Krentz, Andrew J.
Since I first attended this meeting (back in 2004) the soi-disant World Congress on Insulin Resistance has grown in stature and authority. This was readily evident from the impressive lineup of world-class investigators who assembled in Los Angeles (USA), on the occasion of the 11th congress in the series.
Here I offer a few brief highlights from what was one of the most stimulating metabolism conferences I have attended in some time. Such was the range of topics, which testifies to the position insulin resistance has assumed in the pathogenesis of so many human diseases, that this report must be selective. The clinical disorders of greatest relevance from a public health perspective – that is, diabetes and cardiovascular disease – are now incorporated into the title of the conference. Other topics, such as the role of insulin resistance in cancer, lipid metabolism obesity and fatty liver disease, were also well represented over the course of the 3 days. Although some reminders of lessons from the past were included, the conference was perhaps notable above all for the plethora of new data on areas that connected molecular biology to clinical syndromes and to proven and novel therapeutic options. Discussion of the topics presented was both lively and of the highest scientific standard. As expected, more questions remain than were unequivocally answered in what was a state-of-the-art summary of this diverse and fascinating, and still largely enigmatic, topic.
Brain regulation of glucose metabolism
One of the first lectures was delivered by Dr Michael Schwartz from the University of Washington (USA). The topicality of the lecture was underscored by the fact that the corresponding paper in the journal Nature, on which Dr Schwartz’s talk was based, was published just the day before 1.
On the basis of rodent experiments, Dr Schwartz hypothesized an underappreciated role for the brain in the regulation of whole-body glucose metabolism. Although seemingly novel, to some at least, this concept can be traced back to the seminal experiments of the French physiologist Claude Bernard in the mid 19th century. Bernard was able to induce diabetes by stimulating the floor of the fourth brain ventricle, from where the vagus (as well as other) nerve fibres were known to originate, with a needle. This ‘piqûre diabetes’, as it was called, found little application in clinical practice, apart perhaps from the well-recognized transient hyperglycaemia that may accompany a major intracerebral vascular event 2, a fact I well recall from my early clinical training.
Although certain assumptions, including differences between rodent versus human physiology and the validity of the quantification of so-called ‘glucose effectiveness’ using the intravenous glucose tolerance test/minimal model approach, can be challenged (and indeed was by an eminent investigator), this research contributes to the increasing realization within the diabetes research community that the role of the brain in the pathogenesis of type 2 diabetes is worthy of more scrutiny.
A novel biomarker of diabetes, cardiovascular disease and breast cancer
Dr Alan Maisel, Professor of Medicine at the University of California (San Diego, USA), presented a lecture based largely on an intriguing 2012 publication in The Journal of the American Medical Association 3. In the population-based Malmö Diet and Cancer Study, fasting levels of proneurotensin were significantly associated with the development of diabetes, cardiovascular disease, breast cancer and with total and cardiovascular mortality among women. The instability of neurotensin led the investigators to measure levels of the related peptide, proneurotensin, which is more stable and produced in the same quantities as neurotensin. Neurotensin is the ligand for a receptor known as sortilin-1 (NT3 receptor), which has been implicated in the development of cardiovascular disease. Within hepatocytes, sortilin participates in the degradation of nascent very-low density lipoprotein particles. The protein is also involved in myocyte insulin-responsive glucose transport. Elevated proneurotensin levels, which are normally higher in women than in men (putatively estrogen-related), are associated with hyperinsulinaemia (an indicator of insulin resistance) and higher fasting plasma glucose levels. Another receptor for neurotensin – the NT1 receptor – is highly expressed in breast cancer tumours. In animal models blockade of the NT1 receptor retards tumour growth.
A facet of the rapidly evolving links between diabetes and cancer is that survivors of breast cancer experience an increased risk of developing diabetes. In parentheses, the Chair of the World Congress and, incidentally, President-elect of the American Association of Clinical Endocrinology, Dr Yeheuda Handelsman, chaired a Task Force on Diabetes and Cancer that reported in 2013 4. Currently, Dr Maisel and his collaborators are studying the predictive effects of proneurotensin in a trial of medical nutrition therapy in breast cancer survivors that is nearing completion. Whether the association between proneurotensin and oncocardiometabolic disease is causal remains to be determined. If causality is confirmed in ongoing genetic studies, proneurotensin and neurotensin could represent new targets for drug therapy and biomarkers for risk prediction.
Simple biochemical markers of insulin resistance
Dr Gerald M. Reaven, Professor Emeritus at Stanford University (USA) Diabetes Association, famously coined the term ‘Syndrome X’ to denote clustering of cardiometabolic risk factors in insulin-resistant subjects in his 1988 Banting lecture to the American Diabetes Association 5. Dr Reaven is a well-known proponent of the steady-state plasma glucose (SSPG) method for quantifying whole-body insulin resistance. This is a pharmacological investigative method that involves suppressing endogenous insulin secretion using somatostatin with concomitant infusion of exogenous insulin to achieve a predetermined state of hyperinsulinaemia. It is reasoned that the SSPG concentration that results from these interventions reflects net insulin sensitivity; the higher the plasma glucose, the more insulin resistant the individual. Using this technique Dr Reaven has estimated that ∼25–30% of otherwise apparently healthy individuals may be at increased risk of a range of insulin resistance-associated adverse long-term clinical outcomes.
