Prevalence and Clinicopathological Characteristics of Islet Amyloid in Chinese Patients With Type 2 Diabetes

Zhao, Hai-Lu; Lai, Fernand M.M.; Tong, Peter C.Y.; Zhong, Dingrong; Yang, Dan; Tomlinson, Brian; Chan, Juliana C.N.

doi:10.2337/diabetes.52.11.2759

Cited by 110 publications

(89 citation statements)

References 38 publications

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“…The human islet pancreas in T2DM is characterized by the histologic findings of islet amyloid, intra-and peri-islet fibrosis, islet adipogenesis, arteriolosclerosis, and atherosclerosis [47]. Furthermore, a recent human case report demonstrated a previously unreported finding that the insulo-acinar-portal islet efferent vessels, which carry pancreatic islet contents (including insulin) to the liver, were involved with both peri-islet fibrosis and peri-islet amyloid deposition.…”

Section: Structural Remodeling Of the Endocrine Pancreasmentioning

confidence: 99%

Treating hypertension while protecting the vulnerable islet in the cardiometabolic syndrome

Hayden

Sowers

2008

Journal of the American Society of Hypertension

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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 is 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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Section: Structural Remodeling Of the Endocrine Pancreasmentioning

confidence: 99%

Treating hypertension while protecting the vulnerable islet in the cardiometabolic syndrome

Hayden

Sowers

2008

Journal of the American Society of Hypertension

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“…The amount of amyloid deposited varies, but it is present to some degree in 40 -95% of the patients (1)(2)(3), and a decrease in the number of ␤-cells follows the accumulation of islet amyloid (4 -6). The main amyloid constituent is the 37-amino acid polypeptide hormone islet amyloid polypeptide (IAPP) (7) or amylin (8).…”

mentioning

confidence: 99%

Aberrant Processing of Human Proislet Amyloid Polypeptide Results in Increased Amyloid Formation

2005

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The amyloid present in the islets of Langerhans in type 2 diabetes is polymerized islet amyloid polypeptide (IAPP). The precursor protein proIAPP is posttranslationally modified, a process involving the removal of NH 2 -and COOH-terminal flanking peptides. This step is performed by the prohormone convertases PC2 and PC1/3. PC2 processes proIAPP preferably at the NH 2 -terminal processing site, and PC1/3 processes proIAPP exclusively at the COOH-terminal site. Little is known regarding the exact circumstances leading to islet amyloid formation. In this study, we have examined the possible significance of aberrant processing of proIAPP on amyloid formation in several in vitro cellular systems. In our studies, human (h)-proIAPP was transfected into ␤-TC-6 cells expressing both prohormone convertases and in which proIAPP is processed into IAPP. Additionally P ancreatic islet amyloid is a frequent and characteristic pathological feature of type 2 diabetes. The amount of amyloid deposited varies, but it is present to some degree in 40 -95% of the patients (1-3), and a decrease in the number of ␤-cells follows the accumulation of islet amyloid (4 -6). The main amyloid constituent is the 37-amino acid polypeptide hormone islet amyloid polypeptide (IAPP) (7) or amylin (8). This ␤-cell product is stored (9) and released together with insulin upon stimulation (10,11). In humans, IAPP is synthesized as a 67-amino acid proIAPP molecule from which NH 2 -terminal and COOH-terminal flanking peptides are subsequently removed proteolytically (12). This posttranslational processing within the secretory granules occurs at di-basic amino acids and is performed by the prohormone convertases 2 and 1/3 (PC2 and PC1/3). These are the same enzymes that process proinsulin to insulin at the same cellular location (13). In in vitro studies on the processing of human proIAPP (h-proIAPP) by recombinant converting enzymes, PC2 favored processing at the NH 2 -terminal flanking region and PC1/3 had its initial activity at the COOH-terminal region. However, during extended incubation time, both PC2 and PC1/3 could, to some degree, process proIAPP at both cleavage sites (14). In contrast, the in vivo results from studies on the processing of proIAPP performed in PC2 (15) and PC1/3 (16) null mice showed that PC2 is required for cleavage at the NH 2 -terminal region and that PC1/3 processes the COOHterminal flanking region. However, in the absence of PC1/3, this cleavage site can be processed by PC2.Little is known about the mechanisms that precede the deposition of islet amyloid. The use of human IAPP (h-IAPP)-expressing transgenic animals has demonstrated that increased expression of IAPP by itself is not sufficient for amyloid to develop (17-19). However, introduction of the h-IAPP gene into mouse strains with diabetic traits resulted in the formation of islet amyloid (20,21). Amyloid was also detected in transgenic animals fed a high-fat diet (22). In mouse IAPP (mIAPP)-null mice expressing the gene for h-IAPP, amyloid developed within 9 months ...

