Phloridzin Improves Hyperglycemia But Not Hepatic Insulin Resistance in a Transgenic Mouse Model of Type 2 Diabetes

Insulin resistance and loss of β-cell mass cause Type 2 diabetes (T2D). The objective of this study was to generate a nongenetic mouse model of T2D. Ninety-six 6-month-old C57BL/6N males were assigned to 1 of 12 groups including (1) low-fat diet (LFD; low-fat control; LFC), (2) LFD with 1 i.p. 40 mg/kg BW streptozotocin (STZ) injection, (3), (4), (5), (6) LFD with 2, 3, 4, or 5 STZ injections on consecutive days, respectively, (7) high-fat diet (HFD), (8) HFD with 1 STZ injection, (9), (10), (11), (12) HFD with 2, 3, 4, or 5 STZ injections on consecutive days, respectively. After 4 weeks, serum insulin levels were reduced in HFD mice administered at least 2 STZ injections as compared with HFC. Glucose tolerance was impaired in mice that consumed HFD and received 2, 3, or 4 injections of STZ. Insulin sensitivity in HFD mice was lower than that of LFD mice, regardless of STZ treatment. Islet mass was not affected by diet but was reduced by 50% in mice that received 3 STZ injections. The combination of HFD and three 40 mg/kg STZ injections induced a model with metabolic characteristics of T2D, including peripheral insulin resistance and reduced β-cell mass.

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Association between new markers of cardiovascular risk and hepatic insulin resistance in those at high risk of developing type 2 diabetes

Endocrine ◽

10.1007/s12020-021-02868-x ◽

2021 ◽

Author(s):

Lucilla D. Monti ◽

Camillo Bechi Genzano ◽

Barbara Fontana ◽

Elena Galluccio ◽

Serena Spadoni ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Cardiovascular Risk ◽

High Risk ◽

Hepatic Insulin Resistance

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An integrative transcriptional logic model of hepatic insulin resistance

10.1101/2021.03.15.435438 ◽

2021 ◽

Author(s):

TAKUMI KITAMOTO ◽

Taiyi Kuo ◽

Atsushi Okabe ◽

Atsushi Kaneda ◽

Domenico Accili

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Regulatory Elements ◽

Hepatic Insulin Resistance ◽

Dependent Manner ◽

Metabolic Genes ◽

Target Sites ◽

Common Pathogenesis ◽

Glucose Abnormalities

Abnormalities of lipid/lipoprotein and glucose metabolism are hallmarks of hepatic insulin resistance in type 2 diabetes. The former antedate the latter, but the latter become progressively refractory to treatment and contribute to therapeutic failures. It's unclear whether the two processes share a common pathogenesis and what underlies their progressive nature. In this study, we investigated the hypothesis that genes in the lipid/lipoprotein pathway and those in the glucose metabolic pathway are governed by different transcriptional logics that affect their response to physiologic (fasting/refeeding) as well as pathophysiologic cues (insulin resistance and hyperglycemia). To this end, we obtained genomic and transcriptomic maps of the key insulin-regulated transcription factor, FoxO1, and integrated them with those of CREB, PPARα, and glucocorticoid receptor. We found an enrichment of glucose metabolic genes among those regulated by intergenic and promoter enhancers in a fasting-dependent manner, while lipid genes were enriched among fasting-dependent intron enhancers and fasting-independent enhancer-less introns. Glucose genes also showed a remarkable transcriptional resiliency, i.e., an enrichment of active marks at shared PPARα/FoxO1 regulatory elements when FoxO1 was inactivated. Surprisingly, the main features associated with insulin resistance and hyperglycemia were a ″spreading″ of FoxO1 binding to enhancers, and the emergence of target sites unique to this condition. We surmise that this unusual pattern correlates with the progressively intractable nature of hepatic insulin resistance. This transcriptional logic provides an integrated model to interpret the combined lipid and glucose abnormalities of type 2 diabetes.

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