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1
Otani, Kenichi, Rohit N. Kulkarni, Aaron C. Baldwin, Jan Krutzfeldt, Kohjiro Ueki, Markus Stoffel, C. Ronald Kahn, and Kenneth S. Polonsky. "Reduced β-cell mass and altered glucose sensing impair insulin-secretory function in βIRKO mice." American Journal of Physiology-Endocrinology and Metabolism 286, no. 1 (January 2004): E41—E49. http://dx.doi.org/10.1152/ajpendo.00533.2001.
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Pancreatic β-cell-restricted knockout of the insulin receptor results in hyperglycemia due to impaired insulin secretion, suggesting that this cell is an important target of insulin action. The present studies were undertaken in β-cell insulin receptor knockout (βIRKO) mice to define the mechanisms underlying the defect in insulin secretion. On the basis of responses to intraperitoneal glucose, ∼7-mo-old βIRKO mice were either diabetic (25%) or normally glucose tolerant (75%). Total insulin content was profoundly reduced in pancreata of mutant mice compared with controls. Both groups also exhibited reduced β-cell mass and islet number. However, insulin mRNA and protein were similar in islets of diabetic and normoglycemic βIRKO mice compared with controls. Insulin secretion in response to insulin secretagogues from the isolated perfused pancreas was markedly reduced in the diabetic βIRKOs and to a lesser degree in the nondiabetic βIRKO group. Pancreatic islets of nondiabetic βIRKO animals also exhibited defects in glyceraldehyde- and KCl-stimulated insulin release that were milder than in the diabetic animals. Gene expression analysis of islets revealed a modest reduction of GLUT2 and glucokinase gene expression in both the nondiabetic and diabetic mutants. Taken together, these data indicate that loss of functional receptors for insulin in β-cells leads primarily to profound defects in postnatal β-cell growth. In addition, altered glucose sensing may also contribute to defective insulin secretion in mutant animals that develop diabetes.
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Norris, Nicholas, Belinda Yau, and Melkam Alamerew Kebede. "Isolation and Proteomics of the Insulin Secretory Granule." Metabolites 11, no. 5 (April 30, 2021): 288. http://dx.doi.org/10.3390/metabo11050288.
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Insulin, a vital hormone for glucose homeostasis is produced by pancreatic beta-cells and when secreted, stimulates the uptake and storage of glucose from the blood. In the pancreas, insulin is stored in vesicles termed insulin secretory granules (ISGs). In Type 2 diabetes (T2D), defects in insulin action results in peripheral insulin resistance and beta-cell compensation, ultimately leading to dysfunctional ISG production and secretion. ISGs are functionally dynamic and many proteins present either on the membrane or in the lumen of the ISG may modulate and affect different stages of ISG trafficking and secretion. Previously, studies have identified few ISG proteins and more recently, proteomics analyses of purified ISGs have uncovered potential novel ISG proteins. This review summarizes the proteins identified in the current ISG proteomes from rat insulinoma INS-1 and INS-1E cell lines. Here, we also discuss techniques of ISG isolation and purification, its challenges and potential future directions.
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Byrne, M. M., J. Sturis, R. J. Sobel, and K. S. Polonsky. "Elevated plasma glucose 2 h postchallenge predicts defects in beta-cell function." American Journal of Physiology-Endocrinology and Metabolism 270, no. 4 (April 1, 1996): E572—E579. http://dx.doi.org/10.1152/ajpendo.1996.270.4.e572.
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Studies were performed in subjects with no known family history of diabetes, normoglycemic subjects who have first-degree relatives with non-insulin-dependent diabetes mellitus (NIDDM), and subjects with nondiagnostic oral glucose tolerance tests (NDX) or impaired glucose tolerance (IGT). Insulin sensitivity index (SI) was similar in all four groups. However, a number of defects in insulin secretion were seen in the NDX and IGT groups, including reduced first-phase insulin secretory responses in intravenous glucose in relation to the degree of insulin resistance, and reduced normalized spectral power of insulin secretion during oscillatory glucose infusion. The latter finding demonstrates a decreased ability of the beta-cell to detect and respond to the successive increases and decreases in glucose and therefore to be entrained by the exogenous glucose infusion. The ability of a low-dose glucose infusion to prime the insulin secretory response to a subsequent glucose stimulus was normal in subjects with IGT but reduced or absent in subjects with overt NIDDM. These studies demonstrate that a number of alterations in beta-cell function are detectable in nondiabetic first-degree relatives of subjects with NIDDM with mild elevations in the 2-h postchallenge glucose level, and these abnormalities antedate the onset of overt hyperglycemia and clinical diabetes.
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Flatt, P. R., and B. D. Green. "Nutrient regulation of pancreatic β-cell function in diabetes: problems and potential solutions." Biochemical Society Transactions 34, no. 5 (October 1, 2006): 774–78. http://dx.doi.org/10.1042/bst0340774.
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Increasing prevalence of obesity combined with longevity will produce an epidemic of Type 2 (non-insulin-dependent) diabetes in the next 20 years. This disease is associated with defects in insulin secretion, specifically abnormalities of insulin secretory kinetics and pancreatic β-cell glucose responsiveness. Mechanisms underlying β-cell dysfunction include glucose toxicity, lipotoxicity and β-cell hyperactivity. Defects at various sites in β-cell signal transduction pathways contribute, but no single lesion can account for the common form of Type 2 diabetes. Recent studies highlight diverse β-cell actions of GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide). These intestinal hormones target the β-cell to stimulate glucose-dependent insulin secretion through activation of protein kinase A and associated pathways. Both increase gene expression and proinsulin biosynthesis, protect against apoptosis and stimulate replication/neogenesis of β-cells. Incretin hormones therefore represent an exciting future multi-action solution to correct β-cell defect in Type 2 diabetes.
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Sturis, J., W. L. Pugh, J. Tang, and K. S. Polonsky. "Prevention of diabetes does not completely prevent insulin secretory defects in the ZDF rat." American Journal of Physiology-Endocrinology and Metabolism 269, no. 4 (October 1, 1995): E786—E792. http://dx.doi.org/10.1152/ajpendo.1995.269.4.e786.
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The rapid insulin secretory pulses that occur in the perfused rat pancreas can be entrained by an oscillatory glucose concentration in pancreata from nondiabetic rats but not from X diabetic Zucker diabetic fatty (ZDF) rats. To investigate whether this defect is present in prediabetic ZDF rats and whether treatment with either pioglitazone or acarbose can prevent or reverse this defect, 39 ZDF and 5 lean ZDF control rats were studied. The ZDF rats were divided into six groups depending on age, form of therapy used, and the time at which pioglitazone was started in relation to the onset of diabetes. The pancreas was isolated and perfused using a sine wave-shaped glucose concentration (mean 7 mM, period 10 min, amplitude 10%). The results, assessed by spectral analysis, revealed that in prediabetic animals and in controls, entrainment of pulsatile insulin secretion was normal. Initiation of pioglitazone therapy in ZDF rats at the time of weaning or before diabetes onset prevented hyperglycemia. However, entrainment was only partially retained. Thus, in these two groups, the spectral power at 10 min was greater than in untreated animals but lower than in prediabetic and control animals. Treatment with acarbose before or with pioglitazone after diabetes onset improved but did not normalize glucose levels, and it did not improve entrainment. The results demonstrate the presence of insulin secretory defects in 13-wk-old ZDF rats in which hyperglycemia was prevented.
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Okura, Tsuyoshi, Etsuko Ueta, Risa Nakamura, Yohei Fujioka, Keisuke Sumi, Kazuhisa Matsumoto, Kyoko Shoji, et al. "High Serum Advanced Glycation End Products Are Associated with Decreased Insulin Secretion in Patients with Type 2 Diabetes: A Brief Report." Journal of Diabetes Research 2017 (2017): 1–7. http://dx.doi.org/10.1155/2017/5139750.
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Objective. Advanced glycation end products (AGEs) are important in the pathophysiology of type 2 diabetes mellitus (T2DM). They directly cause insulin secretory defects in animal and cell culture models and may promote insulin resistance in nondiabetic subjects. We have developed a highly sensitive liquid chromatography-tandem mass spectrometry method for measuring AGEs in human serum. Here, we use this method to investigate the relationship between AGEs and insulin secretion and resistance in patients with T2DM. Methods. Our study involved 15 participants with T2DM not on medication and 20 nondiabetic healthy participants. We measured the AGE carboxyethyllysine (CEL), carboxymethyllysine (CML), and methyl-glyoxal-hydro-imidazolone (MG-H1). Plasma glucose and insulin were measured in these participants during a meal tolerance test, and the glucose disposal rate was measured during a euglycemic-hyperinsulinemic clamp. Results. CML and CEL levels were significantly higher in T2DM than non-DM participants. CML showed a significant negative correlation with insulin secretion, HOMA-%B, and a significant positive correlation with the insulin sensitivity index in T2DM participants. There was no correlation between any of the AGEs measured and glucose disposal rate. Conclusions. These results suggest that AGE might play a role in the development or prediction of insulin secretory defects in type 2 diabetes.
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Gerich, John E. "Contributions of Insulin-Resistance and Insulin-Secretory Defects to the Pathogenesis of Type 2 Diabetes Mellitus." Mayo Clinic Proceedings 78, no. 4 (April 2003): 447–56. http://dx.doi.org/10.4065/78.4.447.
