Hepatic Lipoprotein Export and Remission of Human Type 2 Diabetes after Weight Loss

Al‐Mrabeh, Ahmad; Zhyzhneuskaya, Sviatlana; Peters, Carl; Barnes, Alison C.; Melhem, Shaden; Jesuthasan, Aaron; Aribisala, Benjamin S.; Hollingsworth, Kieren G.; Lietz, Georg; Mathers, John C.; Sattar, Naveed; Lean, Michael E. J.; Taylor, Roy

doi:10.1016/j.cmet.2019.11.018

Cited by 118 publications

(117 citation statements)

References 80 publications

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“…40 In men, inhibition of 5α-reductase resulted in hepatic insulin resistance, hepatic lipid accumulation, and decreased adipose lipid mobilization. 41,42 A recent study has demonstrated the close association between weight loss, hepatic lipoprotein [43][44][45] The present results showed profound and sustained weight loss with long-term TTh in patients with TD and T2DM, consistent with previously published data from our registry study in patients with TD and with or without T2DM. 46 It is important to note that this registry study has some limitations.…”

Section: Discussionsupporting

confidence: 92%

Remission of type 2 diabetes following long‐term treatment with injectable testosterone undecanoate in patients with hypogonadism and type 2 diabetes: 11‐year data from a real‐world registry study

Haider¹,

Haider²,

Saad

et al. 2020

Diabetes Obesity Metabolism

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Aims: To investigate whether testosterone therapy (TTh) in men with hypogonadism and type 2 diabetes mellitus (T2DM) improves glycaemic control and insulin sensitivity, and results in remission of T2DM. Material and Methods: A total of 356 men who had total testosterone levels ≤12.1 nmol/L (350 ng/dL) and symptoms of hypogonadism were included in the study and followed up for 11 years. All patients received standard diabetes treatment and 178 patients additionally received parenteral testosterone undecanoate 1000 mg every 12 weeks following an initial 6-week interval. A control group comprised 178 hypogonadal patients who opted not to receive TTh. Results: Patients with hypogonadism and T2DM treated with testosterone had significant progressive and sustained reductions in fasting glucose, glycated haemoglobin (HbA1c) and fasting insulin over the treatment period. In the control group, fasting glucose, HbA1c and fasting insulin increased. Among the patients treated with testosterone 34.3% achieved remission of their diabetes and 46.6% of patients achieved normal glucose regulation. Of the testosterone-treated group, 83.1% reached the HbA1c target of 47.5 mmol/mol (6.5%) and 90% achieved the HbA1c target of 53.0 mmol/mol (7%). In contrast, no remission of diabetes or reductions in glucose or HbA1c levels were noted in the control group. There were fewer deaths, myocardial infarctions, strokes and diabetic complications in the testosterone-treated group. Conclusions: Long-term TTh in men with T2DM and hypogonadism improves glycaemic control and insulin resistance. Remission of diabetes occurred in one-third of the patients. TTh is potentially a novel additional therapy for men with T2DM and hypogonadism.

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Section: Discussionsupporting

confidence: 92%

Remission of type 2 diabetes following long‐term treatment with injectable testosterone undecanoate in patients with hypogonadism and type 2 diabetes: 11‐year data from a real‐world registry study

Haider¹,

Haider²,

Saad

et al. 2020

Diabetes Obesity Metabolism

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“…As depicted in Figure 1, excess hepatic fat production (i.e., de novo lipogenesis) may be an early common pathway of non-alcoholic fatty liver disease (NAFLD), atherogenic dyslipidemia, pancreatic b cell dysfunction, insulin resistance, and associated ASCVD risk in the high-risk phenotype. 10,14 AT secretome. While subcutaneous AT is largely neutral, or in the case of lower body AT even protective with respect to cardiovascular risk, 15 expansion of visceral and/or ectopic dysfunctional AT is closely linked to poor cardiometabolic health and MetS 9,16 (Fig.…”

Section: An Integrative View On Atherosclerosismentioning

confidence: 99%

“…21,31 In the ectopic adiposity phenotype, excess dietary starch, sugar, and protein are converted into fatty acids (FA)-in particular palmitic acid (C16:0)-during a metabolic process referred to as hepatic de novo lipogenesis. 14,31 This is another mechanism by which proinflammatory signaling pathways are activated in the phenotype with ectopic adiposity and NAFLD in particular. Inflammasome activation within macrophages leads to the release of proinflammatory cytokines, such as IL-1b, which are chemotactic for other inflammatory cells; this includes T cells and B cells, which further sustain the chronic inflammatory response by expression of proinflammatory cytokines and eicosanoids.…”

