathologic states and its experimental reproduction may lead to the recognition of what appear to be important physiologic relationships. In this instance the participation of amino acids in control of secretion of insulin (and also of growth hormone and glucagon) have evolved.

Scope and heterogeneous nature of MODY

This review summarizes aspects of the phenotypic expression, natural history, recognition, pathogenesis, and heterogeneous nature of maturity-onset diabetes of the young (MODY), which is inherited in an autosomal-dominant pattern. There are differences in metabolic, hormonal, and vascular abnormalities in different ethnic groups and even among White pedigrees. In MODY patients with low insulin responses, there are delayed and decreased insulin and C-peptide secretory responses to glucose from childhood or adolescence even before glucose intolerance appears, which may represent the basic genetic defect. When followed for decades, nondiabetic siblings have normal insulin responses. The fasting hyperglycemia of some MODY patients has been treated successfully with sulfonylureas for up to 30 yr. In a few patients, after years or decades of diabetes, the insulin and C-peptide responses to glucose are so low that they resemble those of early insulin-dependent diabetes mellitus. The progression of the insulin secretory defect over time distinguishes between these two types of diabetes. In contrast are patients from families who have very high insulin responses to glucose, despite glucose intolerance and fasting hyperglycemia similar to that seen in patients with low insulin responses. In many of these patients, there is in vivo and in vitro evidence of insulin resistance. Whatever its mechanism, the compensatory insulin responses to nutrients must be insufficient to maintain normal carbohydrate tolerance. This suggests that diabetes occurs only in those patients who have an additional islet cell defect, i.e., insufficient β-cell reserve and secretory capacity. In a few MODY pedigrees with high insulin responses to glucose and lack of evidence of insulin resistance, a structurally abnormal mutant insulin molecule that is biologically ineffective is secreted. No associations have been found between specific HLA antigens and MODY in White, Black, and Asian pedigrees. Linkage studies of the insulin gene, insulin-receptor gene, erythrocyte/HepG2 glucose-transporter locus, and apolipoprotein B locus have shown no association with MODY. Vascular disease may be as prevalent as in conventional non-insulin-dependent diabetes mellitus. Because of autosomal-dominant transmission and penetrance at a young age, MODY is a good model for further investigations of etiologic and pathogenetic factors in non-insulin-dependent diabetes mellitus, including the use of genetic linkage strategies to identify diabetogenic genes.

MODY History, genetics, pathophysiology, and clinical decision making

Studies conducted at the University of Michigan for 60 years and at the University of Chicago for approximately 25 years form the basis of this review. As no field of study can develop or progress in isolation, we have included selected investigations performed in other centers. In the academic year 1949–1950, one of us (S.S.F.), while a first-year Fellow in Endocrinology and Metabolism at the University of Michigan (Jerome W. Conn, Division Chief), initiated a prospective, long-term study on the diagnosis, natural history, and clinical genetics of diabetes. Starting with known diabetic patients from the Diabetes Clinic, I recruited their apparently healthy and asymptomatic first-degree relatives (parents, brothers, sisters, and children) for routine oral glucose tolerance tests (OGTTs). As control subjects, I recruited young individuals, many of them students, physicians, nurses, dietitians, and their spouses, who did not have a family history of diabetes or of large newborn babies. The initial objectives were 1 ) to define the normal range for the OGTT, 2 ) to attempt to unmask the potential diabetic subjects who manifest normal glucose tolerance by the standard OGTT and determine whether the diabetogenic activity of cortisone could be used to uncover a subclinical defect in the metabolism of glucose, and 3 ) to carry out periodic follow-up over many years of the apparently healthy first-degree relatives of diabetic patients. In our first publication in 1954 (1), 19% of 152 relatives of known diabetic patients were found to have diabetes by OGTT and, moreover, some were as young as 10 years of age. The same prevalence of 19% was found when testing a larger sample of 438 relatives of known diabetic patients (2). In 1960, we reported that mild, asymptomatic diabetes occurs in nonobese children, adolescents, and young adults. Their diabetic glucose tolerance and fasting hyperglycemia improved or normalized …