Long-term effects of high-fat or high-carbohydrate diets on glucose tolerance in mice with heterozygous carnitine palmitoyltransferase-1a deficiency

Background: Abnormal fatty acid metabolism is an important feature in the mechanisms of insulin resistance and β-cell dysfunction. Carnitine palmitoyltransferase-1a (CPT-1a, liver isoform) has a pivotal role in the regulation of mitochondrial fatty acid oxidation. We investigated the role of CPT-1a in the development of impaired glucose tolerance using a mouse model for CPT-1a deficiency when challenged by either a high-carbohydrate (HCD) or a high-fat diet (HFD) for a total duration of up to 46 weeks

Diet-Induced and Age-Related Changes in the Quadriceps Muscle: MRI and MRS in a Rat Model of Sarcopenia

Background: Knowledge about the molecular pathomechanisms of sarcopenia is still sparse, especially with regard to nutritional risk factors and the subtype of sarcopenic obesity. Objective: The aim of this study was to characterize diet-induced and age-related changes on the quality and quantity of the quadriceps muscle in a rat model of sarcopenia by different magnetic resonance (MR) techniques. Methods: A total of 36 6-month-old male Sprague-Dawley rats were randomly subdivided into 2 groups and received either a high-fat diet (HFD) or a control diet (CD). At the age of 16 months, 15 HFD and 18 CD rats underwent MR at 1.5 T. T1-weighted images as well as T2 relaxation time maps were acquired perpendicular to the long axis of the quadriceps muscles. Maximum cross-sectional area (CSA) of the quadriceps muscle was measured on T1-weighted images, and T2 relaxation times of muscle were assessed in a region without visible intramuscular fat (T2lean muscle) and across the complete CSA (T2muscle). Furthermore, 1H-MR spectroscopy was performed to evaluate the relative lipid content of the quadriceps muscles. These measurements were repeated 5 months later in the surviving 8 HFD and 14 CD rats. Results: HFD rats revealed significantly decreased CSA and CSA per body weight (BW) as well as prolonged T2 relaxation times of muscle. A higher weight gain (upper tertile during the first 6 months of diet in CD rats) resulted in a significant change of T2muscle, but had no relevant impact on CSA. Advancing age up to 21 months led to significantly decreased BW, CSA and CSA/BW, significantly prolonged T2muscle and T2lean muscle and enlarged lipid content in the quadriceps muscle. Conclusions: In an experimental setting a chronically fat-enriched diet was shown to have a relevant and age-associated influence on both muscle quantity and quality. By translational means the employed MR techniques give rise to the possibility of an early detection and noninvasive quantification of sarcopenia in humans, which is highly relevant for the field of geriatrics

β-Cells with Relative Low HIMP1 Overexpression Levels in a Transgenic Mouse Line Enhance Basal Insulin Production and Hypoxia/Hypoglycemia Tolerance

Rodent pancreatic β-cells that naturally lack hypoglycemia/hypoxia inducible mitochondrial protein 1 (HIMP1) are susceptible to hypoglycemia and hypoxia influences. A linkage between the hypoglycemia/hypoxia susceptibility and the lack of HIMP1 is suggested in a recent study using transformed β-cells lines. To further illuminate this linkage, we applied mouse insulin 1 gene promoter (MIP) to control HIMP1-a isoform cDNA and have generated three lines (L1 to L3) of heterozygous HIMP1 transgenic (Tg) mice by breeding of three founders with C57BL/6J mice. In HIMP1-Tg mice/islets, we performed quantitative polymerase chain reaction (PCR), immunoblot, histology, and physiology studies to investigate HIMP1 overexpression and its link to β-cell function/survival and body glucose homeostasis. We found that the HIMP1 level increased steadily in β-cells of L1 to L3 heterozygous HIMP1-Tg mice. HIMP1 overexpression at relatively lower levels in L1 heterozygotes results in a negligible decline in blood glucose concentrations and an insignificant elevation in blood insulin levels, while HIMP1 overexpression at higher levels are toxic, causing hyperglycemia in L2/3 heterozygotes. Follow-up studies in 5–30-week-old L1 heterozygous mice/islets found that HIMP1 overexpression at relatively lower levels in β-cells has enhanced basal insulin biosynthesis, basal insulin secretion, and tolerances to low oxygen/glucose influences. The findings enforced the linkage between the hypoglycemia/hypoxia susceptibility and the lack of HIMP1 in β-cells, and show a potential value of HIMP1 overexpression at relatively lower levels in modulating β-cell function and survival

