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Ishibashi C, Yoneda S, Fujita Y, Fujita S, Mitsushio K, Ozawa H, Baden MY, Nammo T, Kozawa J, Eguchi H, Shimomura I. Decreased islet amyloid polypeptide staining in the islets of insulinoma patients. Islets 2024; 16:2379650. [PMID: 39028826 PMCID: PMC11262209 DOI: 10.1080/19382014.2024.2379650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 05/28/2024] [Accepted: 07/09/2024] [Indexed: 07/21/2024] Open
Abstract
Islet amyloid polypeptide (IAPP) is a factor that regulates food intake and is secreted from both pancreatic islets and insulinoma cells. Here, we aimed to evaluate IAPP immunohistochemically in islets or insulinoma cells in association with clinical characteristics. We recruited six insulinoma patients and six body mass index-matched control patients with pancreatic diseases other than insulinoma whose glucose tolerance was confirmed to be normal preoperatively. IAPP and IAPP-insulin double staining were performed on pancreatic surgical specimens. We observed that the IAPP staining level and percentage of IAPP-positive beta cells tended to be lower (p = 0.1699) in the islets of insulinoma patients than in those of control patients, which might represent a novel IAPP expression pattern under persistent hyperinsulinemia and hypoglycemia.
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Affiliation(s)
- Chisaki Ishibashi
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Sho Yoneda
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Japan
- Yoneda Clinic, Osaka, Japan
| | - Yukari Fujita
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Shingo Fujita
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Kento Mitsushio
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Harutoshi Ozawa
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Japan
- Department of Lifestyle Medicine, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Megu Y Baden
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Japan
- Department of Lifestyle Medicine, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Takao Nammo
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Junji Kozawa
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Japan
- Department of Diabetes Care Medicine, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Iichiro Shimomura
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Japan
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Khudiakova AD, Polonskaya YV, Shramko VS, Shcherbakova LV, Garbuzova EV, Kashtanova EV, Ragino YI. Associations of Adipocytokines with The Development of Cardiovascular Events in Young People. J Pers Med 2023; 13:1582. [PMID: 38003897 PMCID: PMC10672268 DOI: 10.3390/jpm13111582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 10/30/2023] [Accepted: 11/03/2023] [Indexed: 11/26/2023] Open
Abstract
The research was aimed to study the associations of adipocytokines with the risk of cardiovascular events and to determine the threshold values of adipocytes for the prognosis of cardiovascular events in a young population. MATERIALS AND METHODS The study is an epidemiological cohort study. The analysis included 1240 people aged 25-44 years. The endpoint was combined and included: death from cardiovascular disease, myocardial infarction, probable myocardial infarction, acute cerebrovascular accident, hospitalization for cardiovascular disease, and revascularization. Adipocytokines were determined with a MILLIPLEX panel. RESULTS In the examined population, 1.7% of cases of cardiovascular events were detected during cohort observation, of which 28.6% were fatal events. In men, cardiovascular endpoints were recorded 4.3 times more often than in women (17 (81%) vs. 4 (19%), p = 0.003). In individuals with cardiovascular events, arterial hypertension (2.6 times), diabetes mellitus (8.6 times), and overweight/obesity (1.5 times) were more often recorded compared to individuals without cardiovascular events. For tumor necrosis factor-alpha (TNFa), the threshold value was 2.5 pg/mL, with sensitivity assessment (Se) at 85.7% and specificity (Sp) at 83.3%. For amylin, the threshold value was 10.5 pg/mL, with Se at 73.7% and Sp at 67.0%. For pancreatic polypeptide (PP), the threshold value was 43.7 pg/mL, with Se at 85.7% and Sp at 56.7%. CONCLUSION A method for assessing the risk of cardiovascular events in young people includes determining the levels of amylin, PP, and TNFa in blood serum. The cut-off points for predicting cardiovascular events were levels of amylin above 10.5 pg/mL, PP above 43.7 pg/mL, or a decrease in TNFa below 3.8 pg/mL.
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Affiliation(s)
- Alena D. Khudiakova
- Research Institute of Internal and Preventive Medicine—Branch of the Federal Research Center Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (IIPM—Branch of the IC&G SB RAS), st. B.Bogatkova 175/1, 630089 Novosibirsk, Russia; (Y.V.P.); (V.S.S.); (L.V.S.); (E.V.G.); (E.V.K.); (Y.I.R.)
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Association of Islet Amyloid Polypeptide to C-Peptide Ratio With Cystic Fibrosis-Related Diabetes: A Prospective Cross-sectional Study. Pancreas 2022; 51:1029-1036. [PMID: 36607950 DOI: 10.1097/mpa.0000000000002134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
OBJECTIVES Early detection of cystic fibrosis (CF) related diabetes (CFRD) improves health outcomes and reduces CF-related mortality. The study aims to evaluate the ratio of islet amyloid polypeptide (IAPP) to C-peptide in CF patients with diabetes and without diabetes. METHODS Cross-sectional analysis was carried out in a prospective cohort of 33 participants (CF [n = 16] and CFRD [n = 18]). We examined the association of plasma IAPP:C-peptide ratio with clinical information, including glycated hemoglobin, and lung function markers. RESULTS The median (interquartile range) IAPP:C-peptide ratio was significantly (P = 0.004) higher in people with CFRD (4.8 [4.5]) compared with participants without CFRD (12.1 [19.7]). The ratio of IAPP to C-peptide significantly accounted for a 38% variation in the diabetes status in patients with CF (r2 = 0.399, P < 0.001). Islet amyloid polypeptide is strongly correlated with serum ferritin levels (r = 0.683, P = 0.005) and forced expiratory volume in CFRD, but not in nondiabetic participants with CF. CONCLUSIONS Islet amyloid polypeptide:C-peptide ratio could be a potential marker of CFRD in adults with CF. Further research requires validation of this marker in longitudinal cohort studies to confirm the capability of IAPP:C-peptide to predict CFRD.
