In a Prediabetic Model, Empagliflozin Improves Hepatic Lipid Metabolism Independently of Obesity and before Onset of Hyperglycemia.

Recent studies suggest that treatment with SGLT-2 inhibitors can reduce hepatic lipid storage and ameliorate non-alcoholic fatty liver disease (NAFLD) development beyond their glycemic benefits. However, the exact mechanism involved is still unclear. We investigated the hepatic metabolic effect of empagliflozin (10 mg/kg/day for eight weeks) on the development of NAFLD and its complications using HHTg rats as a non-obese prediabetic rat model. Empagliflozin treatment reduced neutral triacylglycerols and lipotoxic diacylglycerols in the liver and was accompanied by significant changes in relative mRNA expression of lipogenic enzymes (Scd-1, Fas) and transcription factors (Srebp1, Pparγ). In addition, alterations in the gene expression of cytochrome P450 proteins, particularly Cyp2e1 and Cyp4a, together with increased Nrf2, contributed to the improvement of hepatic lipid metabolism after empagliflozin administration. Decreased circulating levels of fetuin-A improved lipid metabolism and attenuated insulin resistance in the liver and in peripheral tissues. Our results highlight the beneficial effect of empagliflozin on hepatic lipid metabolism and lipid accumulation independent of obesity, with the mechanisms understood to involve decreased lipogenesis, alterations in cytochrome P450 proteins, and decreased fetuin-A. These changes help to alleviate NAFLD symptoms in the early phase of the disease and before the onset of diabetes.

Familial hypertriglyceridaemia and type 2 diabetes in pregnancy: prevention of acute pancreatitis with diet control and omega-3 fatty acids.

Acute pancreatitis in pregnancy is rare and can be caused by hypertriglyceridaemia. The management of hypertriglyceridaemia in pregnancy is complex and challenging as many lipid-lowering medications have been found to be unsafe in pregnancy. Patients who present with hypertriglyceridaemia commonly have multiple risk factors such as, diabetes, alcohol excess and hypothyroidism which pose a greater challenge to the management of these patients. We present a case of a 31-year-old woman presenting with familial hypertriglyceridaemia and type 2 diabetes mellitus in her third pregnancy. She had an uneventful pregnancy with the use of omega-3 fatty acids nutritional support, low-fat diet and tight glucose control with insulin and metformin.

Fenotipo hipertrigliceridemia cintura abdominal alterada y su asociación con los factores de riesgo cardiovasculares / Hypertriglyceridemic waist phenotype and its association with cardiovascular risk factors

Introducción: el fenotipo clínico hipertrigliceridemia cintura abdominal alterada guarda relación con la presencia de hiperinsulinemia, hipertrigliceridemia e hipercolesterolemia, y en consecuencia, es un riesgo de enfermedades cardiovasculares y diabetes mellitus tipo 2. Objetivo: determinar la asociación del fenotipo hipertrigliceridemia cintura abdominal alterada con los principales factores de riesgo cardiovasculares. Material y Métodos: se realizó un estudio descriptivo correlacional, con una muestra probabilística obtenido por un método polietápico. La muestra quedó conformada por 1108 sujetos entre 15 y 74 años, incluidos dentro del componente de vigilancia de enfermedades no transmisibles de la iniciativa CARMEN, pertenecientes al municipio de Cienfuegos. Las variables evaluadas fueron las siguientes: sexo, color de la piel, tabaquismo, hipertensión arterial, obesidad, actividad física, diabetes mellitus, índice de masa corporal, circunferencia abdominal, colesterol total y triglicéridos. Se determinó la razón de prevalencia para las diferentes variables. El nivel de significación exigido fue del 95 por ciento. Resultados: La razón de probabilidad demostró mayor riesgo de presentar el fenotipo en el sexo femenino (2,31), así como en los sujetos mayores de 45 años (2,92), obesos (19,24), hipertensos (2,96) y diabéticos (2,30). Conclusiones: existe una relación significativa entre el fenotipo hipertrigliceridemia cintura abdominal alterada y los principales factores de riesgo cardiovasculares, tales como el incremento de la edad, el índice aterogénico, los niveles de colesterol, la diabetes mellitus y la hipertensión arterial(AU)

