β-Cell dysfunction vs insulin resistance in type 2 diabetes: the eternal “chicken and egg” question




Erol CERASI,MD, PhD, DHC
Endocrine Services Department of Medicine
Hebrew University Hadassah Medical Centre
Jerusalem, ISRAEL

by E. Cerasi, Israel

The idea that type 2 diabetes (T2DM) is mainly due to insulin resistance stems from the 1930s, but became dominating from the 1980s. However, evidence since the 1960s indicates that insulin response to glucose is markedly diminished from the earliest signs of glucose intolerance. Insulin pump treatment induces near-normoglycemia in T2DM with doses similar to type 1 diabetes, indicating that hyperglycemia is caused by lack of insulin, insulin resistance acting as an amplifier. Insulin secretion is genetically controlled. T2DM risk gene polymorphisms hint toward mechanisms of reduced insulin secretion in diabetes-prone subjects, in whominsulin response decreases as the number of diabetic alleles increases. I hypothesize that the genetic background of the β cell determines its adaptation capacity to increased insulin demand imposed by augmented caloric intake and insulin resistance; failure to adapt eventually leads to T2DM. Therefore, I regard the “prediabetic” β cell as a normal cell with limited adaptability, diabetes risk being entirely context-dependent (nutritional load and insulin sensitivity). Once hyperglycemia is established, β cells are exposed to continuous nutrient stimulation, with consequent oxidative and endoplasmic reticulum (ER) stresses. The result is increasing functional deficiencies and β-cell apoptosis, hence reduced β-cellmass. Some of itsmechanisms are discussed. An intriguing as yet unanswered question is whether the mechanisms of β-cell deficit in the diabetic environment operate before hyperglycemia in overfed, insulin-resistant subjects. Therapeutic agents preventing β-cell oxidative and ER stress could stop the progression and perhaps initiation of T2DM.

Medicographia. 2011;33:35-41 (see French abstract on page 41)

The formal separation of type 1 diabetes as an autoimmune entity is of relatively recent date1; nevertheless, the heterogeneity of diabetes, as well as the fact that for some patients insulin treatment is a lifesaving procedure while others may more or less control their metabolic state with dietary or pharmacological means, has been known to clinicians and clinical investigators since long ago. As insulin became more widely used it also appeared that in many patients whom today we identify as typical type 2 diabetics, achieving metabolic control with insulin treatment was difficult, sometimes impossible. Thus, several decades before the insulin receptor and its signaling pathways were identified, an astute clinician such as H. P. Himsworth could write “…I would suggest the possibility of the existence of a type of diabetes due not to diminished secretion of insulin by the pancreas, but to a greater or less impairment of the organism’s susceptibility to insulin.”2,3 In short, the idea that diabetes may be the result of insulin resistance is not new. Indeed, the presence of obesity in the vast majority of patients with type 2 diabetes (T2DM) makes it a reasonable assumption that some degree of insulin resistance must exist in this disorder.

The striking advancements over the past three decades in the field of insulin action, including the detailed understanding of the molecular biology of the insulin receptor and its signaling pathways as well as of the regulation of glucose transporters, have naturally further attracted the attention of investigators to insulin resistance as a main pathophysiological factor in type 2 diabetes, sometimes presented as the sole factor. Thus, as recently as 2000, the Journal of Clinical Investigation stressed this by publishing a “Perspective” series entitled On diabetes: insulin resistance.4 Yet, many investigators demonstrated as soon as insulin immunoassays became available in the early 1960s that the insulin response to a glucose challenge is markedly reduced in type 2 diabetics, including in normoglycemic subjects with glucose intolerance (IGT) only.5-9 The adoption of dogmatic, monolithic views by many investigators of both “camps” did not facilitate the development of open-minded approaches to analyze the etiopathology of diabetes in its full physiological context, notwithstanding some balanced views10-12 pointing to the fact that the biology of type 2 diabetes is not simple, and that pure β-cell deficit or exclusive insulin resistance are rare events since in fact these two factors are interlinked, as would be expected from any closed-loop feedback regulatory system.

