Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. 1992.

In this contribution we put forward a novel hypothesis concerning the aetiology of Type 2 (non-insulin dependent) diabetes mellitus. The concept underlying our hypothesis is that poor foetal and early post-natal nutrition imposes mechanisms of nutritional thrift upon the growing individual. We propose that one of the major long-term consequences of inadequate early nutrition is impaired development of the endocrine pancreas and a greatly increased susceptibility to the development of Type 2 diabetes. In the first section we outline our research which has led to this hypothesis. We will then review the relevant literature. Finally we show that the hypothesis suggests a reinterpretation of some findings and an explanation of others which are at present not easy to understand.

[1]  P. Beck,et al.  Immunoassay of serum polypeptide hormones by using 125I-labelled anti(-immunoglobulin G) antibodies. , 1975, The Biochemical journal.

[2]  A. Rubenstein,et al.  Circulating proinsulin in patients with maturity onset diabetes. , 1977, The American journal of medicine.

[3]  C. Hales,et al.  RADIOIMMUNOASSAY MAY OVERESTIMATE INSULIN IN NON‐INSULIN‐DEPENDENT DIABETICS , 1990, Clinical endocrinology.

[4]  G. Meschia,et al.  Principal substrates of fetal metabolism. , 1978, Physiological reviews.

[5]  M. Ballmann,et al.  Preferential release of proinsulin relative to insulin in non-insulin-dependent diabetes mellitus. , 1988, Acta endocrinologica.

[6]  P. Bennett,et al.  Congenital Susceptibility to NIDDM: Role of Intrauterine Environment , 1988, Diabetes.

[7]  S. Nolan,et al.  Insulin Patterns in Equivocal Glucose Tolerance Tests (Chemical Diabetes) , 1973, Diabetes.

[8]  S. Dubinett,et al.  TUMOUR-INFILTRATING LYMPHOCYTES AND INTERLEUKIN-2 IN TREATMENT OF ADVANCED CANCER , 1989, The Lancet.

[9]  B. Reusens,et al.  Effect of a low protein diet during pregnancy on the fetal rat endocrine pancreas. , 1990, Biology of the neonate.

[10]  G. Reaven,et al.  Relationship between heterogeneity of insulin responses and insulin resistance in normal subjects and patients with chemical diabetes , 1977, Diabetologia.

[11]  E. Kraegen,et al.  Physiological Importance of Deficiency in Early Prandial Insulin Secretion in Non-Insulin-Dependent Diabetes , 1988, Diabetes.

[12]  G. Pardi,et al.  Umbilical amino acid concentrations in appropriate and small for gestational age infants: a biochemical difference present in utero. , 1988, American journal of obstetrics and gynecology.

[13]  I. Swenne,et al.  Persistent Impairment of Insulin Secretory Response to Glucose in Adult Rats After Limited Period of Protein-Calorie Malnutrition Early in Life , 1987, Diabetes.

[14]  D. Kipnis,et al.  Plasma insulin responses to oral and intravenous glucose: studies in normal and diabetic sujbjects. , 1967, The Journal of clinical investigation.

[15]  C. Hales,et al.  Blood-glucose, plasma-insulin and growth hormone concentrations of individuals with minor abnormalities of glucose tolerance , 1968, Diabetologia.

[16]  I. Pastan,et al.  "Big insulin": a new component of plasma insulin detected by immunoassay. , 1968, Proceedings of the National Academy of Sciences of the United States of America.

[17]  W. James,et al.  Persistent impairment of insulin secretion and glucose tolerance after malnutrition. , 1970, The American journal of clinical nutrition.

[18]  C. Osmond,et al.  INFANT MORTALITY, CHILDHOOD NUTRITION, AND ISCHAEMIC HEART DISEASE IN ENGLAND AND WALES , 1986, The Lancet.

[19]  C. Milstein,et al.  Continuous cultures of fused cells secreting antibody of predefined specificity , 1975, Nature.

[20]  A. Fowden,et al.  The role of insulin in prenatal growth. , 1989, Journal of developmental physiology.

[21]  W. van Mieghem,et al.  Insulin excess as the initial lesion in diabetes. , 1972, Lancet.

