Bioengineered Pancreas–Liver Crosstalk in a Microfluidic Coculture Chip Identifies Human Metabolic Response Signatures in Prediabetic Hyperglycemia

Aberrant glucose homeostasis is the most common metabolic disturbance affecting one in ten adults worldwide. Prediabetic hyperglycemia due to dysfunctional interactions between different human tissues, including pancreas and liver, constitutes the largest risk factor for the development of type 2 diabetes. However, this early stage of metabolic disease has received relatively little attention. Microphysiological tissue models that emulate tissue crosstalk offer emerging opportunities to study metabolic interactions. Here, a novel modular multitissue organ‐on‐a‐chip device is presented that allows for integrated and reciprocal communication between different 3D primary human tissue cultures. Precisely controlled heterologous perfusion of each tissue chamber is achieved through a microfluidic single “synthetic heart” pneumatic actuation unit connected to multiple tissue chambers via specific configuration of microchannel resistances. On‐chip coculture experiments of organotypic primary human liver spheroids and intact primary human islets demonstrate insulin secretion and hepatic insulin response dynamics at physiological timescales upon glucose challenge. Integration of transcriptomic analyses with promoter motif activity data of 503 transcription factors reveals tissue‐specific interacting molecular networks that underlie β‐cell stress in prediabetic hyperglycemia. Interestingly, liver and islet cultures show surprising counter‐regulation of transcriptional programs, emphasizing the power of microphysiological coculture to elucidate the systems biology of metabolic crosstalk. Hyperglycemia caused by dysfunctional interactions between pancreas and liver is the largest risk factor for type 2 diabetes. By coculture of primary human liver spheroids and intact primary human pancreatic islets in a microfluidic device with heterologous perfusion, the authors recapitulate functional human tissue crosstalk ex vivo and reveal the molecular networks that underlie prediabetic glycemic stress.