The importance of the β-cell in the pathogenesis of type 2 diabetes mellitus

doi:10.1016/S0002-9343(00)00336-3

The American Journal of Medicine

Volume 108, Issue 6, Supplement 1, 17 April 2000, Pages 2-8

https://doi.org/10.1016/S0002-9343(00)00336-3 Get rights and content

Abstract

β-cell dysfunction and insulin resistance are two central, interrelated defects in the pathophysiology of type 2 diabetes. By the time a patient’s hyperglycemia is recognized, disruption of the normal relationship between β-cell function and insulin sensitivity is already well established. The pathophysiology and progression of defects in glucose metabolism from normal glucose tolerance to impaired glucose tolerance to frank type 2 diabetes have been studied extensively. Insulin sensitivity has wide intersubject variability, and many individuals at risk for type 2 diabetes are insulin resistant. β-cell changes in patients with type 2 diabetes include defects in insulin secretion, proinsulin conversion to insulin, and amyloid deposition in the islet. Studies in several ethnic groups have established that the progression from normal glucose tolerance to frank type 2 diabetes results from a gradual deterioration in β-cell function in the presence of insulin resistance. Furthermore, the recently completed landmark United Kingdom Prospective Diabetes Study demonstrated that type 2 diabetes is a progressive disease and that this progression is due to declining β-cell function.

Section snippets

Impact of insulin sensitivity on β-cell function

The development of the insulin radioimmunoassay sparked considerable debate as to the pathogenesis of this disease.2, 3 Contrary to prevailing medical beliefs of the time, Yalow and Berson in 1960 studied insulin secretion during the oral glucose tolerance test (OGTT) and showed that patients with type 2 diabetes produced insulin (Figure 1). 2 Several years later, the work of Bagdade et al3 demonstrated that the β-cell does not respond normally to a glucose challenge during the OGTT in patients

Hyperproinsulinemia as a predictor of type 2 diabetes

Not only have the classic defects in the insulin responses been well characterized as measures of β-cell dysfunction in type 2 diabetes, but a disproportionate increase in the β-cell release of proinsulin (PI) relative to insulin has also been shown to be a feature of the disease process.10, 11 This abnormality has been demonstrated in the basal state and after acute release of β-cell granule content in patients with type 2 diabetes compared with healthy controls (Table 1). 10, 11, 12

With

The islet lesion and the progressive nature of β-cell dysfunction

Although islet dysfunction is clearly present in type 2 diabetes, it is not clear whether the decline in insulin secretion results from a reduction in the number of β-cells, progressive dysfunction of a number of β-cells, or a combination of the two.1 Studies of potential mechanisms responsible for these changes have suggested that β-cell mass replacement by islet amyloid may be important; glucose per se may have a detrimental effect on secretory function (“glucose desensitization” or “glucose

Summary

The hyperglycemia that ultimately leads to type 2 diabetes results from the interaction of two defects: insulin resistance and β-cell dysfunction. Both insulin resistance and β-cell dysfunction are genetically and environmentally determined. A considerable amount of clinical evidence has demonstrated that β-cell dysfunction is present in individuals at high risk before the disease develops. In the presence of insulin resistance, progressive loss of β-cell function is associated with a

