Ketone Bodies in Diabetes Mellitus: Friend or Foe?

In glucose-deprived conditions, ketone bodies are produced by the liver mitochondria, through the catabolism of fatty acids, and are used peripherally, as an alternative energy source. Ketones are produced in the body under normal conditions, including during pregnancy and the neonatal period, when following a ketogenic diet (KD), fasting, or exercising. Additionally, ketone synthesis is also augmented under pathological conditions, including cases of diabetic ketoacidosis (DKA), alcoholism, and several metabolic disorders. Nonetheless, diet is the main regulator of total body ketone concentrations. The KDs are mimicking the fasting state, altering the default metabolism towards the use of ketones as the primary fuel source. Recently, KD has gained recognition as a medical nutrition therapy for a plethora of metabolic conditions, including obesity and diabetes mellitus (DM). The present review aims to discuss the role of ketones, KDs, ketonemia, and ketonuria in DM, presenting all the available new evidence in a comprehensive manner.

Impaired vagal adaptation to an exercise task in women with gestational diabetes mellitus versus women with uncomplicated pregnancies.

PURPOSE: Gestational diabetes mellitus (GDM) is associated with an increased risk for maternal and fetal complications. Patients with GDM have an increased cardiovascular risk in later life. The aim of this study was to investigate cardiac autonomic nervous system (ANS) function at rest and during exercise in women with GDM vs. women with uncomplicated pregnancies. METHODS: Thirty-six normotensive pregnant women (21 with GDM and 15 age- and parity-matched women with an uncomplicated pregnancy) were enrolled in this case-control study. Continuous beat-by-beat blood pressure (BP) measurements were recorded during rest, intermittent handgrip exercise, and recovery (via photoplethysmography, Finapres®). Heart rate variability (HRV) (Kubios®) was used for the assessment of autonomic nervous system function. RESULTS: The groups were similar in age, gestational week, and handgrip strength. At rest, no differences in HRV indices [root mean square of successive differences (RMSSD), standard deviation Poincaré plot 1, and 2 (SD1, SD2), SD2/SD1 ratio] were detected between women with GDM and women with an uncomplicated pregnancy. However, during exercise, a different pattern in the HRV responses was detected: in the control group, RMSSD and SD1 (indices of parasympathetic function) significantly decreased (p < 0.001) during handgrip exercise and returned to baseline during recovery. In contrast, in GDM, the above HRV indices remained unaltered throughout the protocol. CONCLUSION: Normotensive women with GDM present impaired parasympathetic system ability to adapt to an exercise stimulus, as suggested by the blunted sensitivity in RMSSD and SD1. This finding suggests early alterations in ANS may exist in women with GDM, even when no differences are detected in resting conditions.

Pregnancy and post-partum muscle and cerebral oxygenation during intermittent exercise in gestational diabetes: A pilot study.

OBJECTIVE: This pilot, prospective, observational, cohort study aimed to examine, for the first time, the in vivo alterations in the oxygenation of the forearm skeletal muscles and the prefrontal lobes during intermittent exercise in women diagnosed with gestational diabetes mellitus (GDM), during and after pregnancy. STUDY DESIGN: Nine pregnant women, diagnosed with GDM, performed a 3-min intermittent handgrip exercise protocol (at 35% of Maximal Voluntary Contraction) during pregnancy (mean 27th gestational week) and following labor (mean 71 weeks). During the protocol, muscle and cerebral oxygenation were assessed with near-infrared spectroscopy. Resting vascular parameters [carotid intima-media thickness (cIMT) and hemodynamic parameters (using rheocardiography)], and hematological/biochemical parameters during pregnancy and after delivery have been compared. RESULTS: Although changes were observed in certain hematological parameters (p< 0.05), cIMT and hemodynamic parameters were not altered post-partum. In addition, both muscle and cerebral oxygenation parameters during handgrip were not significantly altered post-partum. CONCLUSIONS: Despite significant changes in specific hematological parameters in women with GDM, impairments in muscle and cerebral oxygenation during exercise remained at one year after labor. These results indicate that alterations in vascular parameters and muscle/cerebral oxygenation associated with GDM do not entirely reverse post-partum. Future studies are needed to examine which interventions will lead to improvements in microvascular parameters and prevent type 2 diabetes.

Gestational diabetes mellitus: Multi-disciplinary treatment approaches.

