Severe Metabolic Complications Research Articles

Therapeutic Potential of Metformin in COVID-19: Reasoning for Its Protective Role.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections present with increased disease severity and poor clinical outcomes in diabetic patients compared with their nondiabetic counterparts. Diabetes/hyperglycemia-triggered endothelial dysfunction and hyperactive inflammatory and immune responses are correlated to twofold to threefold higher intensive care hospitalizations and more than twice the mortality among diabetic coronavirus disease 2019 (COVID-19) patients. While comorbidities such as obesity, cardiovascular disease, and hypertension worsen the prognosis of diabetic COVID-19 patients, COVID-19 infections are also associated with new-onset diabetes, severe metabolic complications, and increased thrombotic events in the backdrop of aberrant endothelial function. While several antidiabetic medications are used to manage blood glucose levels, we discuss the multifaceted ability of metformin to control blood glucose levels and possibly attenuate endothelial dysfunction, inhibit viral entry and infection, and modify inflammatory and immune responses during SARS-CoV-2 infections. These actions make metformin a viable candidate drug to be considered for repurposing and gaining ground against the SARS-CoV-2-induced tsunami in diabetic COVID-19 patients.

Genetic Susceptibility to Joint Occurrence of Polycystic Ovary Syndrome and Hashimoto’s Thyroiditis: How Far Is Our Understanding?

Polycystic ovary syndrome (PCOS) and Hashimoto’s thyroiditis (HT) are endocrine disorders that commonly occur among young women. A higher prevalence of HT in women with PCOS, relative to healthy individuals, is observed consistently. Combined occurrence of both diseases is associated with a higher risk of severe metabolic and reproductive complications. Genetic factors strongly impact the pathogenesis of both PCOS and HT and several susceptibility loci associated with a higher risk of both disorders have been identified. Furthermore, some candidate gene polymorphisms are thought to be functionally relevant; however, few genetic variants are proposed to be causally associated with the incidence of both disorders together.

Endolysosomal Disorders Affecting the Proximal Tubule of the Kidney: New Mechanistic Insights and Therapeutics.

Epithelial cells that line the proximal tubule of the kidney rely on an intertwined ecosystem of vesicular membrane trafficking pathways to ensure the reabsorption of essential nutrients. To function effectively and to achieve homeostasis, these specialized cells require the sorting and recycling of a wide array of cell surface proteins within the endolysosomal network, including signaling receptors, nutrient transporters, ion channels, and polarity markers. The dysregulation of the endolysosomal system can lead to a generalized proximal tubule dysfunction, ultimately causing severe metabolic complications and kidney disease.In this chapter, we highlight the biological functions of the genes that code endolysosomal proteins from the perspective of understanding - and potentially reversing - the pathophysiology of endolysosomal disorders affecting the proximal tubule of the kidney. These insights might ultimately lead to potential treatments for currently intractable diseases and transform our ability to regulate kidney homeostasis and health.

Increased Growth Differentiation Factor 15 in Patients with Hypoleptinemia-Associated Lipodystrophy.

Objective. Similar to obesity, lipodystrophy (LD) causes adipose tissue dysfunction and severe metabolic complications. Growth differentiation factor 15 (GDF15) belongs to the transforming growth factor β superfamily and is dysregulated in metabolic disease including obesity and diabetes mellitus. Circulating levels in LD and the impact of leptin treatment have not been investigated so far. Material and Methods. GDF15 serum levels were quantified in 60 LD patients without human immunodeficiency virus infection and 60 controls matched for age, gender, and body mass index. The impact of metreleptin treatment on circulating GDF15 was assessed in a subgroup of patients. GDF15 mRNA expression was determined in metabolic tissues of leptin-deficient lipodystrophic aP2-nSREBP1c-Tg mice, obese ob/ob mice, and control C57Bl6 mice. Results. Median GDF15 serum concentrations were significantly higher in LD patients (819 ng/L) as compared to the control group (415 ng/L) (p < 0.001). In multiple linear regression analysis, an independent and positive association remained between GDF15 on one hand and age, patient group, hemoglobin A1c, triglycerides, and C-reactive protein on the other hand. Moreover, there was an independent negative association between GFD15 and estimated glomerular filtration rate. Circulating GDF15 was not significantly affected by metreleptin treatment in LD patients. Gdf15 was upregulated in leptin-deficient lipodystrophic mice as compared to controls. Moreover, Gdf15 mRNA expression was downregulated by leptin treatment in lipodystrophic and obese animals. Conclusions. Serum concentrations of GDF15 are elevated in LD patients and independently associated with markers of metabolic dysfunction. Gdf15 expression is higher in lipodystrophic mice and downregulated by leptin treatment.

