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1
Khin, Phyu Phyu, Jong Han Lee, and Hee-Sook Jun. "Pancreatic Beta-cell Dysfunction in Type 2 Diabetes." European Journal of Inflammation 21 (January 30, 2023): 1721727X2311541. http://dx.doi.org/10.1177/1721727x231154152.
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Pancreatic β-cells produce and secrete insulin to maintain blood glucose levels within a narrow range. Defects in the function and mass of β-cells play a significant role in the development and progression of diabetes. Increased β-cell deficiency and β-cell apoptosis are observed in the pancreatic islets of patients with type 2 diabetes. At an early stage, β-cells adapt to insulin resistance, and their insulin secretion increases, but they eventually become exhausted, and the β-cell mass decreases. Various causal factors, such as high glucose, free fatty acids, inflammatory cytokines, and islet amyloid polypeptides, contribute to the impairment of β-cell function. Therefore, the maintenance of β-cell function is a logical approach for the treatment and prevention of diabetes. In this review, we provide an overview of the role of these risk factors in pancreatic β-cell loss and the associated mechanisms. A better understanding of the molecular mechanisms underlying pancreatic β-cell loss will provide an opportunity to identify novel therapeutic targets for type 2 diabetes.
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Masoodi, Shariq Rashid. "Decline in Beta-Cell Function among Adolescents with Type 2 Diabetes Mellitus." JMS SKIMS 20, no. 2 (December 9, 2017): 115–16. http://dx.doi.org/10.33883/jms.v20i2.211.
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It is well known that beta-cell function declines over time in adults with type 2 diabetes mellitus (T2DM). The beta-cell dysfunction, initially characterized by impairment in the first phase of insulin secretion following glucose stimulation, advances to a decline in second phase insulin secretion as the disease progresses. But whether this decline in beta-cell function occurs in adolescents with T2DM is uncertain. Investigators prospectively compared beta-cell functioning over time between 39 adolescents with newly diagnosed T2DM (mean age, 15 years; body-mass index z-score, 2.4) and 32 obese adolescents without T2DM of comparable body-mass index, gender, and race (mean age, 14) during a 2-year period. Recently, researchers from Duke University School of Medicine, Durham North Carolina reported that adolescents with newly diagnosed T2DM had a 25% annual decline in beta-cell function despite receiving treatment. In this study, the results of which were first presented at the American Diabetes Association (ADA), the participants were adolescents with T2DM, more than half of whom were being treated with insulin whereas 80% were taking oral anti-diabetes medications. Beta-cell function in this study, assessed at baseline and 6, 12, and 24 months was measured by insulin secretion in response to an intravenous glucose load adjusted for insulin sensitivity (disposition index). The authors observed that adolescents with T2DM had significantly higher levels of both insulin resistance and fasting glucose at baseline compared with controls. But during the two-year study, the study subjects experienced a significant increase in fasting glucose and a 25 percent annual decline in disposition index. Understandably, both these indicators remained unchanged among the controls. JMS 2017;20(2):116
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Yan, Li-hui, Biao Mu, Da Pan, Ya-nan Shi, Ji-hong Yuan, Yue Guan, Wang Li, Xiao-yi Zhu, and Lei Guo. "Association between small intestinal bacterial overgrowth and beta-cell function of type 2 diabetes." Journal of International Medical Research 48, no. 7 (July 2020): 030006052093786. http://dx.doi.org/10.1177/0300060520937866.
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Aims Previous studies suggest that small intestinal bacterial overgrowth (SIBO) is associated with type 2 diabetes. However, few studies have evaluated the association between SIBO and beta-cell function in type 2 diabetes. The aim of this study was to evaluate whether beta-cell function was associated with SIBO. Materials and methods One hundred four patients with type 2 diabetes were included in this study. Based on the presence of SIBO, the patients were divided into SIBO-positive and SIBO-negative groups. Oral glucose tolerance tests were performed. Insulin sensitivity was measured using 1/homeostasis model assessment of insulin resistance (1/HOMA-IR) and the insulin sensitivity index (ISIM). Insulin release was calculated by HOMA-β, early-phase insulin secretion index InsAUC30/GluAUC30, and total-phase insulin secretion index InsAUC120/GluAUC120. Results Compared with the SIBO-negative group, patients in the SIBO-positive group showed a higher glucose level at 120 minutes, HbA1c, 1/HOMA-IR, and ISIM and a lower HOMA-β level, early-phase InsAUC30/GluAUC30, and total-phase InsAUC120/GluAUC120. Multiple linear regression analysis showed that body mass index, glucose at 0 minutes, and SIBO were independently associated with the early-phase and total-phase insulin secretion. Conclusion SIBO may be involved in lower levels of insulin release and worse glycemic control.
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Popovic, Ljiljana, Miroslava Zamaklar, Katarina Lalic, and Olga Vasovic. "Analysis of the effect of diabetes type 2 duration on beta cell secretory function and insulin resistance." Srpski arhiv za celokupno lekarstvo 134, no. 5-6 (2006): 219–23. http://dx.doi.org/10.2298/sarh0606219p.
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Diabetes type 2 is a chronic metabolic disorder. Pathogenesis of diabetes type 2 results from the impaired insulin secretion, impaired insulin action and increased endogenous glucose production. Diabetes evolves through several phases characterized by qualitative and quantitative changes of beta cell secretory function. The aim of our study was to analyze the impact of diabetes duration on beta cell secretory function and insulin resistance. The results indicated significant negative correlation of diabetes duration and fasting insulinemia, as well as beta cell secretory function assessed by HOMA ? index. Our study also found significant negative correlation of diabetes duration and insulin resistance assessed by HOMA IR index. Significant positive correlation was established between beta cell secretory capacity (fasting insulinemia and HOMA ?) and insulin resistance assessed by HOMA IR index, independently of diabetes duration. These results indicate that: beta cell secretory capacity, assessed by HOMA ? index, significantly decreases with diabetes duration. In parallel with decrease of fasting insulinemia, reduction of insulin resistance assessed by HOMA IR index was found as well.
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Konenkov, Vladimir Iosifovich, Vadim Valerievich Klimontov, Svetlana Viktorovna Michurina, M. A. Prudnikova, and I. Ju Ishenko. "Melatonin and diabetes: from pathophysiology to the treatment perspectives." Diabetes mellitus 16, no. 2 (June 15, 2013): 11–16. http://dx.doi.org/10.14341/2072-0351-3751.
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Pineal hormone melatonin synchronizes insulin secretion and glucose homeostasis with solar periods. Misalliance between melatonin-mediated circadian rhythms and insulin secretion characterizes diabetes mellitus type 1 (T1DM) and type 2 (T2DM). Insulin deficiency in T1DM is accompanied by increased melatonin production. Conversely, T2DM is characterized by diminished melatonin secretion. In genome-wide association studies the variants of melatonin receptor MT2 gene (rs1387153 and rs10830963) were associated with fasting glucose, beta-cell function and T2DM. In experimental models of diabetes melatonin enhanced beta-cell proliferation and neogenesis, improved insulin resistance and alleviated oxidative stress in retina and kidneys. However, further investigation is required to assess the therapeutic value of melatonin in diabetic patients.
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Shvarts, V. "Inflammation of adipose tissue. Part 2. Pathogenetic role in type 2 diabetes mellitus." Problems of Endocrinology 55, no. 5 (October 15, 2009): 43–48. http://dx.doi.org/10.14341/probl200955543-48.
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This review deals with the role of adipose tissue inflammation (ATI) in the development of type 2 diabetes mellitus (DM2). ATI is regarded as a link between obesity and DM2. The review illustrates the involvement of main adipokines in pathogenesis of DM2 and provides a detailed description of such factors as impaired adiponectin and stimulation of cytokine production responsible for metabolic disorders, activation of lipolysis, in adipocytes, increased fatty acid and triglyceride levels, suppression of insulin activity at the receptor and intracellular levels. Adipokines, in the first place cytokines, act on the insulin signal pathway and affect the intracellular inflammatory kinase cascade. At the intercellular level, ATI stimulates JNK and IKK-beta/kB responsible for the development of insulin resistance via such mechanisms as activation of cytokine secretion in the adipose tissue, oxidative stress, and induction of endoplasmic reticulum enzymes. The key role of JNK and IKK-beta/kB in the inhibition of the insulin signal pathway is mediated through inactivation of insulin receptor substrate 1. Also, it is shown that ATI modulates B-cell function and promotes progressive reduction of insulin secretion.
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Makaji, Emilija, Sandeep Raha, Michael G. Wade, and Alison C. Holloway. "Effect of Environmental Contaminants on Beta Cell Function." International Journal of Toxicology 30, no. 4 (June 24, 2011): 410–18. http://dx.doi.org/10.1177/1091581811405544.
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There is an increasing concern that chemicals in the environment are contributing to the global rise in the prevalence of type 2 diabetes (T2D). However, there is limited evidence for direct effects of these chemicals on beta cell function. Therefore, the goals of this study were (1) to test the hypothesis that environmental contaminants can directly affect beta cell function and (2) examine mechanistic pathways by which these contaminants could affect beta cell function. Using mouse beta TC-6 cells, we examined the acute effects of 6 substances (benzo[a]pyrene, bisphenol A [BPA], propylparaben, methylparaben, perfluorooctanoic acid, and perfluorooctyl sulfone) on insulin secretion. Only BPA treatment directly affected insulin secretion. Furthermore, chronic exposure to BPA altered the expression of key proteins in the cellular and endoplasmic reticulum stress response. These data suggest that long-term BPA exposure may be detrimental to beta cell function and ultimately be an important contributor to the etiology of T2D.
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Tarlton, Jamie M. R., Steven Patterson, and Annette Graham. "MicroRNA Sequences Modulated by Beta Cell Lipid Metabolism: Implications for Type 2 Diabetes Mellitus." Biology 10, no. 6 (June 15, 2021): 534. http://dx.doi.org/10.3390/biology10060534.
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Alterations in lipid metabolism within beta cells and islets contributes to dysfunction and apoptosis of beta cells, leading to loss of insulin secretion and the onset of type 2 diabetes. Over the last decade, there has been an explosion of interest in understanding the landscape of gene expression which influences beta cell function, including the importance of small non-coding microRNA sequences in this context. This review sought to identify the microRNA sequences regulated by metabolic challenges in beta cells and islets, their targets, highlight their function and assess their possible relevance as biomarkers of disease progression in diabetic individuals. Predictive analysis was used to explore networks of genes targeted by these microRNA sequences, which may offer new therapeutic strategies to protect beta cell function and delay the onset of type 2 diabetes.