Introduction: The hypertriglyceridemic waist phenotype is related to the presence of hyperinsulinemia, hypertriglyceridemia, and hypercholesterolemia and consequently, it is a risk of cardiovascular diseases and type 2 diabetes mellitus. Objective: To determine the association of hypertriglyceridemic waist phenotype with the main cardiovascular risk factors. Material and Methods: A descriptive study was carried out with a probabilistic sample obtained from a multi-stage method. The sample consisted of 1108 subjects between 15 and 74 years old, included in the surveillance component for noncommunicable diseases (NCDs) from the CARMEN initiative in Cienfuegos. The variables evaluated were: sex, skin color, smoking, hypertension, obesity, physical activity, diabetes mellitus, body mass index, abdominal circumference, total cholesterol, and triglycerides. The Prevalence Ratio (PR) was determined for the different variables. The level of significance required was 95 percent. The research was approved by the Scientific Council of the University of Medical Sciences of Cienfuegos and the Research Ethics Committee. The results are presented in tables and figures. Results: PR showed a greater risk of presenting the phenotype in females (2,31), as well as in subjects over 45 years (2,92), obese (19,24), and hypertensive and diabetics for a PR of (2.96 and 2.30), respectively. Conclusions: There is a significant relationship between hypertriglyceridemic waist phenotype and the main cardiovascular risk factors such as increasing age, atherogenic index, cholesterol levels, diabetes mellitus, and hypertension(AU)

Chewing the Fat: A Case Report of Therapeutic Plasma Exchange in Hypertriglyceridemia-Induced Pancreatitis.

Hypertriglyceridemia is the third most common etiology of acute pancreatitis, but lacks a clear, evidence-based treatment approach. We present the case of a 25-year-old man who was admitted eleven times over seven years for hypertriglyceridemia-induced pancreatitis. In his first ten admissions, he received conservative therapy. During his eleventh admission, he underwent therapeutic plasma exchange with lowering of serum triglycerides from 5080 to 332 mg/dL. He was discharged on hospital day five and was noted to have persistently lowered triglyceride levels upon follow up. The case affirms plasma exchange's ability to rapidly lower serum triglyceride levels and provides future research opportunities for examining the long-term effects of this treatment.

Tamoxifen precipitation of familial hypertriglyceridaemia: a rare cause of acute pancreatitis.

Drug-induced pancreatitis is uncommon, and is estimated to account for between 0.1% and 5% of cases. Tamoxifen is commonly used in the management of oestrogen receptor-positive breast cancer. We present a rare case of tamoxifen-related hyperlipidaemia resulting in repeated episodes of pancreatitis, which, to the best of our knowledge, has only been documented a few times in the literature. A 36-year-old woman with familial hypertriglyceridaemia presented with recurrent episodes of abdominal pain, modest increases in serum amylase levels and normal liver function tests. The patient had recently been diagnosed with breast carcinoma and was managed with wide local excision (WLE), adjuvant radiotherapy and tamoxifen. On each admission, the patient's symptoms were confirmed either biochemically and/or radiologically. Analysis of the case led to a diagnosis of precipitation of familial hypertriglyceridaemia from tamoxifen use resulting in pancreatitis. Management was altered with tamoxifen cessation and initiation of second-line hormonal therapy. Tamoxifen use needs consideration, especially in those with familial hyperlipidaemia.

Normalizing metabolism in diabetic pregnancy: is it time to target lipids?

