Search

Context: Tirzepatide substantially reduced hemoglobin A1c (HbA1c) and body weight in subjects with type 2 diabetes (T2D) compared with the glucagon-like peptide 1 receptor agonist dulaglutide. Improved glycemic control was associated with lower circulating triglycerides and lipoprotein markers and improved markers of beta-cell function and insulin resistance (IR), effects only partially attributable to weight loss. Objective: Assess plasma metabolome changes mediated by tirzepatide. Design: Phase 2b trial participants were randomly assigned to receive weekly subcutaneous tirzepatide, dulaglutide, or placebo for 26 weeks. Post hoc exploratory metabolomics and lipidomics analyses were performed. Setting: Post hoc analysis. Participants: 259 subjects with T2D. Intervention(s): Tirzepatide (1, 5, 10, 15 mg), dulaglutide (1.5 mg), or placebo. Main Outcome Measure(s): Changes in metabolite levels in response to tirzepatide were assessed against baseline levels, dulaglutide, and placebo using multiplicity correction. Results: At 26 weeks, a higher dose tirzepatide modulated a cluster of metabolites and lipids associated with IR, obesity, and future T2D risk. Branched-chain amino acids, direct catabolic products glutamate, 3-hydroxyisobutyrate, branched-chain ketoacids, and indirect byproducts such as 2-hydroxybutyrate decreased compared to baseline and placebo. Changes were significantly larger with tirzepatide compared with dulaglutide and directly proportional to reductions of HbA1c, homeostatic model assessment 2-IR indices, and proinsulin levels. Proportional to metabolite changes, triglycerides and diglycerides were lowered significantly compared to baseline, dulaglutide, and placebo, with a bias toward shorter and highly saturated species. Conclusions: Tirzepatide reduces body weight and improves glycemic control and uniquely modulates metabolites associated with T2D risk and metabolic dysregulation in a direction consistent with improved metabolic health. [ABSTRACT FROM AUTHOR]

Objective: Sex differences in insulin sensitivity are present throughout the life-span, with men having a higher prevalence of insulin resistance and diabetes compared with women. Differences in lean mass, fat mass, and fat distribution-particularly ectopic fat-have all been postulated to contribute to the sexual dimorphism in diabetes risk. Emerging data suggest ectopic lipid composition and subcellular localization are most relevant; however, it is not known whether they explain sex differences in obesity-induced insulin resistance.Methods: To address this gap, this study evaluated insulin sensitivity and subcellular localization of intramuscular triacylglycerol, diacylglycerol, and sphingolipids as well as muscle acylcarnitines and serum lipidomics in people with obesity.Results: Insulin sensitivity was significantly lower in men (P < 0.05); however, no sex differences were found in localization of intramuscular triacylglycerol, diacylglycerol, or sphingolipids in skeletal muscle. In contrast, men had higher total muscle acylcarnitine (P < 0.05) and long-chain muscle acylcarnitine (P < 0.05), which were related to lower insulin sensitivity (r = -0.42, P < 0.05). Men also displayed higher serum ceramide (P = 0.05) and lysophosphatidylcholine (P < 0.01).Conclusions: These data reveal novel sex-specific associations between lipid species involved in the coupling of mitochondrial fatty acid transport, β-oxidation, and tricarboxylic acid cycle flux that may provide therapeutic targets to improve insulin sensitivity. [ABSTRACT FROM AUTHOR]

As demand for access to colleges and universities prompts higher education systems for creative and efficient solutions, we examine technologycentric approaches to education delivery and their implications for policy, student outcomes, and resource allocation. Our work is framed by Kingdon's adapted multiple streams theory of national policymaking. However, the real elephant in the room may be the skyrocketing costs of administration that may need wrangling before resources can be directed to the future potential savings obtained through developing infrastructure for, and delivery of, tech-centric teaching approaches. We provide examples and strategies, policy implications, and recommendations for research and practice. [ABSTRACT FROM AUTHOR]

