[Association between metabolic syndrome and hyperhomocysteinemia in an Algerian population]. / Association entre syndrome métabolique et hyperhomocystéinémie dans une population algérienne.

INTRODUCTION: Metabolic syndrome (MS) is a phenomenon of insulin resistance, a harbinger of serious cardiovascular events. The lifestyle of Algerian becoming increasingly occidental, SM becomes a major problem of public health in our country. Furthermore, hyperhomocysteinemia is also recognized as a cardiovascular risk factor. The objective of this study was to determine the prevalence of hyperhomocysteinemia in patients with SM in our people and to seek a possible relationship between these two risk factors. PATIENTS AND METHODS: We performed a prospective study that was focused on 62 hospitalized patients with SM, composed of 33 men and 29 women. Clinical data were collected and laboratory tests were also performed. RESULTS: The average age of our patients was 52±20 years; the average waist circumference was 103.4±10.1cm in men and 91.5±8.42cm in women. In this study, 53.2%, 54.4%, 25.8% and 51.6% of patients had respectively hypertension, hyperglycemia, low HDL-C levels and hypertriglyceridemia. The prevalence of hyperhomocysteinemia was 62.9% in our patients. This prevalence is correlated with age and the number of the SM components. Multivariate linear regression analysis showed no significant association between hyperhomocysteinemia and SM components studied separately. CONCLUSION: The prevalence of hyperhomocysteinemia in patients with an SM is important in our population. It increases with age and number of SM components, without a relationship between hyperhomocysteinemia and SM components studied separately.

Partial lipodystrophy: Clinical presentation and treatment.

Lipodystrophic syndromes are acquired or genetic rare diseases, characterized by a generalized or partial lack of adipose tissue leading to metabolic alterations linked to strong insulin resistance. They are probably underdiagnosed, especially for partial forms. They are characterized by a lack of adipose tissue or a lack of adipose development leading to metabolic disorders associated with often severe insulin resistance, hypertriglyceridemia and hepatic steatosis. In partial forms of lipodystrophy, these mechanisms are aggravated by excess visceral adipose tissue and/or subcutaneous adipose tissue in the upper part of the body. Diagnosis is based on clinical examination, pathological context and comorbidities, and on results of metabolic investigations and genetic analyses, which together determine management and genetic counseling. Early lifestyle and dietary measures focusing on regular physical activity, and balanced diet avoiding excess energy intake are crucial. They are accompanied by multidisciplinary follow-up adapted to each clinical form. When standard treatments have failed to control metabolic disorders, the orphan drug metreleptin, an analog of leptin, can be effective in certain forms of lipodystrophy syndromes.

Leptin replacement therapy in the management of lipodystrophy syndromes.

Lipodystrophy syndromes are rare diseases of genetic or acquired origin, characterized by quantitative and qualitative defects in adipose tissue. The metabolic consequences of lipodystrophy syndromes, such as insulin resistant diabetes, hypertriglyceridemia and hepatic steatosis, are frequently very difficult to treat, resulting in significant risks of acute and/or chronic complications and of decreased quality of life. The production of leptin by lipodystrophic adipose tissue is decreased, more severely in generalized forms of lipodystrophy, where adipose tissue is absent from almost all body fat depots, than in partial forms of the disease, where lipoatrophy affects only some parts of the body and can be associated with increased body fat in other anatomical regions. Several lines of evidence in preclinical and clinical models have shown that leptin replacement therapy could improve the metabolic complications of lipodystrophy syndromes. Metreleptin, a recombinant leptin analogue, was approved as an orphan drug to treat the metabolic complications of leptin deficiency in patients with generalized lipodystrophy in the USA or with either generalized or partial lipodystrophy in Japan and Europe. In this brief review, we will discuss the benefits and limitations of this therapy, and the new expectations arising from the recent development of a therapeutic monoclonal antibody able to activate the leptin receptor.

Primary disease of adipose tissue: When to think about and how to evaluate it in clinical practice?

