Effects of a multi-component exercise program and calcium–vitamin-D3-fortified milk on bone mineral density in older men : a randomised controlled trial

Summary We examined the independent and combined effects of a multi-component exercise program and calcium&ndash;vitamin-D3-fortified milk on bone mineral density (BMD) in older men. Exercise resulted in a 1.8% net gain in femoral neck BMD, but additional calcium&ndash;vitamin D3 did not enhance the response in this group of older well-nourished men.Introduction This 12-month randomised controlled trial assessed whether calcium&ndash;vitamin-D3-fortified milk could enhance the effects of a multi-component exercise program on BMD in older men.Methods Men (n&thinsp; =&thinsp;180) aged 50&ndash;79 years were randomised into: (1) exercise + fortified milk; (2) exercise; (3) fortified milk; or (4) controls. Exercise consisted of high intensity progressive resistance training with weight-bearing impact exercise. Men assigned to fortified milk consumed 400 mL/day of low fat milk providing an additional 1,000 mg/day calcium and 800 IU/day vitamin D3. Femoral neck (FN), total hip, lumbar spine and trochanter BMD and body composition (DXA), muscle strength 25-hydroxyvitamin D and parathyroid hormone (PTH) were assessed.Results There were no exercise-by-fortified milk interactions at any skeletal site. Exercise resulted in a 1.8% net gain in FN BMD relative to no-exercise (p&thinsp;&lt;&thinsp;0.001); lean mass (0.6 kg, p&thinsp;&lt;&thinsp;0.05) and muscle strength (20&ndash;52%, p&thinsp;&lt;&thinsp;0.001) also increased in response to exercise. For lumbar spine BMD, there was a net 1.4&ndash;1.5% increase in all treatment groups relative to controls (all p&thinsp;&lt;&thinsp;0.01). There were no main effects of fortified milk at any skeletal site.Conclusion A multi-component community-based exercise program was effective for increasing FN BMD in older men, but additional calcium&ndash;vitamin D3 did not enhance the osteogenic response.<br /

A1 beta-casein milk protein and other environmental pre-disposing factors for type 1 diabetes

Globally type 1 diabetes incidence is increasing. It is widely accepted that the pathophysiology of type 1 diabetes is influenced by environmental factors in people with specific human leukocyte antigen haplotypes. We propose that a complex interplay between dietary triggers, permissive gut factors and potentially other influencing factors underpins disease progression. We present evidence that A1 &beta;-casein cows\u27 milk protein is a primary causal trigger of type 1 diabetes in individuals with genetic risk factors. Permissive gut factors (for example, aberrant mucosal immunity), intervene by impacting the gut\u27s environment and the mucosal barrier. Various influencing factors (for example, breastfeeding duration, exposure to other dietary triggers and vitamin D) modify the impact of triggers and permissive gut factors on disease. The power of the dominant trigger and permissive gut factors on disease is influenced by timing, magnitude and/or duration of exposure. Within this framework, removal of a dominant dietary trigger may profoundly affect type 1 diabetes incidence. We present epidemiological, animal-based, in vitro and theoretical evidence for A1 &beta;-casein and its &beta;-casomorphin-7 derivative as dominant causal triggers of type 1 diabetes. The effects of ordinary milk containing A1 and A2 &beta;-casein and milk containing only the A2 &beta;-casein warrant comparison in prospective trials

Dietary cows\u27 milk protein A1 beta-casein increases the incidence of T1D in NOD mice

The contribution of cows\u27 milk containing beta-casein protein A1 variant to the development of type 1 diabetes (T1D) has been controversial for decades. Despite epidemiological data demonstrating a relationship between A1 beta-casein consumption and T1D incidence, direct evidence is limited. We demonstrate that early life exposure to A1 beta-casein through the diet can modify progression to diabetes in non-obese diabetic (NOD) mice, with the effect apparent in later generations. Adult NOD mice from the F0 generation and all subsequent generations (F1 to F4) were fed either A1 or A2 beta-casein supplemented diets. Diabetes incidence in F0⁻F2 generations was similar in both cohorts of mice. However, diabetes incidence doubled in the F3 generation NOD mice fed an A1 beta-casein supplemented diet. In F4 NOD mice, subclinical insulitis and altered glucose handling was evident as early as 10 weeks of age in A1 fed mice only. A significant decrease in the proportion of non-conventional regulatory T cell subset defined as CD4⁺CD25-FoxP3⁺ was evident in the F4 generation of A1 fed mice. This feeding intervention study demonstrates that dietary A1 beta-casein may affect glucose homeostasis and T1D progression, although this effect takes generations to manifest

Modulation of the Kinetics of Inositol 1,4,5-Trisphosphate-Induced [Ca(2+)](i) Oscillations by Calcium Entry in Pituitary Gonadotrophs

Inositol 1,4,5-trisphosphate (InsP(3)) binds to its receptor channels and causes liberation of Ca(2+) from intracellular stores, frequently in an oscillatory manner. In addition to InsP(3), the activation and inactivation properties of these intracellular channels are controlled by Ca(2+). We studied the influence of Ca(2+) entry on the kinetics of InsP(3)-triggered oscillations in cytosolic calcium ([Ca(2+)](i)) in gonadotrophs stimulated with gonadotropin-releasing hormone, an agonist that activates InsP(3) production. The natural expression of voltage-gated Ca(2+) channels (VGCC) in these cells was employed to manipulate Ca(2+) entry by voltage clamping the cells at different membrane potentials (V(m)). Under physiological conditions, the frequency of the GnRH-induced oscillations increased with time, while the amplitude decreased, until both reached stable values. However, in cells with V(m) held at -50 mV or lower, both parameters progressively decreased until the signal was abolished. These effects were reverted by a depolarization of the membrane positive to -45 mV in both agonist- and InsP(3)-stimulated gonadotrophs. Depolarization also led to an increase in the fraction of time during which the [Ca(2+)](i) remained elevated; this effect originated from both an increase in the mean duration of spikes and a decrease in the interval between spikes. The frequency and amplitude of spiking depended on the activity of VGCC, but displayed different temporal courses and voltage relationships. The depolarization-driven recovery of the frequency was instantaneous, whereas the recovery of the amplitude of spiking was more gradual. The midpoints of the V(m) sensitivity curve for amplitude and duration of spiking (-15 mV) were close to the value observed for L-type Ca(2+) current and for depolarization-induced increase in [Ca(2+)](i), whereas this parameter was much lower (-35 mV) for interval between spikes and frequency of oscillations. These observations are compatible with at least two distinct effects of Ca(2+) entry on the sustained [Ca(2+)](i) oscillations. Calcium influx facilitates its liberation from intracellular stores by a direct and instantaneous action on the release mechanism. It also magnifies the Ca(2+) signal and decreases the frequency because of its gradual effect on the reloading of intracellular stores