0 1 2 3 4 5

M-low (mg/kg EMBS per minute)

Fig. 2. Relationship between a measure of insulin sensitivity on the X axis and insulin secretion on the Y axis. The curved lines show the normal relationship among these parameters, which is termed the "disposition index." Forty-eight normal glucose tolerant Pima Indians were followed for 5 years, with 17 going on to develop type 2 diabetes (progressors) whereas 31 maintained normal glucose tolerance (nonprogressors). These findings reinforce key issues discussed in the text: 6-cell function is the major determinant of the blood glucose level in persons who are at risk for type 2 diabetes, and 6-cell dysfunction occurs before blood glucose values rise into the prediabetes range. From ref 56.

(56). Seventeen developed type 2 diabetes (progressors) whereas 31 maintained normal glucose tolerance (nonpro-gressors). The groups were comparably obese and insulin resistant at the start of the study. Nonprogressors gained a little weight, and became a little more insulin resistant during the study, but stayed on the disposition curve, i.e., had perfect B-cell compensation (Fig. 2). Progressors instead started below the insulin secretion part of the curve, and fell even further as their glycemia worsened, clearly showing that their deterioration in glucose tolerance resulted from worsening B-cell function. It is particularly notable that the progressors started the study already off the normal curve, showing that despite their entering the study with glucose tolerance in the normal range, there was already subtle B-cell dysfunction that had not yet resulted in a measured degree of glucose intolerance.

This latter concept has been observed in many other populations. One notable series of studies cross-sectionally examined Mexican-Americans and Caucasians across a wide range of glycemia from normal glucose tolerance to diabetes (57,58). B-cell function was determined as the insulin response to an OGTT that was adjusted for each subject's insulin sensitivity (based on glucose clamp testing) and 2-hour postmeal glucose values. B-cell function was observed to fall as glycemia rose ever so slightly within the normal glucose tolerance range; subjects with 2-hour glucose values of 101-120 mg/dL had 60% lower adjusted mealtime insulin responses than those with 2-hour glucose values <100 mg/dL (normal glucose tolerance is defined by a 2-hour value of <140 mg/dL). Studies in other populations (59,60), and a cross-sectional analysis of fasting glucose values (61), had similar results.

Thus, it is now clear that insulin resistance and B-cell dysfunction both precede measured defects in glucose tolerance. Defective B-cell mass or function must be present for blood glucose values to rise even minimally above normal, given the precision of a healthy glucose homeostasis system. Therefore, the current definition of normal glucose tolerance is insensitive to early defects in glucose homeostasis. A recent study documented a several fold higher risk for type 2 diabetes with fasting blood glucose values at the high range of normal versus the low range ( >87 mg/dL vs <81 mg/dL), especially in the presence of obesity or hypertriglyceridemia (62).

The question of which defect occurs first, and which is dominant, remains. One related long-standing argument is whether prolonged insulin resistance causes B-cell failure through "exhaustion" (i.e., continued stimulation of otherwise normal B-cells resulting in permanent dysfunction). The available facts do not support this proposal. Many morbidly obese highly insulin resistant subjects never develop diabetes. One thus assumes that it is necessary for the B-cell compensatory ability to be compromised in some way for diabetes to develop. Stated another way, if one has healthy B-cells, it appears to be virtually impossible to develop type 2 diabetes with the usual lifestyle and environmental influences. Thus, the key to a better understanding of type 2 diabetes is to define what constitutes "susceptible" B-cells.

