Metabolic syndrome and the older male population

Introduction

The basic definition of the term ‘syndrome’ involves a specific set of conditions that usually occur together and may point to the presence of a certain disease or an increased chance of developing that disease in the future. Therefore, the term ‘metabolic syndrome’ is exactly what its name implies – it is a constellation of metabolic factors, including insulin resistance, dyslipidemia, and hypertension, that together constitute a greater probability of future consequences, mainly type 2 diabetes mellitus and cardiovascular disease. The prevalence of metabolic syndrome increases with age with over 40% of persons older than 60 years being diagnosed with the syndrome. Up to 70 years of age it is more common in men than women [1].

What is the underlying cause of insulin resistance in the geriatric population?

Metabolic syndrome has been the focus of a great amount of research for most of the twentieth century because of the major morbidity and mortality implications of cardiovascular disease. However, the recognition of a ‘hypertriglyceridemia’ syndrome can be dated back to the mid sixteenth century, to be followed by an association seen between increased visceral obesity and hypertension in the seventeenth century. Countless studies ensued throughout the following years to culminate in the identification of a risk factor clustering known as ‘syndrome X’ in the 1980s. Insulin resistance was seen to be common in not only patients with type 2 diabetes, but also in those patients with impaired glucose tolerance, as a result of the pancreatic β-cell's attempt to maintain glucose homeostasis in the face of chronic hyperglycemia and increased free-fatty acids (FFAs). Increased low-density lipoprotein (LDL), decreased high-density lipoprotein (HDL), and hypertension were noted to be concomitant variables that may be present in one individual and may be very important to the development of not only diabetes, but cardiovascular disease in that person [2]. Clinical criteria were eventually established and currently exist for these components of high-risk state by the third report of the National Cholesterol Education Program's Adult Treatment Panel (NCEP-ATP III), the World Health Organization (WHO), and the International Diabetes Foundation (Table I) [3-5]. As highlighted by the International Diabetes Foundation, the key component of the metabolic syndrome is central obesity as defined by waist circumference. Debate ensued with regard to the ambiguity of these criteria; therefore it should be added that, in practice, all cardiovascular risk factors should treated by clinicians without ‘syndrome’ qualification [6].

Table I.  National Cholesterol Education Program (NCEP), World Health Organization (WHO), and International Diabetes Foundation definitions of metabolic syndrome.

NCEP definition	WHO definition	International Diabetes Foundation definition
At least 3 of following:	Hyperinsulinemia or fasting plasma glucose ≥ 110 mg/dL	Central obesity (Waist circumference >94 cm in Caucasian men and >90 cm in Asian men and >80 cm for women).
• Fasting glucose greater than or equal to ≥110 mg/dL	PLUS
• Abdominal obesity with waist circumference	At least 2 of the following:	PLUS any 2 of the following:
○ >102 cm in men
○ >88 cm in women	• Abdominal obesity with waist to hip ratio	• Triglycerides >1.7 nmol/L (150 mg/dl)
• Serum triglycerides ≥ 150 mg/dL	○ >0.9 in men	• Reduced HDL < 1.03 nmol/L (40 mg/dl) in males or <1.22 nmol/L (50 mg/dl) in females
• Serum HDL < 40 mg/dL	○ >0.85 in women	• Raised blood pressure >130 mmHg systolic or 85 mmHg diastolic
• Blood pressure ≥ 130/85 mmHg	• Dyslipidemia	• Raised fasting blood glucose >5.6 nmol/L (100 mg/dl)
	○ Serum triglycerides ≥ 150 mg/dL or HDL cholesterol < 35 mg/dL
	• Blood pressure ≥ 140/90 mmHg
	• Serum triglycerides ≥ 150 mg/dL or HDL cholesterol < 35 mg/dL

