The microRNA-29 (miR-29) family is among the most abundantly expressed microRNA in the pancreas and liver. Here, we investigated the function of miR-29 in glucose regulation using miR-29a/b-1 (miR-29a)-deficient mice and newly generated miR-29b-2/c (miR-29c)-deficient mice. We observed multiple independent functions of the miR-29 family, which can be segregated into a hierarchical physiologic regulation of glucose handling. miR-29a, and not miR-29c, was observed to be a positive regulator of insulin secretion in vivo, with dysregulation of the exocytotic machinery sensitizing β-cells to overt diabetes after unfolded protein stress. By contrast, in the liver both miR-29a and miR-29c were important negative regulators of insulin signaling via phosphatidylinositol 3-kinase regulation. Global or hepatic insufficiency of miR-29 potently inhibited obesity and prevented the onset of diet-induced insulin resistance. These results demonstrate strong regulatory functions for the miR-29 family in obesity and diabetes, culminating in a hierarchical and dose-dependent effect on premature lethality.

Type 1 (T1D) and type 2 (T2D) diabetes share pathophysiological characteristics, yet mechanistic links have remained elusive. T1D results from autoimmune destruction of pancreatic beta cells, whereas beta cell failure inT2D is delayed and progressive. Here we find a new genetic component of diabetes susceptibility in T1D non-obese diabetic (NOD) mice, identifying immune-independent beta cell fragility. Genetic variation in Xrcc4 and Glis3 alters the response of NOD beta cells to unfolded protein stress, enhancing the apoptotic and senescent fates. The same transcriptional relationships were observed in human islets, demonstrating the role of beta cell fragility in genetic predisposition to diabetes.

The study of plant diseases is almost as old as agriculture itself. Advancements in molecular biology have given us much more insight into the plant immune system and how it detects the many pathogens plants may encounter. Members of the primary family of plant resistance (R) proteins, NLRs, contain three distinct domains, and appear to use several different mechanisms to recognize pathogen effectors and trigger immunity. Understanding the molecular process of NLR recognition and activation has been greatly aided by advancements in structural studies, with ZAR1 recently becoming the first full-length NLR to be visualized. Genetic and biochemical analysis identified many critical components for NLR activation and homeostasis control. The increased study of helper NLRs has also provided insights into the downstream signaling pathways of NLRs. This review summarizes the progress in the last decades on plant NLR research, focusing on the mechanistic understanding that has been achieved.