Endocrinology

Molecular genetics can facilitate a successful switch to oral diabetes therapy The increase in type 1 and type 2 diabetes in childhood has been well documented worldwide and in Australia.1,2 In addition, the separate entity of monogenic diabetes is increasingly recognised in paediatric diabetes, and now encompasses neonatal diabetes mellitus and maturity onset diabetes of the young (MODY)3 (Box 1). Monogenic diabetes is defined as diabetes caused by a single gene defect. A diagnosis of monogenic diabetes should be considered in a child who is diabetes-associated-autoantibody negative, is diagnosed with diabetes in the first 6 months of life, has a parent with diabetes, and/or is not markedly obese. Although uncommon — its frequency is estimated to be 1%–3% of all childhood diabetes3 — the clinical relevance of this condition is that at least some of those affected (in particular, those with MODY1 and MODY3) can achieve very good diabetes control with sulfonylurea rather than insulin therapy. Neonatal diabetes mellitus presents in the first 6 months of life with signs of hyperglycaemia — polyuria, dehydration, failure to thrive and, in many, frank diabetic ketoacidosis. Diabetic ketoacidosis is an important diagnosis to consider in an infant who presents critically unwell because the clinical picture may mimic sepsis. While the reported incidence of neonatal diabetes mellitus is one in 500 000 newborns,4 the estimated incidence is thought to be a lot higher, and it may be the cause of some unexplained infant deaths. About half of affected patients will have transient neonatal diabetes mellitus, where insulin treatment can be discontinued within a median of 3 months (although diabetes mellitus may recur in the second or third decade of life). In contrast, patients with permanent neonatal diabetes mellitus have, until recently, required insulin therapy for life. The revolution in patient management we describe here is due to molecular genetic analysis of the ATP-sensitive potassium (KATP) channel of the pancreatic beta cell (Box 2). Sulfonylureas have traditionally been used to treat type 2 diabetes mellitus. They act by binding the sulfonylurea receptor (SUR1), which closes KATP channels, thereby stimulating endogenous insulin production from the pancreatic beta cell. Gloyn et al demonstrated that some patients with Kir6.2 potassium channel activating mutations secreted insulin in response to the intravenous sulfonylurea tolbutamide.5 Subsequently, the Neonatal Diabetes International Collaborative Group conducted a trial of glibenclamide, an oral sulfonylurea, in 49 patients with Kir6.2 mutations. This trial included two Australian centres, with three children — one white and two of Middle Eastern ethnicity. An impressive 90% of the trial patients were successfully switched from insulin to glibenclamide.8 Importantly, the responsiveness in vitro of mutant ATP channels to tolbutamide was proportionate to the patient’s response to glibenclamide. This enables a degree of predictability of whether a patient is likely to successfully switch from insulin to oral therapy. Not only was oral therapy welcomed by families of patients, but the switch from insulin resulted in significant improvement of metabolic control, with glycated haemoglobin levels dropping from 8.1% to 6.4% after 12 weeks of treatment.8 Insulin response to oral glucose load was increased in those tested. Continuous glucose monitoring has also shown fewer fluctuations in postprandial glucose,9 which families report improves the child’s general wellbeing. However, the story is not all rosy — some patients with Kir6.2 activating mutations known to have poor in-vitro response to tolbutamide may not be able to switch to oral therapy. It is therefore important to determine the exact genetic mutation involved, so that families can be counselled about the chances of a successful switch. In our experience, such counselling was helpful in lessening the disappointment when a 7-year-old girl with a Kir6.2 mutation, who had presented with ketoacidosis at 7 months of age, remained insulin-dependent despite maximal glibenclamide dose. The diagnosis of neonatal diabetes mellitus should be considered in any critically ill infant, and the International Society for Pediatric and Adolescent Diabetes recommends that all infants who develop diabetes mellitus in the first 6 months of life be tested for a genetic mutation in the KATP channel.10 DNA from peripheral blood can be sent to a diabetes research laboratory in Exeter in the United Kingdom for testing (see http://www.diabetesgenes.org). To date, 20 Australian children, who had been insulin-dependent from less than 6 months of age, have been genotyped. Seven tested positive for mutations in Kir6.2 and three for mutations in SUR1 (Professor Andrew Hattersley, Peninsula Medical School, Exeter, UK, personal communication), and some have gained insulin independence. While molecular genetics can now help classify and facilitate management of childhood diabetes, regardless of the type of diabetes (type 1, type 2, or monogenic), all children who present with severe fasting hyperglycaemia and ketoacidosis will initially require insulin therapy to reverse the metabolic abnormalities. 1 Classification of primary diabetes mellitus in children Type 1 diabetes is characterised by the presence of diabetes-associated autoantibodies (islet cell, insulin, glutamic acid decarboxylase, and tyrosine phosphatase). A number of children with type 1 diabetes may be obese at diagnosis. Type 2 diabetes is characterised by obesity, negative antibodies and raised C-peptide levels. It is more common in non-white people than type 1 diabetes. Comorbid obesity can make the distinction between these two types of diabetes difficult. Monogenic diabetes is caused by a single gene abnormality. Maturity onset diabetes of the young (MODY) 1 and MODY3 are due to transcription factor mutations. Children with monogenic diabetes are not generally obese. Some children with monogenic diabetes present in the neonatal period with ketoacidosis. 2 Subunit structure of the ATP-sensitive potassium (KATP) channel of the pancreatic beta cell* The KATP channel consists of four sulfonylurea receptor (SUR1) subunits and four potassium channel (Kir6.2) subunits. Closure of the KATP channel is required for glucose-stimulated insulin secretion from the pancreatic beta cell. Conversely, opening of the KATP channel inhibits insulin secretion. Inactivating mutations of genes encoding both SUR1 (ABCC8) and Kir6.2 (KCNJ11) subunits keep the channel closed and are known to cause uncontrolled insulin secretion, resulting in congenital hyperinsulinism. It was hypothesised that activating mutations of these genes would keep the KATP channel open and cause permanent neonatal diabetes mellitus (PNDM). In 2004, Gloyn et al reported six novel heterozygous mutations in 10 of 29 patients with PNDM, including a 5-year-old Sydney girl who had been treated with insulin from 6 weeks of age.5 Subsequently, Proks et al reported a patient with activating mutations of ABCC8,6 and Babenko et al reported ABCC8 mutations in two of 29 patients with PNDM and seven of 44 patients with transient neonatal diabetes mellitus.7 KATP channels are also found in skeletal muscle and neurones throughout the brain, and some patients with Kir6.2 activating mutations have extrapancreatic features — motor skill and language delay, muscle contractures, epilepsy, and dysmorphic features — leading to the description of a new syndrome, known as DEND (Developmental delay, Epilepsy, Neonatal Diabetes) syndrome. In-vitro studies of mutant KATP channels have shown a correlation between the degree of KATP channel insensitivity and severity of the clinical phenotype.5 * Adapted from: Sperling MA. ATP-sensitive potassium channels — neonatal diabetes mellitus and beyond [editorial]. N Engl J Med 2006; 355: 507-510. PIP2 = phosphatidyl-inositol-4,5-bisphosphate.

Shubha Srinivasan MB BS, MRCP, FRACP · Kim C Donaghue MB BS, PhD, FRACP

Prediabetes, the presence of impaired fasting glucose/glycaemia and/or impaired glucose tolerance, affects about 16.4% of Australian adults. People with prediabetes are at increased risk of developing diabetes, and cardiovascular and other macrovascular disease. Management includes reducing cardiovascular disease risk factors, specifically lipid and blood pressure abnormalities, and smoking-cessation counselling. To help prevent progression to diabetes, people with prediabetes who are overweight or obese require intensive lifestyle intervention. Medication to help prevent diabetes may also be used, but only after a minimum of 6 months of lifestyle intervention. In people with prediabetes, there is no role for routinely testing: capillary blood glucose; glycated haemoglobin (HbA1c) levels; serum insulin or pancreatic C-peptide levels; or testing for ischaemic heart disease or the microvascular complications of diabetes. Follow-up assessment of glycaemia in prediabetes requires a formal 75 g oral glucose tolerance test, initially performed annually, with subsequent individualised testing frequency.

Stephen M Twigg MB BS, FRACP, PhD · Maarten C Kamp FRACP, MHA · Timothy M Davis FRACP · Elizabeth K Neylon DAA, CDE · Jeffrey R Flack FRACP, MMed

To the Editor: On behalf of the Endocrine Society of Australia, I would like to endorse the views expressed by Stockigt that the Therapeutic Goods Administration (TGA)-approved information sources for thyroid-related medications are outdated.1 His examples are compelling evidence that statements within product information (PI) sources are inconsistent with current practice. The consequences of these statements range from confusing to potentially dangerous. The current process for updating PI appears to exclude expert advice from specialist practitioners who are most likely to be aware of recent developments regarding the use of medications specific to their practice. In most areas of medicine, specialist societies representing these practitioners provide an excellent potential “first port of call” for the TGA and suppliers to source expert, evidence-based assistance in updating PI. Certainly, the Endocrine Society of Australia is willing to act in this capacity for endocrine-related drugs, and I would be very surprised if this were not the case for other specialist societies. In summary, a partnership between all parties involved in the provision of quality care is needed to ensure that PI is contemporary and accurate.

Leon A Bach

To the Editor: I concur with Professor Stockigt’s recent article1 outlining the shortcomings of product information (PI) for thyroid-related drugs. I often need to contradict incorrect or even hazardous PI advice given to patients. An example is the consumer medicine information (CMI) available on the MIMS website, the “myDr” service.2 Although Hysone (hydrocortisone, Alphapharm) is often used for cortisol replacement, rather than as anti-inflammatory therapy, much of the CMI makes no distinction between these two uses. This may, in part, underlie the potentially dangerous advice: “Do not take Hysone if you have any infections that are not being treated or are not responding to treatment”.2 This instruction implies that patients should stop taking Hysone when they have an infection; this may be disastrous for those with adrenal insufficiency because it could lead to an adrenal crisis.3 It is necessary to increase replacement dosages in the event of an infection, intercurrent illness or surgery.3 The CMI for Cortate (cortisone acetate, Aspen Pharmacare), the alternative glucocorticoid replacement drug, has similar information: “Do not take CORTATE if you have an uncontrolled infection”.4 In the editorial accompanying Stockigt’s article,5 Dowden acknowledges that PI needs to be kept up to date, but I think that PI and CMI will remain inadequate without expert professional review, in addition to that currently mandated by the Therapeutic Goods Administration. Patients with adrenal insufficiency need reliable information about the replacement medications they take long term. The CMI for these two drugs is in need of urgent revision in the interests of patient safety.