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Kim, Yong Kyung, Lori Sussel, and Howard W. Davidson. "Inherent Beta Cell Dysfunction Contributes to Autoimmune Susceptibility." Biomolecules 11, no. 4 (March 30, 2021): 512. http://dx.doi.org/10.3390/biom11040512.
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The pancreatic beta cell is a highly specialized cell type whose primary function is to secrete insulin in response to nutrients to maintain glucose homeostasis in the body. As such, the beta cell has developed unique metabolic characteristics to achieve functionality; in healthy beta cells, the majority of glucose-derived carbons are oxidized and enter the mitochondria in the form of pyruvate. The pyruvate is subsequently metabolized to induce mitochondrial ATP and trigger the downstream insulin secretion response. Thus, in beta cells, mitochondria play a pivotal role in regulating glucose stimulated insulin secretion (GSIS). In type 2 diabetes (T2D), mitochondrial impairment has been shown to play an important role in beta cell dysfunction and loss. In type 1 diabetes (T1D), autoimmunity is the primary trigger of beta cell loss; however, there is accumulating evidence that intrinsic mitochondrial defects could contribute to beta cell susceptibility during proinflammatory conditions. Furthermore, there is speculation that dysfunctional mitochondrial responses could contribute to the formation of autoantigens. In this review, we provide an overview of mitochondrial function in the beta cells, and discuss potential mechanisms by which mitochondrial dysfunction may contribute to T1D pathogenesis.
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Grubelnik, Vladimir, Jan Zmazek, Rene Markovič, Marko Gosak, and Marko Marhl. "Mitochondrial Dysfunction in Pancreatic Alpha and Beta Cells Associated with Type 2 Diabetes Mellitus." Life 10, no. 12 (December 14, 2020): 348. http://dx.doi.org/10.3390/life10120348.
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Type 2 diabetes mellitus is a complex multifactorial disease of epidemic proportions. It involves genetic and lifestyle factors that lead to dysregulations in hormone secretion and metabolic homeostasis. Accumulating evidence indicates that altered mitochondrial structure, function, and particularly bioenergetics of cells in different tissues have a central role in the pathogenesis of type 2 diabetes mellitus. In the present study, we explore how mitochondrial dysfunction impairs the coupling between metabolism and exocytosis in the pancreatic alpha and beta cells. We demonstrate that reduced mitochondrial ATP production is linked with the observed defects in insulin and glucagon secretion by utilizing computational modeling approach. Specifically, a 30–40% reduction in alpha cells’ mitochondrial function leads to a pathological shift of glucagon secretion, characterized by oversecretion at high glucose concentrations and insufficient secretion in hypoglycemia. In beta cells, the impaired mitochondrial energy metabolism is accompanied by reduced insulin secretion at all glucose levels, but the differences, compared to a normal beta cell, are the most pronounced in hyperglycemia. These findings improve our understanding of metabolic pathways and mitochondrial bioenergetics in the pathology of type 2 diabetes mellitus and might help drive the development of innovative therapies to treat various metabolic diseases.
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Suleiman, Mara, Lorella Marselli, Miriam Cnop, Decio L. Eizirik, Carmela De Luca, Francesca R. Femia, Marta Tesi, Silvia Del Guerra, and Piero Marchetti. "The Role of Beta Cell Recovery in Type 2 Diabetes Remission." International Journal of Molecular Sciences 23, no. 13 (July 4, 2022): 7435. http://dx.doi.org/10.3390/ijms23137435.
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Type 2 diabetes (T2D) has been considered a relentlessly worsening disease, due to the progressive deterioration of the pancreatic beta cell functional mass. Recent evidence indicates, however, that remission of T2D may occur in variable proportions of patients after specific treatments that are associated with recovery of beta cell function. Here we review the available information on the recovery of beta cells in (a) non-diabetic individuals previously exposed to metabolic stress; (b) T2D patients following low-calorie diets, pharmacological therapies or bariatric surgery; (c) human islets isolated from non-diabetic organ donors that recover from “lipo-glucotoxic” conditions; and (d) human islets isolated from T2D organ donors and exposed to specific treatments. The improvement of insulin secretion reported by these studies and the associated molecular traits unveil the possibility to promote T2D remission by directly targeting pancreatic beta cells.
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Chandrika A., Mary, and B. Shanthi. "A study of insulin resistance and pancreatic beta cell function in diabetics and non-diabetics." Biomedicine 39, no. 3 (November 14, 2020): 497–502. http://dx.doi.org/10.51248/.v39i3.178.
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Introduction and Aim: The most common non-communicable disease affecting large population is type 2 diabetes mellitus. This metabolic disorder is characterized by hyperglycemia with disturbances of carbohydrate, fat and protein metabolism. The causes of diabetes mellitus can vary greatly but always include either defects in insulin secretion of the pancreas or the cells of the body not responding properly to the insulin produced or in both at some point in the course of the disease.
Materials and Methods: 200 participants who were divided into two groups, non-diabetics with and without family history of diabetes were involved in this study. The outcomes of fasting plasma glucose, postprandial plasma glucose, glycated hemoglobin, fasting plasma insulin, serum c-peptide, HOMA -IR, HOMA-B were compared between both the groups.
Results: All these parameters were significantly correlated between the groups with the level of significance p<0.05%. Non-diabetic off-springs of type 2 diabetes were found to have hyperinsulinemia, increased level of serum c-peptide level, moderate insulin resistance and pancreatic beta cell dysfunction than non-diabetics without the family history of diabetes. The fasting hyperinsulinemia, known to reflect decreased insulin sensitivity constitute the strongest independent predictor of type 2 diabetes.
Conclusion: The above findings show that insulin resistance is the primary abnormality in type 2 Diabetes Mellitus.
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Glaser, Benjamin, Gil Leibovich, Rafael Nesher, Svend Hartling, Christian Binder, and Erol Cerasi. "Improved beta-cell function after intensive insulin treatment in severe non-insulin-dependent diabetes." Acta Endocrinologica 118, no. 3 (July 1988): 365–73. http://dx.doi.org/10.1530/acta.0.1180365.
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Abstract. In Type II, non-insulin-dependent diabetes, insulin secretion is often reduced to the point where oral hypoglycaemic agents fail to control the plasma glucose level. We studied 12 patients (age 41–66 years; 4 lean, 8 obese) with Type II diabetes mellitus for 1–25 years who were uncontrolled despite maximal dose glibenclamide and metformin. After withdrawal of medication, blood glucose control was determined by measuring glucose before and 2 h after each meal for 48 h, and beta-cell function by insulin or C-peptide response to glucagon and to iv glucose. Following these tests, intensive insulin treatment (CSII) was initiated, and near-euglycaemia (mean of 7 daily glucose determinations < 7.7 mmol/l) was maintained for 16.6 ± 1.5 days, at which time the tests were repeated. Mean daily insulin requirement was 61 ± 9 IU (0.81 ± 0.09 IU/kg). Glucose control was improved after cessation of CSII (mean glucose 12.7 ± 0.6 mmol/l after vs 20 ± 1.5 mmol/l before, P <0.005). Maximum incremental C-peptide response improved both to glucagon (214 ± 32 after vs 134 ± 48 pmol/l before, P = 0.05) and to glucose iv bolus injection (284 ± 53 vs 113 ± 32 pmol/l, P < 0.05). Peak insulin response, measured after iv glucose infusion, also tended to be higher in the post-CSII test (42 ± 18 vs 22 ± 5.6 mU/l). Basal and stimulated proinsulin concentrations were high relative to C-peptide levels during the pre-treatment period, but returned to normal after CSII. Thus: 1) adequate blood glucose control could be obtained in most of our patients using moderate doses of insulin even in those who were obese; 2) short-term euglycaemia resulted in improved insulin response to both glucagon and glucose, and reduction of the relative proinsulin secretion; 3) although beta-cell function improved in most patients, only 6 could be adequately controlled with oral agents after hospital discharge. In those patients who do not respond well to conventional treatment, CSII is an attractive alternative.
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So, Wing Yan, Wai Nam Liu, Adrian Kee Keong Teo, Guy A. Rutter, and Weiping Han. "Paired box 6 programs essential exocytotic genes in the regulation of glucose-stimulated insulin secretion and glucose homeostasis." Science Translational Medicine 13, no. 600 (June 30, 2021): eabb1038. http://dx.doi.org/10.1126/scitranslmed.abb1038.
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The paired box 6 (PAX6) transcription factor is crucial for normal pancreatic islet development and function. Heterozygous mutations of PAX6 are associated with impaired insulin secretion and early-onset diabetes mellitus in humans. However, the molecular mechanism of PAX6 in controlling insulin secretion in human beta cells and its pathophysiological role in type 2 diabetes (T2D) remain ambiguous. We investigated the molecular pathway of PAX6 in the regulation of insulin secretion and the potential therapeutic value of PAX6 in T2D by using human pancreatic beta cell line EndoC-βH1, the db/db mouse model, and primary human pancreatic islets. Through loss- and gain-of-function approaches, we uncovered a mechanism by which PAX6 modulates glucose-stimulated insulin secretion (GSIS) through a cAMP response element–binding protein (CREB)/Munc18-1/2 pathway. Moreover, under diabetic conditions, beta cells and pancreatic islets displayed dampened PAX6/CREB/Munc18-1/2 pathway activity and impaired GSIS, which were reversed by PAX6 replenishment. Adeno-associated virus–mediated PAX6 overexpression in db/db mouse pancreatic beta cells led to a sustained amelioration of glycemic perturbation in vivo but did not affect insulin resistance. Our study highlights the pathophysiological role of PAX6 in T2D-associated beta cell dysfunction in humans and suggests the potential of PAX6 gene transfer in preserving and restoring beta cell function.
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Brüning, Dennis, Kathrin Hatlapatka, Verena Lier-Glaubitz, Vincent Andermark, Stephan Scherneck, Ingo Ott, and Ingo Rustenbeck. "Pharmacological inhibition of thioredoxin reductase increases insulin secretion and diminishes beta cell viability." Naunyn-Schmiedeberg's Archives of Pharmacology 394, no. 6 (January 19, 2021): 1133–42. http://dx.doi.org/10.1007/s00210-020-02046-2.