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Mizukami H, Kudoh K. Diversity of pathophysiology in type 2 diabetes shown by islet pathology. J Diabetes Investig 2021; 13:6-13. [PMID: 34562302 PMCID: PMC8756316 DOI: 10.1111/jdi.13679] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 09/19/2021] [Indexed: 12/18/2022] Open
Abstract
The etiology of type 2 diabetes is multifactorial, in which environmental and genetic factors are involved to varying degrees. This suggests that its pathophysiology might vary depending on the individuals. Knowledge of the differences is critical, because these differences are directly linked to the care and treatment of the patients. Recent studies have attempted to carry out subclassifications of type 2 diabetes based on clinical and genetic differences. However, there is no pathological evidence to support these subclassifications. The pathophysiology of type 2 diabetes is generally divided into insulin resistance in peripheral tissues and pancreatic islet dysfunction. Among them, islet dysfunction causes a deficit in insulin secretion from β-cells. In particular, a deficit in insulin secretion is ascribed to a combination of disruption of the insulin secretory machinery and a decrease in β-cell volume in type 2 diabetes. Recent research has suggested that transdifferentiation and dedifferentiation are involved in the decrease in β-cell volume, and that it might change dynamically depending on the glucose metabolic state. However, it is possible that the numbers of islet cells are decreased in type 2 diabetes. In particular, the loss of endocrine cells due to islet amyloid deposits is an important pathological change in type 2 diabetes in humans. These results show that pathological changes of the islets can be different in each individuals with type 2 diabetes and reflect each pathophysiology, which is useful in establishing further subclassifications and developing tailor-made therapies for type 2 diabetes.
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Affiliation(s)
- Hiroki Mizukami
- Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Kazuhiro Kudoh
- Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
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Rahman I, Athar MT, Islam M. Type 2 Diabetes, Obesity, and Cancer Share Some Common and Critical Pathways. Front Oncol 2021; 10:600824. [PMID: 33552973 PMCID: PMC7855858 DOI: 10.3389/fonc.2020.600824] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 11/24/2020] [Indexed: 12/13/2022] Open
Abstract
Diabetes and cancer are among the most frequent and complex diseases. Epidemiological evidence showed that the patients suffering from diabetes are significantly at higher risk for a number of cancer types. There are a number of evidence that support the hypothesis that these diseases are interlinked, and obesity may aggravate the risk(s) of type 2 diabetes and cancer. Multi-level unwanted alterations such as (epi-)genetic alterations, changes at the transcriptional level, and altered signaling pathways (receptor, cytoplasmic, and nuclear level) are the major source which promotes a number of complex diseases and such heterogeneous level of complexities are considered as the major barrier in the development of therapeutic agents. With so many known challenges, it is critical to understand the relationships and the commonly shared causes between type 2 diabetes and cancer, which is difficult to unravel and understand. Furthermore, the real complexity arises from contended corroborations that specific drug(s) (individually or in combination) during the treatment of type 2 diabetes may increase or decrease the cancer risk or affect cancer prognosis. In this review article, we have presented the recent and most updated evidence from the studies where the origin, biological background, the correlation between them have been presented or proved. Furthermore, we have summarized the methodological challenges and tasks that are frequently encountered. We have also outlined the physiological links between type 2 diabetes and cancers. Finally, we have presented and summarized the outline of the hallmarks for both these diseases, diabetes and cancer.
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Affiliation(s)
- Ishrat Rahman
- Department of Basic Dental Sciences, College of Dentistry, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
| | - Md Tanwir Athar
- Scientific Research Center, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
| | - Mozaffarul Islam
- Scientific Research Center, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
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Ling W, Huang YM, Qiao YC, Zhang XX, Zhao HL. Human Amylin: From Pathology to Physiology and Pharmacology. Curr Protein Pept Sci 2019; 20:944-957. [DOI: 10.2174/1389203720666190328111833] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 03/12/2019] [Accepted: 03/15/2019] [Indexed: 12/18/2022]
Abstract
The histopathological hallmark of type 2 diabetes is islet amyloid implicated in the developing treatment options. The major component of human islet amyloid is 37 amino acid peptide known as amylin or islet amyloid polypeptide (IAPP). Amylin is an important hormone that is co-localized, copackaged, and co-secreted with insulin from islet β cells. Physiologically, amylin regulates glucose homeostasis by inhibiting insulin and glucagon secretion. Furthermore, amylin modulates satiety and inhibits gastric emptying via the central nervous system. Normally, human IAPP is soluble and natively unfolded in its monomeric state. Pathologically, human IAPP has a propensity to form oligomers and aggregate. The oligomers show misfolded α-helix conformation and can further convert themselves to β-sheet-rich fibrils as amyloid deposits. The pathological findings and physiological functions of amylin have led to the introduction of pramlintide, an amylin analog, for the treatment of diabetes. The history of amylin’s discovery is a representative example of how a pathological finding can translate into physiological exploration and lead to pharmacological intervention. Understanding the importance of transitioning from pathology to physiology and pharmacology can provide novel insight into diabetes mellitus and Alzheimer's disease.