Gestational diabetes mellitus (GDM) is the most common metabolic disease of pregnancy, associated with several perinatal complications. Adequate glycemic control has been proved to decrease risk of GDM-related complications. Several studies have shown the beneficial effect of exercise and medical nutrition treatment on glycemic and weight control in GDM-affected women. Moreover, pharmacological agents, such as insulin and specific oral anti-diabetic agents can be prescribed safely during pregnancy, decreasing maternal blood glucose and, thus, perinatal adverse outcomes. Multi-disciplinary treatment approaches that include both lifestyle modifications (medical nutritional therapy and daily physical exercise) and pharmacological treatment, in cases of failure of the former, constitute the most effective approach. Insulin is the gold standard pharmacological agent for GDM treatment. Metformin and glyburide are two oral anti-diabetic agents that could serve as alternative, although not equal in terms of effectiveness and safety, treatment for GDM. As studies on short-term safety of metformin are reassuring, in some countries it is considered as first-line treatment for GDM management. More studies are needed to investigate the long-term effects on offspring. As safety issues have been raised on the use of glyburide during pregnancy, it must be used only when benefits surpass possible risks.

Blunted cerebral oxygenation during exercise in women with gestational diabetes mellitus: associations with macrovascular function and cardiovascular risk factors.

AIM/HYPOTHESIS: This cross-sectional, observational, controlled study examined cerebral oxygenation during exercise, an index of cerebrovascular function and cortical activation, in pregnancies complicated by gestational diabetes mellitus (GDM) and unaffected pregnancies. The association of cerebral oxygenation with macrovascular and cardiovascular function indices was also evaluated. MATERIAL AND METHODS: Vascular function and structure [aortic pulse-wave-velocity (PWV), augmentation index (AI), carotid intima-media thickness], as well as 24-hour ambulatory blood pressure (BP) were assessed in women with GDM (n = 21) and uncomplicated pregnancies (n = 16), at 26-32 gestational weeks. Changes in cerebral oxygenation [oxy- (O2Hb), deoxy- (HHb) and total- (tHb) hemoglobin] were continuously recorded by near-infrared spectroscopy (NIRS) during intermittent handgrip exercise. Beat-by-beat BP and systemic vascular resistance (SVR) were assessed (Finapres). RESULTS: Women with GDM had higher AI than controls. During exercise, women with GDM maintained a smaller force (p < 0.05), despite similar ratings of perceived exertion. Despite similar increases in BP during exercise, the GDM group exhibited a lower average and total (AUC) increase in cerebral-O2Hb than controls (p < 0.05). In addition, GDM exhibited a slower rate of cerebral-O2Hb decay during recovery (p < 0.05). SVR was lower in GDM compared to controls throughout the protocol (p < 0.01). Cerebral oxygenation indices were correlated with PWV and AI (p < 0.05). CONCLUSIONS: This study provided novel evidence for blunted cerebral oxygenation during exercise in women with GDM compared to uncomplicated pregnancies, suggesting a link between reduced cerebrovascular function with exercise intolerance in GDM. Cerebral oxygenation during physical stress was correlated with macrovascular function and cardiovascular risk factors. More studies are needed to examine whether this impaired cerebral oxygenation reflects early cerebrovascular disease.

Impairments in microvascular function and skeletal muscle oxygenation in women with gestational diabetes mellitus: links to cardiovascular disease risk factors.

