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Diabesity 2016; 2 (1): 1- 11 doi: 10.15562/diabesity.2016.21 www.diabesity.ejournals.ca REVIEW

Hyperinsulinemia: Best management practice

Catherine A.P Crofts*1, Caryn Zinn1, Mark C Wheldon2, Grant M Schofield1

ABSTRACT

Chronic hyperinsulinemia associated with resistance is directly and indirectly associated with many metabolic disorders that contribute to significant morbidity and mortality. Because hyperinsulinemia is not widely recognised as an independent health risk, there are few studies that assess management strategies. Medication management may not address the multiple issues associated with hyperinsulinemia. Lifestyle management includes physical activity, especially high intensity interval training, and dietary management. Reducing quantity and increasing nutrient density are discussed with carbohydrate-restricted and Mediterranean diets conferring additional benefits to a low- diet. Physical activity and dietary management provide the foundation for hyperinsulinemia management and may work synergistically. Of these principles, a combination of resistance and high intensity interval training, and carbohydrate restriction provide the two most effective frontline management strategies for managing hyperinsulinemia. Keywords: Hyperinsulinemia, , type 2 , , secretagogue, syndrome x

symptomatic improvement of conditions associated Introduction with hyperinsulinemia such as polycystic ovarian Compensatory hyperinsulinemia (further syndrome (PCOS). referred to as "hyperinsulinemia") is associated, There are two main strategies for managing mechanistically and epidemiologically, with many hyperinsulinemia: maximising insulin sensitivity and chronic metabolic diseases.1, 2 The aetiology of reducing glycemic load. Insulin sensitivity can be hyperinsulinemia is likely heterogeneous2 and in the maximised via up-regulating GLUT4 or insulin earliest stages asymptomatic.3 Early management of receptors, or by preventing (further) insulin resistance. hyperinsulinemia may prevent, delay, or mitigate the Glycemic load may occur through two main pathways, severity of subsequent pathologies. Although endogenous through metabolic pathways such as hyperinsulinemia is a common co-pathology with gluconeogenesis, glycolysis, or renal reabsorption4, and impaired glycemic control, this paper focuses on the exogenous via dietary intake. management of hyperinsulinemia in the presence of There are three main mechanisms to achieve normal glucose tolerance. each of these strategies: Physical activity, diet, and There are several different states that depict medicines and other supplements. the continuum that reflects healthy insulin response through to hyperinsulinemia. It is proposed that Methodology people transition between different states, which may Literature was reviewed on hyperinsulinemia be either acute or chronic, depending on the and insulin resistance, targeting full-text English circumstances at the time, and may be subject to language studies. There was no date criterion. Articles change. The close relationship between the two were selected on the basis of having a minimum of different states of hyperinsulinemia and insulin both a plausible biological mechanism and established resistance can also be noted. This means that as well as clinical association. An academic database search targeting insulin levels directly, strategies that improve included EBSCO, Medline and Google Scholar, using insulin sensitivity, especially the up-regulation of variants of the terms “hyperinsulinemia,” “insulin glucose transporter type 4 (GLUT4), will also reduce resistance,” “,” and “metabolic hyperinsulinemia. As there are few studies that directly syndrome,” and each of these terms in conjunction assess hyperinsulinemia management strategies, this with variants of “diet,” “nutrition,” “physical activity,” review will include strategies that improve glycemic “pharmacology,” and “treatment.” References were control in the absence of evidence of increased insulin based on the authors’ judgment of relevance, secretion. It will also consider strategies that provide