Primary diseases of adipose tissue are rare disorders resulting from impairments in the physiological functions of adipose tissue (lipid stockage and endocrine function). It mainly refers to lipodystrophy syndromes with subcutaneous adipose tissue atrophy and/or altered body distribution of adipose tissue leading to insulin resistance, diabetes, hepatic steatosis, dyslipidemia, cardiovascular complications and polycystic ovary syndrome in women. Those syndromes are congenital or acquired, and lipoatrophy is partial or generalized. The diagnosis of lipodystrophy syndromes is often unrecognized, delayed and/or inaccurate, while it is of major importance to adapt investigations to search for specific comorbidities, in particular cardiovascular involvement, and set up multidisciplinary care, and in some cases specific treatment. Physicians have to recognize the clinical and biological elements allowing to establish the diagnosis. Lipodystrophic syndromes should be considered, notably, in patients with diabetes at a young age, with a normal or low BMI, negative pancreatic autoantibodies, presenting clinical signs of lipodystrophy and insulin resistance (acanthosis nigricans, hyperandrogenism, hepatic steatosis, high insulin doses). The association of diabetes and a family history of severe and/or early cardiovascular disease (coronary atherosclerosis, cardiomyopathy with rhythm and/or conduction disorders) may reveal Dunnigan syndrome, the most frequent form of familial lipodystrophy, due to LMNA pathogenic variants. Clinical assessment is primarily done through clinical examination: acanthosis nigricans, abnormal adipose tissue distribution, lipoatrophy, muscular hypertrophy, acromegaloid or Cushingoid features, lipomas, highly visible subcutaneous veins, may be revealing signs. The amount of circulating adipokines may reflect of adipose dysfunction with low leptinemia and adiponectinemia. Other biological metabolic parameters (hypertriglyceridemia, hyperinsulinemia, increased glycemia and hepatic enzymes) may also represent markers of insulin resistance. Quantification of total body fat by impedancemetry or dual-photon X-ray absorptiometry (DEXA) reveals decreased total body mass, in correlation with adipose tissue atrophy; metabolic magnetic resonance imaging can also quantify intraperitoneal and abdominal fat and the degree of hepatic steatosis. Histological analysis of adipose tissue showing structural abnormalities should be reserved for clinical research. Acquired lipodystrophic syndromes most often lead to similar clinical phenotype as congenital syndromes with generalized or partial lipoatrophy. The most frequent causes are old anti-HIV therapy or glucocorticoid treatments. Family history, history of treatments and clinical examination, including a careful physical examination, are keys for diagnosis.

Association Between Low-Grade Inflammation and Hyperuricemia in Adults With Metabolic Syndrome in Yucatán, México.

BACKGROUND: Hyperuricemia (HUA) is commonly diagnosed among individuals with obesity, type 2 diabetes (T2D) and metabolic syndrome (MetS). Nevertheless, the association of HUA in individuals with MetS among the Mexican population is mostly unexplored. Low-grade inflammation has been postulated to have a key role in the pathogenesis of MetS and has been linked to insulin resistance (IR). However, it is uncertain whether HUA is associated with elevated levels of interleukin-6 and -10 (IL-6 and IL-10, respectively) and high-sensitivity C-reactive protein (hs-CRP) in individuals with MetS. Our main goal was to assess the values of inflammatory markers in a Mexican adult population without and with MetS and HUA. METHODS: A cross-sectional study including 250 adults (77 men, 173 women) was carried out at a tertiary hospital in Mérida, Yucatán, México. Serum levels of IL-6, IL-10 and hs-CRP were evaluated by an enzyme-linked immunosorbent assay. The association between different conditions and inflammatory markers was analyzed using the point-biserial correlation (rpb) among patients. RESULTS: IR was positively associated with higher levels of serum uric acid (SUA). Serum levels of IL-6 and hs-CRP were found to be significantly associated with MetS, HUA and combined clinical conditions of MetS and HUA in women. Inter-relationships were stronger in women than in men. CONCLUSIONS: An association between levels of IL-6 and hs-CRP in women with MetS and HUA was found. Therefore, screening and monitoring of SUA and these markers in patients with MetS may be an alternative for treatment of these metabolic conditions.