Diabetes mellitus in its very essence is a metabolic disorder. Although type 1 diabetes is thought to be autoimmune in nature, characterized by a decreased or lack of insulin secretion, and usually seen in young people, type 2 diabetes is associated with age and obesity (Figure 1). The vast majority of patients seem to have a genetic risk as well that unveils an existing defect in insulin secretion [7]. There are additional environmental factors that interact with genetic susceptibility in the pathogenesis of type 2 diabetes. These factors are mainly associated with a pre-existing obesity, including an elevation in free fatty acids (FFAs), as stated above, increased release of tumour necrosis factor-α (TNFα), increased synthesis of interleukin-1-β (ILβ) by the β-cell, and a deficiency of adiponectin, in addition to a multitude of other factors in the milieu [8,9].

Figure 1. The increasing incidence of obesity in conjunction with increasing age overlaps to contribute to the presence of metabolic syndrome, which in turn directly increases rates of type 2 diabetes, as well as cardiovascular disease.

Key to the development of overt diabetes is the eventual time course of insulin resistance associated with obesity. This is not only an association in modern Western society where nutrition for many individuals is in excess, but can be observed in striking similarity, when that caloric-rich accessibility is applied to the wild. In a study looking at the effects of an abundant food supply in wild baboons, a metabolic-like syndrome evolves as is evidenced with comparative increased levels of glucose, insulin and lipid levels [10].

Actual body fat distribution and ectopic fat distribution are helpful in evaluating the level of insulin sensitivity. Studies using proton magnetic resonance spectroscopy (MRS) to allow non-invasive quantifications of non-fat tissues, including muscle and liver, have shown this modality to be helpful in gaining further insight. In the muscle, MRS can differentiate between extramyocellular and intramyocellular lipid, and, in euglycemic-hyperinsulinemia clamp conditions, permits the observation that fat infiltration in muscle fibres correlates with decreased insulin sensitivity [11]. Furthermore, MRS demonstrates that higher liver fat correlates with lower insulin sensitivity, adding to existing knowledge of the importance of insulin sensitivity in the suppression of endogenous hepatic glucose production [12].

Insulin resistance appears to be associated with increased age, as is backed by numerous population studies; however, the exact age-associated mechanism is not definite, although defects in mitochondrial oxidative and phosphorylation may be an influence [13]. In a comparison to lean young controls, elderly subjects matched for properties, including lean body mass and fat mass, not only had higher circulating insulin concentrations during glucose challenge and higher basal glucose and FFA levels, but also an increase in intramyocellular and liver fat levels by MRS. Interestingly, assessment of both mitochondrial oxidative activity and phosphorylation activity were decreased by about 40%, supporting an association with aging and related insulin resistance [14].

A field of research that is further adding to our current understanding of the biochemical aspects of insulin resistance is the study of adipocytes. An adipocyte is a specialized cell that is able to store excess energy in the form of lipids and, unfortunately or not, has an almost unlimited capacity for growth in accordance with metabolic needs. The adipocyte has numerous types of receptors, including receptors for traditional endocrine hormones, such as insulin, glucagon, and thyroid-stimulating hormone (TSH), as well as nuclear hormone receptors, cytokine receptors, and catecholamine receptors, which allow adipose tissue to receive both central and peripheral signalling [15]. In response, adipocytes can produce adipocyte-specific proteins known as adipokines, that have been found to have local and systemic effects important to glucose homeostasis (Table II).

Table II.  Table of adipocyte-derived proteins with significant endocrine function in metabolic syndrome.