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AbstractApparently, both a decrease in beta cell function and in beta cell mass contribute to the progressive worsening of type 2 diabetes. So, it is of particular interest to define factors which are relevant for the regulation of insulin secretion and at the same time for the maintenance of beta cell mass. The NADPH-thioredoxin system has a candidate role for such a dual function. Here, we have characterized the effects of a highly specific inhibitor of thioredoxin reductase, AM12, on the viability and function of insulin-secreting MIN6 cells and isolated NMRI mouse islets. Viability was checked by MTT testing and the fluorescent live-dead assay. Apoptosis was assessed by annexin V assay. Insulin secretion of perifused islets was measured by ELISA. The cytosolic Ca2+ concentration was measured by the Fura technique. Acute exposure of perifused pancreatic islets to 5 μM AM12 was without significant effect on insulin secretion. Islets cultured for 24 h in 0.5 or 5 μM AM12 showed unchanged basal secretion during perifusion, but the response to 30 mM glucose was significantly enhanced by 5 μM. Twenty-four-hour exposure to 5 μM AM12 proved to be without effect on the viability of MIN6 cells, whereas longer exposure was clearly toxic. Islets were more susceptible, showing initial signs of apoptosis after 24-h exposure to 5 μM AM12. The activity of the NADPH-thioredoxin system is indispensable for beta cell viability but may have a limiting effect on glucose-induced insulin secretion.
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Sanlioglu, Ahter D., Bahri Karacay, Mustafa Kemal Balci, Thomas S. Griffith, and Salih Sanlioglu. "Therapeutic potential of VIP vs PACAP in diabetes." Journal of Molecular Endocrinology 49, no. 3 (September 18, 2012): R157—R167. http://dx.doi.org/10.1530/jme-12-0156.
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Type 2 diabetes (T2D) is characterized by chronic insulin resistance and a progressive decline in beta-cell function. Although rigorous glucose control can reduce morbidity and mortality associated with diabetes, achieving optimal long-term glycemic control remains to be accomplished in many diabetic patients. As beta-cell mass and function inevitably decline in T2D, exogenous insulin administration is almost unavoidable as a final outcome despite the use of oral antihyperglycemic agents in many diabetic patients. Pancreatic islet cell death, but not the defect in new islet formation or beta-cell replication, has been blamed for the decrease in beta-cell mass observed in T2D patients. Thus, therapeutic approaches designed to protect islet cells from apoptosis could significantly improve the management of T2D, because of its potential to reverse diabetes not just ameliorate glycemia. Therefore, an ideal beta-cell-preserving agent is expected to protect beta cells from apoptosis and stimulate postprandial insulin secretion along with increasing beta-cell replication and/or islet neogenesis. One such potential agent, the islet endocrine neuropeptide vasoactive intestinal peptide (VIP) strongly stimulates postprandial insulin secretion. Because of its broad spectrum of biological functions such as acting as a potent anti-inflammatory factor through suppression of Th1 immune response, and induction of immune tolerance via regulatory T cells, VIP has emerged as a promising therapeutic agent for the treatment of many autoimmune diseases including diabetes.
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Ladwa, Meera, Oluwatoyosi Bello, Olah Hakim, Fariba Shojaee-Moradie, Maria Linda Boselli, Geoff Charles-Edwards, Janet Peacock, et al. "Ethnic differences in beta cell function occur independently of insulin sensitivity and pancreatic fat in black and white men." BMJ Open Diabetes Research & Care 9, no. 1 (March 2021): e002034. http://dx.doi.org/10.1136/bmjdrc-2020-002034.
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IntroductionIt is increasingly recognized that type 2 diabetes (T2D) is a heterogenous disease with ethnic variations. Differences in insulin secretion, insulin resistance and ectopic fat are thought to contribute to these variations. Therefore, we aimed to compare postprandial insulin secretion and the relationships between insulin secretion, insulin sensitivity and pancreatic fat in men of black West African (BA) and white European (WE) ancestry.Research design and methodsA cross-sectional, observational study in which 23 WE and 23 BA men with normal glucose tolerance, matched for body mass index, underwent a mixed meal tolerance test with C peptide modeling to measure beta cell insulin secretion, an MRI to quantify intrapancreatic lipid (IPL), and a hyperinsulinemic-euglycemic clamp to measure whole-body insulin sensitivity.ResultsPostprandial insulin secretion was lower in BA versus WE men following adjustment for insulin sensitivity (estimated marginal means, BA vs WE: 40.5 (95% CI 31.8 to 49.2) × 103 vs 56.4 (95% CI 48.9 to 63.8) × 103 pmol/m2 body surface area × 180 min, p=0.008). There was a significantly different relationship by ethnicity between IPL and insulin secretion, with a stronger relationship in WE than in BA (r=0.59 vs r=0.39, interaction p=0.036); however, IPL was not a predictor of insulin secretion in either ethnic group following adjustment for insulin sensitivity.ConclusionsEthnicity is an independent determinant of beta cell function in black and white men. In response to a meal, healthy BA men exhibit lower insulin secretion compared with their WE counterparts for their given insulin sensitivity. Ethnic differences in beta cell function may contribute to the greater risk of T2D in populations of African ancestry.
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Chen, Xi, Enrique Maldonado, Ralph A. DeFronzo, and Devjit Tripathy. "Impaired Suppression of Glucagon in Obese Subjects Parallels Decline in Insulin Sensitivity and Beta-Cell Function." Journal of Clinical Endocrinology & Metabolism 106, no. 5 (February 1, 2021): 1398–409. http://dx.doi.org/10.1210/clinem/dgab019.
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Abstract Aim To examine the relationship between plasma glucagon levels and insulin sensitivity and insulin secretion in obese subjects. Methods Suppression of plasma glucagon was examined in 275 obese Hispanic Americans with varying glucose tolerance. All subjects received a 2-hour oral glucose tolerance test (OGTT) and a subset (n = 90) had euglycemic hyperinsulinemic clamp. During OGTT, we quantitated suppression of plasma glucagon concentration, Matsuda index of insulin sensitivity, and insulin secretion/insulin resistance (disposition) index. Plasma glucagon suppression was compared between quartiles of insulin sensitivity and beta-cell function. Results Fasting plasma glucagon levels were similar in obese subjects with normal glucose tolerance (NGT), prediabetes, and type 2 diabetes (T2D), but the fasting glucagon/insulin ratio decreased progressively from NGT to prediabetes to T2D (9.28 ± 0.66 vs 6.84 ± 0.44 vs 5.84 ± 0.43; P < 0.001). Fasting and 2-hour plasma glucagon levels during OGTT progressively increased and correlated positively with severity of insulin resistance (both Matsuda index and euglycemic hyperinsulinemic clamp). The fasting glucagon/insulin ratio declined with worsening insulin sensitivity and beta-cell function, and correlated with whole-body insulin sensitivity (Matsuda index, r = 0.81; P < 0.001) and beta-cell function (r = 0.35; P < 0.001). The glucagon/insulin ratio also correlated and with beta-cell function during OGTT at 60 and 120 minutes (r = −0.47; P < 0.001 and r = −0.32; P < 0.001). Conclusion Insulin-mediated suppression of glucagon secretion in obese subjects is impaired with increasing severity of glucose intolerance and parallels the severity of insulin resistance and beta-cell dysfunction.
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Kahleova, Hana, Andrea Tura, Marta Klementova, Lenka Thieme, Martin Haluzik, Renata Pavlovicova, Martin Hill, and Terezie Pelikanova. "A Plant-Based Meal Stimulates Incretin and Insulin Secretion More Than an Energy- and Macronutrient-Matched Standard Meal in Type 2 Diabetes: A Randomized Crossover Study." Nutrients 11, no. 3 (February 26, 2019): 486. http://dx.doi.org/10.3390/nu11030486.
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Diminished postprandial secretion of incretins and insulin represents one of the key pathophysiological mechanisms behind type 2 diabetes (T2D). We tested the effects of two energy- and macronutrient-matched meals: A standard meat (M-meal) and a vegan (V-meal) on postprandial incretin and insulin secretion in participants with T2D. A randomized crossover design was used in 20 participants with T2D. Plasma concentrations of glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1), amylin, and gastric inhibitory peptide (GIP) were determined at 0, 30, 60, 120, and 180 min. Beta-cell function was assessed with a mathematical model, using C-peptide deconvolution. Repeated-measures ANOVA was used for statistical analysis. Postprandial plasma glucose responses were similar after both test meals (p = 0.64). An increase in the stimulated secretion of insulin (by 30.5%; 95% CI 21.2 to 40.7%; p < 0.001), C-peptide (by 7.1%; 95% CI 4.1 to 9.9%; p < 0.001), and amylin (by 15.7%; 95% CI 11.8 to 19.7%; p < 0.001) was observed following consumption of the V-meal. An increase in stimulated secretion of GLP-1 (by 19.2%; 95% CI 12.4 to 26.7%; p < 0.001) and a decrease in GIP (by −9.4%; 95% CI −17.3 to −0.7%; p = 0.02) were observed after the V-meal. Several parameters of beta-cell function increased after the V-meal, particularly insulin secretion at a fixed glucose value 5 mmol/L, rate sensitivity, and the potentiation factor. Our results showed an increase in postprandial incretin and insulin secretion, after consumption of a V-meal, suggesting a therapeutic potential of plant-based meals for improving beta-cell function in T2D.
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Robles-Cervantes, J. A., M. G. Ramos-Zavala, M. González-Ortiz, E. Martínez-Abundis, C. Valencia-Sandoval, A. Torres-Chávez, C. Espinel-Bermúdez, N. J. Santiago-Hernández, and S. O. Hernández-González. "Relationship between Serum Concentration of Uric Acid and Insulin Secretion among Adults with Type 2 Diabetes Mellitus." International Journal of Endocrinology 2011 (2011): 1–4. http://dx.doi.org/10.1155/2011/107904.
