Recent genome-wide association studies demonstrated that common variants of solute carrier family 30 member 8 gene (SLC30A8) increase susceptibility to type 2 diabetes. SLC30A8 encodes zinc transporter-8 (ZnT8), which delivers zinc ion from the cytoplasm into insulin granules. Although it is well known that insulin granules contain high amounts of zinc, the physiological role of secreted zinc remains elusive. In this study, we generated mice with β cell–specific Slc30a8 deficiency (ZnT8KO mice) and demonstrated an unexpected functional linkage between Slc30a8 deletion and hepatic insulin clearance. The ZnT8KO mice had low peripheral blood insulin levels, despite insulin hypersecretion from pancreatic β cells. We also demonstrated that a substantial amount of the hypersecreted insulin was degraded during its first passage through the liver. Consistent with these findings, ZnT8KO mice and human individuals carrying rs13266634, a major risk allele of SLC30A8, exhibited increased insulin clearance, as assessed by c-peptide/insulin ratio. Furthermore, we demonstrated that zinc secreted in concert with insulin suppressed hepatic insulin clearance by inhibiting clathrin-dependent insulin endocytosis. Our results indicate that SLC30A8 regulates hepatic insulin clearance and that genetic dysregulation of this system may play a role in the pathogenesis of type 2 diabetes.

/pdf/the-diabetes-susceptible-gene-slc30a8-znt8-regulates-hepatic-1hqcdjiqu5.pdf

The diabetes-susceptible gene SLC30A8/ZnT8 regulates hepatic insulin clearance.

Most of the literature related to high altitude medicine is devoted to the short-term effects of high-altitude exposure on human physiology. However, long-term effects of living at high altitudes may be more important in relation to human disease because more than 400 million people worldwide reside above 1500 m. Interestingly, individuals living at higher altitudes have a lower fasting glycemia and better glucose tolerance compared with those who live near sea level. There is also emerging evidence of the lower prevalence of both obesity and diabetes at higher altitudes. The mechanisms underlying improved glucose control at higher altitudes remain unclear. In this review, we present the most current evidence about glucose homeostasis in residents living above 1500 m and discuss possible mechanisms that could explain the lower fasting glycemia and lower prevalence of obesity and diabetes in this population. Understanding the mechanisms that regulate and maintain the lower fasting glycemia in individuals w...

/pdf/glucose-homeostasis-during-short-term-and-prolonged-exposure-4pcgaujfkt.pdf

Glucose homeostasis during short-term and prolonged exposure to high altitudes.

Zinc plays an indispensable role in life. It regulates a great number of protein functions including transcription factors, enzymes, adapters, receptors, and growth factors as a structural or catalytic factor. Recently, a further function of zinc has received extensive interest and attention because of its potential importance as a signaling mediator. Zinc plays a dynamic role as an extracellular and intracellular signaling factor, which enables communication between cells in an autocrine, paracrine, or endocrine fashion, conversion of extracellular stimuli to intracellular responses, and regulation of various intracellular signaling pathways. These zinc functions are recognized as “zinc signaling,” which has critical roles in physiology, and thus their imbalance can cause a variety of problems with regard to human health. This book extensively reviews the field from the basic aspects to the crucial roles of zinc signaling in biological processes, discussing the future directions and questions at both the molecular and the physiological level.

Zinc Signals in Cellular Functions and Disorders

African Americans (AAs) tend to have higher plasma insulin concentrations than European Americans (EAs); the increased insulin concentrations have been attributed to increased secretion and/or decreased insulin clearance by liver or other tissues. This work characterizes the contributions of hepatic versus extrahepatic insulin degradation related to ethnic differences between AAs and EAs. By using a recently developed mathematical model that uses insulin and C-peptide measurements from the insulin-modified, frequently sampled intravenous glucose tolerance test (FSIGT), we estimated hepatic versus extrahepatic insulin clearance in 29 EA and 18 AA healthy women. During the first 20 min of the FSIGT, plasma insulin was approximately twice as high in AAs as in EAs. In contrast, insulin was similar in AAs and EAs after the 20-25 min intravenous insulin infusion. Hepatic insulin first-pass extraction was two-thirds lower in AAs versus EAs in the overnight-fasted state. In contrast, extrahepatic insulin clearance was not lower in AAs than in EAs. The difference in insulin degradation between AAs and EAs can be attributed totally to liver clearance. The mechanism underlying reduced insulin degradation in AAs remains to be clarified, as does the relative importance of reduced liver clearance to increased risk for type 2 diabetes.

/pdf/hepatic-but-not-extrahepatic-insulin-clearance-is-lower-in-46ue3gkrz4.pdf

Hepatic but Not Extrahepatic Insulin Clearance Is Lower in African American Than in European American Women

Role of fatty liver in the association between obesity and reduced hepatic insulin clearance

The liver plays a pivotal role in determining postprandial insulin levels because it is responsible for the extraction of a large (approximately 50%) fraction of the newly secreted insulin by the pancreas. Evidence exists that hepatic insulin extraction is not constant during a meal, but is inhibited because of saturable receptor-mediated mechanisms and/or increase in hepatic blood flow. The aim of the present study was to exploit the ability of mathematical model simulation to shed light on the role of a variable hepatic insulin extraction during a meal. Mathematical models of insulin secretion and kinetics were coupled to provide predictions for the concentration of insulin in plasma following a meal under the assumptions of either a constant or a time-varying hepatic insulin clearance. Our results indicate that a 20% inhibition in hepatic clearance is able to remarkably enhance the plasma insulin level following a meal. These results emphasise the need for simple and accurate methods to measure the time course of hepatic insulin extraction under nonsteady-state conditions.

Effect of a variable hepatic insulin clearance on the postprandial insulin profile: insights from a model simulation study.

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Effect of a variable hepatic insulin clearance on the postprandial insulin profile: insights from a model simulation study.