To test the antidiabetic potential of Gardenia latifolia extract (GLE) in rats with type 2 diabetes mellitus (T2DM) induced by a high-fat diet (HFD) + streptozotocin (STZ).
The study was carried out in June 2021. Gardenia latifolia powdered leaves were subjected to Soxhlet extraction using ethanol. Male rats were administered a low dose-40 mg/kg STZ by intraperitoneal route following 2 weeks of HFD to induce type-2 diabetic rats (T2DR). Rats were randomized into 5 groups (n=6). Group 1 (normal control; 10 ml/kg normal saline); Group 2 (diabetic control: DC); Group 3 (standard; DR + metformin, 100 mg/kg per oral); Group 4 (DR + GLE 250 mg/kg); Group 5 (DR + GLE 500 mg/kg). The treatment period extended for 2 weeks. Body weight and fasting blood glucose were determined on days 0, 7, and 14. Fasting serum insulin (FSI) levels, fasting blood glucose (FBG), HOMA-IR, antioxidant enzyme level, Insulin tolerance test (ITT), and intraperitoneal glucose tolerance test (IPGTT) tests were estimated.
Gardenia latifolia extract exhibited a marked decrease (p<0.001) in fasting blood glucose levels. T2DR receiving a higher dose of GLE showed a greater improvement in metabolic indices (FSI, FBG, Homeostatic Model Assessment of insulin resistance). The ITT and IPGTT results demonstrated that GLE could significantly enhance insulin tolerance, glucose tolerance, and antioxidant enzyme levels in T2DR.
Gardenia latifolia can be an ideal medicinal plant candidate for treating T2DM, and it should be investigated further for its therapeutic potential.
Copyright: © Saudi Medical Journal.

Pregnancy is a dynamic state involving multiple metabolic adaptions in various tissues including the endocrine pancreas. However, a detailed characterization of the maternal islet metabolome in relation to islet function and the ambient circulating metabolome during pregnancy has not been established.
A timed-pregnancy mouse model was studied, and age-matched non-pregnant mice were used as controls. Targeted metabolomics was applied to fasting plasma and purified islets during each trimester of pregnancy. Glucose homeostasis and islet function was assessed. Bioinformatic analyses were performed to reveal the metabolic adaptive changes in plasma and islets, and to identify key metabolic pathways associated with pregnancy.
Fasting glucose and insulin were found to be significantly lower in pregnant mice compared to non-pregnant controls, throughout the gestational period. Additionally, pregnant mice had superior glucose excursions and greater insulin response to an oral glucose tolerance test. Interestingly, both alpha and beta cell proliferation were significantly enhanced in early to mid-pregnancy, leading to significantly increased islet size seen in mid to late gestation. When comparing the plasma metabolome of pregnant and non-pregnant mice, phospholipid and fatty acid metabolism pathways were found to be upregulated throughout pregnancy, whereas amino acid metabolism initially decreased in early through mid pregnancy, but then increased in late pregnancy. Conversely, in islets, amino acid metabolism was consistently enriched throughout pregnancy, with glycerophospholid and fatty acid metabolism was only upregulated in late pregnancy. Specific amino acids (glutamate, valine) and lipids (acyl-alkyl-PC, diacyl-PC, and sphingomyelin) were found to be significantly differentially expressed in islets of the pregnant mice compared to controls, which was possibly linked to enhanced insulin secretion and islet proliferation.
Beta cell proliferation and function are elevated during pregnancy, and this is coupled to the enrichment of islet metabolites and metabolic pathways primarily associated with amino acid and glycerophospholipid metabolism. This study provides insight into metabolic adaptive changes in glucose homeostasis and islet function seen during pregnancy, which will provide a molecular rationale to further explore the regulation of maternal metabolism to avoid the onset of pregnancy disorders, including gestational diabetes.
Copyright © 2022 Zhang, Piro, Dai and Wheeler.

