Institute of Diabetes for Older People

Report from the annual scientific meeting of the Endocrine Society, June 2010, San Diego, USA

This report focuses on topics presented at the ENDO scientific meeting in San Diego that have particular, but not exclusive, relevance to older people with diabetes and associated endocrine disorders.

Rapidly increasing numbers of older people in developed nations mandates effective measures to (a) prevent and (b) safely and effectively treat highly prevalent long-term conditions (LTCs) such as obesity and diabetes.  Dyslipidaemia, hypertension, kidney and liver disease are also often encountered in affected subjects compounding their adverse clinical impact.  These co-morbidities result in a need for drug therapies in addition to usual glucose-lowering polypharmacy.  These closely inter-related metabolic and endocrine disorders increase the risk of microvascular and cardiovascular disease, notably coronary heart disease and stroke.  These complications have created an unprecedented public health burden that is consuming ever-greater healthcare resources.  Clinical practice reminds us on a daily basis of the toll, both physical and psychological, associated with diabetes.  Notwithstanding progress in unravelling the aetiology and pathogenesis of the disorder, current therapeutic strategies remain inadequate. Paradoxically, we have entered an era wherein ever more sophisticated drug therapy, surgical, and other technological solutions are being brought to bear on LTCs that clearly have their origins in behavioural and societal factors.  Associated endocrine disorders such as male hypogonadism and infertility in females underline the inter-connection between metabolic and hormonal systems.

This conference highlighted many aspects of the aforementioned points, and providing timely reminders of the challenges posed by these disorders for patients and clinicians.  Progress is being made, but many unanswered needs remain.

Novel insights into disordered fat metabolism

Professor Barbara Kahn of Beth Israel Hospital reviewed experimental data showing that aspects of glucose metabolism, specifically in fat adipose tissue are downregulated, i.e. become metabolically less responsive.  Impaired insulin action (insulin resistance) is regarded as a key defect in obesity-associated type 2 diabetes. Exercise and the recently introduced GPL-1 receptors agonists, e.g. exenatide independently reduce body weight and increase the levels of recently discovered receptors in fat cells.  The clinical relevance of these findings remains uncertain.  No studies have specifically examined this effect in older people.

Treatment of common lipid disorders

This topic has considerable implications for people of all ages.  The place of drugs such as statins requires a more robust evidence base. The putative role of nutritional therapies - extending beyond maintenance of normal body weight to cardiovascular protection - was considered in an symposium of experts including Daniel Steinberg, professor emeritus at the University of California San Diego (UCSD), who pointed to the benefits of dietary fish oil but commented that the amount in the average Western diet is low.  Sterols added to so-called functional foods lower blood cholesterol, a goal practically unachievable to any great extent by diet alone, may have undesirable direct effects on vascular function. Clinical trials of antioxidant therapy have failed to produce clarity on the question of dietary supplementation.  Inevitably, much more research is required. As for lipid-lowering drugs as adjuncts to medical nutrition therapy unanticipated benefits, which remain to be confirmed, of fibrates in diabetes were reviewed, along with a reminder of safety issues in patients with co-existing conditions, especially renal impairment.  The observation that subgroups of patients in the ACCORD study with subtypes of lipid profiles often associated with type 2 diabetes who were treated with combined statin + fibrate therapy appeared to derive clinical benefits; this possibility generates further hypotheses.  This issue is not yet settled although universal adoption of the latter strategy finds less evidence-based support.

Hyperandrogenism in postmenopausal women

This topic has been a major personal research interest of mine in recent years.  It was reiterated that most causes of clinically significant elevations of testosterone and related hormones in the older women have benign causes.  My colleagues and I at UCSD have proposed a novel phenotype analogous to classic polycystic ovary syndrome (PCOS) in postmenopausal women. This is a common disorder in which elevated androgen levels are a cardinal feature. PCOS is well recognized to confer a considerably increased probability of type 2 diabetes.  The prevalence of major modifiable CVD risk factors is also increased.  Whether rates of clinical CVD events, i.e. myocardial infarction and stroke, are higher in older women with the phenotype remains uncertain, as do optimal strategies for the prevention of PCOS in women during their reproductive years. In another session at the conference, Professor Elizabeth Barrett-Connor (my chief collaborator at UCSD) reviewed data comparing conventional and newer methods for assessing CVD risk.

