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.

/pdf/type-2-non-insulin-dependent-diabetes-mellitus-the-thrifty-wkzyogfl8p.pdf

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

Blood flow measurements with radionuclide-labeled particles.

Partitioning of Nutrients During Pregnancy and Lactation: A Review of Mechanisms Involving Homeostasis and Homeorhesis

Techniques are described for insertion of vinyl catheters into the umbilical and limb vessels of the fetus of the sheep or the goat through small uterine incisions, with the ewes under spinal analg...

https://www.ahajournals.org/doi/pdf/10.1161/01.RES.21.2.163

The Circulation of the Fetus in Utero METHODS FOR STUDYING DISTRIBUTION OF BLOOD FLOW, CARDIAC OUTPUT AND ORGAN BLOOD FLOW

Conceptus energy and nitrogen de- mands in late pregnancy are mostly met by placental uptake of maternal glucose and amino acids. The resulting 30 to 50% increase in maternal requirements for these nutrients is met partly by increased volun- tary intake and partly by an array of maternal metabolic adaptations. The latter include increased hepatic gluconeogenesis from endogenous substrates, decreased peripheral tissue glucose utilization, in- creased fatty acid mobilization from adipose tissue, and, possibly, increased amino acid mobilization from muscle. Within 4 d of parturition, mammary demands for glucose, amino acids, and fatty acids are several- fold those of the pregnant uterus before term. Even unusual postparturient increases in voluntary intake cannot satisfy this increased nutrient demand. There- fore, rates of hepatic gluconeogenesis and adipose fat mobilization are greatly accelerated. Concomitant changes in amino acid metabolism include increased hepatic protein synthesis and, possibly, decreased amino acid catabolism, and increased peripheral mobilization of amino acids. Insulin resistance in adipose tissue and muscle, developed during late pregnancy, continues postpartum; adipose lipolytic responsiveness and sensitivity to adrenergic agents are increased postpartum beyond their levels during late pregnancy. Before parturition, these homeorhetic adjustments may be coordinated with lactogenesis by increased secretion of estradiol and prolactin. Their amplification and reinforcement at and soon after parturition may be regulated mostly by somatotropin.

/pdf/regulation-of-organic-nutrient-metabolism-during-transition-3cjtw7rd0r.pdf

Regulation of organic nutrient metabolism during transition from late pregnancy to early lactation

Blood flow to fetal organs as a function of arterial oxygen content

Principal substrates of fetal metabolism.

The whole blood concentrations of 22 amino acids were measured in a chronic, unstressed fetal lamb preparations. Samples were taken daily from the umbilical artery, umbilical vein, and maternal artery over the latter quarter of gestation. 73 sets of samples (from the umbilical artery and vein and the maternal artery) from 13 animals were analyzed for amino acid levels. Oxygen contents were determined simultaneously in 48 sets (umbilical artery and vein) to relate fetal oxygen consumption to amino acid uptake via the umbilical circulation. The results indicate that there is no umbilical uptake of the acidic amino acids, glutamate and aspartate; there is, in fact, a net flux of glutamate out of the fetus into the placenta. As both of these amino acids are major constituents of body proteins, the data indicate that they are formed within the fetus. The umbilical uptake of some neutral and basic amino acids (e.g., valine, leucine, isoleucine, arginine, phenylalanine, and tyrosine) is in considerable excess of estimated growth requirements, suggesting that some amino acids undergo extensive transamination and oxidative degradation in the fetus. Finally, the net uptake of nitrogen, carbon, and calories by the growing ovine fetus in the form of amino acids, glucose, and lactate is compared to estimated requirements as determined in previous studies.

/pdf/umbilical-uptake-of-amino-acids-in-the-unstressed-fetal-lamb-1x1ncnkt8x.pdf

Umbilical uptake of amino acids in the unstressed fetal lamb.

A method of estimating the magnitude and distribution of umbilical blood flow by means of radioactive microspheres in sheep fetuses in utero is described. Simultaneous measurements of total umbilical flow by this method and the steady-state diffusion technique showed agreement within ±11%. In 11 fetuses of 90 to 150 days gestational age, the distribution of umbilical flow to the intercotyledonary chorion was 6.2±0.8% of the total. This information has been used to estimate the effect of venous admixture of cotyledonary and noncotyledonary blood on the umbilical vein-uterine vein concentration difference of inert molecules with flow-limited transplacental clearance.

Measurement of Umbilical Arterial Blood Flow to the Sheep Placenta and Fetus in Utero: DISTRIBUTION TO COTYLEDONS AND THE INTERCOTYLEDONARY CHORION

A method is described for the simultaneous estimation of uterine and umbilical blood flows and oxygen uptakes. A test stubstance, antipyrine, was infused at constant rate in the fetal circutlation. About 50 min. after starting the infusion a steady state was attained in which the rate of transplacental diffusion of the test substance was equal, blut for small corrections, to the rate of infusion. During the steady state, blood samples were collected from uterine and umbilical arteries and veins and analyzed for antipyrine and oxygen. Flows and oxygen uptakes were calculated according to Fick's principle. Thie results of sixteen experiments on sheep and goats sh1ow that: (1) transplacental diffusion of antipyrine is mainly flow-limited, (2) the placenta simulates a concturrent system of exchange, and (3) the oxygen uptakes of the fetus and the utero-placental mass were, in many cases, of similar magnitude.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/expphysiol.1967.sp001877

Giacomo Meschia

Papers

Blood flow to fetal organs as a function of arterial oxygen content

Principal substrates of fetal metabolism.

Umbilical uptake of amino acids in the unstressed fetal lamb.

Measurement of Umbilical Arterial Blood Flow to the Sheep Placenta and Fetus in Utero: DISTRIBUTION TO COTYLEDONS AND THE INTERCOTYLEDONARY CHORION

Simultaneous measurement of uterine and umbilical blood flows and oxygen uptakes