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Keywords:

  • β-cell;
  • insulin resistance;
  • insulin secretion;
  • pathogenesis (Type 2 diabetes)

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. What is the initiating insult in Type 2 diabetes?
  5. Beta-cell pulsatility
  6. Effect of insulin on the β-cell
  7. Evidence from physiological studies
  8. Evidence from epidemiological studies
  9. How might basal hyperinsulinaemia induce insulin resistance?
  10. Current therapy
  11. Discussion
  12. Implications for therapy
  13. Dietary advice for the prevention of insulin resistance
  14. Competing interests
  15. References

Diabet. Med. 29, 972–979 (2012)

Abstract

For many years, the development of insulin resistance has been seen as the core defect responsible for the development of Type 2 diabetes. However, despite extensive research, the initial factors responsible for insulin resistance development have not been elucidated. If insulin resistance can be overcome by enhanced insulin secretion, then hyperglycaemia will never develop. Therefore, a β-cell defect is clearly required for the development of diabetes. There is a wealth of evidence to suggest that disorders in insulin secretion can lead to the development of decreased insulin sensitivity. In this review, we describe the potential initiating defects in Type 2 diabetes, normal pulsatile insulin secretion and the effects that disordered secretion may have on both β-cell function and hepatic insulin sensitivity. We go on to examine evidence from physiological and epidemiological studies describing β-cell dysfunction in the development of insulin resistance. Finally, we describe how disordered insulin secretion may cause intracellular insulin resistance and the implications this concept has for diabetes therapy. In summary, disordered insulin secretion may contribute to development of insulin resistance and hence represent an initiating factor in the progression to Type 2 diabetes.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. What is the initiating insult in Type 2 diabetes?
  5. Beta-cell pulsatility
  6. Effect of insulin on the β-cell
  7. Evidence from physiological studies
  8. Evidence from epidemiological studies
  9. How might basal hyperinsulinaemia induce insulin resistance?
  10. Current therapy
  11. Discussion
  12. Implications for therapy
  13. Dietary advice for the prevention of insulin resistance
  14. Competing interests
  15. References

Insulin resistance appears central to the development of Type 2 diabetes and is intimately associated with obesity. It can be defined as a decreased tissue effect of insulin per unit delivered (i.e. reduced cellular and tissue insulin sensitivity). The underlying mechanisms for the development of insulin resistance in different clinical conditions are currently poorly understood, but the milieu of serum components known to influence whole body insulin sensitivity includes endocrine factors (insulin, glucagon and adipokines), inflammatory mediators (interleukin 6 and tumour necrosis factor α), nutrients (glucose and free fatty acids) and ageing. Prior to the development of diabetes, there is a progressive increase in insulin resistance, although the initiating steps leading to the generation of resistance associated with increased risk of developing diabetes remain elusive (but in most cases seem to be associated with poor diet and obesity). Whole body hyperglycaemia is a late step in the development of Type 2 diabetes, with years of normoglycaemia in the presence of insulin resistance before insufficient compensation through increasing insulin secretion results in hyperglycaemia. Hence, hyperinsulinaemia is present prior to the development of diabetes, and it has been known for some time that hyperinsulinaemia can lead to insulin resistance [1]. This may occur as a normal mechanism to overcome developing insulin resistance, but also possibly as a result of defective insulin secretion or turnover in response to dietary influences, and as such could be one of the initiating factors of resistance generation. It is important to recognize that the minute-to-minute variations in the portal levels of insulin are crucial to proper hepatic insulin signalling.

Many endocrine systems require the pulsatile delivery of hormones for proper function and there are inherent feedback controls that prevent chronic activation of a number of signalling pathways. Indeed, the negative feedback of endocrine systems is in place to prevent hyperstimulation of an individual endocrine system. For example, the continuous administration of gonadotropin-releasing hormone (GnRH) analogues in precocious puberty shuts off the gonadotrophin axis by overriding the underlying pulsatile delivery of GnRH to the gonads. Furthermore, this also explains why hyperparathyroidism, in which there is continuous delivery of parathyroid hormone (PTH) to the bone, leads to osteoporosis, but teriparatide (recombinant PTH) can be useful in the treatment of osteoporosis because of its once-daily administration and short half-life. However, insulin resistance differs from other endocrine systems as there is not a complete loss of the action of insulin, but a shift in the insulin response curve. This review presents data on the current evidence regarding the effect of basal hyperinsulinaemia and loss of proper insulin secretion on the potential development of insulin resistance and Type 2 diabetes.