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To determine the relationship between serum concentrations of uric acid and insulin secretion with hyperglycaemic clamp technique among adults with type 2 diabetes mellitus (DM2) without hyperuricemia, we carried out a cross-sectional study on 45 patients of both gender. We observed correlation between uric acid with male genderr=0.710(P=0.001). Also correlation between uric acid and total insulin secretion was positiver=0.295(P=0.049). As well as a positive correlation adjusted for body mass index was demonstrated for the first, second, and total phases of insulin secretion, respectively,r=0.438(P=0.022),r=0.433(P=0.022), andr=0.439(P=0.024). Serum concentration of uric acid showed a positive relationship with the total phase of insulin secretion; even in states prior to hyperuricemia, uric acid can play an important role in the function of the beta cell in patients with DM2.
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Zhang, Irina X., Jianhua Ren, Suryakiran Vadrevu, Malini Raghavan, and Leslie S. Satin. "ER stress increases store-operated Ca2+ entry (SOCE) and augments basal insulin secretion in pancreatic beta cells." Journal of Biological Chemistry 295, no. 17 (March 16, 2020): 5685–700. http://dx.doi.org/10.1074/jbc.ra120.012721.
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Type 2 diabetes mellitus (T2DM) is characterized by impaired glucose-stimulated insulin secretion and increased peripheral insulin resistance. Unremitting endoplasmic reticulum (ER) stress can lead to beta-cell apoptosis and has been linked to type 2 diabetes. Although many studies have attempted to link ER stress and T2DM, the specific effects of ER stress on beta-cell function remain incompletely understood. To determine the interrelationship between ER stress and beta-cell function, here we treated insulin-secreting INS-1(832/13) cells or isolated mouse islets with the ER stress–inducer tunicamycin (TM). TM induced ER stress as expected, as evidenced by activation of the unfolded protein response. Beta cells treated with TM also exhibited concomitant alterations in their electrical activity and cytosolic free Ca2+ oscillations. As ER stress is known to reduce ER Ca2+ levels, we tested the hypothesis that the observed increase in Ca2+ oscillations occurred because of reduced ER Ca2+ levels and, in turn, increased store-operated Ca2+ entry. TM-induced cytosolic Ca2+ and membrane electrical oscillations were acutely inhibited by YM58483, which blocks store-operated Ca2+ channels. Significantly, TM-treated cells secreted increased insulin under conditions normally associated with only minimal release, e.g. 5 mm glucose, and YM58483 blocked this secretion. Taken together, these results support a critical role for ER Ca2+ depletion–activated Ca2+ current in mediating Ca2+-induced insulin secretion in response to ER stress.
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Mohtarin, Sabreena, Md Matiur Rahman, Subrata Kumar Biswas, Forhadul Hoque Mollah, and M. Iqbal Arslan. "Study of phases of insulin secretion in pre-diabetes and newly diagnosed type 2 diabetes mellitus." Bangabandhu Sheikh Mujib Medical University Journal 8, no. 2 (July 26, 2016): 85. http://dx.doi.org/10.3329/bsmmuj.v8i2.28927.
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<p><strong>Background:</strong> Insulin is released from the pancreas in a biphasic manner in response to arterial glucose concentration. The assumption has been generally made that the 30-minute response reflected first-phase insulin release, whereas the 120-minute response reflected second-phase insulin release.</p><p><strong>Objectives:</strong> The aim of this study was to identify the defect in first and second phases of insulin secretion in pre-diabetes and newly diagnosed T2DM.</p><p><strong>Methods:</strong> This case-control study was conducted in the department of Biochemistry, Bangabandhu Sheikh Mujib Medical University, Shahbag, Dhaka from March 2013 to June 2014. All the study subjects (n = 94) were collected from the one point centre, BSMMU as newly diagnosed T2DM, pre-diabetes and healthy normal glucose tolerant subjects according to fasting plasma glucose and 2 hour plasma glucose status. A total of 32 newly diagnosed T2DM and 32 pre-diabetes were included on the basis of inclusion criteria as cases. Another 30 healthy normal glucose tolerant subjects were emolled as control. Fasting blood samples were collected from study subjects to estimate the plasma glucose and insulin level. Again blood samples were taken for measurement of plasma glucose and insulin level at 30 minute and 120 minute on OGTT.</p><p><strong>Results:</strong> Fasting plasma insulin was significantly higher in pre-diabetes than control and T2DM (p = 0.011). Plasma insulin at 30 minute and 120 minute of OGTT were significantly lower in T2DM than control and pre- diabetes (p = 0.001 & 0.016). The insulin secretion in first and second phases were significantly lower in T2DM patients than controls and pre-diabetes (p = 0.000). Beta-cell function was also significantly lower in T2DM than controls and pre-diabetes (p = 0.000). Median values of HOMA-IR were higher in pre-diabetes (1.68) and T2DM (1.53) than control (1.37), but not statistically significant (p = 0.153). There was significant positive correlation of both phases of insulin secretion with FPI, beta-cell function and insulin resistance in T2DM, pre-diabetes and controls.</p><p><strong>Conclusions:</strong> The study reveals that 1st and 2nd phase insulin secretory defect was detected in T2DM, but in pre-diabetes, we have failed to identify insulin secretory defects in both phases.</p>
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Sjöstrand, M., K. Carlson, H. J. Arnqvist, S. Gudbjörnsdottir, M. Landin-Olsson, S. Lindmark, L. Nyström, M. K. Svensson, J. W. Eriksson, and J. Bolinder. "Assessment of beta-cell function in young patients with type 2 diabetes: arginine-stimulated insulin secretion may reflect beta-cell reserve." Journal of Internal Medicine 275, no. 1 (August 30, 2013): 39–48. http://dx.doi.org/10.1111/joim.12116.
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Ladwa, M., O. Hakim, S. A. Amiel, and L. M. Goff. "A Systematic Review of Beta Cell Function in Adults of Black African Ethnicity." Journal of Diabetes Research 2019 (October 20, 2019): 1–17. http://dx.doi.org/10.1155/2019/7891359.
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Background. Understanding ethnic differences in beta cell function has important implications for preventative and therapeutic strategies in populations at high risk of type 2 diabetes (T2D). The existing literature, largely drawn from work in children and adolescents, suggests that beta cell function in black African (BA) populations is upregulated when compared to white Europeans (WE). Methods. A systematic literature search was undertaken in June 2018 to identify comparative studies of beta cell function between adults (>age 18 years) of indigenous/diasporic BA and WE ethnicity. All categories of glucose tolerance and all methodologies of assessing beta cell function in vivo were included. Results. 41 studies were identified for inclusion into a qualitative synthesis. The majority were studies in African American populations (n=30) with normal glucose tolerance (NGT)/nondiabetes (n=25), using intravenous glucose stimulation techniques (n=27). There were fewer studies in populations defined as only impaired fasting glucose/impaired glucose tolerance (IFG/IGT) (n=3) or only T2D (n=3). Although BA broadly exhibited greater peripheral insulin responses than WE, the relatively small number of studies which measured C-peptide to differentiate between beta cell insulin secretion and hepatic insulin extraction (n=14) had highly variable findings. In exclusively IGT or T2D cohorts, beta cell insulin secretion was found to be lower in BA compared to WE. Conclusions. There is inconsistent evidence for upregulated beta cell function in BA adults, and they may in fact exhibit greater deficits in insulin secretory function as glucose intolerance develops.
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Ibfelt, Tobias, Christian P. Fischer, Peter Plomgaard, Gerrit van Hall, and Bente Klarlund Pedersen. "The Acute Effects of Low-Dose TNF-αon Glucose Metabolism andβ-Cell Function in Humans." Mediators of Inflammation 2014 (2014): 1–7. http://dx.doi.org/10.1155/2014/295478.
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Type 2 diabetes is characterized by increased insulin resistance and impaired insulin secretion. Type 2 diabetes is also associated with low-grade inflammation and increased levels of proinflammatory cytokines such as TNF-α. TNF-αhas been shown to impair peripheral insulin signalingin vitroandin vivo. However, it is unclear whether TNF-αmay also affect endogenous glucose production (EGP) during fasting and glucose-stimulated insulin secretion (GSIS)in vivo. We hypothesized that low-dose TNF-αwould increase EGP and attenuate GSIS. Recombinant human TNF-αor placebo was infused in healthy, nondiabetic young men (n=10) during a 4-hour basal period followed by an intravenous glucose tolerance test (IVGTT). TNF-αlowered insulin levels by 12% during the basal period (P<0.05). In response to the IVGTT, insulin levels increased markedly in both trials, but there was no difference between trials. Compared to placebo, TNF-αdid not affect EGP during the basal period. Our results indicate that TNF-αacutely lowers basal plasma insulin levels but does not impair GSIS. The mechanisms behind this are unknown but we suggest that it may be due to TNF-αincreasing clearance of insulin from plasma without impairing beta-cell function or hepatic insulin sensitivity.
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Puddu, Alessandra, Roberta Sanguineti, Fabrizio Montecucco, and Giorgio Luciano Viviani. "Evidence for the Gut Microbiota Short-Chain Fatty Acids as Key Pathophysiological Molecules Improving Diabetes." Mediators of Inflammation 2014 (2014): 1–9. http://dx.doi.org/10.1155/2014/162021.
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In type 2 diabetes, hyperglycemia, insulin resistance, increased inflammation, and oxidative stress were shown to be associated with the progressive deterioration of beta-cell function and mass. Short-chain fatty acids (SCFAs) are organic fatty acids produced in the distal gut by bacterial fermentation of macrofibrous material that might improve type 2 diabetes features. Their main beneficial activities were identified in the decrease of serum levels of glucose, insulin resistance as well as inflammation, and increase in protective Glucagon-like peptide-1 (GLP-1) secretion. In this review, we updated evidence on the effects of SCFAs potentially improving metabolic control in type 2 diabetes.
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Cabanas, E. Ann. "Maturity-Onset Diabetes of the Young: Recent Findings Indicate Insulin Resistance/Obesity Are Not Factors." Diabetes Educator 24, no. 4 (August 1998): 477–80. http://dx.doi.org/10.1177/014572179802400405.
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Maturity-onset diabetes of the young (MODY) is a relatively rare subtype of type 2 diabetes characterized by an early age of onset and autosomal dominant inheritance. Unlike type 2 diabetes, which is often associated with insulin resistance, MODY is caused by a primary defect in pancreatic beta-cell function resulting in a decrease in insulin secretion. Obesity is not a feature of MODY. However, environmental stressors that increase the demand for insulin, such as illness or puberty, may unmask the genetically limited insulin secretory reserve of the undiagnosed MODY patient. Euglycemia is the primary goal of therapy, and diet is the cornerstone of glycemic control. Sulfonylureas and/or exogenous insulin may also be required depending on the degree of dysfunction of the beta cells.
