Naim Shehadeh

Genetically Determined Heterogeneity in Hemoglobin Scavenging and Susceptibility to Diabetic Cardiovascular Disease

Abstract —A major function of haptoglobin (Hp) is to bind hemoglobin (Hb) to form a stable Hp‐Hb complex and thereby prevent Hb‐induced oxidative tissue damage. Clearance of the Hp‐Hb complex can be mediated by the monocyte/macrophage scavenger receptor CD163. We recently demonstrated that diabetic individuals homozygous for the Hp 2 allele (Hp 2–2) were at 500% greater risk of cardiovascular disease (CVD) compared with diabetic individuals homozygous for the Hp 1 allele (Hp 1–1). No differences in risk by Hp type were seen in individuals without diabetes. To understand the relationship between the Hp polymorphism and diabetic CVD, we sought to identify differences in antioxidant and scavenging functions between the Hp types and to determine how these functions were modified in diabetes. The scavenging function of Hp was assessed using rhodamine‐tagged and 125I‐Hp in cell lines stably transfected with CD163 and in macrophages expressing endogenous CD163. We found that the rate of clearance of Hp 1–1‐Hb by CD163 is markedly greater than that of Hp 2–2‐Hb. Diabetes is associated with an increase in the nonenzymatic glycosylation of serum proteins, including Hb. The antioxidant function of Hp was assessed with glycosylated and nonglycosylated Hb. We identified a severe impairment in the ability of Hp to prevent oxidation mediated by glycosylated Hb. We propose that the specific interaction between diabetes, CVD, and Hp genotype is the result of the heightened urgency of rapidly clearing glycosylated Hb‐Hp complexes from the subendothelial space before they can oxidatively modify low‐density lipoprotein to atherogenic oxidized low‐density lipoprotein. (Circ Res. 2003;92:1193–1200.)

Abdominal Fat and Sleep Apnea: the Chicken or the Egg?

Obstructive sleep apnea (OSA) syndrome is a disorder characterized by repetitive episodes of upper airway obstruction that occur during sleep. Associated features include loud snoring, fragmented sleep, repetitive hypoxemia/hypercapnia, daytime sleepiness, and cardiovascular complications. The prevalence of OSA is 2–3% and 4–5% in middle-aged women and men, respectively. The prevalence of OSA among obese patients exceeds 30%, reaching as high as 50–98% in the morbidly obese population. Obesity is probably the most important risk factor for the development of OSA. Some 60–90% of adults with OSA are overweight, and the relative risk of OSA in obesity (BMI >29 kg/m2) is ≥10. Numerous studies have shown the development or worsening of OSA with increasing weight, as opposed to substantial improvement with weight reduction. There are several mechanisms responsible for the increased risk of OSA with obesity. These include reduced pharyngeal lumen size due to fatty tissue within the airway or in its lateral walls, decreased upper airway muscle protective force due to fatty deposits in the muscle, and reduced upper airway size secondary to mass effect of the large abdomen on the chest wall and tracheal traction. These mechanisms emphasize the great importance of fat accumulated in the abdomen and neck regions compared with the peripheral one. It is the abdomen much more than the thighs that affect the upper airway size and function. Hence, obesity is associated with increased upper airway collapsibility (even in nonapneic subjects), with dramatic improvement after weight reduction. Conversely, OSA may itself predispose individuals to worsening obesity because of sleep deprivation, daytime somnolence, and disrupted metabolism. OSA is associated with increased sympathetic activation, sleep fragmentation, ineffective sleep, and insulin resistance, potentially leading to diabetes and aggravation of obesity. Furthermore, OSA may be associated with changes in leptin, ghrelin, and orexin levels; increased appetite and caloric intake; and again exacerbating obesity. Thus, it appears that obesity and OSA form a vicious cycle where each results in worsening of the other.

