Uncovering the molecular basis for nutritional reprogramming of pancreatic β-cells

Kari Østerli Frafjord

Research output: ThesisPh.D. thesis

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Type 2 diabetes is one of the leading health concerns in the world. Diabetes causes millions of deaths each year and the number of type 2 diabetes patients is rapidly increasing. Diabetes is characterized by a failure of the pancreatic β-cells to produce enough insulin to meet increased demands for nutrient storage. The increase in nutrient availability is suggested to be an important driver of β-cells adaptation to increased needs for insulin. However, excess nutrients can also induce a stress response, eventually leading to β-cell dysfunction. Thus, expanding our knowledge of the underlying mechanisms regulating β-cell adaptation to nutrients is important for understanding how type 2 diabetes develops.

In this Ph.D. project, we have used different approaches to investigate β-cell adaptation to nutrient overload. Glucose stimulation is known to reprogram β-cells eventually leading to both increased proliferation and repression of β-cell function. The first study demonstrate that high glucose stimulation leads to a reprogramming of the β-cell genome, and that the glucose response is biphasic. By integrative genomics, we identified novel transcriptional regulators of the late phase of the glucose response in β-cells. We focused on the nuclear receptor RORγ, and with loss-of-function studies, we demonstrate that RORγ is a novel regulator of β-cell proliferation in the INS-1E cell line and in primary rat β-cells.
The second study is a continuation of the first study, where we have applied a mass spectrometrybased strategy, rapid immunoprecipitation mass spectrometry of endogenous proteins (RIME), to identify other regulators of the transcriptional response to glucose response in β-cells. Here we used the Mediator complex subunit MED1, as bait to capture proteins associated with MED1 and thereby activate enhancers in INS-1E cells. Combining loss-of-function studies with genome-wide analysis reveals that knockdown of the top transcriptional MED1-RIME candidate, Mybbp1a, leads to transcriptomic changes in the glucose response, and affect the ability of INS-1E cells to proliferate.

The mechanisms underlying nutritional reprogramming in β-cells in vivo remain to be investigated. A third study aimed to investigate nutritional reprogramming in vivo our in-house developed mouse model, the Ins1CreTRAP mouse, which allows for in situ detection of β-cell-specific genomic changes. We performed metabolic phenotyping of the Ins1CreTRAP mice, and we demonstrate that mice have impaired glucose tolerance and increased β-cell proliferation after short-term high fat diet feeding. Unfortunately, we were not able to establish the protocols related to Ins1CreTRAP model. Therefore, other strategies based on single-cell technologies are currently being performed as an alternative for investigating β-cell-specific genomic changes in response to nutrients.
Translated title of the contributionUndersøgelse af de molekylære mekanismer bag ernæringsinduceret omprogrammering af bugspytkirtlens β-celler
Original languageEnglish
Awarding Institution
  • University of Southern Denmark
  • Mandrup, Susanne, Principal supervisor
  • Madsen, Jesper Grud Skat, Co-supervisor
Date of defence17. May 2022
Publication statusPublished - 8. Apr 2022


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