scholarly journals Interorgan Crosstalk Contributing to β-Cell Dysfunction

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
Katsuya Tanabe ◽  
Kikuko Amo-Shiinoki ◽  
Masayuki Hatanaka ◽  
Yukio Tanizawa
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Current Knowledge ◽  
Cell Mass ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Circulating Levels ◽  
Insulin Secretory Capacity ◽  
Secretory Capacity

Type 2 diabetes mellitus (T2DM) results from pancreatic β-cell failure in the setting of insulin resistance. In the early stages of this disease, pancreatic β-cells meet increased insulin demand by both enhancing insulin-secretory capacity and increasing β-cell mass. As the disease progresses, β-cells fail to maintain these compensatory responses. This involves both extrinsic signals and mediators intrinsic to β-cells, which adversely affect β-cells by impairing insulin secretion, decreasing proliferative capacities, and ultimately causing apoptosis. In recent years, it has increasingly been recognized that changes in circulating levels of various factors from other organs play roles in β-cell dysfunction and cellular loss. In this review, we discuss current knowledge of interorgan communications underlying β-cell failure during the progression of T2DM.

Analysis of compensatory β-cell response in mice with combined mutations of Insr and Irs2

2007 ◽  
Vol 292 (6) ◽  
pp. E1694-E1701 ◽  
Author(s):  
Jane J. Kim ◽  
Yoshiaki Kido ◽  
Philipp E. Scherer ◽  
Morris F. White ◽  
Domenico Accili
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Cell Response ◽  
Cell Mass ◽  
Comprehensive Treatment ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Impaired Insulin

Type 2 diabetes results from impaired insulin action and β-cell dysfunction. There are at least two components to β-cell dysfunction: impaired insulin secretion and decreased β-cell mass. To analyze how these two variables contribute to the progressive deterioration of metabolic control seen in diabetes, we asked whether mice with impaired β-cell growth due to Irs2 ablation would be able to mount a compensatory response in the background of insulin resistance caused by Insr haploinsufficiency. As previously reported, ∼70% of mice with combined Insr and Irs2 mutations developed diabetes as a consequence of markedly decreased β-cell mass. In the initial phases of the disease, we observed a robust increase in circulating insulin levels, even as β-cell mass gradually declined, indicating that replication-defective β-cells compensate for insulin resistance by increasing insulin secretion. These data provide further evidence for a heterogeneous β-cell response to insulin resistance, in which compensation can be temporarily achieved by increasing function when mass is limited. The eventual failure of compensatory insulin secretion suggests that a comprehensive treatment of β-cell dysfunction in type 2 diabetes should positively affect both aspects of β-cell physiology.

scholarly journals Risk Factors for Type 2 Diabetes Mellitus Preceded by β-Cell Dysfunction, Insulin Resistance, or Both in Older Adults

2013 ◽  
Vol 177 (12) ◽  
pp. 1418-1429 ◽  
Author(s):  
Fumiaki Imamura ◽  
Kenneth J. Mukamal ◽  
James B. Meigs ◽  
José A. Luchsinger ◽  
Joachim H. Ix ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Risk Factors ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Older Adults ◽  
Type 2 Diabetes Mellitus ◽  
Β Cell ◽  
Cell Dysfunction

scholarly journals Five stages of progressive β-cell dysfunction in the laboratory Nile rat model of type 2 diabetes

2016 ◽  
Vol 229 (3) ◽  
pp. 343-356 ◽  
Author(s):  
Kaiyuan Yang ◽  
Jonathan Gotzmann ◽  
Sharee Kuny ◽  
Hui Huang ◽  
Yves Sauvé ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Pancreatic Islet ◽  
Cell Mass ◽  
Β Cell ◽  
High Fiber ◽  
Insulin Resistant ◽  
Cell Dysfunction