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Štrbák, Vladimír. "Pancreatic Thyrotropin Releasing Hormone and Mechanism of Insulin Secretion." Cellular Physiology and Biochemistry 50, no. 1 (2018): 378–84. http://dx.doi.org/10.1159/000494013.
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Thyrotropin releasing hormone (TRH; pGlu-His-ProNH2) is expressed also in pancreatic β cells where it is colocalized in secretory granules with insulin. High perinatal changes of the TRH gene expression and TRH concentrations in rat pancreatic islets coincide with the perinatal maturation of the adequate insulin secretory responsiveness to glucose and other nutrient secretagogues. TRH secretion from pancreatic islets is stimulated by glucose and inhibited by insulin. Disruption of the TRH gene in knockout mice results in hyperglycemia accompanied by impaired insulin secretory response to glucose. Progress in understanding TRH - insulin relations may be substantial for improving knowledge of pathophysiological mechanisms included in changes of insulin secretion with possible clinical impact. Block of the last step of biosynthesis of α-amidated peptides, including TRH by disulfiram (DS) treatment of adult male rats subcutaneously with 200 mg/kg for five days in our experiments resulted in barely detectable levels of peptidyl-glycine α-amidating monooxygenase (PAM) in their pancreatic islets. TRH in physiological concentration (1 nM) does not affect basal insulin secretion from intact rat pancreatic islets. In contrast, basal insulin secretion from islets of DS-treated rats is four times higher compared to controls and could not be further stimulated by high-glucose. The addition of 1 nM TRH into medium decreased immediately basal insulin secretion in DS (TRH lacking) islets to control level and normalized also their response to glucose. Interestingly, absence of the secretory response to glucose in islets from TRH depleted rats was connected with their increase of insulin content during stimulation. Glucose stimulation together with 1 nM TRH normalized also insulin content in DS islets. Apparently, high insulin content in islets from TRH depleted animals is a result of block of regulatory secretion pathway redirected to constitutional secretion which was corrected by the addition of TRH. Type 2 diabetes mellitus is a disease characterized by various range from predominant insulin resistance with relative insulin deficiency to a predominant secretory defect with insulin resistance. These symptoms suggest a possible role of TRH dysregulation. In conclusion, presence of TRH in β cells ensures appropriate low basal (constitutive) insulin secretion. Release of TRH induced by glucose and possibly by other secretagogues has autocrine effect resulting in directing insulin secretion to regulatory pathway reacting to stimulation. If some defects of insulin secretion could be treated by TRH, various ways of applications (also oral and nasal) could be utilized. Moreover, positive side effects shown in animal experiments may accompany the treatment: TRH has the potential to prevent apoptosis and promotes insulin-producing cell proliferation and has also aging-reversing properties.
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Nguyen, Tuyet Thi, Xianglan Quan, Kyu-Hee Hwang, Shanhua Xu, Ranjan Das, Seong-Kyung Choi, Andreas Wiederkehr, Claes B. Wollheim, Seung-Kuy Cha, and Kyu-Sang Park. "Mitochondrial oxidative stress mediates high-phosphate-induced secretory defects and apoptosis in insulin-secreting cells." American Journal of Physiology-Endocrinology and Metabolism 308, no. 11 (June 1, 2015): E933—E941. http://dx.doi.org/10.1152/ajpendo.00009.2015.
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Inorganic phosphate (P i) plays an important role in cell signaling and energy metabolism. In insulin-releasing cells, P i transport into mitochondria is essential for the generation of ATP, a signaling factor in metabolism-secretion coupling. Elevated P i concentrations, however, can have toxic effects in various cell types. The underlying molecular mechanisms are poorly understood. Here, we have investigated the effect of P i on secretory function and apoptosis in INS-1E clonal β-cells and rat pancreatic islets. Elevated extracellular P i (1∼5 mM) increased the mitochondrial membrane potential (ΔΨm), superoxide generation, caspase activation, and cell death. Depolarization of the ΔΨm abolished P i-induced superoxide generation. Butylmalonate, a nonselective blocker of mitochondrial phosphate transporters, prevented ΔΨm hyperpolarization, superoxide generation, and cytotoxicity caused by P i. High P i also promoted the opening of the mitochondrial permeability transition (PT) pore, leading to apoptosis, which was also prevented by butylmalonate. The mitochondrial antioxidants mitoTEMPO or MnTBAP prevented P i-triggered PT pore opening and cytotoxicity. Elevated extracellular P i diminished ATP synthesis, cytosolic Ca2+ oscillations, and insulin content and secretion in INS-1E cells as well as in dispersed islet cells. These parameters were restored following preincubation with mitochondrial antioxidants. This treatment also prevented high-P i-induced phosphorylation of ER stress proteins. We propose that elevated extracellular P i causes mitochondrial oxidative stress linked to mitochondrial hyperpolarization. Such stress results in reduced insulin content and defective insulin secretion and cytotoxicity. Our data explain the decreased insulin content and secretion observed under hyperphosphatemic states.
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Alcarraz‐Vizán, Gema, Paola Casini, Lisa Cadavez, Montse Visa, Joel Montane, Joan‐Marc Servitja, and Anna Novials. "Inhibition of BACE2 counteracts hIAPP‐induced insulin secretory defects in pancreatic β‐cells." FASEB Journal 29, no. 1 (October 23, 2014): 95–104. http://dx.doi.org/10.1096/fj.14-255489.
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Colombo, Carla, Gianfranco Alicandro, Simone Gambazza, Palmiro Mileto, Andrea Mari, Eleonora Grespan, Erica Nazzari, Maria Chiara Russo, and Alberto Battezzati. "Ventilation inhomogeneity is associated with OGTT-derived insulin secretory defects in cystic fibrosis." Pediatric Pulmonology 54, no. 2 (December 21, 2018): 141–49. http://dx.doi.org/10.1002/ppul.24212.
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Ehrmann, D. A., J. Sturis, M. M. Byrne, T. Karrison, R. L. Rosenfield, and K. S. Polonsky. "Insulin secretory defects in polycystic ovary syndrome. Relationship to insulin sensitivity and family history of non-insulin-dependent diabetes mellitus." Journal of Clinical Investigation 96, no. 1 (July 1, 1995): 520–27. http://dx.doi.org/10.1172/jci118064.
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Battezzati, A., A. Mari, L. Zazzeron, G. Alicandro, L. Claut, P. M. Battezzati, and C. Colombo. "Identification of insulin secretory defects and insulin resistance during oral glucose tolerance test in a cohort of cystic fibrosis patients." European Journal of Endocrinology 165, no. 1 (July 2011): 69–76. http://dx.doi.org/10.1530/eje-10-1003.
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BackgroundCystic fibrosis (CF)-related diabetes is a leading complication of CF and is associated with pulmonary and nutritional deterioration, years before an evident hyperglycemia, possibly because of insulin deficiency and resistance.AimTo evaluate glucose tolerance, insulin secretion, and insulin sensitivity by a widely applicable method suitable for accurate and prospective measurements in a CF population.MethodsA total of 165 CF subjects (80 females) aged 17±5 years and 18 age- and sex-matched healthy controls (CON) received an oral glucose tolerance test with glucose, insulin and C-peptide determinations. Insulin sensitivity was defined on the basis of glucose and insulin concentrations using the oral glucose insulin sensitivity index, whereas β-cell function was determined on the basis of a model relating insulin secretion (C-peptide profile) to glucose concentration.ResultsFifteen percent of CF patients had glucose intolerance and 6% had diabetes without fasting hyperglycemia and 3% had diabetes with fasting hyperglycemia. β-cell function was reduced in CF patients compared with CON (70.0±4.1 vs 117.9±11.6 pmol/min per m2 per mM, P<0.001) and decreased significantly with age by −2.7 pmol/min per m2 per mM per year (confidence interval (CI) −4.5 to −0.82), i.e. almost 4% yearly. The early insulin secretion index was also reduced. Insulin sensitivity was similar to CON. CF patients who attained glucose tolerance comparable to CON had lower β-cell function and higher insulin sensitivity.ConclusionThe major alteration in insulin secretion and insulin sensitivity of CF patients is slowly declining β-cell function, consisting of delayed and reduced responsiveness to hyperglycemia, that in CF patients with normal glucose tolerance may be compensated by an increased insulin sensitivity.
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Chang, Annette M., and Jeffrey B. Halter. "Aging and insulin secretion." American Journal of Physiology-Endocrinology and Metabolism 284, no. 1 (January 1, 2003): E7—E12. http://dx.doi.org/10.1152/ajpendo.00366.2002.
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Glucose tolerance progressively declines with age, and there is a high prevalence of type 2 diabetes and postchallenge hyperglycemia in the older population. Age-related glucose intolerance in humans is often accompanied by insulin resistance, but circulating insulin levels are similar to those of younger people. Under some conditions of hyperglycemic challenge, insulin levels are lower in older people, suggesting β-cell dysfunction. When insulin sensitivity is controlled for, insulin secretory defects have been consistently demonstrated in aging humans. In addition, β-cell sensitivity to incretin hormones may be decreased with advancing age. Impaired β-cell compensation to age-related insulin resistance may predispose older people to develop postchallenge hyperglycemia and type 2 diabetes. An improved understanding of the metabolic alterations associated with aging is essential for the development of preventive and therapeutic interventions in this population at high risk for glucose intolerance.
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Dieterle, C., M. Veitenhansl, B. Gutt, H. Arbogast, G. Meier, W. D. Illner, A. Schlamp, J. Seissler, and R. Landgraf. "Impaired Glucose Tolerance in Pancreas Grafted Diabetic Patients is Due to Insulin Secretory Defects." Experimental and Clinical Endocrinology & Diabetes 115, no. 10 (November 30, 2007): 647–53. http://dx.doi.org/10.1055/s-2007-982501.