[22]  A Lucas,et al.  Programming by early nutrition in man. , 2007, Ciba Foundation symposium.

[23]  P. Zimmet,et al.  Decline in incidence of epidemic glucose intolerance in Nauruans: implications for the "thrifty genotype". , 1991, American journal of epidemiology.

[24]  D. Owens,et al.  Sensitive and specific two-site immunoradiometric assays for human insulin, proinsulin, 65-66 split and 32-33 split proinsulins. , 1989, The Biochemical journal.

[25]  J. Henquin,et al.  Cell populations in the endocrine pancreas of human neonates and infants , 1981, Diabetologia.

[26]  K. Johansen Normal initial plasma insulin response in mild diabetes. , 1972, Metabolism: clinical and experimental.

[27]  G. Henderson,et al.  Placental amino acid uptake in normal and complicated pregnancies. , 1988, The American journal of the medical sciences.

[28]  M. Gardner,et al.  Incidence of diabetes amongst people aged 18–50 years in nine British towns: A collaborative study , 1982, Diabetologia.

[29]  N. Morton,et al.  Evidence for an autosomal recessive gene regulating the persistence of the insulin response to glucose in man , 1982, Clinical genetics.

[30]  D. Owens,et al.  INSULIN DEFICIENCY IN NON-INSULIN-DEPENDENT DIABETES , 1989, The Lancet.

[31]  M. Löhr,et al.  Islet pathology and the pathogenesis of type 1 and type 2 diabetes mellitus revisited. , 1985, Survey and synthesis of pathology research.

[32]  R. Milner Mechanisms of overgrowth , 1989 .

[33]  D. Barker,et al.  Relation of fetal and infant growth to plasma fibrinogen and factor VII concentrations in adult life. , 1992, BMJ.

[34]  W. Duckworth,et al.  Direct measurement of plasma proinsulin in normal and diabetic subjects. , 1972, The American journal of medicine.

[35]  P. Savage,et al.  Hyperinsulinemia and Hypoinsulinemia: Insulin Responses to Oral Carbohydrate Over a Wide Spectrum of Glucose Tolerance , 1975, Diabetes.

[36]  J. Najarian,et al.  Effects of hemipancreatectomy on insulin secretion and glucose tolerance in healthy humans. , 1990, The New England journal of medicine.

[37]  M Winick,et al.  Cellular response in rats during malnutrition at various ages. , 1966, The Journal of nutrition.

[38]  K. Kosaka,et al.  Insulin Responses in Equivocal and Definite Diabetes, with Special Reference to Subjects Who Had Mild Glucose Intolerance but Later Developed Definite Diabetes , 1977, Diabetes.

[39]  C. Hales,et al.  The preparation and properties of purified 125-I-labelled antibodies to insulin. , 1968, The Biochemical journal.

[40]  R. Milner,et al.  Metabolic and Hormonal Responses to Glucose and Glucagon in Patients with Infantile Malnutrition , 1971, Pediatric Research.

[41]  Hales Cn,et al.  Two site assay of human growth hormone. , 1971 .

[42]  C. Hales,et al.  Plasma insulin in minor abnormalities of glucose tolerance: a 5 year follow-up , 1974, Diabetologia.

[43]  N. Day,et al.  Height and glucose tolerance in adult subjects , 1991, Diabetologia.

[44]  J. Leahy,et al.  Experimental reduction of B-cell mass: implications for the pathogenesis of diabetes. , 1986, Diabetes/metabolism reviews.

[45]  P. Savage,et al.  Diet-induced improvement of abnormalities in insulin and glucagon secretion and in insulin receptor binding in diabetes mellitus. , 1979, The Journal of clinical endocrinology and metabolism.

[46]  K. Siddle,et al.  PROINSULIN IN HUMAN SERUM: PROBLEMS IN MEASUREMENT AND INTERPRETATION , 1984, Clinical endocrinology.

[47]  K. Eriksson,et al.  The importance of diabetes heredity in lean subjects on insulin secretion, blood lipids and oxygen uptake in the pathogenesis of glucose intolerance. , 1986, Diabetes research.

[48]  I. Swenne,et al.  Pancreatic Beta-cell growth and diabetes mellitus , 1992, Diabetologia.