David Torpy

Inhalation is an attractive alternative to injection, but significant issues will limit its use Insulin is an excellent therapeutic agent with few significant side effects, apart from hypoglycaemia. However, it has one major disadvantage — it needs to be given by injection. Patients’ fears or reservations often mean doctors are reluctant to initiate insulin therapy, even when it is clearly indicated. Not surprisingly, many attempts have been made to find an alternate method of insulin delivery, through nasal, oral, buccal, transdermal or inhaled routes. Inhaled insulin is a theoretically attractive approach, mainly because of the large absorptive surface of the lung alveoli with relatively little proteolytic activity to cause insulin degradation, and it is the most advanced alternative method for insulin delivery in development. One such product, Exubera (Pfizer), has already been granted approval for clinical use in the United States and the European Union, and other products (AERx [Novo Nordisk] and AIR [Eli Lilly]) are in advanced stages of clinical trials. The technology required for administering inhaled insulin is more exacting than that for other inhalation medications, such as those used in treating asthma. As the dose–response curve to insulin is a near linear one, it is critical that the right amount of insulin be consistently delivered to the alveoli and blood stream. The size of the inhaled insulin particles is of paramount importance to this, as particles that are too large adhere to the upper airway and are not absorbed, while those too small will be exhaled before absorption. Manufacturers have used different technologies to address this, and clinical studies have shown that variability of inhaled insulin absorption is similar to that for subcutaneous insulin.1 Pharmacokinetic studies have shown inhaled insulin to be similar to the rapid-onset insulin analogues, such as insulin lispro or insulin aspart, but with a slightly longer duration of action. In other words, inhaled insulin is essentially a rapid-acting insulin suitable for control of postprandial hyperglycaemia. More recent clinical studies suggest that inhaled insulin also slightly lowers fasting plasma glucose levels,2 but the clinical significance of this finding has yet to be fully explored. Inhaled insulin has so far been used in combination with injections of long-acting insulin, and this practice will continue, particularly for patients with type 1 diabetes. In this context, inhaled insulin has been shown to be equivalent to subcutaneous insulin in the control of hyperglycaemia in a number of relatively long-term trials (1–2 years) encompassing all major clinical scenarios encountered in type 1 or type 2 diabetes. However, no clinical trials have shown that inhaled insulin is superior to conventional insulin administration in metabolic control. Clinical trials and theoretical considerations have raised a few potential problems with inhaled insulin, including:3 Insulin delivered via the lungs is more antigenic and results in increased development of anti-insulin antibodies, a problem largely eliminated from conventional insulin treatment by the use of purified insulin. However, these antibodies have not been found to cause major problems, such as allergy reactions or insulin resistance, and they are also unlikely to play a dominant role in the evolution of diabetic complications. Long-term delivery of a foreign substance to the respiratory tract can potentially cause damage. There is little doubt that treatment with inhaled insulin is associated with a small (about 5%) decline in lung function, when measured by parameters such as the diffusing capacity of the lung for carbon monoxide, and forced expiratory volume in 1 second.3 Fortunately, it appears that this relatively minor decline is reversible when inhaled insulin treatment is suspended.4 There is a theoretical increased risk of formation or promotion of cancer with chronic use, especially since insulin is a relatively potent growth factor. This potential danger has not eventuated after use of inhaled insulin in thousands of patients, however it is prudent to carefully monitor for this possible side effect. There are also practical issues with use of inhaled insulin. Smoking immediately before inhalation of insulin increases insulin absorption, although passive or chronic smoking, asthma, and chronic airways disease decrease absorption.4-6 Inhaled insulin therapy is not associated with increased respiratory tract infection but often causes a mild, usually transient cough. Upper respiratory tract infections have shown no significant effect on insulin absorption in clinical trials, but tangible experience is relatively limited. These confounders of insulin absorption have been carefully avoided or controlled in clinical trials, but their potential to cause hypoglycaemia or hyperglycaemia in real-world use is obvious. Some problems with inhaled insulin are highlighted by the commercially available Exubera. Due to its formulation and method of delivery, the dosage of Exubera needs to be measured in milligrams rather than the customary units. It is available in capsules of 1 mg (equal to 3 units) or 3 mg (equal to 8 units), and the product information recommends a commencing dosage based on the patient’s body weight rather than the carbohydrate content of meals. To make things even more confusing, as noted above, three 1 mg capsules are more potent than one 3 mg capsule, complicating interchange of capsules of different strengths. These limitations make minor adjustments in insulin dosage more difficult, especially in patients with labile type 1 diabetes who can develop severe hypoglycaemia with insulin dose adjustment of as little as one or two units at a time. For patients with type 2 diabetes with a high insulin requirement, multiple (more time-consuming) inhalations are needed. Most of the devices used to administer inhaled insulin are relatively large and cumbersome, and they require both time and skill to master. These factors will limit their uptake. In times past, routine tasks in the diabetic clinic included checking the glass syringe, usually carried in an alcohol solution in a special container, and inspecting the needle for sharpness. There has been an obvious improvement in the devices used to inject insulin subcutaneously, and it would be unfortunate if this trend were reversed with the use of inhaled insulin. All these practical issues with inhaled insulin will probably be overcome in time, but at the moment they remain significant. In addition, absorption of inhaled insulin is not as efficient as subcutaneous injection. Indeed, only about 10% of the dose is absorbed. This poor absorption and the high cost of development will inevitably make inhaled insulins much more expensive than their subcutaneous counterparts. This is almost certain to limit their use, particularly in Australia where government subsidy of a new pharmaceutical product largely depends on demonstration of its cost-effectiveness in comparison with existing alternative products. Although qualitative surveys have shown that patients given the choice of inhaled or injected insulin overwhelmingly prefer the former,4,7,8 this has not been shown to translate to wider or earlier acceptance of insulin treatment or a consequent lower glycated haemoglobin level for the diabetic community. The need for caution in the use of inhaled insulin in young patients and the relative lack of flexibility in adjusting dosage by a small amount make it more likely to be used as the initial insulin therapy for patients with type 2 rather than type 1 diabetes. However, for most doctors, who all too often see patients refuse insulin injections when they are needed, the availability of inhaled insulin will be a step forward, at least for some of their patients. In summary, we predict that inhaled insulin therapy will become part of our therapeutic armamentarium, albeit with a small niche market. A small proportion of patients with well controlled type 1 diabetes may use the inhaled route exclusively. Others may use inhaled insulin as a supplement, or to have a much needed “injection holiday”. Subcutaneously injected insulin will remain the major route of administration for the foreseeable future. The inhaled insulins currently available will primarily be used by adult patients with type 2 diabetes who have the financial means — and who are willing to pay — to avoid injections. We suggest that the regulatory authorities could make inhaled insulin available to individual patients for a limited time through the Pharmaceutical Benefits Scheme, to allow patients and their doctors to trial inhaled insulin therapy and assess its benefits.

Aidan McElduff MB BS, FRACP, PhD · Dennis K Yue PhD, FRACP

Objective: To assess whether a diagnosis of the metabolic syndrome (MetS) improves the prediction of cardiovascular disease or total mortality beyond that already provided by conventional risk factors.Design and setting: A longitudinal cohort study conducted in Dubbo, New South Wales.Participants: 2805 men and women aged 60 years and older living in the community, first assessed in 1988–1989 and followed for 16 years.Main outcome measures: Coronary heart disease (CHD) events, ischaemic stroke events, and total mortality.Results: MetS was present in 31% of men and 34% of women. Crude CHD, ischaemic stroke, and total mortality rates were higher in the presence of MetS in men and women. In proportional hazards models that included conventional risk factors, but excluded variables used to define the presence of MetS, MetS was a significant predictor of CHD, stroke and total mortality. In men, the respective hazard ratios were 1.64 (95% CI, 1.37–1.96), 1.31 (95% CI, 0.97–1.77), and 1.53 (95% CI, 1.30–1.79). In women, the respective hazard ratios were 1.70 (95% CI, 1.43–2.02), 1.37 (95% CI, 1.04–1.82), and 1.35 (95% CI, 1.15–1.59). The use of MetS variables on an ordinal scale produced broadly similar conclusions.Conclusions: A diagnosis of MetS provides additional prediction of CHD events, stroke events, and total mortality beyond that provided by other conventional risk factors.