Isosteviol Has Beneficial Effects on Palmitate-Induced α-Cell Dysfunction and Gene Expression

BACKGROUND: Long-term exposure to high levels of fatty acids impairs insulin secretion and exaggerates glucagon secretion. The aim of this study was to explore if the antihyperglycemic agent, Isosteviol (ISV), is able to counteract palmitate-induced α-cell dysfunction and to influence α-cell gene expression. METHODOLOGY/PRINCIPAL FINDINGS: Long-term incubation studies with clonal α-TC1-6 cells were performed in the presence of 0.5 mM palmitate with or without ISV. We investigated effects on glucagon secretion, glucagon content, cellular triglyceride (TG) content, cell proliferation, and expression of genes involved in controlling glucagon synthesis, fatty acid metabolism, and insulin signal transduction. Furthermore, we studied effects of ISV on palmitate-induced glucagon secretion from isolated mouse islets. Culturing α-cells for 72-h with 0.5 mM palmitate in the presence of 18 mM glucose resulted in a 56% (p<0.01) increase in glucagon secretion. Concomitantly, the TG content of α-cells increased by 78% (p<0.01) and cell proliferation decreased by 19% (p<0.05). At 18 mM glucose, ISV (10(-8) and 10(-6) M) reduced palmitate-stimulated glucagon release by 27% (p<0.05) and 27% (p<0.05), respectively. ISV (10(-6) M) also counteracted the palmitate-induced hypersecretion of glucagon in mouse islets. ISV (10(-6) M) reduced α-TC1-6 cell proliferation rate by 25% (p<0.05), but ISV (10(-8) and 10(-6) M) had no effect on TG content in the presence of palmitate. Palmitate (0.5 mM) increased Pcsk2 (p<0.001), Irs2 (p<0.001), Fasn (p<0.001), Srebf2 (p<0.001), Acaca (p<0.01), Pax6 (p<0.05) and Gcg mRNA expression (p<0.05). ISV significantly (p<0.05) up-regulated Insr, Irs1, Irs2, Pik3r1 and Akt1 gene expression in the presence of palmitate. CONCLUSIONS/SIGNIFICANCE: ISV counteracts α-cell hypersecretion and apparently contributes to changes in expression of key genes resulting from long-term exposure to palmitate. ISV apparently acts as a glucagonostatic drug with potential as a new anti-diabetic drug for the treatment of type 2 diabetes

The Disproportionate Impact of Toxins in Consumer Products

The number of chemicals used in everyday products has grown exponentially over the last century. Many of these chemicals are known endocrine disrupting compounds (EDC’s) and they have not been proven to be safe for humans or for the environment. Rather, many of these chemicals have been linked to negative human health outcomes and damage to the environment. Corporate America is responsible for the production and liberal use of these chemicals in consumer and personal care products. The federal government has failed to provide effective or meaningful standards or regulations for the myriad chemicals of concern that make their way into innumerable daily-use products. The negative impacts from these failures by corporate America and the federal government are suffered disproportionately by women and children. Women use more products than men. Women and children are uniquely impacted by the hormone disruption caused by EDC’s. Women’s bodies carry more “foreign chemicals” than their male counterparts. Women are also disproportionately impacted by the care-giving burden associated with these negative health outcomes. While women shoulder a disproportionate share of the negative consequences, they at the same time, are underrepresented in the decision-making process regarding the manufacture and regulation of these chemicals. Through collective action, women can effect change and reduce exposures to toxins in products