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Edlund, A., M. Barghouth, M. Hühn, M. Abels, J. S. E. Esguerra, I. G. Mollet, E. Svedin, et al. "Defective exocytosis and processing of insulin in a cystic fibrosis mouse model." Journal of Endocrinology 241, no. 1 (April 2019): 45–57. http://dx.doi.org/10.1530/joe-18-0570.
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Cystic fibrosis-related diabetes (CFRD) is a common complication for patients with cystic fibrosis (CF), a disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). The cause of CFRD is unclear, but a commonly observed reduction in first-phase insulin secretion suggests defects at the beta cell level. Here we aimed to examine alpha and beta cell function in the Cftr tm1 EUR/F508del mouse model (C57BL/6J), which carries the most common human mutation in CFTR, the F508del mutation. CFTR expression, beta cell mass, insulin granule distribution, hormone secretion and single cell capacitance changes were evaluated using islets (or beta cells) from F508del mice and age-matched wild type (WT) mice aged 7–10 weeks. Granular pH was measured with DND-189 fluorescence. Serum glucose, insulin and glucagon levels were measured in vivo, and glucose tolerance was assessed using IPGTT. We show increased secretion of proinsulin and concomitant reduced secretion of C-peptide in islets from F508del mice compared to WT mice. Exocytosis and number of docked granules was reduced. We confirmed reduced granular pH by CFTR stimulation. We detected decreased pancreatic beta cell area, but unchanged beta cell number. Moreover, the F508del mutation caused failure to suppress glucagon secretion leading to hyperglucagonemia. In conclusion, F508del mice have beta cell defects resulting in (1) reduced number of docked insulin granules and reduced exocytosis and (2) potential defective proinsulin cleavage and secretion of immature insulin. These observations provide insight into the functional role of CFTR in pancreatic islets and contribute to increased understanding of the pathogenesis of CFRD.
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McCarty, Mark F., and James J. DiNicolantonio. "Maintaining Effective Beta Cell Function in the Face of Metabolic Syndrome-Associated Glucolipotoxicity—Nutraceutical Options." Healthcare 10, no. 1 (December 21, 2021): 3. http://dx.doi.org/10.3390/healthcare10010003.
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In people with metabolic syndrome, episodic exposure of pancreatic beta cells to elevated levels of both glucose and free fatty acids (FFAs)—or glucolipotoxicity—can induce a loss of glucose-stimulated insulin secretion (GSIS). This in turn can lead to a chronic state of glucolipotoxicity and a sustained loss of GSIS, ushering in type 2 diabetes. Loss of GSIS reflects a decline in beta cell glucokinase (GK) expression associated with decreased nuclear levels of the pancreatic and duodenal homeobox 1 (PDX1) factor that drives its transcription, along with that of Glut2 and insulin. Glucolipotoxicity-induced production of reactive oxygen species (ROS), stemming from both mitochondria and the NOX2 isoform of NADPH oxidase, drives an increase in c-Jun N-terminal kinase (JNK) activity that promotes nuclear export of PDX1, and impairs autocrine insulin signaling; the latter effect decreases PDX1 expression at the transcriptional level and up-regulates beta cell apoptosis. Conversely, the incretin hormone glucagon-like peptide-1 (GLP-1) promotes nuclear import of PDX1 via cAMP signaling. Nutraceuticals that quell an increase in beta cell ROS production, that amplify or mimic autocrine insulin signaling, or that boost GLP-1 production, should help to maintain GSIS and suppress beta cell apoptosis in the face of glucolipotoxicity, postponing or preventing onset of type 2 diabetes. Nutraceuticals with potential in this regard include the following: phycocyanobilin—an inhibitor of NOX2; agents promoting mitophagy and mitochondrial biogenesis, such as ferulic acid, lipoic acid, melatonin, berberine, and astaxanthin; myo-inositol and high-dose biotin, which promote phosphatidylinositol 3-kinase (PI3K)/Akt activation; and prebiotics/probiotics capable of boosting GLP-1 secretion. Complex supplements or functional foods providing a selection of these agents might be useful for diabetes prevention.
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Lin, Edward, S. Scott Davis, Jahnavi Srinivasan, John F. Sweeney, Thomas R. Ziegler, Lawrence S. Phillips, and Nana Gletsu-Miller. "Dual Mechanism for Type-2 Diabetes Resolution after Roux-en-Y Gastric Bypass." American Surgeon 75, no. 6 (June 2009): 498–503. http://dx.doi.org/10.1177/000313480907500608.
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Resolution of Type-2 diabetes mellitus (DM) after weight loss surgery is well documented, but the mechanism is elusive. We evaluated the glucose-insulin metabolism of patients undergoing a Roux-en-Y gastric bypass (RYGB) using the intravenous glucose tolerance test (IVGTT) and compared it with patients who underwent laparoscopic adjustable gastric band (AB) placement. Thirty-one female patients (age range, 20 to 50 years; body mass index, 47.2 kg/m2) underwent RYGB. Nine female patients underwent AB placement and served as control subjects. All patients underwent IVGTT at baseline and 1 month and 6 months after surgery. Thirteen patients undergoing RYGB and one patient undergoing AB exhibited impaired glucose tolerance or DM defined by the American Diabetes Association. By 6 months post surgery, diabetes was resolved in all but one patient undergoing RYGB but not in the patient undergoing AB. Patients with diabetes undergoing RYGB demonstrated increased insulin secretion and β-cell responsiveness 1 month after surgery and continued this trend up to 6 months, whereas none of the patients undergoing AB had changes in β-cell function. Both patients undergoing RYGB and those undergoing AB demonstrated significant weight loss (34.6 and 35.0 kg/m2, respectively) and improved insulin sensitivity at 6 months. RYGB ameliorates DM resolution in two phases: 1) early augmentation of beta cell function at 1 month; and 2) attenuation of peripheral insulin resistance at 6 months. Patients undergoing AB only exhibited reduction in peripheral insulin resistance at 6 months but no changes in insulin secretion.
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Velikova, Tsvetelina V., Plamena P. Kabakchieva, Yavor S. Assyov, and Tsvetoslav А. Georgiev. "Targeting Inflammatory Cytokines to Improve Type 2 Diabetes Control." BioMed Research International 2021 (September 13, 2021): 1–12. http://dx.doi.org/10.1155/2021/7297419.
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Type 2 diabetes (T2D) is one of the most common chronic metabolic disorders in adulthood worldwide, whose pathophysiology includes an abnormal immune response accompanied by cytokine dysregulation and inflammation. As the T2D-related inflammation and its progression were associated with the balance between pro and anti-inflammatory cytokines, anticytokine treatments might represent an additional therapeutic option for T2D patients. This review focuses on existing evidence for antihyperglycemic properties of disease-modifying antirheumatic drugs (DMARDs) and anticytokine agents (anti-TNF-α, anti-interleukin-(IL-) 6, -IL-1, -IL-17, -IL-23, etc.). Emphasis is placed on their molecular mechanisms and on the biological rationale for clinical use. Finally, we briefly summarize the results from experimental model studies and promising clinical trials about the potential of anticytokine therapies in T2D, discussing the effects of these drugs on systemic and islet inflammation, beta-cell function, insulin secretion, and insulin sensitivity.
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Okura, Tsuyoshi, Risa Nakamura, Yuichi Ito, Sonoko Kitao, Mari Anno, Satomi Endo, Natsuka Taneda, et al. "Significance of pancreatic duodenal homeobox-1 (PDX-1) genetic polymorphism in insulin secretion in Japanese patients with type 2 diabetes." BMJ Open Diabetes Research & Care 10, no. 5 (September 2022): e002908. http://dx.doi.org/10.1136/bmjdrc-2022-002908.
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IntroductionPancreatic and duodenal homeobox factor-1 (PDX-1) is an imperative gene for insulin secretion in maturity-onset diabetes of the young 4. PDX-1 gene polymorphism was associated with lower first-phase insulin secretion in a genome-wide association study of intravenous glucose tolerance test. It was not associated with type 2 diabetes risk and insulin secretion in a genome-wide oral glucose tolerance test study. However, there have been no reports of overt type 2 diabetes and insulin resistance evaluation using a glucose clamp. We investigated PDX-1 polymorphism, insulin secretion, and insulin resistance in overt type 2 diabetes.Research design and methodsWe performed a meal tolerance test (MTT) and hyperinsulinemic–euglycemic clamping on 63 Japanese subjects, 30 with type 2 diabetes and 33 non-diabetic. We analyzed the rs1124607 PDX-1 gene polymorphism and defined A/C and C/C as the high-risk group and A/A as the low-risk group.ResultsHOMA-beta (homeostatic model assessment beta-cell function) was significantly lower in the high-risk group than in the low-risk group for all subjects (72.9±54.2% vs 107.0±63.5%, p<0.05). Glucose levels and glucose area under the curve (AUC) were not significantly different between both the risk groups. The insulin levels at 60 and 120 min and the insulin AUC after MTT were remarkably lower in the high-risk group than those in the low-risk group for all subjects (AUC 75.7±36.7 vs 112.7±59.5, p<0.05). High-risk subjects with type 2 diabetes had significantly lower insulin levels at 30 and 60 min and insulin AUC than low-risk subjects. Non-diabetic high-risk subjects depicted significantly lower insulin levels at 120 and 180 min. There were negligible differences in insulin resistance between the risk groups.ConclusionsThese results suggest that the PDX-1 genetic polymorphism is crucial for insulin secretion in Japanese patients with type 2 diabetes.
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Schultz, Julia, Rica Waterstradt, Tobias Kantowski, Annekatrin Rickmann, Florian Reinhardt, Vladimir Sharoyko, Hindrik Mulder, Markus Tiedge, and Simone Baltrusch. "Precise expression of Fis1 is important for glucose responsiveness of beta cells." Journal of Endocrinology 230, no. 1 (July 2016): 81–91. http://dx.doi.org/10.1530/joe-16-0111.
