Effects of first-line diabetes therapy with biguanides, sulphonylurea and thiazolidinediones on the differentiation, proliferation and apoptosis of islet cell populations

Abstract

Aims Metformin, rosiglitazone and sulfonylureas enhance either insulin action or secretion and thus have been used extensively as early stage anti-diabetic medication, independently of the aetiology of the disease. When administered to newly diagnosed diabetes patients, these drugs produce variable results. Here, we examined the effects of the three early stage oral hypoglycaemic agents in mice with diabetes induced by multiple low doses of streptozotocin, focusing specifically on the developmental biology of pancreatic islets. Methods Streptozotocin-treated diabetic mice expressing a fluorescent reporter specifically in pancreatic islet α-cells were administered the biguanide metformin (100 mg/kg), thiazolidinedione rosiglitazone (10 mg/kg), or sulfonylurea tolbutamide (20 mg/kg) for 10 days. We assessed the impact of the treatment on metabolic status of the animals as well as on the morphology, proliferative potential and transdifferentiation of pancreatic islet cells, using immunofluorescence. Results The effect of the therapy on the islet cells varied depending on the drug and included enhanced pancreatic islet β-cell proliferation, in case of metformin and rosiglitazone; de-differentiation of α-cells and β-cell apoptosis with tolbutamide; increased relative number of β-cells and bi-hormonal insulin + glucagon + cells with metformin. These effects were accompanied by normalisation of food and fluid intake with only minor effects on glycaemia at the low doses of the agents employed. Conclusions Our data suggest that metformin and rosiglitazone attenuate the depletion of the β-cell pool in the streptozotocin-induced diabetes, whereas tolbutamide exacerbates the β-cell apoptosis, but is likely to protect β-cells from chronic hyperglycaemia by directly elevating insulin secretion.

Taurine rescues pancreatic β‐cell stress by stimulating α‐cell transdifferentiation

“…Multiple low-dose injections of STZ induced a severe diabetes reflected in the elevated fluid and food intake and hyperglycemia alongside decreased body weight. 46,48 The diabetic phenotype was unaffected by a relatively lowdose 60 dietary administration of taurine, as we deemed to separate potential direct effects of the latter on pancreatic islet biology and physiology from the indirect ones, mediated by the changes in such systemic factors as glucose or insulin. Notably, circulating glucagon levels were also decreased (Figure 1F) by STZ-induced depletion of the β-cell population (Figure 2B), a trend observed in our earlier reports.…”

“…45 For cluster analysis (Figure 7F), we used the mean values for 25 phenotypic characteristics presented in this study (Figures 1-4), inclusive of global animal physiological indexes as well as proliferative, apoptotic and differentiation parameters from current study and our earlier works. [46][47][48][49] The analysis was performed using the kmeans function of the R core and visualized using the factoextra library. The optimal number of clusters was calculated using the elbow method.…”

Differential effects of RYGB surgery and best medical treatment for obesity-diabetes on intestinal and islet adaptations in obese-diabetic ZDSD rats

“…The reasons for this are unclear but may be related to the different animal models used, their age and effects on islet cell transitioning events. In this respect, it is interesting that both liraglutide and metformin have been shown to exert positive effects on islet cell trans differentiation [ 74 ].…”

Relative Molecular Similarity in Compound Structures Modulating Neurodegenerative Apoptosis

“…MPTP (1-methyl-4phenyl-1,2,3,6-tetrahydropyridine) [26], paraquat [26], rotenone [26], ethidium bromide [27], cuprizone [28], 3-nitro-L-tyrosine [29], streptozotocin [30], pentylenetetrazole (PTZ) [31], metamphetamine [32], lysophosphatidylcholine [33], sphingosine [34]. Compounds providing protection against experimentally induced diabetes and β-cell apoptosis: loganin [1], taurine [2], silibinin [3], 17β-estradiol [6], vitamin D3 [7], mdivi-1 [12], metformin [12], gliclazide [35], nicotinamide [36], telmisartan [37].…”