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Affiliation(s)
- Wei Ling
- Center for Diabetic Systems Medicine, Guangxi Key Laboratory of Excellence, Guilin Medical University, Guilin 541004, China
| | - Yan-Mei Huang
- Center for Diabetic Systems Medicine, Guangxi Key Laboratory of Excellence, Guilin Medical University, Guilin 541004, China
| | - Yong-Chao Qiao
- Department of Laboratory, the Affiliated Hospital of Guilin Medical University, Guilin 541004, China
| | - Xiao-Xi Zhang
- Center for Diabetic Systems Medicine, Guangxi Key Laboratory of Excellence, Guilin Medical University, Guilin 541004, China
| | - Hai-Lu Zhao
- Center for Diabetic Systems Medicine, Guangxi Key Laboratory of Excellence, Guilin Medical University, Guilin 541004, China
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Affiliation(s)
- Jian Yang
- Department of Nutrition, Daping Hospital, The Third Military Medical University, Chongqing, China.,Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China
| | - Pedro A Jose
- Division of Renal Disease & Hypertension, The George Washington University School of Medicine and Health Sciences, Washington, DC
| | - Chunyu Zeng
- Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China
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Brunetti L, Di Nisio C, Orlando G, Ferrante C, Vacca M. The Regulation of Feeding: A Cross Talk between Peripheral and Central Signalling. Int J Immunopathol Pharmacol 2016; 18:201-12. [PMID: 15888244 DOI: 10.1177/039463200501800203] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Feeding and energy expenditures are modulated by the interplay of hormones and neurotransmitters in the central nervous system (CNS), where the hypothalamus plays a pivotal role in the transduction of peripheral afferents into satiety and feeding signals. Aminergic neurotransmitters such as dopamine (DA), norepinephrine (NE) and serotonin (5-hydroxytryptamine, 5-HT) are historically considered to play a key role, but a number of peptides are involved in finely tuning feeding regulation. This review summarizes the current understanding of the CNS mechanisms of orexigenic peptides, such as neuropeptide Y, orexins, and ghrelin, as well as anorectic peptides, such as leptin, neurotensin (NT), cocaine- and amphetamine regulated transcript (CART) peptide, thyrotropin-releasing hormone (TRH), corticotropin-releasing hormone (CRH), urocortin, amylin.
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Affiliation(s)
- L Brunetti
- Department of Drug Sciences, G. D'Annunzio University, Chieti, Italy
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9
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Zhang XX, Pan YH, Huang YM, Zhao HL. Neuroendocrine hormone amylin in diabetes. World J Diabetes 2016; 7:189-97. [PMID: 27162583 PMCID: PMC4856891 DOI: 10.4239/wjd.v7.i9.189] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Revised: 03/16/2016] [Accepted: 04/05/2016] [Indexed: 02/05/2023] Open
Abstract
The neuroendocrine hormone amylin, also known as islet amyloid polypeptide, is co-localized, co-packaged and co-secreted with insulin from adult pancreatic islet β cells to maintain glucose homeostasis. Specifically, amylin reduces secretion of nutrient-stimulated glucagon, regulates blood pressure with an effect on renin-angiotensin system, and delays gastric emptying. The physiological actions of human amylin attribute to the conformational α-helix monomers whereas the misfolding instable oligomers may be detrimental to the islet β cells and further transform to β-sheet fibrils as amyloid deposits. No direct evidence proves that the amylin fibrils in amyloid deposits cause diabetes. Here we also have performed a systematic review of human amylin gene changes and reported the S20G mutation is minor in the development of diabetes. In addition to the metabolic effects, human amylin may modulate autoimmunity and innate inflammation through regulatory T cells to impact on both human type 1 and type 2 diabetes.
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Fernandes-Santos C, Zhang Z, Morgan DA, Guo DF, Russo AF, Rahmouni K. Amylin acts in the central nervous system to increase sympathetic nerve activity. Endocrinology 2013; 154:2481-8. [PMID: 23645151 PMCID: PMC3689285 DOI: 10.1210/en.2012-2172] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The pancreatic hormone amylin acts in the central nervous system (CNS) to decrease food intake and body weight. We hypothesized that amylin action in the CNS promotes energy expenditure by increasing the activity of the sympathetic nervous system. In mice, ip administration of amylin significantly increased c-Fos immunoreactivity in hypothalamic and brainstem nuclei. In addition, mice treated with intracerebroventricular (icv) amylin (0.1 and 0.2 nmol) exhibited a dose-related decrease in food intake and body weight, measured 4 and 24 hours after treatment. The icv injection of amylin also increased body temperature in mice. Using direct multifiber sympathetic nerve recording, we found that icv amylin elicited a significant and dose-dependent increase in sympathetic nerve activity (SNA) subserving thermogenic brown adipose tissue (BAT). Of note, icv injection of amylin also evoked a significant and dose-related increase in lumbar and renal SNA. Importantly, icv pretreatment with the amylin receptor antagonist AC187 (20 nmol) abolished the BAT SNA response induced by icv amylin, indicating that the sympathetic effects of amylin are receptor-mediated. Conversely, icv amylin-induced BAT SNA response was enhanced in mice overexpressing the amylin receptor subunit, RAMP1 (receptor-activity modifying protein 1), in the CNS. Our data demonstrate that CNS action of amylin regulates sympathetic nerve outflow to peripheral tissues involved in energy balance and cardiovascular function.