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Mitochondrial network functionality is vital for glucose-stimulated insulin secretion in pancreatic beta cells. Altered mitochondrial dynamics in pancreatic beta cells are thought to trigger the development of type 2 diabetes mellitus. Fission protein 1 (Fis1) might be a key player in this process. Thus, the aim of this study was to investigate mitochondrial morphology in dependence of beta cell function, after knockdown and overexpression of Fis1. We demonstrate that glucose-unresponsive cells with impaired glucose-stimulated insulin secretion (INS1-832/2) showed decreased mitochondrial dynamics compared with glucose-responsive cells (INS1-832/13). Accordingly, mitochondrial morphology visualised using MitoTracker staining differed between the two cell lines. INS1-832/2 cells formed elongated and clustered mitochondria, whereas INS1-832/13 cells showed a homogenous mitochondrial network. Fis1 overexpression using lentiviral transduction significantly improved glucose-stimulated insulin secretion and mitochondrial network homogeneity in glucose-unresponsive cells. Conversely, Fis1 downregulation by shRNA, both in primary mouse beta cells and glucose-responsive INS1-832/13 cells, caused unresponsiveness and significantly greater numbers of elongated mitochondria. Overexpression of FIS1 in primary mouse beta cells indicated an upper limit at which higher FIS1 expression reduced glucose-stimulated insulin secretion. Thus, FIS1 was overexpressed stepwise up to a high concentration in RINm5F cells using the RheoSwitch system. Moderate FIS1 expression improved glucose-stimulated insulin secretion, whereas high expression resulted in loss of glucose responsiveness and in mitochondrial artificial loop structures and clustering. Our data confirm that FIS1 is a key regulator in pancreatic beta cells, because both glucose-stimulated insulin secretion and mitochondrial dynamics were clearly adapted to precise expression levels of this fission protein.
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Kufe, Clement N., Lisa K. Micklesfield, Maphoko Masemola, Tinashe Chikowore, Andre P. Kengne, Fredrik Karpe, Shane A. Norris, Nigel J. Crowther, Tommy Olsson, and Julia H. Goedecke. "Increased risk for type 2 diabetes in relation to adiposity in middle-aged Black South African men compared to women." European Journal of Endocrinology 186, no. 5 (May 1, 2022): 523–33. http://dx.doi.org/10.1530/eje-21-0527.
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Aims Despite a higher prevalence of overweight/obesity in Black South African women compared to men, the prevalence of type 2 diabetes (T2D) does not differ. We explored if this could be due to sex differences in insulin sensitivity, clearance and/or beta-cell function and also sex-specific associations with total and regional adiposity. Methods This cross-sectional study included 804 Black South African men (n = 388) and women (n = 416). Dual-energy X-ray absorptiometry was used to measure total and regional adiposity. Insulin sensitivity (Matsuda index), secretion (C-peptide index) and clearance (C-peptide/insulin ratio) were estimated from an oral glucose tolerance test. Results After adjusting for sex differences in the fat mass index, men were less insulin sensitive and had lower beta-cell function than women (P < 0.001), with the strength of the associations with measures of total and central adiposity being greater in men than women (P < 0.001 for interactions). Further, the association between total adiposity and T2D risk was also greater in men than women (relative risk ratio (95% CI): 2.05 (1.42–2.96), P < 0.001 vs 1.38 (1.03–1.85), P = 0.031). Conclusion With increasing adiposity, particularly increased centralisation of body fat linked to decreased insulin sensitivity and beta-cell function, Black African men are at greater risk for T2D than their female counterparts.
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Bonora, Enzo, Maddalena Trombetta, Marco Dauriz, Daniela Travia, Vittorio Cacciatori, Corinna Brangani, Carlo Negri, et al. "Chronic complications in patients with newly diagnosed type 2 diabetes: prevalence and related metabolic and clinical features: the Verona Newly Diagnosed Type 2 Diabetes Study (VNDS) 9." BMJ Open Diabetes Research & Care 8, no. 1 (August 2020): e001549. http://dx.doi.org/10.1136/bmjdrc-2020-001549.
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IntroductionWe explored the presence of chronic complications in subjects with newly diagnosed type 2 diabetes referred to the Verona Diabetes Clinic. Metabolic (insulin secretion and sensitivity) and clinical features associated with complications were also investigated.Research design and methodsThe comprehensive assessment of microvascular and macrovascular complications included detailed medical history, resting ECG, ultrasonography of carotid and lower limb arteries, quantitative neurological evaluation, cardiovascular autonomic tests, ophthalmoscopy, kidney function tests. Insulin sensitivity and beta-cell function were assessed by state-of-the-art techniques (insulin clamp and mathematical modeling of glucose/C-peptide curves during oral glucose tolerance test).ResultsWe examined 806 patients (median age years, two-thirds males), of whom prior clinical cardiovascular disease (CVD) was revealed in 11.2% and preclinical CVD in 7.7%. Somatic neuropathy was found in 21.2% and cardiovascular autonomic neuropathy in 18.6%. Retinopathy was observed in 4.9% (background 4.2%, proliferative 0.7%). Chronic kidney disease (estimated glomerular filtration rate <60 mL/min/1.73 m2) was found in 8.8% and excessive albuminuria in 13.2% (microalbuminuria 11.9%, macroalbuminuria 1.3%).Isolated microvascular disease occurred in 30.8%, isolated macrovascular disease in 9.3%, a combination of both in 9.1%, any complication in 49.2% and no complications in 50.8%.Gender, age, body mass index, smoking, hemoglobin A1c and/or hypertension were independently associated with one or more complications. Insulin resistance and beta-cell dysfunction were associated with macrovascular but not microvascular disease.ConclusionsDespite a generally earlier diagnosis for an increased awareness of the disease, as many as ~50% of patients with newly diagnosed type 2 diabetes had clinical or preclinical manifestations of microvascular and/or macrovascular disease. Insulin resistance might play an independent role in macrovascular disease.Trial registration numberNCT01526720.
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Oh, Yoon Sin, and Hee-Sook Jun. "Role of Bioactive Food Components in Diabetes Prevention: Effects on Beta-Cell Function and Preservation." Nutrition and Metabolic Insights 7 (January 2014): NMI.S13589. http://dx.doi.org/10.4137/nmi.s13589.
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Bioactive compounds found in fruits and vegetables can have anti-oxidant, anti-inflammatory, and anti-carcinogenic effects and can be protective against various diseases and metabolic disorders. These beneficial effects make them good candidates for the development of new functional foods with potential protective and preventive properties for type 1 and type 2 diabetes. This review summarizes the most relevant results concerning the effects of various bioactive compounds such as flavonoids, vitamins, and carotenoids on several aspects of beta-cell functionality. Studies using animal models with induced diabetes and diabetic patients support the hypothesis that bioactive compounds could ameliorate diabetic phenotypes. Published data suggest that there might be direct effects of bioactive compounds on enhancing insulin secretion and preventing beta-cell apoptosis, and some compounds might modulate beta-cell proliferation. Further research is needed to establish any clinical effects of these compounds.
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Oberhauser, Lucie, and Pierre Maechler. "Lipid-Induced Adaptations of the Pancreatic Beta-Cell to Glucotoxic Conditions Sustain Insulin Secretion." International Journal of Molecular Sciences 23, no. 1 (December 28, 2021): 324. http://dx.doi.org/10.3390/ijms23010324.
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Over the last decades, lipotoxicity and glucotoxicity emerged as established mechanisms participating in the pathophysiology of obesity-related type 2 diabetes in general, and in the loss of β-cell function in particular. However, these terms hold various potential biological processes, and it is not clear what precisely they refer to and to what extent they might be clinically relevant. In this review, we discuss the basis and the last advances of research regarding the role of free fatty acids, their metabolic intracellular pathways, and receptor-mediated signaling related to glucose-stimulated insulin secretion, as well as lipid-induced β-cell dysfunction. We also describe the role of chronically elevated glucose, namely, glucotoxicity, which promotes failure and dedifferentiation of the β cell. Glucolipotoxicity combines deleterious effects of exposures to both high glucose and free fatty acids, supposedly provoking synergistic defects on the β cell. Nevertheless, recent studies have highlighted the glycerolipid/free fatty acid cycle as a protective pathway mediating active storage and recruitment of lipids. Finally, we discuss the putative correspondence of the loss of functional β cells in type 2 diabetes with a natural, although accelerated, aging process.
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Marrano, Nicola, Rosaria Spagnuolo, Giuseppina Biondi, Angelo Cignarelli, Sebastio Perrini, Leonardo Vincenti, Luigi Laviola, Francesco Giorgino, and Annalisa Natalicchio. "Effects of Extra Virgin Olive Oil Polyphenols on Beta-Cell Function and Survival." Plants 10, no. 2 (February 3, 2021): 286. http://dx.doi.org/10.3390/plants10020286.
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Extra virgin olive oil (EVOO) is a major component of the Mediterranean diet and is appreciated worldwide because of its nutritional benefits in metabolic diseases, including type 2 diabetes (T2D). EVOO contains significant amounts of secondary metabolites, such as phenolic compounds (PCs), that may positively influence the metabolic status. In this study, we investigated for the first time the effects of several PCs on beta-cell function and survival. To this aim, INS-1E cells were exposed to 10 μM of the main EVOO PCs for up to 24 h. Under these conditions, survival, insulin biosynthesis, glucose-stimulated insulin secretion (GSIS), and intracellular signaling activation (protein kinase B (AKT) and cAMP response element-binding protein (CREB)) were evaluated. Hydroxytyrosol, tyrosol, and apigenin augmented beta-cell proliferation and insulin biosynthesis, and apigenin and luteolin enhanced the GSIS. Conversely, vanillic acid and vanillin were pro-apoptotic for beta-cells, even if they increased the GSIS. In addition, oleuropein, p-coumaric, ferulic and sinapic acids significantly worsened the GSIS. Finally, a mixture of hydroxytyrosol, tyrosol, and apigenin promoted the GSIS in human pancreatic islets. Apigenin was the most effective compound and was also able to activate beneficial intracellular signaling. In conclusion, this study shows that hydroxytyrosol, tyrosol, and apigenin foster beta-cells’ health, suggesting that EVOO or supplements enriched with these compounds may improve insulin secretion and promote glycemic control in T2D patients.
