The Impact of ILO 169 on State Commitments and Policies in Nepal

Nepal adopted ILO Convention No. 169 in 2007, and its principles have been applied in national legislation and policies to enhance the acknowledgment of indigenous peoples' rights in practice. The research highlights the changes in Nepal's acknowledgment and protection of indigenous peoples' rights after the country ratified of ILO 169. Thus, it will investigate the Nepalese government's adoption of legislative measures including constitutional, legal, and institutional commitments. Similarly, it will shed light on government measures aimed at integrating legislative commitment to various policies and programs. In addition, I will point out the difficulties involved with the implementation of program policies aimed at addressing Indigenous peoples' rights

A critical role of hepatic GABA in the metabolic dysfunction and hyperphagia of obesity

Hepatic lipid accumulation is a hallmark of type II diabetes (T2D) associated with hyperinsulinemia, insulin resistance, and hyperphagia. Hepatic synthesis of GABA, catalyzed by GABA-transaminase (GABA-T), is upregulated in obese mice. To assess the role of hepatic GABA production in obesity-induced metabolic and energy dysregulation, we treated mice with two pharmacologic GABA-T inhibitors and knocked down hepatic GABA-T expression using an antisense oligonucleotide. Hepatic GABA-T inhibition and knockdown decreased basal hyperinsulinemia and hyperglycemia and improved glucose intolerance. GABA-T knockdown improved insulin sensitivity assessed by hyperinsulinemic-euglycemic clamps in obese mice. Hepatic GABA-T knockdown also decreased food intake and induced weight loss without altering energy expenditure in obese mice. Data from people with obesity support the notion that hepatic GABA production and transport are associated with serum insulin, homeostatic model assessment for insulin resistance (HOMA-IR), T2D, and BMI. These results support a key role for hepatocyte GABA production in the dysfunctional glucoregulation and feeding behavior associated with obesity

Hepatocyte membrane potential regulates serum insulin and insulin sensitivity by altering hepatic GABA release

Hepatic lipid accumulation in obesity correlates with the severity of hyperinsulinemia and systemic insulin resistance. Obesity-induced hepatocellular lipid accumulation results in hepatocyte depolarization. We have established that hepatocyte depolarization depresses hepatic afferent vagal nerve firing, increases GABA release from liver slices, and causes hyperinsulinemia. Preventing hepatic GABA release or eliminating the ability of the liver to communicate to the hepatic vagal nerve ameliorates the hyperinsulinemia and insulin resistance associated with diet-induced obesity. In people with obesity, hepatic expression of GABA transporters is associated with glucose infusion and disposal rates during a hyperinsulinemic euglycemic clamp. Single-nucleotide polymorphisms in hepatic GABA re-uptake transporters are associated with an increased incidence of type 2 diabetes mellitus. Herein, we identify GABA as a neuro-hepatokine that is dysregulated in obesity and whose release can be manipulated to mute or exacerbate the glucoregulatory dysfunction common to obesity

The Role of GABA Shunt and Hepatic GABA Transporters on Hyperinsulinemia and Insulin Resistance

Hepatic lipid accumulation, a hallmark of type 2 diabetes (T2D), increases hepatic gamma-aminobutyric acid (GABA) production through the GABA shunt and release by electrogenic GABA transporters. Inhibition of either GABA production or GABA release limits obesity-associated hyperinsulinemia and insulin resistance in obese mice. In turn, we assessed the role of GABA producing enzymes within the GABA shunt and GABA transporters (TAUT, CRT, BGT1 and GAT2) in development of hyperinsulinemia and insulin resistance in diet induced obese mice. We established that liver slice GABA release was increased in obesity, and positively associated with serum insulin and insulin tolerance test area under the curve (ITT AUC). To understand the regulation of GABA production we showed that media GABA was positively associated with Aldh5a1 mRNA and negatively associated with Abat mRNA. In turn, Aldh5a1 mRNA expression was positively associated with 4h fasted insulin, HOMA-IR, and ITT AUC, while Abat mRNA was negatively associated with 4h fasted insulin, and ITT AUC. Because we have previously shown that SLC6A6 was associated with worsened insulin resistance and SLC6A12 was associated with improved insulin sensitivity in humans, we created adeno associated virus (AAVs) to induce hepatic overexpression of hSLC6A6 and hSLC6A12 in mice. Surprisingly, after 3 weeks of HFD exposure, mice expressing hSLC6A6 had improved insulin sensitivity as assessed by ITT or HOMA-IR. Still despite the improved insulin sensitivity, both hSLC6A6 and hSLC6A12 expression worsened glucose tolerance in 3-week high fat diet fed mice. Together the data presented here supports a role for the GABA shunt and electrogenic GABA transporters in regulating glucose homeostasis

The Impact of ILO 169 on State Commitments and Policies in Nepal

Nepal adopted ILO Convention No. 169 in 2007, and its principles have been applied in national legislation and policies to enhance the acknowledgment of indigenous peoples' rights in practice. The research highlights the changes in Nepal's acknowledgment and protection of indigenous peoples' rights after the country ratified of ILO 169. Thus, it will investigate the Nepalese government's adoption of legislative measures including constitutional, legal, and institutional commitments. Similarly, it will shed light on government measures aimed at integrating legislative commitment to various policies and programs. In addition, I will point out the difficulties involved with the implementation of program policies aimed at addressing Indigenous peoples' rights