bims-stacyt 2020-11-08 papers

Metabolites. 2020 Nov 04. pii: E444. [Epub ahead of print]10(11):

Developmental Programming and Glucolipotoxicity: Insights on Beta Cell Inflammation and Diabetes.

Stimuli or insults during critical developmental transitions induce alterations in progeny anatomy, physiology, and metabolism that may be transient, sometimes reversible, but often durable, which defines programming. Glucolipotoxicity is the combined, synergistic, deleterious effect of simultaneously elevated glucose (chronic hyperglycemia) and saturated fatty acids (derived from high-fat diet overconsumption and subsequent metabolism) that are harmful to organs, micro-organs, and cells. Glucolipotoxicity induces beta cell death, dysfunction, and failure through endoplasmic reticulum and oxidative stress and inflammation. In beta cells, the misfolding of pro/insulin proteins beyond the cellular threshold triggers the unfolded protein response and endoplasmic reticulum stress. Consequentially there is incomplete and inadequate pro/insulin biosynthesis and impaired insulin secretion. Cellular stress triggers cellular inflammation, where immune cells migrate to, infiltrate, and amplify in beta cells, leading to beta cell inflammation. Endoplasmic reticulum stress reciprocally induces beta cell inflammation, whereas beta cell inflammation can self-activate and further exacerbate its inflammation. These metabolic sequelae reflect the vicious cycle of beta cell stress and inflammation in the pathophysiology of diabetes.

Keywords: ER stress; beta cell death; beta cell dysfunction; beta cell failure; hyperglycemia; obesity; oxidative stress; saturated fatty acids

DOI: https://doi.org/10.3390/metabo10110444

Cell. 2020 Oct 28. pii: S0092-8674(20)31322-2. [Epub ahead of print]

Neurons Release Serine to Support mRNA Translation in Pancreatic Cancer.

Robert S Banh, Douglas E Biancur, Keisuke Yamamoto, Albert S W Sohn, Beth Walters, Miljan Kuljanin, Ajami Gikandi, Huamin Wang, Joseph D Mancias, Robert J Schneider, Michael E Pacold, Alec C Kimmelman.

Pancreatic ductal adenocarcinoma (PDAC) tumors have a nutrient-poor, desmoplastic, and highly innervated tumor microenvironment. Although neurons can release stimulatory factors to accelerate PDAC tumorigenesis, the metabolic contribution of peripheral axons has not been explored. We found that peripheral axons release serine (Ser) to support the growth of exogenous Ser (exSer)-dependent PDAC cells during Ser/Gly (glycine) deprivation. Ser deprivation resulted in ribosomal stalling on two of the six Ser codons, TCC and TCT, and allowed the selective translation and secretion of nerve growth factor (NGF) by PDAC cells to promote tumor innervation. Consistent with this, exSer-dependent PDAC tumors grew slower and displayed enhanced innervation in mice on a Ser/Gly-free diet. Blockade of compensatory neuronal innervation using LOXO-101, a Trk-NGF inhibitor, further decreased PDAC tumor growth. Our data indicate that axonal-cancer metabolic crosstalk is a critical adaptation to support PDAC growth in nutrient poor environments.

Keywords: mRNA translation; metabolic crosstalk; neurons; pancreatic cancer; serine

DOI: https://doi.org/10.1016/j.cell.2020.10.016

Pharmacol Rep. 2020 Nov 03.

Altered glucose metabolism and insulin resistance in cancer-induced cachexia: a sweet poison.

Tamhida Masi, Bhoomika M Patel.

Cancer cachexia is a wasting disorder characterised by specific skeletal muscle and adipose tissue loss. Cancer cachexia is also driven by inflammation, altered metabolic changes such as increased energy expenditure, elevated plasma glucose, insulin resistance and excess catabolism. In cachexia, host-tumor interaction causes release of the lactate and inflammatory cytokines. Lactate released by tumor cells takes part in hepatic glucose production with the help of gluconeogenic enzymes. Thus, Cori cycle between organs and cancerous cells contributes to increased glucose production and energy expenditure. A high amount of blood glucose leads to increased production of insulin. Overproduction of insulin causes inactivation of PI3K/Akt/m-TOR pathway and finally results in insulin resistance. Insulin is involved in maintaining the vitality of organs and regulate the metabolism of glucose, protein and lipids. Insulin insensitivity decreases the uptake of glucose in the organs and results in loss of skeletal muscles and adipose tissues. However, looking into the complexity of this metabolic syndrome, it is impossible to rely on a single variable to treat patients having cancer cachexia. Hence, it becomes greater a challenge to produce a clinically effective treatment for this metabolic syndrome. Thus, the present paper aims to provide an understanding of pathogenesis and mechanism underlining the altered glucose metabolism and insulin resistance and its contribution to the progression of skeletal muscle wasting and lipolysis, providing future direction of research to develop new pharmacological treatment in cancer cachexia.

Keywords: Cancer cachexia; Futile cycle; Gluconeogenesis; Insulin resistance; Muscle wasting

DOI: https://doi.org/10.1007/s43440-020-00179-y