β-cell development and turnover during prenatal life in humans

Abstract

Introduction: b-cell regeneration is an area under active investigation for the future treatment of diabetes, but little is known about the patterns and dynamics of prenatal b-cell development in humans.In particular, the quantitative changes in b-cell mass in the developing pancreas have not been elucidated in detail. We addressed the following questions in prenatal humans: i) what is the timing of b-cell occurrence and islet growth? ii) What are the dynamics of b-cell replication and apoptosis? Methods: Pancreatic tissue was obtained from 65 human embryos and foetuses aged between 8 weeks post conception (p.c.) and birth. Sections were stained for insulin, glucagon, Ki67 (proliferation marker), TUNEL (apoptosis marker) and CD31 (blood vessel marker), and morphometric analyses were performed. Results: b-cells were detected from gestational week 9 onward, whereas glucagon expression was detected already at week 8. The fractional b-cell area of the pancreas increased in a linear fashion until birth (rZ0.60, P!0.001). The first endocrine cells were found within or adjacent to the primitive ductal epithelium. b-cell replication was readily detected in the newly forming islets already starting at week 9 p.c. (average frequency 2.8G0.4%). A small percentage of cells co-expressed insulin and glucagon during the early foetal period. There was a close relationship between the development of endocrine islets and blood vessels during all stages of prenatal pancreas development suggesting a possible interaction between both cell types. The frequency of b-cell apoptosis was relatively high throughout all ages (1.5G0.3%). Conclusions: b-cell differentiation in humans occurs from week 9 p.c. onward. The first endocrine cells are closely associated with the ductal epithelium suggesting differentiation from precursor cells. High rates of b-cell replication suggest that this mechanism plays an important role in the prenatal expansion of b-cell mass.

Activation of Nicotinic Acetylcholine Receptors Decreases Apoptosis in Human and Female Murine Pancreatic Islets

“…These differences might reflect the fact that nicotine negatively influences the physiological ␤-cell replication and neogenesis that leads to an increase in ␤-cell mass during prenatal life (41) and soon after birth (42). In contrast, the effect of nACh-R activation seems to be different on adult ␤-cells, outside the critical window of the initial ␤-cell mass expansion.…”

The regulation of pre- and post-maturational plasticity of mammalian islet cell mass

“…In humans, a high rate of proliferation characterises late embryogenesis [20] and begins to decline postnatally [16,21]. Specifically, proliferation of insulin-expressing cells occurs at relatively high rates during early development and decreases to low levels by 24 weeks [22,23]. Analysing human pancreatic samples using Ki67 + insulin-expressing cells, Gregg et al [21] detected a high level of beta cell proliferation in neonates and in children of up to about 2 years of age that has been considered responsible for doubling human beta cells by 5 years of age to establish an organism's beta cell mass.…”

“…Highest rate of beta cell proliferation [21,22] Increased insulin secretion, which is, in part, due to transient insulin resistance [44,45] Doubling of beta cell mass by 5 years of age [22] Several-fold increase in beta cell mass from birth to adulthood [50,51] Increase in beta cells per islet and in islet size [51,52] Evidence of beta cell neogenesis and a regenerative response in diabetes [53] Mature beta cells are sensitive to perturbations in cell cycle control [60] Pro-survival effects of lactogen hormones on beta cells [99,100] but not alpha cells [102] Cytoprotective effect of GLP-1 on beta cells [104] GIP stimulates glucagon secretion [113], while GLP-1 inhibits secretion [112] Increase in beta cell mass reported in obesity [119] Reduction in beta cell mass and relative increase in alpha cell mass in diabetes [74] Decline in beta cell function; decline in beta cell replication Beta cell mass remains relatively constant in healthy humans [121] No major alterations in beta cell size [120] Beta cell apoptosis is low and remains constant throughout life [21] In diabetes: Mitochondrial dysfunction, oxidative stress, ER stress and accumulation of intermediate-sized amyloid particles [127] Neonatal age Puberty Adolescence Adulthood Old age diabetes coupled with high expression of IL-6 receptors on alpha cells suggest that this cytokine could contribute to the increased alpha cell mass observed in diabetes [88]. This notion is supported by fasting hypoglucagonaemia and an inability of mice lacking IL-6 to increase their alpha cell mass.…”

Cell cycle control of β-cell replication in the prenatal and postnatal human pancreas

“…Pancreatic tissue was fixed in formalin and embedded in paraffin (34). Sequential 4-m sections were cut (34) and stained as follows.…”

“…This approach was chosen because prenatal ␤-cells represent the only physiological sys-tem in which ␤-cell replication is constantly upregulated. On that basis, it was possible to compare the expression rates of these cell cycle proteins between two conditions exhibiting high (prenatal state) or very low (adult state) rates of ␤-cell replication (24,34).…”