High Prevalence of Insulin Resistance in Asymptomatic Patients with Acute Intermittent Porphyria and Liver-Targeted Insulin as a Novel Therapeutic Approach

Acute porphyria attacks are associated with the strong up-regulation of hepatic heme synthesis and over-production of neurotoxic heme precursors. First-line therapy is based on carbohydrate loading. However, altered glucose homeostasis could affect its efficacy. Our first aim was to investigate the prevalence of insulin resistance (IR) in an observational case-control study including 44 Spanish patients with acute intermittent porphyria (AIP) and 55 age-, gender- and BMI-matched control volunteers. Eight patients (18.2%) and one control (2.3%, p = 0.01) showed a high HOMA-IR index (cut-off ≥ 3.4). Patients with IR and hyperinsulinemia showed clinically stable disease. Thus, the second aim was to evaluate the effect of the co-administration of glucose and a fast-acting or new liver-targeted insulin (the fusion protein of insulin and apolipoprotein A-I, Ins-ApoAI) in AIP mice. The combination of glucose and the Ins-ApoAI promoted partial but sustained protection against hepatic heme synthesis up-regulation compared with glucose alone or co-injected with fast-acting insulin. In a prevention study, Ins-ApoAI improved symptoms associated with a phenobarbital-induced attack but maintained high porphyrin precursor excretion, probably due to the induction of hepatic mitochondrial biogenesis mediated by apolipoprotein A-I. In conclusion, a high prevalence of IR and hyperinsulinemia was observed in patients with AIP. The experimental data provide proof-of-concept for liver-targeted insulin as a way of enhancing glucose therapy for AIP.

Download Full-text

Features of Thrombi and Diagnostic Accuracy of Impedance Plethysmography in Symptomatic and Asymptomatic Deep Vein Thrombosis

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649563 ◽

1993 ◽

Vol 70 (02) ◽

pp. 266-269 ◽

Cited By ~ 21

Author(s):

Giancarlo Agnelli ◽

Benilde Cosmi ◽

Stefano Radicchia ◽

Franca Veschi ◽

Enrico Boschetti ◽

...

Keyword(s):

Deep Vein Thrombosis ◽

Diagnostic Accuracy ◽

High Sensitivity ◽

Impedance Plethysmography ◽

Surveillance Programme ◽

Vein Thrombosis ◽

Asymptomatic Patients ◽

High Prevalence ◽

The Mean ◽

Deep Vein

SummaryImpedance plethysmography (IPG) has high sensitivity and specificity in patients with symptomatic deep vein thrombosis (DVT) while it fails to detect asymptomatic DVT. The aim of this study was to determine whether the features of thrombi such as location, size and occlusiveness could explain the different accuracy of IPG in symptomatic and asymptomatic DVT patients. One-hundred and seventeen consecutive outpatients with a clinical suspicion of DVT and 246 consecutive patients undergoing hip surgery were admitted to the study. In symptomatic patients IPG was performed on the day of referral, followed by venography, while in asymptomatic patients IPG was performed as a surveillance programme, followed by bilateral venography.A venography proved DVT was observed in 37% of the symptomatic patients and 34% of the asymptomatic limbs. A significantly higher proportion of proximal DVTs was found in symptomatic patients than in asymptomatic patients (78% vs 46%; p = 0.001). The mean Marder score, taken as an index of thrombus size, was significantly higher in symptomatic patients than in asymptomatic patients (19.0 vs 9.6; p = 0.0001). A significantly higher proportion of occlusive DVTs was observed in symptomatic than in asymptomatic patients (69% vs 36%; p = 0.001).We conclude that the unsatisfactory diagnostic accuracy of IPG in asymptomatic DVT is due to the high prevalence of distal, small and non occlusive thrombi. Such thrombi are unlikely to cause a critical obstruction of the venous outflow and therefore to produce a positive IPG.