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Affiliation(s)
- Caroline Fernandes-Santos
- Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
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12
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Gutiérrez-Rojas I, Lozano D, Nuche-Berenguer B, Moreno P, Acitores A, Ramos-Álvarez I, Rovira A, Novials A, Martín-Crespo E, Villanueva-Peñacarrillo ML, Esbrit P. Amylin exerts osteogenic actions with different efficacy depending on the diabetic status. Mol Cell Endocrinol 2013. [PMID: 23178165 DOI: 10.1016/j.mce.2012.11.013] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Amylin displays osteogenic features, but its role in diabetic osteopenia is unclear. We examined the possible osteogenic action of amylin infusion for 3days into fructose-induced insulin-resistant (IR) and streptozotocin-induced type 2 diabetic (T2D) and normal (N) rats. Amylin failed to affect glycaemia or parathyroid hormone levels in any group, but reduced hyperinsulinemia in IR rats. In N rats, amylin increased bone formation rate and reduced osteoclast surface and erosive surface in the femoral metaphysis, and increased osteoprotegerin (OPG)/receptor activator of NFκB ligand (RANKL) mRNA ratio in the tibia. In T2D rats, amylin normalized trabecular structure parameters and increased osteoblast number and osteocalcin (OC) expression in long bones. In contrast, in IR rats, no apparent osteogenic effect of amylin in the femur was observed, although both OC and OPG/RANKL ratio were increased in the tibia. Our findings demonstrate a different osteogenic efficacy of amylin in two diabetic settings.
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Affiliation(s)
- I Gutiérrez-Rojas
- Departamento de Metabolismo, Nutrición y Hormonas, Instituto de Investigación Sanitaria (IIS)-Fundación Jiménez Díaz, Madrid, Spain
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Moreno P, Acitores A, Gutiérrez-Rojas I, Nuche-Berenguer B, El Assar M, Rodriguez-Mañas L, Gomis R, Valverde I, Visa M, Malaisse WJ, Novials A, González N, Villanueva-Peñacarrillo ML. Amylin effect in extrapancreatic tissues participating in glucose homeostasis, in normal, insulin-resistant and type 2 diabetic state. Peptides 2011; 32:2077-85. [PMID: 21939703 DOI: 10.1016/j.peptides.2011.09.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2011] [Revised: 09/06/2011] [Accepted: 09/07/2011] [Indexed: 12/13/2022]
Abstract
Amylin is co-secreted with insulin, responds to the same stimuli, is anorectic, lowers body weight by reducing fat mass, and is proposed for diabetes treatment. We examined the effect of a 3-day constant infusion of close to physiological doses of amylin in Wistar rats, on glucotransporter expression, glycogen content (G), glycogen synthase a activity (GSa) and glucose transport (GT), in liver, muscle and fat from insulin resistant (IR) and type 2 diabetic (T2D) models, compared to normal (N) animals; plasma glucose and insulin were measured. Plasma insulin in IR was higher than in N or T2D, and amylin normalized the value. In both, IR and T2D, liver G was lower than normal, accompanied by GLUT-2, mRNA and protein, higher and lower, respectively, than in N; amylin normalized G in both groups, without changes in GLUT-2, except for an mRNA increase in T2D. In IR and T2D, muscle GSa was reduced, together with respective over- and under-GLUT-4 expression; amylin induced only a trend toward GSa normalization in both groups. In isolated adipocytes, GT and GLUT-4 in IR and T2D were lower and higher, respectively, than in N; after amylin, not only GT was normalized in both groups but also the response to insulin was much more pronounced, including that in N, without major changes in GLUT-4. This suggests that the beneficial effect of amylin in states running with altered glucose homeostasis could occur by partially acting on the hexose metabolism of the liver and mainly on that of the adipose tissue.
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Affiliation(s)
- P Moreno
- Departamento Metabolism, Nutrition & Hormones, IIS-Fundación Jiménez Díaz, Madrid, Spain
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James S, Moralez J, Nagamani M. Increased secretion of amylin in women with polycystic ovary syndrome. Fertil Steril 2009; 94:211-5. [PMID: 19338997 DOI: 10.1016/j.fertnstert.2009.02.086] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2008] [Revised: 02/25/2009] [Accepted: 02/25/2009] [Indexed: 10/21/2022]
Abstract
OBJECTIVE To investigate amylin secretion in women with polycystic ovary syndrome (PCOS). DESIGN Prospective, case-control study. SETTING Academic institution. PATIENT(S) Twenty women with PCOS and 10 with ovulatory cycles who matched for body mass index. INTERVENTION(S) An oral glucose tolerance test was performed, and glucose, insulin, and amylin levels were measured at fasting and after glucose ingestion. The area under the curve for insulin, amylin, and glucose was calculated. Ten women with PCOS were treated with metformin and 10 women with rosiglitazone for 6 months. Amylin levels were measured before and after treatment. RESULT(S) Fasting amylin levels and amylin response to oral glucose were significantly increased in women with PCOS. At fasting, there was significant positive correlation between insulin and amylin levels both in women with PCOS and control subjects. After glucose ingestion, amylin response correlated with the glucose response in women with PCOS. Amylin levels decreased with metformin but not with rosiglitazone treatment. CONCLUSION(S) In women with PCOS, [1] there is increased secretion of amylin, [2] insulin and amylin secretion is coregulated in the fasting state, [3] after glucose ingestion, glucose levels regulate amylin release, and [4] the insulin-sensitizing agent metformin, but not rosiglitazone, reduces amylin secretion.
