Type 2 diabetes mellitus (T2DM) is an expanding global health problem, closely linked to the epidemic of obesity. Individuals with T2DM are at high risk for both microvascular complications (including retinopathy, nephropathy and neuropathy) and macrovascular complications (such as cardiovascular comorbidities), owing to hyperglycaemia and individual components of the insulin resistance (metabolic) syndrome. Environmental factors (for example, obesity, an unhealthy diet and physical inactivity) and genetic factors contribute to the multiple pathophysiological disturbances that are responsible for impaired glucose homeostasis in T2DM. Insulin resistance and impaired insulin secretion remain the core defects in T2DM, but at least six other pathophysiological abnormalities contribute to the dysregulation of glucose metabolism. The multiple pathogenetic disturbances present in T2DM dictate that multiple antidiabetic agents, used in combination, will be required to maintain normoglycaemia. The treatment must not only be effective and safe but also improve the quality of life. Several novel medications are in development, but the greatest need is for agents that enhance insulin sensitivity, halt the progressive pancreatic β-cell failure that is characteristic of T2DM and prevent or reverse the microvascular complications. For an illustrated summary of this Primer, visit: http://go.nature.com/V2eGfN.

Type 2 diabetes mellitus.

Diabetic autonomic neuropathy

This document has been developed as an expert consensus document by the American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA), in collaboration with the American Academy of Neurology (AAN), the American College of Physicians (ACP), the American Geriatrics Society (AGS), the American Society of Hypertension (ASH), the American Society of Nephrology (ASN), the American Society for Preventive Cardiology (ASPC), the Association of Black Cardiologists (ABC), and the European Society of Hypertension (ESH). Expert consensus documents are intended to inform practitioners, payers, and other interested parties of the opinion of ACCF and document cosponsors concerning evolving areas of clinical practice and/or technologies that are widely available or new to the practice community. Topics chosen for coverage by expert consensus documents are so designed because the evidence base, the experience with technology, and/or clinical practice are not considered sufficiently well developed to be evaluated by the formal ACCF/AHA practice guidelines process. Often the topic is the subject of considerable ongoing investigation. Thus, the reader should view the expert consensus document as the best attempt of the ACCF and document cosponsors to inform and guide clinical practice in areas where rigorous evidence may not yet be available or evidence to date is not widely applied to clinical practice. When feasible, expert consensus documents include indications or contraindications. Typically, formal recommendations are not provided in expert consensus documents as these documents do not formally grade the quality of evidence, and the provision of “Recommendations” is felt to be more appropriately within the purview of the ACCF/AHA practice guidelines. However, recommendations from ACCF/AHA practice guidelines and ACCF appropriate use criteria are presented where pertinent to the discussion. The writing committee is in agreement with these recommendations. Finally, some topics covered by expert consensus documents will be addressed subsequently by the ACCF/AHA …

ACCF/AHA Expert Consensus Document ACCF/AHA 2011 Expert Consensus Document on Hypertension in the Elderly A Report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents

Magnesium is the fourth most abundant mineral in the body. It has been recognized as a cofactor for more than 300 enzymatic reactions, where it is crucial for adenosine triphosphate (ATP) metabolism. Magnesium is required for DNA and RNA synthesis, reproduction, and protein synthesis. Moreover, magnesium is essential for the regulation of muscular contraction, blood pressure, insulin metabolism, cardiac excitability, vasomotor tone, nerve transmission and neuromuscular conduction. Imbalances in magnesium status-primarily hypomagnesemia as it is seen more common than hypermagnesemia-might result in unwanted neuromuscular, cardiac or nervous disorders. Based on magnesium's many functions within the human body, it plays an important role in prevention and treatment of many diseases. Low levels of magnesium have been associated with a number of chronic diseases, such as Alzheimer's disease, insulin resistance and type-2 diabetes mellitus, hypertension, cardiovascular disease (e.g., stroke), migraine headaches, and attention deficit hyperactivity disorder (ADHD).

https://www.mdpi.com/2072-6643/7/9/5388/pdf

Magnesium in Prevention and Therapy

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ACCF/AHA 2011 expert consensus document on hypertension in the elderly: A report of the american college of cardiology foundation task force on clinical expert consensus documents

