Temporal metabolic and transcriptomic characteristics crossing islets and liver reveal dynamic pathophysiology in diet-induced diabetes

Abstract

Summary To investigate the molecular mechanisms underlying islet dysfunction and insulin resistance in diet-induced diabetes, we conducted temporal RNA sequencing of tissues responsible for insulin secretion (islets) and action (liver) every 4 weeks in mice on high-fat (HFD) or chow diet for 24 weeks, linking to longitudinal profile of metabolic characteristics. The diverse responses of α, β, and δ cells to glucose and palmitate indicated HFD-induced dynamic deterioration of islet function from dysregulation to failure. Insulin resistance developed with variable time course in different tissues. Weighted gene co-expression network analysis and Ingenuity Pathway Analysis implicated islets and liver jointly programmed β-cell compensatory adaption via cell proliferation at early phase and irreversible islet dysfunction by inappropriate immune response at later stage, and identified interconnected molecules including growth differentiation factor 15. Frequencies of T cell subpopulation showed an early decrement in Tregs followed by increases in Th1 and Th17 cells during progression to diabetes.

It’s What and When You Eat: An Overview of Transcriptional and Epigenetic Responses to Dietary Perturbations in Pancreatic Islets

“…HS diets (10-60% sucrose or fructose, 3-10% fat) have also been demonstrated to induce β-cell dysfunction due to impairments in first-phase GSIS ( 39 – 41 ) and increased β-cell apoptosis ( 39 , 75 ). Other endocrine cell types of the islet, particularly the pancreatic α-cell, are also affected by long-term HF and HS diets as highlighted by the development of basal hyperglucagonemia and impaired glucose-induced suppression of glucagon secretion with both dietary interventions ( 31 , 76 , 77 ). As highlighted below, our understanding of the physiological, transcriptional, and epigenetic changes of the non β islet cells are currently lacking and additional studies will be needed to understand their contribution to the homeostatic response to dietary interventions associated with T2DM.…”

“…The effects of HF and HFHS diets on islet function and mass are associated with distinct changes in the islet’s transcriptional programs. At the initial onset of HF diet, the islet transcriptionally activates compensatory proliferative and protein biosynthesis pathways to increase overall insulin production and secretion ( 31 ). Indeed, within one-week of HF diet transcripts associated with cell proliferation are upregulated (e.g.…”

“…Indeed, the circadian transcription factor BMAL1 which canonically binds to E-box motifs has also been demonstrated to be required for compensatory β-cell expansion in response to HF diet ( 19 ). Although there is an overall increase in β-cell number and insulin transcriptional levels with HF diet, the islets are characterized by an immature transcriptional signature highlighted by declines in identity factors such as neuronal differentiation 1 ( Neurod1 ) and forkhead box A2 (Foxa2) along with impairments in glucose oxidation (i.e., glucokinase) and mitochondrial function ( 31 ). These are features also observed in failing, dedifferentiating β-cells in T2DM which results in decoupling of glucose intake from insulin secretion ( 25 , 78 ).…”

“…Continued long-term (> 10 weeks) HF-diet feeding eventually leads to islet transcriptional decompensation and eventual failure with enrichment for pathways regulating inflammatory and adaptive immune response, such as CXC chemokine receptor (CXCR) signaling, which has previously reported as a key feature of long-term vs short-term HF diet administration in other metabolic tissues due, in part, to increased immune cell infiltration and activation ( 31 , 80 ). Importantly, activation of CXCR signaling has recently been demonstrated to facilitate β-cell functional failure and may contribute to β-cell demise with long-term HF diet ingestion ( 81 ).…”

“…Amongst the remaining ‘responders’, a major subpopulation of HF diet exposed α-cells had an immature islet transcriptional signature with increased Neurogenin 3 (Ngn3) and reduced Ero1b levels ( 91 , 92 ). Although the functional significance and origin of this subpopulation remains unclear, it may precipitate the α-cell dysfunction and hyperglucagonemia typically observed with HF diet interventions ( 31 , 76 ). As such, additional studies are urgently needed to reveal and target subpopulations of endocrine cell types driving metabolic dysfunction in response to HF-feeding.…”