Therapies to prevent diabetes in particular the progressive loss of β-cell mass and function and/or to improve the dysregulated metabolism associated with diabetes are highly sought. The incretin-based therapy comprising GLP-1R agonists and DPP-4 inhibitors have represented a major focus of pharmaceutical R&D over the last decade. The incretin hormone GLP-1 has powerful antihyperglycemic effect through direct stimulation of insulin biosynthesis and secretion within the β-cells; it normalizes β-cell sensitivity to glucose, has an antiapoptotic role, stimulates β-cell proliferation and differentiation, and inhibits glucagon secretion. However, native GLP-1 therapy is inappropriate due to the rapid post-secretory inactivation by DPP-4. Therefore, incretin mimetics developed on the backbone of the GLP-1 or exendin-4 molecule have been developed to behave as GLP-1R agonists but to display improved stability and clinical efficacy. New formulations of incretins and their analogs based on micro- and nanomaterials (i.e., PEG, PLGA, chitosan, liposomes and silica) and innovative encapsulation strategies have emerged to achieve a better stability of the incretin, to improve its pharmacokinetic profile, to lower the administration frequency or to allow another administration route and to display fewer adverse effects. An important advantage of these formulations is that they can also be used at the targeted non-invasive imaging of the beta-cell mass. This review therefore focuses on the current state of these efforts as the next step in the therapeutic evolution of this class of antidiabetic drugs.

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SGLT2 inhibitors reduce insulin resistance and may improve beta-cell function in humans with T2D. We studied the effects of Canagliflozin (Cana) on glucose homeostasis, islet architecture and endocrine cell fate in male TallyHO/JngJ (TH) mice, a new model of T2D, which mimics many aspects of polygenic T2D in humans. By 8 weeks of age, all TH mice developed moderate obesity and hyperglycemia compared to control SWR/J mice; ∼60% of TH mice converted quickly to overt diabetes, characterized by elevated BG values (>400mg/dL) (HG mice), while the remaining cohort maintained lower BG values (250-400mg/dL) until the end of the study (LG mice). Mice from both groups (HG, LG) were then randomized to receive Chow or Chow-containing Cana (100ppm) diet for 10 weeks, prior to sacrifice. Cana treatment significantly decreased the fasting BG levels only in the HG mice (HG/Cana) compared with untreated HG/Chow mice (207.7±34.6 vs. 452.2±163.4mg/dL, p<0.0001), improved glucose and insulin excursion curves during an ipGTT (p<0.0001 for AUC values) and decreased HbA1c values (4.3±0.7 vs. 6.2±0.93%, p<0.0001). Non-fasting plasma insulin and C-peptide levels, pancreatic insulin content and HOMA-B index were all significantly higher in HG/Cana than in HG/Chow mice, suggesting improved beta-cell function by Cana. Immunofluorescence staining for islet hormones showed that, compared to untreated animals, Cana reestablished the islet area and the beta-cell number/islet in HG mice (possibly due to reduced apoptosis of beta-cells), in addition to decreased number of alpha- and delta-cells/islet. In HG/Cana mice, the majority of Ins+ cells expressed the glucose transporter Glut2, while its expression was undetectable in Ins+ cells of the HG/Chow mice, further suggesting an improvement in glucose sensing capability of beta-cells with Cana treatment. Our study shows that Cana has beneficial effects on preserving beta-cell mass, identity and function in a model of early onset T2D. Disclosure I. Popescu: None. G.M. Mussman: None. C.B. Hughes: None. T.J. Janes: None. P. Ray: None. R. Bunn: None. J. Fowlkes: None. K.M. Thrailkill: None.