Associations Between Erythrocyte Membrane Fatty Acid Compositions and Biomarkers of Vascular Health in Adults With Type 1 Diabetes With and Without Insulin Resistance: A Cross-Sectional Analysis.

OBJECTIVES: The aim of this study was to assess the relationship between specific erythrocyte fatty acid levels and vascular health in type 1 diabetes (T1D) with and without insulin resistance (IR). METHODS: We analyzed baseline pretreatment data in a subset of 23 patients with T1D from a previously published randomized controlled trial consisting of comprehensive erythrocyte-derived fatty acid profiles and a panel of inflammation-associated endothelial markers. Estimated glucose disposal rate was used to identify and categorize patients with IR. We utilized principal component analysis (PCA) to cluster vascular biomarkers to compute a single "vascular signal" and utilized univariate linear regression models to investigate the association with IR and fatty acid profiles. RESULTS: Subjects with IR displayed significantly higher levels of linoleic acid (p=0.001), lower levels of eicosapentaenoic acid (EPA) (p<0.001), lower levels of omega-3 polyunsaturated fatty acid (n-3PUFA) (p<0.006) and an increased omega-6 (n-6)PUFA:n-3PUFA ratio (p=0.001). IR was associated with significantly higher linoleic acid levels, total n-6PUFA and an increased ratio of n-6PUFA:n-3PUFA, and negatively associated with arachidonic acid and EPA levels, total saturated fatty acid and total n-3PUFA. The PCA-derived vascular biomarker cluster was positively associated with linoleic acid and n-6PUFA:n-3PUFA ratio, and inversely associated with EPA. CONCLUSIONS: Specific erythrocyte membrane fatty acid compositions are associated with impaired vascular health and IR in adults with T1D. These findings suggest that IR and risk of associated complications may be influenced by specific fatty acid profiles, and thus potentially modified by the selective targeting of dietary fatty acids.

Rosemary extract activates AMPK, inhibits mTOR and attenuates the high glucose and high insulin-induced muscle cell insulin resistance.

Impaired action of insulin in skeletal muscle, termed insulin resistance, leads to increased blood glucose levels resulting in compensatory increase in insulin levels. The elevated blood glucose and insulin levels exacerbate insulin resistance and contribute to the pathogenesis of type 2 diabetes mellitus. In previous studies we found attenuation of free fatty acid-induced muscle cell insulin resistance by rosemary extract (RE). In the present study we investigated the effects of RE on high glucose (HG) and high insulin (HI)-induced muscle cell insulin resistance. Exposure of L6 myotubes to 25 mmol/L glucose and 100 nmol/L insulin for 24 h, to mimic hyperglycemia and hyperinsulinemia, abolished the acute insulin-stimulated glucose uptake, increased the serine phosphorylation of IRS-1 and the phosphorylation/activation of mTOR and p70S6K. Treatment with RE significantly improved the insulin-stimulated glucose uptake and increased the acute insulin-stimulated tyrosine phosphorylation while reducing the HG+HI-induced serine phosphorylation of IRS-1 and phosphorylation of mTOR and p70S6K. Additionally, treatment with RE significantly increased the phosphorylation of AMPK, its downstream effector ACC and the plasma membrane GLUT4 levels. Our data indicate a potential of RE to counteract muscle cell insulin resistance and more studies are required to investigate its effectiveness in vivo. Novelty: RE phosphorylated muscle cell AMPK and ACC under both normal and HG+HI conditions. The HG+HI-induced serine phosphorylation of IRS-1 and activation of mTOR and p70S6K were attenuated by RE. RE restored the insulin-stimulated glucose uptake by enhancing GLUT4 glucose transporter translocation to plasma membrane.

Greater Nutritional Risk Scores in 2-Year-Old Children Exposed to Gestational Diabetes Mellitus In Utero and Their Relationship to Homeostasis Model Assessment for Insulin Resistance at Age 5 Years.