Oral Insulin Supplementation Attenuates Atherosclerosis Progression in Apolipoprotein E-Deficient Mice

Objective—The role of insulin in atherosclerosis progression in diabetes is uncertain. We examined the effects of oral insulin supplementation on atherogenesis in apolipoprotein E-deficient (E0) mice. Methods and Results—One-month-old male E0 mice were orally supplemented with human insulin (0.1, 0.5, and 1 U/mL) or placebo for 3 months. At the end of the study, serum and macrophage oxidative stress and atherosclerosis progression were studied. Insulin reduced lesion size by 22% to 37% (P <0.05) in all study groups. Lipid peroxides serum levels were 18% lower (P <0.01), and serum paraoxonase activity was 30% higher (P <0.01) in mice supplemented with 1.0 U/mL insulin compared with controls. Insulin reduced mouse peritoneal macrophage (MPM) lipid peroxides content and superoxide anion release by up to 44% and 62%, respectively (P <0.01). In addition, oral insulin reduced MPM cholesterol content and cholesterol biosynthesis by up to 36% and 53%, respectively (P <0.01). In vitro incubation of E0 mice MPM with increasing insulin concentrations (0 to 100 &mgr;U/mL) resulted in a dose-dependent reduction of cholesterol synthesis by up to 66% (P <0.05). Conclusions—In E0 mice, oral insulin supplementation attenuates the atherosclerotic process. This may be attributable to insulin-mediated reduction of oxidative stress in serum and macrophages as well as reduction in macrophage cholesterol content.

Neurosecretory dysfunction of growth hormone secretion in thalassemia major

ABSTRACT. The growth retardation of children with thalassemia major is multifactorial. Along the endocrine axis of growth hormone (GH), serum somatomedin has been shown to be deficient and GH response to GH‐relasing hormone impaired, while GH response to provocative stimuli is normal. We studied the spontaneous secretion of GH in seven patients with thalassemia major and growth retardation. Three of the patients were hypothyroid, and the other four were euthyroid. Spontaneous secretion of GH in all seven patients was subnormal: the number of pulses, the mean pulse amplitude, and the integrated concentration of GH were all lower than in 14 age‐ and sex‐matched (10 pubertal and 4 prepubertal) control subjects. GH response to provocative stimuli was normal in the euthyroid patients. This pattern of response corresponds with the definition of neurosecretory dysfunction of GH secretion. It is concluded that the growth retardation of patients with thalassemia major is partly due to neurosecretory dysfunction of GH secretion.

Pyomyositis caused by vigorous exercise in a boy

We report on a 12‐year‐old boy who suffered from staphylococcal pyomyositis in both arms following vigorous exercise. No trauma or skin lesions were observed. In non‐tropical areas, the etiology of pyomyositis can be related to muscle injury caused merely by exercise, without any other predisposing factors.

Evaluation of a Diet Containing Probiotics and Zinc for the Treatment of Mild Diarrheal Illness in Children Younger Than One Year of Age

Objectives: Supplementation of probiotics and supplementation of zinc during acute gastroenteritis in children have been shown to exert positive effects on diarrhea duration and severity. Our aim was to evaluate a new diet enriched with zinc and probiotic bacteria in the treatment of acute gastroenteritis in young children. Methods: In a double blind prospective study, 65 children aged 6–12 months were randomized to receive 6 × 109 colony forming units of Streptococcus thermophilus, Bifidobacterium lactis, Lactobacillus acidophilus (2 × 109 of each strain), 10 mg of zinc/day, and 0.3 grams of fructo-oligosaccharides in the supplemented group (n = 33) or placebo (n = 32), given in a soy protein based rice cereal. For each child, age, sex, weight, degree of dehydration, the presence of fever or vomiting, stool frequency and consistency were recorded daily until diarrhea resolution. Results: Diarrhea resolution occurred after 1.43 ± 0.71 days in the supplemented group vs. 1.96 ± 1.24 in the control group (p = 0.017). In the subset of children who presented with vomiting, time to vomiting resolution was 0.27 ± 0.59 vs. 0.81 ± 0.91 days in the supplemented and control groups, respectively (p = 0.06). On day 3, there was only 1 child with watery stools in the supplemented group versus 10 children in the control group (p = 0.02). Conclusions: In our series, the feeding of a cereal containing Streptococcus thermophilus, Bifidobacterium lactis, Lactobacillus acidophilus and zinc, reduced the severity and duration of acute gastroenteritis in young children. However, whether this combination is better than either the addition of probiotics or zinc alone is yet to be determined.