SUN-LB111 Comparison of Phenotype and Metabolic Abnormalities Among Familial Partial Lipodystrophy Due to LMNA or PPARG Variants

Familial partial lipodystrophy (FPLD), a rare autosomal dominant disorder, is characterized by marked loss of subcutaneous (sc) fat from the extremities, and predisposition to insulin resistance, diabetes mellitus, dyslipidemia and hepatic steatosis. FPLD2 and FPLD3 due to causal variants in LMNA and PPARG, respectively, are the two most common subtypes. Due to extremely rare prevalence of FPLD3 and limited reports in the literature, whether there are phenotypic differences between the two subtypes remain unclear. Therefore, we compared the anthropometric measurements and prevalence of metabolic abnormalities among 32 FPLD3 subjects (4 M, 28 F; mean ± SD age, 41 ± 17.2 y; body mass index (BMI), 26 ± 4.0 kg/m2) with 271 FPLD2 subjects (66 M, 205 F; age, 37.4 ± 17.0 y; BMI, 26 ± 5.0 kg/m2) from two referral centers in the United States. As compared to those with FPLD2, FPLD3 subjects had borderline higher prevalence of hypertriglyceridemia (66% vs 84%; P = 0.063), but significantly higher prevalence of diabetes (44% vs 72%; P = 0.004), past history of acute pancreatitis (13% vs 52%; P <0.001), and polycystic ovarian syndrome (26% vs 52%; P = 0.011). As compared to FPLD2, FPLD3 subjects had similar fasting triglyceride levels (median 208 vs 255 mg/dL; P=0.15), but lower high-density lipoprotein cholesterol levels (median 37.5 vs 30 mg/dL; P = 0.001), higher fasting glucose (median 95 vs 115 mg/dL; P = 0.05) and HbA1c (median 5.7 vs 7.0 %; P = 0.005) levels. Regional body fat was measured by dual energy X-ray absorptiometry in 19 FPLD3 and 105 FPLD2 subjects. In comparison to FPLD2, FPLD3 subjects had higher total fat (median 21.6% vs 26.1 %; P = 0.018); upper limb fat (median 20.3% vs 27.3%; P = 0.003) and lower limb fat (median 16.0% vs 20.8%; P = 0.007). Skinfold thickness measurements by calipers also revealed less severe fat loss from both the upper and lower extremities in FPLD3 subjects compared to FPLD2 subjects. As compared to FPLD2, FPLD3 subjects had significantly higher triceps skinfold thickness (median 5.5 mm vs 7.5 mm; P = 0.015); and thigh skinfold thickness (median 5.8 mm vs 11.3 mm; P = 0.001). There were no significant differences in the prevalence of fatty liver, plasma alanine aminotransferase and aspartate aminotransferase levels in the two subtypes. We conclude that compared to FPLD2 subjects, those with FPLD3 have milder lipodystrophy phenotype but paradoxically present with more severe metabolic complications, especially diabetes, dyslipidemia and polycystic ovarian syndrome. It is likely that this discrepancy could be due to early recognition of FPLD2 because of severe fat loss versus initial diagnosis of FPLD3 subjects due to severe metabolic complications leading to discovery of milder fat loss.

Current Diagnosis, Treatment and Clinical Challenges in the Management of Lipodystrophy Syndromes in Children and Young People

Lipodystrophy is a heterogeneous group of disorders characterized by lack of body fat in characteristic patterns, which can be genetic or acquired. Lipodystrophy is associated with insulin resistance that can develop in childhood and adolescence, and usually leads to severe metabolic complications. Diabetes mellitus, hypertriglyceridemia, and hepatic steatosis ordinarily develop in these patients, and most girls suffer from menstrual abnormalities. Severe complications develop at a relatively young age, which include episodes of acute pancreatitis, renal failure, cirrhosis, and complex cardiovascular diseases, and all of these are associated with serious morbidity. Treatment of lipodystrophy consists of medical nutritional therapy, exercise, and the use of anti-hyperglycemic and lipid-lowering agents. New treatment modalities, such as metreleptin replacement, promise much in the treatment of metabolic abnormalities secondary to lipodystrophy. Current challenges in the management of lipodystrophy in children and adolescents include, but are not limited to: (1) establishing specialized centers with experience in providing care for lipodystrophy presenting in childhood and adolescence; (2) optimizing algorithms that can provide some guidance for the use of standard and novel therapies to ensure adequate metabolic control and to prevent complications; (3) educating patients and their parents about lipodystrophy management; (4) improving patient adherence to chronic therapies; (5) reducing barriers to access to novel treatments; and (5) improving the quality of life of these patients and their families.

