Pancreatic alpha-cell mass across adult human lifespan

Abstract

Aim To establish pancreatic alpha-cell mass in lean, non-diabetic humans over the adult lifespan, performed as a follow-up study to beta-cell mass across the adult human lifespan. Methods We examined human pancreatic autopsy tissue from 66 lean, non-diabetic individuals aged from 30 to 102 years, grouped into deciles: 3rd (30–39 years), 4th (40–49 years), 5th (50–59 years), 6th (60–69 years), 7th (70–79 years), 8th (80–89 years) and 9th deciles (90+ years). Sections of pancreas were immunostained for glucagon and analyzed for fractional alpha-cell area. Population-based pancreatic volume data were used to calculate alpha-cell mass. Results With advanced age, the exocrine pancreas undergoes atrophy demonstrated by increased fat area (as % exocrine area) (0.05 ± 0.01 vs 1.6 ± 0.7% fat area of total exocrine pancreas, 3rd vs 9th decile, P < 0.05). Consequently, islet density increases with age (2.7 ± 0.4 vs 10.5 ± 3.3 islets/mm2, 3rd vs 9th decile, P < 0.05). Alpha-cell fractional area increases with advanced age (0.34 ± 0.05% vs 0.73 ± 0.26%, 3rd vs 9th decile, P < 0.05). However, alpha-cell mass remains constant at ~190 mg throughout the adult lifespan in lean, non-diabetic humans. Within islets, alpha-cell distribution between mantle and core is unchanged across deciles (1862 ± 220 vs 1945 ± 200 vs 1948 ± 139 alpha cells in islet mantle/mm2, 3rd vs 6th vs 9th decile, P = 0.93 and 1912 ± 442 vs 1449 ± 123 vs 1514 ± 168 alpha cells in islet core/mm2, 3rd vs 6th vs 9th decile, P = 0.47), suggesting that human islets retain their structural organization in the setting of age-related exocrine atrophy. Conclusions Consistent with our previous findings for beta-cell mass, alpha-cell mass remains constant in humans, even with advanced age. Pancreatic endocrine cells are much more robustly preserved than exocrine cells in aged humans, and islets maintain their structural integrity throughout life.

Insulitis and lymphoid structures in the islets of Langerhans of a 66-year-old patient with long-standing type 1 diabetes

“…Lymphocytic infiltrates are most frequently seen in the islets of patients with recent-onset disease [ 2 , 8 ], and only two cases with moderate insulitis with an age of onset over 40 years and a long-standing (> 1 year) T1D have previously been reported [ 9 , 10 ]. The patient was also characterized by a substantial residual beta cell mass in combination with alpha cell hyperplasia, with a substantially higher relative alpha cell area in the tail of the gland compared with the other pancreatic regions, and to values reported in non-diabetic controls [ 11 ]. Residual beta cells are not uncommon in patients with long-standing T1D, with approximately 50% of patients having low numbers of residual beta cells, often in a focal or lobular distribution pattern [ 8 , 12 , 13 ].…”

Modeling MEN1 with Patient-Origin iPSCs Reveals GLP-1R Mediated Hypersecretion of Insulin

“…The percentages of pancreatic endocrine cells change upon aging and health conditions [ 63 ], whether MEN1 affects pancreatic endocrine cell proportions remains unknown, and whether differences in the composition of its endocrine cells contribute to differences in the onset phenotype of MEN1 remains unknown. Given that in vitro differentiation protocols have certain limitations, we did not discriminate β-cells and α-cells as well as their endocrine progenitors well.…”

High-resolution glucose tracing and in situ imaging reveals regulated lactate production in human pancreatic β cells

“…To allow such lactate -> pyruvate conversion, human β cells must express sufficient LDH, and in particular LDHB, as shown here It is also possible that other cell types within the islets, such as α-cells, contribute to the accumulation of lactate. In particular, human α cells account for ~35% of the entire islet and express LDHA at levels six times higher than β cells (Moin et al, 2020;Sanchez et al, 2021). However, a major source of α cell lactate is via monocarboxylate transporters (Pullen and Rutter, 2013;Schuit et al, 2012;Zaborska et al, 2020), which are unlikely to play a role here as lactate was absent from the tracing medium.…”

“…It is possible that α-cells contribute to the accumulation of lactate. Human α cells account for ~35% of the entire islet and express LDHA at levels six times higher than β cells 54,55 .…”

“…It is possible that α-cells contribute to the accumulation of lactate. Human α cells account for ∼35% of the entire islet and express LDHA at levels six times higher than β cells 54,55 . However, a major source of α cell lactate is via monocarboxylate transporters 9,56,57 , which are unlikely to play a role here as lactate was absent from the tracing medium.…”