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Affiliation(s)
- Summer James
- Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas 77555-0587, USA
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Hoogwerf BJ, Doshi KB, Diab D. Pramlintide, the synthetic analogue of amylin: physiology, pathophysiology, and effects on glycemic control, body weight, and selected biomarkers of vascular risk. Vasc Health Risk Manag 2008; 4:355-62. [PMID: 18561511 PMCID: PMC2496974 DOI: 10.2147/vhrm.s1978] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Pramlintide is a synthetic version of the naturally occurring pancreatic peptide called amylin. Amylin and pramlintide have similar effects on lowering postprandial glucose, lowering postprandial glucagon and delaying gastric emptying. Pramlintide use in type 1 and insulin requiring type 2 diabetes mellitus (DM) is associated with modest reductions in HbA1c often accompanied by weight loss. Limited data show a neutral effect on blood pressure. Small studies suggest small reductions in LDL-cholesterol in type 2 DM and modest reductions in triglycerides in type 1 DM. Markers of oxidation are also reduced in conjunction with reductions in postprandial glucose. Nausea is the most common side effect. These data indicate that pramlintide has a role in glycemic control of both type 1 and type 2 DM. Pramlintide use is associated with favorable effects on weight, lipids and other biomarkers for atherosclerotic disease.
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Affiliation(s)
- Byron J Hoogwerf
- Department of Endocrinology, Diabetes and Metabolism, Cleveland Clinic Foundation, Cleveland, USA.
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Hayden MR, Sowers JR. Treating hypertension while protecting the vulnerable islet in the cardiometabolic syndrome. JOURNAL OF THE AMERICAN SOCIETY OF HYPERTENSION : JASH 2008; 2:239-66. [PMID: 20409906 PMCID: PMC2867460 DOI: 10.1016/j.jash.2007.12.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/12/2007] [Revised: 12/06/2007] [Accepted: 12/06/2007] [Indexed: 12/19/2022]
Abstract
Hypertension, a multifactorial-polygenic disease, interacts with multiple environmental stressors and results in functional and structural changes in numerous end organs, including the cardiovascular system. This can result in coronary heart disease, stroke, peripheral vascular disease, congestive heart failure, end-stage renal disease, insulin resistance, and damage to the pancreatic islet. Hypertension is the most important modifiable risk factor for major health problems encountered in clinical practice. Whereas hypertension was once thought to be a medical condition based on discrete blood pressure readings, a new concept has emerged defining hypertension as part of a complex and progressive metabolic and cardiovascular disease, an important part of a cardiometabolic syndrome. The central role of insulin resistance, oxidative stress, endothelial dysfunction, metabolic signaling defects within tissues, and the role of enhanced tissue renin-angiotensin-aldosterone system activity as it relates to hypertension and type 2 diabetes mellitus are emphasized. Additionally, this review focuses on the effect of hypertension on functional and structural changes associated with the vulnerable pancreatic islet. Various classes of antihypertensive drugs are reviewed, especially their roles in delaying or preventing damage to the vulnerable pancreatic islet, and thus delaying the development of type 2 diabetes mellitus.
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Affiliation(s)
- Melvin R. Hayden
- University of Missouri School of Medicine, Diabetes and Cardiovascular Disease Research Center and VA Medical Center, Columbia, Missouri
| | - James R. Sowers
- University of Missouri School of Medicine, Diabetes and Cardiovascular Disease Research Center and VA Medical Center, Columbia, Missouri
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Neural Correlates of Visuospatial Working Memory in Healthy Young Adults at Risk for Hypertension. Brain Imaging Behav 2008. [DOI: 10.1007/s11682-008-9025-4] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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18
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Matuszek MA, Boutcher SH. Elevated levels of circulating cortisol in young normotensive adult men with a family history of hypertension. Clin Exp Pharmacol Physiol 2007; 35:280-6. [PMID: 18067596 DOI: 10.1111/j.1440-1681.2007.04823.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
1. Differences in blood lipids, glucose, insulin, amylin, adrenocorticotropic hormone (ACTH), cortisol, aldosterone, angiotensin II, metabolites of nitric oxide (nitrate, nitrite), asymmetric dimethyl arginine, endothelial leucocyte adhesion molecule-1, vascular cell adhesion molecule-1, C-reactive protein, homocysteine and oxidative status (urate, vitamin A, vitamin E, beta-carotene and total anti-oxidant capacity) were investigated in men (aged 18-25 years) with (+) or without (-) a family history (FH) of hypertension. 2. In the present study, FH+ was defined as having at least one parent or grandparent taking medication for hypertension. Blood (60 mL) was sampled (0800-1000 hours) from a cannulated forearm vein after an overnight fast and 24 h abstinence from caffeine-containing products and alcohol. 3. Comparing FH+ with FH-, systolic blood pressure (124 +/- 1 vs 117 + 3 mmHg, respectively; n = 50 and 14, respectively; P < 0.05) and plasma cortisol (377 +/- 23 vs 298 +/- 24 nmol/L, respectively; n = 43 and 12, respectively; P < 0.05) were found to be significantly higher in the former group. 4. No significant difference was found between the two groups for body mass index, resting heart rate, diastolic and mean blood pressures or any of the biochemical measures studied. 5. A significant correlation was found between cortisol and ACTH (r = 0.73). No correlation was found between cortisol and any other parameter measured. 6. These data indicate that elevated cortisol levels are characteristic of young lean normotensive FH+ men. The future impact of this on their vascular health and hypertension remains to be determined.