What is the initiating insult in Type 2 diabetes?

  1. Top of page
  2. Abstract
  3. Introduction
  4. What is the initiating insult in Type 2 diabetes?
  5. Beta-cell pulsatility
  6. Effect of insulin on the β-cell
  7. Evidence from physiological studies
  8. Evidence from epidemiological studies
  9. How might basal hyperinsulinaemia induce insulin resistance?
  10. Current therapy
  11. Discussion
  12. Implications for therapy
  13. Dietary advice for the prevention of insulin resistance
  14. Competing interests
  15. References

The development of insulin resistance, in most people, occurs over a period of time and a number of insults have been shown to have effects on insulin sensitivity. The obese, insulin-resistant individual has disordered insulin secretion [2], higher levels of free fatty acids and increased inflammation. The plasma and tissue levels of free fatty acids can be increased by the consumption of a high-fat diet and this contributes to hepatic insulin resistance [3,4]. Lipolysis is also increased because of a reduction in the inhibition of hormone-sensitive lipase, and adipocytes lipogenesis is decreased as a result of a reduction in the activity of transcription factors such as peroxisome proliferator activated receptor (PPAR)γ [5]. Tissue macrophages are also recruited to visceral adipose tissue where free fatty acids activate Toll-like receptors and promote the production of pro-inflammatory cytokines, tumour necrosis factor (TNF) α, interleukin (IL)-1β, IL-6 and monocyte chemotactic protein (MCP), via the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) [6]. TNFα induces hepatic insulin resistance by phosphorylation of insulin receptor substrate (IRS)-1 at the inhibitory Ser307 site and also by increasing protein-phosphoTyr phosphatase (PTP) 1B production leading to the dephosphorylation of the active insulin receptor [7,8]. Finally, a number of adipokines are disordered in obesity. In particular, the levels of adiponectin are lower and leptin levels higher in the obese (probably generating leptin resistance) [9]. Therefore, a number of factors contribute to insulin resistance and it remains unclear as to the relative importance of each, whether it is the same problem in all obese individuals or whether it is an accumulative effect that promotes insulin resistance in the obese population.

Beta-cell pulsatility

  1. Top of page
  2. Abstract
  3. Introduction
  4. What is the initiating insult in Type 2 diabetes?
  5. Beta-cell pulsatility
  6. Effect of insulin on the β-cell
  7. Evidence from physiological studies
  8. Evidence from epidemiological studies
  9. How might basal hyperinsulinaemia induce insulin resistance?
  10. Current therapy
  11. Discussion
  12. Implications for therapy
  13. Dietary advice for the prevention of insulin resistance
  14. Competing interests
  15. References

Insulin delivery to the liver occurs via the portal circulation. The normal β-cell secretes insulin in response to glucose, fatty acids and other nutrient stimulation in a strictly controlled fashion. The β-cell has an intrinsic rhythm of intracellular calcium oscillations secondary to periodic depolarization, occurring every 2–5 min [10,11]. This depolarization occurs as a result of the effects of ATP on ATP sensitive K+ channels [12]. Individually, β-cells all have differing pulse times, but once formed into aggregates with other β-cells, and therefore exhibiting cell–cell contact, the pulse rhythm develops into the recognizable c. 4-min cycles and similar changes can be seen in glucagon-secreting α-cells [13]. This is probably attributable to diffusible factors acting on adjacent cells or mediated by gap junctions between cells [14]. It follows suit that large islets, as one may see in Type 2 diabetes, do not have sufficient mechanisms to integrate the calcium influx required for proper pulsatile function [15], showing the need for close cell proximity and sufficient conditions for diffusion of paracrine signals. Therefore, single islets are able to coordinate pulsatile insulin secretion, but the integration of all islets is required to ensure that the pancreas releases insulin, and other islet hormones, in a regulated fashion. This integration is mediated by the autonomic nervous system [16] and coordinates the pulsatile release of insulin and, at the same time the anti-synchronous release of glucagon, from the pancreas [17]. Interestingly, the inverse relationship of glucagon and insulin secretion is lost in subjects with Type 2 diabetes [18].