OBJECTIVES: Exposure to gestational diabetes mellitus (GDM) in utero may impact nutritional intake and lifestyle habits in early childhood. However, it is unclear whether nutritional status predicts greater risk for metabolic disturbances, such as insulin resistance (IR). The primary objectives were: 1) to determine parent-reported nutritional risk scores in 2-year-old children born to women with and without GDM and 2) to assess whether these scores predict IR in 5-year-old children. METHODS: Children exposed (n=34) and unexposed (n=46) to GDM were screened at 2 years of age using the Toddler version of the Nutrition Screening Tool for Every Preschooler (NutriSTEP). At a 5-year follow up, IR was assessed using the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). RESULTS: Total NutriSTEP scores ranged from 6 to 33, with higher scores indicating greater risk. After controlling for infant birthweight, sex of the child, child ethnicity, maternal age at time of pregnancy, breastfeeding status and maternal prepregnancy body mass index, average NutriSTEP scores were higher in children exposed to GDM compared with those unexposed (13.8±1.1 vs 11.2±1.1, p=0.03). NutriSTEP scores at 2 years emerged as a positive independent predictor of HOMA-IR at 5 years. For each unit increase in NutriSTEP score, suggesting greater nutritional risk, we saw a 0.48 (95% confidence interval, 0.17 to 0.80; p=0.003) increase in score on the HOMA-IR. CONCLUSIONS: Parent-reported nutritional risk is greater in GDM-exposed children, and these nutritional behaviours developed during the first years of life may predispose to metabolic disturbance in early childhood.

Substitution of parts of aerobic training by resistance training lowers fasting hyperglycemia in individuals with metabolic syndrome.

We sought to determine the effects of substituting parts of aerobic training (AT) by resistance training (RT) on metabolic syndrome (MetS) factors. MetS patients (aged 56 ± 7 years; body mass index 33 ± 5 kg·m-2 and 3.9 ± 0.8 MetS factors) were randomized to undergo 1 of the following isocaloric, 16-week long exercise programs: (i) cycling 4 bouts of 4-min at 90% of maximal heart rate (HRmax) followed by 3 sets of 12 repetitions of 3 lower limb free-weight exercises (high-intensity interval training (HIIT)+RT group; n = 33), (ii) cycling 5 bouts of 4 min at 90% of HRmax (HIIT+HIIT group; n = 33), or (iii) no exercise control group (n = 21). We measured the evolution of all 5 MetS components (z score), cardiorespiratory fitness (maximal oxygen uptake), leg strength and power (leg press 1-repetition maximum (1RM) and countermovement jump (CMJ)), fasting blood glucose (FG), fasting insulin, and insulin resistance (homeostasis model assessment 2). Both training groups improved maximal oxygen uptake similarly (170 ± 310 and 190 ± 210 mL O2·min-1; P < 0.001) and z score (-0.12 ± 0.29 and -0.12 ± 0.31 for HIIT+RT and HIIT+HIIT, respectively; P < 0.02). However, only HIIT+RT improved CMJ (P = 0.002) and leg press 1RM above the HIIT+HIIT group (21% vs 6%; P < 0.001). Furthermore, FG only decreased in the HIIT+RT group (5%; P = 0.026, time × group). Our findings suggest that substitution of part of HIIT by leg RT improves glucose control in MetS individuals. Novelty Most studies addressing the efficacy of endurance versus resistance training are not matched by energy expenditure. We found that substituting 20% of AT with RT reduces hyperglycemia in MetS individuals. Training recommendations to regain glycemic control in MetS individuals should include resistance training.

Prior ingestion of a ketone monoester supplement reduces postprandial glycemic responses in young healthy-weight individuals.