Among these, it is well documented that plasma lipid profiles are often altered in association with insulin resistance. Specifically, high-density lipoprotein (HDL) cholesterol tends to be reduced, whereas triglycerides (TG) are not infrequently elevated. In a 2003 study using the SSPG technique, Dr Reaven and his colleagues reported that TG concentration, ratio of TG to HDL-cholesterol concentrations and insulin concentration were the most useful metabolic markers in identifying insulin-resistant individuals. Since this report, several research groups have evaluated the TG to HDL-cholesterol (HDL-C) ratio, reporting good correlations with homeostasis model assessment and the quantitative insulin sensitivity check index (QUICKI), which are modelling approaches based on fasting insulin and glucose measurements.
There is a need in clinical metabolic research to identify individuals who are insulin resistant. This is not easily accomplished. Moreover, in clinical medicine, establishing the most suitable candidates for insulin-sensitizing drugs remains problematic. In his lecture, Dr Reaven explored the utility of the TG/HDL-C ratio as a marker of insulin resistance and associated cardiometabolic risk in college students of Mexican Mestizo ancestry 6. In this collaborative study investigating 2244 healthy students (17–24-year-olds) cardiometabolic risk factors were more adverse in men and women whose TG/HDL-C ratios exceeded 3.5 and 2.5, respectively. Approximately one-third of the sample was identified as being insulin resistant. The metabolic syndrome identified fewer individuals as being insulin resistant, but their risk profile was accentuated. Dr Reaven concluded that the findings suggest that the TG/HDL-C ratio may serve as a simple and clinically useful approach for identifying apparently healthy, young individuals who are insulin resistant and at increased risk for cardiometabolic events.
Nuclear receptors, insulin sensitizers, and exercise mimetics
Dr Ronald Evans, Professor and Director of the Gene Expression Laboratory at the Salk Institute in La Jolla, gave two wide-ranging lectures on the role of nuclear receptors in human disease. Humans have an innate need to move, he reminded his audience: man is the only predatory primate. Dr Evans’s laboratory is credited with the discovery of a large family of receptors that are regulated by steroid hormones, vitamin A (which acts like a hormone) and thyroid hormones. These hormones help control glucose, salt, calcium and fat metabolism; thus, they impact our daily health as well as treatment of disease. More recently, Dr Evans and his team identified a protein that became known as fibroblast growth factor 1 (FGF1). FGF1 activity is induced in adipose tissue in response to a high-fat diet. Mice lacking FGF1 develop diabetes coupled to aberrant adipose expansion when challenged with a high-fat diet. This suggests that FGF1 is a crucial regulator of insulin sensitivity and glucose metabolism. The thiazolidinedione class of insulin-sensitizing glucose-lowering drugs regulates FGF1 7. However, as is all too well known to clinicians, all members of this class, that is troglitazone, pioglitazone and rosiglitazone, have been found to have serious side effects that limit their use. The discovery of the interaction between the target of thiazolidinediones and FGF1 may hence open the door for the development of novel drug therapies.
Dr Evans went on to discuss the potential that so-called insulin mimetic drugs may have in the treating metabolic diseases. An early example of an exercise mimetic was the PPARδ agonist GW501516, which markedly increased exercise tolerance of mice on a treadmill. The drug’s side effect profile put paid to clinical development, but this has not deterred athletes from abusing the drug, which apparently can be obtained through the internet for use in research.
Dr Evans reminded his audience of the depressing fact recognized by US author Mark Twain a century ago:
‘The only way to keep your health is to eat what you don’t want, drink what you don’t like, and do what you’d rather not’.
Miscellaneous cardiometabolic points arising from the conference
Current evidence concerning the safety of DPP-4 inhibitors in heart failure is apparently conflicting, with data ranging from suggestions of potential harm to possible benefit. In the wake of the EXamination of cArdiovascular outcoMes with alogliptIN versus standard of carE in patients with type 2 diabetes mellitus and acute coronary syndrome (EXAMINE) 8 and Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR-TIMI 53) 9 trials, the multinational TECOS trial is awaited, which may provide evidence on whether the reported signal of heart failure observed with saxagliptin (increased risk for hospitalization) is a class effect 9. The Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) is comparing the impact of adding sitagliptin as part of usual care versus usual care without sitagliptin on cardiovascular outcomes. TECOS is an event-driven trial that will continue until data on 1300 confirmed cardiovascular events have been gathered 10.
Sitagliptin has an antiplatelet effect ‘comparable to aspirin’.
New European Society for Cardiology Guidelines on diabetes, prediabetes and cardiovascular diseases, developed in collaboration with the European Association for the Study of Diabetes, were published in 2013 11.
Diabetes mellitus and the metabolic syndrome are regarded as ‘Stage A heart failure’ by the American College of Cardiology/American Heart Association.
Metformin: since 2007, heart failure not requiring pharmacological therapy has not been regarded as contraindication to metformin in the USA. Use of metformin in patients with renal impairment will undergo regulatory review with an expectation that current restrictions may be relaxed.
After more than 50 years in clinical use, the metabolic basis for metformin’s insulin-sensitizing effects continues to be unraveled 12.
Fractures ‘should be added to the list of potential complications of diabetes’, independent of reported iatrogenic effects of thiazolidinediones.
If careful metabolic assessments are made using multiple techniques ‘less than 10% of obese subjects can be regarded as metabolically normal’. Update: the notion of ‘healthy obesity’ has been further challenged by a recent paper from Toronto 13.
Approximately 50% of people with systemic hypertension have ‘clinically significant’ insulin resistance.
Obese children have stiff left ventricles than may impair their capacity to undertake physical exercise.
Conflicts of interest
There are no conflicts of interest.
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