 Corresponding Author, E-mail: [email protected]. 1Human Potential Centre & 2Biostatistics and Epidemiology, Auckland University of Technology (AUT), PO Box 92006, Auckland 1142, New Zealand. Copyright: © 2015 The Authors. This is an open-access article distributed under the terms of the Creative Commons Attribution License. Hyperinsulinemia: Best management practice … Catherine Crofts et al. completeness, and compatibility with clinical, other studies comparing aerobic to resistance training, epidemiological, pathological and biochemical criteria. which only showed improvements in glucose disposal when the results were expressed per kilo of fat-free- Physical activity mass. Physical activity is well-documented for While resistance training is believed to improving insulin sensitivity. Mechanistically this enhance cellular metabolic capacity by mechanisms occurs via GLUT4 up-regulation, increased such as GLUT4 mobilization9, potentially negative hexokinase gene transcription5, increased fuel effects by way of increased cortisol are also observed. consumption and, if sustained, decreases to insulin Crucially, fewer repetitions and longer rest periods secretion.6 Conversely, sustained physical activity can between sets elicit a lower cortisol response, which also increase glucagon, cortisol and catecholamine may be important for beginners to resistance secretion.6 These can all increase training.10 Increased catecholamine and/or insulin gluconeogenesis and if unbalanced, impair rather than secretion may also be observed with resistance improve insulin sensitivity. Very intense physical training. These changes may also be -dose activity stimulates insulin production, especially in the dependent and may attenuate as training adaptation presence of hyperglycemia. Without question, physical occurs. An elevated insulin response is associated with activity will be a key component for managing /carbohydrate supplementation. Elevated hyperinsulinemia, but the question remains whether hormonal responses may also be associated with different forms of physical activity can maximize overtraining.10 sensitivity while minimizing counter-hormones. Physical activity can be broadly divided into Aerobic exercise two main classifications that have considerable Aerobic exercise can be broadly described as overlap: resistance training and aerobic activity. The light to moderate intensity activities that can be latter has a further subset: high intensity interval performed for extended periods of time. Examples of training (HIIT). aerobic exercise include walking, jogging and swimming. There is a large body of literature on the Resistance training type and amount of aerobic activity required to Resistance training is characterized by muscles maintain health. Conventional wisdom suggests that a contracting against an external resistance causing brief minimum of 30 accumulated minutes of moderate and isolated activity of single muscle groups.7 The intensity activity (ie. brisk walking) should occur on health-benefits of resistance training are well- most days to achieve health benefits11, although the recognized. These can include decreases to HbA1c, efficacy of this volume has since been questioned.12 weight, body fat, and blood pressure.8 Other Aerobic exercise is believed to improve metabolic improvements include increases to bone mineral health via the same mechanisms as resistance training. density, and lean body mass. There are also potential A meta-analysis comparing resistance training benefits to mood and cognition, balance and falls-risk, to aerobic exercise concluded that clinically, there were and overall self-esteem. no advantages between resistance training and aerobic Resistance training may improve exercise for lowering HbA1c or impacting hyperinsulinemia through three main mechanisms: cardiovascular risk.7 However, aerobic exercise was increasing, or maintaining muscle mass, glucose modestly advantageous for lowering BMI. Resistance expenditure and enhancing the cellular metabolic training may confer greater benefit to those with capacity. It is estimated that inactive adults lose 3-8% limited mobility as many of the can be of muscle mass per decade accompanied by a performed by the sedentary. reduction in resting metabolic rate8 Losing muscle mass means that glucose disposal will be harder High intensity interval training (HIIT) resulting in increased adiposity. Increased muscle mass HIIT protocols are a subset of aerobic is posited as one explanation for the improvements in exercise characterized by short, maximal-intensity, glucose disposal rates for resistance training.9 This is anaerobic exercise sessions separated by medium or because both weight lifters and long-distance runners low intensity periods for recovery. There are several show increased glucose disposal rates compared to advantages to HIIT protocols compared to controls; however, this difference remains only for the conventional aerobic exercise: time; glucose utilization long-distance runners after differences in lean-body- and cellular metabolic capacity. Lack of time is the mass are taken into account. This is consistent with biggest reason cited for not exercising.9 HIIT protocols allow for greater power output for an Diabesity 2016; 2 (1): 1-11. doi: 10.15562/diabesity.2016.21 www.diabesity.ejournals.ca 2