Download Full-text

Metabolic Syndrome and Prediabetes Fail to Detect a High Prevalence of Early Insulin Resistance—The PREMIER Study

Diabetes ◽

10.2337/db18-1534-p ◽

2018 ◽

Vol 67 (Supplement 1) ◽

pp. 1534-P

Author(s):

DAVID P. CISTOLA ◽

ALOK K. DWIVEDI ◽

JAMY D. ARD

Keyword(s):

Insulin Resistance ◽

Metabolic Syndrome ◽

High Prevalence

Download Full-text

Insulin Resistance and Glucose Homeostasis in Peritoneal Dialysis

Peritoneal Dialysis International ◽

10.1177/089686080902902s28 ◽

2009 ◽

Vol 29 (2_suppl) ◽

pp. 145-148 ◽

Cited By ~ 38

Author(s):

Paulo Cezar Fortes ◽

Thyago Proença de Moraes ◽

Jamille Godoy Mendes ◽

Andrea E. Stinghen ◽

Silvia Carreira Ribeiro ◽

...

Keyword(s):

Risk Factors ◽

Insulin Resistance ◽

Peritoneal Dialysis ◽

Metabolic Disorders ◽

Patient Survival ◽

Metabolic Abnormalities ◽

Dialysis Fluid ◽

Altered Glucose ◽

Insulin Homeostasis ◽

Therapeutic Measures

Cardiovascular disease (CVD) is the main cause of death in peritoneal dialysis (PD) patients, a situation that can be explained by a combination of traditional and nontraditional risk factors for CVD in these patients. Glucose and insulin homeostasis are altered in chronic kidney disease (CKD) patients even in the early stages of CKD, leading to insulin resistance by various pathways. Several factors have been implicated in the pathogenesis of insulin resistance, including anemia, dyslipidemia, uremia, malnutrition, excess of parathyroid hormone, vitamin D deficiency, metabolic acidosis, and increase in plasma free fatty acids and proinflammatory cytokines. Insulin resistance and dyslipidemia are observed and increase with the progression of CKD, playing an important role in the pathogenesis of hypertension and atherosclerosis. Particularly in PD patients, exposure to glucose from dialysis fluid accentuates the foregoing metabolic abnormalities. In conclusion, insulin resistance and altered glucose metabolism are frequently observed in CKD, and although dialysis partly corrects those disturbances, the use of glucose PD solutions intensifies a series of harmful metabolic consequences. New therapeutic measures aimed at reducing metabolic disorders are urgently needed and perhaps will improve PD patient survival.

Download Full-text

Metabolic syndrome and insulin resistance in pre-pubertal children with psoriasis

European Journal of Pediatrics ◽

10.1007/s00431-020-03924-w ◽

2021 ◽

Author(s):

Francesca Caroppo ◽

Alfonso Galderisi ◽

Laura Ventura ◽

Anna Belloni Fortina

Keyword(s):

Metabolic Disease ◽

Insulin Resistance ◽

Metabolic Syndrome ◽

Model Assessment ◽

Limited Data ◽

Single Center ◽

Increased Risk ◽

High Prevalence ◽

Homeostatic Model Assessment ◽

Homeostatic Model

AbstractPsoriasis in adults is associated with an increased risk of metabolic disease. Various cardiometabolic comorbidities have been reported in childhood psoriasis, but only a few studies have analyzed the prevalence of metabolic syndrome. We performed a single-center prospective study investigating the prevalence of metabolic syndrome and insulin resistance in children with psoriasis. The prevalence of metabolic syndrome was evaluated in 60 pre-pubertal children with psoriasis (age: 3–10 years), accordingly to recently established criteria for the diagnosis of metabolic syndrome in children. Insulin resistance was considered altered when the homeostatic model assessment (HOMA-IR) for insulin resistance was ≥ 90th sex- and age-specific percentile and HOMA 2-IR was > 1.8. Eighteen (30%) children with psoriasis were found to have metabolic syndrome. Sixteen (27%) children were found to have insulin resistance.Conclusion: Our data underline the importance of assessing metabolic syndrome not only in adults and adolescents but also in young children with psoriasis. What is Known:• Psoriasis in adults is strongly associated with metabolic disease and insulin resistance.• Very limited data are available on the prevalence of metabolic syndrome and insulin resistance in pre-pubertal children with psoriasis. What is New:• This study reports that in pre-pubertal children with psoriasis, there is a high prevalence of metabolic syndrome and insulin resistance.• In children with psoriasis metabolic syndrome risk factors should be assessed.