The partnership between international and national groups has always had its moments of diffi culty, but the typical geographic divide between the two types of groups has usually led to a natural and healthy division of labor. This article analyzes several factors that are now challenging this equilibrium, e.g., these days the largest international groups are placing more of their staff outside the West, and the people conducting research and advocacy for international organizations are increasingly from the global South. Tensions between international and national groups occur primarily in relation to media attention and fundraising. Yet, there are ways to strength partnerships between national and international organizations, such as by active strategizing together, sharing information and resources that may more readily be available to international groups, establishing staff exchange programs, sharing donor prospects and fundraising leads, and speaking and publishing jointly, and assisting each other with the promotion of work through tools like social media. [ABSTRACT FROM AUTHOR]

A parceria entre grupos nacionais e internacionais sempre teve seus momentos de dificuldade, mas a divisão geográfica típica entre os dois tipos de grupos tem levado geralmente a uma divisão de trabalho natural e saudável. Este artigo analisa diversos fatores que atualmente estão desafiando esse equilíbrio; por exemplo, os maiores grupos internacionais estão colocando mais gente de suas equipes fora do Ocidente, e as pessoas que fazem pesquisa e advocacy para organizações internacionais são cada vez mais do Sul Global. As tensões entre grupos nacionais e internacionais ocorrem principalmente no que diz respeito à atenção da mídia e à captação de recursos. No entanto, existem maneiras de fortalecer parcerias entre as organizações nacionais e internacionais, como a criação conjunta de estratégias, o compartilhamento de informações e recursos que podem ser mais facilmente disponíveis para grupos internacionais, o estabelecimento de programas de intercâmbio de pessoal, o compartilhamento de possíveis doadores e de alternativas de captação de recursos, falar e publicar em parceria e ajuda mútua na promoção do trabalho por meio de ferramentas como as mídias sociais. [ABSTRACT FROM AUTHOR]

Today, virtually every government wants to be seen as a democracy, but many resist allowing the basic human rights that would make democracy meaningful because that might jeopardize their grasp on power. Instead, governments use a variety of subterfuges to manage or undermine the electoral process. Their task is facilitated by the lack of a broadly accepted definition of ‘democracy’ akin to the detailed rules of international human rights law. But much of the problem lies in the fact that, because of commercial or strategic interests, the world's established democracies often close their eyes to electoral manipulation, making it easier for sham democrats to pass themselves off as the real thing. That acquiescence undermines the efforts to promote human rights because it can be more difficult for human rights organizations to stigmatize a government for its human rights violations when that government can hold itself up as an accepted ‘democracy.’ The challenge facing the human rights movement is to highlight the ploys used by dictatorial regimes to feign democratic rule and to build pressure on the established democracies to refuse to admit these pretenders into the club of democracies on the cheap. [ABSTRACT FROM PUBLISHER]

The article focuses on the issue concerning the approach to fight against terrorism by the U.S. government under the administration of President George W. Bush. It explores the concept of the counter terrorism policy by the government. It examines the legality of the indicated approach and identifies if it is moral. Furthermore, the author discusses how the approach is working.

This article assesses whether the 2003 invasion of Iraq can be justified as a humanitarian intervention. Because of the potential loss of life inherent in any military action, the author contends that a threshold test of a humanitarian intervention is whether it is necessary to stop ongoing or imminent mass slaughter. Although that test might have been met, say, at the time of the 1988 genocide against the Kurds, there was no ongoing or imminent mass slaughter in Iraq in March 2003. That lack is decisive in undermining claims that the invasion of Iraq was a humanitarian intervention. Apart from this threshold test, the author also considers several secondary factors: whether force was the last resort, whether the invasion was guided primarily by a humanitarian purpose, whether it was conducted with maximum respect for international human rights and humanitarian law, whether it was likely to produce more good than harm, and whether, ideally though not necessarily, it was endorsed by the UN Security Council. The author concludes that the invasion of Iraq fails most of these secondary tests as well: the war as conceived in early 2003 was not primarily about stopping atrocities; non-military options for achieving its other stated purposes had not been exhausted; although the invading forces generally respected international humanitarian law, there were certain major exceptions; and the UN Security Council was never asked to contemplate a humanitarian intervention in Iraq. At most, it was reasonable to conclude in March 2003 that overthrowing Saddam Hussein might do more good than harm. On balance, therefore, the author concludes that the Iraq war cannot be justified as a humanitarian intervention. [ABSTRACT FROM AUTHOR]