The main objective of this study was to determine whether acute ingestion of a ketone monoester (KME) supplement impacted mixed-meal tolerance test (MMTT) glucose area under the curve (AUC). Nineteen healthy young volunteers (10 males/9 females; age, 24.7 ± 4.9 years; body mass index, 22.7 ± 2.4 kg/m2) participated in a double-blind, placebo-controlled crossover study. Following overnight fasting (≥10 h), participants consumed 0.45 mL/kg of a KME supplement or taste-matched placebo followed by an MMTT 15 min later. Blood samples were collected every 15-30 min over 2.5 h. KME supplementation acutely raised ß-hydroxybutyrate AUC (590%, P < 0.0001, d = 2.4) and resulted in decreases in blood glucose AUC (-9.4%, P = 0.03, d = 0.56) and nonesterified fatty acid (NEFA) AUC (-27.3%, P = 0.023, d = 0.68) compared with placebo. No differences were found for plasma insulin AUC (P = 0.70) or gastric emptying estimated by co-ingested acetaminophen AUC (P = 0.96) between ketone and placebo. Overall, results indicate that KME supplementation attenuates postprandial glycemic and NEFA responses when taken 15 min prior to a mixed meal in young healthy individuals. Future studies are warranted to investigate whether KME supplementation may benefit individuals with impaired glycemic control. Novelty: Acute ketone monoester supplementation 15 min prior to a mixed meal decreased postprandial glucose and NEFA levels without significantly impacting postprandial insulin or estimates of gastric emptying. Glucose- and NEFA-lowering effects of ketone monoester supplementation are apparently not mediated by changes in insulin release or gastric emptying.

Does high dietary protein intake contribute to the increased risk of developing prediabetes and type 2 diabetes?

Insulin resistance is a complex metabolic disorder implicated in the development of many chronic diseases. While it is generally accepted that body mass loss should be the primary approach for the management of insulin resistance-related disorders in overweight and obese individuals, there is no consensus among researchers regarding optimal protein intake during dietary restriction. Recently, it has been suggested that increased plasma branched-chain amino acids concentrations are associated with the development of insulin resistance and type 2 diabetes. The exact mechanism by which excessive amino acid availability may contribute to insulin resistance has not been fully investigated. However, it has been hypothesised that mammalian target of rapamycin (mTOR) complex 1 hyperactivation in the presence of amino acid overload contributes to reduced insulin-stimulated glucose uptake because of insulin receptor substrate (IRS) degradation and reduced Akt-AS160 activity. In addition, the long-term effects of high-protein diets on insulin sensitivity during both weight-stable and weight-loss conditions require more research. This review focusses on the effects of high-protein diets on insulin sensitivity and discusses the potential mechanisms by which dietary amino acids can affect insulin signalling. Novelty: Excess amino acids may over-activate mTOR, resulting in desensitisation of IRS-1 and reduced insulin-mediated glucose uptake.

[Corticosteroid-induced diabetes: Novelties in pathophysiology and management]. / Diabète et corticoïdes : nouveautés et aspects pratiques.

Diabetes frequently occurs during corticosteroid treatment, sometimes necessitating urgent therapeutic management, with insulin for example. Corticosteroids induce insulin resistance in the liver, adipocytes and skeletal muscle, and have direct deleterious effects on insulin secretion. The development of insulin resistance during corticosteroid treatment, and the insufficient adaptation of insulin secretion, are key elements in the pathophysiology of corticosteroid-induced diabetes. The capacity of pancreatic ß-cells to increase insulin secretion in response to insulin resistance is partly genetically determined. A familial history of type 2 diabetes is, therefore, a major risk factor for diabetes development on corticosteroid treatment. Corticosteroid treatments are usually initiated at a fairly high dose, which is subsequently decreased to the lowest level sufficient to achieve disease control. Pharmacological management of diabetes is needed in patients with blood glucose levels exceeding 2.16 g/l (12 mmol/l) and insulin therapy can be started when blood glucose levels are higher than 3.6 g/l (20 mmol/l) with clinical symptoms of diabetes. Insulin can then be replaced with oral hypoglycemic compounds when both blood glucose levels and corticosteroid dose have decreased. Patient education is essential, particularly for the management of hypoglycemia when corticosteroids are withdrawn or their dose tapered.

Lipodystrophic syndromes: From diagnosis to treatment.