Insulin resistance, plasma insulin levels, and β-cell function

The variability of the insulin response to glucose as well as that of the sensitivity to insulin is remarkably large in the normal population.13-15 he obese, while insulin sensitivity is reduced and insulin response is augmented, variation is as wide, with considerable overlap with the levels of lean subjects. Thus, there exist substantial numbers of subjects with either a markedly low insulin response or a low sensitivity to insulin who nevertheless retain normal glucose tolerance. Indeed, at least 2/3 of obese subjects never develop IGT or type 2 diabetes; yet they are insulin resistant and hyperinsulinemic. In type 2 diabetic patients, except in its very severe forms, both fasting and postprandial plasma insulin levels are normal or higher than normal. This observation provides the rationale for insulin resistance in diabetes: if blood glucose remains high despite substantial levels of insulin, hormone action must be defective. This is a static view of a highly dynamic regulatory system, confusing cause and effect: what are “substantial” levels of insulin, ie, what degree of hyperinsulinemia is adequate for a given degree of hyperglycemia? Glucose vs insulin dose-response curves have been constructed from acute experiments (eg, see reference 16); however, lacking data on long-term experimentally induced hyperglycemia in normal subjects, how can we determine whether a given plasma insulin value in a chronically hyperglycemic diabetic is higher or lower than normally expected?

Figure 1
Figure 1. Fasting plasma insulin levels in 15 type 2 diabetic patients
prior to and following 6-month treatment with the sulfonylurea
gliclazide. Data calculated from reference 17.

Abbreviation: T2DM, type 2 diabetes mellitus.

Two examples strikingly demonstrate how lack of consideration for physiological regulation leads to erroneous conclusion. The first relates to fasting insulin concentration. Many investigators, including our group, find that the fasting plasma insulin level in type 2 diabetic patients is higher than normal; however, fasting glucose also is higher: does it contribute to the fasting hyperinsulinemia of the patient? In 15 mildly obese type 2 diabetics treated with the sulfonylurea gliclazide for 6 months we found that, in parallel with the normalization of blood glucose, the initially high fasting plasma insulin levels fell to the range found in weight-matched normoglycemic controls despite the use of the β-cell stimulator gliclazide17; this is illustrated in Figure 1. Thus, fasting insulin is also under the control of ambient blood glucose concentration. The second example relates to the bell-shaped insulin curve often used to describe changes in β-cell function during the fall of glucose tolerance from normal to IGT and T2DM. This is an artefact due to the use of 120-minute plasma insulin values in the oral glucose tolerance test (OGTT): patients with IGT having higher glucose levels throughout the test generate a strong signal for amplifying the secretion of insulin at a time when blood glucose is still high enough to stimulate the β-cell, resulting in a typical late insulin peak. In fact, if earlier (eg, 30 min) time points are chosen, the insulin response to OGTT shows a linear fall from normal via IGT to T2DM.18-20 In short, provided the plasma insulin data are interpreted with full reference to the physiology of regulated insulin secretion, it becomes clear that β-cell responsiveness to glucose is lower than normal in IGT, and even less so in T2DM.

Table I
Table I. Effect of continuous subcutaneous insulin infusion (CSII) treatment on fasting and postprandial blood glucose control in moderately obese type 2 diabetic patients (calculated from references 17, 21, and 22; Mean ±SEM).

Abbreviation: CSII, continuous subcutaneous insulin infusion.

Figure 2
Figure 2. Schematic illustration of the plasma insulin response to a hyperglycemic clamp, showing the gradual decrease in firstphase as well as second-phase insulin secretion as glucose tolerance deteriorates from normal to IGT and further to mild and advanced diabetes.

Abbreviations: IGT, impaired glucose tolerance; NGT, normal glucose tolerance; T2DM, type 2 diabetes mellitus.

The above discussion does not mean that I negate the existence of insulin resistance in type 2 diabetic patients; the scientific literature is replete with data convincingly showing that insulin resistance is part of the pathogenesis of T2DM. Nevertheless, I remain convinced that T2DM is a disorder of insulin deficit, the input of insulin resistance to its pathogenesis increasing with the severity of obesity. To my mind, the best demonstration of the above was achieved in mildly obese type 2 diabetic patients treated with continuous subcutaneous insulin infusion (CSII). In pilot studies in 23 white patients, we could achieve fasting and postprandial normoglycemia with a mean daily insulin dose around 0.6 units per kg body weight.17,21 Similar results were obtained in a larger group of Chinese patients.22 The amounts of insulin administered through CSII in these studies were not strikingly higher than the doses routinely used in insulin pump–treated type 1 diabetic patients (Table I). Thus, a similar degree of insulin deficit seems to exist in both types of diabetes, which leads me to conclude that insulin resistance in T2DM is not the main factor inducing hyperglycemia.

