Liver insulinization as a driver of triglyceride dysmetabolism.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is an increasingly prevalent fellow traveller with the insulin resistance that underlies type 2 diabetes mellitus. However, the mechanistic connection between MAFLD and impaired insulin action remains unclear. In this Perspective, we review data from humans to elucidate insulin's aetiological role in MAFLD. We focus particularly on the relative preservation of insulin's stimulation of triglyceride (TG) biosynthesis despite its waning ability to curb hepatic glucose production (HGP). To explain this apparent 'selective insulin resistance', we propose that hepatocellular processes that lead to TG accumulation require less insulin signal transduction, or 'insulinization,' than do those that regulate HGP. As such, mounting hyperinsulinaemia that barely compensates for aberrant HGP in insulin-resistant states more than suffices to maintain hepatic TG biosynthesis. Thus, even modestly elevated or context-inappropriate insulin levels, when sustained day and night within a heavily pro-lipogenic metabolic milieu, may translate into substantial cumulative TG biosynthesis in the insulin-resistant state.

ß-cell failure in type 2 diabetes: postulated mechanisms and prospects for prevention and treatment.

OBJECTIVE: This article examines the foundation of ß-cell failure in type 2 diabetes (T2D) and suggests areas for future research on the underlying mechanisms that may lead to improved prevention and treatment. RESEARCH DESIGN AND METHODS: A group of experts participated in a conference on 14-16 October 2013 cosponsored by the Endocrine Society and the American Diabetes Association. A writing group prepared this summary and recommendations. RESULTS: The writing group based this article on conference presentations, discussion, and debate. Topics covered include genetic predisposition, foundations of ß-cell failure, natural history of ß-cell failure, and impact of therapeutic interventions. CONCLUSIONS: ß-Cell failure is central to the development and progression of T2D. It antedates and predicts diabetes onset and progression, is in part genetically determined, and often can be identified with accuracy even though current tests are cumbersome and not well standardized. Multiple pathways underlie decreased ß-cell function and mass, some of which may be shared and may also be a consequence of processes that initially caused dysfunction. Goals for future research include to (1) impact the natural history of ß-cell failure; (2) identify and characterize genetic loci for T2D; (3) target ß-cell signaling, metabolic, and genetic pathways to improve function/mass; (4) develop alternative sources of ß-cells for cell-based therapy; (5) focus on metabolic environment to provide indirect benefit to ß-cells; (6) improve understanding of the physiology of responses to bypass surgery; and (7) identify circulating factors and neuronal circuits underlying the axis of communication between the brain and ß-cells.

ß-cell failure in type 2 diabetes: postulated mechanisms and prospects for prevention and treatment.

OBJECTIVE: This article examines the foundation of ß-cell failure in type 2 diabetes (T2D) and suggests areas for future research on the underlying mechanisms that may lead to improved prevention and treatment. RESEARCH DESIGN AND METHODS: A group of experts participated in a conference on 14-16 October 2013 cosponsored by the Endocrine Society and the American Diabetes Association. A writing group prepared this summary and recommendations. RESULTS: The writing group based this article on conference presentations, discussion, and debate. Topics covered include genetic predisposition, foundations of ß-cell failure, natural history of ß-cell failure, and impact of therapeutic interventions. CONCLUSIONS: ß-Cell failure is central to the development and progression of T2D. It antedates and predicts diabetes onset and progression, is in part genetically determined, and often can be identified with accuracy even though current tests are cumbersome and not well standardized. Multiple pathways underlie decreased ß-cell function and mass, some of which may be shared and may also be a consequence of processes that initially caused dysfunction. Goals for future research include to 1) impact the natural history of ß-cell failure; 2) identify and characterize genetic loci for T2D; 3) target ß-cell signaling, metabolic, and genetic pathways to improve function/mass; 4) develop alternative sources of ß-cells for cell-based therapy; 5) focus on metabolic environment to provide indirect benefit to ß-cells; 6) improve understanding of the physiology of responses to bypass surgery; and 7) identify circulating factors and neuronal circuits underlying the axis of communication between the brain and ß-cells.

Markers of increased cardiovascular risk: are we measuring the most appropriate parameters?

The vital task of evaluating cardiovascular disease risk in individual patients is challenging in light of the ever-growing list of risk factors. Some of the traditional measures of cardiovascular risk, such as blood lipid levels, have been further refined to provide better risk assessments. Certain specific parameters, such as lipoprotein buoyancy, seem to be better predictors of cardiovascular disease than total lipoprotein levels. Furthermore, as the contribution of systemic inflammation to the pathogenesis of atherosclerosis is increasingly recognized, several inflammatory markers have become associated with disease risk. Consequently, many studies have attempted to determine the individual merits of these factors in predicting cardiovascular risk.