Leon A Simons MD, FRACP · Judith Simons MACS · Yechiel Friedlander PhD · John McCallum DPhil

To the Editor: The views expressed by Samaras et al1 underscore the call for national guidelines on diagnosing polycystic ovary syndrome (PCOS). Insulin resistance is the underlying metabolic disturbance in most patients with PCOS, but the disease is widely under-recognised. Our association, the Polycystic Ovarian Syndrome Association of Australia (POSAA), hears weekly from individuals who have known for months, in some cases years, that they have a serious medical problem. Yet it is through their own persistence, not a thorough history-taking, that their condition is eventually diagnosed. “Go home, lose weight” is the usual advice, but it is neither helpful nor appropriate. There is an urgent need among health care professionals and patients for greater understanding of fertility prospects, the risk of type 2 diabetes, and the need for lifelong exercise and permanent dietary changes. Even though women with PCOS cannot change their genetic makeup, they can take personal responsibility, which is more powerful than any drug in tackling this lifelong condition. Our members tell us that many doctors regard PCOS as an issue of reproduction, with little regard to its metabolic characteristics. All women newly diagnosed with PCOS should be screened for insulin resistance or diabetes, as early identification allows them the best possible chance of living healthy, long lives. As the incidence of PCOS and insulin resistance is rising, there should be national agreement on diagnosis and treatment. This should include an awareness campaign on what to look for, how to diagnose metabolic problems like PCOS and insulin resistance, and, crucially, how to treat them. Guides like the one given to POSAA by Kidson and Talbot2 and that published by the Amercian Association of Clinical Endocrinologists3 should be endorsed for Australian doctors. POSAA has agreement from the Royal Australian College of General Practitioners, the Royal Australian and New Zealand College of Obstetricians and Gynaecologists, and most state health ministers on the need for guidelines on diagnosing and treating PCOS. The MJA has copies of these letters. Yet, the federal government says “there is no specific funding allocation within the Department”, and Diabetes Australia says that current National Health and Medical Research Council (NHMRC) guidelines are appropriate. POSAA believes these guidelines are outdated. Australia’s hidden epidemic of PCOS will only grow, matched by a ballooning financial burden on taxpayers, until governments, in partnership with the medical profession and groups like POSAA, work together to improve the health prospects of women with PCOS, and their families.

Sabra M Lane

To the Editor: We read with interest the recent article on insulin resistance,1 and we strongly support the argument that there is no current clinical utility to measuring fasting insulin levels. However, we are concerned about the statement that “otherwise well patients whom we see in practice are demanding (and receiving) metformin, or are being told they need it, particularly for polycystic ovary syndrome” (PCOS). Therapy in PCOS targets symptoms. Although Samaras et al imply that metformin is not required in “well patients”,1 the “well patient” is not defined. Most women with PCOS are, by definition, symptomatic, and most benefit from therapy. We contend that, although measurement of insulin levels is not justified, insulin resistance is established in PCOS, and metformin is an effective treatment for women with PCOS. This contention is well supported in the literature. It is recognised that most women with PCOS have insulin resistance leading to hyperinsulinaemia and that insulin resistance plays a central aetiological role in the clinical manifestations of PCOS.2 However, as outlined by Samaras et al,1 the insulin level is not an appropriate marker for insulin resistance (a challenging parameter to measure in routine clinical practice) and, consequently, insulin resistance is not included in the diagnostic criteria for PCOS. Strategies to decrease insulin resistance have proven effective in studies where patients are selected based on clinical diagnostic criteria for PCOS, not insulin levels. Indeed, reducing insulin resistance with both lifestyle change3 and insulin sensitisers4 is emerging as a promising treatment strategy.2 Although not yet “approved” for treating PCOS in Australia, metformin is an effective treatment for anovulatory cycles and infertility, and induces a mild decline in hyperandrogenaemia. This is supported by a recent Cochrane review.4,5 Increasingly, metformin is recommended as a first- or second-line therapy in anovulatory infertility4,6 because, in contrast to conventional infertility therapies, it does not increase multiple pregnancy rates. In summary, metformin treatment in PCOS is supported by a significant evidence base, but the use of metformin should be based on clinical indications, independent of an individual’s insulin levels.

Samantha K Hutchison · Sophia Zoungas · Helena J Teede

To the Editor: As the person who introduced metformin as adjunctive therapy for polycystic ovary syndrome (PCOS) in Australia in 1996,1 and subsequently introduced measurement of insulin levels during glucose tolerance testing,2 I would like to respond to the article by Samaras et al.3 These nine endocrinologists and epidemiologists have a patient population that is mostly middle-aged and older, quite different to my practice in PCOS, in which 80% of patients are aged between 12 and 45 years. For 80%–85% of women with PCOS, the condition is a result of hyperinsulinaemia secondary to inherited insulin resistance. However, a significant proportion of PCOS is caused by dysfunction of the hypothalamic centre for control of fertility. This may be a result of incomplete maturation, stress, excessive exercise, or previous anorexia and bulimia. These women will not respond to restrictive diets, weight loss, or more exercise, or to metformin. Hence, they must be differentiated from women with insulin resistance or hyperinsulinaemia4 by history, examination, and measurement of insulin and sex hormone binding globulin (SHBG) levels. More than 30% of insulin-resistant women with PCOS are not obese, and elevated insulin levels or depressed SHBG levels are often the only means to distinguish them from women with PCOS from other causes. For insulin-resistant women with PCOS, lowering insulin levels restores regular ovulatory cycles, clears acne and slowly reverses hirsutism, while preserving beta cell function. Reducing insulin levels must, therefore, be the objective of therapy, initially with diet and exercise. Metformin may be added if lifestyle change is ineffective. Although I agree that the fasting insulin test does not completely correlate with the “gold standard” research tests, mathematical computations involving both fasting insulin and fasting glucose, such as the HOMA and QUICKI indices, do correlate extremely well with these tests, and require nothing more than a desk calculator.5 The best gold standard correlation in PCOS is achieved with the area under the insulin curve during a 3-hour glucose tolerance test.6 This formula, ½ fasting + 1-hour + 2-hour + ½ 3-hour insulin, gives far greater numerical emphasis to the 1- and 2-hour insulin values than to the fasting insulin level, contradicting the assertions by Samaras et al that 1- and 2-hour insulin measurements are useless.3 In summary, insulin levels are elevated in adolescence and early adulthood in women with PCOS, and often in their siblings and children. This can give an earlier warning of future metabolic and cardiovascular problems than by conventional screening, at an age when people are less resistant to implementing lifestyle change, and giving a longer period for preventing pathology.

Warren J Kidson

To the Editor: I congratulate Samaras et al for opening the debate on insulin levels, insulin resistance and the metabolic syndrome.1 It is true that, when measuring insulin levels, by the hyperinsulinaemic eu-glycaemic clamp, we define the lowest quartile of the population as insulin resistant. As insulin resistance is frequently a component of the metabolic syndrome, this method is already an underestimate. In 1999–2000, the prevalence of the metabolic syndrome among adults in the United States was 26.7%.2 The prevalence of the metabolic syndrome among participants of the Framingham Offspring Study and San Antonio Heart Study ranged from 21.3% to 32.8% during the early to mid 1990s.3 Various indices have been developed as surrogate markers of insulin resistance. HOMA-IR (homeostatic model approach — insulin resistance) is highly correlated with insulin resistance as measured by the euglycaemic clamp. HOMA-IR was useful in predicting type 2 diabetes and impaired glucose tolerance in the Mexico City Diabetes Study.4 Another study using HOMA-IR found that insulin resistance was positively associated with carotid plaque formation in subjects with normal fasting glucose and normal glucose tolerance. The associations remained significant even after adjusting for known atherogenic risk factors.5 Reducing insulin resistance reduces cardio-vascular risk factors. The United Kingdom Prospective Diabetes Study reported that metformin is associated with a significant reduction in combined diabetes-related end points, diabetes-related deaths, all-cause deaths and myocardial infarction.6 By the time patients present to endocrinologists, they commonly already have many, if not all, of the elements of the metabolic syndrome. In primary care, we commonly see patients who only have one or two of those elements. Identifying insulin resistance early in at-risk patients is vital to prevent development of glucose intolerance as well as the various elements of the metabolic syndrome. Patients and their family doctors are interested in disease prevention and would like to know whether they are at risk of diabetes or the metabolic syndrome. As there is evidence which suggests that insulin sensitisers in conjunction with lifestyle modifications may be helpful in preventing progression to diabetes and reducing cardiovascular risk factors, their “demand’ is not unjustified. Further, in obese, non-diabetic patients with insulin resistance, hyperinsu-linaemia may act as a barrier to successful weight loss.7 Identifying insulin resistance in these patients is important, as metformin may have a role in assisting weight loss. Primary prevention of diabetes and the metabolic syndrome is possible and achiev-able in the primary care setting.

Chee L Khoo

To the Editor: I was pleased to read the article discouraging the measurement of insulin levels in the metabolic syndrome and obesity,1 as it concurs with my previous opinion.2 In parallel with the adult burden is the ever increasing paediatric obesity epidemic, which looms large across the world, with rates in Australia of up to 25%.3 This translates into a significant number of oral glucose tolerance tests being performed, often with measurement of insulin levels. There is a distinct lack of evidence on the validity of this test in obese older children and adolescents in terms of defining cardiovascular and metabolic morbidity and mortality. The implementation and inter-pretation often stem from extrapolation of adult data.4 Furthermore, the administration of glucose to this age group is often impractical, as it is weight-based (1.75 g/kg, to a maximum dose of 75 g), and may induce morbidities such as nausea and vomiting, with subsequent failure to complete the test, multiple traumatic venepunctures, and unwarranted stress (both financially and emotionally) on the parents. Individual variations in gastric emptying and insulin secretion rate add to the poor accuracy and reproducibility of this so-called diagnostic test. If sufficient care is not taken, the analysis and processing of the insulin assay can give an incorrect result, and thus a low level can be misguiding when clinical findings indicate otherwise. A high level merely confirms the syndrome where body mass indices and waist circumferences are equally valid measurements.5 Either way, this test cannot be recommended as routine, and management should be based on clinical features. Although not flawless, perhaps fasting plasma glucose levels are more appropriate as diagnostic tools, with oral glucose tolerance tests reserved for high-risk and atypical groups. These tests should be done without measuring insulin levels and with the previously mentioned confounders in mind. Although it is recognised that insulin resistance is central to the disease clustering seen in the metabolic syndrome, unless the syndromal terms that bear the subtext “insulin” are renamed, insulin testing in clinical practice will continue unabated at a costly rate. In contrast to international bodies6,7 and this well-founded opinion,1 the National Health and Medical Research Council (NHMRC) still recommends insulin measurement,8 albeit in selected circumstances.