The article discusses the evolution of the international system of justice. Accordingly, the creation of the concept of international justice was motivated by the unwillingness of the international community to take the necessary steps in stopping genocide in the early 1990s. Since then many international actions had taken place, including the establishment of tribunals for Rwanda, the former Yugoslavia, and Sierra Leone and the involvement of the United Nations in the justice process in Kosovo and East Timor. The most important of all these developments was the establishment of the International Criminal Court through a treaty ratified by more than 60 governments. Such development is significant not only in responding to the pleas of victims and their families but also in promoting deterrence.

Discusses the opposition of the administration of U.S. President George W. Bush to the International Criminal Court treaty. Background on criminal prosecution with regard to international standards; Information on the measures implemented by the international court to avoid unjustified prosecution; Details on the objections of the U.S. concerning the international court.

The article explores the reasons for the reluctance of the U.S. to permit the international human rights system to improve the rights of U.S. citizens. It is argued by the author that such an approach reflects an attitude toward international human rights law of fear and arrogance. The U.S. government's approach to the ratification of international human rights treaties, which involves the attachment of reservations, is described. The article also cites ways to give meaning to the ratification of human rights treaties.

This article presents a response to Leonard S. Rubenstein, a famous social scientist by Kenneth Roth, the executive director of "Human Rights Watch." The author states that Rubenstein offers a thoughtful response to his article on how international monitoring and advocacy organizations that use a methodology of public shaming can best advance economic, social, and cultural (ESC) rights. Roth said that three points can be made out of the article written by Rubenstein. The first is that such organizations can make useful contributions beyond exposing government misconduct and subjecting it to public opprobrium. In second point it was contended by Rubenstein that such international organizations need not be as concerned with advocating tradeoffs among competing ESC rights because fears of limited resources a "zero-sum game"-are overblown. In the third, he has disagreed with Roth, and perceived preference for condemning "arbitrary" government conduct to the exclusion of violations of particular ESC rights. Roth in his response said that on the first point he largely agreed with him, on the second he regretfully suspect he has an overly sanguine view of the problem. And on the third, he feared that Rubenstein has misunderstood the author.

It is not just in the West that we are seeing this rejection of rights and liberalism. There is the emergence of strongmen, an odd term because it often is a product of weakness that people like Erdoğan in Turkey, Putin in Russia, al‐Sisi in Egypt, or even going a bit further afield Xi Jinping in China resort to these authoritarian methods. [ABSTRACT FROM AUTHOR]

