Decreased serum glucose and glycosylated hemoglobin levels in patients with Chuvash polycythemia: a role for HIF in glucose metabolism

McClain, Donald A.; Abuelgasim, Khadega A.; Nouraie, Mehdi; Salomon-Andonie, Juan; Niu, Xiaomei; Miasnikova, Galina Y.; Polyakova, Lydia A.; Sergueeva, Adelina; Okhotin, Daniel J.; Cherqaoui, Rabia; Okhotin, David; Cox, James E.; Świerczek, Sabina; Song, Jihyun; Simon, M. Celeste; Huang, Jingyu; Simcox, Judith; Yoon, Donghoon; Prchal, Josef T.; Gordeuk, Victor R.

doi:10.1007/s00109-012-0961-5

Cited by 43 publications

(49 citation statements)

References 36 publications

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“…These findings might be explained to some extent by altered HIF activities. Many genes encoding glycolytic enzymes are upregulated by HIF-1 (42), whereas hypoglycemia is seen in Chuvash polycythemia (CP), an autosomal recessive disorder in which HIF degradation is impaired (43). Taken together, our findings suggest an increased reliance on glucose by Lowlanders under resting conditions at altitude compared with Sherpas but a greater capacity for lactate production in Sherpas, which may prove effective upon exertion.…”

Section: Resultsmentioning

confidence: 87%

Metabolic basis to Sherpa altitude adaptation

Horscroft

Kotwica

Laner

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

180

219

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The Himalayan Sherpas, a human population of Tibetan descent, are highly adapted to life in the hypobaric hypoxia of high altitude. Mechanisms involving enhanced tissue oxygen delivery in comparison to Lowlander populations have been postulated to play a role in such adaptation. Whether differences in tissue oxygen utilization (i.e., metabolic adaptation) underpin this adaptation is not known, however. We sought to address this issue, applying parallel molecular, biochemical, physiological, and genetic approaches to the study of Sherpas and native Lowlanders, studied before and during exposure to hypobaric hypoxia on a gradual ascent to Mount Everest Base Camp (5,300 m). Compared with Lowlanders, Sherpas demonstrated a lower capacity for fatty acid oxidation in skeletal muscle biopsies, along with enhanced efficiency of oxygen utilization, improved muscle energetics, and protection against oxidative stress. This adaptation appeared to be related, in part, to a putatively advantageous allele for the peroxisome proliferator-activated receptor A (PPARA) gene, which was enriched in the Sherpas compared with the Lowlanders. Our findings suggest that metabolic adaptations underpin human evolution to life at high altitude, and could have an impact upon our understanding of human diseases in which hypoxia is a feature. metabolism | altitude | skeletal muscle | hypoxia | mitochondria

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Section: Resultsmentioning

confidence: 87%

Metabolic basis to Sherpa altitude adaptation

Horscroft

Kotwica

Laner

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

180

219

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“…HIF1α and HIF2α are the two major HIF isoforms that regulate numerous genes involved in cell survival, glucose metabolism, inflammation, angiogenesis and erythropoiesis (Ackerman and Simon, 2014; Prabhakar and Semenza, 2015; Zheng et al, 2015). One of the common clinical manifestations in Chuvash polycythemia is hypoglycemia (McClain et al, 2013). Recent studies demonstrated that activation of hepatic HIF2α in the liver increases insulin sensitivity and improves glucose homeostasis via activation of the insulin receptor substrate (IRS2)-AKT signaling pathway (Taniguchi et al, 2013; Wei et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

HIF2 α Is an Essential Molecular Brake for Postprandial Hepatic Glucagon Response Independent of Insulin Signaling

et al. 2016

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Glucagon drives hepatic gluconeogenesis and maintains blood glucose levels during fasting. The mechanism that attenuates glucagon action following refeeding is not understood. The present study demonstrates an increase in perivenous liver hypoxia immediately after feeding which stabilizes hypoxia-inducible factor (HIF)2α in liver. The transient postprandial increase in hepatic HIF2α attenuates glucagon signaling. Hepatocyte-specific disruption of HIF2α increases postprandial blood glucose and potentiates the glucagon response. Independent of insulin/AKT signaling, activation of hepatic HIF2α resulted in lower blood glucose, improved glucose tolerance and decreased gluconeogenesis due to blunted hepatic glucagon action. Mechanistically, HIF2α abrogated glucagon-PKA signaling by activating cAMP-phosphodiesterases in a MEK/ERK-dependent manner. Repression of glucagon signaling by HIF2α ameliorated hyperglycemia in streptozotocin-induced diabetes and acute insulin resistant animal models. This study reveals that HIF2α is essential for the acute postprandial regulation of hepatic glucagon signaling, and suggests HIF2α as a potential therapeutic target in the treatment of diabetes.

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“…Also similar to SCD, Chuvash polycythemia subjects with normal BMI have improved glucose tolerance (McClain et al 2013). Our a priori hypothesis was that comparing genetic and transcriptional responses in SCD and Chuvash polycythemia would help identify novel pathways of disease risk.…”

Section: Resultsmentioning

confidence: 99%

“…Our a priori hypothesis was that comparing genetic and transcriptional responses in SCD and Chuvash polycythemia would help identify novel pathways of disease risk. Measurements of hemoglobin A1C and serum concentrations of total cholesterol and triglyceride were available in our Chuvash polycythemia cohort (McClain et al 2013). We tested the correlation of these variables with expression levels of APOB in PBMCs derived from the Chuvash polycythemia cohort.…”

Section: Resultsmentioning

confidence: 99%

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Genetic polymorphism of APOB is associated with diabetes mellitus in sickle cell disease

Zhang

Saraf

et al. 2015

Hum Genet

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Environmental variations have strong influences in the etiology of type 2 diabetes mellitus. In this study, we investigated the genetic basis of diabetes in patients with sickle cell disease (SCD), a Mendelian disorder accompanied by distinct physiological conditions of hypoxia and hyperactive erythropoiesis. Compared to the general African-American population, the prevalence of diabetes as assessed in two SCD cohorts of 856 adults was low, but it markedly increased with older age and overweight. Meta-analyses of over 5 million single nucleotide polymorphisms (SNPs) in the two SCD cohorts identified a SNP, rs59014890, the C allele of which associated with diabetes risk at P= 3.2×10-8 and, surprisingly, associated with decreased APOB expression in peripheral blood mononuclear cells (PBMCs). The risk allele of the APOB polymorphism was associated with overweight in 181 SCD adolescents, with diabetes risk in 592 overweight, non-SCD African Americans ≥45 years of age, and with elevated plasma lipid concentrations in general populations. In addition, lower expression level of APOB in PBMCs was associated with higher values for percent hemoglobin A1C and serum total cholesterol and triglyceride concentrations in patients with Chuvash polycythemia, a congenital disease with elevated hypoxic responses and increased erythropoiesis at normoxia. Our study reveals a novel, environment-specific genetic polymorphism that may affect key metabolic pathways contributing to diabetes in SCD.

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Decreased serum glucose and glycosylated hemoglobin levels in patients with Chuvash polycythemia: a role for HIF in glucose metabolism

Cited by 43 publications

References 36 publications

Metabolic basis to Sherpa altitude adaptation

Metabolic basis to Sherpa altitude adaptation

HIF2 α Is an Essential Molecular Brake for Postprandial Hepatic Glucagon Response Independent of Insulin Signaling

Genetic polymorphism of APOB is associated with diabetes mellitus in sickle cell disease

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