Download Full-text

Incidence of diabetes in South Asian young adults compared to Pima Indians

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2020-001988 ◽

2021 ◽

Vol 9 (1) ◽

pp. e001988

Author(s):

K M Venkat Narayan ◽

Dimple Kondal ◽

Sayuko Kobes ◽

Lisa R Staimez ◽

Deepa Mohan ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Secretion ◽

South Asians ◽

Diabetes Incidence ◽

Pima Indians ◽

Men And Women ◽

High Prevalence ◽

History Of ◽

Indian Men ◽

Design And Methods

IntroductionSouth Asians (SA) and Pima Indians have high prevalence of diabetes but differ markedly in body size. We hypothesize that young SA will have higher diabetes incidence than Pima Indians at comparable body mass index (BMI) levels.Research design and methodsWe used prospective cohort data to estimate age-specific, sex, and BMI-specific diabetes incidence in SA aged 20–44 years living in India and Pakistan from the Center for Cardiometabolic Risk Reduction in South Asia Study (n=6676), and compared with Pima Indians, from Pima Indian Study (n=1852).ResultsAt baseline, SA were considerably less obese than Pima Indians (BMI (kg/m2): 24.4 vs 33.8; waist circumference (cm): 82.5 vs 107.0). Age-standardized diabetes incidence (cases/1000 person-years, 95% CI) was lower in SA than in Pima Indians (men: 14.2, 12.2–16.2 vs 37.3, 31.8–42.8; women: 14.8, 13.0–16.5 vs 46.1, 41.2–51.1). Risk of incident diabetes among 20–24-year-old Pima men and women was six times (relative risk (RR), 95% CI: 6.04, 3.30 to 12.0) and seven times (RR, 95% CI: 7.64, 3.73 to 18.2) higher as compared with SA men and women, respectively. In those with BMI <25 kg/m2, however, the risk of diabetes was over five times in SA men than in Pima Indian men. Among those with BMI ≥30 kg/m2, diabetes incidence in SA men was nearly as high as in Pima men. SA and Pima Indians had similar magnitude of association between age, sex, BMI, and insulin secretion with diabetes. The effect of family history was larger in SA, whereas that of insulin resistance was larger in Pima IndiansConclusionsIn the background of relatively low insulin resistance, higher diabetes incidence in SA is driven by poor insulin secretion in SA men. The findings call for research to improve insulin secretion in early natural history of diabetes.

Download Full-text

Ketohexokinase knockout mice, a model for essential fructosuria, exhibit altered fructose metabolism and are protected from diet-induced metabolic defects

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00027.2018 ◽

2018 ◽

Vol 315 (3) ◽

pp. E386-E393 ◽

Cited By ~ 15

Author(s):

Corin O. Miller ◽

Xiaodong Yang ◽

Ku Lu ◽

Jin Cao ◽

Kithsiri Herath ◽

...

Keyword(s):