β-Cell function during the development of type 2 diabetes

The earliest modifications of the insulin response to glucose that can be detected as glucose tolerance starts deviating from normal are the early or first-phase insulin response, and the physiological oscillations of secretion.5,6,8,23,24 The latter requires numerous blood samplings, and therefore has not gained popularity among clinicians and investigators. In contrast, early insulin response to glucose can be measured during oral or IV glucose tolerance tests; however, glucose clamps allow the most detailed definition of the kinetics of the plasma insulin response to glucose. The first-phase response is markedly reduced in subjects with IGT, and further diminishes as fasting hyperglycemia appears. At these stages of the disease, the later or second-phase insulin response to glucose is normal, but with the progression of the severity of diabetes also this phase collapses. These changes are schematically illustrated in Figure 2.

Low first-phase insulin response is found also in some subjects with normal glucose tolerance.5,6 Several studies over the past few years have demonstrated that a low insulin response is a predictor of future glucose intolerance and T2DM, both in lean and obese subjects belonging to various ethnic groups.25-27 In our study, lean and physically active Swedish subjects with normal glucose tolerance were followed for a mean period of 25 years; the only initial parameter that was significantly correlated to later glucose intolerance was first-phase insulin response corrected for insulin sensitivity (disposition index).25 These results are summarized in Table II (page 38).

What is the genetic/molecular basis of the low insulin response in nondiabetic subjects? Extensive studies over 4 decades in family members related or unrelated to diabetic patients, in-cluding in monozygotic twin pairs, have shown that several aspects of the insulin response to glucose in man are under strong genetic control.28-31 However, it is only now that we are gaining some insight into the possible cellular mechanisms that may be responsible for the decrease of β-cell function in subjects at risk of developing diabetes. Indeed, the numerous whole genome association studies that have been performed over the past decade have identified allelic variants of several genes, mostly involved in β-cell development, function and survival, that collectively participate in the risk of diabetes development. As the number of risk alleles that a subject carries increases, several aspects of β-cell function deteriorate; most pertinently, the insulin response to oral or IV glucose decreases in proportion to the number of risk alleles.32,33

Table II
Table II. Prediction of the 2-hour blood glucose concentration
during OGTT in 269 healthy lean subjects after a mean of 25 years.

The data relate to the initial test values. The P value denotes the relation between the initial (ΔI5/ΔG5)/HOMA-IR and the 2-hour blood glucose level of OGTT
performed 25 years later.
Abbreviations: (ΔI5/ΔG5)/HOMA-IR: glucose-induced insulin response measured at 5 minutes of a glucose clamp, corrected for HOMA-IR; HOMA-IR, homeostasis model assessment of insulin resistance; NS, nonsignificant; OGTT, oral glucose tolerance test.
Modified from reference 25: Alvarsson et al. Diabetologia. 2005;48:2262-2268. © 2005, Springer-Verlag.

By which cellular mechanisms these risk alleles impair insulin secretion is not known. However, recent findings from Gloyn et al suggest that, at least regarding the highest-risk gene, transcription factor 7–like 2 (TCF7L2), the association of insulin granules with the voltage-gated calcium channels in the β may be disturbed, thus reducing the efficiency of the insulin exocytotic machinery.34 stands to reason that within a short space of time, the mechanisms of low insulin response to glucose, which is a strong risk factor for T2DM, will be fully clarified at the molecular level.

Progression of diabetes and deterioration of β-cell function: decrease in cell function or cell mass?

It has been the experience of most clinicians that as the duration of diabetes increases so does the severity of the disease. This old observation has received its scientific approval through the United Kingdom Prospective Diabetes Study (UKPDS): whatever the treatment modality chosen, the level of HbA1c increases with time (for a review, see reference 35). However, it is also the experience of most clinicians that, whatever the treatment modality chosen, induction of strict normoglycemia throughout the day over a period of years in type 2 diabetics is nearly impossible; therefore, it is not clear whether T2DM is an inherently progressive disorder due to the nature of its pathogenesis, or whether progression is secondary to the unregulated metabolic state which reflects our inability to provide adequate treatment (the latter is my belief, entirely unproven). Whether primary or secondary, the progression of diabetes is paralleled by the progressive decline of β-cell function, as measured by the plasma insulin response to glucose35 (see Figure 2 also). Plasma insulin may decrease either because β-cell function, ie, the function of individual β cells, is reduced, or because the number of β cells declines, ie, β-cell mass is reduced.