Examples of metabolic syndrome regulators produced by adipose tissue
Adiponectin
Leptin
Resistin
Apelin
Visfatin
TNF-α
Plasminogen activator inhibitor (PAI)-1
Retinol-binding protein (RBP) – 4
FFAs

Adiponectin is one adipokine that has been the focus of many studies within recent years. It is 30-kDa adipose-specific secreted protein that circulates in human serum at 5–30 nM concentrations. This adipokine was initially characterized in 1995/1996 by four groups using different methods and, as such, has multiple names-apM1 (adipose most abundant gene transcript 1), Acrp30 (adipocyte complement-related protein of 30 kDa), adipoQ, and GBP28 (gelatin binding protein of 28 kDa). An inverse association exists between adiponectin and insulin resistance [16]. Adiponectin enhances insulin-mediated repression of glucose production in the liver. In vitro research using primary hepatocytes exposed to differing levels of insulin in adiponectin presence or absence show that adiponectin enhances even very small amounts of insulin significantly [17]. Other than weight loss, the only other current approach shown to significantly improve adiponectin levels is use of activators of peroxisome proliferator-activated receptor-γ (PPAR-γ) [18].

Hypogonadism and metabolic syndrome

With aging there is a decline in testosterone levels [19],[20]. Recently, a number of studies in men have suggested that low testosterone may be associated with insulin resistance and testosterone replacement may enhance insulin action [21-25]. A recent study has shown that males with prostate cancer treated with a GnRH agonist are at increased risk of diabetes mellitus [26],[27]. These studies suggest that the hypogonadism associated with aging may play a role in the pathophysiology of the metabolic syndrome in older men.

Why is metabolic syndrome in the geriatric population important?

Metabolic syndrome is a high risk condition for type 2 diabetes and complications of cardiovascular disease. Diabetes is commonly referred to as an epidemic in medicine today and over 50% of persons with diabetes mellitus are over 60 years of age [28]. It is a complex chronic illness that across the board affects most races and generations. Twenty million individuals have diabetes and an additional twenty-six per cent of the US population has an impaired fasting glucose. Approximately twenty per cent of patients over sixty-five years of age suffer from diabetes, with it being slightly more common in males than females [29],[30]. It poses a significant health burden on the basis of increases in morbidity, mortality, and cost, a fact that has been proven repeatedly [31]. In addition, diabetes mellitus is associated with functional impairment in the aging male [32-34]. The objective of the Third National Health and Nutrition Examination Survey 1988–1994 (NHANES III), to examine the prevalence and time trends for diagnosed and undiagnosed diabetes according to age, sex, race or ethnic groups in the US population, showed that the prevalence significantly increases with age, in addition to being higher among certain racial minority populations. The health care use, including office and inpatient visits, attributed to diabetes in an older population was also demonstrated to be substantial [35],[36]. NHANES 1999–2000 proceeded to show that an inability to control risk factors, such as blood pressure and cholesterol, in conjunction with a rise in the prevalence of type 2 diabetes at an earlier age leads to time-dependent vascular complications, which in turn increases as the population ages and the general lifespan increases. Further studies demonstrate that although individuals with diabetes are at increased risk for vascular disease, including macrovascular (CAD and stroke) and microvascular (retinopathy, neuropathy, nephropathy), improved glycemic control definitely and positively impacts these complications [37], [38]. Finally, there is emerging evidence that three central factors of the metabolic syndrome, viz. hyperglycemia, hypertriglyceridemia and hyperinsulinemia, are associated with cognitive impairment [39-41]. This is due, in part, because the memory enhancing effects of leptin are blocked by hypertriglyceridemia [42],[43].

What are current and prospective interventions in the treatment of metabolic syndrome in the geriatric population?

Since type 2 diabetes is a disease with such a serious and expensive course, especially in the older population, the best treatment is the prevention of metabolic dysregulation to this point [44]. One of the strongest and highly studied interventions to date is lifestyle modification. The Diabetes Prevention Program Research Group investigated, on a large, randomized scale, the effects of lifestyle modifications, medical treatment with metformin, or placebo in the development of diabetes in high risk individuals. Over half of the population was actually determined to have metabolic syndrome in a later study [45]. However, although both lifestyle changes and biguanide therapy deterred or prevented diabetes in the overall studied population, modifications in lifestyle most strongly influenced patients over 60 years of age (DPP) [46]. The importance of lifestyle modifications in this study similarly reflected prior findings in Finland and China [47],[48]. Metformin, which decreases insulin resistance and produces anorexia and weight loss, possibly through its effects on nitric oxide synthase [49],[50], was not useful in delaying the onset of diabetes in persons over 60 years of age [51].