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Affiliation(s)
- Maria A Matuszek
- School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.
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19
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Novials A, Rodriguez-Mañas L, Chico A, El Assar M, Casas S, Gomis R. Amylin and hypertension: association of an amylin -G132A gene mutation and hypertension in humans and amylin-induced endothelium dysfunction in rats. J Clin Endocrinol Metab 2007; 92:1446-50. [PMID: 17213278 DOI: 10.1210/jc.2006-1980] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
CONTEXT Amylin has been linked to the development of hypertension in several pathological states related to hypertension and insulin resistance, although there is scant data regarding its potential mechanisms of action. The -132 G/A mutation located within an activator domain of the amylin gene's promoter was first identified in a small cohort of Spanish patients with type 2 diabetes. OBJECTIVE The objective of the study was to test the interference of amylin peptide with endothelium-dependent responses as an added potential mechanism for amylin-induced hypertension. DESIGN A total of 384 patients with type 2 diabetes and 207 healthy controls were subjected to clinical analysis and genetic screening for the -132 G/A mutation of the amylin gene. The effect of amylin on endothelium-dependent responses was analyzed in aortic rings and mesenteric microvessels from nondiabetic rats. RESULTS The prevalence of the mutation was 10.1 vs. 0.9% in the control population (P<0.001). Hypertension was higher in a diabetic population carrying the mutation than in diabetic noncarriers (74 vs. 57%; P<0.05). Diabetic carriers showed higher fasting amylin levels than diabetic noncarriers (11.4+/-7 vs. 8.2+/-3 pmol/liter; P<0.05). Preincubation with 20 pmol/liter amylin impaired the relaxant responses induced by acetylcholine in rat aorta and mesenteric microvessels. This effect was abolished in both vascular beds in the presence of 100 micromol/liter NG-nitro-L-arginine methyl ester. CONCLUSIONS We propose that amylin levels and hypertension may be linked by a novel mechanism involving the capacity of amylin to induce endothelial dysfunction by interfering with nitric oxide-mediated responses.
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Affiliation(s)
- Anna Novials
- Institute of Diabetes, Sardà Farriol Foundation, Passeig Bonanova 69, 6th floor, 08017 Barcelona, Spain.
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20
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Understanding essential hypertension from the perspective of the cardiometabolic syndrome. JOURNAL OF THE AMERICAN SOCIETY OF HYPERTENSION : JASH 2007; 1:120-34. [PMID: 20409842 DOI: 10.1016/j.jash.2007.01.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/16/2006] [Revised: 01/19/2007] [Accepted: 01/19/2007] [Indexed: 02/06/2023]
Abstract
Hypertension (HTN) is an important modifiable risk factor for major health problems such as coronary heart disease, stroke, congestive heart failure, end-stage renal disease, and peripheral vascular disease. Because of the associated morbidity and mortality, and the cost to society, HTN is an important public health challenge. HTN is frequently associated with other cardiovascular disease risk factors constituting the cardiometabolic syndrome, which individually and synergistically influence the pathophysiology of HTN, and the resultant increased redox stress contributes to the remodeling changes in key organs such as the heart and kidney. Remodeling at the subcellular level, and extracellular matrix in the heart and kidney of the hypertensive Ren2 transgenic rat model of tissue angiotensin II overexpression (TG(mREN-2)27), compared with the Sprague Dawley control rat model, has been observed by light and electron microscopy and are discussed. A better understanding of the pathophysiology of HTN may provide clinician and researcher, tools to effectively investigate and manage this complicated disease process.