Management of diabetic ketoacidosis after the introduction of local hospital protocol in the secondary care hospital

Background: Diabetic ketoacidosis (DKA) is an acute, severe and life-threatening metabolic complication of diabetes. Objective: The objective of this study was to conduct a clinical audit of the management of DKA based on the hospital protocol in the selected secondary care hospital. Design: An observational retrospective longitudinal study design was used to review the data of the patients admitted with DKA. Settings: The study was conducted in a secondary care government hospital, which has 200 beds, including 48 beds in medical ward and 6 beds in the high dependency unit. Materials and Methods: A survey questionnaire was used based on local hospital protocol, and the data was collected from patients admission notes between January 2010 and December 2014, using electronic patients records. Outcome Measures: The study looked at outcomes such as how DKA protocol was followed, complications, adherence, causes, investigations carried out or not, severity, readmissions, and duration of the stay. Sample Size: The audit selected 49 patients from a total of 83 admission notes with DKA who fits the sampling criteria. Results: Of 49 patients, 38 patients were having type 1 diabetes mellitus and 11 patients having type 2 diabetes mellitus. The most common cause in both groups is omission of insulin. Intravenous 0.9% sodium chloride was initiated in the early first hour of diagnosis of DKA for most patients. Readmission rate was 25%. Insulin was commenced in less than 1h for two-thirds of the total patients. Poor adherence to the protocol such as monitoring serum sodium bicarbonate, serum potassium levels and replacement of potassium levels in the early period of management were observed. Conclusion: Continued evidence-based practice and education for medical and paramedical staffs is needed to reduce the complications of DKA and efficiently resolve DKA, improve patient outcomes, and reduce the length of hospital stay. New DKA protocol has been introduced in the hospital as the result of this audit.

Ablation of Bscl2/seipin in hepatocytes does not cause metabolic dysfunction in congenital generalised lipodystrophy.

ABSTRACTMutations affecting the BSCL2 gene cause the most severe form of congenital generalised lipodystrophy (CGL). Affected individuals develop severe metabolic complications including diabetes and hepatic steatosis. Bscl2-deficient mice almost entirely reproduce the CGL phenotype. Adipose tissue-specific loss of Bscl2 is also sufficient to cause early-onset generalised lipodystrophy in mice. However, these mice do not show severe metabolic dysfunction, even when challenged with a high-fat diet. Germline Bscl2 loss in mice and BSCL2 disruption in humans causes severe hepatic steatosis, and the encoded protein, seipin, has acknowledged roles in lipid accumulation. Given the critical role of the liver in glucose regulation, we speculated that intact hepatic Bscl2 expression may protect adipose tissue-specific Bscl2-deficient mice from metabolic disease. To investigate this, we generated a novel mouse model in which Bscl2 has been deleted in both adipose tissue and hepatocytes simultaneously using an adeno-associated viral vector. Despite achieving efficient disruption of Bscl2 in the liver, hepatic lipid accumulation and metabolic homeostasis was unaffected in mice fed a high-fat diet for 4 weeks. We also investigated the consequences of BSCL2 ablation in the human hepatocyte HepG2 cell line using CRISPR/Cas9 genome editing. No significant increases in lipid accumulation were observed in BSCL2 knockout cell lines. Overall, we reveal that Bscl2/BSCL2 does not appear to play a cell-autonomous role in the regulation of lipid accumulation in the liver. Loss of hepatic BSCL2 is therefore unlikely to contribute significantly to the development of hepatic steatosis or metabolic dysfunction in this form of CGL.