Huy A Tran

To the Editor: Samaras et al1 state that individuals at risk of diabetes and atherosclerotic cardiac disease can be identified simply and inexpensively by history-taking, physical examination, and very basic investigations. However, insulin resistance and beta cell failure are the hidden causes, and predate the development of overt diabetes by more than a decade.2 Doctors should help patients to understand that the progression of these conditions can be halted by significant changes to lifestyle.3 These will reduce the need for expensive medications, and in some cases even obviate their use. As most obese individuals have battled unsuccessfully to lose weight, and non-obese individuals may also be insulin resistant,4 an assessment of glucose and insulin responses in an oral glucose tolerance test should assist the physician in developing a treatment plan. Unfortunately, few clinicians take the time to explain the difficult concept of insulin resistance. Until the recent Enhanced Primary Care program, few individuals were able to afford the advice of dietitians or an exercise physio-logist. Most clinicians have given up attempts to motivate patients to exercise regularly and lose weight, and many take the easy course of prescribing medications. Although Reaven first described insulin resistance as the basic pathophysiology of type 2 diabetes in 1988,5 it is only since the advent of the glitazones that clinicians have embraced the concept. Furthermore, not one person with type 2 diabetes that I have encountered has heard of the term insulin resistance. An explanation of insulin resistance assumes new meaning when illustrated with a patient’s own glucose and insulin responses after a glucose drink or their usual breakfast. The medical profession is constantly under scrutiny to make effective use of the health dollar. The cost of measuring insulin levels can be justified if this leads to better clinical practice, patient compliance with lifestyle changes, and reduced prescribing. Prescribing of metformin or other drugs and supplements should not be a first priority in controlling insulin resistance. Initial attempts should be directed at changes to diet, exercise and weight, with particular attention to loss of abdominal adiposity.

Allen E Gale

To the Editor: The authors of the article on insulin resistance1 challenge users of serum insulin levels to demonstrate benefit in clinical practice. The problem for those of us who see patients with the metabolic syndrome (and occasionally find time to take a history and perform an examination) is that we are spectacularly unsuccessful in getting patients to lose weight. Everyone is able to lose some weight in the first flush of enthusiasm or when taking part in a trial with lots of encouraging assistants monitoring them, but they almost invariably run out of steam, and the weight goes back on — with interest. I use the “worse still” measurement of insulin responses during an oral glucose tolerance test not to diagnose the metabolic syndrome, but as a method of motivating patients about the seriousness of the condition. A graph that shows the insulin response “off the page” makes a very effective propaganda tool (Box). An elevated fasting insulin level or, even better, very high insulin levels during an otherwise normal glucose tolerance test, is also very effective in indicating to parents of well children with obesity that diabetes is threatened. Otherwise, we are left with vague references to increased risk, which means little to the parents. One picture is worth a thousand words. A typical glucose tolerance test result showing the insulin response “off the page” Dots = measured glucose levels; dotted lines = glucose normal range. Crosses = measured insulin levels; shaded area = insulin normal range.

Chris Strakosch

In reply: We are pleased that our article stimulated debate regarding the inappropriate measurement of insulin levels in clinical practice. Lane, representing the Polycystic Ovarian Syndrome Association of Australia (POSAA), presents an impassioned plea for more effective diagnosis and treatment of polycystic ovary syndrome (PCOS). Her concerns focus on the general lack of know-ledge about diagnostic criteria and the condition itself. We support the wider recognition of this condition, the greatest cause of infertility in this country. However, PCOS cannot be diagnosed or measured in any way by insulin levels, even though about 80% of patients are insulin resistant. Lane also calls for Australian guidelines for diagnosis of PCOS; these are not necessary, as simple, widely accepted international guidelines exist.1 As pointed out by Hutchison et al, estimates of insulin resistance are not required for diagnosis of PCOS. PCOS is common and costly, both in absolute fiscal terms (eg, in-vitro fertilisation) and in quality of life and other, inestimable “human” terms. We recognise the great suffering of women with PCOS, and the heartbreaking difficulties of infertility, with its intrusive and expensive management. These factors make these women vulnerable as consumers, so it is important to inform POSAA and other consumer groups of useless measures that have no evidence base in diagnosis and treatment. Rightly, Lane expects medical practitioners and departments of health to agree on diagnostic guidelines for PCOS, and Hutchison et al anticipate the approval of metformin therapy in PCOS with clinical indications such as anovulatory infertility. The role of metformin in treating PCOS is not in dispute here. However, independent of symptoms or signs of PCOS, prescribing metformin after “diagnosis” of insulin resistance based on insulin levels is negligent. We agree unanimously with Hutchison et al that “use of metformin should be based on clinical indications”. Kidson agrees that insulin measures are unreliable. His referenced comments highlight that insulin measures only have an evidence base in epidemiology. Again, we invite evidence for utility of measuring insulin levels in clinical practice, if it “can ever be presented”. Tran points to the dominant role of the obesity epidemic, the overwhelmingly large elephant in the room we have thus far ignored. Obesity causes (and worsens) insulin resistance, and causes diabetes, heart disease, stroke and some cancers. With 60% of the adult Australian population now overweight or obese, we can expect a greater frequency of insulin resistance in the community. Tran presents a convincing, well researched argument against measuring insulin levels, either fasting or during an oral glucose tolerance test. Measures of central abdominal obesity (eg, waist circumference) have been shown in long-term studies to be the best predictors of heart disease, diabetes, cancer and all-cause mortality. Any strategy that assists obese people to lose weight will reduce insulin resistance and components of the metabolic syndrome, particularly diabetes and heart disease. Motivating patients in lifestyle change is a difficult and perpetual challenge for the clinician. Nevertheless, we find it astonishing that clinicians use insulin levels to enhance motivation, as suggested by Strakosch. This is truly invoking phantoms. We encourage all clinicians in our difficult task of counselling and motivating lifestyle change. The creation of a facilitating environment to offset the Australian obesity and diabetes epidemic is a high political priority.2 We also thank Gale for emphasising the importance of lifestyle management in diabetes and related pre-diabetes conditions. However, his comment that the cost of measuring insulin levels can be justified is not supported by any evidence, and leads to a question as to who should bear the cost. Who is bearing the cost of measuring insulin levels? This burden falls mainly on the Health Insurance Commission (HIC). If patients were made to bear the cost, they might demand greater clinician scrutiny of its validity. Is it appropriate for the Austra-lian taxpayer and the precious medical budget to fund an unvalidated and unreli-ably poor estimate of an entity that, by best practice, does not need to be measured? We acknowledge that insulin levels have a role in epidemiology and research — but only there, and the HIC has very clear guidelines that it is inappropriate to fund research through Medicare.

Katherine Samaras · Timothy A Welborn · Aidan McElduff · Joseph Proietto · Stephen M Twigg · Paul Zimmet · Lesley V Campbell

Objective: To estimate the incidence of diabetes and impaired fasting glucose (IFG), and increased risk associated with the metabolic syndrome, in a representative population-based sample of older Australians.Design, setting and participants: The Blue Mountains Eye Study examined 3654 residents aged 49 + years (82.4% response rate) during 1992–1994, and re-examined 2335 (75.1% of survivors) during 1997–1999 and 1952 (75.6% of survivors) during 2002–2004; 2123 participants with normal blood glucose levels at baseline were considered at risk of developing incident diabetes.Main outcome measures: Incident diabetes (or IFG) was defined in participants at risk who were newly diagnosed by a physician during the follow-up or found to have a fasting blood glucose level ≥ 7.0 mmol/L (or 5.6–6.9 mmol/L). Kaplan–Meier cumulative 10-year incidence was calculated.Results: The overall 10-year incidence of diabetes and IFG was 9.3% and 15.8%, respectively. Participants with metabolic syndrome at baseline had a higher risk of incident diabetes than those without metabolic syndrome (29.2% v 8.6%). Baseline factors associated with incident diabetes were elevated fasting glucose level (adjusted odds ratio [OR], 4.5; 95% CI, 3.4–6.1 per mmol/L), obesity (OR, 2.0; 95% CI, 1.3–2.8), diabetes family history (OR, 1.7; 95% CI, 1.2–2.5), current smoking (OR, 1.6; 95% CI, 1.0–2.7) and high density lipoprotein cholesterol level < 1.0 mmol/L (OR, 2.4; 95% CI, 1.5–3.8). Similar baseline factors were associated with incident IFG.Conclusion: This population-based study provides data on the incidence of diabetes and IFG in an older, predominantly white population, and confirms that metabolic and lifestyle factors are major risk factors for diabetes.

Sudha Cugati MB BS, MS · Jie Jin Wang MMed, PhD · Elena Rochtchina MApplStat · Paul Mitchell MD, PhD

Product information (PI) for thyroid-related medications endorsed by the Therapeutic Goods Administration, as reproduced in the commonly used compilation publications June 2006 MIMS (Monthly index of medical specialties) annual, MIMS Online and the Australian prescription products guide 2006, was evaluated to see whether it reflects contemporary therapeutic practice. Compared with current medical literature, these PI-based sources provide inadequate, inaccurate or outdated therapeutic directives. Examples include: Incorrect advice that thyroxine therapy should always begin at very low dosage. Failure to recommend increased thyroxine dosage early in pregnancy (thus placing the offspring of women being treated for hypothyroidism at risk of impaired fetal brain development). Incorrect and potentially unsafe advice to treat thyrotoxicosis with stable iodide in late pregnancy. Failure to advise serial adjustment of antithyroid drug dosage until after a patient becomes euthyroid (this can result in iatrogenic thyroid dysfunction). Outdated advice that antithyroid drugs are not compatible with breastfeeding. Recent initiatives to upgrade consumer medicine information (CMI) appear to accept PI-based sources as a reliable benchmark for CMI. That inference is not warranted for thyroid-related medications. Accountability for the updating of clinical information in PI needs to be defined, and the process for updating PI may need to be modified. Quality drug information, both PI and CMI, depends on fluent, evidence-based collaboration between suppliers, regulators, prescribers, specialist clinicians and consumers.

