M. Desai

Organ-selective growth in the offspring of protein-restricted mothers

Recent epidemiological studies in people whose birth weights were recorded many years ago suggest links between impaired growth during early life and the development of diseases, including diabetes, much later in life. The long-term effects of retarded early growth are proposed to result from malnutrition at critical periods of fetal or infant development leading to reduction in the growth of organs and permanent changes in their metabolism or structure, or both. In order to investigate this, a rat model was established which involved feeding either a diet containing 200 g protein/kg or an isoenergetic diet containing 80 g protein/kg to pregnant and lactating rats. In addition, cross-fostering techniques were employed which allowed a separate evaluation of the prenatal or the postnatal periods. The offspring were studied at 21 d of age or were weaned onto a normal laboratory chow and studied at 11 months of age. The 80 g protein/kg diet during pregnancy did not affect the overall reproductive although more subtle differences were evident. Permanent growth retardation was evident in offspring subjected to maternal protein restriction during the postnatal period. At 21 d of age the offspring of protein-restricted mothers exhibited selective changes in organ growth: compared with the body weight, the lung and brain experienced a smaller decrease in weight: the heart, kidney and thymus decreased proportionately: whereas, the pancreas, spleen, muscle and liver showed a greater reduction in weight. In older animals the muscle weight was lower in the male rats and the relative weight of pancreas was increased in the female rats.

Gluconeogenesis, glucose handling, and structural changes in livers of the adult offspring of rats partially deprived of protein during pregnancy and lactation.

Maternal protein restriction is a model of fetal programming of adult glucose intolerance. Perfused livers of 48-h- starved adult offspring of rat dams fed 8% protein diets during pregnancy and lactation produced more glucose from 6 mM lactate than did control livers from rats whose dams were fed 20% protein. In control livers, a mean of 24% of the glucose formed from lactate in the periportal region of the lobule was taken up by the most distal perivenous cells; this distal perivenous uptake was greatly diminished in maternal low protein (MLP) livers, accounting for a major fraction of the increased glucose output of MLP livers. In control livers, the distal perivenous cells contained 40% of the total glucokinase of the liver; this perivenous concentration of glucokinase was greatly reduced in MLP livers. Intralobular distribution of phosphenolpyruvate carboxykinase was unaltered, though overall increased activity could have contributed to the elevated glucose output. Hepatic lobular volume in MLP livers was twice that in control livers, indicating that MLP livers had half the normal number of lobules. Fetal programming of adult glucose metabolism may operate partly through structural alterations and changes in glucokinase expression in the immediate perivenous region.

Early and late nutritional windows for diabetes susceptibility

Our epidemiological studies have led us to propose that events in early (fetal and infant) life are major factors determining susceptibility to non-insulin-dependent diabetes (NIDDM) in adult life (Brown et al. 1991; Hales et al. 1991; Robinson et al. 1992; Barker et al. 1993; Phillips et al. 1994; Law et al. 1995; Yajnik et al. 1995). It has been suggested that fetal growth restriction due to poor nutrition (either maternal or fetal or both) is environmentally determined and has at least two major consequences: (1) selective growth of major organs such as the brain at the expense of others such as the liver and kidney, (2) a permanent change in the endocrine and/or metabolic setting of the offspring in a direction likely to aid survival in a nutrient-deficient environment. The conflict between this setting and exposure to good or supra-normal nutrition was envisaged as a major route leading to NIDDM (Hales & Barker, 1992). It has been objected that whilst it is conceivable that nutritional deprivation might have an impact in populations with clear problems of obtaining adequate nutrition, such as the underdeveloped countries (and which also have severe problems with NIDDM emerging in ‘epidemic’ proportions; Zimmet & McCarty, 1995), such a mechanism is very unlikely to be of any importance in the developed Western world. It has also been thought highly improbable that processes occurring so early in life could determine aspects of health 5070 years later. Therefore, in addressing the issue of what life-time ‘windows’ are important in producing NIDDM we shall first consider whether nutrition during pregnancy could be an issue in the Western world and whether processes at this early stage could be of long-term importance.