Tissue-Specific Splicing and Dietary Interaction of a Mutant As160 Allele Determine Muscle Metabolic Fitness in Rodents

<a>Ethnic groups are physiologically and genetically adapted to their diets. Inuit bear a frequent AS160^R684X mutation that causes type 2 diabetes. Whether this</a> mutation evolutionarily confers adaptation in Inuit and how it causes metabolic disorders upon dietary changes are unknown due to limitations in human studies. Here, we develop a genetically-modified rat model bearing an orthologous AS160^R693X mutation, which mimics human patients exhibiting postprandial hyperglycemia and hyperinsulinemia. Importantly, a sugar-rich diet aggravates metabolic abnormalities in AS160^R693X rats. The AS160^R693X mutation diminishes a dominant long-variant AS160 without affecting a minor short-variant AS160 in skeletal muscle, which suppresses muscle glucose utilisation but induces fatty acid oxidation. This fuel switch suggests a possible adaptation in Inuit who traditionally had lipid-rich hypoglycemic diets. Finally, induction of the short-variant AS160 restores glucose utilisation in rat myocytes and a mouse model. Our findings have implications for development of precision treatments for patients bearing the AS160^R684X mutation.

Tissue-Specific Splicing and Dietary Interaction of a Mutant As160 Allele Determine Muscle Metabolic Fitness in Rodents

<a>Ethnic groups are physiologically and genetically adapted to their diets. Inuit bear a frequent AS160^R684X mutation that causes type 2 diabetes. Whether this</a> mutation evolutionarily confers adaptation in Inuit and how it causes metabolic disorders upon dietary changes are unknown due to limitations in human studies. Here, we develop a genetically-modified rat model bearing an orthologous AS160^R693X mutation, which mimics human patients exhibiting postprandial hyperglycemia and hyperinsulinemia. Importantly, a sugar-rich diet aggravates metabolic abnormalities in AS160^R693X rats. The AS160^R693X mutation diminishes a dominant long-variant AS160 without affecting a minor short-variant AS160 in skeletal muscle, which suppresses muscle glucose utilisation but induces fatty acid oxidation. This fuel switch suggests a possible adaptation in Inuit who traditionally had lipid-rich hypoglycemic diets. Finally, induction of the short-variant AS160 restores glucose utilisation in rat myocytes and a mouse model. Our findings have implications for development of precision treatments for patients bearing the AS160^R684X mutation.

Dietary Protein Level and Dietary Interaction Affect Quinolinic Acid Concentration in Rats

During tryptophan-niacin conversion, hepatic α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) [EC4.1.1.45] plays a key role in regulating NAD biosynthesis. ACMSD activity is greatly affected by many factors such as nutritional status and disease. The tryptophan catabolite quinolinic acid has been reported to be associated with the pathogenesis of various disorders and is a potential endogenous toxin. However the effects of dietary protein levels or dietary interaction between protein levels and fatty acid type to this process have not been investigated and are still unknown. In this study, we examined whether dietary protein level, fatty acid type, namely saturated fatty acid and polyunsaturated fatty acid, and their interaction affect serum quinolinic acid concentration in rats. Male Sprague-Dawley rats (4-weeks old) were fed with 20% casein + 10% stearic acid diet (20C10S), 20% casein + 10% linoleic acid diet (20C10L), 40% casein + 10%stearic acid diet (40C10S), or 40% casein + 10% linoleic acid diet (40C10L) for 8 days, and serum quinolinic acid concentration and ACMSD activity were determined. Serum quinolinic acid concentration was significantly increased in the 40C10L group compared with other three groups. There was also the negative correlation between the sum of liver and kidney ACMSD activities, and serum quinolinic acid concentration per tryptophan intake (r = 0.8209, p < 0.01). Increased serum QA concentrations are probably due to a decreased ACMSD activity.

Liability in Prescribing Choice: The Example of the Antidepressants

Objective: The aim of this study is to review issues of legal liability in prescribing choice. Prescribing not only occurs in a medical setting, but also in a social and legal context in this era of evidence-based medicine and greater consumer awareness. Prescribers may be unaware of the legal consequences of medical decision-making and prescribing choice. This issue affects all areas of medicine and can be illustrated by antidepressant choice for major depression. Method: A review was undertaken of liability issues that may arise in the context of prescribing, with particular reference to prescribing antidepressants. Results: There are legal precedents which illustrate prescribers' potential liability. These impose duties on the prescriber including those of care, to inform, and to respond to patients' wishes. In particular, the duty of care requires that if medicines are of equal efficacy, one should prescribe the best tolerated and least toxic medicine that is most likely to be taken at an effective dose for an adequate duration. While older and newer antidepressants are generally of equal efficacy, the newer agents have higher tolerability, lower toxicity and are less likely to be associated with treatment failure (due to sub-therapeutic dose regimens, or the patient discontinuing medication), disabling psychomotor impairment, dietary interaction or fatal overdose. Conclusions: There needs to be compelling reasons for prescribing medicines with a greater likelihood of adverse outcomes such as the older antidepressants (e.g. tri-cyclics) rather than the newer antidepressants such as RIMAs, SSRls, SNRls and 5HT2 receptor antagonists. The higher likelihood of an adverse outcome of treatment where an older antidepressant has been prescribed raises the potential for professional negligence claims to be brought against medical practitioners who prescribe such medicines for reasons other than established medical need.