HYPOREFLEXIA, HYPOTONIA, AND HYPONATREMIA: A CASE OF GUILLAIN-BARRÉ SYNDROME AND SIADH

SESSION TITLE: Wednesday Fellows Case Report Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: 10/23/2019 09:45 AM - 10:45 AM INTRODUCTION: Guillain-Barré Syndrome (GBS) is an acute inflammatory radiculoneuropathy that is characterized by acute or subacute areflexic paralysis with albumin-cytologic dissociation evident on cerebrospinal fluid (CSF) analysis. In patients with critical neurologic disease, hyponatremia is one of the most severe metabolic complications. Even with mild hyponatremia the consequences can be grave ranging from severe neurologic deficits to death. The association between hyponatremia and GBS has been reported in the past, however, the underlying pathophysiology is not completely understood. CASE PRESENTATION: A 57-year-old female presented to the emergency department due to bilateral distal extremity weakness, worse in the lower extremities, and unsteady gait. The patient stated that her symptoms progressed over the last week with significant numbness, tingling, and weakness bilaterally and difficulty walking. Other than a recent upper respiratory tract infection, she had not experienced any other changes in lifestyle or medications. Upon arrival, CT and MRI of the head and spine were negative for acute changes. Initial labs were within normal limits. Lumbar puncture was performed and the patient was noted to have a CSF protein of 116 mg/dL, WBC 2 per μL, RBC 6 per μL, and glucose 65 mg/dL. Based on these results, the patient was diagnosed with GBS. Over the next 24 hours, the patient’s sodium level dropped from 136 to 119 mEq/L. Urine sodium was greater than 40 mEq and serum osmolality was 248 mOsm/kg. Intravenous immunoglobulin (IVIG) and hypertonic saline were initiated. Over the next 4 days the patient’s hyponatremia resolved with the initiation of fluid restriction and hypertonic saline. Her neurologic symptoms substantially improved prior to discharge. DISCUSSION: The incidence of hyponatremia in GBS patients is reported to be as high as 48% and is typically present in more severe cases. The mechanism of hyponatremia is usually attributed to syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and has been documented as an initial symptom prior to flaccid paralysis. The association between SIADH and GBS is attributed to hypothalamic inflammation. Risk factors for hyponatremia in the setting of GBS include: age > 50 years and preexisting co-morbidities including anemia, alcohol abuse, hypertension, and coagulopathy. Administration of IVIG is associated with a 33% increased likelihood of hyponatremia in patients with GBS. It has been demonstrated that hyponatremia is an indicator of more severe pathology regardless of the underlying disease. CONCLUSIONS: Hyponatremia can occur in the setting of GBS, typically in association with severe clinical states. Although SIADH is the most common cause of hyponatremia in GBS, the exact underlying pathophysiology is unknown. Treatment should be directed at the underlying cause. Reference #1: Sejvar JJ. Population incidence of GBS: a systematic review and meta-analysis. Neuroepidemiology. 2011;36:123-33 Reference #2: Hiew F, Winer J, Rajabally Y. Hyponatremia in Guillain-Barre syndrome revisited. Acta Neurol Scand. 2015;133:295-301. Reference #3: Rabinstein AA. Hyponatremia in critically ill neurological patients. Neurologist. 2003;290-300. DISCLOSURES: No relevant relationships by Hussein Asad, source=Web Response No relevant relationships by Daniel Griffin, source=Web Response

Acute Kidney Damage: Definition, Classification and Optimal Time of Hemodialysis

Abstract Acute damage to the kidney is a serious complication in patients in intensive care units. The causes of acute kidney damage in these patients may be prerenal, renal and postrenal. Sepsis is the most common cause of the development of acute kidney damage in intensive care units. For the definition and classification of acute kidney damage in clinical practice, the RIFLE, AKIN and KDIGO classifications are used. There is a complex link between acute kidney damage and other organs. Acute kidney damage is induced by complex pathophysiological mechanisms that cause acute damage and functional disorders of the heart (acute heart failure, acute coronary syndrome and cardiac arrhythmias), brain (whole body cramps, ischaemic stroke and coma), lung (acute damage to the lung and acute respiratory distress syndrome) and liver (hypoxic hepatitis and acute hepatic insufficiency). New biomarkers, colour Doppler ultrasound diagnosis and kidney biopsy have significant roles in the diagnosis of acute kidney damage. Prevention of the development of acute kidney damage in intensive care units includes maintaining an adequate haemodynamic status in patients and avoiding nephrotoxic drugs and agents (radiocontrast agents). The complications of acute kidney damage (hyperkalaemia, metabolic acidosis, hypervolaemia and azotaemia) are treated with medications, intravenous solutions, and therapies for renal function replacement. Absolute indications for acute haemodialysis include resistant hyperkalaemia, severe metabolic acidosis, resistant hypervolaemia and complications of high azotaemia. In the absence of an absolute indication, dialysis is indicated for patients in intensive care units at stage 3 of the AKIN/KDIGO classification and in some patients with stage 2. Intermittent haemodialysis is applied for haemodynamically stable patients with severe hyperkalaemia and hypervolaemia. In patients who are haemodynamically unstable and have liver insufficiency or brain damage, continuous modalities of treatment for renal replacement are indicated.