Hypoglycaemia in sulphonylurea-treated subjects with type 2 diabetes undergoing Ramadan fasting: a five-country observational study

Abstract Objectives: To determine the incidence of hypoglycaemia during Ramadan in Muslim subjects with type 2 diabetes treated with a sulphonylurea. Methods: In an observational study, eligible subjects were Muslims with type 2 diabetes (age ≥18 years) who were treated with glimepiride, gliclazide, or glibenclamide with or without metformin and who expressed their intention to fast during Ramadan in 2009. Subjects were recruited by clinicians in India, Malaysia, Israel, the United Arab Emirates (UAE), and Saudi Arabia. Each day during Ramadan, patients completed diary cards, which collected information regarding hypoglycaemic symptoms and complications, time from last meal and from last medication, self-monitored blood glucose measurements, and need for assistance. The overall incidence of symptomatic hypoglycaemia recorded during Ramadan was the primary endpoint of interest. Results: Of the enrolled subjects (N = 1397), 1378 returned their diary cards at study end and were included in the analysis. Overall, 89% of subjects who expressed their intention to fast prior to Ramadan reported that they observed the fast during Ramadan. A total of 271 subjects (19.7%) experienced one or more symptomatic hypoglycaemic events during Ramadan, with incidences of 25.6%, 16.8%, and 14.0% observed in subjects treated with glibenclamide, glimepiride, and gliclazide, respectively. By country, the highest incidence of hypoglycaemia was reported by subjects from Israel (40%) followed by those from Malaysia (24%), the UAE (18%), India (13%), and Saudi Arabia (10%). The overall incidence of severe hypoglycaemic events (i.e., events requiring medical or non-medical assistance) was 6.7%, with the highest incidence occurring in the glibenclamide group. Limitations: This was an observational study and as such subjects were not randomised to treatments. While baseline measures appeared comparable, it is possible that differences in measured and unmeasured patient characteristics (e.g., measures of glycaemic control) could partially explain these results. Lastly, no inferential testing was performed on the comparisons between sulphonylurea types and/or countries. Conclusions: In this five-country observational study, nearly 20% of sulphonylurea-treated Muslim subjects with type 2 diabetes experienced symptomatic hypoglycaemia while fasting during Ramadan, with variations across sulphonylureas and countries.

Glycemic control in adolescents with type 1 diabetes mellitus improves lipid serum levels and oxidative stress

Introduction:  Atherosclerosis begins in childhood, and diabetes is a risk factor for coronary heart disease. Dyslipidemia is prevalent in children with type 1 diabetes mellitus (T1DM), with an association between elevated hemoglobin A1c (HbA1c), serum lipid levels, and oxidative stress. Our aim was to examine the effect of metabolic control on serum lipid levels and oxidative stress in adolescents with T1DM.

Importance of insulin content in infant diet: suggestion for a new infant formula

Oral insulin promotes intestinal maturation and may prevent diabetes in animal models. The aim of this study was to evaluate the concentration of insulin in human milk and in different infant formulas. Our results show that the concentration of insulin in human milk is significantly higher (60.23 ± 41.05 μU/ml mean ± SD) compared with cows milk (16.32 + 5.98 μU/ml mean ± SD) and that insulin is hardly detectable in infant formulas.

Insulin in human milk and the prevention of type 1 diabetes

Abstract: Although controversial, exclusive breast milk feeding was shown to exert a protective effect in preventing type 1 diabetes. In contrast, an early introduction of cows milk‐based formula in young infants may enhance the risk of disease, especially in genetically susceptible children, presumably by an increase of intestinal permeability to macromolecules such as bovine serum albumin and β‐casein, which may arouse autoimmunity. We have shown that human milk contains insulin in substantial concentrations, while insulin is barely detectable (if at all) in infant formulas. Orally administered insulin was demonstrated to promote gut maturation and to reduce intestinal permeability to macromolecules. Furthermore, oral insulin may induce tolerance to insulin and protect against the development of type 1 diabetes. We herewith raise a hypothesis that human milk is protective against the development of type 1 diabetes by virtue of the effects of its substantial content of insulin.