To summarize, both beta-cell dysfunction and insulin resistance occur long before blood glucose values reach prediabetes. One has not been shown to precede, or cause, the other. As such, type 2 diabetes is considered a "dual-defect disease" with both defects of equal importance (63). However, it is unclear from this understanding whether early intervention for diabetes prevention would be most effective focusing on improving B-cell function or insulin resistance. To date, the most effective treatment found for prevention of type 2 diabetes is diet and exercise (2,31,32), which improves insulin sensitivity. Alternatively, viewing one defect as independent from the other may be overly simplistic, as B-cell function and insulin resistance are linked by the disposition index. The best example of this is a series of studies of Hispanic women in Los Angeles with prior gestational diabetes (an extremely high risk group for type 2 diabetes) who were treated with the insulin sensitizers Troglitazone or Pioglitazone. Both drugs markedly decreased progression to permanent type 2 diabetes (64,65). One might expect that the conclusion of these studies would highlight the importance of insulin resistance. Instead, the main reported benefit was prevention of B-cell dysfunction as shown by sequential analysis of B-cell function and insulin sensitivity, believed secondary to "B-cell rest".


Studies over many years have described the B-cell dysfunction in type 2 diabetes (66). The major defects are:

1. Insulin is normally secreted in a pulsatile fashion, with oscillations every 11-14 minutes that provide for normal regulation of hepatic glucose production (67,68). Also large bursts (termed ultradian oscillations) occur several times daily, especially after meals, and maximize nutrient clearance (69). The pulsatile patterns are disrupted early in type 2 diabetes, with near-total elimination of the oscillations even in normoglycemic first degree relatives (70,71).

2. An acute rise in glucose normally causes a burst of insulin secretion lasting 5-10 minutes ("first phase"), followed by another rise in insulin output lasting the duration of the hyperglycemic stimulus ("second phase"). The characteristic B-cell defect in type 2 diabetes is loss of the first phase (48,66), which occurs early in the course of the disease, with the first phase being reduced in half with fasting blood glucose levels above 100 mg/dL, and absent at values greater than 115 mg/dL (46). The first phase serves an important role during food ingestion, to control the postmeal glycemic excursion. Selectively disrupting the first phase in healthy subjects causes glucose intolerance (72,73), whereas restoring it in persons with type 2 diabetes markedly improves postprandial glycemia (74). Importantly, Vague and Moulin (75) found a substantial recovery of the first phase following a period of intensive glucose control. As such, loss of first phase insulin secretion is the earliest identified aspect of the previously discussed acquired B-cell defects. Furthermore, this defect provides a pathophysiological explanation for the transition from normal glucose tolerance to IGT.

3. As the disease progresses and hyperglycemia worsens over time, additional B-cell defects occur. Indeed, a defining feature of type 2 diabetes is a relentless slow deterioration of B-cell function that is blamed for the typical clinical course of eventual waning of responses to oral antidiabetic agents (76). Also, this worsening explains why so many patients ultimately require insulin therapy for glucose control. These defects have been investigated almost exclusively in diabetic animals and cell systems. (A major obstacle to a better understanding of the B-cell dysfunction is an inability to perform human pancreas biopsies because of risk of pancreatitis and/or leakage of digestive juices.) Animal studies have shown that there is a hierarchy of B-cell defects at different glucose levels: modest hyperglycemia coexists with impaired glucose-induced insulin secretion that mimics human type 2 diabetes, and higher levels are associated with additional defects in proinsulin biosynthesis and B-cell viability (66).

Lowered fi-Cell Mass In Type 2 Diabetes

In addition to ^-cell dysfunction, reduced B-cell mass may also contribute to the development of type 2 diabetes. Measurement of B-cell mass in humans is technically difficult and must be done on autopsy specimens; until recently, there were few studies, with a limited number of subjects. Furthermore, in many of these studies, controls were poorly matched. An increased B-cell mass is part of the normal B-cell compensation to insulin resistance. Weight-matching of control and diabetic subjects is now mandatory to minimize differences in insulin sensitivity, but was often not done in older studies. An important recent study by Butler et al of nearly 160 weight-matched control and type 2 diabetes subjects reported a 40-60% lowered B-cell mass in this disease (Fig. 3) along with a 3-fold increase in B-cell apoptosis (77). Also, a recent study from Korea reported a large reduction in B-cell mass in type 2 diabetic subjects, and also reported the novel finding that the mass of the glucagon-producing a-cells was increased (78). Notwithstanding the limitations of the older studies, these studies confirmed the conclusion of most, but not all, prior work that B-cell mass is lowered in type 2 diabetes.