Therefore, the normal pattern of insulin secretion is one of rapid oscillations from basal levels to a peak concentration and back to basal levels approximately every 4 min [19]. These bursts of insulin release lead to insulin concentrations in the portal circulation ranging from c. 200 to 500 pm in the fasting state and from c. 1000 to 5000 pm in the fed state [19,20]. Indeed, the basal delivery of insulin normally makes up only 30% of the total insulin delivered via the portal circulation, with the remaining 70% coming from the pulsed output [21]. However, if these oscillations become disordered, such as an increase in the basal insulin secretion, or an increase in total insulin levels, but with a loss of pulse mass, this may affect both hepatic and peripheral insulin sensitivity. It is worth noting that, as insulin resistance is usually measured in large part by fasting insulin levels, pulsatile insulin secretion defects can thus confound simple assessment of insulin sensitivity. In Type 2 diabetes there is approximately a 65% reduction in β-cell mass before the onset of hyperglycaemia [22]. Furthermore, these cells are not only fewer in number, but also suffer from a disorder in their insulin secreting ability. Despite losing their normal pulsatile insulin secretion profile, the levels of insulin produced are higher, crucially resulting in increased insulin entering the portal circulation [2,18,23,24]. In addition, the ratio of secretion of proinsulin to insulin also increases [23].

However, there is evidence that, while a reduction in β-cell mass may be sufficient for the development of disordered insulin secretion, it is not necessary in all cases. In fact, there is a reduction in the glucose-stimulated insulin secretion (β-cell glucose insensitivity) as glycaemia increases [25]. Furthermore, insulin secretion rates are less responsive to changes in glucose level in patients with diabetes compared with subjects without diabetes [25]. Therefore, much greater glucose concentrations are required to achieve similar insulin concentrations and, even then, maximal insulin secretion rarely reaches the levels seen in individuals without diabetes. Whether these effects are attributable to a reduction in cell mass or decreased cell glucose sensitivity remains unclear [26].

In the normal individual, the peripheral insulin level is much lower than portal insulin levels, as approximately 80% of insulin is cleared on first pass through the liver, with the remainder available to act on peripheral tissues, with the size of the insulin pulse mass determining hepatic insulin clearance [27]. Therefore, the loss of insulin pulse mass, duration or frequency would have a dual effect, both on the insulin sensitivity of the liver and also on the amount of insulin delivered to other insulin-responsive tissues. For example, in those with disordered insulin secretion promoting basal hyperinsulinaemia, there is a subsequent reduction in the magnitude of insulin pulse mass leading to a reduced clearance of insulin from the liver and ultimately peripheral hyperinsulinaemia [28]. In contrast, as insulin resistance increases with age in mice with normal β-cell function, there is an associated 12-fold rise in insulin pulse magnitude. However, this increase is largely offset by a 4-fold increase in hepatic insulin clearance [29]. Therefore, it is only in those with a β-cell deficit that hyperglycaemia becomes apparent, but it remains undefined whether this is a cause or consequence of disordered insulin secretion.

Effect of insulin on the β-cell

  1. Top of page
  2. Abstract
  3. Introduction
  4. What is the initiating insult in Type 2 diabetes?
  5. Beta-cell pulsatility
  6. Effect of insulin on the β-cell
  7. Evidence from physiological studies
  8. Evidence from epidemiological studies
  9. How might basal hyperinsulinaemia induce insulin resistance?
  10. Current therapy
  11. Discussion
  12. Implications for therapy
  13. Dietary advice for the prevention of insulin resistance
  14. Competing interests
  15. References

The β-cell is crucial to the development of Type 2 diabetes as, without a relative deficiency of insulin production, hyperglycaemia would not occur. There is currently evidence for both negative and positive feedback effects of insulin on β-cells [30]. Performing these experiments is not without difficulties as they tend to be performed in isolated β-cells cultured in growth media invariably containing insulin. Thus far, it has not been possible to repeat them in vivo in humans However, it is easy to see how an immediate positive feedback, and subsequent later negative feedback, would be a useful physiological arrangement to regulate pulsatile secretion. Autocrine action of insulin on its own receptor increases secretion of preformed mature insulin packed into granules, thus leading to the first-phase insulin response, followed by negative feedback to prevent continuous insulin secretion. The pulsatile secretion of insulin may maintain the responsiveness of β-cells to glucose and insulin by preventing the desensitization of the signalling cascade. This β-cell rest is important, and lack of it may explain why there is an increased level of proinsulin in diabetes, as there is less time for adequate intracellular insulin processing. Indeed, in patients with Type 2 diabetes, the overnight infusion of somatostatin to induce β-cell rest leads to a restoration of insulin pulse mass, thus restoring normal insulin secretion [28].