Jim R Stockigt MD, FRACP, FRCPA

Looking back over my life, I am struck by how important chance has been. Chance creates opportunities — and my life has been abundant with opportunities. I have had the rare experience of changing careers several times. I have been associated with the birth of several new organisations and seen them become successful.1 My decision to study medicine was considerably influenced by my father, Kenneth Hetzel, a consultant physician at the Royal Adelaide Hospital, who became Dean of the Faculty of Medicine at the University of Adelaide (1953–1959). A greatly respected clinical teacher with a passionate interest in medical research, he was an inspiration to me.1 I graduated from the University of Adelaide at the end of 1944. Early in my course, I had enlisted in the Royal Australian Air Force, but after being diagnosed with pulmonary tuberculosis in 1945, I was unable to undertake military service. Many of my contemporaries did not return from war service. This left me with a strong desire to make the world a better place! As a student, through membership of the Student Christian Movement, I adopted a Christian commitment. This led me to a holistic medical perspective that I have consolidated with fairly extensive reading in philosophy and theology, with particular reference to the interaction between science and religion.1 My holistic perspective led to an interest in endocrinology, including “stress”. I became aware of the ideas of Hans Selye, who had first recognised the importance of the role of the adrenal cortex in the body’s response to stressful stimuli. This followed the earlier work of Walter Cannon, who established the role of adrenalin. Selye proposed the concept of “diseases of adaptation”, including essential hypertension as the result of “adrenal exhaustion”. I conducted an investigation of the adrenal cortex in hypertensive patients using a bioassay in mice for glucocorticoids (cortisol), which was a considerable challenge. The studies revealed normal adrenal function except in Cushing syndrome.2 There was considerable interest in stress at the time, and I had many requests for reprints! My finding was later confirmed by others. In 1951, I received a Fulbright Research Scholarship and proceeded to the New York Hospital Cornell Medical Center to work as a Research Fellow in Medicine under Professor Harold Wolff. He was leading a systematic study of physiological changes in a variety of organs and systems during different emotional states associated with stressful life experiences. I was assigned to study the endocrine (adrenal, thyroid) and metabolic systems. I believe I was the first to report an increase in cortisone secretion in humans associated with emotional states such as apprehension and exhilaration.3 These changes were accompanied by an increase in metabolic rate and other changes similar to those observed in physical trauma.4 After a period of training in clinical endocrinology at St Thomas’ Hospital in London, I returned to Australia in 1956 to become a Michell Research Scholar in the newly established Department of Medicine at the University of Adelaide under Professor H N Robson, the Foundation Professor of Medicine. In 1959, I was appointed Head of the Department of Medicine at the newly opened Queen Elizabeth Hospital (QEH) at Woodville, first as Reader and then, in 1964, as Michell Professor of Medicine. My point of view in practice, teaching and research was a holistic one embracing the whole person — body, mind and spirit. My clinical teaching also took account of the social environment in relation to the occurrence and management of disease. It involved the health care team and included the hospital chaplain. My clinical teaching paid special attention to the personal and social aspects of a patient’s illness. I emphasised to my students that there is both a “scientific diagnosis” of the mechanism of disease and a “personal diagnosis” of the personal and social situation of the patient, both diagnoses being equally important. My research team at the QEH included graduate students and was particularly focused on the pathogenesis of Graves disease (hyperthyroidism), which was shown to be an autoimmune disease.5 My interest in thyroid disorders led to my involvement (from 1964 to 1972) in studies of severe iodine deficiency in the Papua New Guinea (PNG) highlands in relation to goitre and brain damage (cretinism). Confronting the challenge of trying to improve public health in a developing country had a permanent impact on me. I was a member of the Foundation Council of the new University of Papua New Guinea (1965–1972) and assisted in the establishment of a university medical school from the previous Papuan Medical College, following the model in Fiji.1 The challenge of public health in AustraliaMy interest in public health arose from a number of factors. Firstly, although trained in internal medicine and endocrinology, I had a strong interest in psychosocial aspects of health and disease. This interest became explicit during my 3 years as a Research Fellow in New York studying the relationship between psychosocial stress and physical illness.1 Secondly, my experience in PNG stimulated my interest in the health services of developing countries, particularly when I first clearly recognised the importance of the organisation of health services. I was impressed with the very effective organisation of services in PNG, including the provision of services at village level through the Aid Post Orderly and the organisation at district and regional level, with the result that PNG had a major public health program embracing the whole country. The Director was Roy Scragg, from Adelaide, who provided visionary leadership over 12 years. Finally, Australian Frontier (1963–1972), established by the Australian Council of Churches, provided me with experience of a social mechanism for helping communities develop their own ways of dealing with social problems through promoting human values. Special health problems explored by Australian Frontier included the needs of migrants and Indigenous people, as well as elderly, young, disadvantaged, poor and disabled people — a good introduction to social medicine! In 1967, these experiences together led me to apply for and then be appointed to the Foundation Chair of Social and Preventive Medicine in the new medical school at Monash University, Melbourne. In teaching with a small, dedicated staff, we adopted the “ecological model” of health, which included human biology, environment, lifestyle and health services.1 This involved the discipline of epidemiology. I was particularly interested in bridging the gap between research and action. At Monash University, between 1968 and 1976, we conducted various epidemiological studies related to the rapidly expanding metropolis of Melbourne. We began with studies of suicidal behaviour and the management of traffic casualties. These were followed by studies of the mental health of students, the health and health behaviour of Indigenous people, the reproductive behaviour of Greek migrant women, and more general studies of women’s health.1 All of these projects required epidemiological data. Studies were carried out by a series of research fellows who completed higher degrees with the assistance of Tony Ryan, a Senior Lecturer who had recently had postgraduate training in epidemiology at the Harvard School of Public Health. These studies led at the time to innovations in the provision of community services — such as the Lifeline Service in Melbourne; an Aboriginal Health Service managed by Indigenous people in Alice Springs; interpreter services for Greek and other migrants in Melbourne hospitals; and improved services at the Alfred Hospital emergency department for traffic casualties and victims of self-poisoning. In addition, we developed a Community Health Centre in Prahran, following an earlier health survey that showed the need for both health and social services to be available at one site.6 This was a very hot political potato at the time (1973–1974), in the face of opposition from most of the local general practitioners and an Australian Medical Association resolution condemning me for the initiative! After an uncertain beginning, the centre became well established in meeting the needs of the people of Prahran. I became interested in the challenge of bridging the gap between epidemiological findings and their public health application, with particular reference to road safety campaigns. The first major success in this area was in 1971, when legislation was introduced to make the wearing of seatbelts compulsory. I developed my “wheel” model for the social learning process in relation to seatbelt legislation and then proceeded to apply it to the development of random breath testing (RBT) legislation (Box 1). The process begins with collecting and analysing epidemiological data, then disseminating them in suitable form through the media. This leads to wide public discussion. When a consensus emerges, a plan is designed to tackle the problem that has been defined by the data and the discussion. Political agreement is required before the necessary legislation can be passed. After the legislation has been introduced, the program is implemented and evaluated. Evaluation requires collection of new data, which then provide the basis for the next cycle. I used this model in relation to a series of public health issues.1 1 My “wheel” model, showing the social process involved in public health advancement in relation to blood alcohol levels and random breath testing legislation Much later, I was able to review subsequent data on alcohol consumption, which indicated that up to 1975 there had been a steady increase in national consumption to the level of 10 L per person per year. By 1997, this figure had dropped to 7.6 L. The fall began in 1983, which was after the adoption of RBT in Victoria (1979), South Australia (1981) and New South Wales (1982). There had therefore been a change in drinking behaviour after the introduction of RBT, and this change has persisted. Such a change in Australian drinking habits would not previously have been thought possible! The invitation to give the 1971 Boyer Lectures for the Australian Broadcasting Commission was a big shock! I chose the topic “Life and health in Australia”, which was based on the teaching and research work of the young Monash University department (Box 2).7 The lectures were later expanded into a book, Health and Australian society,8 first published in 1974, with two subsequent editions in 1976 and 1980. The first book of its kind, it was used as a student text for teachers, nurses, social workers, physiotherapists and medical students. I was pleased to discover it was also read by politicians! 2 “Life and health in Australia”, my presentation for the 1971 ABC Boyer Lectures The Boyer Lectures and the book, together with other press coverage of our work, introduced public health and epidemiology to the public in the form of major modern Australian epidemics such as traffic crashes, suicidal behaviour, coronary heart disease and cancer of the lung. In the 1970s, this was new information to the public and caught media attention. Public perceptions of epidemiology have expanded greatly since then, so that the media are now well aware of the discipline in relation to heart disease, cancer, the effects of Agent Orange, infectious diseases and many other problems. This greater public awareness has been very important for public health. Public health nutrition in AustraliaThe redirection of the Animal Nutrition Division of the Commonwealth Scientific and Industrial Research Organisation (CSIRO) to become the Division of Human Nutrition gave me a remarkable opportunity — unprecedented for a medical graduate — when I was appointed Chief and took up my position in 1976. In my plan, I proposed a study of the relationship between diet and “diseases of affluence” (particularly coronary heart disease and cancer) using a multidisciplinary approach involving epidemiology, behavioural science, nutrition, physiology and biochemistry. A staff of 80 enabled me to develop this approach. A book called The LS factor — lifestyle and health, written by Senior Epidemiologist Tony McMichael and myself, described research at the Division over a 10-year period (1976–1985). It covered areas such as diet; diet and cardiovascular disease; diet and cancer; alcohol and tobacco consumption; stress; and the development of preventive services.9 Our book has even been translated into Chinese! Iodine deficiency in PNGOur work in New Guinea, carried out in collaboration with the PNG Public Health Department, raised my awareness of the problem of iodine deficiency. This problem eventually took over my life after I formally retired from the CSIRO at the end of 1985. Combating iodine deficiency has been for me a great personal adventure in international health. It all began in 1963, when I was asked by the Editor of the Medical Journal of Australia to review an article by Terry McCullagh on the use of injections of iodised oil (Lipiodol) in