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Lillie EO, O'Connor DT. Early phenotypic changes in hypertension: a role for the autonomic nervous system and heredity. Hypertension 2006; 47:331-3. [PMID: 16446388 DOI: 10.1161/01.hyp.0000203980.44717.aa] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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22
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23
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Hayden MR, Whaley-Connell A, Sowers JR. Renal redox stress and remodeling in metabolic syndrome, type 2 diabetes mellitus, and diabetic nephropathy: paying homage to the podocyte. Am J Nephrol 2005; 25:553-69. [PMID: 16210838 DOI: 10.1159/000088810] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2005] [Accepted: 08/24/2005] [Indexed: 12/20/2022]
Abstract
Type 2 diabetes mellitus has reached epidemic proportions and diabetic nephropathy is the leading cause of end-stage renal disease. The metabolic syndrome constitutes a milieu conducive to tissue redox stress. This loss of redox homeostasis contributes to renal remodeling and parallels the concurrent increased vascular redox stress associated with the cardiometabolic syndrome. The multiple metabolic toxicities, redox stress and endothelial dysfunction combine to weave the complicated mosaic fabric of diabetic glomerulosclerosis and diabetic nephropathy. A better understanding may provide both the clinician and researcher tools to unravel this complicated disease process. Cellular remodeling of podocyte foot processes in the Ren-2 transgenic rat model of tissue angiotensin II overexpression (TG(mREN-2)27) and the Zucker diabetic fatty model of type 2 diabetes mellitus have been observed in preliminary studies. Importantly, angiotensin II receptor blockers have been shown to abrogate these ultrastructural changes in the foot processes of the podocyte in preliminary studies. An integrated, global risk reduction, approach in therapy addressing the multiple metabolic abnormalities combined with attempts to reach therapeutic goals at an earlier stage could have a profound effect on the development and progressive nature to end-stage renal disease and ultimately renal replacement therapy.
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Affiliation(s)
- Melvin R Hayden
- Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, Diabetes and Cardiovascular Disease Center, University of Missouri School of Medicine, Columbia, 65212, USA.
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24
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Deng PY, Li YJ. Calcitonin gene-related peptide and hypertension. Peptides 2005; 26:1676-85. [PMID: 16112410 DOI: 10.1016/j.peptides.2005.02.002] [Citation(s) in RCA: 78] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2004] [Revised: 01/31/2005] [Accepted: 02/01/2005] [Indexed: 11/19/2022]
Abstract
Capsaicin-sensitive sensory nerves participate in the regulation of cardiovascular functions both in the normal state and the pathophysiology of hypertension through the actions of potent vasodilator neuropeptides, including calcitonin gene-related peptide (CGRP). CGRP, a very potent vasodilator, is the predominant neurotransmitter in capsaicin-sensitive sensory nerves, and plays an important role in the initiation, progression and maintenance of hypertension via: (1) the alterations in its synthesis and release and/or in vascular sensitivity response to it; (2) interactions with pro-hypertensive systems, including renin-angiotensin-aldosterone system, sympathetic nervous system and endothelin system; and (3) anti-hypertrophy and anti-proliferation of vascular smooth muscle cells. The decrease in CGRP synthesis and release contributes to the elevated blood pressure, as shown in the spontaneously hypertensive rats, alpha-CGRP knockout mice, Dahl-salt or phenol-induced hypertensive rats. In contrast, the increase in CGRP levels or the enhancement of vascular sensitivity response to CGRP plays a beneficial compensatory depressor role in the development of hypertension, as shown in deoxycorticosterone-salt, sub-total nephrectomy-salt, N(omega)-nitro-L-arginine methyl ester or two-kidney, one-clip models of hypertension in rats. We found that rutaecarpine causes a sustained depressor action by stimulation of CGRP synthesis and release via activation of vanilloid receptor subtype 1 (VR1) in hypertensive rats, which reveals the therapeutic implications of VR1 agonists for treatment of hypertension.
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Affiliation(s)
- Pan-Yue Deng
- Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Xiang-Ya Road #90, Changsha, Hunan 410078, China
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25
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Abstract
There is considerable evidence that hyperglycemia represents the main cause of complications of diabetes mellitus (DM), and oxidative stress resulting from increased generation of reactive oxygen species plays a crucial role in their pathogenesis. In fact, in the absence of an appropriate response from endogenous antioxidant mechanisms, the redox imbalance causes the activation of stress-sensitive intracellular signaling pathways. The latter play a key role in the development of late complications of DM, as well as in mediating insulin resistance (i.e., resistance to insulin-mediated glucose uptake by some cells) and impaired insulin secretion. This review, focused on lipid peroxidation in DM, will examine the mechanisms and clinical readouts of oxidative stress in this setting, the relationship between lipid peroxidation and antioxidant status in type 1 and type 2 DM, the effects of hyperglycemia and metabolic control on in vivo markers of lipid peroxidation (i.e., isoprostanes), and the association between isoprostane formation and platelet activation. Finally, possible targets of antioxidant therapy for diabetic vascular complications will be discussed.
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Affiliation(s)
- Giovanni Davì
- Center of Excellence on Aging, University of Chieti "G. D'Annunzio" School of Medicine, Chieti, Italy.
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Zhao HL, Lai FMM, Tong PCY, Zhong DR, Yang D, Tomlinson B, Chan JCN. Prevalence and clinicopathological characteristics of islet amyloid in chinese patients with type 2 diabetes. Diabetes 2003; 52:2759-66. [PMID: 14578294 DOI: 10.2337/diabetes.52.11.2759] [Citation(s) in RCA: 91] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Islet amyloid has been suggested to be an important link between insulin resistance and beta-cell dysfunction in type 2 diabetes. To investigate the prevalence and clinicopathological characteristics of islet amyloid, we examined consecutive autopsies of 235 Chinese patients with type 2 diabetes and 533 nondiabetic subjects. Islet amyloid deposits were identified using Congo red staining and quantitated by image analysis. We found that 3.0% of the nondiabetic subjects versus 39.6% of the diabetic patients displayed islet amyloid (P < 0.001). In diabetic patients, the amyloid deposits occupied a mean islet area of 36.2%, which was positively associated with BMI, blood pressure, and glycemic control. Pancreatic fibrosis and fat infiltration were more frequently found in diabetic patients with islet amyloid than those without islet amyloid, whereas pancreatic arteriosclerosis was identified in all diabetic patients. These findings suggest that islet amyloid deposits reflect greater insulin resistance and islet failure in a subgroup of type 2 diabetic patients. Islet failure may also have been exacerbated by fat infiltration, fibrosis, and arteriosclerosis. Optimal blood pressure and metabolic control may reduce these pathological changes and help preserve islet cell mass.