_ Is β-cell mass reduced in type 2 diabetes?

There is consensus that some degree of β-cell mass reduction does occur at some stage in T2DM,36-38 but there is also considerable disagreement as to the extent of the reduction and its significance for diabetes development. Presently the dominating view, most strongly advocated by the Butler group in Los Angeles,37 is that β-cell mass is markedly reduced already at the stage of IGT, a further deficit being apparent in overt diabetes even if treated only by diet. By contrast, studies in Europe36,38 find considerably less reduction in β-cell mass. It has to be stressed that real β-cell mass was calculated only by Rahier et al,38 while Butler et al37 measured β-cell area, which reflects β-cell mass less adequately. Perhaps more importantly, the Rahier laboratory in Brussels points to the extraordinarily wide range of β-cell masses
both in the diabetic and nondiabetic groups, with the existence of major overlap between the hyperglycemic and normoglycemic subjects. These observations make it difficult to ascribe a definitive role to reduced β-cell mass in the genesis of hyperglycemia. Obviously, it may be argued that the hyperglycemia of the patient should have driven β-cell mass to increase substantially as a compensatory mechanism, which is not observed.

To gain some insight into the dynamics of β-cell mass changes during the development of diabetes, we utilized an animal model of nutrition-dependent type 2 diabetes, the gerbil Psammomys obesus. These animals have an inborn insulin resistance, but retain normal glucose tolerance under caloric restriction; when given a diet with circa 40% higher calories and low fiber content, they rapidly become hyperglycemic.39 Figure 3 shows that as the animals develop hyperglycemia, they rapidly lose pancreatic insulin stores, since the cells are forced to secrete all their insulin granules in the face of the unrelenting hyperglycemic stimulation. Nevertheless, β-cell mass remains normal for a considerable period; it even increases slightly due to increased β-cell proliferation induced by the high glucose levels.39 β-Cell mass collapses only after prolonged diabetes, with severe worsening of the hyperglycemia (so-called end-stage diabetes). Thus in this model, possibly in analogy with European type 2 diabetic patients, from a pathophysiological viewpoint significant β-cell mass reduction occurs only in long-standing and advanced T2DM. In earlier stages, the β-cell deficiency seems to be more of a functional nature. I therefore prefer to use the term “function- al β-cell mass” to denote a globally insufficient insulin delivery situation, until we gain access to in vivo imaging techniques to allow in situ β-cell mass determination in our patients.

Figure 3
Figure 3. The evolution of nutritional diabetes in Psammomys obesus.

When these gerbils are switched from a low-caloric diet to a high-energy (HE) diet, blood glucose increases sharply, paralleled by the marked loss of pancreatic insulin stores. In contrast, -cell mass remains stable and even slightly increases, until late in the evolution of diabetes. As the animal reaches end-stage diabetes with severe hyperglycemia (and increased FFA, not shown), -cell
mass also collapses.
Abbreviations: FFA, free fatty acid; HE, high energy.
Modified from reference 39: Kaiser et al. Diabetes. 2005;54:138-145. © 2005,
American Diabetes Association.

Why do β cells die in a diabetic environment?