PNG.10 This was new technology proposed to help control the severe goitre problem (Box 3) in remote villages in the highlands where iodised salt (the usual remedy for the problem) could not be easily introduced. An initial controlled trial carried out by McCullagh, at the request of the Director of Public Health, John Gunther, showed that one injection of iodised oil would prevent goitre for up to 3 years.10 However, in 1963, it was not known whether iodine deficiency was present in PNG. 3 Severely iodine-deficient mother and child, Papua New Guinea The mother has a large goitre and the child is also affected. Cretinism in a child can be prevented by correcting iodine deficiency before the onset of pregnancy.1 In due course, our laboratory studies in collaboration with the PNG Public Health Department revealed that there was severe iodine deficiency and that it could be corrected for up to 5 years by a single dose of Lipiodol.11 Apart from the very large and frequent goitres seen in the villagers, there were many severely brain-damaged people who were also deaf-mute and often had a squint and a spastic weakness of the limbs (Box 4). This condition (“cretinism”) was being reported at the time in similar remote mountainous regions of South America, India and China, and had been observed earlier in Europe.12 There was considerable dispute as to whether or not the condition was related to iodine deficiency. It had apparently spontaneously disappeared in various parts of central and southern Europe without any known correction of the iodine deficiency. After we had successfully demonstrated the long duration of the effect of a single iodine injection, I realised that with iodised oil we had the means to carry out a controlled trial (which would not have been possible with iodised salt) to see whether correcting severe iodine deficiency would prevent cretinism. After approval by the PNG Research Advisory Committee, the trial was set up in the Western Highlands north of Mount Hagen. In collaboration with the PNG Public Health Department, we began the trial at the time of the first census in 1966. Families were alternately given injections of iodised oil or saline. Over the next 3 years, follow-up assessments of brain damage in young infants were carried out without knowledge of which injections the mother had received (ie, double-blinded). Particular attention was paid to the motor milestones, such as age of sitting up and walking. Any evidence of deafness reported by the mother was confirmed by a simple tuning-fork test. This critical phase was undertaken double-blind with great skill and dedication by Peter Pharoah, an experienced PNG medical officer who was seconded to this work by the Public Health Department at my request. After more than 3 years of careful and laborious work, involving Pharoah in extensive climbing to reach the mountain villages, the code was broken. There was no doubt that mental retardation (evident in 26 cases in the control group) had been prevented by injection of iodised oil before pregnancy. In six of the seven retarded infants born to mothers treated with iodised oil, the mothers were already obviously pregnant when injected, and there was doubt about the birth date of the seventh infant. 4 A young Papua New Guinean cretin with squint, ataxia and mental deficiency After completion of the study, injections of iodised oil were given to 120 000 people in the highlands, and an iodised salt program was introduced. The report of this work was published in the Lancet13 and was duly accepted as definitive.14 The spontaneous decline in iodine deficiency in Europe has since been attributed to diversification of the diet, associated with economic and social development, and the use of iodine supplements.12 The finding clearly demonstrated, for the first time, that the cretinism observed was the result of fetal iodine deficiency in the first half of pregnancy. The trial also showed the effectiveness of prevention by correction of the deficiency before pregnancy. Unfortunately, although this form of cretinism is preventable, it is not reversible.12 Animal modelsDuring the 1970s, it became apparent to me that there was a great gap between our knowledge of the effects of iodine deficiency on brain development and its application in the developing world. More evidence was needed. One of the factors leading me to take the position at the CSIRO was the possibility of developing an animal model to confirm the effect of iodine deficiency on fetal brain development. This was duly done (for the first time) both in the sheep and the marmoset monkey over the period 1976–1985 by an excellent CSIRO team with past experience of trace element deficiencies in sheep.15 These animal studies indicated the significant effects of iodine deficiency on growth and development. The effects on the brain were part of a spectrum of effects including abortion and stillbirths as well as goitre, brain damage and growth retardation of the fetus. A new concept — the iodine deficiency disordersClearly, a new concept beyond that of “iodine deficiency and goitre” was needed to better reflect the increase in knowledge that had occurred over the preceding 25 years, particularly in relation to brain development. After much pondering and two stimulating visits to China, and with the sympathetic encouragement of colleagues, I proposed the epidemiological concept of “iodine deficiency disorders” (IDDs) to denote all the effects of iodine deficiency on the growth (and especially brain development) of a population that could be totally prevented by correcting the iodine deficiency (Box 5).16 This concept was rapidly adopted internationally — the term was even used in China without translation! My Chinese colleague pointed out that Confucius would have approved of the term, as it referred to the primary cause and would therefore lead to appropriate measures for control! International actionThe announcement by the World Health Organization of the global eradication of smallpox in 1980 encouraged me to raise the possibility of eradicating IDDs with available technology using iodised salt or iodised oil.16 In China (1981–1984) and Indonesia (1976–1981) I had seen the massive nature of the problem of iodine deficiency. The WHO subsequently estimated that there were two billion people at risk in 130 countries and recognised iodine deficiency as the most common preventable cause of brain damage.17 Preventive measures suitable for mass application (use of iodised salt or iodised oil) and simple methods of epidemiological monitoring and surveillance (salt iodine and urine iodine measurements) were available. However, there was great delay in applying existing knowledge on IDDs to preventive programs in areas of need — to the detriment of the many millions in developing countries who were suffering irreversible brain damage due to iodine deficiency. In a report to the United Nations (UN) Nutrition Subcommittee, I stressed my concern about the gap between knowledge and application. To help bridge the gap, I proposed that an expert consultative group of scientists and other public health professionals be established to help develop national IDD control programs in collaboration with the WHO and UNICEF.1 The International Council for Control of Iodine Deficiency DisordersThe decision to establish the International Council for Control of Iodine Deficiency Disorders (ICCIDD) was made in Delhi, India, in March 1985, when I put the proposal to a group of 10 consultants and advisers who were attending a WHO/UNICEF workshop on the control of IDDs in South-East Asia. This was followed by an inaugural meeting, supported by WHO and UNICEF, in Kathmandu, Nepal, in 1986 (Box 6).18 I became Executive Director, and later Chairman, of the ICCIDD. The ICCIDD now consists of a multidisciplinary international expert network of 700 endocrinologists, epidemiologists, nutritionists, public health administrators, technologists, communicators, economists and others from 100 countries, with a majority from developing countries, who are committed to helping national governments and international agencies develop national programs to eliminate IDDs as a public health problem.19 Since 1986, the ICCIDD has held a series of regional meetings with the WHO and UNICEF to foster the development of national control programs. The meetings have been attended by ministry of health representatives from countries in the region. I adapted my social process wheel model (Box 1) to the IDD elimination program.19 Particular importance was given to political will, which had been lacking in the past but had now been mobilised through the UN system, particularly the World Summit for Children, held in 1990. The outcome of the Summit was a declaration signed by 71 heads of state and eventually by 88 other governments. The declaration accepted a series of goals for the better health and education of children throughout the world, including the virtual elimination of IDDs by the year 2000. A report to the 1999 World Health Assembly (WHA) indicated that, of the 130 countries that had a significant IDD public health problem, two-thirds had introduced universal salt iodisation programs. Between 1990 and 1998, the number of countries with salt iodisation programs had increased from 46 to 93.17 However, there is a need to ensure the sustainability of this achievement. This depends on epidemiological surveillance with urine iodine measurements to confirm the absence of iodine deficiency. Sustainable elimination of IDDs is only possible if surveillance continues — recurrence can readily occur, and has indeed occurred.17,19,20 In 2001, the ICCIDD adopted a mandate for the future dedicated to the elimination of iodine deficiency as a cause of brain damage (Box 7).20 At the 2005 WHA, Canada and Australia proposed a resolution requiring countries to report to the WHA on the monitoring of their iodine deficiency elimination programs in 2007 and every 3 years thereafter. The resolution was adopted and provides the necessary political support for future sustainability of the programs. I believe the non-government organisation model is relevant to many other international health problems. A multidisciplinary group of concerned scientists and public health professionals can come together to define a problem and then develop a program designed to solve the problem in collaboration with UN agencies.12,19,20 ConclusionIt has been a great experience to assist in the development of a UN program to eliminate iodine deficiency — the most common preventable cause of brain damage. The program was made possible by targeted research that established the relationship between iodine deficiency and brain damage — research that included epidemiological study in the field in PNG and later studies in animal models. Rapid development of the elimination program was made possible by the effectiveness of introducing iodised salt as a population measure and the application of a simple laboratory method to determine urine iodine levels as a marker for iodine deficiency and to correct any deficiency in populations. A dedicated group of multidisciplinary professionals in the ICCIDD provided the scientific leadership in collaboration with national governments, the WHO and UNICEF, assisted especially by aid programs of Australia, Canada and the World Bank. I have been very fortunate, for more than 50 years, in the people I have been associated with — my family, friends and colleagues have always been a support and inspiration to me. 5 Iodine deficiency disorders by stage of human development16 Fetus Abortions Stillbirths Congenital anomalies Increased perinatal mortality Neurological cretinism (mental deficiency, deaf-mutism, spastic diplegia, squint) Hypothyroid cretinism (dwarfism, mental deficiency) Psychomotor defects Neonate Goitre Hypothyroidism Child and adolescent Goitre Hypothyroidism Impaired mental function Retarded physical development Adult Goitre Hypothyroidism Impaired mental function Iodine-induced hyperthyroidism All ages Increased susceptibility to nuclear radiation 6 Inauguration of the International Council for Control of Iodine Deficiency Disorders (ICCIDD), Kathmandu, Nepal, 1986 L – R: Basil Hetzel, Executive Director (Australia), John Dunn, Secretary (USA), and John Stanbury, Chairman (USA). Inset: the logo adopted by the ICCIDD emphasises the importance of the effects of iodine deficiency on the brain. 7 International Council for Control of Iodine Deficiency Disorders (ICCIDD) mandate, 2001 The vision of the ICCIDD is a world virtually free from iodine deficiency disorders, with national endeavours in each country to maintain optimal iodine nutrition, primarily through universal consumption of iodised salt. The mission of the ICCIDD is to advocate to governments, citizens and development agencies a priority commitment to normal iodine nutrition through a multidisciplinary approach that involves all relevant partners. The ICCIDD believes that country programs must be fully supported nationally for sustained success and will work with all partners and national entities towards that end.