Outcomes in pregnancies complicated by preexisting diabetes (type 1 and type 2) and gestational diabetes mellitus have improved, but there is still excess morbidity compared with normal pregnancy. Management strategies appropriately focus on maternal glycemia, which demonstrably improves pregnancy outcomes for mother and infant. However, we may be reaching the boundaries of obtainable glycemic control for many women. It has been acknowledged that maternal lipids are important in pregnancies complicated by diabetes. Elevated maternal lipids are associated with preeclampsia, preterm delivery, and large-for-gestational-age infants. Despite this understanding, assessment of management strategies targeting maternal lipids has been neglected to date. Consideration needs to be given to whether normalizing maternal lipids would further improve pregnancy outcomes. This review examines the dyslipidemia associated with pregnancy complicated by diabetes, reviews possible therapies, and considers whether it is time to start actively managing this aspect of maternal metabolism.

Management of familial hypertriglyceridemia-induced pancreatitis during pregnancy with therapeutic plasma exchange: a case report and review of literature.

Familial severe hypertriglyceridemia (levels greater than 1000 mg/dL) is a known cause of acute pancreatitis. Pregnancy can dysregulate controlled lipid levels in women with familial hypertriglyceridemia and lead to acute pancreatitis and significant morbidity in both mother and fetus. We report a case of hypertriglyceridemia-induced pancreatitis during pregnancy that was successfully treated using therapeutic plasma exchange, resulting in delivery of a healthy preterm infant. Therapeutic plasma exchange is an effective approach to treat gestational hypertriglyceridemia-induced pancreatitis. Other treatment options include combined heparin and insulin infusion. Moreover, particular caution should be applied when interpreting the results of prothrombin time in the setting of severe hypertriglyceridemia as false elevation with testing methods could happen.

[Acute hypertrygliceridemic pancreatitis]. / Pancreatitis aguda por hipertrigliceridemia.

Acute hypertriglyceridemic pancreatitis is the third cause of acute pancreatitis in the Western population. There is usually an underlying alteration in lipid metabolism and a secondary factor. Clinical presentation is similar to that of pancreatitis of other etiologies, but the course of acute hypertriglyceridemic pancreatitis seems to be worse and more recurrent. Some laboratory data can be artefacts, leading to diagnostic errors. This is the case of amylase, which can show false low levels. Treatment is based on intense fluidotherapy and analgesia. When there is no response to conservative management, other methods to lower triglyceride levels should be used. Several options are available, such as plasmapheresis, insulin, and heparin. The present article provides a review of the current literature on this entity.

Serum ferritin is a major determinant of lipid phenotype in familial combined hyperlipidemia and familial hypertriglyceridemia.

Familial combined hyperlipidemia (FCH) and familial hypertriglyceridemia (FHTG) share pathogenic mechanisms and a high interaction with components of the metabolic syndrome. The metabolic syndrome associates increased serum ferritin concentration and high cardiovascular risk. The objective was to describe the frequency of iron overload and the relationship between serum ferritin and the phenotype in patients with FCH and FHTG. The study was composed of 211 consecutive unrelated patients aged at least 18 years with primary hypertriglyceridemia, 149 with FCH, and 62 with FHTG. The prevalence of the metabolic syndrome and hyperferritinemia was very high in both hypertriglyceridemic groups (51.7% and 20.1% in FCH and 62.9% and 16.1% in FHTG, respectively), without significant statistical differences between them. Serum ferritin concentration did not show any significant association with the number of metabolic syndrome criteria. Subjects in the highest tertile of ferritin concentration (ferritin >200 mug/L) presented higher concentrations of triglycerides and liver enzymes than subjects in the first tertile of ferritin concentration (ferritin <90 mug/L). The highest positive correlation coefficient for triglycerides was found with ferritin in FCH and in FHTG subjects (R = 0.317 [P < .001] when combined). Ferritin was also the covariate that showed the highest independent association with triglycerides in FCH and FHTG. In contrast, ferritin was not associated with carotid intima-media thickness. In summary, serum ferritin is commonly increased in FCH and in FHTG, it is not related with the presence of metabolic syndrome, and it is highly correlated with liver enzymes.

Oligo-arthritis and type IV hyperlipoproteinemia.