SUN-087 Effects of Leptin Replacement on Circulating Plasma Inhibitors of Lipoprotein Lipase in Patients with Lipodystrophy

Lipodystrophy syndromes (LD) result from selective deficiency of adipose tissue, leading to low leptin. Low leptin leads to hyperphagia and ectopic lipid storage, causing severe insulin resistance and metabolic complications including high triglycerides (TG) and subsequent pancreatitis. Replacement of leptin using metreleptin (ML) in LD decreases TG. TG are broken down to non-esterified fatty acids (NEFA) by lipoprotein lipase (LPL). We previously demonstrated that patients with LD had high apoCIII and ANGPLT8 (inhibitors of LPL) that decreased with ML, suggesting that ML may lower TG by reducing inhibition of LPL activity. We hypothesized that plasma from patients with LD would cause greater inhibition of LPL compared to controls, and that ML would ameliorate this. We further hypothesized that net inhibition of LPL in LD would be reflected by a decreased ratio of apoCII (an LPL stimulator) to apoCIII (an LPL inhibitor) vs. controls. METHODS: Plasma from ML-naive patients with LD (n=14) and a pooled high-TG control group (651 mg/dL, n=10) were diluted to the same concentration of TG. Samples were incubated with bovine LPL, and NEFA produced was measured enzymatically over 1hr at 37⁰C. Because the concentrations of added LPL and TG were equal in each patient sample, NEFA generation (nmole) reflected the net effect of LPL stimulators and inhibitors in plasma. To test the effects of ML, the same method was applied to samples from patients with LD after ML 5 mg Q12h for 2 weeks and 6 months. ApoCII and apoCIII were compared in patients with LD (n=14) versus healthy controls (TG = 74 [54, 97] mg/dL, n=28). RESULTS: Patients with LD had baseline TG 492 [208, 1016] mg/dL which decreased to 279 [171, 648] after 2 weeks of ML (n=14, p=.0023) and to 223 [118, 335] after 6 months of ML (n=11, p=0.15). Prior to ML, patients with LD had higher NEFA generation vs. controls (patients 0.79 ± 0.08; controls 0.59 ± 0.1; p<0.0001), consistent with less net inhibition of LPL. NEFA generation did not change with ML therapy after 2 weeks (0.77 ± 0.09) or 6 months (0.78 ± 0.12) compared to baseline (p>0.05). ApoCII:apoCIII ratio did not differ in LD vs controls (0.63±0.31 vs 0.54±0.17, p=0.6), and did not change after ML. CONCLUSIONS: Counter to our hypothesis, patients with LD had higher NEFA generation compared to high TG controls, consistent with less net inhibition of LPL, while the ratio of LPL activator (apoCII) to inhibitor (apoCIII) did not differ in LD vs normal TG controls. Furthermore, NEFA generation and apoCII:apoCIII ratio did not change after ML therapy, suggesting no net change in inhibition of LPL with ML. These findings suggest that changes in circulating activators and inhibitors of LPL are not a major mechanism by which ML lowers TG in LD. Studies including direct measurement of LPL activity after heparin stimulation are needed to further explore the role of LPL in regulating TG in LD.

SUN-135 Dual Energy X-Ray Absorptiometry (DEXA) as a Diagnostic Tool for Familial Partial Lipodystrophy, Dunnigan Variety (FPLD2)

