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In spite of the worldwide impact of diabetes on human health, the mechanisms behind glucose toxicity remain elusive. Here we show that C. elegans mutants lacking paqr-2, the worm homolog of the adiponectin receptors AdipoR1/2, or its newly identified functional partner iglr-2, are glucose intolerant and die in the presence of as little as 20 mM glucose. Using FRAP (Fluorescence Recovery After Photobleaching) on living worms, we found that cultivation in the presence of glucose causes a decrease in membrane fluidity in paqr-2 and iglr-2 mutants and that genetic suppressors of this sensitivity act to restore membrane fluidity by promoting fatty acid desaturation. The essential roles of paqr-2 and iglr-2 in the presence of glucose are completely independent from daf-2 and daf-16, the C. elegans homologs of the insulin receptor and its downstream target FoxO, respectively. Using bimolecular fluorescence complementation, we also show that PAQR-2 and IGLR-2 interact on plasma membranes and thus may act together as a fluidity sensor that controls membrane lipid composition., Author Summary Using the nematode C. elegans as a model, we show that glucose decreases the fluidity of cellular membranes, which suggests a novel mechanism for the glucose toxicity observed in diabetics. We also show that the membrane proteins PAQR-2 and IGLR-2 are located together on cellular membranes and regulate fluidity in the presence of glucose. This is an important finding because PAQR-2 is a worm homolog of AdipoR1 and AdipoR2, themselves important anti-diabetic proteins of which the cellular mechanism of action has been difficult to elucidate. Thus in one stroke our work may explain glucose toxicity, describes a cellular mechanism that counteracts it, helps clarify the anti-diabetic roles of AdipoR1/2, and identifies IGLR-2 as a PAQR-2 co-receptor.