[49]  J. Neel Diabetes mellitus: a "thrifty" genotype rendered detrimental by "progress"? , 1962, American journal of human genetics.

[50]  Clive Osmond,et al.  Fetal and placental size and risk of hypertension in adult life. , 1990, BMJ.

[51]  I. Swenne,et al.  Islet Cell Replication and Diabetes , 1988 .

[52]  T. Rosenkrantz,et al.  Effects of Fetal Insulin Deficiency on Growth in Fetal Lambs , 1991, Diabetes.

[53]  J. Roth,et al.  Circulating proinsulin-like component in man: Increased proportion in hypoinsulinemic states , 1974, Diabetologia.

[54]  G. Grodsky,et al.  Excessive Insulin Response to Glucose in Obese Subjects as Measured by Immunochemical Assay , 1963, Diabetes.

[55]  C. Hales,et al.  The relationships of concentrations of insulin, intact proinsulin and 32–33 split proinsulin with cardiovascular risk factors in Type 2 (non-insulin-dependent) diabetic subjects , 1990, Diabetologia.

[56]  C. Hales,et al.  Labelled Antibodies and Immunological Assay Systems , 1968, Nature.

[57]  D. Steiner,et al.  Evidence for proinsulin in human urine and serum. , 1968, Lancet.

[58]  D. Steiner,et al.  The biosynthesis of insulin and a probable precursor of insulin by a human islet cell adenoma. , 1967, Proceedings of the National Academy of Sciences of the United States of America.

[59]  Y. Iwamoto,et al.  Serum proinsulin levels at fasting and after oral glucose load in patients with Type 2 (non-insulin-dependent) diabetes mellitus , 1988, Diabetologia.

[60]  D. Barker The Intrauterine Origins of Cardiovascular and Obstructive Lung Disease in Adult Life , 1991, Journal of the Royal College of Physicians of London.

[61]  C. Hales,et al.  Measurement of human proinsulin by an indirect two-site immunoradiometric assay , 2005, Diabetologia.

[62]  D. Barker,et al.  WEIGHT IN INFANCY AND DEATH FROM ISCHAEMIC HEART DISEASE , 1989, The Lancet.

[63]  G. Reaven,et al.  Nonketotic diabetes mellitus: insulin deficiency or insulin resistance? , 1976, The American journal of medicine.

[64]  G. Reaven Role of Insulin Resistance in Human Disease , 1988, Diabetes.

[65]  M. Tzagournis,et al.  Excessive Serum Insulin Response to Oral Glucose in Obesity and Mild Diabetes Study of 501 Patients , 1970, Diabetes.

[66]  C Osmond,et al.  Fetal and infant growth and impaired glucose tolerance at age 64. , 1991, BMJ.

[67]  M. de Gasparo,et al.  Effect of glucose and amino acids on foetal rat pancreatic growth and insulin secretion in vitro. , 1978, The Journal of endocrinology.

[68]  E. Stern,et al.  High Prevalence of Diabetes in Young Adult Ethiopian Immigrants to Israel , 1988, Diabetes.

[69]  M. Shipley,et al.  CORONARY-HEART-DISEASE RISK AND IMPAIRED GLUCOSE TOLERANCE The Whitehall Study , 1980, The Lancet.

[70]  H. Halkin,et al.  Hyperinsulinemia. A link between hypertension obesity and glucose intolerance. , 1985, The Journal of clinical investigation.

[71]  J. Alcolado,et al.  Importance of maternal history of non-insulin dependent diabetic patients. , 1991, BMJ.

[72]  E. Widdowson,et al.  Cellular Development of Some Human Organs Before Birth , 1972, Archives of disease in childhood.

[73]  K. Godfrey,et al.  The effect of maternal anaemia and iron deficiency on the ratio of fetal weight to placental weight , 1991, British journal of obstetrics and gynaecology.

[74]  L. Aerts,et al.  The fetal endocrine pancreas. , 1979, Contributions to gynecology and obstetrics.

[75]  V. Mohan,et al.  Serum immunoreactive insulin responses to a glucose load in Asian Indian and European Type 2 (non-insulin-dependent) diabetic patients and control subjects , 1986, Diabetologia.