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    Subjects: Pathology
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    Submitted by: Joseph AMJL Janssen


    For many years, the dogma has been that insulin resistance precedes the development of hyperinsulinemia. However, recent data suggest a reverse order and place hyperinsulinemia mechanistically upstream of insulin resistance. Genetic background, consumption of the “modern” Western diet and over-nutrition may increase insulin secretion, decrease insulin pulses and/or reduce hepatic insulin clearance, thereby causing hyperinsulinemia. Hyperinsulinemia disturbs the balance of the insulin–GH–IGF axis and shifts the insulin : GH ratio towards insulin and away from GH. This insulin–GH shift promotes energy storage and lipid synthesis and hinders lipid breakdown, resulting in obesity due to higher fat accumulation and lower energy expenditure. Hyperinsulinemia is an important etiological factor in the development of metabolic syndrome, type 2 diabetes, cardiovascular disease, cancer and premature mortality.

    1. Introduction

    Subjects with insulin resistance and hyperinsulinemia are at high risk of developing obesity, type 2 diabetes, cardiovascular disease, cancer and premature mortality [1][2][3][4][5][6][7][8][9]. The dogma has been for many years that insulin resistance is first and precedes hyperinsulinemia and type 2 diabetes mellitus. In this view, hyperinsulinemia was secondary and represented a compensatory mechanism to overcome systemic (peripheral) insulin resistance [10]. Insulin resistance was considered to be the primary etiological factor in the development of obesity, type 2 diabetes, cardiovascular disease and cancer, whereas the compensatory hyperinsulinemia was thought to be a direct consequence of insulin resistance [11]. However, recently the correctness of this view has been called into question [12][13][14]. It has even been proposed that hyperinsulinemia per se is primary and causes (and is not a consequence of) insulin resistance [13]. In this new concept, insulin resistance is proposed to be a physiological defense mechanism of the body that tries to prevent the development of hypoglycemia and to protect critical tissues from metabolic stress and nutrient-induced injury [15][16]. This opens the possibility that (early) interventions able to normalize/reduce plasma insulin concentrations might play a key role in the prevention and treatment of obesity, type 2 diabetes, cardiovascular disease, cancer and premature mortality [10][17].

    2. How to Define Circulating Hyperinsulinemia

    Diagnosing hyperinsulinemia is not easy in clinical practice. There is no precise and universally accepted definition of hyperinsulinemia [18]. When cut-offs are available for hyperinsulinemia, these are in most cases based on fasting insulin levels [19]. The “normal” range of fasting insulin in healthy subjects varies considerably between labs, but has been reported to vary in a range between 3 and 30 µU/mL (18–180 pmol/L) [19]. In the National Health and Nutrition Examination Surveys (NHANES), fasting circulating insulin levels in healthy adult persons have been reported to be in a range between approx. 25 and 70 pmol/L [20]. Many studies define hyperinsulinemia based on arbitrarily chosen cut-off fasting insulin concentrations or 2 h insulin concentrations after an oral glucose load (for example, >67th percentile, >75th percentile or >90th percentile for non-diabetic subjects) [21][22]. In addition, as discussed above, laboratory standardization of insulin measurements remains a problem. It has been found that serum insulin measurement with different assays shows maximal 1.8-fold variation and therefore caution should be exercised when comparing results of insulin levels from different research labs/studies [23]. Moreover, differences in the circumstances of blood sampling and handling of blood samples before the actual measurement of insulin may further play a role in the variation of insulin measurements [3].