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GA attenuates T2DM, possibly by improving antioxidant status through the Nrf2 pathway and attenuation of inflammation.
A minimal model of glucose-stimulated insulin secretion process explores factors responsible for the development of type 2 diabetes
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Type 2 diabetes (T2D) is a global health problem caused primarily due to the inability of pancreatic beta-cells to secrete adequate amounts of insulin during insulin resistance (IR). However, IR alone is not responsible for the development of T2D, rather gradual loss of beta-cell function in IR leads toward T2D. Impaired glucose-stimulated insulin secretion (GSIS) is responsible for beta-cell failure and one of the major causes of developing T2D in the presence of IR. The mechanisms underlying the progressive failure of beta-cells in insulin resistance-induced prolonged hyperglycemic conditions remain unresolved. The current study aimed to capture key factors responsible for the progression of diabetes in the IR condition. So, we proposed and analysed the GSIS process through a six-dimensional model incorporating calcium and ATP. We established our model by simulating both the normal and the insulin resistance-induced hyperglycemic conditions. Our analysis revealed the possible factors responsible for the impaired GSIS process in IR, whose dysfunction can lead to T2D. Finally, using the parameter recalibration analysis, we uncovered the potential therapeutic strategies for compensating the insulin secretion-reducing alterations that could eventually help prevent the disease progression.
Uncoupling protein 2 and aldolase B impact insulin release by modulating mitochondrial function and Ca<sup>2+</sup> release from the ER
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Uncoupling protein 2 (UCP2), a mitochondrial protein, is known to be upregulated in pancreatic islets of patients with type 2 diabetes (T2DM); however, the pathological significance of this increase in UCP2 expression is unclear. In this study, we highlight the molecular link between the increase in UCP2 expression in β-cells and β-cell failure by using genetically engineered mice and human islets. β-cell-specific UCP2-overexpressing transgenic mice (βUCP2Tg) exhibited glucose intolerance and a reduction in insulin secretion. Decreased mitochondrial function and increased aldolase B (AldB) expression through oxidative-stress-mediated pathway were observed in βUCP2Tg islets. AldB, a glycolytic enzyme, was associated with reduced insulin secretion via mitochondrial dysfunction and impaired calcium release from the endoplasmic reticulum (ER). Taken together, our findings provide a new mechanism of β-cell dysfunction by UCP2 and AldB. Targeting the UCP2/AldB axis is a promising approach for the recovery of β-cell function.
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Citation Excerpt :
Type 2 diabetes is a metabolic disorder characterized by impaired glucose tolerance (Kahn, 2000).
Glucose homeostasis is initially regulated by the pancreatic hormone insulin. Glucose-stimulated insulin secretion in β-cells is composed of two cellular mechanisms: a high glucose concentration not only depolarizes the membrane potential of the β-cells by ATP-sensitive K⁺ channels but also induces cell inflation, which is sufficient to release insulin granules. However, the molecular identity of the stretch-activated cation channel responsible for the latter pathway remains unknown. Here, we demonstrate that Tentonin 3/TMEM150C (TTN3), a mechanosensitive channel, contributes to glucose-stimulated insulin secretion by mediating cation influx. TTN3 is expressed specifically in β-cells and mediates cation currents to glucose and hypotonic stimulations. The glucose-induced depolarization, firing activity, and Ca²⁺ influx of β-cells were significantly lower in Ttn3^−/− mice. More importantly, Ttn3^−/− mice show impaired glucose tolerance with decreased insulin secretion in vivo. We propose that TTN3, as a stretch-activated cation channel, contributes to glucose-stimulated insulin secretion.
Mice lacking the proton channel Hv1 exhibit sex-specific differences in glucose Homeostasis
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Sex as a physiologic factor has a strong association with the features of metabolic syndrome. Our previous study showed that loss of the voltage-gated proton channel Hv1 inhibits insulin secretion and leads to hyperglycemia and glucose intolerance in male mice. However, there are significant differences in blood glucose between male and female Hv1-knockout (KO) mice. Here, we investigated the differences in glucose metabolism and insulin sensitivity between male and female KO mice and how sex steroids contribute to these differences. We found that the fasting blood glucose in female KO mice was visibly lower than that in male KO mice, which was accompanied by hypotestosteronemia. KO mice in both sexes exhibited higher expression of gluconeogenesis-related genes in liver compared with WT mice. Also, the livers from KO males displayed a decrease in glycolysis-related gene expression and an increase in gluconeogenesis-related gene expression compared with KO females. Furthermore, exogenous testosterone supplementation decreased blood glucose levels in male KO mice, as well as enhancing insulin signaling. Taken together, our data demonstrate that knockout of Hv1 results in higher blood glucose levels in male than female mice, despite a decreased insulin secretion in both sexes. This sex-related difference in glucose homeostasis is associated with the glucose metabolism in liver tissue, likely due to the physiological levels of testosterone in KO male mice.
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¹: Supported in part by National Institutes of Health grants DK-02654, DK-17047, DK-50703, and the Medical Research Service of the Department of Veterans Affairs.

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The importance of the β-cell in the pathogenesis of type 2 diabetes mellitus1

Abstract

Section snippets

Impact of insulin sensitivity on β-cell function

Hyperproinsulinemia as a predictor of type 2 diabetes

The islet lesion and the progressive nature of β-cell dysfunction

Summary

Am J Med

Lancet

Diabetes Res Clin Pract

Immunoassay of endogenous plasma insulin in man

J Clin Invest

The significance of basal insulin levels in the evaluation of the insulin response to glucose in diabetic and nondiabetic subjects

J Clin Invest

Pathophysiology of insulin secretion in non-insulin-dependent diabetes mellitus

Diabetes Care

Non-insulin-dependent diabetes mellitus—a genetically programmed failure of the β cell to compensate for insulin resistance

N Engl J Med

Regulation of β-cell function in vivofrom health to disease

Diabetes Rev

Quantification of the relationship between insulin sensitivity and β-cell function in human subjectsevidence for a hyperbolic function

Diabetes

Reduced amylin release is a characteristic of impaired glucose tolerance and type 2 diabetes in Japanese Americans

Diabetes

Disproportionate elevation of immunoreactive proinsulin in type 2 (non-insulin-dependent) diabetes mellitus and in experimental insulin resistance

Diabetologia

Disproportionately elevated proinsulin in Pima Indians with noninsulin-dependent diabetes mellitus

J Clin Endocrinol Metab

Release of incompletely processed proinsulin is the cause of the disproportionate proinsulinemia of NIDDM

Diabetes

Serum proinsulin levels at fasting and after oral glucose load in patients with type 2 (non-insulin-dependent) diabetes mellitus

Diabetologia

The importance of the β-cell in the pathogenesis of type 2 diabetes mellitus¹