Synchronized proinsulin trafficking reveals delayed Golgi export accompanies β-cell secretory dysfunction in rodent models of hyperglycemia

Boyer, Cierra K.; Bauchle, Casey J.; Zhang, Jianchao; Wang, Yanzhuang; Stephens, Samuel B.

doi:10.1038/s41598-023-32322-z

Cited by 5 publications

(2 citation statements)

References 67 publications

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“…A recent study characterized the disrupted protein trafficking observed in islets of diabetic LepR KO db/db mice and uncovered distended and vesiculated Golgi very similar to what we see in our KD mice. 60 Misfolded proinsulin released from the ER is put forth as cause of Golgi dilation and altered morphology. 60 Incidentally, misfolded proinsulin has been suggested to occur in early stages of T2D, 61 so it is possible that increases in misfolded proinsulin cause Golgi swelling and further impair insulin trafficking and secretion.…”

Section: Discussionmentioning

confidence: 99%

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Long-term ketogenic diet causes hyperlipidemia, liver dysfunction, and glucose intolerance from impaired insulin trafficking and secretion in mice

Gallop,

Vieira,

Matsuzaki

et al. 2024

Preprint

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SummaryA ketogenic diet (KD) is a very low-carbohydrate, very high-fat diet proposed to treat obesity and type 2 diabetes. While KD grows in popularity, its effects on metabolic health are understudied. Here we show that, in male and female mice, while KD protects against weight gain and induces weight loss, over long-term, mice develop hyperlipidemia, hepatic steatosis, and severe glucose intolerance. Unlike high fat diet-fed mice, KD mice are not insulin resistant and have low levels of insulin. Hyperglycemic clamp andex vivoGSIS revealed cell-autonomous and whole-body impairments in insulin secretion. Major ER/Golgi stress and disrupted ER-Golgi protein trafficking was indicated by transcriptomic profiling of KD islets and confirmed by electron micrographs showing a dilated Golgi network likely responsible for impaired insulin granule trafficking and secretion. Overall, our results suggest long-term KD leads to multiple aberrations of metabolic parameters that caution its systematic use as a health promoting dietary intervention.

show abstract

Section: Discussionmentioning

confidence: 99%

“…60 Misfolded proinsulin released from the ER is put forth as cause of Golgi dilation and altered morphology. 60 Incidentally, misfolded proinsulin has been suggested to occur in early stages of T2D, 61 so it is possible that increases in misfolded proinsulin cause Golgi swelling and further impair insulin trafficking and secretion.…”

Section: Discussionmentioning

confidence: 99%

Long-term ketogenic diet causes hyperlipidemia, liver dysfunction, and glucose intolerance from impaired insulin trafficking and secretion in mice

Gallop,

Vieira,

Matsuzaki

et al. 2024

Preprint

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Independent activation of CREB3L2 by glucose fills a regulatory gap in mouse β-cells by co-ordinating insulin biosynthesis with secretory granule formation

Sue,

Thai,

Saito

et al. 2024

Molecular Metabolism

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Loss of the Golgi-localized v-ATPase subunit does not alter insulin granule formation or pancreatic islet β-cell function

Boyer,

Blom,

Machado

et al. 2024

American Journal of Physiology-Endocrinology and Metabolism

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Delayed Golgi export of proinsulin has recently been identified as an underlying mechanism leading to insulin granule loss and β-cell secretory defects in Type 2 diabetes (T2D). Because acidification of the Golgi lumen is critical for proinsulin sorting and delivery into the budding secretory granule, we reasoned that dysregulation of Golgi pH may contribute to proinsulin trafficking defects. In this report, we examined pH regulation of the Golgi and identified a partial alkalinization of the Golgi lumen in a diabetes model. To further explore this, we generated a β-cell specific KO of the v0a2 subunit of the v-ATPase pump, which anchors the v-ATPase to the Golgi membrane. While loss of v0a2 partially neutralized Golgi pH and was accompanied by distension of the Golgi cisternae, proinsulin export from the Golgi and insulin granule formation were not affected. Furthermore, β-cell function was well-preserved. β-cell v0a2 KO mice exhibited normal glucose tolerance in both sexes, no genotypic difference to diet-induced obesity, and normal insulin secretory responses. Collectively, our data demonstrate the v0a2 subunit contributes to β-cell Golgi pH regulation but suggest that additional disturbances to Golgi structure and function contribute to proinsulin trafficking defects in diabetes.

show abstract

Synchronized proinsulin trafficking reveals delayed Golgi export accompanies β-cell secretory dysfunction in rodent models of hyperglycemia

Cited by 5 publications

References 67 publications

Long-term ketogenic diet causes hyperlipidemia, liver dysfunction, and glucose intolerance from impaired insulin trafficking and secretion in mice

Long-term ketogenic diet causes hyperlipidemia, liver dysfunction, and glucose intolerance from impaired insulin trafficking and secretion in mice

Independent activation of CREB3L2 by glucose fills a regulatory gap in mouse β-cells by co-ordinating insulin biosynthesis with secretory granule formation

Loss of the Golgi-localized v-ATPase subunit does not alter insulin granule formation or pancreatic islet β-cell function

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