Insulin Resistance ◽

De Novo ◽

Liver Weight ◽

De Novo Lipogenesis ◽

Chow Diet ◽

Fructose Metabolism ◽

Metabolic Defects ◽

Glucose And Lipid Metabolism ◽

High Fructose ◽

Altered Glucose

Fructose consumption in humans and animals has been linked to enhanced de novo lipogenesis, dyslipidemia, and insulin resistance. Hereditary deficiency of ketohexokinase (KHK), the first enzymatic step in fructose metabolism, leads to essential fructosuria in humans, characterized by elevated levels of blood and urinary fructose following fructose ingestion but is otherwise clinically benign. To address whether KHK deficiency is associated with altered glucose and lipid metabolism, a Khk knockout (KO) mouse line was generated and characterized. NMR spectroscopic analysis of plasma following ingestion of [6-13C] fructose revealed striking differences in biomarkers of fructose metabolism. Significantly elevated urine and plasma 13C-fructose levels were observed in Khk KO vs. wild-type (WT) control mice, as was reduced conversion of 13C-fructose into plasma 13C-glucose and 13C-lactate. In addition, the observation of significant levels of fructose-6-phosphate in skeletal muscle tissue of Khk KO, but not WT, mice suggests a potential mechanism, whereby fructose is metabolized via muscle hexokinase in the absence of KHK. Khk KO mice on a standard chow diet displayed no metabolic abnormalities with respect to ambient glucose, glucose tolerance, body weight, food intake, and circulating trigylcerides, β-hydroxybutyrate, and lactate. When placed on a high-fat and high-fructose (HF/HFruc) diet, Khk KO mice had markedly reduced liver weight, triglyceride levels, and insulin levels. Together, these results suggest that Khk KO mice may serve as a good model for essential fructosuria in humans and that inhibition of KHK offers the potential to protect from diet-induced hepatic steatosis and insulin resistance.

Download Full-text

HIV Drug Resistance Mutations in Patients with HIV and HIV-TB Coinfection After Failure of First-Line Therapy: A Prevalence Study in a Resource-Limited Setting

Journal of the International Association of Providers of AIDS Care (JIAPAC) ◽

10.1177/2325958219849061 ◽

2019 ◽

Vol 18 ◽

pp. 232595821984906

Author(s):

Nawaid Hussain Khan ◽

Mikashmi Kohli ◽

Kartik Gupta ◽

Bimal Kumar Das ◽

Ravindra Mohan Pandey ◽

...

Keyword(s):

Reverse Transcriptase ◽

Drug Resistant ◽

Resistance Mutations ◽

Reverse Transcriptase Inhibitors ◽

Nucleoside Reverse Transcriptase Inhibitors ◽

First Line Therapy ◽

Resource Limited ◽

High Prevalence ◽

Hiv 1 ◽

Limited Setting

Introduction: The present study aimed to report the prevalent HIV-1 drug-resistant mutations in patients with HIV-1 alone and tuberculosis (TB) coinfection alone to improve our understanding of the mutation patterns and aid treatment decisions. Methods: Patients with HIV-1 and HIV-TB on treatment for more than 1 year with suspected failure were recruited. Sequencing of protease and two-thirds of the region of reverse transcriptase gene was done for drug-resistant mutations. Results: In the HIV-TB group (n = 25), 88%, 92%, and 12% had mutations to nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs), respectively. In the HIV-alone group (n = 25), 84%, 100%, and 4% had mutations to NRTIs, NNRTIs, and PIs, respectively. M184V, M41L, D67N, G190A, A98G, and K103N were the most common mutations seen. Conclusion: There is a high prevalence of drug-resistant mutations in HIV and HIV-TB coinfected patients.

Download Full-text

The Carnivore Connection Hypothesis: Revisited

Journal of Obesity ◽

10.1155/2012/258624 ◽

2012 ◽

Vol 2012 ◽

pp. 1-9 ◽

Cited By ~ 8

Author(s):

Jennie C. Brand-Miller ◽

Hayley J. Griffin ◽

Stephen Colagiuri

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Selection Pressure ◽

Glycemic Load ◽

Dietary Carbohydrate ◽

Recent Exposure ◽

Agricultural Revolution ◽

High Prevalence ◽

Selection Of

The “Carnivore Connection” hypothesizes that, during human evolution, a scarcity of dietary carbohydrate in diets with low plant : animal subsistence ratios led to insulin resistance providing a survival and reproductive advantage with selection of genes for insulin resistance. The selection pressure was relaxed at the beginning of the Agricultural Revolution when large quantities of cereals first entered human diets. The “Carnivore Connection” explains the high prevalence of intrinsic insulin resistance and type 2 diabetes in populations that transition rapidly from traditional diets with a low-glycemic load, to high-carbohydrate, high-glycemic index diets that characterize modern diets. Selection pressure has been relaxed longest in European populations, explaining a lower prevalence of insulin resistance and type 2 diabetes, despite recent exposure to famine and food scarcity. Increasing obesity and habitual consumption of high-glycemic-load diets worsens insulin resistance and increases the risk of type 2 diabetes in all populations.

Download Full-text