Basil S Hetzel AC, MD, FRCP, FRACP, FFPHM, FAFPHM, FTSE

1 Café-au-lait spots with “coast of Maine” appearance 2 Computed tomography scan of the thorax showing multiple rib lesions A 46-year-old man presented with generalised bone pain which had been present for approximately 15 years. His past history was significant for a precocious puberty, with full development of secondary sexual characteristics by 9 years of age. His adult height was 165 cm. Physical examination showed multiple café-au-lait spots with typical “coast of Maine” appearance (Figure 1). Routine laboratory tests gave normal results, except for levels of inorganic phosphate (0.71 mmol/L; reference range, 0.81–1.45 mmol/L) and alkaline phosphatase (286 U/L; reference range, 31–93 U/L). A chest x-ray showed multiple ill-defined radiolucent lesions in the ribs. A computed tomography scan of the thorax showed multiple expansile lytic rib lesions, with a peripheral rim of calcification consistent with polyostotic fibrous dysplasia (Figure 2). The coexistence of precocious puberty, café-au-lait spots and polyostotic fibrous dysplasia constitutes the McCune–Albright syndrome.1 The pathogenesis involves mutation in the Gsα gene located at chromosome 20q13.2-13.3. All cells carrying this mutation manifest dysplastic features. This case highlights the importance of history and physical examination in establishing a correct diagnosis, which in this case was missed for several years.

Mehdi Hamadani MD · Lubna Chaudhary MD

Objective: To determine the influence of obesity on the diagnosis of age-related androgen deficiency (AD) in symptomatic men according to current Australian guidelines.Design, setting and participants: A community-based cohort of healthy ageing men with symptoms suggestive of AD was studied between May 2001 and February 2003. Men were classified as obese or non-obese according to body mass index (BMI) or waist circumference (WC).Main outcome measure: Diagnosis of AD according to Endocrine Society of Australia (ESA) guidelines.Results: 223 men aged 54–86 years with mean BMI 27.3 ± 0.2 kg/m2 (range 20.5–36.2 kg/m2) were recruited; 99 men were obese (BMI ≥ 30.0 kg/m2 or WC ≥ 102 cm) and 124 men were non-obese. Obese men had lower total testosterone (TT) (12.7 ± 0.4 v 15.0 ± 0.4 nmol/L); P < 0.001) and calculated free testosterone (275.7 ± 7.8 v 299.3 ± 7.4 pmol/L); P = 0.03) levels than non-obese men. TT levels < 8 nmol/L were recorded in 12% of obese men and 1% of non-obese men. Applying the ESA guidelines for the diagnosis of age-related AD, 15 obese men (15%) and 4 non-obese men (3%) were classified as being eligible for androgen therapy supported by the Pharmaceutical Benefits Scheme (PBS); the relative risk in obese men was 1.92 (95% CI, 1.44–2.55; P < 0.001).Conclusion: Obesity is an important determinant of serum TT levels in ageing men. Almost one in seven obese men but only one in 30 non-obese men in our study were eligible for PBS-supported androgen therapy according to Australian guidelines. Although obese men are more likely to have biochemical hypoandrogenism, the clinical implications of this remain uncertain. Studies of testosterone therapy in this group of ageing men are needed to determine whether androgen replacement is beneficial.

Carolyn A Allan PhD, FRACP · Boyd J Strauss PhD, FRACP · Henry G Burger MD, FRACP · Elise A Forbes RN · Robert I McLachlan PhD, FRACP

Metabolic syndrome (MS) refers to the clustering of cardiometabolic risk factors — including abdominal obesity, hyperglycaemia, dyslipidaemia and elevated blood pressure — that are thought to be linked to insulin resistance. MS is associated with increased risk of cardiovascular disease and type 2 diabetes. MS is common, affecting a quarter to a third of adults, and its prevalence is rising, in parallel with increasing obesity and population ageing. Operational definitions of MS have been proposed by the World Health Organization and the National Cholesterol Education Program. Recently, the International Diabetes Federation proposed a global definition that emphasised the importance of central adiposity. In cardiovascular risk assessment, MS encapsulates the contribution of non-traditional risk factors and provides a clinically useful framework for early identification of people at increased long-term risk. It should be used in conjunction with standard algorithms based on conventional risk factors, which better predict short-term risk. Management of MS should emphasise lifestyle interventions (eg, physical activity, healthy diet and weight reduction) to reduce long-term risk of cardiovascular disease and diabetes. Those at increased short-term risk should also have individual risk factors treated according to established guidelines.

Gerard T Chew MB BS(Hons), FRACP · Seng Khee Gan MB BS, FRACP, PhD · Gerald F Watts DSc, MD, FRACP

Objective: To review the management of glycaemia, blood pressure and serum lipids in a hospital outpatient diabetes clinic, the director of which co-authored the current national diabetes management guidelines.Design: Retrospective audit.Setting: Outpatient diabetes clinic in a tertiary referral teaching hospital, Sydney, NSW.Study population: 96 patients with type 1 diabetes (mean age, 44.4 [SD, 12.8] years) and 509 patients with type 2 diabetes (mean age, 64.4 [SD, 12.0] years) attending the clinic in 2003, who had undergone formal review of complications.Main outcome measures: Weight, height, control and treatment of glycaemia, blood pressure and serum lipids, and prevalence of diabetic microvascular complications.Results: Glycated haemoglobin (HbA1c) was < 7% in 13% of type 1 and 30% of type 2 diabetes patients, and > 8% in 47% and 34%, respectively. 35% of patients with type 1 diabetes and 71% of patients with type 2 diabetes were treated with antihypertensive agents. Of these patients, 29% and 24%, respectively, had blood pressure readings ≤ 130/80 mmHg. Among patients not treated with hypertensive agents, blood pressure readings were ≤ 130/80 mmHg in 60% of type 1 and 38% of type 2 diabetes patients. About 30% of patients with type 1 diabetes and 50% of those with type 2 diabetes were being treated with lipid-lowering agents; of these, about 60% had low-density lipoprotein (LDL) cholesterol levels < 2.6 mmol/L. Among patients not treated with lipid-lowering agents, about 40% had LDL cholesterol levels < 2.6 mmol/L. Retinopathy was documented in 52% and 18%, and nephropathy in 9% and 36% of type 1 and type 2 diabetes patients, respectively.Conclusions: Despite the demonstrated benefits of tight glucose, blood pressure and lipid control in reducing the risk of macrovascular and microvascular complications in type 1 and type 2 diabetes, our results suggest that treatment targets are not being met in a large proportion of patients attending a tertiary referral hospital. Responsible practice suggests that treatment targets and the current means to achieve them should both be examined.

Wendy Bryant,* RN, CDE, GradDipDiabetesEdManagement · Jerry R Greenfield,* PhD, FRACP · Donald J Chisholm FRACP · Lesley V Campbell FRCP, FRACP

To the Editor: The Australian Fracture Prevention Summit held in 2002 recognised osteoporosis as a major public health issue. Despite this, several Australian studies have found that a majority of patients with osteoporosis-related fractures do not receive appropriate evaluation and treatment as recommended by the clinical guidelines.1-4 In 2003, the Queen Elizabeth Hospital, a tertiary referral hospital which services the north-western suburbs of metropolitan Adelaide, implemented a novel approach to improve the secondary prevention management of patients admitted to the orthopaedic unit with fragility fractures. The strategy was based on the “plan-do-study-action” principle of medical quality improvement, with the primary goal of enhancing performance.5 Before commencing, a retrospective case-note review of 40 consecutive patients who had been admitted to the orthopaedic unit with osteoporotic fractures revealed that, at discharge, none were receiving any medication for osteoporosis. Patients over the age of 50 years who had been admitted with fragility fractures were identified from computer records. With the support of a physician and junior medical staff, a clinical pharmacist provided individual counselling, written materials and osteoporosis therapy. The rate of medication prescription was initially assessed at discharge. In a follow-up telephone interview, participants were queried about the continuation of osteoporosis therapy, performance of investigations by general practitioners, and history of falls. Over a 10-month period, of 259 patients admitted with fragility fractures, 228 patients (88%) were prescribed osteoporosis therapy (calcium, vitamin D and risedronate) on discharge. Of those eligible, 65 patients participated in the follow-up audit. Forty-eight patients (74%) continued to take medications for osteoporosis as initially prescribed; only 28% had had laboratory investigations for osteoporosis and 31% a bone mineral density test. In addition, three patients had experienced recurrent falls complicated by further fragility fractures. The appointment of an allied health champion with clinical backup from a general physician appeared to have achieved a high level of initiation and continuation of osteoporosis pharmacotherapy in at-risk patients during hospital admission. The low rate of follow-up investigations is consistent with previously published data suggesting poor community-based follow-up after hospital discharge of patients admitted for osteoporotic fractures. The major limitation of this clinical pathway is the low rate of patient participation in the follow-up audit. Therefore, the results of follow-up data cannot be said to be representative of the cohort. This study highlights the importance of the participation of GPs in maintaining patient compliance with hospital-initiated programs, especially those involving chronic illnesses.

