Brief description of insulin mRNA quantity and qualityMany factors may contribute to the control of insulin mRNA levels (1, 2), including transcriptional networks that control β cell function (3) as well as mRNA stability (4). While a detailed analysis of the transcriptional regulation of β cell development, differentiation, and dedifferentiation is beyond the scope of this Review, it is certainly clear that PDX1 and NEUROD1 can act together to directly stimulate transcription from the INS promoter (5). Moreover, PDX1, in combination with NKX2.2 (downstream of NEUROG3; ref. 6) and FOXA2, stimulates the expression of the β cell-specific activator MafA (7); in turn, MafA homodimers (or MafA/MafB heterodimers) help support β cell INS gene transcription (8) (two alleles in humans, four alleles in mice and rats), along with additional upstream factors (9). A number of human diabetes-related genes associated with INS mRNA expression are summarized in Table 1.Classic studies of the islets of insulin-resistant C57BL/KsJ db/db mice, a genetic model of type 2 diabetes (T2D), have shown that at 5 weeks of age (when glycemia is not yet significantly perturbed and pancreatic insulin content is still similar to that in +/db controls), there is an elevation of Ins mRNA that is likely

and anti-proinsulin immunoblotting is shown below, highlighting the presence of aberrant disulfidelinked proinsulin complexes. B) Quantitation of islet proinsulin and insulin protein levels (each point an independent male animal) by Western blotting as in panel A (mean ± s.d.; * p < 0.05; ** p < 0.01). Supplement Fig. S2. Circulating proinsulin, and proinsulin-to-insulin ratio, from 11.5 week old HFD-fed Ins2-proinsulin-R(B22)E heterozygous males (pink symbols), superimposed onto the data reproduced from Figs 2G and H. Horizontal asterisks represent statistical differences (mean ± s.d.) along the X-axis (blood glucose); vertical asterisks indicate statistical differences along the Y-axis (proinsulin level, or proinsulin-to-insulin ratio). Supplement Fig. S3. Transmission electron micrographs of islets cells from the genotypes (and diet) included in this study. Random blood glucose at the time of euthanasia is indicated on each figure. Scale bars are shown on all figures. A) Typical β-cell from male WT mouse and Ins2proinsulin-R(B22)E heterozygote on normal chow diet (age 4 weeks). B) Another typical β-cell from the animals analyzed in panel A, at higher magnification to highlight ER and secretory granule morphology. C) β-cell from WT mouse fed a HFD for 6 weeks with organelles labeled on the figure. ISG = immature secretory granule. VTCs are a pre-Golgi compartment. D) Upper left image: low-power of islet from HFD-fed male Ins2-proinsulin-R(B22)E heterozygote (age 6 weeks). "Cell A and B" are β-cells; "Cell C" is an α-cell. Note that Cell B is poorly granulated.

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Advanced glycation end-products (AGEs) form when glucose reacts non-enzymatically with proteins, leading to abnormal protein function, oxidative stress, and inflammation. AGEs are associated with aging and age-related diseases; their formation is aggravated during diabetes. Therefore, drugs preventing AGE formation can potentially treat diabetic complications, positively affecting health. Earlier, we demonstrated that rifampicin and its analogs have potent anti-glycating activities and increase the life span of Caenorhabditis elegans. This study aimed to investigate the effects of rifampicin during hyperglycemia in C. elegans and in a mouse model of obesity-induced type 2 diabetes. The effects of rifampicin were assessed by determining the life span of C. elegans cultured in the presence of glucose and by measuring HbA1c, AGE levels, and glucose excursions in the diabetic mouse model. Our results show that rifampicin protects C. elegans from glucose-induced toxicity and increases life span. In mice, rifampicin reduces HbA1c and AGEs, improves insulin sensitivity, and reduces indications of diabetic nephropathy without inducing hepatotoxicity. Rifampicin quinone, an analog with lower anti-microbial activity, also reduces HbA1c levels, improves glucose homeostasis and insulin sensitivity, and lowers indications of diabetic nephropathy, without adversely affecting the liver of the diabetic mice. Altogether, our results indicate that rifampicin and its analog have protective roles during diabetes without inflicting hepatic damage and may potentially be considered for repositioning to treat hyperglycemia-related complications in patients.

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