The increased risk of cardiovascular mortality in patients with inflammatory joint disease indicates a need for routine investigations to detect conventional cardiovascular risk factors. These investigations may provide the classification of the disease. We report a case of oligoarticular arthritis with type IV hyperlipoproteinemia, a condition of which only 15 cases are described in the literature. The patient had oligoarthritis, laboratory signs of severe inflammation, and type IV hyperlipoproteinemia (triglycerides, 24.6 mmol/L; and total cholesterol, 10.7 mmol/L). The clinical and laboratory test abnormalities resolved under fenofibrate therapy.

Acute pancreatitis in a cohort of 129 patients referred for severe hypertriglyceridemia.

OBJECTIVES: The aim of this study was to assess retrospectively the prevalence and the predictive factors of acute pancreatitis (AP) in a population of patients referred in our endocrinology department for evaluation of very high triglyceride (TG) levels. METHODS: One hundred twenty-nine patients (119 with type IV phenotypes and 10 with type V phenotypes according to Fredrickson's classification) were referred to our hospital between 2000 and 2005. RESULTS: Twenty-six subjects (20.2% of the population) presented with AP. This population was significantly younger at diagnosis of hyperlipidemia (32 vs 40 years, P < 0.001) and at age of investigation (43 vs 48 years, P = 0.05) and had maximum TG levels greater than the population without AP (44.7 vs 24.5, P < 0.001). Subjects of the third tertile of TG levels had a 4.0-fold increased risk (95% confidence interval, 1.3-12.3) of AP compared with the first tertile. Severe pancreatitis (need for intensive care, C-reactive protein >150 mg/L, or Balthazar score >C) was observed in 71.5% of the patients. CONCLUSIONS: Twenty percent of patients with severe hypertriglyceridemia experience at least 1 attack of AP. Pancreatitis seems to occur in young patients at higher levels of TG than previously thought (85% of patients >30 g/L) and is associated with a severe clinical course.

[Familial hypertriglyceridemia and diabetes mellitus type 2]. / La hipertrigliceridemia familiar no se asocia a mayor prevalencia de complicaciones macrovasculares en la diabetes mellitus tipo 2.

Hypertriglyceridemia is a cardiovascular risk factor in type-2 diabetes. However, this abnormality may be caused by several mechanisms. In familial hypertriglyceridemia, a hyperlipidemia associated with type-2 diabetes, plasma accumulation of non atherogenic particles explains the presence of hypertriglyceridemia. Our objective was to compare the prevalence of coronary insufficiency and carotid artery stenosis in patients with type-2 diabetes with or without familial hypertriglyceridemia. Controls were paired against cases based on age, gender, diabetes duration, treatment and other cardiovascular risk factors. Controls had either a normal lipid profile (n=48) or hyperlipidemia (n=15). The intima-media thickness of the carotid arteries was significantly lower in cases compared to controls (0.55 +/- 0.12 vs 0.63 +/- 0.22 in normolipidemic controls and 0.66 +/- 0.18 mm in hyperlipidemic subjects (p=0.02)). Exercise treadmill testing was abnormal in a similar proportion of cases and controls (4.8 vs 6.2%). Incidence of cardiovascular complications was not different between groups. We therefore conclude that severe hypertriglyceridemia due to familial hypertriglyceridemia is not associated with an increased prevalence of symptomatic atherosclerosis in patients with type-2 diabetes.

High frequency of Fredrickson's phenotypes IV and IIb in Brazilians infected by human immunodeficiency virus.