Lipodystrophic syndromes are acquired or genetic rare diseases, characterised by a generalised or partial lack of adipose tissue leading to metabolic alterations linked to strong insulin resistance. They encompass a variety of clinical entities due to primary defects in adipose differentiation, in the structure and/or regulation of the adipocyte lipid droplet, or due to immune-inflammatory aggressions, chromatin deregulations and/or mitochondrial dysfunctions affecting adipose tissue. Diagnosis is based on clinical examination, pathological context and comorbidities, and on results of metabolic investigations and genetic analyses, which together determine management and genetic counselling. Early lifestyle and dietary measures focusing on regular physical activity and avoiding excess energy intake are crucial. They are accompanied by multidisciplinary follow-up adapted to each clinical form. In case of hyperglycemia, antidiabetic medications, with metformin as a first-line therapy in adults, are used in addition to lifestyle and dietary modifications. When standard treatments have failed to control metabolic disorders, the orphan drug metreleptin, an analog of leptin, can be effective in certain forms of lipodystrophy syndrome. Metreleptin therapy indications, prescription and monitoring were recently defined in France, representing a major improvement in patient care.

Hypoglycaemic effect of catalpol in a mouse model of high-fat diet-induced prediabetes.

Type 2 diabetes mellitus is a major health problem and a societal burden. Individuals with prediabetes are at increased risk of type 2 diabetes mellitus. Catalpol, an iridoid glycoside, has been reported to exert a hypoglycaemic effect in db/db mice, but its effect on the progression of prediabetes is unclear. In this study, we established a mouse model of prediabetes and examined the hypoglycaemic effect, and the mechanism of any such effect, of catalpol. Catalpol (200 mg/(kg·day)) had no effect on glucose tolerance or the serum lipid level in a mouse model of impaired glucose tolerance-stage prediabetes. However, catalpol (200 mg/(kg·day)) increased insulin sensitivity and decreased the fasting glucose level in a mouse model of impaired fasting glucose/impaired glucose tolerance-stage prediabetes. Moreover, catalpol increased the mitochondrial membrane potential (1.52-fold) and adenosine triphosphate content (1.87-fold) in skeletal muscle and improved skeletal muscle function. These effects were mediated by activation of the insulin receptor-1/glucose transporter type 4 (IRS-1/GLUT4) signalling pathway in skeletal muscle. Our findings will facilitate the development of a novel approach to suppressing the progression of diabetes at an early stage. Novelty Catalpol prevents the progression of prediabetes in a mouse model of prediabetes. Catalpol improves insulin sensitivity in skeletal muscle. The effects of catalpol are mediated by activation of the IRS-1/GLUT4 signalling pathway.

Weight loss efficacy of alternate day fasting versus daily calorie restriction in subjects with subclinical hypothyroidism: a secondary analysis.

This study compared the weight loss efficacy of alternate-day fasting (ADF) versus daily calorie restriction (CR) in adults with subclinical hypothyroidism. After 6 months, body weight decreased (P < 0.001) similarly by ADF (-7% ± 1%) and CR (-8% ± 2%). Insulin resistance decreased (P < 0.05) more by ADF versus CR. Free thyroxin and thyroid-stimulating hormone remained unchanged. Thus, ADF and CR produce similar weight loss in this population, without affecting thyroid hormone levels. Novelty Intermittent fasting and daily restriction produce similar reductions in body weight in subjects with subclinical hypothyroidism.

The effects of chromium and vitamin D3 co-supplementation on insulin resistance and tumor necrosis factor-alpha in type 2 diabetes: a randomized placebo-controlled trial.

The current study was conducted to assess the effects of simultaneous usage with vitamin D3 and chromium picolinate (CrPic) supplementations on homeostasis model assessment of insulin resistance (HOMA-IR), fasting blood glucose (FBS), hemoglobin A1c (HbA1c), tumor necrosis factor-α (TNF-α), and lipid profile in type 2 diabetes mellitus (T2DM). Ninety-two patients with T2DM were randomly allocated to the following 4 groups for 4 months: (I) placebo of vitamin D3 (n = 23); (II) vitamin D3 supplement at a dose of 50 000 IU/week (n = 23); (III) CrPic supplement at a dose of 500 µg/day (n = 23); and (IV) both vitamin D3 at a dose of 50 000 IU/week and CrPic at a dose of 500 µg/day (n = 23). HOMA-IR levels increased significantly in groups I and II after the intervention. However, this increase in group I was significantly higher than that in group II after the treatment. HOMA-IR levels were controlled in groups III and IV during the intervention. TNF-α decreased significantly in groups II, III, and IV after the intervention. FBS, HbA1c, and lipid profile did not change significantly in total groups after the intervention. It seems that chromium and vitamin D3 co-supplementation are probably effective in controlling HOMA-IR by decreasing TNF-α in T2DM. Novelty Chromium alone and/or in simultaneous pretreatment with vitamin D3 is more effective than vitamin D3 in controlling HOMA-IR in T2DM. Chromium and vitamin D3 alone and/or in simultaneous pretreatment decrease TNF-α in T2DM.