We compared the evolution of insulin resistance, hyperglycemia, and pancreatic β-cell dysfunction in the Nile rat (Arvicanthis niloticus), a diurnal rodent model of spontaneous type 2 diabetes (T2D), when maintained on regular laboratory chow versus a high-fiber diet. Chow-fed Nile rats already displayed symptoms characteristic of insulin resistance at 2 months (increased fat/lean mass ratio and hyperinsulinemia). Hyperglycemia was first detected at 6 months, with increased incidence at 12 months. By this age, pancreatic islet structure was disrupted (increased α-cell area), insulin secretion was impaired (reduced insulin secretion and content) in isolated islets, insulin processing was compromised (accumulation of proinsulin and C-peptide inside islets), and endoplasmic reticulum (ER) chaperone protein ERp44 was upregulated in insulin-producing β-cells. By contrast, high-fiber-fed Nile rats had normoglycemia with compensatory increase in β-cell mass resulting in maintained pancreatic function. Fasting glucose levels were predicted by the α/β-cell ratios. Our results show that Nile rats fed chow recapitulate the five stages of progression of T2D as occurs in human disease, including insulin-resistant hyperglycemia and pancreatic islet β-cell dysfunction associated with ER stress. Modification of diet alone permits long-term β-cell compensation and prevents T2D.

scholarly journals Beta-Cell Mass in Obesity and Type 2 Diabetes, and Its Relation to Pancreas Fat: A Mini-Review

Nutrients ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3846
Author(s):  
Jun Inaishi ◽  
Yoshifumi Saisho
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Beta Cell ◽  
Current Knowledge ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Beta Cell Dysfunction ◽  
Cell Dysfunction ◽  
Pancreatic Fat

Type 2 diabetes (T2DM) is characterized by insulin resistance and beta-cell dysfunction. Although insulin resistance is assumed to be a main pathophysiological feature of the development of T2DM, recent studies have revealed that a deficit of functional beta-cell mass is an essential factor for the pathophysiology of T2DM. Pancreatic fat contents increase with obesity and are suggested to cause beta-cell dysfunction. Since the beta-cell dysfunction induced by obesity or progressive decline with disease duration results in a worsening glycemic control, and treatment failure, preserving beta-cell mass is an important treatment strategy for T2DM. In this mini-review, we summarize the current knowledge on beta-cell mass, beta-cell function, and pancreas fat in obesity and T2DM, and we discuss treatment strategies for T2DM in relation to beta-cell preservation.

scholarly journals Insulin: The Friend and the Foe in the Development of Type 2 Diabetes Mellitus

2020 ◽  
Vol 21 (5) ◽  
pp. 1770
Author(s):  
Nadia Rachdaoui
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Insulin Secretion ◽  
Cell Mass ◽  
Β Cells ◽  
Β Cell ◽  
Peripheral Insulin Resistance

Insulin, a hormone produced by pancreatic β-cells, has a primary function of maintaining glucose homeostasis. Deficiencies in β-cell insulin secretion result in the development of type 1 and type 2 diabetes, metabolic disorders characterized by high levels of blood glucose. Type 2 diabetes mellitus (T2DM) is characterized by the presence of peripheral insulin resistance in tissues such as skeletal muscle, adipose tissue and liver and develops when β-cells fail to compensate for the peripheral insulin resistance. Insulin resistance triggers a rise in insulin demand and leads to β-cell compensation by increasing both β-cell mass and insulin secretion and leads to the development of hyperinsulinemia. In a vicious cycle, hyperinsulinemia exacerbates the metabolic dysregulations that lead to β-cell failure and the development of T2DM. Insulin and IGF-1 signaling pathways play critical roles in maintaining the differentiated phenotype of β-cells. The autocrine actions of secreted insulin on β-cells is still controversial; work by us and others has shown positive and negative actions by insulin on β-cells. We discuss findings that support the concept of an autocrine action of secreted insulin on β-cells. The hypothesis of whether, during the development of T2DM, secreted insulin initially acts as a friend and contributes to β-cell compensation and then, at a later stage, becomes a foe and contributes to β-cell decompensation will be discussed.

scholarly journals Revisiting regulators of human β-cell mass to achieve β-cell-centric approach toward type 2 diabetes

2021 ◽  
Author(s):  
Hironobu Sasaki ◽  
Yoshifumi Saisho ◽  
Jun Inaishi ◽  
Hiroshi Itoh
Keyword(s):  
Type 2 Diabetes ◽  
Racial Differences ◽  
Low Birthweight ◽  
Current Knowledge ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Cell Protection ◽  
Β Cell ◽  
Cell Dysfunction