Hyperinsulinemia: Best management practice … Catherine Crofts et al. equivalent amount of energy expenditure but in a finally 9. causes sufficient satiety so that hormones, shorter period of time13 resulting in greater receptors and transporters are not over stimulated. improvements to cardiorespiratory fitness.14 Other Adherence factors, including adverse benefits of HIIT compared to conventional aerobic reactions should also be considerations. Adherence is training include greater reductions of skinfold recognized as being key to weight-loss.27 Traditionally, thickness and decreased AUCinsulin.15, 16 HIIT protocols is seen as the driver of many metabolic may have further advantages over traditional aerobic diseases, so weight-loss is the first step to improved exercise regimes as they can be used safely and health.28 However, the metabolic theory of disease effectively in people following cardiac stenting, states that metabolic changes including coronary artery grafting and myocardial infarction. hyperinsulinemia may precede weight gain. Under this Musculoskeletal injuries were no more common than model, weight-gain is the first visible symptom of that found with other forms of exercise.14, 17-19 These metabolic disease, therefore weight-loss should also results demonstrate that HIIT is safe and effective indicate health improvements. This means that dietary when performed under controlled conditions. adherence will also be associated with improvements Patients new to HIIT may require specific assessment to hyperinsulinemia. and/or instructions from an exercise physiologist or Dietary research is complicated as many physiotherapist. studies use “standard” diets as the control. This GLUT4 adaptation can occur with single “standard” diet is generally low in fruits and vegetables bouts of exercise and effects persist for up to 40 and high in and refined .29 As this hours.20, 21 This suggests that, especially in the early diet will likely be lacking in essential nutrients and days of adopting physical activity, varying the activities fiber, cause acute hyperglycemia, and have excessive undertaken may maximize GLUT4 adaptation while calories, any dietary regime that reverses these trends minimizing effects from over-secretion of cortisol or will show improvements to health. Furthermore, diet- glucagon. While the literature suggests the ideal health research often employs weight loss as the activity should comprise a combination of resistance primary end-point, rather than other metabolic training and HITT protocols, the final selection of markers, yet improvements to metabolic markers are physical activities may be influenced by personal possible without significant weight changes.30 circumstances, including preference, health status and However, any dietary approach that causes weight levels of training required. loss, will improve hyperinsulinemia as body fat can only be stored, rather than oxidized in the presence of Diet high insulin levels.31 Therefore both improved There is considerable public and scientific glycemic control and weight loss can be used as debate and discussion concerning the optimal dietary proxies for improved hyperinsulinemia. approach for the management of metabolic There are three distinct dietary approaches dysregulation. Without discussing macronutrient (low fat; Mediterranean; and carbohydrate-restricted) proportions, it is generally agreed that a healthy diet that are shown to improve glycemic control. should predominantly be comprised of the following: Improved glycemic control may indicate improved 1. whole foods22, 2. adequate protein and other insulin response, so these diets should be considered currently established essential nutrients including for managing hyperinsulinemia. Although there is water, specific vitamins, minerals, electrolytes and fatty some evidence to support high protein diets for the acids23, 3. adequate energy, 4. aequate fiber, although treatment of diabetes, excess protein will induce fiber may not be considered aequate, there is sufficient gluconeogenesis, thus breaching criterion 4. evidence to support its inclusion.24-26 A diet that limits Therefore, only moderate protein diets will be the risk of, or manages the effects of, hyperinsulinemia considered in this review. As few studies directly should also consider the following: 5. prevents acute target hyperinsulinemia, the question remains are any hyperglycemia, whether via either exogenous of these three approaches superior to the others for carbohydrate or gluconeogenesis, thus preventing managing hyperinsulinemia? acute hyperinsulinemia, 6. prevents caloric overload, thus limiting both the amount of energy to be stored Low-fat as fat and the potential for hyperglycemia, 7. limits Currently, the low fat, high carbohydrate dietary items known to down-regulate GLUT4 or insulin approach is considered to be standard practice for receptors (e.g. arachidonic acid), 8. promotes items managing diabetes by many authorities. For adults known to up-regulate GLUT4 or insulin receptors and (aged 19 and older) this regime generally comprises 20-35% fat, (< 10% saturated fats), 10-35% protein Diabesity 2016; 2 (1): 1-11. doi: 10.15562/diabesity.2016.21 www.diabesity.ejournals.ca 3

