The aim of this study was to assess multifactorial β-cell responses to metabolic perturbations in primary rat and human islets. Treatment of dispersed rat islet cells with elevated glucose and free fatty acids (FFAs, oleate:palmitate = 1:1 v/v) resulted in increases in the size and the number of lipid droplets in β-cells in a time- and concentration-dependent manner. Glucose and FFAs synergistically stimulated the nutrient sensor mammalian target of rapamycin complex 1 (mTORC1). A potent mTORC1 inhibitor, rapamycin (25 nM), significantly reduced triglyceride accumulation in rat islets. Importantly, lipid droplets accumulated only in β-cells but not in α-cells in an mTORC1-dependent manner. Nutrient activation of mTORC1 upregulated the expression of adipose differentiation related protein (ADRP), known to stabilize lipid droplets. Rat islet size and new DNA synthesis also increased under nutrient overload. Insulin secretion into the culture medium increased steadily over a 4-day period without any significant difference between glucose (10 mM) alone and the combination of glucose (10 mM) and FFAs (240 μM). Insulin content and insulin biosynthesis, however, were significantly reduced under the combination of nutrients compared with glucose alone. Elevated nutrients also stimulated lipid droplet formation in human islets in an mTORC1-dependent manner. Unlike rat islets, however, human islets did not increase in size under nutrient overload despite a normal response to nutrients in releasing insulin. The different responses of islet cell growth under nutrient overload appear to impact insulin biosynthesis and storage differently in rat and human islets.

Considering that sex differences in glucose metabolism are observed in mice, researchers unconsciously use male mice to reduce variations by an estrogen cycle in female mice. In this study, we investigated the sex differences in glucose homeostasis in streptozotocin (STZ)-induced diabetes inbred mice (C57BL/6J). The C57BL/6J male and female mice were injected with or without STZ (40 mg/kg) for 5 consecutive days. Levels of fasting blood glucose (FBG), glycosylated hemoglobin (HbA1C), lipid profiles, oral glucose tolerance, and insulin resistance were measured at 3 and 6 weeks after STZ treatment. The FBG level in the STZ-induced male (M-STZ) group was significantly higher than that in the STZ-induced female (F-STZ) group during the entire experimental period. Furthermore, HbA1C and glucose tolerance levels in the M-STZ group were significantly higher than those in the F-STZ group at 3 and 6 weeks after STZ treatment. The glucagon/insulin ratio in the M-STZ group was significantly higher than that in the F-STZ group. Values of the homeostatic model assessment-insulin resistance, an indicator of β-cell function and insulin resistance, significantly increased in both the M-STZ and F-STZ groups at 3 weeks after STZ treatment. However, insulin resistance was observed in the M-STZ group, but not in the F-STZ group, at 6 weeks after STZ treatment. Taken together, our results indicate that glucose metabolism in the M-STZ group was worse than that in the F-STZ group, indicating that estrogen may have an important role in glucose metabolism by STZ treatment.

Background: ␤-Cell apoptosis, a critical contributor to T1D, involves iPLA 2 ␤ activation and is suppressed by Bcl-x(L). Results: iPLA 2 ␤-derived lipids activate an alternative 5Ј-splice site, reducing protective Bcl-x(L) protein. Conclusion:Modulation of Bcl-x splicing is another key mechanism by which iPLA 2 ␤-derived lipids promote ␤-cell apoptosis. Significance: Delineation of molecular mechanisms underlying iPLA 2 ␤-regulated splicing will elucidate novel strategies to counter ␤-cell death in T1D.

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Ethyl 2-((4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)thio)acetate (3) which was synthesized starting from anthranilic acid (1) via 2-thioxo-3-phenylquinazolin-4(3H)-one (2) reacted with hydrazine hydrate to afford 2-((4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)thio)acetohydrazide (4). Reaction of (4) with thiocarbonyl-bis-thioglycolic acid gave a new compound name N-(4-oxo-2-thioxothiazolidin-3-yl)-2-((4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)thio)acetamide (5). Knoevenagel condensation of (5) with appropriate aldehydes gave fourteen (Z)-N-(5-arylidene-4-oxo-2-thioxothiazolidin-3-yl)-2-((4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)thio)acetamide compounds (6a–o) with moderate yield. The chemical structure of the compounds was elucidated on the basis of IR, 1H-NMR, 13C-NMR, and HR-MS spectral data. The 5-arylidene-2-thioxothiazolidinone compounds exhibited mild-to-moderate cytotoxic activity against both K562 (chronic myelogenous leukemia) cells and MCF7 (breast cancer) cells.