Abstract Type 2 diabetes (T2DM) is characterized by insulin resistance and β-cell dysfunction. Since patients with T2DM have inadequate beta cell mass (BCM), and β-cell dysfunction worsens glycemic control and makes treatment difficult, therapeutic strategies to preserve and restore BCM are needed.In rodent models, obesity increases BCM about 3-fold, but the increase in BCM in humans is limited. Besides, obesity-induced changes in BCM may show racial differences between East Asians and Caucasians. Recently, the Developmental Origins of Health and Disease hypothesis, which states that the risk of developing non-communicable diseases including T2DM is influenced by the fetal environment, has been proposed. It is known in rodents that animals with low birthweight have reduced BCM through epigenetic modifications, making them more susceptible to diabetes in the future. Similarly, in humans, we revealed that individuals born with low birthweight have lower BCM in adulthood. Since β-cell replication is more frequently observed in the five years after birth, and β-cells are found to be more plastic in that period, a history of childhood obesity increases BCM. BCM in patients with T2DM is reduced by 20-65% compared with that in individuals without T2DM. However, since BCM starts to decrease from the stage of borderline diabetes, early intervention is essential for β-cell protection. In this review, we summarize the current knowledge on regulatory factors of human β-cell mass in health and diabetes, and propose the β-cell centric concept of diabetes to enhance a more pathophysiology-based treatment approach for T2DM.

Abstract 008: Risk Factors for Type 2 Diabetes Mellitus Preceded by β-cell Dysfunction, Insulin Resistance, or Both: The Cardiovascular Health Study

Circulation ◽  
2012 ◽  
Vol 125 (suppl_10) ◽  
Author(s):  
Fumiaki Imamura ◽  
Kenneth J Mukamal ◽  
James B Meigs ◽  
Jose A Luchsinger ◽  
Joachim H Ix ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Risk Factors ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Older Adults ◽  
Fasting Glucose ◽  
Β Cell ◽  
Cell Dysfunction

Background: Type 2 diabetes mellitus (DM) results from insulin resistance (IR), pancreatic β-cell dysfunction, or both. We hypothesized that risk factors could differ for DM preceded predominantly by IR, β-cell dysfunction, or both. This hypothesis is particularly important for older adults, in whom β-cell dysfunction may be relatively common. Methods: During 18 years of follow-up among 3,899 older adults free of DM (mean±sd age =73.0±5.8), we identified 274 incident DM cases by DM medication use, fasting glucose (≥126 mg/dL), or 2-hour post-challenge glucose (≥200 mg/dL), for whom homeostatic model assessments for IR (HOMA-IR) and β-cell function (HOMA-B) were assessed after baseline and before DM diagnosis. Using median cutoffs of the follow-up HOMA-IR and HOMA-B, we subclassified incident DM into DM preceded by IR only (n=112), β-cell dysfunction only (n=70), or both (n=77). Using multivariate competing-risk Cox models, we tested whether DM risk factors were differentially associated with risk of each DM subclass. Results: Elevated triglyceride levels (≥150 mg/dL) and impaired fasting glucose (100-125 mg/dL) were each positively associated with DM, irrespective of the DM subclass. Other DM risk factors of older age, overweight, obesity, low HDL cholesterol, and hypertension had substantially varying relationships with risk of different DM subclasses (p<0.001 for the variations). For example, overweight (BMI=25-29.9 kg/m2) and obesity (BMI≥30 kg/m2) were each positively associated with DM preceded by IR only (hazard ratio [95% CI]= 2.21 [1.25-3.92] and 5.02 [2.81-9.00], respectively), but with a significant inverse association with DM preceded by β-cell dysfunction only (0.61 [0.37-1.00] and 0.33 [0.14-0.80], respectively) (Figure). Conclusions: Among older adults, some DM risk factors differ substantially depending on HOMA-IR or HOMA-B subclassification. These findings support our hypothesis of heterogeneity in incident DM, especially among older adults.

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