BACKGROUND: Human immunodeficiency virus (HIV) infection is very prevalent in Brazil. HIV therapy has been recently associated with coronary heart disease (CHD). Dyslipidemia is a major risk factor for CHD that is frequently described in HIV positive patients, but very few studies have been conducted in Brazilian patients evaluating their lipid profiles. METHODS: In the present work, we evaluated the frequency and severity of dyslipidemia in 257 Brazilian HIV positive patients. Two hundred and thirty-eight (93%) were submitted to antiretroviral therapy (224 treated with protease inhibitors plus nucleoside reverse transcriptase inhibitors, 14 treated only with the latter, 12 naive and 7 had no records of treatment). The average time on drug treatment with antiretroviral therapy was 20 months. None of the patients was under lipid lowering drugs. Cholesterol, triglyceride, phospholipid and free fatty acids were determined by enzymatic colorimetric methods. Lipoprotein profile was estimated by the Friedewald formula and Fredrickson's phenotyping was obtained by serum electrophoresis on agarose. Apolipoprotein B and AI and lipoprotein "a" were measured by nephelometry. RESULTS: The Fredrickson phenotypes were: type IIb (51%), IV (41%), IIa (7%). In addition one patient was type III and another type V. Thirty-three percent of all HIV+ patients presented serum cholesterol levels >or= 200 mg/dL, 61% LDL-cholesterol >or= 100 mg/dL, 65% HDL-cholesterol below 40 mg/dL, 46% triglycerides >or= 150 mg/dL and 10% have all these parameters above the limits. Eighty-six percent of patients had cholesterol/HDL-cholesterol ratio >or= 3.5, 22% increased lipoprotein "a", 79% increased free fatty acids and 9% increased phospholipids. The treatment with protease inhibitors plus nucleoside reverse transcriptase inhibitors increased the levels of cholesterol and triglycerides in these patients when compared with naïve patients. The HDL-cholesterol (p = 0.01) and apolipoprotein A1 (p = 0.02) levels were inversely correlated with the time of protease inhibitor therapy while total cholesterol levels had a trend to correlate with antiretroviral therapy (p = 0.09). CONCLUSION: The highly varied and prevalent types of dyslipidemia found in Brazilian HIV positive patients on antiretroviral therapies indicate the urgent need for their early diagnosis, the identification of the risk factors for CHD and, when needed, the prompt intervention on their lifestyle and/or with drug treatment.

La hipertrigliceridemia familiar no se asocia a mayor prevalencia de complicaciones macrovasculares en la diabetes mellitus tipo 2 / Familial hypertriglyceridemia and diabetes mellitus type 2

La hipertrigliceridemia es un factor de riesgo cardiovascular en la diabetes. Esta anormalidad es causada por varios mecanismos. En la hipertrigliceridemia familiar, la elevación extrema de triglicéridos se debe a acúmulo de lipoproteínas poco aterogénicas. Nuestro objetivo fue comparar el grosor de la capa íntima y media de la carótida y la prevalencia de insuficiencia coronaria o de estenosis carotídea en pacientes diabéticos con hipertrigliceridemia familiar (n=41) vs controles hiperlipidémicos (n=15) o normolipidémicos (n=48) pareados por edad, sexo, tiempo de evolución de la diabetes y otros factores de riesgo cardiovascular. Además se midió la incidencia a cinco años de eventos cardiovasculares. La prueba de esfuerzo resultó anormal en una proporción similar en casos y controles (4.8 vs 6.2%). El grosor de la capa íntima y media de la carótida fue menor en los casos con hipertrigliceridemia familiar (0.55±0.12 vs 0.63±0.22 en controles normolipidémicos y 0.66 ±0.18 mm en controles hiperlipidémicos (p=0.02)). La incidencia de complicación cardiovascular fue similar en los tres grupos. La hipertrigliceridemia familiar no se asocia a un aumento substancial en el número de complicaciones macrovasculares en personas con diabetes tipo 2, pese a la presencia de concentraciones extremas de triglicéridos y niveles bajos de colesterol HDL.

Hypertriglyceridemia is a cardiovascular risk factor in type 2 diabetes. However, this abnormality may be caused by several mechanisms. In familial hypertriglyceridemia, a hyperlipidemia associated with type-2 diabetes, plasma accumulation of non atherogenic particles explains the presence of hypertriglyceridemia. Our objective was to compare the prevalence of coronary insufficiency and carotid artery stenosis in patients with type-2 diabetes with or without familial hypertriglyceridemia. Controls were paired against cases based on age, gender, diabetes duration, treatment and other cardiovascular risk factors. Controls had either a normal lipid profile (n=48) or hyperlipidemia (n=15). The intima media thickness of the carotid arteries was significantly lower in cases compared to controls (0.55±0.12 vs 0.63± 0.22 in normolipidemic controls and 0.66 ±0.18 mm in hyperlipidemic subjects (p=0.02)). Exercise treadmill testing was abnormal in a similar proportion of cases and controls (4.8 vs 6.2%). Incidence of cardiovascular complications was not different between groups. We therefore conclude that severe hypertriglyceridemia due to familial hypertriglyceridemia is not associated with an increased prevalence of symptomatic atherosclerosis in patients with type-2 diabetes.

