Arshag D. Mooradian

Background:  The cause of obesity‐related low HDLc in the absence of hypertriglyceridemia is not known. Subjects & methods:  A total of 32 subjects with a body mass index (BMI)(kg/m ² ) greater than 30 and normal serum triglycerides (Results:  People with low HDLc (n = 16) compared to those with normal HDLc (n = 16) had higher BMI (37.53 ± 4.54 vs. 33.99 ± 3.65 kg/m ² , p < 0.021), higher body fat weight (42.59 ± 9.51 vs. 34.76 ± 8.7 kg, p < 0.023), and higher insulin resistance index (3.75 ± 2.51 vs. 1.95 ± 1.10, p < 0.013). Seven subjects with low HDLc and none of those with normal HDLc, had elevated serum tumor necrosis factor alpha and/or interleukin‐6 (p < 0.010). Conclusions:  Low HDLc levels can occur in obesity independently of elevated serum triglycerides and may be secondary to elevated serum levels of inflammatory cytokines.

There are several problems facing aging men, especially sexual dysfunction, hypogonadism, and psychologic changes. This constellation of changes is sometimes referred to as “manopause” or “andropause.” Unlike the dramatic changes in the hormonal milieu occurring during menopause in women, the age-related changes in reproductive hormones of men are subtle and occur gradually throughout the years of mature life. It has been estimated that circulating testosterone (T) declines longitudinally from age 19 at an average rate of 1% per year. The free or dialyzable fraction of serum T and the bioavailable (the sum of free fraction and loosely bound to albumin fraction) T decline more rapidly with age. Although the essential role of androgens in reproductive tissue development and emergence of secondary sex characteristics is well known, their role in adult sexual function seems to be primarily facultative. The effect of T on the central nervous system extends beyond sexual behavior. T has been shown to alter mood, memory, ability to concentrate, and the overall sense of vigor and well being that may interact with a host of other psychologic changes associated with aging. Disordered erectile function is not generally an endocrine problem but rather vascular, neurologic, and psychogenic in origin. It also may be the first sign of systemic vascular disease. The clinical management of andropause requires an individualized approach. In some men, the main problem may be psychologic, whereas in others, hypogonadism may play an important role. Many with erectile failure, suffer silently regardless of its etiology. In this review, we suggest some practical guidelines for the management of these conditions.

One of the factors contributing to the increased risk of developing premature atherosclerosis is low plasma concentrations of high-density lipoprotein (HDL) cholesterol (HDLc). Multiple potential mechanisms account for the cardioprotective effects of HDL and its main protein apolipoprotein A-I (apo A-I). The low plasma concentrations of HDL could be the result of increased fractional clearance and reduced expression of apo A-I. To this end, nutrients play an important role in modulating the fractional clearance rate, as well as the rate of apo A-I gene expression. Because medical nutrition therapy constitutes the cornerstone of management of dyslipidemias, it is essential to understand the mechanisms underlying the changes in HDL level in response to alterations in dietary intake. In this review, we will discuss the effect of select nutrients on serum HDLc and apo A-I levels. Specifically, we will review the literature on the effect of carbohydrates, fatty acids, and ketones, as well as some of the nutrient-related metabolites, such as glucosamine and the prostanoids, on apo A-I gene expression. Because there are multiple mechanisms involved in the regulation of serum HDLc levels, changes in gene transcription do not necessarily correlate with clinical observations on serum levels of HDLc.

Statins may have favorable effects on endothelial barrier function. The effect of rosuvastatin and simvastatin therapy (10 mg/kg) for 5 weeks on blood-brain barrier (BBB), blood-retinal barrier (BRB), and cardiac muscle permeability of streptozotocin-induced diabetic rats was studied. The size-selective permeability of different vascular beds to a group of fluorescein isothiocyanate dextrans of varying molecular weights was measured. The volume of distribution of 250-, 70-, and 40-kDa dextrans in the cerebral tissue of diabetic rats were significantly increased. The volume of distribution of these dextrans in cerebral tissue was normalized by both statins. Diabetes did not significantly alter the BRB, but both statins decreased the volume of distribution of 70- and 40-kDa dextrans in the retina. The volume of distribution of 40 kDa in cardiac muscle was increased in diabetes, and this change was prevented with statin treatment. Treatment with rosuvastatin and mevalonate (150 mg/kg in drinking water for 5 weeks) did not alter the volume of distribution measurements. We concluded that 1) diabetes in rats is associated with significant changes in the BBB permeability; 2) statin treatment improves the endothelial barrier function in cerebral tissue, retina, and cardiac muscle; and 3) this statin effect could not be attributed to HMGCoA reductase inhibition.