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Perreault, Leigh, Bryan C. Bergman, Mary C. Playdon, Chiara Dalla Man, Claudio Cobelli, and Robert H. Eckel. "Impaired fasting glucose with or without impaired glucose tolerance: progressive or parallel states of prediabetes?" American Journal of Physiology-Endocrinology and Metabolism 295, no. 2 (August 2008): E428—E435. http://dx.doi.org/10.1152/ajpendo.90354.2008.
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Our objective was to determine whether defects underlying impaired fasting glucose (IFG) are maintained and additive when combined with impaired glucose tolerance (IGT) (representing a progressive form of prediabetes) or are distinct in IFG/IGT (reflecting a parallel form of prediabetes). Volunteers with IFG ( n = 10), IFG/IGT ( n = 14), or normal glucose tolerance (NGT; n = 15) were matched for demographics and anthropometry. Insulin secretion was assessed using the glucose step-up protocol and insulin action through the use of a two-stage hyperinsulinemic euglycemic clamp with infusion of [6,6-2H2]glucose. Modeling of insulin secretory parameters revealed similar basal (Φb) but diminished dynamic (Φd) components in both IFG and IFG/IGT ( P = 0.05 vs. NGT for both). Basal glucose rate of appearance (Ra) was higher in IFG compared with NGT ( P < 0.01) and also, surprisingly, with IFG/IGT ( P < 0.04). Moreover, glucose Ra suppressed more during the low-dose insulin clamp in IFG ( P < 0.01 vs. NGT, P = 0.08 vs. IFG/IGT). Insulin-stimulated glucose uptake [glucose rate of disappearance (Rd)] was similar in IFG, IFG/IGT, and NGT throughout the clamp. We conclude that nuances of β-cell dysfunction observed in IFG were also noted in IFG/IGT. A trend for additional insulin secretory defects was observed in IFG/IGT, possibly suggesting progression in β-cell failure in this group. In contrast, basal glucose Ra and its suppressability with insulin were higher in IFG, but not IFG/IGT, compared with NGT. Together, these data indicate that IFG/IGT may be a distinct prediabetic syndrome rather than progression from IFG.
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Axen, K. V., X. Li, K. Fung, and A. Sclafani. "The VMH-dietary obese rat: a new model of non-insulin-dependent diabetes mellitus." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 266, no. 3 (March 1, 1994): R921—R928. http://dx.doi.org/10.1152/ajpregu.1994.266.3.r921.
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A model of non-insulin-dependent diabetes mellitus (NIDDM) has been developed in adult rats by combining bilateral electrolytic lesions of the ventromedial hypothalamus (VMH) and high fat-high sucrose diets. VMH-dietary obese rats showed fasting hyperinsulinemia (> or = 540 pM) and hypertriglyceridemia (> or = 180 mg/dl) generally within 3 wk on the protocol. Fasting hyperglycemia (> or = 10 mM) was observed in the majority of animals in seven consecutive experiments. Hyperglycemic animals showed impaired glucose tolerance despite high prevailing insulin levels. Pancreatic islets isolated from VMH-dietary obese rats showed a loss of insulin secretory response to glucose by week 5, before the onset of hyperglycemia. Islets from hyperglycemic rats no longer responded to an increase in glucose concentration and failed to suppress insulin release normally in response to 15 nM norepinephrine or to a decrease in glucose concentration. This model mimics the major characteristics of obesity-associated human NIDDM as well as several stages of its progression, rendering it useful for studying the etiology of the metabolic and secretory defects in the syndrome.
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Gorogawa, Shin-ichi, Yoshio Fujitani, Hideaki Kaneto, Yoji Hazama, Hirotaka Watada, Yasuhide Miyamoto, Kiyoshi Takeda, et al. "Insulin secretory defects and impaired islet architecture in pancreatic β-cell-specific STAT3 knockout mice." Biochemical and Biophysical Research Communications 319, no. 4 (July 2004): 1159–70. http://dx.doi.org/10.1016/j.bbrc.2004.05.095.
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Hasnin, K., F. Jebunnesa, L. Ali, and Rezaul Karim. "Insulin Secretory Defects and Determinants of Attending at a Tertiary Hospital in Northern Region of Bangladesh." Anwer Khan Modern Medical College Journal 10, no. 2 (November 20, 2019): 131–37. http://dx.doi.org/10.3329/akmmcj.v10i2.44125.
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Background: Bangladesh has one of the largest diabetic populations in the world and its Rajshahi region has distinct geographical and cultural identity. Determinants and basic defects of the disorder which vary substantially among populations due to racial and environmental heterogeneity.
Materials & Methods: This study was conducted to characterize the new patients attending the Rajshahi Diabetic Center which gives an idea about the proportion and risk indicators of DM among people in the Rajshahi region. It was a hospital based observational analytic study with a hybrid research strategy having both cross-sectional and nested case-control designs. A multistage sampling technique was followed with 660 subjects.
Results: Out of the total subjects attending the OPD of RDC for the first time, 65% were found to suffer from T2 DM. mostly (75%) of middle age (37% within 30-40 yrs and 37% within 41-50 yrs), only 2% cases had age <30 yrs and 23% had age >51yrs. The mean ±SD calorie consumption (2549±637) of the diabetic subjects was higher than that in non-T2 DM subjects and it came mainly from CHO (59.3%) and fat (55.9%). 47.3% of subjects were normal weight, 36.1% over weight and 16.6% obese. Fasting serum Insulin was significantly higher in the T2 DM group as compared to non-T2DM (Serum Insulin level µIU/ml, M±SD) (13.5±4.9) subjects (p=<0.001). HOMA%B was (37±17) significantly lower in the T2 DM subjects as compared to non-T2 DM subjects. HOMA%S was (41±13) significantly lower in the T2 DM subjects as compared to non-T2 DM subjects.
Conclusion: Both (HOMA%B) and (IR) constitute the basic defects of diabetes in Rajshahi population, but (HOMA%B) seems to be more predominant in these subjects. (HOMA%B) in Rajshahi population is associated with males and level of education and insulin resistance (IR) is associated with males and daily CHO intake.
Anwer Khan Modern Medical College Journal Vol. 10, No. 2: July 2019, P 131-137
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Roe, M. W., J. F. Worley, Y. Tokuyama, L. H. Philipson, J. Sturis, J. Tang, I. D. Dukes, G. I. Bell, and K. S. Polonsky. "NIDDM is associated with loss of pancreatic beta-cell L-type Ca2+ channel activity." American Journal of Physiology-Endocrinology and Metabolism 270, no. 1 (January 1, 1996): E133—E140. http://dx.doi.org/10.1152/ajpendo.1996.270.1.e133.
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Development of non-insulin-dependent diabetes mellitus (NIDDM) is associated with defects in glucose-stimulated insulin secretion. We have investigated Zucker diabetic fatty rats (ZDF), an animal model of NIDDM, and found that, compared with control islets, the expression of mRNA encoding C- and D-isoforms of alpha 1-subunits of beta-cell L-type voltage-dependent Ca2+ channels (VDCC) was significantly reduced in islets isolated from ZDF rats. This correlated with a substantial reduction of L-type Ca2+ currents (ICa) in ZDF beta-cells. Intracellular Ca2+ concentration responses in ZDF islets after glucose, KCI, or BAY K 8644 stimulation were markedly attenuated, whereas responses evoked by carbachol were unimpaired, consistent with a specific decrease in ICa in the diabetic islets. This reduction was accompanied by loss of pulsatile insulin secretion from ZDF islets treated with oscillatory increases of external glucose concentration. Our findings suggest that the attenuation of ICa in diabetic islets may contribute to the abnormal glucose-dependent insulin secretory responses associated with NIDDM and indicate that this defect is caused by decreased expression of genes encoding beta-cell VDCC alpha 1-subunits.
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Rutter, G. A., A. Varadi, T. Tsuboi, L. Parton, and M. Ravier. "Insulin secretion in health and disease: genomics, proteomics and single vesicle dynamics." Biochemical Society Transactions 34, no. 2 (March 20, 2006): 247–50. http://dx.doi.org/10.1042/bst0340247.
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Defective insulin secretion from pancreatic islet β-cells is a sine qua non of Type II (non-insulin-dependent) diabetes. Digital imaging analysis of the nanomechanics of individual exocytotic events, achieved using total internal reflection fluorescence microscopy, has allowed us to demonstrate that insulin is released via transient or ‘cavicapture’ events whereby the vesicle and plasma membranes fuse transiently and reversibly. Such studies reveal that an increase in the number of abortive fusion events contributes to defective insulin secretion in in vitro models of Type II diabetes. Complementary analyses of genome-wide changes in β-cell gene expression, at both the mRNA and protein levels, are now facilitating the identification of key molecular players whose altered expression may contribute to the secretory defects in the diabetic β-cell.
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Rutter, Guy A., and Elaine V. Hill. "Insulin Vesicle Release: Walk, Kiss, Pause … Then Run." Physiology 21, no. 3 (June 2006): 189–96. http://dx.doi.org/10.1152/physiol.00002.2006.