Section: Nonresolving Inflammation and Plaque Phenotypementioning

confidence: 99%

High-Risk Atherosclerosis and Metabolic Phenotype: The Roles of Ectopic Adiposity, Atherogenic Dyslipidemia, and Inflammation

Lechner

McKenzie²,

Kränkel

et al. 2020

Metabolic Syndrome and Related Disorders

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Current algorithms for assessing risk of atherosclerotic cardiovascular disease (ASCVD) and, in particular, the reliance on low-density lipoprotein (LDL) cholesterol in conditions where this measurement is discordant with apoB and LDL-particle concentrations fail to identify a sizeable part of the population at high risk for adverse cardiovascular events. This results in missed opportunities for ASCVD prevention, most notably in those with metabolic syndrome, prediabetes, and diabetes. There is substantial evidence that accumulation of ectopic fat and associated metabolic traits are markers for and pathogenic components of high-risk atherosclerosis. Conceptually, the subset of advanced lesions in high-risk atherosclerosis that triggers vascular complications is closely related to a set of coordinated high-risk traits clustering around a distinct metabolic phenotype. A key feature of this phenotype is accumulation of ectopic fat, which, coupled with age-related muscle loss, creates a milieu conducive for the development of ASCVD: atherogenic dyslipidemia, nonresolving inflammation, endothelial dysfunction, hyperinsulinemia, and impaired fibrinolysis. Sustained vascular inflammation, a hallmark of high-risk atherosclerosis, impairs plaque stabilization in this phenotype. This review describes how metabolic and inflammatory processes that are promoted in large measure by ectopic adiposity, as opposed to subcutaneous adipose tissue, relate to the pathogenesis of high-risk atherosclerosis. Clinical biomarkers indicative of these processes provide incremental information to standard risk factor algorithms and advanced lipid testing identifies atherogenic lipoprotein patterns that are below the discrimination level of standard lipid testing. This has the potential to enable improved identification of high-risk patients who are candidates for therapeutic interventions aimed at prevention of ASCVD.

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“…Findings from DiRECT indicate that significant weight loss can result in a reduction in the levels of fat within the pancreas and liver [6], and in turn, improve β‐cell function [7]. However, a small number of DiRECT participants who lost significant weight did not go into remission; reduced levels of fat within their pancreas and liver did not result in improved β‐cell function.…”

Section: Research Priorities and Recommendationsmentioning

confidence: 99%

Improving understanding of type 2 diabetes remission: research recommendations from Diabetes UK’s 2019 remission workshop

et al. 2020

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Aim To describe the process and outputs of a workshop convened to identify key priorities for future research in the area of remission of type 2 diabetes, and provide recommendations to researchers and research funders on how best to address them. With the ultimate aim of enabling the remission of type 2 diabetes to become a possibility for more people. Methods A 1-day research workshop was conducted, bringing together 31 researchers, people living with diabetes, healthcare professionals and members of staff from Diabetes UK to identify and prioritize recommendations for future research into remission of type 2 diabetes. Results Workshop attendees identified 10 key themes for further research. Four of these themes were prioritized for further focus: (i) understanding how to personalize lifestyle approaches based on biology, patient choice and subtypes; (ii) understanding the biology of remission; (iii) understanding the most effective approaches to implementation of lifestyle interventions; and (iv) understanding the best approaches to combining therapies (gut hormones, other drugs, lifestyle approaches and bariatric surgery). Conclusions This paper outlines recommendations to address the current gaps in knowledge related to remission of type 2 diabetes.

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Hepatic Lipoprotein Export and Remission of Human Type 2 Diabetes after Weight Loss

Cited by 118 publications

References 80 publications

Remission of type 2 diabetes following long‐term treatment with injectable testosterone undecanoate in patients with hypogonadism and type 2 diabetes: 11‐year data from a real‐world registry study

Remission of type 2 diabetes following long‐term treatment with injectable testosterone undecanoate in patients with hypogonadism and type 2 diabetes: 11‐year data from a real‐world registry study

High-Risk Atherosclerosis and Metabolic Phenotype: The Roles of Ectopic Adiposity, Atherogenic Dyslipidemia, and Inflammation

Improving understanding of type 2 diabetes remission: research recommendations from Diabetes UK’s 2019 remission workshop

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