Hyperinsulinemia: Best management practice … Catherine Crofts et al. and 45-65% carbohydrate.32 Fruits, vegetables and hyperinsulinemia is less likely.43. Fewer glucose whole-grains are recommended as carbohydrate and molecules to be absorbed into the cells reduces fiber sources, while vegetable oils (excluding coconut, metabolic stress. MUFA are believed to enhance palm and palm kernel oils) are emphasized as healthy insulin signaling44 whereas using omega-6 rich fat sources.29 Lean protein, including fat-free or low- polyunsaturated oils may lead to an increase in fat dairy products, or vegetable protein sources, are arachidonic acid, which may down regulate GLUT4.45 also recommended. The Mediterranean diet is also associated with a high degree of satiety.46 Satiety may help to prevent Mediterranean overeating and allow longer periods of fasting. Although there are a variety of Restricting carbohydrates have also been shown to “Mediterranean” dietary approaches33, the term confer additional health benefits compared to low-fat generally defines a diet that comprises a high amount diets, especially with respect to weight, lipid profile, of monounsaturated fatty acids (MUFA), glycemic control, and potentially kidney function.47-50 predominantly from olive oil (35%), fruits and There are few large studies that compared the effects vegetables, whole-grains and fish; moderate amounts of carbohydrate restricted diets to the Mediterranean of alcohol and small amounts of red meat, sugars and diet. However, restricting carbohydrates conferred refined grains.34, 35 greater weight loss, a larger decrease in triglycerides and hsCRP, and larger increase to HDL after six Carbohydrate-restriction months of dietary intervention.36 The Mediterranean Like the Mediterranean diet, there is no clear diet favored a decrease in fasting glucose in people definition of a carbohydrate-restricted diet. Daily with diabetes. The differences between the two diets carbohydrate intake has been defined as 12-40% of had narrowed by 24 months but both showed daily energy intake or < 20 -150g/day (36-39). To improvements compared to a low-fat diet. ensure adequate energy, the fat content of the diet is A key hyperinsulinemia management strategy increased, up to about 75% of daily energy content. is to prevent hyperglycemia and insulin secretion. This may explain the additional benefits to carbohydrate Comparison of different dietary strategies restriction. There are concerns regarding carbohydrate Each of these diets have notable benefits for restriction, predominantly concerning high dietary fat. the management of diabetes compared to standard High fat consumption, especially saturated , is diets.40-42 It is traditionally considered that weight traditionally associated with adverse metabolic management is the key driver behind metabolic outcomes. However, studies conducted over two improvements, hence the previous favour of the low- years have not found additional health risks.51 fat (and consequently low-calorie) diet. However, Furthermore, high-fat dairy has been found to emerging research suggests that increased benefits to decrease the incidence of type 2 diabetes and the risk metabolic health can be found from diets higher in of death or hospitalization due to coronary heart fats and lower in carbohydrates. A meta-analysis disease, compared to low-fat dairy.52, 53 It is now compared Mediterranean diets to low-fat diets in believed that there are sub types of saturated fats overweight/obese people (n = 2650, 50% female) over which have different health effects.54 two years of follow-up. Those following the Hyperinsulinemia encompasses a range of Mediterranean diet had greater improvements to body severities. All three dietary strategies discussed above weight and BMI, systolic and diastolic blood pressure, have the potential to improve the disorder. Logically, fasting glucose, total cholesterol, and high-sensitivity carbohydrate consumption in excess of what the body C-reactive protein (hs-CRP).35 While some of the can tolerate, will invoke excessive insulin secretion. effects were modest, the weighted mean differences Therefore restricting carbohydrates to a tolerated level clearly favoured the Mediterranean diet. This suggests should confer maximal health benefit, especially if the that low-fat diets may not be optimal for managing person consumes a whole-food diet based on diabetes, or hyperinsulinemia. Mediterranean principles. However, effective dietary Although this study does not directly assess management may be governed by adherence to the hyperinsulinemia, the improvements to the other chosen regime.27, 55 metabolic markers, especially fasting glucose, imply improvements to hyperinsulinemia. There are several Isolated beneficial nutrients / foods potential mechanisms for these observations. Firstly, Other compounds that have been shown to the lower carbohydrate content and therefore glycemic improve glycemic control include magnesium, load means that acute hyperglycemia, and hence acute chromium, garlic, , and green tea. Diabesity 2016; 2 (1): 1-11. doi: 10.15562/diabesity.2016.21 www.diabesity.ejournals.ca 4

Hyperinsulinemia: Best management practice … Catherine Crofts et al.