The study by Butler et al (77) was the first study to provide data on subjects with IGT, finding a 40% reduced B-cell mass. This novel observation is important for our understanding of the pathogenesis of type 2 diabetes. The sequence of events suggests that reduced ^-cell mass may cause the earliest hyperglycemia, when the blood glucose begins to rise but is still within the normal glucose tolerance range, initiating in some way defective first phase insulin secretion. Postmeal glycemia then rises to a level defined as IGT, with the potential for more acquired defects, worsening of glycemia, and progression to diabetes. Although no additional human data exist, studies of partially pancreatectomized rats support that pattern. After a 60% pancreatectomy, rats normally compensate for the B-cell loss through a combination of partial B-cell regeneration and hyperfunction of the remaining B-cells, and thus remain normoglycemic under normal circumstances. The partial B-cell regeneration results in the B-cell mass rising from 40% immediately after the surgery to 60% of normal, and remains at this level indefinitely. The B-cell compensatory capacity of these rats to a minor dietary change was studied by adding some sugar (10%) to the water supply from which they drank freely (79). Nonpancreatectomized rats given the sugar water drank it identically to the pancreatectomized rats. It is important to appreciate that the diet change was extremely modest: nonpancreatectomized rats given the sugar water over the 6 weeks of the study showed no obesity, hyperinsulinemia, or other metabolic difference compared to rats given tap water. In contrast, 60% pancreatectomy rats given sugar water developed mild hyperglycemia after a few weeks, with morning blood glucose values rising by 15 mg/dL. This small increase in glycemia was associated with a profound (75%) reduction in glucose-induced insulin secretion, analogous, it is proposed, to the process in humans that initiates progression to IGT and subsequent diabetes. Thus, one scenario for "susceptible B-cells" is a reduced B-cell mass

Fig. 3. Blood glucose values (top panel) and B-cell volume (bottom panel) from a large number of autopsy specimens, with the data expressed by the absence or presence of obesity, and by the degree of glucose tolerance (no diabetes, impaired fasting glucose, type 2 diabetes mellitus). Note there is a 40% reduction of B-cell volume in the subjects with impaired fasting glucose (IFG) and 40-60% reduction with type 2 diabetes. From ref 77.

Fig. 3. Blood glucose values (top panel) and B-cell volume (bottom panel) from a large number of autopsy specimens, with the data expressed by the absence or presence of obesity, and by the degree of glucose tolerance (no diabetes, impaired fasting glucose, type 2 diabetes mellitus). Note there is a 40% reduction of B-cell volume in the subjects with impaired fasting glucose (IFG) and 40-60% reduction with type 2 diabetes. From ref 77.

that is incapable of maintaining normoglycemia when faced with environmental factors that have no detrimental metabolic effect when the B-cell mass is normal.

Considerable current research is exploring the pathogenic basis for the lowered B-cell mass in type 2 diabetes and prediabetes, with several proposed mechanisms:

1. Amyloid plaques occur in the islets of persons with type 2 diabetes, along with distorted and shrunken B-cells (80). The amyloid protein, islet associated polypeptide (IAPP), is a 37 amino-acid B-cell-specific protein that is normally packaged in insulin granules and co-secreted with insulin (81,82). The 25- to 28-amino acid sequence is the amyloidogenic portion. It is conserved in many species, all of which develop islet amyloid and diabetes. However, rodents lack the sequence, allowing the creation of transgenic mice that overexpress human IAPP to test the plausibility of IAPP-induced B-cell destruction. Some, but not all, transgenic mice develop islet amyloid plaques with accelerated B-cell apoptosis and diabetes (83,84), engendering substantial interest in a pathogenic role for islet amyloid in type 2 diabetes (85). Lorenzo et al (86) cocultured islets with exogenous IAPP, causing B-cell death, which suggested that external amyloid plaques are cytotoxic. Also, this finding implied that amyloid deposition must be an end-stage part of the disease, not involved in the B-cell reduction in IGT, as islet amyloid is not yet present in autopsy specimens from these subjects. The current view, however, has evolved to small intracellular microfibrils of IAPP being cytotoxic through mitochondrial damage or endoplasmic reticulum stress (87,88), which is more in line with how other amyloid diseases, such as Alzheimer's, are thought to occur. In animal studies, microfibrils occur long before the extracellular amyloid plaques. Unfortunately, showing their presence in human autopsy tissue is an inexact science, and it remains unknown if they are present in IGT. Also, IAPP is normally produced and secreted. The cause of the microfibrils and large amyloid plaques in type 2 diabetes remains unknown. It is not related to the rate of IAPP secretion, as normally glucose tolerant obese subjects with long-term B-cell compensatory hyperfunction for both insulin and IAPP lack islet amyloid at autopsy. Neither is it hyperglycemia per se, as amyloid plaques are often found in insulinomas (89). Genetic mutations in IAPP have been sought, but rarely found. Instead, the expectation is that mutations of other important proteins that normally keep IAPP soluble will be found, for example folding proteins, or others that prevent amyloid formation.

2. Pathological studies of 6-cells in type 2 diabetes have reported increased apoptosis as the cause of the lowered 6-cell mass (77,90). Many mechanisms of cellular apoptosis are known: ER stress from misfolded proteins, oxidative stress, inflammatory mediators, glucolipotoxicity, etc. All are being studied for relevance to type 2 diabetes (91-95).

3. There is no evidence to suggest that the cause of the lowered 6-cell mass is immune-mediated 6-cell destruction analogous to type 1 diabetes, as careful studies have shown the 2 types of diabetes are pathologically distinct.

Cellular Mechanisms of fi-Cell Dysfunction

There has been intense study of potential cellular mechanisms of the 6-cell dysfunction in type 2 diabetes. As already discussed, the inability to get islet tissue from free-living humans is a major impediment. Thus, with rare exceptions, these studies have been carried out in vitro using isolated islets from animals, clonal 6-cell lines exposed to high glucose and/or fatty acid levels, or by studying isolated islets from diabetic animals. There are a few studies of isolated islets from brain dead donors with type 2 diabetes (17,90,96-99). Also, an emerging technique that holds considerable promise is laser capture microdissection to carve out islet-cells from pancreas slides of autopsy material, followed by mRNA amplification and expression profiling. Still, work with islet tissue from humans with type 2 diabetes is just beginning, and there remains a concern that islets obtained at the time of death (for any number of medical reasons) may be misleading in terms of the observed 6-cell physiology compared with the average otherwise healthy subject with type 2 diabetes. Thus current concepts of potential mechanisms are generally based on nonhuman systems. Several have been proposed (66,100):

1. Glucose toxicity. This concept implies a direct effect of a high glucose level to impair one or more necessary aspects of 6-cell signaling, gene expression, cell architecture, etc, for normal insulin secretion. The list of reported 6-cell effects from experimental high glucose is lengthy; essentially every major 6-cell metabolic pathway, key enzyme, and important gene has been reported to be altered (66). A variation on this concept is a series of papers performed in normal rats made hyperglycemic by glucose-infusion or partial pancreatectomy, showing a profoundly altered pattern of transcriptional expression of important 6-cell genes, termed "6-cell dedifferentiation" (101,102).

2. fi-cell exhaustion: This term implies an indirect effect of hyperglycemia to impair 6-cell function by way of the initial compensatory increase in insulin secretion depleting a key substance, metabolite, etc., below a crucial level that is required for continued insulin secretion. It is differentiated from glucose toxicity with an inhibitor of insulin secretion, such as diazoxide. Conceptually, with glucose toxicity, hyperglycemia, and consequently the 6-cell dysfunction, would worsen, but, with exhaustion, the "beta-cell rest" improves 6-cell function regardless of the blood glucose level. There is strong experimental support in both animal models and humans with type 2 diabetes for the exhaustion concept (100,103-106).