Familial type IV hypertriglyceridemia presenting as hemiparesis with cerebellar signs.

Stroke in pediatric patients is distinctive as compare to adults. The authors report a rare case of familial hypertriglyceridemia type IV who had left hemiparesis with cerebellar signs. There was no history of oral trauma, head injury, convulsions, acute gastroenteritis, meningitis or otitis media.

Increased endothelial tetrahydrobiopterin synthesis by targeted transgenic GTP-cyclohydrolase I overexpression reduces endothelial dysfunction and atherosclerosis in ApoE-knockout mice.

OBJECTIVE: Increased production of reactive oxygen species and loss of endothelial nitric oxide (NO) bioactivity are key features of vascular disease states such as atherosclerosis. Tetrahydrobiopterin (BH4) is a required cofactor for NO synthesis by endothelial nitric oxide synthase (eNOS); pharmacologic studies suggest that reduced BH4 availability may be an important mediator of endothelial dysfunction in atherosclerosis. We aimed to investigate the importance of endothelial BH4 availability in atherosclerosis using a transgenic mouse model with endothelial-targeted overexpression of the rate-limiting enzyme in BH4 synthesis, GTP-cyclohydrolase I (GTPCH). METHODS AND RESULTS: Transgenic mice were crossed into an ApoE knockout (ApoE-KO) background and fed a high-fat diet for 16 weeks. Compared with ApoE-KO controls, transgenic mice (ApoE-KO/GCH-Tg) had higher aortic BH4 levels, reduced endothelial superoxide production and eNOS uncoupling, increased cGMP levels, and preserved NO-mediated endothelium dependent vasorelaxations. Furthermore, aortic root atherosclerotic plaque was significantly reduced in ApoE-KO/GCH-Tg mice compared with ApoE-KO controls. CONCLUSIONS: These findings indicate that BH4 availability is a critical determinant of eNOS regulation in atherosclerosis and is a rational therapeutic target to restore NO-mediated endothelial function and reduce disease progression.

Lipoprotein lipase activity and common gene variants in severely hypertriglyceridemic patients with and without diabetes.

OBJECTIVES: In severe type IV hypertriglyceridemia (triglyceride levels >10 g/l), it is yet unknown whether lipoprotein lipase (LPL) differs according to the presence or not of diabetes. METHODS: We compared LPL activity and the presence of four common variants in the LPL gene (Asp 9 Asn (exon 2), Gly 188 Glu (exon 5), Asn 291 Ser (exon 6) and Ser 447 Ter (exon 9)) in a group of 34 patients of whom 17 presented diabetes mellitus. RESULTS: Maximum triglyceride, cholesterol levels and distribution of apolipoprotein E phenotypes did not differ between the two subgroups. Mean post-heparin LPL activity was lower in non-diabetic compared to diabetic patients (9.74 vs. 12.98 micromol FFA/ml/h, p=0.033). Four patients were carrying a mutation in exon 9 (1 non-diabetic), 6 patients in exon 2 (4 non-diabetic) and 1 patient in the non-diabetic subgroup in exon 5. All mutations were at the heterozygous state. CONCLUSION: We found that LPL activity was lower in type IV hyperlipidemia in the absence of diabetes. Genetic defects in the LPL gene that could lead to this lower LPL tended to be more frequently observed in patients without diabetes. These data suggest that the pathomechanisms which contribute to severe type IV hyperlipidemia are different according to the presence or not of diabetes.