Figure 1: Glucose and insulin response curves following an oral glucose tolerance test in a patient with type 2 diabetes on insulin who inadvertently injected her normal morning insulin prior to the test. Data reproduced from Kraft77

Magnesium is believed to improve GLUT4 glycemic control without aggravating hyperinsulinemia expression in rodent studies independently to insulin may optimize health. Other medications that affect action.56 Chromium may improve insulin receptor hyperinsulinemia may not be prescribed for metabolic sensitivity.57 There is some evidence to suggest many disease; however, understanding this adverse effect is people are chromium deficient, especially if they eat important. highly refined foods, which, are not only unlikely to There are two main medication strategies for contain sufficient chromium, can also exacerbate its managing hyperinsulinemia: eliminating those that loss.58 Emerging evidence suggests that magnesium aggravate insulin resistance or contribute directly to and chromium may work synergistically to improve hyperinsulinemia; and prescribing medications that glycemic control.59 Foods rich in these minerals are key improve insulin sensitivity. The latter should be components of the Mediterranean diet, especially nuts considered second-line to lifestyle management. and whole grains. Green tea supplements, garlic and Medication management will be limited especially if cinnamon60-62 may also be beneficial improving insulin hyperglycemia, or other clinical conditions, need to be sensitivity, but the mechanisms are not fully considered. For example, both antipsychotic elucidated. medications, and longer courses of prednisone are There are a number of traditional remedies known to aggravate insulin resistance and increase the for treating type 2 diabetes that may be beneficial for risk of developing type 2 diabetes.71 However, managing hyperinsulinemia including (but not limited stopping these medications in many patients may be to) berberine63, 64, fenugreek65, 66, bilberries67, and black inappropriate so alternative strategies need to be cumin.68, 69 While the mechanism of actions of these considered. products are not fully elucidated, they are posited to include 5' adenosine monophosphate-activated protein Medications that theoretically worsen kinase (AMPK), (berberine) similar to that of hyperinsulinemia metformin70 or preventing carbohydrate absorption Medications may induce hyperinsulinemia by: (bilberries, fenugreek). It is necessary to further assess GLUT4 down-regulation; hyperglycemia (via increased the effect of these remedies on insulin release as both appetite, or affecting hormones such as adrenaline or berberine and black cumin are posited to increase cortisol); or directly increasing insulin secretion. insulin release, although reports are mixed. These properties, especially GLUT4 down-regulation, may be difficult to discern from medication data Medications sheets. If listed side-effects include weight gain or an As previously stated, this review is increased risk of developing type 2 diabetes, then predominantly concerned with hyperinsulinemia in the hyperinsulinemia should be a reasonable suspicion. presence of normal glucose tolerance. However, as people with impaired glycemic control, are likely to be hyperinsulinemic3 plausibly, strategies that improve

Diabesity 2016; 2 (1): 1-11. doi: 10.15562/diabesity.2016.21 www.diabesity.ejournals.ca 5

Improved by Worsened by Indeterminate

Time Hyperglycemia Insulin receptor Chromium Hyperinsulinemia

availability MUFA Cortisol Highly refined foods

Magnesium Excessive physical GLUT4 up regulation activity Physical activity Arachidonic acid Time

Excessive physical Carbohydrate-restricted diets activity Mediterranean diet High-carbohydrate, Low fat Hyperglycemia Excessive protein Physical activity diets Excessive carbohydrate Black cumin

Insulin Insulin secretagogues Insulin mimetics Berberine Hyperinsulinemia Very intense physical Black cumin activity Excessive protein Excessive carbohydrate

AMPK activation Berberine

Carbohydrate-restricted diets Reduced carbohydrate Bilberries Excessive dietary absorption Fenugreek carbohydrate

Green tea Mechanism unknown Garlic Cinnamon

Table 1: Summary of management strategies for managing hyperinsulinemia

Medications known to down regulate GLUT4 include: used in type 2 diabetes can produce insulin spikes > clozapine72; ritonavir73; statins74; and corticosteroids.75 400 µU/mL for a number of hours following a 100g Plasma insulin is increased by exogenous glucose load77 as shown in Figure 1. The maximal insulin, insulin secretagogues, or insulin mimetics, insulin concentration remains unknown as the prescribed to manage hyperglycemia. Although the reference standard was only calibrated to a maximum insulin secretagogues such as sulphonylureas are less of 400 µU/mL. commonly used.76, little is known about the effects of Despite this degree of serum insulin elevation, these medications on hyperinsulinemia. An it can be noted that the patient did not attain a normal unpublished case report suggests exogenous insulin glycemic profile. The combination of hyperglycemia