The importance of insulin on β-cell function can be elucidated from knock-out studies. Specifically, knocking out the insulin receptor in β-cells leads to both a defect in insulin secretion, with a loss of first-phase insulin response, and progressive glucose intolerance in the presence of a near normal β-cell mass [31,32]. This suggests that local autocrine effects are important in appropriate insulin secretion and, as such, improper signalling may lead to decreased insulin pulse mass. However, it must be noted that in vivo in healthy human subjects, exposure to exogenous insulin increases glucose-stimulated insulin secretion by approximately 40% [33]. This effect is attenuated in insulin-resistant individuals, both in impaired glucose tolerance and Type 2 diabetes [34]. This adds further credence to a disorder of insulin-regulated insulin secretion in Type 2 diabetes, but also shows the importance of insulin in normal β-cell function, whereas stressed β-cells are unable to produce sufficient insulin to both enhance their own insulin secretion and also, consequently, the effects of peripheral insulin resistance [35].

Evidence from physiological studies

  1. Top of page
  2. Abstract
  3. Introduction
  4. What is the initiating insult in Type 2 diabetes?
  5. Beta-cell pulsatility
  6. Effect of insulin on the β-cell
  7. Evidence from physiological studies
  8. Evidence from epidemiological studies
  9. How might basal hyperinsulinaemia induce insulin resistance?
  10. Current therapy
  11. Discussion
  12. Implications for therapy
  13. Dietary advice for the prevention of insulin resistance
  14. Competing interests
  15. References

A number of physiological experiments have implicated continuous insulin exposure as a contributor to the development of insulin resistance. In hepatocytes, exposure to insulin in a pulsatile fashion increases expression of insulin receptors compared with cells exposed to continuous infusion [36]. Similarly, adipocytes exposed to chronic insulin exposure exhibit a defect in glucose uptake, along with a reduction in levels of the insulin receptor compared with cells exposed to oscillations of insulin [37]. Whole animal studies have also shown the importance of oscillatory portal insulin delivery in the prevention of the development of insulin resistance. For example, in dogs, an increase by as little as 50% in the portal insulin level when given as a continuous infusion has been shown to induce hepatic insulin resistance [38]. In addition, mice with higher portal levels of insulin also exhibit insulin resistance. Mice with extra copies of the human insulin gene develop hyperinsulinaemia, an augmented insulin response to glucose and a reduction in insulin-stimulated glucose metabolism, suggesting that hyperinsulinaemia alone induces insulin resistance, with the problems increasing in line with the number of gene copies [39]. In rats, oscillatory infusions of intraportal insulin improve postprandial (glucose-dependent) insulin secretion, thereby supplying higher levels of insulin to the peripheral tissues and potentially improving peripheral glucose utilization [40]. Furthermore, there are a number of human studies showing that the pulsatile delivery of insulin improves the glucose-lowering ability of insulin when compared with continuous infusion. This effect is seen in both healthy subjects and those with diabetes [41,42]. Similarly, patients with insulinomas who exhibit higher levels of basal insulin with disordered pulsatility [43], also exhibit insulin resistance, because of a decrease in insulin binding and post-receptor defects [44], which is reversible on the removal of the insulinoma, although the weight gain associated with insulinomas is obviously a confounding factor [44].

Evidence from epidemiological studies

  1. Top of page
  2. Abstract
  3. Introduction
  4. What is the initiating insult in Type 2 diabetes?
  5. Beta-cell pulsatility
  6. Effect of insulin on the β-cell
  7. Evidence from physiological studies
  8. Evidence from epidemiological studies
  9. How might basal hyperinsulinaemia induce insulin resistance?
  10. Current therapy
  11. Discussion
  12. Implications for therapy
  13. Dietary advice for the prevention of insulin resistance
  14. Competing interests
  15. References