Tim Yu-Ting Lu · Jennifer A Pink · Lauren E Whitten · Catherine L Hill · Robert J Adams · Catherine Gibb

Clinical record A 15-year-old boy developed recurrent, severe occipital headache, with vomiting, lethargy and blurred vision, after a minor head injury without loss of consciousness. The headache was dull and tense, exacerbated by activity and ameliorated by sleep, but unaffected by a change of posture. A week after the head injury, his general practitioner found him to be neurologically normal. The results of a non-contrast cerebral computed tomography scan were also normal. Based on a history of reversible wheeze and cough, the patient had been diagnosed with asthma at 12 years of age. He was strictly compliant with his prescription of inhaled fluticasone propionate (1000 μg/day via accuhaler) and rinsed his mouth after use. As instructed, he doubled the dose of inhaled corticosteroids during acute attacks, which occurred twice a year. There were no interval symptoms. Nonetheless, his dose of inhaled corticosteroids was never reduced. Before being prescribed inhaled corticosteroids, he had been prescribed nasal steroids for allergic rhinitis and nasal polyps, but rarely required this after a successful surgical intervention. He was not taking any other medications or vitamins. A year before presentation, he had had an episode of witnessed collapse with spontaneous recovery. This was attributed to a vasovagal attack at the time. Paediatric assessment 1 month after the head injury showed that he was lean and healthy. His weight (49 kg) and height (160.2 cm) were on the 25th centiles, and his body mass index (19 kg/m2) was on the 30th centile. His head circumference (56.8 cm) was on the 75th centile. Neurological examination gave normal results. A Mini-Mental State Examination identified a short-term memory deficit (2/3 objects recalled). The results of a cardiovascular examination were normal except for hypertension (140/70 mmHg; > 97th centile). There were no renal bruits. Urinalysis gave normal results. He was clinically euthyroid, and had no cutaneous hypo- or hyperpigmentation or signs of Cushing syndrome. He was diagnosed with postconcussion syndrome and reactive hypertension. An ophthalmological assessment identified normal visual fields and acuity and no papilloedema. The fluticasone propionate dose was reduced to 500 μg/day with a view to gradually stopping it altogether. Over the following 2 weeks, his headache worsened in intensity and frequency. An electroencephalogram and cerebral magnetic resonance scan were normal. Amitriptyline (25 mg/day) was prescribed for the headache, without effect. Two months after the paediatric assessment, lumbar puncture, performed under chloral hydrate sedation when relaxed with the back fully extended, showed an elevated cerebrospinal fluid (CSF) opening pressure of 24 cmH2O (reference range, 10–20 cmH2O).1,2 The procedure resulted in immediate headache relief. Examination of the CSF showed no abnormalities. Benign intracranial hypertension was diagnosed and he was prescribed oral acetazolamide (250 mg four times daily). His inhaled corticosteroid therapy was discontinued. Persistent mild hypertension (130/70 mmHg; 97th centile) was again noted on repeated occasions. The results of investigations (including renal function, urinalysis, renal ultrasound, full blood count, inflammatory markers, complement factors, antinuclear antibody, electrocardiography, chest x-ray, thyroid function, plasma renin activity, and urinary catecholamines) were normal and did not reveal a secondary cause of the hypertension. However, the morning cortisol level was undetectable (< 6 nmol/L). A morning short Synacthen test (250 μg) confirmed adrenal suppression, with a suboptimal cortisol rise from baseline of 175 nmol/L to a 1-hour peak of 275 nmol/L (reference, > 600 nmol/L). A paired adrenocorticotropic hormone (ACTH) level was 15 pmol/L, not consistent with primary adrenal disease. In view of the adrenal suppression, he was prescribed oral hydrocortisone (20 mg three times daily) for periods of acute physiological stress. Over the ensuing months, he required multiple therapeutic lumbar punctures, with immediate headache relief on each occasion. The acetazolamide dose was ceased 2 months after initiation. His hypertension resolved 4 months after presentation and the headaches resolved after 9 months. During recovery, he used “stress” hydrocortisone for two episodes of fever and lethargy. Serial (3-monthly) morning short Synacthen tests (250 μg) were performed. By 12 months, he had a normal peak cortisol response (657 nmol/L) and a baseline ACTH level of 7.3 pmol/L. Steroid precautions were then discontinued. Ophthalmological review now identified a cotton-wool spot on the inferotemporal edge of the right optic disc, suggestive of a past axoplasmic blood flow impediment caused by raised intracranial pressure. The temporal association between his headache severity, CSF opening pressures and cortisol levels is shown in the Box. Benign intracranial hypertension has an incidence of 1 per 100 000 children.3 As “benign” belies the potentially debilitating nature of this disorder, including the risk of irreversible blindness,4 the synonyms “pseudotumor cerebri” and “idiopathic intracranial hypertension” are sometimes preferred. Although the pathophysiological basis has not been determined, benign intracranial hypertension has been associated with vitamin deficiencies and toxicities, obesity, head injury,5 adrenal insufficiency,6 and medications, including topical and systemic steroids.7-9 To the best of our knowledge, this is the first reported association between benign intracranial hypertension and inhaled corticosteroids (we conducted a MEDLINE search, using multiple search terms, of English language publications from 1966 to June 2005). The diagnosis of benign intracranial hypertension in our case was based on modified Dandy’s criteria, an elevated cerebrospinal fluid (CSF) opening pressure (using the paediatric reference range),1,2 and repeated instances of immediate headache relief with lumbar puncture. The ophthalmological findings were non-specific but supported the diagnosis. Magnetic resonance venography would have excluded venous sinus thrombosis (an important cause of benign intracranial hypertension), but there was no reason to suspect a hypercoagulable tendency. As the CSF opening pressure was first measured 2 months after the patient sustained a minor head injury, we cannot determine whether this injury was the trigger for benign intracranial hypertension or incidental to it. However, the injury alone cannot explain the benign intracranial hypertension in this patient, given its mild nature and the absence of any radiological evidence of parenchymal brain injury. The adrenal suppression was most likely secondary to inhaled corticosteroid therapy. This is supported by the gradual adrenal recovery after withdrawal of inhaled corticosteroids. The past history of collapse suggests the onset of the adrenal suppression may have occurred 1 year before presentation. Given the absence of papilloedema at presentation, and the fact that the headache and elevated CSF opening pressure were clearly temporally associated with the withdrawal of inhaled corticosteroids, we suggest that the benign intracranial hypertension was related to the withdrawal of the steroid dose. Benign intracranial hypertension has previously only been reported in cases of primary adrenal insufficiency (Addison disease),6 or in association with the use or withdrawal of topical, oral or intranasal corticosteroids.7-9 Clinicians should be mindful of benign intracranial hypertension as a potential side effect when prescribing inhaled corticosteroids. Our case emphasises the importance of using appropriate inhaled corticosteroid dosage and “back titration”. Patients receiving inhaled corticosteroids require regular review. Dosages should be monitored to achieve the minimal dose for symptom control.10 Temporal association between headache severity, cortisol levels, and cerebrospinal fluid opening pressure Medication: F = fluticasone propionate (initially 1000 μg/day); A = acetazolamide (initially 1000 mg/day). CSF = cerebrospinal fluid.

Patrick Patradoon-Ho FRACP · Hasantha Gunasekera MIPH(Hons), FRACP · Monique M Ryan MMed, FRACP · Geoffrey R Ambler MD, FRACP

Insulin resistance is considered a core component in the pathophysiology of the metabolic syndrome. Some clinicians measure serum insulin concentrations in the mistaken belief that they can be used to diagnose insulin resistance. Serum insulin levels are poor measures of insulin resistance. Furthermore, there is no clinical benefit in measuring insulin resistance in clinical practice. Measurements of fasting serum insulin levels should be reserved for large population-based epidemiological studies, where they can provide valuable data on the relationship of insulin sensitivity to risk factors for diabetes and cardiovascular disease. Clinicians should shift from identifying “insulin resistance” to identifying risk factors, such as fasting glucose and lipid levels, hypertension and central obesity. These proven risk factors converge within the metabolic syndrome. Individuals “at risk” of diabetes and atherosclerotic cardiac disease can be identified simply and inexpensively, using classic clinical techniques, such as history-taking, physical examination, and very basic investigations.

Katherine Samaras MB BS, PhD, FRACP · Aidan McElduff MB BS, PhD, FRACP · Stephen M Twigg MB BS, PhD, FRACP · Joseph Proietto MB BS, PhD, FRACP · John B Prins MB BS, PhD, FRACP · Timothy A Welborn MB BS, PhD, FRACP · Paul Zimmet AO, MB BS, MD, FRACP · Donald J Chisholm MB BS, MRACP, FRACP · Lesley V Campbell MRCP, FRCP, FRACP

Objective: To assess the impact of structured diabetes care in a rural general practice.Design and setting: A cohort study of structured diabetes care (care plans, multidisciplinary involvement and regular patient recall) in a large general practice in a medium-sized Australian rural town. Medical care followed each doctor’s usual practice.Participants: The first 404 consecutive patients with type 2 diabetes who consented to take part in the program were evaluated 24 months after enrolment in July 2002 to December 2003.Main outcome measures: Change in cardiovascular disease risk factors (waist circumference, body mass index, serum lipid levels, blood pressure); change in indicators of risks associated with poorly controlled diabetes (glycated haemoglobin [HbA1c] concentration, foot lesions, clinically significant hypoglycaemia); change in 5-year cardiovascular disease risk.Results: Women had a lower 5-year risk of a cardiovascular event at enrolment than men. Structured care was associated with statistically significant reductions in mean cardiovascular disease risk factors (waist circumference, − 2.6 cm; blood pressure [systolic, − 3 mmHg; diastolic − 7 mmHg]; and serum lipid levels [total cholesterol, − 0.5 mmol/L; HDL cholesterol, 0.02 mmol/L; LDL cholesterol, − 0.4 mmol/L; triglycerides, − 0.3 mmol/L]); and improvements in indicators of diabetic control (proportion with severe hypoglycaemic events, − 2.2%; proportion with foot lesions, − 14%). The greatest improvements in risk factors occurred in patients with the highest calculated cardiovascular risk. There was a statistically significant increase in the proportion of patients with “ideal” blood pressure (systolic, < 130 mmHg; diastolic, < 80 mmHg) and LDL cholesterol level (< 2.5 mmol/L) of 6.4% and 20.5%, respectively.Conclusions: Implementing structured care in this rural general practice coincided with improved risk factor management, and may have contributed to the improvement. The greatest benefits were in patients with high cardiovascular risk.

Evan W Ackermann FRACGP, DRACOG · Geoffrey K Mitchell FRACGP, PhD