FPLD2 is a rare autosomal dominant disorder characterized by loss of subcutaneous (sc) fat from the extremities but increased fat deposition in the face, neck and abdomen. Most FPLD2 patients (~75%) have “typical” heterozygous missense LMNA mutations affecting the arginine 482 residue and have severe loss of sc fat from the extremities and develop moderate to severe metabolic complications. Other patients have “atypical” mutations with variable loss of sc fat from the extremities and mild to severe metabolic complications. Since genetic testing is expensive, the diagnosis of FPLD2 is usually missed or delayed. Thus, there exists a need for an objective screening tool which can aid in the diagnosis of FPLD2. Therefore, we determined the predictive value of skinfold thickness measurements and various DEXA-based regional body fat parameters for diagnosis of FPLD2. We compared body fat data of 49 adult females (F) and 5 males (M) with FPLD2 to the sex- and age-matched controls (2,459 F, 3,459 M) from the National Health and Nutrition Examination Survey (NHANES) 2005-2010. Thirty nine patients had “typical” heterozygous p.R482W or p.R482Q LMNA mutation. The other heterozygous LMNA mutations included p.R582S (n = 1), p.R582H (n = 1), p.S583L (n = 3), p.R349W (n = 1), p.R25L (n = 1), p.G523R (n = 2), p.D192V (n = 1), p.L241P (n = 1), p.R62G (n = 2) and p.K515E (n = 2). The mean ± SD age and body mass index of affected F was 42 ± 13.5 y and 25.6 ± 4.5 kg/m2, respectively; and of affected M was 45.4 ± 11.6 y and 29.2 ± 7.0 kg/m2, respectively. Hypertriglyceridemia and diabetes mellitus were present in 74% and 52% of the FPLD2 patients, respectively. Our data revealed that the lower limb fat %, as well as the ratio of lower limb fat %/ truncal fat %, in all affected females were ≤ 1st percentile (%ile) of the controls, except in two patients, one of whom had a p.G523R mutation, and the other had a p.R482Q mutation but had an unusual excess fat accumulation in the medial part of the thighs and knees. All FPLD2 females had triceps skinfold thickness values ≤ 1st %ile of NHANES except in three patients. The subscapular skinfold thickness values in females on the other hand, were between the 5th to 99th %ile of NHANES. Unfortunately, data for thigh skinfold thickness were not available from NHANES. The lower limb fat % in affected males was below 25th %ile of controls. We conclude that DEXA-derived lower limb fat % and the ratio of lower limb fat %/ truncal fat % are the best predictors of FPLD2 diagnosis in females but not in males. Women with values of lower limb fat % (~ 20% or less) and the ratio of lower limb fat %/ truncal fat % (~ 0.85 or less), both of which are below the 1st %ile of NHANES data, should be further evaluated for diagnosis of FPLD2, especially if presenting with metabolic complications.

Visceral fat does not contribute to metabolic disease in lipodystrophy.

SummaryObjectivesLipodystrophies are characterized by regional or generalized loss of adipose tissue and severe metabolic complications. The role of visceral adipose tissue (VAT) in the development of metabolic derangements in lipodystrophy is unknown. The study aim was to investigate VAT contribution to metabolic disease in lipodystrophy versus healthy controls.MethodsAnalysis of correlations between VAT volume and biomarkers of metabolic disease in 93 patients and 93 age/sex‐matched healthy controls.ResultsPatients with generalized lipodystrophy (n = 43) had lower VAT compared with matched controls, while those with partial lipodystrophy (n = 50) had higher VAT versus controls. Both groups with lipodystrophy had lower leg fat mass versus controls (p < 0.05 for all; unpaired t‐test). In both generalized and partial lipodystrophy, there was no correlation between VAT and glucose, triglycerides or high‐density lipoprotein cholesterol (p > 0.05 for all; Spearman correlation). In controls matched to patients with generalized or partial lipodystrophy, VAT correlated with glucose (R = 0.42 and 0.36), triglycerides (R = 0.36 and 0.60) and high‐density lipoprotein cholesterol (R = −0.34 and −0.64) (p < 0.05 for all; Spearman correlation).ConclusionsIn contrast to healthy controls, metabolic derangements in lipodystrophy did not correlate with VAT volume. These data suggest that, in lipodystrophy, impaired peripheral subcutaneous fat deposition may exert a larger effect than VAT accumulation on the development of metabolic complications. Interventions aimed at increasing functional subcutaneous adipose tissue may provide metabolic benefit.

Epidemiological profiles of diabetic ketoacidosis in the Emergency Department

IntroductionL'acidocétose diabétique (ACD) est une complication métabolique grave du diabète. Son incidence est en augmentation ces dernières années, cependant sa mortalité reste faible. L'objectif de cette étude a été de décrire les caractéristiques épidémiologiques, cliniques, thérapeutiques et pronostiques des patients admis aux urgences pour ACD sévère ou modérée.MéthodesIl s'agissait d'une étude prospective, descriptive qui a inclus les ACD modérées ou sévères. Standardisation du protocole de prise en charge thérapeutique. Nous avons étudié les caractéristiques épidémiologiques, cliniques, thérapeutiques et pronostiques chez ces patients.RésultatsNous avons inclus 185 patients avec ACD sévère ou modérée. L'âge moyen a été de 38 +/- 18 ans; le sexe ratio=0,94. Diabète connue= 159 patients (85%) dont 116 étaient des diabétiques type 1. Les facteurs de décompensation les plus fréquents étaient l'arrêt du traitement chez 42% et l'infection chez 32%. La glycémie moyenne a été de 32,7+/-12mmol/L, pH =7,14+/-0,13, HCO3- =7,2+/-3,56 mmol /L. La durée moyenne de l'insuline intraveineuse était de 17,3 +/- 16 heures. L'hypoglycémie a été observée chez 26 patients (14%), l'hypokaliémie chez 80 (43%). La mortalité au cours de l'hospitalisation a été de 2,1%.ConclusionL'acidocétose diabétique survient chez les sujets jeunes traités par insulinothérapie. Le traitement est à base d'insuline par voie intraveineuse en plus de la correction du déficit hydrique. Les complications sont essentiellement l'hypokaliémie et l'hypoglycémie; et la mortalité reste faible.