 Corresponding Author, E-mail: [email protected]. 1Human Potential Centre & 2Biostatistics and Epidemiology, Auckland University of Technology (AUT), PO Box 92006, Auckland 1142, New Zealand. Copyright: © 2015 The Authors. This is an open-access article distributed under the terms of the Creative Commons Attribution License. Hyperinsulinemia: Best management practice … Catherine Crofts et al. and hyperinsulinemia increases the risk of a poor long- another pathology cannot be supported by the current term prognosis for this patient. Further research is literature. required to establish if this is an isolated situation or the standard response for many patients with type 2 Novel mechanisms diabetes. Future targets for pharmacological management of hyperinsulinemia may include insulin degrading Medications potentially beneficial for enzyme (IDE) and the forkhead transcription factor hyperinsulinemia (FOXA-2). IDE mediates multiple hormones Although the somatostatin analogue, including insulin and glucagon. Rodent studies octreotide, is used to treat isolated hyperinsulinemia, indicate impaired IDE, with resultant hyperinsulinemia (e.g. insulinoma)78, 79, compensatory hyperinsulinemia associated with poorer glycemic control (89). cannot be managed without concurrent glycemic However, further research in this field may be able to control. Hyperglycemia is well recognized to have selectively target glucagon. FOXA-2 has been shown adverse pathologies, including diabetic ketoacidosis. to improve insulin sensitivity in a number of mouse But ketoacidosis can be triggered by low insulin levels models by controlling key genes in fatty acid oxidation independent of glycemic status. Increasing levels of and glycolysis.90 glucagon and cortisol may be triggered by cellular starvation, or . These hormones can Concluding remarks induce gluconeogenesis and glycogenolysis leading to Hyperinsulinemia is becoming recognised as overproduction of the ketone bodies acetoacetic acid, an independent risk factor for chronic disease, yet β-hydroxybutyrate and acetone.80 Both acetoacetic acid there are few studies that address its management. and β-hydroxybutyrate are strong acids. Under normal This review evaluated hyperglycemia management circumstances insulin levels help to regulate the methods, including physical activity, diet, and production of these ketone bodies, but in its absence medications while focusing on the mechanisms of potentially fatal ketoacidosis may develop. hyperinsulinemia as summarized in Table 1. First-line Thiazolidinedione-type insulin sensitizers, treatment of hyperinsulinemia should encompass such as rosiglitazone, improve peripheral glucose dietary and physical activity management. Physical uptake without increasing serum insulin levels81 activity should include a combination of aerobic and However, all insulin sensitizers increase substrate resistance activities, with an emphasis on HITT. Care uptake, which has implications for the formation of is needed to avoid over-training, which may exacerbate reactive oxidative species (ROS) and advanced insulin resistance. Further research is needed to glycation end-products (AGEs) and their adverse understand how to obtain the optimal balance. With health effects.82, 83 Furthermore, the use of respect to diet, a carbohydrate-restricted thiazolidinediones is considered controversial because Mediterranean diet theoretically confers greatest of their association with significant adverse effects benefit but further research is needed, especially to such as heart failure, fracture risks, and increased risk determine to what degree carbohydrates need to be of bladder cancer.84, 85 restricted in relation to the degree of hyperinsulinemia. Metformin is the most promising (albeit Although metformin may up-regulate GLUT4, limited) medication to manage hyperinsulinemia as it pharmacological management is not currently justified up-regulates GLUT4.86 However, unlike the due to the risks of cellular nutrition overload. Overall, thiazolidinediones, metformin also inhibits strategies should aim to maximize participant gluconeogenesis in the liver and/or delays glucose adherence for greatest health benefits. absorption from the gastrointestinal tract.87 These latter actions may better reduce overall glucose load and therefore decrease endogenous insulin secretion. Conflict of interest However, emerging research suggests metformin may None Declared. not be beneficial for treating type 2 diabetes.88 Metformin may also cause excessive cellular nutrient References uptake leading to increased ROS and AGEs.83 1. Kelly CT, Mansoor J, Dohm GL, Chapman Iii WHH, Research does support the use of metformin for Pender Iv JR, Pories WJ. Hyperinsulinemic syndrome: treating PCOS, a condition associated with The is broader than you think. hyperinsulinemia.86 However, pharmacological Surgery. 2014 8//;156(2):405-11. management of hyperinsulinemia in the absence of

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Hyperinsulinemia: Best management practice … Catherine Crofts et al.

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