3. Impaired proinsulin biosynthesis: Extensive in vitro data support a hyperglycemia-induced defect in proinsulin transcription (107), although this requires high levels of glycemia (101) (i.e., this is one of the late-onset acquired 6-cell defects). Also, an added effect of excess fatty acids to impair proinsulin transcription, is potentially important (108).

4. Lipotoxicity: There has been great interest in the concept that excess fatty acids are harmful to 6-cell function and viability, so-called lipotoxicity (42). The working concept is that metabolic products of excess fatty acids, such as ceramides or other mediators of oxidative stress, cause 6-cell dysfunction and death (94,109). However, this idea remains controversial, in part because the cellular systems and animal models used to study the subject are often so extreme that the relevance to human type 2 diabetes is unclear. Using in vitro culture of rat islets with high levels of fatty acids, Liu et al found no insulin secretory dysfunction or 6-cell death. Instead, they identified a system in normal 6-cells that protects against fatty acid-induced reductions in glucose metabolism that occur in other tissues (so-called "Randle effect"). In those tissues, excess fatty acids impair the activation of pyruvate dehydrogenase and retard glucose oxidation. In contrast, a relatively specialized feature of 6-cells is the high expression of a second pyruvate metabolism enzyme (pyruvate carboxylase), that allows the block in pyruvate metabolism to be bypassed (110). Furthermore, pyruvate carboxylase is the entry step to mitochondrial metabolic pathways in 6-cells that are believed to be important signals for glucose-induced insulin secretion (111). Therefore, Leahy and his collaborators have proposed that the heightened flow through pyruvate carboxylase not only protects against the detrimental effect of the excess fatty acids on glucose metabolism, but also provides a mechanism for the compensatory increase in insulin secretion that normally accompanies insulin resistance. Subsequent studies in a normoglycemic, insulin resistant rat model, Zucker fatty rats, support this theory (112,113). Thus, excess fatty acids, in concert with normoglycemia, appear to augment 6-cell function, whereas excess fatty acids in the setting of hyperglycemia impair B-cell function, so-called glucolipotoxicity (43,44). This theory shares with the lipotoxicity hypothesis the concept that excess production of fatty acid metabolites such as ceramides causes B-cell dysfunction and death. However, in this concept a high glucose level must be present, as an increased level of the mitochondrial metabolic product of glucose, malonyl-CoA, is needed to inhibit fatty acid oxidation. Otherwise, the excess fatty acids would be oxidized, and thus detoxified. This combined hypothesis is particularly attractive, as it explains the compensatory P-cell hyperfunction of insulin resistance without diabetes (as occurs in obese people who are normoglycemic) and the toxic effect of the same level of hyperlipidemia in type 2 diabetes. 5. Impaired incretin effect: Incretin hormones are gut peptides that are released with eating and have a multitude of effects, including stimulating both the secretion and biosynthesis of insulin (114-116). The best known are glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). A characteristic feature of type 2 diabetes is a reduced incretin effect through 2 known mechanisms. The first is a lowered insulinotropic effectiveness of GIP (117). The time of onset of this change is unclear, as it is present in some nondiabetic first-degree relatives of persons with type 2 diabetes (118), but not women with a history of gestational diabetes (119). The mechanism is not known, although one proposal is defective expression of GIP receptors on B-cells (120). In contrast, sensitivity to GLP-1 is mainly intact in type 2 diabetes (117). However, a second mechanism for defective incretin regulation in type 2 diabetes is a decrease in the secretion of GLP-1 (121). As yet, the molecular mechanisms for both of these observations, when they first occur, and their importance to the B-cell dysfunction of type 2 diabetes, have not been determined.

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