鈴木 敦詞

The intricate link between glucose metabolism, ATP production, and glucose-stimulated insulin secretion (GIIS) in pancreatic β-cells has been well established. However, the effects of other digestible monosaccharides on this mechanism remain unclear. This study examined the interaction between intracellular fructose metabolism and GIIS using MIN6-K8 β-cell lines and mouse pancreatic islets. Fructose at millimolar concentrations potentiated insulin secretion in the presence of stimulatory levels (8.8 mM) of glucose. This potentiation was dependent on sweet taste receptor-activated phospholipase Cβ2 (PLCβ2) signaling. Concurrently, metabolic tracing using 13C-labeled fructose and glucose in conjunction with biochemical analyses demonstrated that fructose blunted the glucose-induced increase in the ATP/ADP ratio. Mechanistically, fructose is substantially converted to fructose 1-phosphate (F1P) at the expense of ATP. F1P directly inhibited PKM2 (pyruvate kinase M2), thereby reducing the later glycolytic flux used for ATP production. Remarkably, F1P-mediated PKM2 inhibition was counteracted by TEPP-46, a small-molecule PKM2 activator. TEPP-46 restored glycolytic flux and the ATP/ADP ratio, leading to the enhancement of fructose-potentiated GIIS in MIN6-K8 cells, normal mouse islets, and fructose-unresponsive diabetic mouse islets. These findings reveal an antagonistic interplay between glucose and fructose metabolism in β-cells, highlighting PKM2 as a crucial regulator and broadening our understanding of the relationship between β-cell fuel metabolism and insulin secretion.

β-adrenergic blockers (β-blockers) are extensively used to inhibit β-adrenoceptor activation and subsequent cAMP production in many cell types. In this study, we characterized the effects of β-blockers on mouse pancreatic β-cells. Unexpectedly, high concentrations (100 μM) of β-blockers (propranolol and bisoprolol) paradoxically increased cAMP levels 5-10 fold, enhanced Ca2+ influx, and stimulated a 2-4 fold increase in glucose- and glimepiride-induced insulin secretion in MIN6-K8 clonal β-cells and isolated mouse pancreatic islets. These effects were observed despite minimal expression of β-adrenoceptors in these cells. Mechanistically, the cAMP increase led to ryanodine receptor 2 (RYR2) phosphorylation via protein kinase A (PKA), triggering Ca2+-induced Ca2+ release (CICR). CICR then activates transient receptor potential cation channel subfamily M member 5 (TRPM5), resulting in increased Ca2+ influx via voltage-dependent Ca2+ channels. These effects contradict the conventional understanding of the pharmacology of β-blockers, highlighting the variability in β-blocker actions depending on the experimental context.

Objectives: We previously reported a high prevalence of hypovitaminosis D (25OHD < 20 ng/mL) in Japanese pregnant women with threatened premature delivery. This study aimed to assess nutritional status and its relationship with bone-related markers and microarchitecture, as measured using quantitative ultrasonography (QUS), in Japanese women during the perinatal period. Methods: We recruited Japanese women who had just delivered at Fujita Health University Hospital (n = 103, cesarean/vaginal delivery = 50/53, age 33.9 ± 4.9 years). On the third day postpartum, their calcaneal QUS was measured, and fasting blood samples were collected. Results: The mean total energy intake (1720 ± 298 kcal/day) was lower than the normal range for Japanese women (2100 kcal/day). Their calcium intake (446 ± 130 mg/day) was significantly below the recommended daily intake (RDI) in Japan (660 mg/day), with 95% of participants consuming less than the RDI. Although the average vitamin D intake (8.7 ± 1.8 μg/day) met the Japanese RDI (8.5 μg/day), 36% of participants consumed less than the RDI. Calcium intake was positively associated with the intake of lipids, protein, and vitamins A, D, and K. Additionally, calcium intake but not vitamin D intake tended to correlate with serum 25-hydroxyvitamin D (25OHD) levels. The QUS indices showed no significant association with calcium or vitamin D intake. Conclusions: During the perinatal period, Japanese women had low calcium intake and relatively low vitamin D intake, accompanied by reduced 25OHD levels. These findings highlight the need for public health recommendations and policies to promote adequate calcium and vitamin D intake during pregnancy.