Ectopic ceramide accumulation in insulin-responsive tissues contributes to the development of obesity and impairs insulin sensitivity. Moreover, pharmacological inhibition of serine palmitoyl transferase (SPT), the first enzyme essential for ceramide biosynthesis using myriocin in rodents reduces body weight and improves insulin sensitivity and associated metabolic indices. Myriocin was originally extracted from fruiting bodies of the fungus Isaria sinclairii and has been found abundant in a number of closely related fungal species such as the Cordyceps. Myriocin is not approved for human use but extracts from Cordyceps are routinely consumed as part of traditional Chinese medication for the treatment of numerous diseases including diabetes. Herein, we screened commercially available extracts of Cordyceps currently being consumed by humans, to identify Cordyceps containing myriocin and test the efficacy of Cordyceps extract containing myriocin in obese mice to improve energy and glucose homeostasis. We demonstrate that commercially available Cordyceps contain variable amounts of myriocin and treatment of mice with a human equivalent dose of Cordyceps extract containing myriocin, reduces ceramide accrual, increases energy expenditure, prevents diet-induced obesity, improves glucose homeostasis and resolves hepatic steatosis. Mechanistically, these beneficial effects were due to increased adipose tissue browning/beiging, improved brown adipose tissue function and hepatic insulin sensitivity as well as alterations in the abundance of gut microbes such as Clostridium and Bilophila. Collectively, our data provide proof-of-principle that myriocin containing Cordyceps extract inhibit ceramide biosynthesis and attenuate metabolic impairments associated with obesity. Moreover, these studies identify commercially available Cordyceps as a readily available supplement to treat obesity and associated metabolic diseases.
© 2022. The Author(s).

Liver physiology is circadian and sensitive to feeding and insulin. Food intake regulates insulin secretion and is a dominant signal for the liver clock. However, how much insulin contributes to the effect of feeding on the liver clock and rhythmic gene expression remains to be investigated. Insulin action partly depends on changes in insulin receptor (IR)-dependent gene expression. Here, we use hepatocyte-restricted gene deletion of IR to evaluate its role in the regulation and oscillation of gene expression as well as in the programming of the circadian clock in the adult mouse liver. We find that, in the absence of IR, the rhythmicity of core-clock gene expression is altered in response to day-restricted feeding. This change in core-clock gene expression is associated with defective reprogramming of liver gene expression. Our data show that an intact hepatocyte insulin receptor is required to program the liver clock and associated rhythmic gene expression.Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

The contribution of beta-cell dysfunction to type 2 diabetes (T2D) is not restricted to insulinopenia in the late stages of the disease. Elevated fasting insulinemia in normoglycemic humans is a major factor predicting the onset of insulin resistance and T2D, demonstrating an early alteration of beta-cell function in T2D. Moreover, an early and chronic increase in fasting insulinemia contributes to insulin resistance in high-fat diet (HFD)-fed mice. However, whether there are genetic factors that promote beta-cell-initiated insulin resistance remains undefined. Human variants of the mitochondrial transporter ABCB10, which regulates redox by increasing bilirubin synthesis, have been associated with an elevated risk of T2D. The effects of T2D ABCB10 variants on ABCB10 expression and the actions of ABCB10 in beta-cells are unknown.
The expression of beta-cell ABCB10 was analyzed in published transcriptome datasets from human beta-cells carrying the T2D-risk ABCB10 variant. Insulin sensitivity, beta-cell proliferation, and secretory function were measured in beta-cell-specific ABCB10 KO mice (Ins1Cre-Abcb10flox/flox). The short-term role of beta-cell ABCB10 activity on glucose-stimulated insulin secretion (GSIS) was determined in isolated islets.
Carrying the T2Drisk allele G of ABCB10 rs348330 variant was associated with increased ABCB10 expression in human beta-cells. Constitutive deletion of Abcb10 in beta-cells protected mice from hyperinsulinemia and insulin resistance by limiting HFD-induced beta-cell expansion. An early limitation in GSIS and H2O2-mediated signaling caused by elevated ABCB10 activity can initiate an over-compensatory expansion of beta-cell mass in response to HFD. Accordingly, increasing ABCB10 expression was sufficient to limit GSIS capacity. In health, ABCB10 protein was decreased during islet maturation, with maturation restricting beta-cell proliferation and elevating GSIS. Finally, ex-vivo and short-term deletion of ABCB10 in islets isolated from HFD-fed mice increased H2O2 and GSIS, which was reversed by bilirubin treatments.
Beta-cell ABCB10 is required for HFD to induce insulin resistance in mice by amplifying beta-cell mass expansion to maladaptive levels that cause fasting hyperinsulinemia.
Copyright © 2021 The Author(s). Published by Elsevier GmbH.. All rights reserved.