The offspring of patients with Type 2 diabetes show both insulin resistance and β-cell dysfunction with higher levels of insulin [45]. Furthermore, the relatives of patients with Type 2 diabetes exhibit impaired pulsatile insulin secretion with a complete loss of regular oscillatory activity [46]. It is of interest that modern gene mining techniques have identified a number of nucleotide polymorphisms that are associated with an increased risk of insulin resistance and Type 2 diabetes, and at this time around 40 Type 2 diabetes risk genes have been proposed, and the seven variants associated with the greatest increase in Type 2 diabetes risk (TCF7L2, CDKAL1, HHEX, CDKNA/2B, IGF2BP2, SLC30A8, JAZF1) all have an effect on β-cell function [47]. This raises the distinct possibility that a β-cell defect in insulin secretion may be a driver of insulin resistance. However, it must be noted that these genes have a number of effects outside of β-cells, such as influencing the growth of many types of cells, but the β-cell centric effects are highlighted in these studies. Furthermore, studies of humans with extreme insulin-resistant phenotypes have not revealed mutations in β-cell genes, rather identifying genes affecting tissue insulin response [48–51].

How might basal hyperinsulinaemia induce insulin resistance?

  1. Top of page
  2. Abstract
  3. Introduction
  4. What is the initiating insult in Type 2 diabetes?
  5. Beta-cell pulsatility
  6. Effect of insulin on the β-cell
  7. Evidence from physiological studies
  8. Evidence from epidemiological studies
  9. How might basal hyperinsulinaemia induce insulin resistance?
  10. Current therapy
  11. Discussion
  12. Implications for therapy
  13. Dietary advice for the prevention of insulin resistance
  14. Competing interests
  15. References

Disruption of the classical signalling pathway is thought to be a likely mechanism leading to the development of insulin resistance. However, because of the number of interdependent factors in the pathway, the molecular development of insulin resistance is also likely to be complex. That said, a number of potential nodes of disturbance have been identified.

The insulin receptor is clearly fundamental for cellular insulin sensing, but the receptor also influences inherent insulin sensitivity in a number of ways. Alterations in receptor number, affinity or signal transmission can all change insulin sensitivity of a given cell and, as with other hormone receptors, continued exposure to its stimulus leads to a down-regulation of receptor numbers, both in vitro and in vivo [52,53], therefore leading to insulin resistance. The insulin receptor has the ability to bind to two separate insulin molecules, one with high and one with low affinity. The net affinity of the receptor for insulin decreases as insulin levels increase because negative cooperativity [54]. Furthermore, continuous basal hyperinsulinaemia induces a switch from the high-affinity receptor type to a lower-affinity receptor isoform [55]. However, the downstream effects of these changes in insulin receptors remain unstudied.

The propagation of the signal from the insulin receptor to downstream effectors depends on the intrinsic tyrosine kinase activity of the insulin receptor. This activity is a balance between phosphorylation, both positive and negative, the effect of interacting factors and dephosphorylation. In the presence of hyperinsulinaemia, the kinase activity of the activated insulin receptor is reduced because of negative feedback, driven by serine phosphorylation [56]. Furthermore, increased action of phosphatases such as PTP1B [57] reduces tyrosine phosphorylation and hence the receptor kinase activity. Also, the effects of negative regulators of insulin signalling, such as SOCS1 [58], reduce the signalling ability of the insulin receptor in response to hyperinsulinaemia.

Likewise, feedback phosphorylation of IRS-1 at several serine residues (including Ser307) in response to prolonged insulin incubation reduces its ability to associate with the insulin receptor [59], thus preventing signal propagation. There are many proposed insulin responsive IRS-1 serine kinases, including c-Jun N-terminal kinase [60,61], mammalian target of rapamycin [62], S6 kinase [63], glycogen synthase kinase 3 [64] and extracellular signal-regulated kinase [65]. All of these are proposed to couple prolonged insulin signalling to down-regulation of signalling and, potentially, if not controlled, leading to insulin resistance.

Therefore, there are a number of potential intracellular mechanisms that would link chronic hyperinsulinaemia to the development of insulin resistance. Delineation of the specific pathways responsible and specifically establishing whether a number of pathways interact are major goals of current research.

