Persistent reduction of pancreatic Beta-cell mass after a limited period of protein-energy malnutrition in the young rat

Abstract

Summary. Kwashiorkor, the human disease of proteinenergy malnutrition, has been implicated in the aetiology of malnutrition-related diabetes mellitus, a form of diabetes not uncommon in developing countries. We have previously demonstrated that temporary protein-energy malnutrition in young rats causes a persisting impairment of insulin secretion. The present study investigates whether this secretory deficiency is accompanied by structural alterations of the endocrine pancreas. Three-week-old rats were weaned onto semi-synthetic diets containing either 15 % or 5 % protein and these diets were maintained for 3 weeks. From 6 weeks of age all rats were fed a commercial chow containing 18 % protein. The endocrine pancreas was investigated by light and electron microscopic morphometry at 3, 6 and 12 weeks of age. In rats not subjected to protein-energy malnutrition there was a progressive increase, with age, of total pancreatic Beta-cell weight and individual Beta-cell size. In 6-week-old rats fed the low protein diet total pancreatic Beta-cell weight and individual Beta-cell size were diminished. In 12-weekold rats previously fed the low protein diet total Beta-cell weight remained lower compared to control rats. It is concluded that protein-energy malnutrition early in life may result in a diminished reserve for insulin production. This may predispose to glucose intolerance or even diabetes in situations with an increased insulin demand.Key words: Malnutrition-related diabetes mellitus, kwashiorkor, protein-calorie malnutrition, rat, pancreatic islets, pancreatic Beta cell, insulin, light microscopy, electron microscopy, morphometry.The relationship between affluent food supply, obesity and diabetes mellitus is well known and has been the subject of numerous studies. The observation made in 1907 [1] that the spectrum of diabetes in tropical regions of the Third World differs from that in western society and that the disease may be related to malnutrition is not as well recognized. However, in recent years the malnutritionrelated diabetic syndromes have been delineated and are now regarded as separate entities [2]. The exact role of malnutrition in the aetiology and pathogenesis of these types of diabetes remains obscure [3].Kwashiorkor, the disease of protein malnutrition in the young, is characterized by, among other symptoms and signs, impaired glucose tolerance and a diminished or even absent insulin secretory response to glucose [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. This appears to be a feature typical of protein deficiency, since balanced malnutrition, as in marasmus, has little or * This work was presented in part at the 26th Annual Meeting of the European Association for the Study of Diabetes in Copenhagen, Denmark 10-13 September 1990 no effect on glucose tolerance and insulin secretion [7,9,11,12,15,18]. Following nutritional rehabilitation, patients with kwashiorkor show a rapid improvement of glucose tolerance and insulin secretory response to glucose within weeks but short-term...

Reduced pancreatic β-cell mass is associated with decreased FoxO1 and Erk1/2 protein phosphorylation in low-protein malnourished rats

“…Our data also confirm previous studies (8,9) showing that rats submitted to a low-protein diet exhibit reduced β-cell mass ( Figure 1C). An increase in the population of small islets and a decrease in the population of large islets were observed by Tse et al (9), as also observed in the present study.…”

“…Malnourishment induces functional and structural alterations in the endocrine pancreas in fetal, neonatal (1)(2)(3)(4) and adult rats (5)(6)(7)(8)(9). We have shown that malnutrition caused by a low-protein diet increases insulin sensitivity in peripheral tissues of adult rats (6,7).…”

Beta-cell mass and proliferation following late fetal and early postnatal malnutrition in the rat

“…It did not differ between C and R animals (not shown). Absolute beta-cell volume was calculated as the ratio of beta-cell mass to pancreatic density, assuming a similar density for the endocrine and exocrine pancreas, as already described by others [5,11]. Individual beta-cell volume at each time point was calculated from the individual beta-cell area with the assumption that beta cells are spherical [12±14].…”

Short-term low-protein diet during pregnancy alters islet area and protein content of phosphatidylinositol 3-kinase pathway in rats

“…Another example of the adaptation of pancreatic islets occurs upon malnutrition, which is associated with important structural changes in the endocrine pancreas. Protein deficiency leads to reduced β-cell mass due to a decrease in the proliferation rate and an increase in apoptosis (Swenne et al 1992, Petrik et al 1999. Additionally, when the data are corrected for age and weight, a reduction in β-cell size and total islet volume, a lower proportion of β-cells per islet, a degranulation of β-cells and β-cells with a preponderance of abnormal pale granules have been observed (Heard and Stewart 1971, Pimstone 1976, Weinkove et al 1977.…”

“…Nutrients such as amino acids and glucose and certain growth factors such as insulin-like growth factor 1 (IGF-1), glucocorticoids, and the somatolactogenic hormones placental lactogen (PL), prolactin (PRL) and growth hormone (GH) increase pancreatic β-cell mitogenesis (Parsons et al 1992, Swenne et al 1992, Scharfmann and Czernichow 1996, Hogg et al 1993, Hugl et al 1998, Brelje et al 1993, Rafacho et al 2007). 17β-estradiol (E2) does not increase β-cell proliferation but does enhance the biosynthesis of insulin and is involved in β-cell survival (Nadal et al 2009).…”