    3. Loss of Pulsatile Insulin Secretion Contributes to Insulin Resistance

    In healthy subjects, insulin secretion into the circulation is pulsatile and normally accounts for 75% of the daily insulin secretion [24]. It has been proposed that pulsatile insulin release may avoid the downregulation of (hepatocyte) insulin receptors compared to the constant delivery of insulin [25]. Prolonged near-physiological pulsatile insulin infusion has a greater hypoglycemic effect than continuous insulin infusion [26]. Moderate pulsatile hyperinsulinemia in nondiabetic human subjects does not induce insulin insensitivity [26]. This is in contrast to what is found after continuous hyperinsulinemia [26]. It has been demonstrated that hyperinsulinemia produced by continuous infusion of insulin (which increased plasma insulin concentrations to levels similar to those observed in insulin-resistant conditions) can produce insulin resistance (decreased insulin receptor sensitivity), and this decrease in insulin action may occur at the receptor and post-receptor level of the insulin receptor and is tissue-specific [27]. The loss of pulsatile insulin secretion is an early feature in the development of type 2 diabetes and may be involved in the (patho)genesis of insulin resistance in a variety of circumstances [27][28]. Intravenous delivery of insulin in a constant versus pulsatile pattern led to delayed activation of hepatic insulin receptor substrate (IRS)-1 and IRS-2 signaling, impaired activation of downstream insulin signaling effector molecules AKT and Foxo1, and decreased expression of glucokinase, suggesting that the physiological pulsatile pattern of insulin delivery is important for normal hepatic insulin signaling and glycemic control and essential to preserve insulin sensitivity [29]. In addition, several lines of evidence suggest that the pattern of insulin secretion by the pancreas determines hepatic insulin clearance: the liver preferentially extracts insulin delivered in pulses [30]. Therefore, the pulse mass of insulin release dictates both hepatic (directly) as well as extrahepatic (peripheral) insulin delivery [30]. Animal studies have also demonstrated the importance of pulsatile insulin delivery in the development of insulin resistance [16]. Although an acute rise in insulin is stimulatory for the insulin receptor, persistently and continuously elevated insulin levels desensitize the insulin receptor through multiple mechanisms, both at receptor and post-receptor level [12][31][32][33]. Continuous and long-term exposure to insulin causes a reduction in the number of insulin receptors at the cellular surface by promoting internalization as well as degradation of insulin receptors [31]. With continuous and long-term exposure to insulin, the kinase activity of the insulin receptor diminishes, probably because of combined effects of phosphorylation on serine residues on the insulin receptor, the dephosphorylation of tyrosines by the action of phosphatases, and the binding of inhibitory molecules [12][34][35][36][37]. All of these effects downregulate insulin receptor signaling and thereby cause insulin resistance.

    4. Hyperinsulinemia Precedes Insulin Resistance

    In healthy subjects, plasma glucose is maintained within narrow ranges by a classic negative feedback system [38]. After meals, insulin secretion by the pancreas is stimulated by a rise in glucose and this brings plasma glucose back to baseline [38]. In this negative feedback system, insulin secretion is controlled and glucose levels remain within the normal range as long as subjects are able to overcome insulin resistance by increasing insulin secretion [38]. However, as soon as subjects have lost this ability, they will progress to impaired glucose tolerance and/or type 2 diabetes [38]. Until very recently, the prevailing view was that insulin resistance (that is, resistance to insulin’s role in promoting glucose uptake by muscle and fat cells) preceded and caused hyperinsulinemia [39]. In this view, insulin resistance was the initial defect leading to the development of metabolic syndrome, hyperglycemia and type 2 diabetes after years or even decades later [40]. However, in genome-wide association studies (GWAS), only a few loci point to insulin resistance as the primary cause of type 2 diabetes, while the majority of the loci identified by GWAS point towards defects of the β-cell of the pancreas [41][42]. This raises the distinct possibility that a β-cell defect in insulin secretion that initially causes inappropriate hypersecretion of insulin at basal plasma glucose concentrations may be a driver of insulin resistance by insulin-induced downregulation of insulin receptors [13][16]. It is important to realize that the actual diagnostic criteria for normal glucose tolerance, impaired glucose tolerance and type 2 diabetes are not defined on the basis of pathophysiological abnormalities [43]. Thus, although cross-sectional studies have postulated that insulin secretion follows an inverted U-pattern (also termed Starling’s curve of the pancreas) during natural progression from normal glucose tolerance to impaired glucose tolerance and type 2 diabetes [34], it has been repeatedly reported that a large part of individuals with normal glucose tolerance already show hyperinsulinemia before the development of impaired glucose tolerance/obesity. For example, Ferrannini et al. found increased plasma insulin levels in subjects with normal or near normal glucose tolerance [43]. In addition, it is difficult to understand how insulin resistance in subjects with normal glucose tolerance could be responsible for increased insulin secretion when blood glucose concentrations are still within the normal range. This is another argument against a primary role for insulin resistance-mediated hyperinsulinemia [44]. In addition, if fat cells were already resistant to insulin in the early phase, it is difficult to understand how hyperinsulinemia could stimulate lipogenesis and induce obesity by driving calories into fat cells [45]. Recently, a new model has been brought forward: in this new model, hyperinsulinemia is considered the primary event that secondarily causes insulin resistance and type 2 diabetes [12][44]. In support of this new model, insulin secretion has been found to be elevated before the development of hyperglycemia in a longitudinal study of Rhesus monkeys, developing a form of type 2 diabetes, which appears to be very similar to that found in humans [46]. In addition, an increasing number of human studies support the hypothesis that basal hyperinsulinemia is primary and that it contributes secondarily to insulin resistance and many diseases and conditions [12].