Bone metabolism

The adverse impact of thiazolidinediones on skeletal metabolism has come a an unwelcome and unanticipated surprise.  In recent years, the role of adipocytokines such as leptin and adiponectin in the regulation of bone health has become apparent.  Professor Barrett-Connor and I intend to test hypotheses examining the impact of the postmenopausal PCOS phenotype, which is associated with alterations in adipocytokine levels, on aspects of bone metabolism; this is another major clinical consideration in older women with potentially important public health implications.

Insulin and cancer

This highly complex and controversial issue was aired by respected investigators including Professor Edwin Gale of the University of Bristol. Efforts directed towards unravelling this concern is hampered by many confounding factors including the realization that obesity and type 2 diabetes, both characterized by elevated blood insulin levels and a plurality of other endocrine defects, are independent risk factors for a range of common cancers.  Moreover, survival appears to be impaired in the presence of diabetes. Given the higher rates of cancer that accompany advancing age future studies, which may also prove difficult to interpret because of confounding factors should stratify results by age.  In contrast to the aforementioned concerns about insulin, increasingly robust epidemiological data suggest a protective effect of metformin against breast cancer.  The biochemical and cellular mechanisms responsible are under investigation.

Diabetes symposium: new therapies

An excellent symposium, chaired by Professor Robert Rizza of the Mayo Clinic, considered the issues surrounding the proliferation of guidelines for the management of type 2 diabetes, and the place of new therapies that target the gastrointestinal incretin hormonal axis.  The latter stimulate or mimic the stimulatory effects of the relevant peptides on insulin secretion.  While there has been great enthusiasm for these novel approaches this is tempered by as yet unquantified reports of adverse effects.   The choice - which is rapidly expanding - of therapy selected when oral glucose lowering drugs prove insufficient was reviewed by Professor Philip Raskin of the University of Texas Southwestern Medical Center, USA.  The merits and drawbacks of insulin therapy and incretin mimetics were examined in detail, with Professor Harold Lebovitz of the State University New York reminding the audience of the need to individualize therapy.  Supplementing this symposium was a session in which glucose lowering agents in development, including the SGLT-2 inhibitors, glucokinase activators nad glycogen phosphorylase inhibitors were discussed.  The recent controversy about the CVD safety of rosiglitazone mandates careful assessments of the efficacy and long-term safety of all new drugs for diabetes.

Bariatric surgery

The application of the major alternative procedures, their relative popularity in the USA, intestinal bypass being generally favoured in the States, and its metabolic consequences were reviewed.  The place of bariatric surgery in the older person with diabetes morbidities remain underexplored.  In collaboration with Professor David Haslam of Luton & Dunstable Hospital (Chair of the UK National Obesity Forum), Professor Alan Sinclair and I plan to examine the bariatric surgery unit’s extensive longitudinal database.  By following patients as they progress during the years following surgery it should be possible to glean insights into the benefits - and adverse nutritional and hormonal consequences - of a therapy increasingly regarded as an option for selected patients.  Comparing surgery with novel weight reducing drugs currently in development merits careful scrutiny, as does the long-term impact of the procedures on diabetes.  Current data suggest that initial improvements in glucose metabolism may not be sustained in all patients.

Impact of menopausal hormone therapy on stroke, cognitive ageing and dementia

An Endocrine Society Scientific Statement on postmenopausal hormone therapy, now know as menopausal hormone therapy (MHT), made the following observations: risk of stroke may be increased in otherwise healthy women.  MHT after natural (as distinct from surgically-induced premature menopause) menopause probably doesn’t have any effect on midlife cognitive function. Initiated after the age of 65 years does not improve memory. The incidence of dementia after 65 years may be increased by MHT. Observational studies suggest a reduction in the risk of Alzheimer’s disease by about one-third when MHT is initiated in early postmenopause. The impact of MHT on late-life dementia risk is unclear. Overall, the picture is incomplete and relies on trials and observational studies that are not always of the most rigorous design. No information was included in the Statement about the impact of MHT in the presence of diabetes.

Andrew Krentz

Senior Research Fellow

IDOP