Extensive work over the past decade has shown that mimicking the diabetic environment in vitro, ie, exposure to high concentrations of glucose and fatty acids over extended periods, causes death of β cells by apoptosis (for a review, see reference 40). Both oxidative stress and endoplasmic reticulum (ER) stress in the β cell, induced by the high nutrient exposure, contribute to initiating programmed cell death. Our laboratory has been interested in &beat;-cell ER stress over the past few years. In β-cells exposed continuously, ie, in a noncyclic manner, to high glucose levels proinsulin biosynthesis is under continuous stimulation; this puts the ER system under high pressure, since proinsulin has to be correctly folded and exported to the Golgi apparatus for processing and further maturation in insulin granules. The ER responds to the increase in proinsulin mRNA translation and chaperone-guided proinsulin folding by what is named the unfolded protein response (UPR), which is an adaptive feedback response aimed at reducing the workload by partially blocking the translation of mRNAs and degrading them, and augmenting chaperones to prevent misfolding of newly formed proteins as well as removing misfolded proteins from the ER. If the load on the ER persists despite these measures, then the UPR activates several mechanisms that end in apoptosis, leading to the removal of the deficient cell (for a short-but-comprehensive overview, see reference 41). We have shown that exposure to chronic high glucose levels activates the inositol-requiring enzyme 1 (IRE-1 ) arm of the UPR both in β-cell lines and in Psammomys obesus islets.42 Furthermore, fatty acids (palmitate) and glucose exhibited a high degree of synergism in activating IRE-1 . This eventually leads to activation of c-jun N-terminal kinase (JNK) and increase in -cell apoptosis; by using specific JNK inhibitors we could demonstrate that JNK is indeed responsible for initiating the caspase cascade and β-cell death.42 Importantly, the effect of glucose on the IRE-1 cascade is mammalian target of rapamycin (mTOR)-dependent, since it could be inhibited by reducing the activity of mTOR complex 1 (mTORC-1) with rapamycin, thus rescuing cells from glucolipotoxicity-induced death.42 This unfortunately does not mean that rapamycin can be used as a therapeutic agent against type 2 diabetes. To our dismay, when we administered rapamycin to diabetic Psammomys obesus, the animals developed even higher hyperglycemia together with extreme lipemia and massive β-cell apoptosis.43 Thus, the in vivo situation is more complex than that observed under well-controlled in vitro experiments. Intensive efforts are ongoing in numerous laboratories to design means for counteracting ER stress (as well as oxidative stress) in cells; these may eventually lead to the generation of new classes of antidiabetic drugs aimed at prolonging the life of the cell, thus preventing the seemingly ineluctable progression of type 2 diabetes.

Conclusions

Is T2DM a disease of insulin deficiency or insulin resistance? Obviously both. Nevertheless, I am comforted in my nearly 50-year-old belief in the primacy of insulin deficiency for the pathogenesis of T2DM by the consensus that has emerged in the last decade over the fact that hyperglycemia is not possible in the absence of β-cell deficiency. Compared to the near-total lack of insulin of the type 1 diabetic, the β-cell deficiency of the type 2 diabetic patient is modest, and therefore would not be sufficient to lead to the full diabetic state in such a high proportion of subjects without additional environmental factors. This is a classic gene-environment interaction. It is a fascinating idea that, had the whole genome association studies been performed immediately after World War II in the undernourished populations of Europe and Asia, none of the polymorphic genes being hotly investigated today would have been found to be associated with type 2 diabetes. Indeed, these polymorphic alleles seem to render the cell somewhat less efficient, ie, place it at the lower end of normal variation in terms of its functional adaptability and resistance to stress; nevertheless, these cells are normal until faced with unreasonable demands. I think too much emphasis is put on insulin resistance; I believe that the greatly augmented caloric intake, ie, the greatly increased nutrient flux in the cell, is the real problem, insulin resistance acting as a potent amplifier. The consequence of this thought is that the risk for an individual to develop T2DM would be inversely correlated with the magnitude of adaptability of his cells and directly correlated with the degree of caloric intake/ insulin resistance to which he would be exposed. Thus, the “stronger” the cell, the greater the degree of obesity that can be tolerated while maintaining normal glucose tolerance. There are cases of lean, insulin-sensitive T2DM, as there are cases of diabetes with severe insulin resistance and extreme hyperinsulinemia. However, these are rare. For the majority of type 2 diabetics, to prevent hyperglycemia and its consequences either food intake has to be reduced drastically, or the cell enforced to cope with the increased workload. Neither seems easy. Almost all research today on the cell in connection with T2DM deals with the cells’ reaction to various stresses, ie, the glucolipotoxicity situation. That this is most relevant to the fate of the cell in the diabetic environment, and therefore to diabetes progression, is clear. A legitimate question does arise, however: Are the various mechanisms of -cell stress discussed above (and in the literature) responsible also for the initiation of hyperglycemia? In other words, is -cell stress a secondary reaction to diabetes (glucolipotoxicity), almost a complication of the disease, or is it the etiopathogenic event that leads to the gradual impairment of glucose homeostasis until glucose intolerance and diabetes appear? This is an important question that awaits its solution through future research. _

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Keywords: insulin secretion; first-phase response; low insulin response; insulin resistance; IGT; type 2 diabetes; &bata-cell function; β-cell mass; ER stress