AIMS/HYPOTHESIS: Gestational diabetes mellitus (GDM) is a risk factor for the development of endothelial dysfunction and cardiovascular disease. However, in vivo microvascular endothelial function in GDM has not been investigated. This study aimed to examine, using near-infrared spectroscopy (NIRS), whether: (1) there are differences in microvascular reactivity and skeletal muscle oxygen consumption (m[Formula: see text]) at rest and during exercise between GDM and uncomplicated pregnancies; and (2) there is an association of NIRS indices with macrovascular function and cardiovascular disease risk factors. METHODS: Twenty-nine pregnant women (13 with GDM and 16 women with uncomplicated pregnancy, 28 ± 2 gestational weeks) underwent arterial stiffness (pulse wave velocity [PWV]) and 24 h ambulatory BP (24 h BP) evaluation. NIRS continuously monitored, non-invasively, changes in muscle oxygenated and deoxygenated haemoglobin and tissue O2 saturation index (TSI, %) during arterial occlusion/reperfusion and intermittent handgrip exercise. m[Formula: see text] and vascular reactivity indices were calculated. RESULTS: During occlusion and reperfusion, women with GDM exhibited slower TSI response (occlusion slope: -0.06 ± 0.02 vs -0.10 ± 0.04, in GDM and controls, respectively; reperfusion slope: 0.65 ± 0.26 vs 1.05 ± 0.41, respectively), lower m[Formula: see text] (1.3 ± 1.2 vs 3.8 ± 2.3 µmol l-1 min-1) and blunted hyperaemia (ΔTSI 6.8 ± 2.9 vs 9.5 ± 3.4) compared with controls (p < 0.01). Despite similar handgrip strength in the GDM and control groups (29.1 ± 8.1 vs 26.2 ± 10.4 kg, respectively), during repeated forearm contractions, women with GDM presented a blunted TSI response (6.5 ± 3.9 vs 19.2 ± 10.9; p < 0.01) and a reduced capacity to maintain the predetermined handgrip (23.4 ± 2.9 vs 27.4 ± 3.8%, p < 0.05). NIRS indices correlated with PWV, 24 h BP and blood glucose concentration earlier in pregnancy (r = 0.40-0.60; p < 0.05). CONCLUSIONS/INTERPRETATION: Women with GDM exhibited a characteristic blunted TSI curve, showing alterations in muscle oxygenation and microvascular responsiveness compared with women with uncomplicated pregnancies. These alterations were manifested during exercise and possibly contribute to the reduced exercise tolerance in GDM. NIRS indices correlated with macrovascular indices (arterial stiffness) and 24 h BP.

Obese Patients with Type 2 Diabetes on Conventional Versus Intensive Insulin Therapy: Efficacy of Low-Calorie Dietary Intervention.

INTRODUCTION: The aim of this prospective study was to assess the results of a standard low-calorie dietary intervention (7.5 MJ/day) on body weight (BW) and the metabolic profile of obese patients with type 2 diabetes mellitus (T2DM) on intensive insulin therapy (IIT: 4 insulin injections/day) versus conventional insulin therapy (CIT: 2/3 insulin injections/day). METHODS: A total of 60 patients (n = 60, 23 males and 37 postmenopausal females) were recruited and categorized into two groups according to the scheme of insulin treatment. Thirty were on IIT (13 males and 17 females) and an equal number on CIT (10 males and 20 females). BW, body mass index (BMI), HbA1c, and metabolic parameters were compared at 6 and 12 months after baseline. RESULTS: Significant reductions were observed in the BW, BMI, HbA1c (p ≤ 0.001 for all) and cholesterol (p ≤ 0.05) at 6 months post-intervention. At 1 year, median BW reduction was 4.5 kg (3.3, 5.8) for patients on IIT and 4.8 kg (3.6, 7.0) for those on CIT. The 12-month dietary intervention increased prevalence of normoglycemia in the IIT group and reduced the prevalence of obesity prevalence among the CIT participants (all p < 0.001). CIT patients with BW reduction ≥5.0% demonstrated 11-fold greater chances of being normoglycemic (odds ratio 11.3, 95% CI 1.1-110.5). BW reduction ≥7.0% was associated with CIT, being overweight, and having normal HDLc, LDLc, and cholesterol levels. A reduction in BW between 5.0% and 6.9% was associated with IIT, normoglycemia, and obesity. CONCLUSION: A 12-month 1800-kcal dietary intervention achieved significant BW and HbA1c reductions irrespectively of insulin regimen. CIT was associated with BW reduction greater than 8.0%, whereas IIT was associated with higher rates of normoglycemia.

Pregnancy-Induced hypertension.