Current therapy

  1. Top of page
  2. Abstract
  3. Introduction
  4. What is the initiating insult in Type 2 diabetes?
  5. Beta-cell pulsatility
  6. Effect of insulin on the β-cell
  7. Evidence from physiological studies
  8. Evidence from epidemiological studies
  9. How might basal hyperinsulinaemia induce insulin resistance?
  10. Current therapy
  11. Discussion
  12. Implications for therapy
  13. Dietary advice for the prevention of insulin resistance
  14. Competing interests
  15. References

Many of the current therapies for Type 2 diabetes are aimed towards reducing hyperglycaemia using insulin secretagogues or insulin analogues. For example, sulphonylureas increase insulin burst mass through regulating the sulphonylurea receptor (SUR) linked to control of β-cell membrane depolarization [66], while incretins function by inducing insulin secretion, albeit in a glucose-dependent manner. Meanwhile, different types of insulin are available for injection therapy. Basal insulins (glargine, detemir) provide a continuous exposure similar to a continuous subcutaneous insulin infusion. Therefore, it is clearly a concern that the use of each of these therapies could increase insulin resistance. Pulsatile insulin therapy may reduce these concerns and at the same time have greater effects on the complications of diabetes such as nephropathy, neuropathy and retinopathy [67].

The dietary management of diabetes also remains a contentious issue. If hyperinsulinaemia is central to the development and maintenance of insulin resistance, then the current lifestyle management of diabetes, and in particular Type 2 diabetes, should be re-evaluated. Current guidelines advocate the ingestion of high levels of complex carbohydrates in the management of diabetes. Indeed, the Framingham offspring study showed that diets with a lower glycaemic index are associated with an increased level of insulin sensitivity [68]. However, this was also associated with an increased intake of cereal fibre, which has also been suggested to have positive effects on pancreatic function [69]. Diets rich in complex carbohydrates and with a low glycaemic index may have positive effects on incretin production [70] and also reduce the rate of lipid absorption, thus aiding insulin secretion. Conversely, a high-protein/low-carbohydrate or a high-fat/low-carbohydrate diet appears to be more effective at reducing insulin resistance than a high-carbohydrate/low-fat diet in obese individuals, although some of these effects may be mediated by an increase in weight loss in those using the non-conventional diet [71]. Furthermore, a high carbohydrate diet has been shown to induce inflammation in the livers of mice when compared with an isocaloric high-fat diet [72]. However, it is not yet evident what the effect of glycaemic index is on β-cell function. More research is required to understand the effects of different dietary constituents on both insulin secretion and insulin sensitivity.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. What is the initiating insult in Type 2 diabetes?
  5. Beta-cell pulsatility
  6. Effect of insulin on the β-cell
  7. Evidence from physiological studies
  8. Evidence from epidemiological studies
  9. How might basal hyperinsulinaemia induce insulin resistance?
  10. Current therapy
  11. Discussion
  12. Implications for therapy
  13. Dietary advice for the prevention of insulin resistance
  14. Competing interests
  15. References

The development of insulin resistance has been closely linked to the development of Type 2 diabetes for many years. However, despite extensive research, a mechanism to fully explain the molecular development of the majority of insulin resistance has remained elusive. We now suggest that the disordered secretion of insulin may be a major initiator of many of the defects found in Type 2 diabetes. Indeed, continuous insulin exposure can either initiate or perpetuate insulin resistance. However, despite genetic and epidemiological evidence supporting β-cell deficits in the development of Type 2 diabetes, this has not yet placed the β-cell as the initial problem, rather it is considered as simply enhancing susceptibility to other insults such as obesity. A proposed model placing the β-cell at the centre of the development of insulin resistance is shown (Fig. 1). The role of insulin resistance in the development of Type 2 diabetes cannot be underestimated. However, it is possible that this may be either a cause or a consequence of disordered insulin secretion. Current dogma suggests that hyperinsulinaemia is a normal response from β-cells to overcome increasing insulin resistance and prevent hyperglycaemia until adequate compensation is no longer possible. However, if the initiating factor is the development of hyperinsulinaemia or disordered insulin secretion, then the development of insulin resistance, initially in the liver, would be an appropriate physiological response to prevent the development of hypoglycaemia. It is possible that both these phenotypes occur in the population with Type 2 diabetes (Fig. 2). Efforts should be made to identify whether this is the case as it may have significant implications for therapy.

image

Figure 1.  Model of proposed effect of disordered insulin secretion on insulin sensitivity. Environmental influences on susceptible β-cells lead to self perpetuating disordered insulin secretion. Via decreased insulin signalling this leads to both hepatic insulin resistance and decreased insulin clearance. This propagates peripheral hyperinsulinaemia leading to peripheral insulin resistance and hyperglycaemia, the downstream effects of this having further potential toxic effects on β-cells.