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Deep, Hardeep Singh, Barjinder Pal Singh, and Shalinder Pal Singh. "Evaluation of serum c-peptide levels in type 2 diabetics in Punjabi population." International Journal of Advances in Medicine 4, no. 4 (July 20, 2017): 1026. http://dx.doi.org/10.18203/2349-3933.ijam20173225.
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Background: Diabetes mellitus is a chronic metabolic and endocrine disorder characterized by chronic hyperglycemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action or both. It is a major cause of mortality and morbidity worldwide. Human insulin and c-peptide are synthesized as a single polypeptide chain known as Proinsulin in the pancreatic beta cells. Serum insulin measurement gives a wrong value of insulin secretion, because insulin after its secretion into the portal vein, passes through the liver where approximately 50% of the delivered insulin is extracted. The measurement of C-peptide, thus provides a better index of endogenous insulin production and pancreatic beta cell function than insulin measurements.Methods: The present study was conducted on 100 adult patients of type 2 diabetes mellitus presenting in OPD and emergency or admitted in Sri Guru Ram Das Institute of Medical Sciences and Research, Amritsar. Type 1 diabetic patients, pregnant females with diabetes, patients presenting with acute infections, septicaemia, patients with acute or chronic pancreatitis, patients with pancreatic carcinoma were excluded from the study. In this study C-Peptide levels were estimated by DRG C-peptide ELISA method.Results: In our study, 38% patients had adequate insulin reserve (Normal C-peptide levels). Only 2% patients had poor insulin reserve (C-peptide levels below normal). 60% patients had c peptide levels more than normal, indicating insulin resistance. Increase in fasting c-peptide levels were associated with increased fasting plasma glucose (due to insulin resistance). A positive correlation exists in our study with r value of 0.523.Conclusions: As majority of patients with elevated FBS and fasting c-peptide were obese, our study infers that obese are more insulin resistant than non-obese. Since c-peptide levels assess the endogenous insulin reserve, it will also be helpful to alter the treatment modality based on it. So, routine c-peptide testing should be done in patients with poor glycaemic control to modify treatment modality accordingly.
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Bosma, Karin J., Cecilia E. Kaiser, Michelle E. Kimple, and Maureen Gannon. "Effects of Arachidonic Acid and Its Metabolites on Functional Beta-Cell Mass." Metabolites 12, no. 4 (April 12, 2022): 342. http://dx.doi.org/10.3390/metabo12040342.
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Arachidonic acid (AA) is a polyunsaturated 20-carbon fatty acid present in phospholipids in the plasma membrane. The three primary pathways by which AA is metabolized are mediated by cyclooxygenase (COX) enzymes, lipoxygenase (LOX) enzymes, and cytochrome P450 (CYP) enzymes. These three pathways produce eicosanoids, lipid signaling molecules that play roles in biological processes such as inflammation, pain, and immune function. Eicosanoids have been demonstrated to play a role in inflammatory, renal, and cardiovascular diseases as well type 1 and type 2 diabetes. Alterations in AA release or AA concentrations have been shown to affect insulin secretion from the pancreatic beta cell, leading to interest in the role of AA and its metabolites in the regulation of beta-cell function and maintenance of beta-cell mass. In this review, we discuss the metabolism of AA by COX, LOX, and CYP, the roles of these enzymes and their metabolites in beta-cell mass and function, and the possibility of targeting these pathways as novel therapies for treating diabetes.
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Voĭchik, É. A. "Victosa: the experience with clinical application in patients with type 2 diabetes mellitus." Problems of Endocrinology 57, no. 3 (June 15, 2011): 37–41. http://dx.doi.org/10.14341/probl201157337-41.
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Type 2 diabetes mellitus that comes from insulin resistance and deficit of insulin secretion has recently been described as associated with reduced incretin effect. The efficiency of traditional hypoglycemic therapy (metformin, secretagogues, glitazones, insulin) gradually decreases due to progressive loss of functioning beta-cell mass. The achievement of target blood glucose levels for the prevention of complications and cardiovascular pathology as a rule leads to such adverse events as increased body weight and hypoglycemia. The search for an «ideal» drug included the study and the use of incretin effect in DM2 patients. Liralglutide, the first analog of human glucagon-like peptide (GPP-1), is an innovative preparation with the desired properties the action of which is not confined to traditional hypoglycemic effects and improvement of glycemic control (as many as 65% of the patients have the targeted HbA1c level <7% at a minimal risk of hypoglycemia). It also prevents a rise in body weight, decreases arterial pressure and trigyceride levels, improves beta-cell function. This paper reports the first experience with clinical application of liraglutide (marketed in this country under commercial name Victosa since November 2010) for the treatment of patients with type 2 diabetes mellitus. Our data confirm results of the randomized placebo-controlled clinical study LEAD 1-6.
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Volpe, Alessandro, Chang Ye, Anthony J. Hanley, Philip W. Connelly, Bernard Zinman, and Ravi Retnakaran. "Changes Over Time in Uric Acid in Relation to Changes in Insulin Sensitivity, Beta-Cell Function, and Glycemia." Journal of Clinical Endocrinology & Metabolism 105, no. 3 (November 13, 2019): e651-e659. http://dx.doi.org/10.1210/clinem/dgz199.
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Abstract Context Serum uric acid has been linked to risk of type 2 diabetes (T2DM), but debate persists as to whether it plays a causal role. Indeed, it is unclear if changes in uric acid relate to the pathophysiologic determinants of T2DM (insulin resistance, beta-cell dysfunction), as would be expected if causal. Objective To evaluate the impact of changes in uric acid over 2 years on changes in insulin sensitivity, beta-cell function, and glycemia in women with and without recent gestational diabetes (GDM), a model of the early natural history of T2DM. Design/Setting/Participants At both 1 and 3 years postpartum, 299 women (96 with recent GDM) underwent uric acid measurement and oral glucose tolerance tests that enabled assessment of insulin sensitivity/resistance (Matsuda index, homeostasis model assessment of insulin resistance [HOMA-IR]), beta-cell function (insulin secretion-sensitivity index-2 [ISSI-2], insulinogenic index/HOMA-IR [IGI/HOMA-IR]), and glucose tolerance. Results Women with recent GDM had higher serum uric acid than their peers at both 1 year (281 ± 69 vs 262 ± 58 µmol/L, P = 0.01) and 3 years postpartum (271 ± 59 vs 256 ± 55 µmol/L, P = 0.03), coupled with lower insulin sensitivity, poorer beta-cell function, and greater glycemia (all P < 0.05). However, on fully adjusted analyses, neither uric acid at 1 year nor its change from 1 to 3 years was independently associated with any of the following metabolic outcomes at 3 years postpartum: Matsuda index, HOMA-IR, ISSI-2, IGI/HOMA-IR, fasting glucose, 2-hour glucose, or glucose intolerance. Conclusion Serum uric acid does not track with changes over time in insulin sensitivity, beta-cell function, or glycemia in women with recent GDM, providing evidence against causality in its association with diabetes.
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Genova, M. P., K. Todorova-Ananieva, B. Atanasova, and K. Tzatchev. "Assessment of Beta-Cell Function During Pregnancy and after Delivery." Acta Medica Bulgarica 41, no. 1 (June 1, 2014): 5–12. http://dx.doi.org/10.2478/amb-2014-0001.
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Summary The aim of the present study was to assess β-cell function using homeostasis model (HOMA-B) and disposition index (DI) in pregnant women with/without gestational diabetes, and after delivery. A total of 102 pregnant women between 24-28 gestational weeks (53 with gestational diabetes mellitus (GDM) and 49 with normal glucose tolerance (NGT) and 22 GDM postpartum women (8-12 weeks after delivery) were included in the study. All postpartum women had a history of GDM. HOMA indexes (insulin resistance - HOMA-IR and HOMA-B for assessing β-cell function) were calculated from fasting glucose and insulin concentrations. To estimate insulin secretion independent of insulin sensitivity, DI was calculated using glucose and insulin levels at 0 and 60 min during the course of a 2 h 75g oral glucose tolerance test (OGTT). In GDM pregnant women HOMA-B was significantly lower compared to NGT women (p = 0.017), but there was no significant difference compared to women after birth (NS). There was difference between NGT and postpartum women (p < 0.05). DI was significantly lower for GDM pregnant women in comparison to NGT and postpartum women (p < 0.0001; p = 0.011), between NGT and women after birth (p < 0.04). In our study, comparison of НОМА-В in NGT and GDM pregnant women demonstrated that the OR of developing GDM was 0.989 (95% CI, 0.980-0.998, P = 0.013), and comparison of DI in healthy pregnant and GDM showed that the OR of developing GDM was 0.967 (95% CI, 0.947-0.988, P = 0.002). Therefore, HOMA-B and DI appear to be protective factors in the risk of developing GDM. According to our results, assessment of β-cell function, using HOMA-B and DI, showed that they are lower in GDM than NGT group and postpartum women. It is important to note that HOMA-B did not show significant difference between GDM pregnant and women after delivery with a history for GDM. We assume that pregnant women with GDM have a pancreatic β-cell defect that remains after birth. These women are at increased risk for developing diabetes mellitus, the most frequent type 2 diabetes, in the future after birth.
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Bronczek, Gabriela Alves, Gabriela Moreira Soares, Carine Marmentini, Antonio Carlos Boschero, and José Maria Costa-Júnior. "Resistance Training Improves Beta Cell Glucose Sensing and Survival in Diabetic Models." International Journal of Molecular Sciences 23, no. 16 (August 21, 2022): 9427. http://dx.doi.org/10.3390/ijms23169427.
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Resistance training increases insulin secretion and beta cell function in healthy mice. Here, we explored the effects of resistance training on beta cell glucose sensing and survival by using in vitro and in vivo diabetic models. A pancreatic beta cell line (INS-1E), incubated with serum from trained mice, displayed increased insulin secretion, which could be linked with increased expression of glucose transporter 2 (GLUT2) and glucokinase (GCK). When cells were exposed to pro-inflammatory cytokines (in vitro type 1 diabetes), trained serum preserved both insulin secretion and GCK expression, reduced expression of proteins related to apoptotic pathways, and also protected cells from cytokine-induced apoptosis. Using 8-week-old C57BL/6 mice, turned diabetic by multiple low doses of streptozotocin, we observed that resistance training increased muscle mass and fat deposition, reduced fasting and fed glycemia, and improved glucose tolerance. These findings may be explained by the increased fasting and fed insulinemia, along with increased beta cell mass and beta cell number per islet, observed in diabetic-trained mice compared to diabetic sedentary mice. In conclusion, we believe that resistance training stimulates the release of humoral factors which can turn beta cells more resistant to harmful conditions and improve their response to a glucose stimulus.