Rare causes of hypoglycemia in adults.

Hypoglycemia is defined by a low blood glucose level associated to clinical symptoms. Hypoglycemia may be related to treatment of diabetes, but also to drugs, alcohol, critical illness, cortisol insufficiency including hypopituitarism, insulinoma, bariatric or gastric surgery, pancreas transplantation or glucagon deficiency, or may be surreptitious. Some hypoglycemic episodes remain unexplained, and genetic, paraneoplastic and immune causes should be considered. Genetic causes may be related to endogenous hyperinsulinism and to inborn errors of metabolism (IEM). Endogenous hyperinsulinism is related to monogenic congenital hyperinsulinism, and especially to mutations of the glucokinase-activating gene or of insulin receptors, both characterised by postprandial hypoglycemia with major hyperinsulinism. In adulthood, IEM-related hypoglycemia can persist in a previously diagnosed childhood disease or may be a presenting sign. It is suggested by systemic involvement (rhabdomyolysis after fasting or exercising, heart disease, hepatomegaly), sometimes associated to a family history of hypoglycemia. The timing of hypoglycemic episodes with respect to the last meal also helps to orientate diagnosis. Fasting hypoglycemia may be related to type 0, I or III glycogen synthesis disorder, fatty acid oxidation or gluconeogenesis disorder. Postprandial hypoglycemia may be related to inherited fructose intolerance. Exercise-induced hyperinsulinism is mainly related to activating mutation of the SLC16A1 gene. Besides exceptional ectopic insulin secretion, paraneoplastic causes involve NICTH (Non-Islet-Cell Tumour Hypoglycemia), caused by Big-IGF2 secretion by a large tumour, with low blood levels of insulin, C-peptide and IGF1. Autoimmune causes involve antibodies against insulin (HIRATA syndrome), especially in case of Graves' disease, or against the insulin receptor. Medical history, timing, and insulin level orientate the diagnosis.

Maternal dyslipidemia during pregnancy and lactation increases blood pressure and disrupts cardiorespiratory and glucose hemostasis in female rat offspring.

Hypertension and metabolic disorders evidenced in adults who have been exposed to nutritional insults during early life may be sex-dependent. We evaluated if blood pressure (BP), cardiorespiratory control, and metabolic parameters are affected in female offspring (FO) from dams fed a dyslipidaemic diet during pregnancy and lactation. FO was obtained from dams who received control (CTL) or dyslipidaemic diets during pregnancy and lactation. The effects of a maternal dyslipidaemic diet on BP, cardiorespiratory control, and biochemical parameters were assessed at 30 and 90 days of age. The experimental protocol based on a dyslipidaemic diet intervention was effective in developing maternal dyslipidemia. At 30 days of age, the FO from dyslipidaemic dams displayed disordered respiratory pattern, enhanced ventilatory response to hypercapnia (P < 0.05), and increased serum levels of total cholesterol and triglycerides (P < 0.05) when compared with CTL female offspring. At 90 days of age, FO from dyslipidaemic dams had augmented BP (P < 0.05), exacerbated cardiorespiratory responses to hypercapnia (P < 0.05), enhanced pressor responses to peripheral chemoreflex activation (P < 0.05), impaired baroreflex (P < 0.05), and larger delta variations in arterial pressure after ganglionic blockade (P < 0.05). Furthermore, during oral glucose and insulin tolerance tests, FO from dyslipidaemic dams exhibited altered glucose tolerance and insulin sensitivity (P < 0.05) when compared with FO from CTL dams. Altered breathing linked to enhanced central and peripheral chemosensitivity, impaired baroreflex, and augmented sympathetic tone may be predisposing factors for increased BP and metabolic disorders in female offspring from dyslipidaemic dams.