Activation of GIP (glucose-dependent insulinotropic peptide) receptor (GIPR) in combination with GLP-1 receptor has demonstrated reduced adiposity and bodyweight in mice. Although the incretin action of GIP in pancreatic beta cells is well characterized, its regulation of adipose tissue metabolism are incompletely understood. Using differentiated human adipocytes we demonstrated GIP suppression of insulin stimulated [14C] glucose and [14C] acetate incorporation into the cellular lipid fraction suggesting GIP/insulin co-regulation of de novo lipogenesis. To further investigate these findings, we employed an NMR and mass spec strategy. Briefly, human adipocytes were differentiated then incubated with [13C] glucose or [13C] acetate overnight in the presence GIP, insulin, GIP + insulin, or control followed by lysate preparation for mass spec and NMR analysis. Isotope label incorporation in lysate fatty acids were determined by HPLC-MS detection of base-hydrolyzed lipids. GIP significantly reduced incorporation of labeled acetate and labeled glucose in fatty acids, both in the presence and absence of insulin. Sample analysis by NMR demonstrated a GIP regulated increase in glycerol production from labeled glucose both in the presence and absence of insulin with little to no acetate incorporation into glycerol under all conditions tested. These findings demonstrate GIP signaling in adipocytes reduces de novo fatty acid synthesis while increasing glycerol formation. This suggests a model whereby GIP suppresses generation of new fatty acids from substrate but enhances appropriate storage capacity of dietary fatty acids by increasing production of glycerol required for triglyceride generation. Further studies will be required to elucidate this potential benefit of GIP to improve nutrient partitioning. Disclosure: P.L. Milligan: Employee; Self; Eli Lilly and Company. K.D. Roth: Employee; Self; Eli Lilly and Company. H. Hu: None. J. Moyers: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. X. Ruan: Employee; Self; Eli Lilly and Company. W.C. Roell: Employee; Self; Eli Lilly and Company. A. Regmi: Employee; Self; Eli Lilly and Company. [ABSTRACT FROM AUTHOR]

Serum lipids and sphingolipids circulate in plasma and are linked with insulin resistance and increased cardiovascular disease risk. We previously reported that dihydroceramides (DHCer) are elevated in people with insulin resistance compared to individuals with obesity and trained athletes. Despite associations with insulin resistance, little is known whether insulin sensitizing lifestyle interventions can improve sphingolipid profiles. Twenty-one individuals with obesity and prediabetes (18F; 46± 2y; 35.0± 0.9 kg/m2; fasting glucose: 113.8± 9.4 mg/dl, 2h OGTT: 143.0± 19.4 mg/dl) participated in a 3-month lifestyle intervention of combined weight loss and exercise. Insulin sensitivity (SI) was assessed by hyperinsulinemic-euglycemic clamps and both targeted and shotgun lipidomics were conducted before and after intervention. BMI and body fat percentage were reduced by 11+1% (mean± SEM) and 9± 1% after intervention (p<0.0001 for both). VO2 peak and SI increased by 14± 3% and 66± 12% following the intervention (p<0.0001 for both). Total serum triacylglyceride, diacylglyceride, DHCer and glucosylceramide were significantly reduced following intervention (p<0.05 for all). Reductions in specific species of ceramide (C18:0), lactosylceramide (C24:0), DHCer (C18:0, C24:1, C24:0) and glucosylceramide (C16:0, C22:0, C23:0, C24:1, C24:0) were also apparent. Of these lipids, glucosylceramide C20:0 and C22:0 were negatively associated with SI (r=-0.491, p<0.05 and r=-0.580, p<0.01, respectively). Furthermore, sphingomyelin C14:0, C16:1, C20:0, C21:0, C22:0, C23:0, C24:3 and C24:4 were negatively associated with SI. These data show that serum sphingolipids species previously linked to insulin resistance in humans can be improved with insulin sensitizing lifestyle interventions. Decreases in serum sphingolipids may explain increased SI and decreased cardiovascular disease risk associated with weight loss and exercise training. Disclosure: J.L. Broussard: Advisory Panel; Self; National Institutes of Health. Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases, Sleep Research Society, Society in Science-The Branco Weiss Fellowship. D.E. Kahn: None. S.A. Newsom: None. J.T. Brozinick: Employee; Self; Eli Lilly and Company. H. Bui: Employee; Self; Eli Lilly and Company. K.D. Roth: Employee; Self; Eli Lilly and Company. L. Perreault: Advisory Panel; Self; Novo Nordisk A/S, Sanofi. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S. B.C. Bergman: Advisory Panel; Spouse/Partner; AstraZeneca, Merck & Co., Inc., Novo Nordisk Inc. Funding: American Diabetes Association (1-14-CE-05 to B.B.); National Institutes of Health (RR-00036, K01DK110138); Colorado Nutrition Obesity Research Center (P30DK048520) [ABSTRACT FROM AUTHOR]