Generalized Diminution in the Response to Nutrients as Insulin-releasing Agents During the Early Neonatal Period in the Rat

Abstract

Glucose-induced insulin secretion is diminished during the fetal and neonatal period. To investigate whether the "defect" in B-cell secretion is specific for glucose and linked to glucose metabolism, the insulinreleasing effect of three nutrient secretagogues, glucose, glyceraldehyde, and leucine, were compared at different ages of the rat in vivo (1-and 7-day neonates) and in vitro (1-and 7-day neonates and adult animals). Intraperitoneal injections produced a marked insulin response to glucose, glyceraldehyde, and leucine in 7-day animals but only small increments that were not significant in 1-day neonates.The accumulation of insulin from isolated islets of 1-day neonates during 60-min incubations was slightly but significantly enhanced by 11.1-34.4 riiM glucose or 40 mM leucine. No response was seen with 1-16 mM glyceraldehyde. By contrast, all three secretagogues markedly stimulated insulin secretion from 7-day and adult islets. However, quantitative relationships differed. Thus, the response from 7-day islets to the highest concentration of glucose was 20%, to glyceraldehyde 10%, and to leucine 50% of adult values. A "basal" concentration of glucose (4.4 mM) amplified glyceraldehyde-or leucine-induced insulin release, but did not influence the age-related differences in secretory response.The nutrient secregogues induced a small percent stimulation of ( 32 P)-orthophosphate efflux from prelabeled islets of 1-day neonates. This stimulation increased progressively with age. However, in 1-and 7-day islets glucose and leucine stimulated the efflux of 32 P more than glyceraldehyde; in adult islets the nutrients were equipotent. Glucose, glyceraldehyde, and leucine increased the accumulation of ( 3 H) cyclic AMP in preiabeled adult but not in 7-or 1-day islets.The foregoing indicates that the obtunded insulin secretion at birth in the rat may apply to all nutrient secretagogues. Because of the difference in metabolic disposition of tested secretagogues, the secretory limitation cannot be ascribed to faulty glycolysis but must involve some communally shared, probably early, step in stimulus-secretion coupling. Continued maturation includes preferential development of the secretory responsiveness to some secretagogues.

Functional characteristics of neonatal rat β cells with distinct markers

“…It has been known for decades that fetal and neonatal b cells, both in rodents and humans, secrete less insulin when stimulated with glucose (Asplund et al 1969, Grill et al 1981, Hellerstrom & Swenne 1991. This glucose unresponsiveness was attributed to an impartial differentiation, in particular relating to specialized features of glucose-sensing b cells such as NADH shuttles (Tan et al 2002), K C ATP channels (Rorsman et al 1989) or general immaturity with expression of disallowed genes (Aye et al 2010, Jermendy et al 2011.…”

“…Here, we studied the b cell in the neonatal pancreas (2-3 days after birth): during the first months of postnatal rat life, the total b cell number expands more than tenfold mainly due to b cell division (Hellmann 1959, Hellman et al 1961, McEvoy 1981, Kaung 1994. Fetal and neonatal b cells have also been reported to have a lower glucose-stimulated insulin secretion (GSIS) than adult b cells (Asplund et al 1969, Grill et al 1981, Hellerstrom & Swenne 1991. Both their higher propensity to proliferate and their lower functional glucose responsiveness are generally considered as two sides of a same coin: both properties are assumed to reflect an incompletely differentiated b cell phenotype that has, on the one hand, not yet assumed full expression of all genes that are quintessential for the specialized glucose--sensing function of a mature b cell (Rorsman et al 1989, Tan et al 2002, Jermendy et al 2011 and, on the other hand, likely maintains expression of protein markers typically encountered in developing tissues.…”

Different Regulated Expression of the Tyrosine Phosphatase-Like Proteins IA-2 and Phogrin by Glucose and Insulin in Pancreatic Islets

“…Insulin secretion in response to glucose and other secretagogues is low throughout fetal life in humans and rodents and these responses increase after birth (27)(28)(29)(30). Poor secretory responses appear not to be a consequence of inadequate insulin content of ␤-cells.…”

Expression of the Protein Tyrosine Phosphatase-like Protein IA-2 During Pancreatic Islet Development

“…Islet development continues after birth and, in the rat, glucose-induced insulin secretion is not apparent until a few days after birth (Asplund 1973;Grill et al 1981). To evaluate the expression of IA-2 during this period, formalin-fixed sections of dissected pancreas from 1-10-day-old and adult rats were labeled for IA-2 expression using the selected MAbs.…”

“…Whether or not the closely related IA-2 is also expressed in the devel-oping pancreas has not been studied. To further investigate the role of the IA-2 family of PTPs in pancreatic islet function, we have analyzed the expression of IA-2 protein during pancreatic islet development in the fetal rat and during the development of regulated insulin secretory responses that occurs after birth (Asplund 1973;Grill et al 1981).…”