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The liver-alpha cell axis associates with liver fat and insulin resistance: a validation study in women with non-steatotic liver fat levels.
Gar, C, Haschka, SJ, Kern-Matschilles, S, Rauch, B, Sacco, V, Prehn, C, Adamski, J, Seissler, J, Wewer Albrechtsen, NJ, Holst, JJ, et al
Diabetologia. 2021;(3):512-520
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Abstract
AIMS/HYPOTHESIS Many individuals who develop type 2 diabetes also display increased glucagon levels (hyperglucagonaemia), which we have previously found to be associated with the metabolic syndrome. The concept of a liver-alpha cell axis provides a possible link between hyperglucagonaemia and elevated liver fat content, a typical finding in the metabolic syndrome. However, this association has only been studied in individuals with non-alcoholic fatty liver disease. Hence, we searched for a link between the liver and the alpha cells in individuals with non-steatotic levels of liver fat content. We hypothesised that the glucagon-alanine index, an indicator of the functional integrity of the liver-alpha cell axis, would associate with liver fat and insulin resistance in our cohort of women with low levels of liver fat. METHODS We analysed data from 79 individuals participating in the Prediction, Prevention and Subclassification of Type 2 Diabetes (PPSDiab) study, a prospective observational study of young women at low to high risk for the development of type 2 diabetes. Liver fat content was determined by MRI. Insulin resistance was calculated as HOMA-IR. We conducted Spearman correlation analyses of liver fat content and HOMA-IR with the glucagon-alanine index (the product of fasting plasma levels of glucagon and alanine). The prediction of the glucagon-alanine index by liver fat or HOMA-IR was tested in multivariate linear regression analyses in the whole cohort as well as after stratification for liver fat content ≤0.5% (n = 39) or >0.5% (n = 40). RESULTS The glucagon-alanine index significantly correlated with liver fat and HOMA-IR in the entire cohort (ρ = 0.484, p < 0.001 and ρ = 0.417, p < 0.001, respectively). These associations resulted from significant correlations in participants with a liver fat content >0.5% (liver fat, ρ = 0.550, p < 0.001; HOMA-IR, ρ = 0.429, p = 0.006). In linear regression analyses, the association of the glucagon-alanine index with liver fat remained significant after adjustment for age and HOMA-IR in all participants and in those with liver fat >0.5% (β = 0.246, p = 0.0.23 and β = 0.430, p = 0.007, respectively) but not in participants with liver fat ≤0.5% (β = -0.184, p = 0.286). CONCLUSIONS/INTERPRETATION We reproduced the previously reported association of liver fat content and HOMA-IR with the glucagon-alanine index in an independent study cohort of young women with low to high risk for type 2 diabetes. Furthermore, our data indicates an insulin-resistance-independent association of liver fat content with the glucagon-alanine index. In summary, our study supports the concept that even lower levels of liver fat (from 0.5%) are connected to relative hyperglucagonaemia, reflecting an imminent impairment of the liver-alpha cell axis.
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Hormonal and Metabolic Responses to a Single Bout of Resistance Exercise in Prader-Willi Syndrome
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Rubin, DA, Clark, SJ, Haqq, AM, Castner, DM, Ng, J, Judelson, DA
Hormone research in paediatrics. 2017;(3):153-161
Abstract
BACKGROUND Prader-Willi syndrome (PWS) is characterized by excessive adiposity. Excess adiposity negatively affects hormonal and metabolic responses to aerobic exercise. This study determined whether PWS and/or adiposity affected hormonal and metabolic responses to resistance exercise. METHODS Eleven children with PWS (11.4 ± 3.1 years, 43.9 ± 7.5% body fat), 12 lean children (9.3 ± 1.4 years, 18.3 ± 4.9% body fat), and 13 obese children (9.6 ± 1.3 years, 40.3 ± 5.2% body fat) participated. The children stepped onto an elevated platform while wearing a weighted vest for 6 sets of 10 repetitions per leg (sets separated by 1 min of rest). For the children with PWS, the platform height was 23.0 cm and vest load was computed as (20% of stature × 50% of lean body mass)/23.0 cm. For the controls, the platform height was 20% of the stature and vest load 50% of the lean body mass. Blood samples were obtained before, immediately after, and during recovery from exercise (+15, +30, and +60 min). RESULTS All groups had similar catecholamine, insulin, and glucagon responses. The groups showed no major differences in glucose and lactate levels. The PWS children demonstrated earlier increases in fatty acids during recovery and higher glycerol and ketone levels than the controls. CONCLUSION The PWS children demonstrated largely intact hormonal, glycolytic, and lipolytic responses to lower-body resistance exercise. In PWS, elevated ketone levels suggest an incomplete fat oxidation.
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Etiology and pathogenesis of necrolytic migratory erythema: review of the literature.
Tierney, EP, Badger, J
MedGenMed : Medscape general medicine. 2004;(3):4
Abstract
CONTEXT Necrolytic migratory erythema (NME) is a characteristic skin condition seen in the presence of a pancreatic glucagonoma. The presence of NME in the absence of a pancreatic tumor has been termed the pseudoglucagonoma syndrome. In such cases, NME is commonly associated with conditions, such as liver disease, inflammatory bowel disease, pancreatitis, malabsorption disorders (ie, celiac sprue), and other malignancies. There are many theories on the pathogenesis of NME, which include the direct action of glucagon in inducing skin necrolysis, hypoaminoacidemia-inducing epidermal protein deficiency and necrolysis, a nutritional or metabolic deficiency of zinc or essential fatty acids, liver disease, glucagon induction of inflammatory mediators, a substance secreted from pancreatic and other visceral tumors associated with NME, and generalized malabsorption. OBJECTIVE To present a review of the literature on the clinical presentation, etiology, pathogenesis, and treatment of NME. DESIGN Review of the literature on NME occurring in patients both with and without a pancreatic glucagonoma. METHODS We performed a PubMed review of the literature on the etiology and pathogenesis of NME to identify case reports and reviews published in both the internal medicine and dermatology literature. RESULTS Our literature review encompassed 17 primary case reports and literature reviews published in the dermatologic and internal medicine literature on NME in patients both with and without a pancreatic glucagonoma. Although we found no clear consensus among the investigators of a universally accepted pathogenesis for NME, we did identify 4 main categories of etiologic/pathogenetic mechanisms for NME (glucagon excess, nutritional deficiencies, inflammatory mediators, and liver disease) that were discussed by many of the investigators and validated by both clinical and scientific evidence. CONCLUSION The exact pathogenesis and treatment of NME remain ill-defined despite many case reports and studies on NME in the literature. The many systemic diseases and nutritional deficiencies that have been found to be associated with NME suggest a multifactorial model for the pathogenesis of the disease. The most comprehensive, postulated mechanism for NME involves a combination of zinc, amino acid, and fatty acid deficiencies (arising from a wide variety of causes, such as dietary insufficiency, malabsorption syndromes, liver disease, elevated glucagon levels, and disorders of metabolism) that contributes to increased inflammation in the epidermis in response to trauma and to the necrolysis observed in NME. The importance of gaining an understanding of the etiology and pathogenesis of NME lies in the fact that there is no universally accepted mechanism of pathogenesis for NME, and that the only treatment reported to resolve the rash in these patients is to adequately identify and treat the underlying associated systemic condition or nutritional deficiency.