    In another study, half of the 4485 subjects showed hyperinsulinemia despite normal glucose clearance, suggesting that hyperinsulinemia likely occurs as a “silent disease” in a substantial proportion of an otherwise healthy population [47]. In Pima Indians with normal glucose tolerance, evidence was found that fasting hyperinsulinemia itself, independent of a low rate of insulin-stimulated glucose uptake, predicted the cumulative incidence of type 2 diabetes during a 7 year follow-up [48]. Therefore, the authors concluded that high fasting plasma insulin concentrations were not a reflection of insulin resistance but rather the consequence of a basal hypersecretion of insulin relative to the degree of insulin resistance [48]. In a fourth study, the prevalence of insulin hypersecretion in nondiabetic, normotensive obese women exceeded the prevalence of insulin resistance, which was relatively low [49].

    5. How Can Hyperinsulinemia Be Modified?

    In humans, there are at present three main strategies to prevent and manage hyperinsulinemia: reducing calorie intake, increasing hepatic insulin clearance and maximizing insulin sensitivity [50]. However, at this moment it is unclear which strategy is the best for preventing/managing hyperinsulinemia. Any dietary approach that causes weight loss improves hyperinsulinemia as body fat can only be stored, rather than oxidized in the presence of high insulin levels [50]. Only a few studies have studied the direct specific effects of a diet on hyperinsulinemia. Although a carbohydrate-restricted Mediterranean diet theoretically may confer the best effects, further research is needed to determine which diet is the best to modify hyperinsulinemia [50]. Studies during short-term very low calorie diets (VLCD) have found an increased hepatic insulin clearance and decline in plasma insulin concentrations, supporting that hepatic insulin clearance can be increased by energy restriction [51]. Furthermore, energy restriction induced by Roux-en-Y gastric bypass increased hepatic insulin clearance in obese subjects with normal glucose tolerance within 1 week [52]. Thus, insulin clearance can be modified within days by reducing energy intake. The early increases in insulin clearance after reduced energy intake result in metabolic changes typical for fasting (i.e., increased lipolysis and free fatty acid oxidation and a lower hepatic triglyceride content independent of weight loss) [53]. Interestingly, pharmacological lowering of hepatic triglyceride content in type 2 diabetes by rosiglitazone, a PPARγ receptor agonist, is also associated with a significant increase in insulin clearance within 16 weeks, and this effect is present without significant weight loss [54]. The pattern of food intake may also be important to reduce insulin levels. Five weeks of early time restricted feeding (6-hr feeding period during the day, with dinner before 3 pm) reduced insulin levels and improved β-cell responsiveness, insulin sensitivity, blood pressure and oxidative stress in prediabetic men even without weight loss [55]. Regular physical activity improves the whole-body metabolic health and can play a key role in the prevention and control of hyperinsulinemia, insulin resistance, prediabetes, type 2 diabetes and diabetes-related complications [56]. In a rodent study, exercise training prevented basal as well as glucose challenged insulin levels induced by a high-energy diet [57]. Two weeks of high-intensity interval or moderate-intensity continuous training improved β-cell function in people with prediabetes and type 2 diabetes [58][59].

    The entry is from 10.3390/ijms22157797


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