Natural helix 9 mutants of PPARγ differently affect its transcriptional activity

ObjectiveThe nuclear receptor PPARγ is the master regulator of adipocyte differentiation, distribution, and function. In addition, PPARγ induces terminal differentiation of several epithelial cell lineages, including colon epithelia. Loss-of-function mutations in PPARG result in familial partial lipodystrophy subtype 3 (FPDL3), a rare condition characterized by aberrant adipose tissue distribution and severe metabolic complications, including diabetes. Mutations in PPARG have also been reported in sporadic colorectal cancers, but the significance of these mutations is unclear. Studying these natural PPARG mutations provides valuable insights into structure-function relationships in the PPARγ protein. We functionally characterized a novel FPLD3-associated PPARγ L451P mutation in helix 9 of the ligand binding domain (LBD). Interestingly, substitution of the adjacent amino acid K450 was previously reported in a human colon carcinoma cell line. MethodsWe performed a detailed side-by-side functional comparison of these two PPARγ mutants. ResultsPPARγ L451P shows multiple intermolecular defects, including impaired cofactor binding and reduced RXRα heterodimerisation and subsequent DNA binding, but not in DBD-LBD interdomain communication. The K450Q mutant displays none of these functional defects. Other colon cancer-associated PPARγ mutants displayed diverse phenotypes, ranging from complete loss of activity to wildtype activity. ConclusionsAmino acid changes in helix 9 can differently affect LBD integrity and function. In addition, FPLD3-associated PPARγ mutations consistently cause intra- and/or intermolecular defects; colon cancer-associated PPARγ mutations on the other hand may play a role in colon cancer onset and progression, but this is not due to their effects on the most well-studied functional characteristics of PPARγ.

Female adipose tissue-specific Bscl2 knockout mice develop only moderate metabolic dysfunction when housed at thermoneutrality and fed a high-fat diet

Mutations affecting the BSCL2 gene cause the most severe form of congenital generalised lipodystrophy. Affected individuals almost completely lack adipose tissue and suffer from severe diabetes and metabolic complications. Likewise, mice lacking Bscl2 in all tissues have dramatically reduced adipose mass, glucose intolerance and hyperinsulinaemia. However, male adipose tissue-specific Bscl2 knockout mice fail to develop the metabolic dysfunction observed in Bscl2 null mice and BSCL2 deficient patients, despite a similar generalised lack of adipose tissues. Clinical reports indicate gender differences frequently exist in cases of lipodystrophy, with female patients more adversely affected than male patients. We therefore generated and characterised female mice lacking Bscl2 specifically in adipose tissue (Ad-B2(−/−)). We show that female Ad-B2(−/−) mice also develop early-onset lipodystrophy when fed a chow diet and are maintained under standard housing conditions (21 °C) or thermoneutrality (30 °C). Despite this, female Ad-B2(−/−) mice fail to develop severe metabolic dysfunction. Only when female Ad-B2(−/−) mice are maintained at thermoneutrality and fed a high-fat diet do subtle alterations to metabolic homeostasis manifest. This is despite a striking inability to expand adipose mass. Our findings provide further evidence that loss of Bscl2 in non-adipose tissues may contribute to the severity of metabolic dysfunction in this condition.

Early 7-day supplemental parenteral nutrition improves body composition and muscle strength in hypophagic cancer patients at nutritional risk.

