SGLT2 Deletion Improves Glucose Homeostasis and Preserves Pancreatic β-Cell Function

Leptin plays an important role in the control of food intake, energy expenditure, metabolism, and body weight. This hormone also has a key function in the regulation of glucose homeostasis. Although leptin acts through central and peripheral mechanisms to modulate glucose metabolism, the pancreatic β-cell of the endocrine pancreas is a critical target of leptin actions. Leptin receptors are present in the β-cell, and their activation directly inhibits insulin secretion from these endocrine cells. The effects of leptin on insulin occur also in the long term, since this hormone inhibits insulin gene expression as well. Additionally, β-cell mass can be affected by leptin through changes in proliferation, apoptosis, or cell size. All these different functions in the β-cell are triggered by leptin as a result of the large diversity of signaling pathways that this hormone is able to activate in the endocrine pancreas. Therefore, leptin can participate in glucose homeostasis owing to different levels of modulation of the pancreatic β-cell population. Furthermore, it has been proposed that alterations in this level of regulation could contribute to the impairment of β-cell function in obesity states. In the present review, we will discuss all these issues with special emphasis on the effects and pathways of leptin signaling in the pancreatic β-cell.

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Sexually dimorphic roles for the type 2 diabetes-associated C2cd4b gene in murine glucose homeostasis

10.1101/2020.05.18.099200 ◽

2020 ◽

Cited By ~ 1

Author(s):

S. Neda Mousavy Gharavy ◽

Bryn Owen ◽

Steven J. Millership ◽

Pauline Chabosseau ◽

Grazia Pizza ◽

...

Keyword(s):

Type 2 Diabetes ◽

Body Weight ◽

Glucose Tolerance ◽

Glucose Homeostasis ◽

Cell Function ◽

Sexually Dimorphic ◽

Pancreatic Β Cell ◽

Β Cell ◽

Β Cell Function

AbstractVariants close to the VPS13C/C2CD4A/C2CD4B locus are associated with altered risk of type 2 diabetes in genome-wide association studies. Whilst previous functional work has suggested roles for VPS13C and C2CD4A in disease development, none has explored the role of C2CD4B. Here, we show that systemic inactivation of C2cd4b in mice leads to marked, but highly sexually dimorphic, changes in body weight and glucose homeostasis. Female C2cd4b mice display unchanged body weight but abnormal glucose tolerance and defective in vivo, but not in vitro, insulin secretion, associated with a marked decrease in follicle stimulating hormone levels. In sharp contrast, male C2cd4b null mice displayed normal glucose tolerance but an increase in body weight and fasting glycemia after maintenance on high fat diet. No metabolic disturbances were observed after global inactivation of C2cd4a in mice, or in pancreatic β cell function at larval stages in C2cd4ab null zebrafish. These studies suggest that C2cd4b may act centrally to influence sex-dependent circuits which control pancreatic β cell function and glucose tolerance in rodents. However, the absence of sexual dimorphism in the impact of diabetes risk variants argues for additional roles for C2CD4A or VPS13C in the control of glucose homeostasis in man.

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