Effect of exercise intensity on circulating hepatokine concentrations in healthy men.

Fibroblast growth factor 21 (FGF21), follistatin and leukocyte cell-derived chemotaxin 2 (LECT2) are novel hepatokines that are modulated by metabolic stresses. This study investigated whether exercise intensity modulates the hepatokine response to acute exercise. Ten young, healthy men undertook three 8-h experimental trials: moderate-intensity exercise (MOD; 55% peak oxygen uptake), high-intensity exercise (HIGH; 75% peak oxygen uptake), and control (CON; rest), in a randomised, counterbalanced order. Exercise trials commenced with a treadmill run of varied duration to match gross exercise energy expenditure between trials (MOD vs HIGH; 2475 ± 70 vs 2488 ± 58 kJ). Circulating FGF21, follistatin, LECT2, glucagon, insulin, glucose and nonesterified fatty acids (NEFA) were measured before exercise and at 0, 1, 2, 4, and 7 h postexercise. Plasma FGF21 concentrations were increased up to 4 h postexercise compared with CON (P ≤ 0.022) with greater increases observed at 1, 2, and 4 h postexercise during HIGH versus MOD (P ≤ 0.025). Irrespective of intensity (P ≥ 0.606), plasma follistatin concentrations were elevated at 4 and 7 h postexercise (P ≤ 0.053). Plasma LECT2 concentrations were increased immediately postexercise (P ≤ 0.046) but were not significant after correcting for plasma volume shifts. Plasma glucagon (1 h; P = 0.032) and NEFA (4 and 7 h; P ≤ 0.029) responses to exercise were accentuated in HIGH versus MOD. These findings demonstrate that acute exercise augments circulating FGF21 and follistatin. Exercise-induced changes in FGF21 are intensity-dependent and may support the greater metabolic benefit of high-intensity exercise.

Copeptin and Estimated Insulin Sensitivity in Adults With and Without Type 1 Diabetes: The CACTI Study.

OBJECTIVES: Copeptin, a surrogate marker for vasopressin, is elevated in participants with insulin resistance (IR) and type 2 diabetes. Whereas adults with type 1 diabetes also demonstrate elevated copeptin concentrations and IR compared to controls without diabetes, the relationship between copeptin and IR in type 1 diabetes is unclear. METHODS: Participants with (n=209) and without (n=244) type 1 diabetes in the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study were assessed for serum copeptin, vitals, estimated glomerular filtration rate, urinary albumin-to-creatinine ratio, glycated hemoglobin and lipid panels. Estimated insulin sensitivity (eIS) was calculated by validated equations in participants with and without type 1 diabetes. The relationships among copeptin, IR, waist circumference (WC) and body mass index (BMI) were examined with unadjusted and adjusted linear regression models. RESULTS: Copeptin was correlated with eIS (R=-0.17, R2=0.029), WC (R=0.16, R2=0.026) and BMI (R=0.22, R2=0.048) for type 1 diabetes and with eIS (R=-0.37, R2=0.14), WC (R=0.40, R2=0.16) and BMI (R=0.25, R2=0.063) in non-type 1 diabetes. In multivariable analysis, copeptin correlated with total cholesterol (beta±SE: -0.12±0.04, p=0.008) and low-density lipoprotein (beta±SE: -0.11±0.04, p=0.01) in type 1 diabetes. In non-type 1 diabetes, copeptin was associated with WC (beta±SE: 0.14±0.04, p=0.0024), BMI (beta±SE: 0.13±0.04, p=0.007) and eIS (beta±SE: -0.14±0.04, p=0.0013). CONCLUSIONS: Copeptin does not correlate with markers of IR in type 1 diabetes but strongly correlates in non-type 1 diabetes. Thus, elevated vasopressin activity and IR appear to be independent risk factors for vascular complications in type 1 diabetes.