It is generally accepted that statin therapy reduces morbidity and mortality associated with cardiovascular disease (CVD). However, there are still two fundamental questions that remain incompletely answered. First, how low should low-density lipoprotein (LDL) cholesterol go to achieve maximal benefits, and second, what, if any, is the relative contribution of noncholesterol-lowering effects of statins (i.e., pleiotropic effects) to their cardioprotective properties. The post hoc analysis of the data from some secondary prevention trials, such as the CARE and the LIPID trials, suggest that the relationship between LDL cholesterol and CVD events is curvilinear with the benefits of statins phasing out at a LDL cholesterol level below approximately 125 mg/dl [Reviewed in (1)]. In contrast, the data in the 4S trial suggest a more linear relationship between the LDL cholesterol level and CVD events, while in the HPS, the simvastatin effect was independent of baseline LDL cholesterol levels and the cardiovascular events were reduced with statin therapy even in those persons with LDL cholesterol levels well within the currently recommended target for high-risk populations of less than 100 mg/dl (1). Finally, convincing evidence has been emerging to indicate that in very high risk groups, such as those experiencing acute coronary syndromes, the LDL cholesterol goal should be reduced from the current guidelines of less than 100 mg/dl to less than 70 mg/dl (2). The latter goal was recently supported by the results of the TNT trial (3). As for the majority of patients requiring primary or secondary prevention, the question of whether to lower LDL cholesterol below 70 or 80 mg/dl still remains unresolved, and will have to be reexamined in soon-to-be completed trials such as the SEARCH trial (4).

Insulin is one of the oldest and best studied treatments for diabetes mellitus. Despite many improvements in the management of diabetes, the nonphysiological time-action profiles of conventional insulins remain a significant obstacle. However, the advent of recombinant DNA technology made it possible to overcome these limitations in the time-action profiles of conventional insulins. Used as prandial (e.g. insulin lispro or insulin aspart) and basal (e.g. insulin glargine) insulin, the analogues simulate physiological insulin profiles more closely than the older conventional insulins. If rapid-acting insulin analogues are used in the hospital, healthcare providers will need a new mind-set. Any error in coordination between timing of rapid-acting insulin administration and meal ingestion may result in hypoglycaemia. However, guidelines regarding in-hospital use of insulin analogues are few. The safety profile of insulin analogues is still not completely established in long-term clinical studies. Several studies have shown conflicting results with respect to the tumourigenic potential of this new class of agents. The clinical implications of these findings are not clear. Although novel insulin analogues are promising ‘designer drugs’ in our armamentarium to overcome some of the limitations of conventional insulin therapy, cost may be a limiting factor for some patients.

Cardiovascular disease continues to be the leading cause of mortality in diabetes. One of the factors contributing to the increased risk is the high prevalence rate of low plasma concentrations of HDL cholesterol. Multiple potential mechanisms account for the cardioprotective effects of HDL and its main protein apolipoprotein (apo) A-I. The reduced plasma concentrations of HDL could be the result of increased fractional clearance of HDL and reduced expression of apo A-I. In animal models of diabetes and in cell cultures treated with high concentrations of glucose, apo A-I expression is reduced. In this review we will discuss the alterations in transcriptional control of apo A-I in diabetes. The role of select nutritional and hormonal alterations commonly found in diabetes will be reviewed. Specifically, we will review the literature on the effect of hyperglycemia, hypoinsulinemia, and ketoacidosis, as well as the role of various mediators of insulin resistance, such as fatty acids, cytokines, and prostanoids, on apo A-I promoter activity. Identifying the mechanisms that modulate apo A-I gene expression will aid in the new development of therapeutic agents that increase plasma apo A-I and HDL concentrations.