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Affiliation(s)
- Hai-Lu Zhao
- Department of Medicine and Therapeutics, The Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.
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Hayden MR, Tyagi SC. Intimal redox stress: accelerated atherosclerosis in metabolic syndrome and type 2 diabetes mellitus. Atheroscleropathy. Cardiovasc Diabetol 2002; 1:3. [PMID: 12392600 PMCID: PMC140143 DOI: 10.1186/1475-2840-1-3] [Citation(s) in RCA: 71] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2002] [Accepted: 09/27/2002] [Indexed: 02/07/2023] Open
Abstract
Metabolic syndrome, insulin resistance, prediabetes, and overt type 2 diabetes mellitus are associated with an accelerated atherosclerosis (atheroscleropathy). This quartet is also associated with multiple metabolic toxicities resulting in the production of reactive oxygen species. The redox stress associated with these reactive oxygen species contribute to the development, progression, and the final fate of the arterial vessel wall in prediabetic and diabetic atheroscleropathy. The prevention of morbidity and mortality of these intersecting metabolic diseases can be approached through comprehensive global risk reduction.
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Affiliation(s)
- Melvin R Hayden
- Adjunct Assistant Professor Department of Family and Community Medicine University of Missouri Columbia, Missouri, USA
| | - Suresh C Tyagi
- Assistant Professor Department of Physiology and Biophysics University of Mississippi Medical Center Jackson, Mississippi 39216-4505, USA
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O'Connor DT, Kailasam MT, Kennedy BP, Ziegler MG, Yanaihara N, Parmer RJ. Early decline in the catecholamine release-inhibitory peptide catestatin in humans at genetic risk of hypertension. J Hypertens 2002; 20:1335-45. [PMID: 12131530 DOI: 10.1097/00004872-200207000-00020] [Citation(s) in RCA: 158] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Hypertension is a complex trait with an ill-defined genetic predisposition, in which adrenergic mechanisms seem to be involved even at the early stages. Chromogranin A is a pro-hormone stored and released with catecholamines by exocytosis; its fragment catestatin, formed in vivo, inhibits further catecholamine release as an antagonist at the physiologic trigger for secretion, the neuronal nicotinic cholinergic receptor. METHODS We measured catestatin by radioimmunoassay in n = 277 subjects stratified by blood pressure (n = 61 hypertensive, n = 216 normotensive), and if normotensive by genetic risk of developing hypertension: family history positive (n = 176) versus negative (n = 40). Maximum likelihood analysis tested for bimodality. Involvement of catestatin in pathophysiology was probed by measurements of catecholamines and leptin, and the hemodynamic responses to environmental (cold) stress. RESULTS The normotensive offspring of patients with hypertension already had diminished catestatin (P = 0.024), and family history was a better predictor of catestatin than age, ethnicity or gender (P = 0.014). Greater catestatin variance among family history-positive individuals (P = 0.021) suggested heterogeneity in this group, and a bimodal distribution (P < 0.001) identified 4.3% of individuals in a lower mode of catestatin values, all with positive family histories (P = 0.05). Catestatin correlated inversely with body mass index (r = -0.215, r(2) = 0.046, n = 276, P < 0.001) and plasma leptin (r = -0.203, r(2) = 0.041, n = 212, P = 0.003), while body mass index and leptin correlated directly (r = 0.59, r(2) = 0.350, n = 212, P < 0.001). Family history-positive individuals had greater epinephrine excretion (P = 0.037) in addition to diminished catestatin, suggesting an inhibitory effect of catestatin on chromaffin cells in vivo. Low plasma catestatin predicted enhanced pressor response to a sympathoadrenal stressor (cold stress; r = -0.184, r(2) = 0.034, n = 211, P = 0.007), suggesting an adrenergic mechanism whereby diminished catestatin might predispose to later development of hypertension. In white subjects, diminished catestatin also predicted greater systemic vascular resistance responses to cold stress (r = -0.307, r(2) = 0.094, n = 75, P = 0.007), a relationship not found in Blacks (r = 0.122, r(2) = 0.015, n = 94, P = 0.243). CONCLUSIONS We conclude that catestatin is diminished early in the course of development of hypertension, even in the normotensive offspring of patients with the disease. Low catestatin predicts augmented adrenergic pressor responses, suggesting a mechanism whereby diminished catestatin might increase the risk for later development of hypertension.
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Affiliation(s)
- Daniel T O'Connor
- Department of Medicine and Center for Molecular Genetics, University of California and V.A. San Diego Healthcare System, San Diego, California, USA.
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