Aging is very often associated with magnesium (Mg) deficit. Total plasma magnesium concentrations are remarkably constant in healthy subjects throughout life, while total body Mg and Mg in the intracellular compartment tend to decrease with age. Dietary Mg deficiencies are common in the elderly population. Other frequent causes of Mg deficits in the elderly include reduced Mg intestinal absorption, reduced Mg bone stores, and excess urinary loss. Secondary Mg deficit in aging may result from different conditions and diseases often observed in the elderly (i.e. insulin resistance and/or type 2 diabetes mellitus) and drugs (i.e. use of hypermagnesuric diuretics). Chronic Mg deficits have been linked to an increased risk of numerous preclinical and clinical outcomes, mostly observed in the elderly population, including hypertension, stroke, atherosclerosis, ischemic heart disease, cardiac arrhythmias, glucose intolerance, insulin resistance, type 2 diabetes mellitus, endothelial dysfunction, vascular remodeling, alterations in lipid metabolism, platelet aggregation/thrombosis, inflammation, oxidative stress, cardiovascular mortality, asthma, chronic fatigue, as well as depression and other neuropsychiatric disorders. Both aging and Mg deficiency have been associated to excessive production of oxygen-derived free radicals and low-grade inflammation. Chronic inflammation and oxidative stress are also present in several age-related diseases, such as many vascular and metabolic conditions, as well as frailty, muscle loss and sarcopenia, and altered immune responses, among others. Mg deficit associated to aging may be at least one of the pathophysiological links that may help to explain the interactions between inflammation and oxidative stress with the aging process and many age-related diseases.

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Magnesium homeostasis and aging

Magnesium (Mg) ions directly influence vascular tone and responsiveness and are cofactors for acetylcholine-induced endothelium-dependent relaxation. Alterations in extracellular Mg are able to modify the formation and release of nitric oxide (NO), altering arterial smooth muscle tone. Previous in vivo studies in humans have shown that parenteral or oral Mg supplementation increase endothelial-dependent vasodilation. The aim of the present study was to evaluate the effects of Mg oral supplementation on endothelial function in elderly diabetic and hypertensive subjects. Sixty elderly (≥ 65 years) diabetic patients were recruited (mean age: 71.1 ± 6.1 years; M/F: 35/25). Endothelial function, evaluated by non-invasive flow-mediated dilatation of the brachial artery, as well as anthropometric and laboratory data, including ionized Mg (Mg-ion), were measured in all patients before and after one-month. Thirty patients underwent oral Mg supplementation with 4.5 g/day of Mg pidolate (368 mg/day of Mg ion), while the rest were used as a control group. The usual management of diabetes and hypertension was not changed during the month of study participation for all the patients. In the group of patients that underwent Mg supplementation, Mg-ion concentration significantly increased from 0.42 ± 0.05 mmol/L to 0.49 ± 0.06 mmol/L; p < 0.05. Mg intervention resulted in a significant improvement of the post-ischemic endothelial-dependent flow-mediated dilation (from 3.3 ± 3.6% to 8.4 ± 3.9%; p < 0.05). No significant differences were found, either in ion-Mg or endothelial function, in the control group. In conclusion, the present study suggests that oral Mg improves endothelial function in diabetic elderly subjects.

Oral magnesium supplementation improves vascular function in elderly diabetic patients.

Developing countries face the double menace of still prevalent infectious diseases and increasing cardiovascular disease (CVD) with epidemic proportions in the near future, linked to demographic changes (expansion and ageing), and to urbanisation and lifestyle modifications. It is estimated that the elderly population will increase globally (over 80% during the next 25 years), with a large share of this rise in the developing world because of expanding populations. Increasing longevity prolongs the time exposure to risk factors, resulting in a greater probability of CVD. As a paradox, increased longevity due to improved social and economical conditions associated with lifestyle changes in the direction of a rich diet and sedentary habits in the last century, is one of the main contributors to the incremental trend in CVD. The variable increase rate of CVD in different nations may reflect different stages of "epidemiological transition" and it is probable that the relatively slow changes seen in developing populations through the epidemiological transition may occur at an accelerated pace in individuals migrating from nations in need to affluent societies (i.e. Hispanics to the USA, Africans to Europe). Because of restrained economic conditions in the developing world, the greatest gains in controlling the CVD epidemic lies in its prevention. Healthy foods should be widely available and affordable, and healthy dietary practices such as increased consumption of fresh fruits and vegetables, reduced consumption of saturated fat, salt, and simple sugars, may be promoted in all populations. Specific strategies for smoking and overweight control may be regulation of marketed tobacco and unhealthy fast food and promotion of an active lifestyle. Greater longevity and economic progress are accompanied by an increasing burden of CVD and other chronic diseases with an important decrease in quality of life, which should question the benefit of these additional years without quality.