Omega-3 polyunsaturated fatty acids (PUFAs) are a group of polyunsaturated fats that can be found in fish sources in the form of eicosapentaenoic acid (EPA) and docosaheaenoic acid (DHA) as well as in some vegetables, oils, and nuts in the form of a alpha-linolenic acid (ALA) [52]. Several studies have evaluated the beneficial impact of PUFAs in fish oil upon secondary prevention of cardiovascular end points. The GISSI study supported the possibility of an anti-arrhythmic effect in addition to a significant reduction in mortality early in the course of treatment with PUFAs in patients recently surviving myocardial infarction [53]. A separate study found a strong association with reduced risk of sudden death in apparently healthy patients [54]. In regard to dosage, three to twelve grams daily PUFAs have been shown to decrease triglycerides when used in adjunct to diet in patients with elevated triglyceride levels [55]. Currently, Omacor is the only fish oil supplement approved by the FDA for the treatment of hypertriglyceridemia. Type 2 diabetes is generally associated with a dyslipidemia that is composed of low HDL, high LDL, as well as hypertriglyceridemia. Fish oil supplementation in this population has been proven statistically significant in lowering triglycerides by almost thirty per cent without significantly increasing fasting glucose or hemoglobin A1c [56]. The elderly population may particularly benefit from this intervention because in addition to the obvious cardiovascular risks, elevated triglyceride levels are associated with poor cognitive performance by way of decreased verbal fluency and impaired memory tasks [57].

Thiazolidinediones (TZDs) are a class of drugs that have proven to be important in the treatment of diabetes today. TZDs work via PPARγ to promote insulin sensitivity at the level of the liver as well as muscle. Increases in adiponectin with TZD administration have pointed to the importance of the adipocyte in this process [18]. These effects on insulin resistance have significant implications in regard to the prevention of type 2 diabetes. The DREAM trial resulted in substantial reductions in the incidence of diabetes in high risk individuals with TZD treatment for 3 years [58]. Further studies lead to the inherent vascular implications. Decreased inflammatory reaction in symptomatic carotid plaques through analysis of ubiquitin-proteasome activity, thereby meaning plaque stabilization, has been associated with TZD treatment [59]. In both patients with diabetes as well as those with metabolic syndrome, improvements in homocysteinemia were recognized with the addition of this pharmacologic agent [60].

Rimonabant is the first in a newly characterized group of drugs known to selectively block the cannabinoid-1 receptor. Through G protein-coupled receptor activation, the endocannabinoid system is involved in the regulation of glucose metabolism both centrally and peripherally [61],[62]. The RIO-North America study, a 2-year randomized, double-blind, placebo-controlled trial, looked at the effects of treatment with 20 mg/day of rimonabant in addition to diet. The selected population of both obese and overweight individuals proved to have a high dropout rate considered secondary to side effects early in the study, such as depression. However, significant reductions in waist circumference and weight, along with improvements in fasting insulin and lipid profiles were observed, thereby strongly suggesting improvement in the composite picture of metabolic syndrome and possible future complications [63]. Long-term effects of rimonabant in the general obese population, including those patients who are older in age, are yet to be fully determined but may show benefits in the future.

In summary, metabolic syndrome is a condition of high risk for the consequences it imposes, especially in the aging population. In males, there is emerging evidence that hypogonadism may play a role in its pathophysiology. The study of metabolic dysregulation and the development of metabolic syndrome is vast, and ongoing research will hopefully elucidate further our current understanding. Aside from prevention, treatment remains best aimed at lifestyle modification, but pharmacologic agents may be useful in the future.