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image

Figure 2.  Possible phenotypes leading to the development of insulin resistance in type 2 diabetes. In the standard model of insulin resistance (a) obesity and genetic susceptibility lead to the development of insulin resistance. There is a consequent rise in insulin secretion to reduce hepatic glucose output and prevent hyperinsulinaemia. In this case treatment of insulin resistance should reduce downstream hyperinsulinaemia. However, if a susceptible β-cell (b) develops disordered insulin secretion, particularly hyperinsulinaemia, then a decrease in hepatic glucose output would occur. To prevent hypoglycaemia there would have to be a rise in hepatic insulin resistance. Simply treating insulin resistance in this case may lead to troublesome hypoglycaemia, and what would be required is a normalisation of insulin secretion.

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Implications for therapy

  1. Top of page
  2. Abstract
  3. Introduction
  4. What is the initiating insult in Type 2 diabetes?
  5. Beta-cell pulsatility
  6. Effect of insulin on the β-cell
  7. Evidence from physiological studies
  8. Evidence from epidemiological studies
  9. How might basal hyperinsulinaemia induce insulin resistance?
  10. Current therapy
  11. Discussion
  12. Implications for therapy
  13. Dietary advice for the prevention of insulin resistance
  14. Competing interests
  15. References

The treatment of Type 2 diabetes with insulin secretagogues and very long-acting insulins is called into question. Interventions should be aimed towards reducing the basal level of insulin secretion either early in the disease or, more importantly, early in the development of insulin resistance, and enhancing glucose-stimulated pulse mass, particularly in the relatives of those with Type 2 diabetes. Indeed, the insulin ‘sensitizers’ thiazolidinediones and metformin have both been shown to restore or prevent impaired islet insulin secretion [73,74]. Furthermore, if hyperinsulinaemia is the major driver of insulin in some individuals, then simply targeting insulin resistance may lead to the development of troublesome hypoglycaemia, much in the same way that supplementing insulin in the already insulin-resistant individual may lead to worsening insulin resistance. There is clearly also an issue with proper control of insulin therapy in Type 1 diabetes to reduce the risk of insulin resistance associated with chronic insulin administration. Current technology could be utilized such that continuous subcutaneous insulin infusion could deliver appropriately timed pulsed boluses of short-acting insulin in an aim to prevent the development of insulin resistance.

Dietary advice for the prevention of insulin resistance

  1. Top of page
  2. Abstract
  3. Introduction
  4. What is the initiating insult in Type 2 diabetes?
  5. Beta-cell pulsatility
  6. Effect of insulin on the β-cell
  7. Evidence from physiological studies
  8. Evidence from epidemiological studies
  9. How might basal hyperinsulinaemia induce insulin resistance?
  10. Current therapy
  11. Discussion
  12. Implications for therapy
  13. Dietary advice for the prevention of insulin resistance
  14. Competing interests
  15. References

Furthermore, if mild continuous hyperinsulinaemia can lead to insulin resistance, then this should be taken into account when developing dietary advice for the prevention of diabetes. For example, if one is continually snacking, or consuming high-sugar drinks and therefore chronically delivering glucose to the pancreas, this will lead to a more persistent level of insulin delivery to the liver and the subsequent development of insulin resistance. The snacking behaviour of populations has increased over recent years, and this may go some way to explaining the increase in Type 2 diabetes in industrialized countries. By feeding a matched diet, either given continuously or at regular intervals, the effects of different eating patterns on human insulin sensitivity could easily be assessed.

In summary, hyperinsulinaemia and the disordered secretion of insulin may be central to the development of insulin resistance. It may be time to consider defective insulin secretion as an initiator in the pathophysiology of insulin resistance and Type 2 diabetes and raise the concept of reducing, rather than increasing, insulin secretion as a clinical goal in Type 2 diabetes, and taking care with the treatment of Type 1 diabetes with insulin to avoid insulin resistance.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. What is the initiating insult in Type 2 diabetes?
  5. Beta-cell pulsatility
  6. Effect of insulin on the β-cell
  7. Evidence from physiological studies
  8. Evidence from epidemiological studies
  9. How might basal hyperinsulinaemia induce insulin resistance?
  10. Current therapy
  11. Discussion
  12. Implications for therapy
  13. Dietary advice for the prevention of insulin resistance
  14. Competing interests
  15. References
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