Ageing, lifestyle modifications, and cardiovascular disease in developing countries.

Magnesium deficiency is present in several chronic, age-related diseases, including cardiovascular, metabolic and neurodegenerative diseases. Alzheimer's disease (AD) is the most common cause of dementia. The aim of the present study was to study magnesium homeostasis in patients with mild to moderate AD. One hundred and one elderly (≥65 years) patients were consecutively recruited (mean age: 73.4±0.8 years; M/F: 42/59). In all patients, a comprehensive geriatric assessment was performed including cognitive and functional status. Admission criteria for the AD group (diagnosed according to the DSM-IV and the NINCDS-ADRDA criteria) included: mild to moderate cognitive impairment (MMSE score: 11-24/30, corrected for age and education). Blood samples were analyzed for serum total magnesium (Mg-tot) and serum ionized magnesium (Mg-ion). AD patients had significantly lower MMSE scores (20.5±0.7 vs 27.9±0.2; p<0.001), and for the physical function tests. Mg-ion was significantly lower in the AD group as compared to age-matched control adults without AD (0.50±0.01 mmol/L vs 0.53±0.01 mmol/L; p<0.01). No significant differences were found in Mg-tot between the two groups (1.91±0.03 mEq/L vs 1.95±0.03 mEq/L; p=NS). For all subjects, Mg-ion levels were significantly and directly related only to cognitive function (Mg-ion/MMSE r=0.24 p<0.05), while no significant correlations were found in this group of patients between magnesium and ADL or IADL. Our results show the presence of subclinical alterations in Mg-ion in patients with mild to moderate AD.

Altered ionized magnesium levels in mild-to-moderate Alzheimer's disease

Fragility fractures, a major public health concern, are expected to further increase due to aging of the world populations because age remains a cardinal, independent determinant of fracture risk. With aging the balance between bone formation and resorption during the remodeling process becomes negative, with increased resorption and reduced formation. Bisphosphonates (BPs) are widely prescribed anti-resorptive agents that inhibit osteoclasts attachment to bone matrix and enhance osteoclast apoptosis. BPs can be divided into nitrogen-containing (N-BPs) and non-nitrogen-containing BPs (non-N-BPs). Both classes induce apoptosis but they evoke it differently. Several studies have examined the molecular mechanisms underlying BPs’ effects on osteoclasts and bone remodeling. N-BPs (alendronate, risedronate, zoledronate) inhibit the intracellular mevalonate pathway and protein isoprenylation, via the enzyme farnesyl pyrophosphate synthase. N-BPs act by competition, binding to the natural substrate-binding site of the enzyme. The less potent non-N-BPs (etidronate, clodronate), do not inhibit the mevalonate pathway and protein isoprenylation, but are metabolized intracellularly to metabolites, which are cytotoxic analogs of ATP. N-BPs represent the first choice treatment for diseases associated with excessive bone resorption, such as fragility fractures (due to postmenopausal-, male, glucocorticoid- and transplant-induced osteoporosis), Paget’s disease of bone, and bone metastasis. Better understanding of BPs’ effects on osteoblasts/osteocytes (e.g., preventing apoptosis) and differential distribution may further help explain anti-fracture benefit and bone quality effects. Lower affinity BPs (e.g., risedronate) may allow better access to osteocyte network. Effects of BPs on bone senescence, cancer cells apoptosis and prevention of cardiovascular calcifications may open new avenues for biogerontological research.

Mario Belvedere

Papers

Magnesium homeostasis and aging

Oral magnesium supplementation improves vascular function in elderly diabetic patients.

Ageing, lifestyle modifications, and cardiovascular disease in developing countries.

Altered ionized magnesium levels in mild-to-moderate Alzheimer's disease

Physiology of the aging bone and mechanisms of action of bisphosphonates.