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The mechanisms by which insulin-containing dense core secretory vesicles approach and finally fuse with the plasma membrane are of considerable current interest: defects in these processes may be one of the contributing factors to Type 2 diabetes. In this review, we discuss the molecular mechanisms involved in vesicle trafficking within the pancreatic β-cell and the mechanisms whereby these may be regulated. We then go on to describe recent evidence that suggests that vesicle fusion at the plasma membrane is a partly reversible process (“kiss and run” or “cavity recapture”). We propose that vesicles may participate in a exo-endocytotic cycle in which a proportion of those that have already undergone an interaction with the plasma membrane may exchange exocytotic machinery with maturing vesicles.
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Salehi, Marzieh, Benedikt A. Aulinger, and David A. D'Alessio. "Targeting β-Cell Mass in Type 2 Diabetes: Promise and Limitations of New Drugs Based on Incretins." Endocrine Reviews 29, no. 3 (February 21, 2008): 367–79. http://dx.doi.org/10.1210/er.2007-0031.
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Abstract Progressive insulin secretory defects, due to either functional abnormalities of the pancreatic β-cells or a reduction in β-cell mass, are the cornerstone of type 2 diabetes. Incretin-based drugs hold the potential to improve glucose tolerance by immediate favorable effect on β-cell physiology as well as by expanding or at least maintaining β-cell mass, which may delay the progression of the disease. Long-term studies in humans are needed to elaborate on these effects.
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Pørksen, Niels, Claus Juhl, Malene Hollingdal, Steve M. Pincus, Jeppe Sturis, Johannes D. Veldhuis, and Ole Schmitz. "Concordant induction of rapid in vivo pulsatile insulin secretion by recurrent punctuated glucose infusions." American Journal of Physiology-Endocrinology and Metabolism 278, no. 1 (January 1, 2000): E162—E170. http://dx.doi.org/10.1152/ajpendo.2000.278.1.e162.
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Insulin is largely secreted as serial secretory bursts superimposed on basal release, insulin secretion is regulated through changes of pulse mass and frequency, and the insulin release pattern affects insulin action. Coordinate insulin release is preserved in the isolated perfused pancreas, suggesting intrapancreatic coordination. However, occurrence of glucose concentration oscillations may influence the process in vivo, as it does for ultradian oscillations. To determine if rapid pulsatile insulin release may be induced by minimal glucose infusions and to define the necessary glucose quantity, we studied six healthy individuals during brief repetitive glucose infusions of 6 and 2 mg ⋅ kg−1⋅ min−1for 1 min every10 min. The higher dose completely synchronized pulsatile insulin release at modest plasma glucose changes (∼0.3 mM = ∼5%), with large (∼100%) amplitude insulin pulses at every single glucose induction ( n = 54) at a lag time of 2 min ( P< 0.05), compared with small (10%) and rare ( n = 3) uninduced insulin excursions. The smaller glucose dose induced insulin pulses at lower significance levels and with considerable breakthrough insulin release. Periodicity shift from either 7- to 12-min or from 12- to 7-min intervals between consecutive glucose (6 mg ⋅ kg−1⋅ min−1) infusions in six volunteers revealed rapid frequency changes. The orderliness of insulin release as estimated by approximate entropy (1.459 ± 0.009 vs. 1.549 ± 0.027, P = 0.016) was significantly improved by glucose pulse induction ( n = 6; 6 mg ⋅ kg−1⋅ min−1) compared with unstimulated insulin profiles ( n = 7). We conclude that rapid in vivo oscillations in glucose may be an important regulator of pulsatile insulin secretion in humans and that the use of an intermittent pulsed glucose induction to evoke defined and recurrent insulin secretory signals may be a useful tool to unveil more subtle defects in β-cell glucose sensitivity.
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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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Eva, Sohely Nazneen, Rahelee Zinnat, Golam Morshed Molla, Muneera Zahir, Fatema Akter, Behterin Rehnuma, and Rukhsana Amin. "Type 2 Diabetes Mellitus is Associated with Lower Serum Adiponectin Level in Bangladeshi Population." Anwer Khan Modern Medical College Journal 6, no. 1 (September 14, 2015): 10–13. http://dx.doi.org/10.3329/akmmcj.v6i1.24978.
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Background: The physiological role of adiponectin is not yet fully clear, but it is now generally accepted that it has a protective role against the development of lifestyle disorders, related to insulin resistance and atherosclerosis. Insulin resistance is one of the basic defects of type 2 diabetes (T2DM) and adiponectin is inversely associated with T2DM. As serum adiponectin level has not yet been investigated in Bangladeshi T2DM subjects,so that the present study has been under taken to find out the association of T2DM with serum adiponectin level in Bangladeshi population.Methodology: In this observational case control study, sixty six (66) T2DM subjects, seventy four (74) healthy control subjects were included. Diabetes was diagnosed and classified as per WHO criteria. Serum Adiponectin was measured by Enzyme Linked Immunosorbent Assay (ELISA) method. Serum glucose was measured by glucose-oxidase method; serum insulin was measured by chemiluminescence-based ELISA technique. The insulin secretory capacity (HOMA%B), insulin sensitivity (HOMA%S) & insulin resistance (HOMA IR) were assayed by homeostasis model assessment method.Results: The study subjects were BMI matched. BMI of the Control subjects and T2DM subjects (Mean±SD) were 25.02±3.55 and 25.85±3.62. Age (year) of the Control subjects and T2DM subjects (Mean±SD) were 42.46±9.24 and 48.49±8.09. Median (range) fasting serum insulin in the control and T2DM was 14.68 (1.86-45.92) and 18.09 (4.10-42.78) respectively which was not statistically significant (p=0.214). Median (range) HOMA%B values in the control and T2DM subjects was 160.10(33.40-493.40) and 100.45(17.70-349.30). Median HOMA%B in the T2DM group was significantly lower compared to the control (p=0.0001). Median (range) HOMA%S values in the control and T2DM subjects was 44.20(9.80- 339.40) and 32.80(14.30-154.70) respectively. Median HOMA%S in the T2DM group was significantly lower compared to the control (p=0.036). Median (range) serum adiponectin (?g/ml) of the control and T2DM subjects was 8.70 (0.76-15.96) and 6.19 (1.13-22.37). Serum adiponectin was significantly lower in T2DM compared to the control (p=0.0001).Conclusions: From this study it may be concluded that, T2DM subjects have both insulin secretory defects and insulin resistance and associated with lower serum adiponectin level in Bangladeshi population.Anwer Khan Modern Medical College Journal Vol. 6, No. 1: January 2015, Pages 10-13
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Kabir, Md Golam, Mosaraf Hossain, Md Omar Faruque, Mohammad Alauddin, and Liaquat Ali. "Association of serum free IGF-1 and IGFBP-1 with insulin sensitivity and insulin secretory defects in Bangladeshi type 2 diabetes mellitus." Journal of Taibah University Medical Sciences 9, no. 2 (June 2014): 132–38. http://dx.doi.org/10.1016/j.jtumed.2013.11.006.
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Swisa, Avital, Zvi Granot, Natalia Tamarina, Sophie Sayers, Nabeel Bardeesy, Louis Philipson, David J. Hodson, et al. "Loss of Liver Kinase B1 (LKB1) in Beta Cells Enhances Glucose-stimulated Insulin Secretion Despite Profound Mitochondrial Defects." Journal of Biological Chemistry 290, no. 34 (July 2, 2015): 20934–46. http://dx.doi.org/10.1074/jbc.m115.639237.
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The tumor suppressor liver kinase B1 (LKB1) is an important regulator of pancreatic β cell biology. LKB1-dependent phosphorylation of distinct AMPK (adenosine monophosphate-activated protein kinase) family members determines proper β cell polarity and restricts β cell size, total β cell mass, and glucose-stimulated insulin secretion (GSIS). However, the full spectrum of LKB1 effects and the mechanisms involved in the secretory phenotype remain incompletely understood. We report here that in the absence of LKB1 in β cells, GSIS is dramatically and persistently improved. The enhancement is seen both in vivo and in vitro and cannot be explained by altered cell polarity, increased β cell number, or increased insulin content. Increased secretion does require membrane depolarization and calcium influx but appears to rely mostly on a distal step in the secretion pathway. Surprisingly, enhanced GSIS is seen despite profound defects in mitochondrial structure and function in LKB1-deficient β cells, expected to greatly diminish insulin secretion via the classic triggering pathway. Thus LKB1 is essential for mitochondrial homeostasis in β cells and in parallel is a powerful negative regulator of insulin secretion. This study shows that β cells can be manipulated to enhance GSIS to supra-normal levels even in the face of defective mitochondria and without deterioration over months.
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Kulkarni, R. N. "Receptors for insulin and insulin-like growth factor-1 and insulin receptor substrate-1 mediate pathways that regulate islet function." Biochemical Society Transactions 30, no. 2 (April 1, 2002): 317–22. http://dx.doi.org/10.1042/bst0300317.
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The insulin/insulin-like growth factor-1 (IGF-1) signalling pathways are present in most mammalian cells and play important roles in the growth and metabolism of tissues. Most proteins in these pathways have also been identified in the β-cells of the pancreatic islets. Tissue-specific knockout of the insulin receptor (βIRKO) or IGF-1 receptor (βIGFRKO) in pancreatic β-cells leads to altered glucose-sensing and glucose intolerance in adult mice, and βIRKO mice show an age-dependent decrease in islet size and β-cell mass. These data indicate that these receptors are important for differentiated function and are unlikely to play a major role in the early growth and/or development of the pancreatic islets. Conventional insulin receptor substrate-1 (IRS-1) knockouts manifest growth retardation and mild insulin resistance. The IRS-1 knockouts also display islet hyperplasia, defects in insulin secretory responses to multiple stimuli both in vivo and in vitro, reduced islet insulin content and an increased number of autophagic vacuoles in the β-cells. Re-expression of IRS-1 in cultured β-cells is able to partially restore the insulin content indicating that IRS-1 is involved in the regulation of insulin synthesis. Taken together, these data provide evidence that insulin and IGF-1 receptors and IRS-1, and potentially other proteins in the insulin/IGF-1 signalling pathway, contribute to the regulation of islet hormone secretion and synthesis and therefore in the maintenance of glucose homeostasis.