The international guidelines recommend the use of supplemental parenteral nutrition (SPN) in cancer patients when they are malnourished and hypophagic and where enteral nutrition is not feasible. However, there are limited data on the short-term effects of SPN in this patient population. The aim of this bicentric single-arm clinical trial (NCT02828150) was to evaluate the effects of early 7-day SPN on bioimpedance vectorial analysis (BIVA)-derived body composition, handgrip strength (HG), and serum prealbumin (PAB) in 131 hypophagic, hospitalized cancer patients at nutritional risk, with contraindications for enteral nutrition. One hundred eighteen patients (90.1%) completed the 7-day SPN support regimen and 102 of them (86.4%) were in advanced disease stage. SPN induced a significant improvement of phase angle (PhA, + 0.25 [95% CI 0.11, 0.39]; p = 0.001), standardized phase angle (SPA, + 0.33 [95% CI 0.13, 0.53]; p = 0.002), HG (+ 2.1kg -95% CI 1.30, 2.81]; p < 0.001), and PAB (+ 3.8mg/dL [95% CI 2.1, 5.6]; p < 0.001). In multivariable analysis, the effects on BIVA parameters were more pronounced in patients (N = 90, 76.3%) in whom estimated protein and calorie requirements were both satisfied (adjusted difference: PhA, + 0.39 [95% CI 0.04, 0.73]; p = 0.030; SPA, + 0.62 [95% CI 0.16, 1.09]; p = 0.009). No significant changes in hydration status were detected and no severe metabolic or other complications occurred. Early 7-day SPN resulted in improved body composition, HG and PAB levels in hypophagic, and hospitalized cancer patients at nutritional risk in the absence of any relevant clinical complications. Further trials, aimed at verifying the efficacy of this early nutritional intervention on mid- and long-term primary clinical endpoints in specific cancer types, are warranted.

Dynamics of quality of life in patients with morbid obesity after biliopancreatic diversion and sleeve gastrectomy

The rapid progress of obesity surgery dictates the necessity to study the quality of life of patients after bariatric procedures. The aim of the study is to assess the dynamics of quality of life of patients with morbid obesity after biliopancreatic diversion in the modification of Hess-Marceau and the sleeve gastrectomy in order to improve the results of surgical treatment of the specified category of patients. The results of surgical treatment of 205 patients with morbid obesity who performed sleeve gastrectomy (main group — 105 patients) or biliopancreatic diversion by Hess-Marceau (comparison group — 100 patients) were analyzed. The study of the dynamics of quality of life of patients was performed in according the Moorehead-Ardelt II method. Statistical data processing was performed using the methods of variational and descriptive statistic using Statistica 6.0 statistical analysis package. Installed that biliopancreatic diversion by Hess-Marceau and sleeve gastrectomy allowed to significantly improve the quality of life of patients with an increase of the quality of life index with -1.5±0.7 in the comparison group and -1.6±0,6 in the main group up to 1.8±0.3 and 2.0±0.4 respectively (p&lt;0.05 compared to pre-operative data) 60 months after surgery. A more pronounced positive dynamics of quality of life in patients of the main group in the time interval of 12–24 months after the operation was achieved due to the absence of severe late metabolic complications and undesirable side effects of biliopancreatic diversion and laparoscopic access for sleeve gastrectomy in 54.3% of patients. Thus, the quality of life of patients with morbid obesity before performing bariatric surgery is critically low and significantly improved after biliopancreatic diversion by Hess-Marceau as well as sleeve gastrectomy. The impact of bariatric surgery on the duration and quality of life of patients requires further multicenter randomized trials.

Late lumen loss in thoracic aortic end graft after endovascular procedure of a traumatic pseudoaneurysm

We report the case of a 23-year-old woman who died due to endograft stenosis 20 months after thoracic endovascular aortic repair. The patient presented with the pseudocoarctation syndrome. Although angioplasty of stenosis endograft was successfully performed, severe metabolic complications were lethal.

100 years of weight loss surgery: Voluntary weight loss, involuntary bone loss

In the past 100 years, there have been myriad medical discoveries—giant steps—from Louis Pasteur’s germ theory, to the understanding of gut physiology and metabolic processes—that are the essential underpinnings of modern day medicine. The beginnings of surgery to promote weight loss, now known as bariatric surgery, date back to the 1880s when it was noted that gut resections resulted in weight loss. It was not long afterward that articles started to appear documenting nutritional “disturbances” and the patient’s likelihood of survival based upon the location and the length of bowel removed. Numerous articles have been penned citing the first bariatric surgeries, but to date, there has not been a comprehensive look back at the origins of the science as well as the severe metabolic complications that furthered understanding, prompted innovative medical and surgical approaches, and ultimately led to modern day practice. This article endeavors to do exactly that. Intestinal bypass surgeries to treat obesity are here to stay. Some of the most profound complications of intestinal bypass manifest in the skeleton and include skeletal demineralization, hyperoxaluria, nephrolithiasis, and fractures. Much has been done to further elucidate the underlying mechanisms, identify preventive strategies, and implement practice guidelines, but this patient population remains at increased risk for metabolic bone disease.