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“…Amylin, also referred to as islet amyloid polypeptide, is a 37-amino acid polypeptide (4,5) secreted from pancreatic islet ␤-cells whose aggregation results in islet amyloid formation in type 2 diabetes (6). Islet amyloid has been reported in 40 -90% of pancreases from type 2 diabetic subjects studied post mortem (7)(8)(9)(10)(11) and has been linked to both decreased ␤-cell mass and ␤-cell dysfunction (12,13). In vitro, human amylin causes apoptosis of islet ␤-cells, and there is growing evidence that this pathogenic process may contribute to the ␤-cell deficit in type 2 diabetes (1,2,14,15).…”

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confidence: 99%

Spontaneous Diabetes in Hemizygous Human Amylin Transgenic Mice That Developed Neither Islet Amyloid nor Peripheral Insulin Resistance

et al. 2008

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OBJECTIVES-We sought to 1) Determine whether solublemisfolded amylin or insoluble-fibrillar amylin may cause or result from diabetes in human amylin transgenic mice and 2) determine the role, if any, that insulin resistance might play in these processes.RESEARCH DESIGN AND METHODS-We characterized the phenotypes of independent transgenic mouse lines that display pancreas-specific expression of human amylin or a nonaggregating homolog, [ 25,28,29 Pro]human amylin, in an FVB/n background.RESULTS-Diabetes occurred in hemizygous human amylin transgenic mice from 6 weeks after birth. Glucose tolerance was impaired during the mid-and end-diabetic phases, in which progressive ␤-cell loss paralleled decreasing pancreatic and plasma insulin and amylin. Peripheral insulin resistance was absent because glucose uptake rates were equivalent in isolated soleus muscles from transgenic and control animals. Even in advanced diabetes, islets lacked amyloid deposits. In islets from nontransgenic mice, glucagon and somatostatin cells were present mainly at the periphery and insulin cells were mainly in the core; in contrast, all three cell types were distributed throughout the islet in transgenic animals.[ 25,28,29 Pro]human amylin transgenic mice developed neither ␤-cell degeneration nor glucose intolerance.CONCLUSIONS-Overexpression of fibrillogenic human amylin in these human amylin transgenic mice caused ␤-cell degeneration and diabetes through mechanisms independent from both peripheral insulin resistance and islet amyloid. These findings are consistent with ␤-cell death evoked by misfolded but soluble cytotoxic species, such as those formed by human amylin in vitro.

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Prevalence and Clinicopathological Characteristics of Islet Amyloid in Chinese Patients With Type 2 Diabetes

Cited by 110 publications

References 38 publications

Treating hypertension while protecting the vulnerable islet in the cardiometabolic syndrome

Treating hypertension while protecting the vulnerable islet in the cardiometabolic syndrome

Aberrant Processing of Human Proislet Amyloid Polypeptide Results in Increased Amyloid Formation

Spontaneous Diabetes in Hemizygous Human Amylin Transgenic Mice That Developed Neither Islet Amyloid nor Peripheral Insulin Resistance

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