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Fakruddin, Md. "Genetics of Type 2 Diabetes: A Review." Journal of Current and Advance Medical Research 6, no. 1 (March 27, 2019): 59–63. http://dx.doi.org/10.3329/jcamr.v6i1.40787.
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Diabetes Mellitus (DM), one of the most non-communicable diseases, is increasing day by day in an alarming way. More than 140 million people are suffering from diabetes throughout the world. It is not a single disease entity, but rather a group of metabolic disorders sharing the common underlying feature of hyperglycemia. Hyperglycemia in diabetes results from defects in insulin secretion, insulin action, or, most commonly, both. The chronic hyperglycemia and attendant metabolic deregulation may be associated with secondary damage in multiple organ systems, especially the kidneys, eyes, nerves, and blood vessels. The pathophysiology of diabetes is not fully elucidated. Insulin secretory dysfunction and insulin resistance or both is main candidate for this metabolic disorder, moreover various genetic and environmental factors may also involve in this process. Racial variations play also an important role as evidenced by various studies. However, the interrelationships between the molecular and metabolic mechanisms in these parameters contributing this life threatening disease still remain a mystery to the scientists.
Journal of Current and Advance Medical Research 2019;6(1):59-63
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Mari, Andrea, Amalia Gastaldelli, Andrea Natali, Torben Ostergard, Ole Schmitz, and Ele Ferrannini. "Characterization of β-cell function impairment in first-degree relatives of type 2 diabetic subjects: modeling analysis of 24-h triple-meal tests." American Journal of Physiology-Endocrinology and Metabolism 288, no. 3 (March 2005): E541—E546. http://dx.doi.org/10.1152/ajpendo.00175.2004.
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To investigate early secretory defects in prediabetes, we evaluated β-Cell function and insulin sensitivity (M value, by euglycemic clamp) in 26 normotolerant first-degree relatives of type 2 diabetic patients (FDR) and 17 age- and weight-matched control subjects. β-Cell function was assessed by modeling analysis of glucose and C-peptide concentrations measured during 24 h of standardized living conditions. Fasting and total insulin secretion (ISR) were increased in FDR, as was ISR at a reference 5 mM glucose level (ISR5, 107 ± 6 vs. 87 ± 6 pmol· min−1·m−2, P < 0.05). ISR5 was inversely related to M in controls (ISR5 = k/M1.23, ρ = −0.74, P < 0.005) but not in FDR; when M was accounted for (by calculating a compensation index ISR5·M1.23), compensation for insulin resistance was impaired in FDR (10.8 ± 1.0 vs. 13.4 ± 0.6 units, P < 0.05). Potentiation of ISR, expressing relative transient increases in glucose-stimulated ISR during meals, was impaired in FDR (1.29 ± 0.08 vs. 1.62 ± 0.08 during 1st meal, P < 0.02). Moreover, the potentiation time course was related to glucose-dependent insulin-releasing polypeptide (GIP) concentrations in both groups, and the sensitivity of potentiation to GIP derived from this relationship tended to be impaired in FDR. Compensation index, potentiation, and sensitivity to GIP were interrelated parameters ( P < 0.05 or less). β-Cell function parameters were also related to mean 24-h glucose levels ( r2 = 0.63, P < 0.0001, multivariate model). In conclusion, although in absolute terms ISR is increased in insulin-resistant FDR, β-cell function shows a cluster of interrelated abnormalities involving compensation for insulin resistance, potentiation, and sensitivity to GIP, suggesting a β-cell defect in the amplifying pathway of insulin secretion.
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Eva, SN, GM Mollah, DK Sunyal, and R. Zinnat. "Type 2 diabetes mellitus is associated with lower serum adiponectin level in Bangladeshi population." Mediscope 2, no. 2 (October 23, 2015): 16–21. http://dx.doi.org/10.3329/mediscope.v2i2.25405.
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The aim of the observational case control study was to find out the association of type 2 diabetes mellitus (T2DM) with serum adiponectin level in Bangladeshi population. This was conducted in the Biomedical Research Group, Research Division, Bangladesh Institute of Research and Rehabilitation in Diabetes, Endocrine and Metabolic Disorders (BIRDEM), Dhaka, Bangladesh. Sixty six T2DM subjects and seventy four healthy control subjects were included. Diabetes was diagnosed and classified as per World Health Organization criteria. Serum adiponectin was measured by Enzyme Linked Immunosorbent Assay (ELISA) method. Serum glucose was measured by glucose-oxidase method; serum insulin was measured by chemiluminescence- based ELISA technique. The insulin secretory capacity (HOMA%B), insulin sensitivity (HOMA%S) & insulin resistance (HOMA-IR) were assayed by homeostasis model assessment method. Statistical analysis was performed using SPSS Windows version 11.5. The median (range) fasting serum insulin of control and T2DM subjects were 14.7 (1.9-45.9) and 18.1 (4.1-42.8), respectively. The median (range) serum adiponectin (?g/ml) of the control and T2DM subjects were 8.7 (0.8-16.0) and 6.2 (1.1-22.4). The serum adiponectin of T2DM was significantly lower than the control subjects (p < 0.001). The median (range) HOMA%B values of control and T2DM subjects were 160.1 (33.4-493.4) and 100.5 (17.7-349.3), respectively. The median HOMA%B of T2DM subjects was significantly lower than the control subjects (p < 0.001). The median (range) HOMA%S values of control and T2DM subjects were 44.2 (9.8-339.4) and 32.8 (14.3-154.7), respectively. The median HOMA%S of T2DM group was significantly lower than the control subjects (p < 0.05). The median (range) HOMA-IR of control and T2DM subjects were 3.5 (0.5-11.4) and 5.8 (1.0-28.3), respectively. The median HOMA-IR of T2DM subjects was significantly higher than the control subjects (p < 0.001). The results of the study suggest that T2DM subjects have both insulin secretory defects, insulin resistance and associated with lower serum adiponectin level in Bangladeshi population.Mediscope Vol. 2, No. 2: July 2015, Pages 16-21
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Chamberlain, L. H., M. E. Graham, S. Kane, J. L. Jackson, V. H. Maier, R. D. Burgoyne, and G. W. Gould. "The synaptic vesicle protein, cysteine-string protein, is associated with the plasma membrane in 3T3-L1 adipocytes and interacts with syntaxin 4." Journal of Cell Science 114, no. 2 (January 15, 2001): 445–55. http://dx.doi.org/10.1242/jcs.114.2.445.
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Adipocytes and muscle cells play a major role in blood glucose homeostasis. This is dependent upon the expression of Glut4, an insulin-responsive facilitative glucose transporter. Glut4 is localised to specialised intracellular vesicles that fuse with the plasma membrane in response to insulin stimulation. The insulin-induced translocation of Glut4 to the cell surface is essential for the maintenance of optimal blood glucose levels, and defects in this system are associated with insulin resistance and type II diabetes. Therefore, a major focus of recent research has been to identify and characterise proteins that regulate Glut4 translocation. Cysteine-string protein (Csp) is a secretory vesicle protein that functions in presynaptic neurotransmission and also in regulated exocytosis from non-neuronal cells. We show that Csp1 is expressed in 3T3-L1 adipocytes and that cellular levels of this protein are increased following cell differentiation. Combined fractionation and immunofluorescence analyses reveal that Csp1 is not a component of intracellular Glut4-storage vesicles (GSVs), but is associated with the adipocyte plasma membrane. This association is stable, and not affected by either insulin stimulation or chemical depalmitoylation of Csp1. We also demonstrate that Csp1 interacts with the t-SNARE syntaxin 4. As syntaxin 4 is an important mediator of insulin-stimulated GSV fusion with the plasma membrane, this suggests that Csp1 may play a regulatory role in this process. Syntaxin 4 interacts specifically with Csp1, but not with Csp2. In contrast, syntaxin 1A binds to both Csp isoforms, and actually exhibits a higher affinity for the Csp2 protein. The results described raise a number of interesting questions concerning the intracellular targeting of Csp in different cell types, and suggest that the composition and synthesis of GSVs may be different from synaptic and other secretory vesicles. In addition, the interaction of Csp1 with syntaxin 4 suggests that this Csp isoform may play a role in insulin-stimulated fusion of GSVs with the plasma membrane.
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Leahy, Jack L., and Mark S. Fineman. "Impaired phasic insulin and amylin secretion in diabetic rats." American Journal of Physiology-Endocrinology and Metabolism 275, no. 3 (September 1, 1998): E457—E462. http://dx.doi.org/10.1152/ajpendo.1998.275.3.e457.