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Picton, Sally F., Peter R. Flatt, and Neville H. McClenaghan. "Differential Acute and Long Term Actions of Succinic Acid Monomethyl Ester Exposure on Insulin-Secreting BRIN-BD11 Cells." International Journal of Experimental Diabetes Research 2, no. 1 (2001): 19–27. http://dx.doi.org/10.1155/edr.2001.19.
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Esters of succinic acid are potent insulin secretagogues, and have been proposed as novel antidiabetic agents for type 2 diabetes. This study examines the effects of acute and chronic exposure to succinic acid monomethyl ester (SAM) on insulin secretion, glucose metabolism and pancreatic beta cell function using the BRIN-BD11 cell line. SAM stimulated insulin release in a dose-dependent manner at both non-stimulatory (1.1mM) and stimulatory (16.7mM) glucose. The depolarizing actions of arginine also stimulated a significant increase in SAM-induced insulin release but 2-ketoisocaproic acid (KIC) inhibited SAM induced insulin secretion indicating a possible competition between the preferential oxidative metabolism of these two agents. Prolonged (18hour) exposure to SAM revealed decreases in the insulin-secretory responses to glucose, KIC, glyceraldehyde and alanine. Furthermore, SAM diminished the effects of nonmetabolized secretagogues arginine and 3-isobutyl-1-methylxanthine (IBMX). While the ability of BRIN-BD11 cells to oxidise glucose was unaffected by SAM culture, glucose utilization was substantially reduced. Collectively, these data suggest that while SAM may enhance the secretory potential of non-metabolized secretagogues, it may also serve as a preferential metabolic fuel in preference to other important physiological nutrients and compromise pancreatic beta cell function following prolonged exposure.
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Sayers, Sophie R., Rebecca L. Beavil, Nicholas H. F. Fine, Guo C. Huang, Pratik Choudhary, Kamila J. Pacholarz, Perdita E. Barran, et al. "Structure-functional changes in eNAMPT at high concentrations mediate mouse and human beta cell dysfunction in type 2 diabetes." Diabetologia 63, no. 2 (November 15, 2019): 313–23. http://dx.doi.org/10.1007/s00125-019-05029-y.
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Abstract Aims/hypothesis Progressive decline in functional beta cell mass is central to the development of type 2 diabetes. Elevated serum levels of extracellular nicotinamide phosphoribosyltransferase (eNAMPT) are associated with beta cell failure in type 2 diabetes and eNAMPT immuno-neutralisation improves glucose tolerance in mouse models of diabetes. Despite this, the effects of eNAMPT on functional beta cell mass are poorly elucidated, with some studies having separately reported beta cell-protective effects of eNAMPT. eNAMPT exists in structurally and functionally distinct monomeric and dimeric forms. Dimerisation is essential for the NAD-biosynthetic capacity of NAMPT. Monomeric eNAMPT does not possess NAD-biosynthetic capacity and may exert distinct NAD-independent effects. This study aimed to fully characterise the structure-functional effects of eNAMPT on pancreatic beta cell functional mass and to relate these to beta cell failure in type 2 diabetes. Methods CD-1 mice and serum from obese humans who were without diabetes, with impaired fasting glucose (IFG) or with type 2 diabetes (from the Body Fat, Surgery and Hormone [BodyFatS&H] study) or with or at risk of developing type 2 diabetes (from the VaSera trial) were used in this study. We generated recombinant wild-type and monomeric eNAMPT to explore the effects of eNAMPT on functional beta cell mass in isolated mouse and human islets. Beta cell function was determined by static and dynamic insulin secretion and intracellular calcium microfluorimetry. NAD-biosynthetic capacity of eNAMPT was assessed by colorimetric and fluorescent assays and by native mass spectrometry. Islet cell number was determined by immunohistochemical staining for insulin, glucagon and somatostatin, with islet apoptosis determined by caspase 3/7 activity. Markers of inflammation and beta cell identity were determined by quantitative reverse transcription PCR. Total, monomeric and dimeric eNAMPT and nicotinamide mononucleotide (NMN) were evaluated by ELISA, western blot and fluorometric assay using serum from non-diabetic, glucose intolerant and type 2 diabetic individuals. Results eNAMPT exerts bimodal and concentration- and structure-functional-dependent effects on beta cell functional mass. At low physiological concentrations (~1 ng/ml), as seen in serum from humans without diabetes, eNAMPT enhances beta cell function through NAD-dependent mechanisms, consistent with eNAMPT being present as a dimer. However, as eNAMPT concentrations rise to ~5 ng/ml, as in type 2 diabetes, eNAMPT begins to adopt a monomeric form and mediates beta cell dysfunction, reduced beta cell identity and number, increased alpha cell number and increased apoptosis, through NAD-independent proinflammatory mechanisms. Conclusions/interpretation We have characterised a novel mechanism of beta cell dysfunction in type 2 diabetes. At low physiological levels, eNAMPT exists in dimer form and maintains beta cell function and identity through NAD-dependent mechanisms. However, as eNAMPT levels rise, as in type 2 diabetes, structure-functional changes occur resulting in marked elevation of monomeric eNAMPT, which induces a diabetic phenotype in pancreatic islets. Strategies to selectively target monomeric eNAMPT could represent promising therapeutic strategies for the treatment of type 2 diabetes.
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Lv, Wu, Jialin Zhang, Ao Jiao, Bowen Wang, Baomin Chen, and Jie Lin. "Resveratrol attenuates hIAPP amyloid formation and restores the insulin secretion ability in hIAPP-INS1 cell line via enhancing autophagy." Canadian Journal of Physiology and Pharmacology 97, no. 2 (February 2019): 82–89. http://dx.doi.org/10.1139/cjpp-2016-0686.
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It has been proved that human islet amyloid polypeptide (hIAPP), the main constituent of islet amyloid deposition, is one of the important factors that can induce type 2 diabetes or graft failure after islet transplantation. As there is no research on whether resveratrol degrading the amyloid deposition by its special chemical structure or enhancing autophagy had been published, we decided to detect the function of resveratrol in degrading the amyloid deposition in pancreatic beta cells. We established stable hIAPP-INS1 cell line via transfecting INS1 cells by lentivirus that overexpresses hIAPP. Our research demonstrates that amyloid deposition existed in hIAPP-INS1 cell by the thioflavin S fluorescent staining, meanwhile the function of insulin secretion of hIAPP-INS1 cells was decreased significantly (p < 0.01). After treatment with resveratrol (20 μM) for 24 h, amyloid deposition in hIAPP-INS1 cells was decreased significantly, and the insulin secretion was restored significantly (p < 0.01). Once inhibited the autophagy of hIAPP-INS1 cells by 3-methyladenine for 24 h, resveratrol does not effectively remove hIAPP deposits again, and cannot improve the function of insulin secretion. These results provide a novel thought that resveratrol can degrade the amyloid deposition in type 2 diabetes and the graft after islet transplantation.
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Chabosseau, Pauline, Guy A. Rutter, and Steven J. Millership. "Importance of Both Imprinted Genes and Functional Heterogeneity in Pancreatic Beta Cells: Is There a Link?" International Journal of Molecular Sciences 22, no. 3 (January 20, 2021): 1000. http://dx.doi.org/10.3390/ijms22031000.
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Diabetes mellitus now affects more than 400 million individuals worldwide, with significant impacts on the lives of those affected and associated socio-economic costs. Although defects in insulin secretion underlie all forms of the disease, the molecular mechanisms which drive them are still poorly understood. Subsets of specialised beta cells have, in recent years, been suggested to play critical roles in “pacing” overall islet activity. The molecular nature of these cells, the means through which their identity is established and the changes which may contribute to their functional demise and “loss of influence” in both type 1 and type 2 diabetes are largely unknown. Genomic imprinting involves the selective silencing of one of the two parental alleles through DNA methylation and modified imprinted gene expression is involved in a number of diseases. Loss of expression, or loss of imprinting, can be shown in mouse models to lead to defects in beta cell function and abnormal insulin secretion. In the present review we survey the evidence that altered expression of imprinted genes contribute to loss of beta cell function, the importance of beta cell heterogeneity in normal and disease states, and hypothesise whether there is a direct link between the two.
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Ohta, Akio, Hiroyuki Kato, Katura Murayama, Eriko Hashimoto, Mariko Murakami, Ami Nishine, Toshihiko Ohshige, et al. "Effect of insulin glargine on endogenous insulin secretion and beta-cell function in Japanese type 2 diabetic patients using oral antidiabetic drugs." Endocrine Journal 61, no. 1 (2014): 13–18. http://dx.doi.org/10.1507/endocrj.ej13-0304.
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Hughes, Alice E., Andrew T. Hattersley, Sarah E. Flanagan, and Rachel M. Freathy. "Two decades since the fetal insulin hypothesis: what have we learned from genetics?" Diabetologia 64, no. 4 (February 11, 2021): 717–26. http://dx.doi.org/10.1007/s00125-021-05386-7.
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AbstractIn 1998 the fetal insulin hypothesis proposed that lower birthweight and adult-onset type 2 diabetes are two phenotypes of the same genotype. Since then, advances in research investigating the role of genetics affecting insulin secretion and action have furthered knowledge of fetal insulin-mediated growth and the biology of type 2 diabetes. In this review, we discuss the historical research context from which the fetal insulin hypothesis originated and consider the position of the hypothesis in light of recent evidence. In summary, there is now ample evidence to support the idea that variants of certain genes which result in impaired pancreatic beta cell function and reduced insulin secretion contribute to both lower birthweight and higher type 2 diabetes risk in later life when inherited by the fetus. There is also evidence to support genetic links between type 2 diabetes secondary to reduced insulin action and lower birthweight but this applies only to loci implicated in body fat distribution and not those influencing insulin resistance via obesity or lipid metabolism by the liver. Finally, we also consider how advances in genetics are being used to explore alternative hypotheses, namely the role of the maternal intrauterine environment, in the relationship between lower birthweight and adult cardiometabolic disease. Graphical abstract