Pregnancy-induced hypertension (PIH) complicates 6-10% of pregnancies. It is defined as systolic blood pressure (SBP) >140 mmHg and diastolic blood pressure (DBP) >90 mmHg. It is classified as mild (SBP 140-149 and DBP 90-99 mmHg), moderate (SBP 150-159 and DBP 100-109 mmHg) and severe (SBP ≥ 160 and DBP ≥ 110 mmHg). PIH refers to one of four conditions: a) pre-existing hypertension, b) gestational hypertension and preeclampsia (PE), c) pre-existing hypertension plus superimposed gestational hypertension with proteinuria and d) unclassifiable hypertension. PIH is a major cause of maternal, fetal and newborn morbidity and mortality. Women with PIH are at a greater risk of abruptio placentae, cerebrovascular events, organ failure and disseminated intravascular coagulation. Fetuses of these mothers are at greater risk of intrauterine growth retardation, prematurity and intrauterine death. Ambulatory blood pressure monitoring over a period of 24 h seems to have a role in predicting deterioration from gestational hypertension to PE. Antiplatelet drugs have moderate benefits when used for prevention of PE. Treatment of PIH depends on blood pressure levels, gestational age, presence of symptoms and associated risk factors. Non-drug management is recommended when SBP ranges between 140-149 mmHg or DBP between 90-99 mmHg. Blood pressure thresholds for drug management in pregnancy vary between different health organizations. According to 2013 ESH/ESC guidelines, antihypertensive treatment is recommended in pregnancy when blood pressure levels are ≥ 150/95 mmHg. Initiation of antihypertensive treatment at values ≥ 140/90 mmHg is recommended in women with a) gestational hypertension, with or without proteinuria, b) pre-existing hypertension with the superimposition of gestational hypertension or c) hypertension with asymptomatic organ damage or symptoms at any time during pregnancy. Methyldopa is the drug of choice in pregnancy. Atenolol and metoprolol appear to be safe and effective in late pregnancy, while labetalol has an efficacy comparable to methyldopa. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II antagonists are contraindicated in pregnancy due to their association with increased risk of fetopathy.

Pathogenesis of propylthiouracil-related hepatotoxicity in children: present concepts.

Propylthiouracil (PTU), carbimazole (CMZ) and methimazole (MMI) are the most common drugs used today in cases of adolescent thyrotoxicosis. Skepticism has been growing regarding the use of PTU in childhood and its association with severe liver failure. The aim of this review is to present all the recent data regarding pathogenesis of PTU hepatotoxicity in children and adolescents. Specifically, reactive drug metabolites and increased oxidative stress can directly activate inflammatory and immunological pathways. Drugs are not only immunogenic because of their chemical reactivity but also because they may bind through electrostatic forces to available T-cell receptors. Redox modulation is also a key regulatory strategy in the adaptive immune system. Subtle changes in the extracellular redox status may cause profound functional changes in redox-sensitive proteins. Genetic factors that affect drug biotransformation could also be implicated in this mechanistic model of PTU-related hepatotoxicity. Further studies are needed to fully understand the pathophysiology of PTU-induced liver damage.

Meta-analysis of cardiovascular disease risk markers in women with polycystic ovary syndrome.

BACKGROUND: The relation between polycystic ovary syndrome (PCOS) and cardiovascular disease (CVD) remains unclear. In an attempt to provide high-quality evidence on the relation between PCOS and CVD, relevant literature for CVD risk markers [C-reactive protein (CRP), homocysteine (Hcy), tumor necrosis factor-alpha (TNF-α), plasminogen activator inhibitor-1 (PAI-1), lipoprotein (a) [Lp(a)], advanced glycation end-products (AGEs), vascular endothelial growth factor (VEGF), interleukin-6 (IL-6), asymmetric dimethylarginine (ADMA), endothelin-1 (ET-1) and fibrinogen] in women with PCOS was reviewed and analyzed. METHODS: A systematic search was conducted electronically using specific eligibility criteria. Weighted mean differences (WMDs) and 95% confidence intervals (CIs) were calculated and combined appropriately. To ensure synthesis of the best available evidence, sensitivity analyses were performed. RESULTS A total of 130 data sets were included in 11 different outcomes, involving 7174 and 5076 CVD markers in women with PCOS and controls, respectively. Women with PCOS demonstrated significantly elevated CRP [WMD (95% CI) 0.99 (0.77-1.21)], Hcy [2.25 (1.46-3.03)], PAI-1 antigen [16.96 (7.25-26.28)], PAI-1 activity [0.71 (0.18-1.23)], VEGF [1.72 (0.96-2.48)], ADMA [0.19 (0.08-0.3)], AGEs [3.91 (2.36-5.45)] and Lp(a) [0.81 (0.58-1.04)] concentrations compared with controls, yet with significant between-study heterogeneity. Borderline significance (not robust in the sensitivity analyses) was detected for TNF-α [0.75 (0.07-1.44)], ET-1 [1.06 (0.52-1.59)] and fibrinogen [0.20 (0.01-0.39)], whereas no difference was detected for IL-6 [0.71 (-0.16 to 1.59)]. CONCLUSIONS Women with PCOS have increased serum concentrations of CVD risk markers compared with controls. Whether this apparent risk is translated into increased incidence of CVD in later life remains to be elucidated.