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We have proposed that a hyperstimulated insulin secretion causing β-cell degranulation is the basis for the impaired glucose-potentiated insulin secretion in type 2 diabetes (“overworked β-cell”). To confirm this idea, we previously investigated tolbutamide-infused euglycemic rats. Two novel kinds of β-cell dysfunction were observed: altered phasic glucose-potentiated insulin secretion with preferential sparing of the first phase and a raised secreted ratio of amylin to insulin. The current study tested these parameters in 90% (intact β-cell insulin stores) and 95% (markedly lowered insulin stores) pancreatectomized (Px) diabetic rats. Rats underwent pancreas perfusion 5–6 wk postsurgery. Controls showed nonchanging insulin secretion during a 20-min perfusion of 16.7 mM glucose + 10 mM arginine. In contrast, both Px groups showed an altered phasic pattern, with the first phase being supernormal (for the β-cell mass) but the second phase reduced in tandem with the insulin content. Amylin secretion from control and 90% Px rats paralleled the insulin output, so that the amylin-to-insulin ratio averaged 0.12 ± 0.03% in the controls and 0.16 ± 0.01% in the 90% Px rats over the two secretory phases. In contrast, the amylin-to-insulin ratio in 95% Px rats equaled that of controls during the first phase (0.12 ± 0.1%) but was twice normal during the second phase (0.32 ± 0.4%). These results confirm the validity of the overworked β-cell schema by showing identical β-cell functional defects in Px rats and tolbutamide-infused normoglycemic rats.
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Morin, L., M. H. Giroix, M. N. Gangnerau, D. Bailbe, and B. Portha. "Impaired phosphoinositide metabolism in glucose-incompetent islets of neonatally streptozotocin-diabetic rats." American Journal of Physiology-Endocrinology and Metabolism 272, no. 5 (May 1, 1997): E737—E745. http://dx.doi.org/10.1152/ajpendo.1997.272.5.e737.
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The effects of nutrient and neurotransmitter stimuli on insulin release, loss of phosphoinositides (PI), and production of inositol phosphates (InsP) were investigated in islets from neonatally streptozotocin-injected (nSTZ) rats. In islets from nSTZ rats, insulin secretory responses to 16.7 mM D-glucose and 10.0 mM D-glyceraldehyde were reduced compared with controls. Contents in phosphatidylinositol 4-monophosphate [PtdIns(4)P] and phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2], but not in phosphatidylinositol, were diminished. Glucose effects on breakdown of PtdIns(4)P and PtdIns(4,5)P2 and on total InsP accumulation were both reduced. D-Glucose was unable to increase the levels of both inositol trisphosphate isomers, Ins(1,3,4)P3 and Ins(1,4,5)P3. Glyceraldehyde also failed to promote InsP formation. By contrast, the ability of 1.0 mM carbachol or 300 nM cholecystokinin to stimulate insulin secretion and InsP generation was still observed. Thus a disturbed coupling between nutrient recognition and activation of phospholipase C, possibly together with a shortage of available polyphosphoinositides, could be responsible for the altered islet PI turnover in the nSTZ rats. It is proposed that such defects may contribute to the impairment of glucose-stimulated insulin secretion in this model of non-insulin-dependent diabetes mellitus.
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Kalwat, Michael A., In Hyun Hwang, Jocelyn Macho, Magdalena G. Grzemska, Jonathan Z. Yang, Kathleen McGlynn, John B. MacMillan, and Melanie H. Cobb. "Chromomycin A2 potently inhibits glucose-stimulated insulin secretion from pancreatic β cells." Journal of General Physiology 150, no. 12 (October 23, 2018): 1747–57. http://dx.doi.org/10.1085/jgp.201812177.
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Modulators of insulin secretion could be used to treat diabetes and as tools to investigate β cell regulatory pathways in order to increase our understanding of pancreatic islet function. Toward this goal, we previously used an insulin-linked luciferase that is cosecreted with insulin in MIN6 β cells to perform a high-throughput screen of natural products for chronic effects on glucose-stimulated insulin secretion. In this study, using multiple phenotypic analyses, we found that one of the top natural product hits, chromomycin A2 (CMA2), potently inhibited insulin secretion by at least three potential mechanisms: disruption of Wnt signaling, interference of β cell gene expression, and partial suppression of Ca2+ influx. Chronic treatment with CMA2 largely ablated glucose-stimulated insulin secretion even after washout, but it did not inhibit glucose-stimulated generation of ATP or Ca2+ influx. However, by using the KATP channel opener diazoxide, we uncovered defects in depolarization-induced Ca2+ influx that may contribute to the suppressed secretory response. Glucose-responsive ERK1/2 and S6 phosphorylation were also disrupted by chronic CMA2 treatment. By querying the FUSION bioinformatic database, we revealed that the phenotypic effects of CMA2 cluster with a number of Wnt–GSK3 pathway-related genes. Furthermore, CMA2 consistently decreased GSK3β phosphorylation and suppressed activation of a β-catenin activity reporter. CMA2 and a related compound, mithramycin, are known to have DNA interaction properties, possibly abrogating transcription factor binding to critical β cell gene promoters. We observed that CMA2 but not mithramycin suppressed expression of PDX1 and UCN3. However, neither expression of INSI/II nor insulin content was affected by chronic CMA2. The mechanisms of CMA2-induced insulin secretion defects may involve components both proximal and distal to Ca2+ influx. Therefore, CMA2 is an example of a chemical that can simultaneously disrupt β cell function through both noncytotoxic and cytotoxic mechanisms. Future therapeutic applications of CMA2 and similar aureolic acid analogues should consider their potential effects on pancreatic islet function.
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Jia, Dong Mei, Akinari Tabaru, Hayato Nakamura, Ken-Ichiro Fukumitsu, Toshiharu Akiyama, and Makoto Otsuki. "Troglitazone prevents and reverses dyslipidemia, insulin secretory defects, and histologic abnormalities in a rat model of naturally occurring obese diabetes." Metabolism 49, no. 9 (September 2000): 1167–75. http://dx.doi.org/10.1053/meta.2000.8599.
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Misler, Stanley. "Unifying concepts in stimulus-secretion coupling in endocrine cells and some implications for therapeutics." Advances in Physiology Education 33, no. 3 (September 2009): 175–86. http://dx.doi.org/10.1152/advan.90213.2008.
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Stimulus-secretion coupling (SSC) in endocrine cells remains underappreciated as a subject for the study/teaching of general physiology. In the present article, we review key new electrophysiological, electrochemical, and fluorescence optical techniques for the study of exocytosis in single cells that have made this a fertile area for recent research. Based on findings using these techniques, we developed a model of SSC for adrenal chromaffin cells that blends features of Ca2+ entry-dependent SSC (characteristic of neurons) with G protein receptor-coupled, Ca2+ release-dependent, and second messenger-dependent SSC (characteristic of epithelial exocrine cells and nucleated blood cells). This model requires two distinct pools of secretory graunules with differing Ca2+ sensitivities. We extended this model to account for SSC in a wide variety of peripheral and hypothalamic/pituitary-based endocrine cells. These include osmosensitive magnocellular neurosecretory cells releasing antidiuretic hormone, stretch-sensitive atrial myocytes secreting atrial natriuretic peptide, K+-sensitive adrenal glomerulosa cells secreting aldosterone, Ca2+-sensitive parathyroid chief cells secreting parathyroid hormone, and glucose-sensitive β- and α-cells of pancreatic islets secreting insulin and glucagon, respectively. We conclude this article with implications of this approach for pathophysiology and therapeutics, including defects in chief cell Ca2+ sensitivity, resulting in the hyperparathyroidism of renal disease, and defects in biphasic insulin secretion, resulting in diabetes mellitus.
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Curtis, S. B., and A. M. J. Buchan. "Proinsulin mRNA and peptide are present in β-cells of diabetic BB rats." Canadian Journal of Physiology and Pharmacology 73, no. 1 (January 1, 1995): 92–97. http://dx.doi.org/10.1139/y95-013.
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Previous studies have demonstrated that islets isolated from newly diabetic BB rat pancreata retain the ability to release insulin in culture, although in vivo the insulin response to stimulation is absent. The purpose of this study was to determine whether the β-cells in these newly diabetic animals were releasing stored insulin or whether they were still capable of insulin biosynthesis, since secretory defects may reflect abnormalities in insulin synthetic capacity. Insulin gene transcription was examined using in situ hybridization to detect preproinsulin mRNA (ppImRNA) at the level of the single cell since this technique provides a valid semiquantitative index of insulin biosynthesis. In situ hybridization with digoxigenin-labeled rat insulin probes resulted in strong labeling of β-cells in normal Wistar rat pancreata; other islet and acinar cells were negative. Double labeling of sections with an antibody to insulin confirmed that the labeled cells were β-cells only. The intensity of the staining was variable between different islets within the same section, and sometimes within an islet. Nondiabetic and diabetic BB islets were also positive for ppImRNA not only in normal islets but also in islets affected by insulitis. Islets that contained very few β-cells also contained ppImRNA. A consistent finding was that the intensity of the hybridization signal in many islets from the diabetic BB rats was stronger than in controls, suggesting that there is more ppImRNA in these islets. β-Cells that were positive for ppImRNA but negative for insulin peptide were also observed; these were in islets that were affected by insulitis. These results indicate that insulin biosynthesis was still present in islets of diabetic animals; therefore, a lack of insulin gene expression was not involved in the loss of glucose-stimulated insulin secretion.Key words: BB rat, in situ hybridization, preproinsulin mRNA.
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Zhang, Peichuan, Barbara McGrath, Sheng'ai Li, Ami Frank, Frank Zambito, Jamie Reinert, Maureen Gannon, Kun Ma, Kelly McNaughton, and Douglas R. Cavener. "The PERK Eukaryotic Initiation Factor 2α Kinase Is Required for the Development of the Skeletal System, Postnatal Growth, and the Function and Viability of the Pancreas." Molecular and Cellular Biology 22, no. 11 (June 1, 2002): 3864–74. http://dx.doi.org/10.1128/mcb.22.11.3864-3874.2002.
