All mixed up: defining roles for β-cell subtypes in mature islets

Abstract

Following differentiation during fetal development, β cells further adapt to their postnatal role through functional maturation. While adult islets are thought to contain functionally mature β cells, recent analyses of transgenic rodent and human pancreata reveal a number of novel heterogeneity markers in mammalian β cells. The marked heterogeneity long after maturation raises the prospect that diverse populations harbor distinct roles aside from glucose-stimulated insulin secretion. In this review, we outline our current understanding of the β-cell maturation process, emphasize recent literature on novel heterogeneity markers, and offer perspectives on reconciling the findings from these two areas.

Keywords: aging; maturation; pancreatic islets; stem cell differentiation; β-cell; β-cell heterogeneity.

Figure 1.

Molecular and metabolic changes associated with functional maturation of rodent β cells. Both immature and mature β cells are lineage-specified but differ in their insulin secretion response to glucose. (A) Mature β cells contain more insulin granules and secrete more insulin when stimulated with high levels of glucose. (B) One of the major differences between immature and mature β cells is the switch in expression from high-affinity hexokinase (HK) to low-affinity glucokinase (GCK). Glucose metabolism is thus only activated in mature cells in the presence of elevated levels of glucose. (C) Glucose-responsive respiration is also enhanced through the up-regulation of metabolic components involved in the tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OxPhos), and electron transport chain (ETC). (D) Changes in the expression pattern of microRNAs (miRs) during β-cell maturation directly regulate metabolic gene targets as well as disallowed genes (Box 1). (E) In addition to expressing canonical β-cell transcription factors that are present in immature cells (Pdx1, Nkx6.1, and Isl1), mature β cells express additional maturation genes such as MafA, urocortin3 (Ucn3), and estrogen-related receptor γ (Errγ). β-Cell-disallowed genes Hk1, monocarboxylate carrier 1 (Mct1), lactate dehydrogenase A (Ldha), repressor element 1 silencing transcription factor (Rest), and platelet-derived growth factor receptor α (Pdgfrα) are also down-regulated during maturation.

Figure 2.

Markers of β-cell heterogeneity in adult islets. Three recent studies identified novel markers of β-cell heterogeneity and new β-cell subtypes (shades of green) in adult islets. (A) Flattop, a Wnt/planar cell polarity (PCP) pathway effector, marks the major subpopulation of mouse β cells with a mature transcriptional profile. The ratio of Flattop-positive (Flattop⁺) to Flattop-negative (Flattop⁻) cells can change in response to different physiological contexts. (B) Differential expression of CD9 and ST8SIA1 demarcate four molecularly and functionally distinct subsets of human β cells. (C) Hub cells are highly connected pacemaker cells that instigate electrical signaling in follower cells in mouse islets. Hub cells express lower levels of some β-cell proteins and have enhanced metabolic response to glucose. (D) Processes such as conversion, selective elimination, and selective expansion can change the relative ratios of β-cell subtypes. Whether these processes occur for the different subtypes described during islet development, maturation, or disease progression remains to be determined.

Figure 3.

Effects of cellular heterogeneity in expression of K_ATP channel mutants on islet Ca²⁺ activation. (A) Dissociated β cells expressing wild-type K_ATP channel subunit Kir6.2 (Kir6.2^WT) should be inactive in Ca²⁺ signaling at low glucose but active at high glucose (green curve). (B) In contrast, β cells expressing Kir6.2^{[ΔN30,K185Q]} are inexcitable; they are resistant to depolarization and Ca²⁺ activation from increases in ATP resulting from increased metabolism in high glucose (red line). (C) β Cells expressing mutant Kir6.2^[AAA] can be depolarized independently of glucose metabolism and are constitutively active (yellow line) even under low-glucose conditions compared with wild-type cells (green dashed curve). (D) Despite the glucose-independent behaviors of individual β cells expressing mutant Kir6.2, multicellular islets containing 70% β cells expressing constitutively active Kir6.2^[AAA] (green and yellow curve) or up to 20% β cells expressing inactive Kir6.2^{[ΔN30,K185Q]} (red and green curve) respond to low and high glucose similar to islets containing 100% Kir6.2^WT β cells (green curve). Mosaic islets maintain glucose responsiveness largely due to cell–cell gap junction coupling. The figure was adapted and created by us from data from Rocheleau et al. (2006), Benninger et al. (2011), and Hraha et al. (2014).