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ABSTRACT Phosphorylation of eukaryotic initiation factor 2α (eIF-2α) is typically associated with stress responses and causes a reduction in protein synthesis. However, we found high phosphorylated eIF-2α (eIF-2α[P]) levels in nonstressed pancreata of mice. Administration of glucose stimulated a rapid dephosphorylation of eIF-2α. Among the four eIF-2α kinases present in mammals, PERK is most highly expressed in the pancreas, suggesting that it may be responsible for the high eIF-2α[P] levels found therein. We describe a Perk knockout mutation in mice. Pancreata of Perk−/− mice are morphologically and functionally normal at birth, but the islets of Langerhans progressively degenerate, resulting in loss of insulin-secreting beta cells and development of diabetes mellitus, followed later by loss of glucagon-secreting alpha cells. The exocrine pancreas exhibits a reduction in the synthesis of several major digestive enzymes and succumbs to massive apoptosis after the fourth postnatal week. Perk−/− mice also exhibit skeletal dysplasias at birth and postnatal growth retardation. Skeletal defects include deficient mineralization, osteoporosis, and abnormal compact bone development. The skeletal and pancreatic defects are associated with defects in the rough endoplasmic reticulum of the major secretory cells that comprise the skeletal system and pancreas. The skeletal, pancreatic, and growth defects are similar to those seen in human Wolcott-Rallison syndrome.
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Delghingaro-Augusto, Viviane, Simon Décary, Marie-Line Peyot, Martin G. Latour, Julien Lamontagne, Nicolas Paradis-Isler, Marianne Lacharité-Lemieux, et al. "Voluntary running exercise prevents β-cell failure in susceptible islets of the Zucker diabetic fatty rat." American Journal of Physiology-Endocrinology and Metabolism 302, no. 2 (January 15, 2012): E254—E264. http://dx.doi.org/10.1152/ajpendo.00360.2011.
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Physical activity improves glycemic control in type 2 diabetes (T2D), but its contribution to preserving β-cell function is uncertain. We evaluated the role of physical activity on β-cell secretory function and glycerolipid/fatty acid (GL/FA) cycling in male Zucker diabetic fatty (ZDF) rats. Six-week-old ZDF rats engaged in voluntary running for 6 wk (ZDF-A). Inactive Zucker lean and ZDF (ZDF-I) rats served as controls. ZDF-I rats displayed progressive hyperglycemia with β-cell failure evidenced by falling insulinemia and reduced insulin secretion to oral glucose. Isolated ZDF-I rat islets showed reduced glucose-stimulated insulin secretion expressed per islet and per islet protein. They were also characterized by loss of the glucose regulation of fatty acid oxidation and GL/FA cycling, reduced mRNA expression of key β-cell genes, and severe reduction of insulin stores. Physical activity prevented diabetes in ZDF rats through sustaining β-cell compensation to insulin resistance shown in vivo and in vitro. Surprisingly, ZDF-A islets had persistent defects in fatty acid oxidation, GL/FA cycling, and β-cell gene expression. ZDF-A islets, however, had preserved islet insulin mRNA and insulin stores compared with ZDF-I rats. Physical activity did not prevent hyperphagia, dyslipidemia, or obesity in ZDF rats. In conclusion, islets of ZDF rats have a susceptibility to failure that is possibly due to altered β-cell fatty acid metabolism. Depletion of pancreatic islet insulin stores is a major contributor to islet failure in this T2D model, preventable by physical activity.
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Wilson, M. R., and S. J. Hughes. "The effect of maternal protein deficiency during pregnancy and lactation on glucose tolerance and pancreatic islet function in adult rat offspring." Journal of Endocrinology 154, no. 1 (July 1997): 177–85. http://dx.doi.org/10.1677/joe.0.1540177.
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Abstract To test the hypothesis that poor foetal–neonatal nutrition predisposes adult animals to impaired glucose tolerance or diabetes, pregnant and lactating rats were fed a low (5%) protein diet and glucose tolerance and pancreatic islet function then assessed in the adult offspring. To expose any underlying defects the offspring were allowed access to a sucrose supplement (35%) or fed a high fat diet. Offspring born to low protein-fed females had significantly lower body weights than controls. In islets from previously malnourished rats, insulin release in batch incubations or perifusion was not significantly different to controls. In islets from previously malnourished animals fed sucrose, glucose-stimulated insulin release was reduced in perifusion by 66% (P<0·01) and batch incubations by 26–52% (6–16 mmol/l glucose, (P<0·01). Similarly, impaired secretory responses were found in islets from previously malnourished animals fed a high fat diet. These did not result from a reduced pool of releasable insulin, as arginine-stimulated secretion was not impaired. Rats previously malnourished showed a normal glucose tolerance. Glucose tolerance was impaired, however, in previously malnourished rats fed sucrose (area under the glucose tolerance test curve was increased by 42%, P<0·05) but despite the reduced islet secretory responses was not significantly different to sucrose-fed controls (area increased by 54%, P<0·05). Glucose tolerance was impaired in previously malnourished animals fed high fat diet (area increased by 48%, P<0·05) more so than in high fat fed-controls (28% increase, NS). These data support the hypothesis that poor foetal–neonatal nutrition leads to impaired pancreatic β-cell function which persists into adult life. Alone this is not sufficient to produce diabetes, but an inability to respond to a highly palatable fat diet may tip the balance towards impaired glucose tolerance. Journal of Endocrinology (1997) 154, 177–185
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Parton, Laura E., Patrick J. McMillen, Yingnian Shen, Elizabeth Docherty, Erin Sharpe, Frédérique Diraison, Celia P. Briscoe, and Guy A. Rutter. "Limited role for SREBP-1c in defective glucose-induced insulin secretion from Zucker diabetic fatty rat islets: a functional and gene profiling analysis." American Journal of Physiology-Endocrinology and Metabolism 291, no. 5 (November 2006): E982—E994. http://dx.doi.org/10.1152/ajpendo.00067.2006.
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Accumulation of intracellular lipid may contribute to defective insulin secretion in type 2 diabetes. Although Zucker diabetic fatty (ZDF; fa/fa) rat islets are fat-laden and overexpress the lipogenic master gene, sterol regulatory element binding protein 1c (SREBP-1c), the contribution of SREBP-1c to the secretory defects observed in this model remains unclear. Here we compare the gene expression profile of lean control ( fa/+) and ZDF rat islets in the absence or presence of dominant-negative SREBP-1c (SREBP-1c DN). ZDF islets displayed elevated basal insulin secretion at 3 mmol/l glucose but a severely depressed response to 17 mmol/l glucose. While SREBP-1c DN reduced basal insulin secretion from ZDF islets, glucose-stimulated insulin secretion was not improved. Of 57 genes differentially regulated in ZDF islets and implicated in glucose metabolism, vesicle trafficking, ion fluxes, and/or exocytosis, 21 were upregulated and 5 were suppressed by SREBP-1c DN. Genes underrepresented in ZDF islets were either unaffected ( Glut-2, Kir6.2, Rab3), stimulated (voltage-dependent Ca2+ channel subunit α1D, CPT2, SUR2, rab9, syt13), or inhibited ( syntaxin 7, secretogranin-2) by SREBP-1c inhibition. Correspondingly, SREBP-1c DN largely corrected decreases in the expression of the transcription factors Pdx-1 and MafA but did not affect the abnormalities in Pax6, Arx, hepatic nuclear factor-1α (HNF1α), HNF3β/Forkhead box-a2 (Foxa2), inducible cyclic AMP early repressor (ICER), or transcription factor 7-like 2 (TCF7L2) expression observed in ZDF islets. We conclude that upregulation of SREBP-1c and mild increases in triglyceride content do not explain defective glucose-stimulated insulin secretion from ZDF rats. However, overexpression of SREBP-1c may contribute to enhanced basal insulin secretion in this model.
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Jia, Dongmei, Masashi Taguchi, and Makoto Otsuki. "Synthetic protease inhibitor camostat prevents and reverses dyslipidemia, insulin secretory defects, and histological abnormalities of the pancreas in genetically obese and diabetic rats." Metabolism 54, no. 5 (May 2005): 619–27. http://dx.doi.org/10.1016/j.metabol.2004.12.005.
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Vauhkonen, Ilkka, Leo Niskanen, Mikael Knip, Leena Moilanen Mykkänen, Steven Haffner, Matti Uusitupa, and Markku Laakso. "Subtle hyperproinsulinaemia characterises the defective insulin secretory capacity in offspring of glutamic acid decarboxylase antibody-positive patients with latent autoimmune diabetes mellitus in adults." European Journal of Endocrinology 153, no. 2 (August 2005): 265–73. http://dx.doi.org/10.1530/eje.1.01972.
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Objective: We set out to assess whether hyperproinsulinaemia is an early finding in latent autoimmune diabetes in adults (LADA). Research design and methods: We measured plasma proinsulin and C-peptide responses during a 2-h oral glucose tolerance test (OGTT) and in the hyperglycaemic clamp in 21 normoglycaemic offspring of LADA patients testing positive for glutamic acid decarboxylase antibodies (GADA) or islet cell antibodies (ICA), and in 17 healthy control subjects without a family history of diabetes. Results: The study groups had comparable areas under the curves of blood glucose, plasma proinsulin, C-peptide and proinsulin/C-peptide in the OGTT. However, the offspring of LADA patients had higher proinsulin/C-peptide in the hyperglycaemic clamp (P < 0.01 versus the control group). The offspring of GADA-positive LADA patients (n = 9) had higher proinsulin and proinsulin/C-peptide than did the control group in the OGTT (P < 0.05 for both comparisons) and in the hyperglycaemic clamp (P < 0.001 and P < 0.05 respectively). They also had higher proinsulin than the offspring of ICA-positive LADA patients (n = 12) (P < 0.001) in the hyperglycaemic clamp. The offspring of ICA-positive LADA patients did not clearly show hyperproinsulinaemia during the tests, but they had lower maximal glucose-stimulated insulin secretory capacity than the control group (P < 0.05) and the offspring of GADA-positive LADA patients (P < 0.05) in the hyperglycaemic clamp. Conclusions: These results suggested that insulin secretion in the offspring of GADA-positive LADA patients is characterised by subtle defects in the processing of insulin precursors. Furthermore, various proinsulin responses among the offspring of LADA patients with different autoimmune markers provided further evidence that LADA is a heterogeneous disorder.
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Chen, Jianguo, Per Bendix Jeppesen, Iver Nordentoft, and Kjeld Hermansen. "Stevioside improves pancreatic β-cell function during glucotoxicity via regulation of acetyl-CoA carboxylase." American Journal of Physiology-Endocrinology and Metabolism 292, no. 6 (June 2007): E1906—E1916. http://dx.doi.org/10.1152/ajpendo.00356.2006.
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Chronic hyperglycemia is detrimental to pancreatic β-cells, causing impaired insulin secretion and β-cell turnover. The characteristic secretory defects are increased basal insulin secretion (BIS) and a selective loss of glucose-stimulated insulin secretion (GSIS). Several recent studies support the view that the acetyl-CoA carboxylase (ACC) plays a pivotal role for GSIS. We have shown that stevioside (SVS) enhances insulin secretion and ACC gene expression. Whether glucotoxicity influences ACC and whether this action can be counteracted by SVS are not known. To investigate this, we exposed isolated mouse islets as well as clonal INS-1E β-cells for 48 h to 27 or 16.7 mM glucose, respectively. We found that 48-h exposure to high glucose impairs GSIS from mouse islets and INS-1E cells, an effect that is partly counteracted by SVS. The ACC dephosphorylation inhibitor okadaic acid (OKA, 10−8 M), and 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR, 10−4 M), an activator of 5′-AMP protein kinase that phosphorylates ACC, eliminated the beneficial effect of SVS. 5-Tetrade-cyloxy-2-furancarboxylic acid (TOFA), the specific ACC inhibitor, blocked the effect of SVS as well. During glucotoxity, ACC gene expression, ACC protein, and phosphorylated ACC protein were increased in INS-1E β-cells. SVS pretreatment further increased ACC gene expression with strikingly elevated ACC activity and increased glucose uptake accompanied by enhanced GSIS. Our studies show that glucose is a potent stimulator of ACC and that SVS to some extent counteracts glucotoxicity via increased ACC activity. SVS possesses the potential to alleviate negative effects of glucotoxicity in β-cells via a unique mechanism of action.
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Tang, Kechun, Teresa Pasqua, Angshuman Biswas, Sumana Mahata, Jennifer Tang, Alisa Tang, Gautam K. Bandyopadhyay, et al. "Muscle injury, impaired muscle function and insulin resistance in Chromogranin A-knockout mice." Journal of Endocrinology 232, no. 2 (February 2017): 137–53. http://dx.doi.org/10.1530/joe-16-0370.
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Chromogranin A (CgA) is widely expressed in endocrine and neuroendocrine tissues as well as in the central nervous system. We observed CgA expression (mRNA and protein) in the gastrocnemius (GAS) muscle and found that performance of CgA-deficient Chga-KO mice in treadmill exercise was impaired. Supplementation with CgA in Chga-KO mice restored exercise ability suggesting a novel role for endogenous CgA in skeletal muscle function. Chga-KO mice display (i) lack of exercise-induced stimulation of pAKT, pTBC1D1 and phospho-p38 kinase signaling, (ii) loss of GAS muscle mass, (iii) extensive formation of tubular aggregates (TA), (iv) disorganized cristae architecture in mitochondria, (v) increased expression of the inflammatory cytokines Tnfα, Il6 and Ifnγ, and fibrosis. The impaired maximum running speed and endurance in the treadmill exercise in Chga-KO mice correlated with decreased glucose uptake and glycolysis, defects in glucose oxidation and decreased mitochondrial cytochrome C oxidase activity. The lack of adaptation to endurance training correlated with the lack of stimulation of p38MAPK that is known to mediate the response to tissue damage. As CgA sorts proteins to the regulated secretory pathway, we speculate that lack of CgA could cause misfolding of membrane proteins inducing aggregation of sarcoplasmic reticulum (SR) membranes and formation of tubular aggregates that is observed in Chga-KO mice. In conclusion, CgA deficiency renders the muscle energy deficient, impairs performance in treadmill exercise and prevents regeneration after exercise-induced tissue damage.
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Chen, Pei-Chun, Erik M. Olson, Qing Zhou, Yelena Kryukova, Heidi M. Sampson, David Y. Thomas, and Show-Ling Shyng. "Carbamazepine as a Novel Small Molecule Corrector of Trafficking-impaired ATP-sensitive Potassium Channels Identified in Congenital Hyperinsulinism." Journal of Biological Chemistry 288, no. 29 (June 6, 2013): 20942–54. http://dx.doi.org/10.1074/jbc.m113.470948.
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ATP-sensitive potassium (KATP) channels consisting of sulfonylurea receptor 1 (SUR1) and the potassium channel Kir6.2 play a key role in insulin secretion by coupling metabolic signals to β-cell membrane potential. Mutations in SUR1 and Kir6.2 that impair channel trafficking to the cell surface lead to loss of channel function and congenital hyperinsulinism. We report that carbamazepine, an anticonvulsant, corrects the trafficking defects of mutant KATP channels previously identified in congenital hyperinsulinism. Strikingly, of the 19 SUR1 mutations examined, only those located in the first transmembrane domain of SUR1 responded to the drug. We show that unlike that reported for several other protein misfolding diseases, carbamazepine did not correct KATP channel trafficking defects by activating autophagy; rather, it directly improved the biogenesis efficiency of mutant channels along the secretory pathway. In addition to its effect on channel trafficking, carbamazepine also inhibited KATP channel activity. Upon subsequent removal of carbamazepine, however, the function of rescued channels was recovered. Importantly, combination of the KATP channel opener diazoxide and carbamazepine led to enhanced mutant channel function without carbamazepine washout. The corrector effect of carbamazepine on mutant KATP channels was also demonstrated in rat and human β-cells with an accompanying increase in channel activity. Our findings identify carbamazepine as a novel small molecule corrector that may be used to restore KATP channel expression and function in a subset of congenital hyperinsulinism patients.
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Roma, L. P., S. M. Pascal, J. Duprez, and J. C. Jonas. "Mitochondrial oxidative stress contributes differently to rat pancreatic islet cell apoptosis and insulin secretory defects after prolonged culture in a low non-stimulating glucose concentration." Diabetologia 55, no. 8 (May 29, 2012): 2226–37. http://dx.doi.org/10.1007/s00125-012-2581-6.
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Dalan, Rinkoo, Stefan R. Bornstein, Ali El-Armouche, Roman N. Rodionov, Alexander Markov, Ben Wielockx, Felix Beuschlein, and Bernhard O. Boehm. "The ACE-2 in COVID-19: Foe or Friend?" Hormone and Metabolic Research 52, no. 05 (April 27, 2020): 257–63. http://dx.doi.org/10.1055/a-1155-0501.
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AbstractCOVID-19 is a rapidly spreading outbreak globally. Emerging evidence demonstrates that older individuals and people with underlying metabolic conditions of diabetes mellitus, hypertension, and hyperlipidemia are at higher risk of morbidity and mortality. The SARS-CoV-2 infects humans through the angiotensin converting enzyme (ACE-2) receptor. The ACE-2 receptor is a part of the dual system renin-angiotensin-system (RAS) consisting of ACE-Ang-II-AT1R axis and ACE-2-Ang-(1–7)-Mas axis. In metabolic disorders and with increased age, it is known that there is an upregulation of ACE-Ang-II-AT1R axis with a downregulation of ACE-2-Ang-(1–7)-Mas axis. The activated ACE-Ang-II-AT1R axis leads to pro-inflammatory and pro-fibrotic effects in respiratory system, vascular dysfunction, myocardial fibrosis, nephropathy, and insulin secretory defects with increased insulin resistance. On the other hand, the ACE-2-Ang-(1–7)-Mas axis has anti-inflammatory and antifibrotic effects on the respiratory system and anti-inflammatory, antioxidative stress, and protective effects on vascular function, protects against myocardial fibrosis, nephropathy, pancreatitis, and insulin resistance. In effect, the balance between these two axes may determine the prognosis. The already strained ACE-2-Ang-(1–7)-Mas in metabolic disorders is further stressed due to the use of the ACE-2 by the virus for entry, which affects the prognosis in terms of respiratory compromise. Further evidence needs to be gathered on whether modulation of the renin angiotensin system would be advantageous due to upregulation of Mas activation or harmful due to the concomitant ACE-2 receptor upregulation in the acute management of COVID-19.