Search PubMed⌕ Search

Biomedical subjects

T D O'Brien

Publications and source records attributed to T D O'Brien.

At least 19 recordsLinked to original sources
PubMed2006

An in vitro model of early islet amyloid polypeptide (IAPP) fibrillogenesis using human IAPP-transgenic mouse islets.

The mechanisms underlying insufficient insulin secretion and loss of beta-cell mass in feline and human type 2 diabetes mellitus are incompletely understood. However, islet amyloid polypeptide (IAPP)-derived islet amyloidosis (IA) has been linked to increased rates of beta-cell apoptosis and, therefore, our goal was to develop an in vitro model of IAPP fibrillogenesis using isolated pancreatic islets from mice transgenic for human IAPP (hIAPP Tg mice). Islets from hIAPP Tg mice, from mice transgenic for non-amyloidogenic murine IAPP (mIAPP Tg mice), and from the FVB background strain were exposed to normal (5.5 mM) or high (28 mM) glucose conditions in cell culture for 8 days. On days 0 and 8, islets were collected for electron microscopy (EM). EM showed no abnormalities in the mIAPP Tg or FVB islets at either time point. On day 8, hIAPP Tg islets cultured at high glucose concentration formed extracellular IAPP-derived flocculent deposits. No significant differences in rates of apoptosis were found between groups. Our findings, therefore, show that in vitro culture of hIAPP Tg mouse islets under high glucose conditions produces a readily available and rapidly inducible model of IAPP-derived fibrillogenesis and enables the study of early phases of the molecular pathogenesis of IA.

Amyloid↗
PubMed2002

Pathogenesis of feline diabetes mellitus.

The common form of spontaneous diabetes mellitus that occurs in domestic cats bears close resemblance clinically and pathologically to human type 2 diabetes mellitus (T2DM). For example, the typical diabetic cat is obese and middle-aged, and has low but detectable circulating insulin levels. However, the most striking similarity is the occurrence of islet amyloidosis (IA) in nearly all diabetic cats and in over 90% of humans with T2DM. IA in both humans and cats is derived from islet amyloid polypeptide (IAPP, or amylin) which is a hormone produced and secreted along with insulin by the pancreatic beta cells. Since all cats and humans normally produce IAPP, additional factors must be invoked in order to explain the development of IA. Several lines of evidence support the concept that IA is caused by chronically increased stimulus for beta cells to secrete IAPP (and insulin). For example, peripheral insulin resistance such as in chronic obesity results in increased IAPP and insulin secretion. A recent study, in which diabetes mellitus was induced in cats, demonstrated that IAPP hypersecretion was induced by treatment with a sulfonylurea drug and resulted in 4/4 cats in this group developing IA. In contrast, cats treated with insulin had low IAPP secretion and minimal IA developed in 1/4 cats. Several human-IAPP transgenic mouse models, in which there is IAPP overexpression, also support the notion that prolonged high expression of IAPP leads to IA. In vitro models of IAPP overexpression also support this mechanism for IA formation and by demonstrating an association between IA formation and beta cell toxicity, suggest a linkage between IA formation and loss of beta cells in T2DM. A recent study has indicated that intermediate-sized IAPP-derived amyloid fibrils can disrupt cell membranes and therefore, may be involved in the destruction of beta cells. Striking parallels between the pathogenesis of IA and beta-amyloid plaque formation in Alzheimer's disease suggest possible parallel pathogenetic mechanisms of cell death and provide potential avenues for future studies into the pathogenesis of IA.

Amyloid↗
PubMed2000

Acute hepatotoxicant exposure induces TNFR-mediated hepatic injury and cytokine/apoptotic gene expression.

Tumor necrosis factor receptor knockout (TNFR KO) mice were used to examine the role of tumor necrosis factor-alpha (TNFalpha) signaling during acute hepatotoxicant exposure. Mice were exposed intraperitoneally (ip) to either vehicle, phosphate-buffered saline (PBS), or dimethylnitrosamine (DMN, 100 mg/kg) for 24 h. Histological evaluation showed that DMN-treated TNFR-2 KO mice had increased liver damage compared to wild type (WT), TNFR-1 KO, or TNFR double KO (DKO) mice. Also, 3 of 8 TNFR-2 KO mice died following DMN treatment, suggesting that hepatic TNFR-2 signaling produces protective responses that counteract TNFR-1-mediated damage. DMN-induced cellular infiltration was absent in TNFR-1-deficient mice, indicating that infiltrating cells do not exacerbate acute hepatotoxic events. In separate experiments, mice were exposed ip to either DMN (5.0 or 100 mg/kg), carbon tetrachloride (CCl4, 0.3 or 1.0 ml/kg), or corresponding PBS/corn oil controls for 6 or 24 h to compare the hepatic mRNA expression of cytokine- and apoptotic-associated genes. Following 24 h of DMN (100 mg/kg) or 6-24 h of CCl4 treatment, hepatic transcripts for TNFalpha, interferon (IFN)-gamma, IL (interleukin)-1RI, and transforming growth factor (TGF)-betaRII were induced. Hepatotoxicant-treated WT and TNFR DKO mice induced liver transcripts for the pro- and anti-apoptotic genes, Bax and Bcl-X(L), respectively, indicating TNF-independent gene activation. The anti-apoptotic gene, Bfl-1, was highly expressed in CCl4-treated, TNFR-positive strains, but minimally expressed in TNFR DKO mice, suggesting that hepatic Bfl-1 is TNF-regulated. Taken together, these data show that acute hepatotoxicant exposure is followed by upregulation of liver cytokine, cytokine receptor, and apoptotic transcripts, and that TNFalpha regulates various aspects of liver inflammation and injury in a TNFR-specific fashion.

Alkylating Agents↗
PubMed1998

Quantitative immunohistochemical analysis of islet amyloid polypeptide (IAPP) in normal, impaired glucose tolerant, and diabetic cats.

Islet amyloid polypeptide (IAPP, "amylin") has been proposed as having important roles in the pathogenesis of type 2 diabetes mellitus via its biological activity and by forming islet amyloid. The domestic cat develops a type of diabetes that closely resembles type 2 diabetes in humans, including the frequent formation of islet amyloid deposits in the impaired glucose tolerant (IGT) and diabetic state. With the aid of computerized image analysis and immunohistochemistry, we examined the IAPP and insulin content in pancreatic islets of normal, IGT and diabetic cats. IAPP immunoreactivity in beta cells from IGT cats was significantly stronger (p < 0.01) as compared with cells from normal cats, while the insulin labelling strength was unchanged. Overtly diabetic cats were usually almost devoid of beta cells. As in humans, cellular IAPP but not IAPP in islet amyloid deposits was labelled by the newly developed monoclonal antibody to IAPP 4A5, thus providing further evidence that IAPP is modified by a yet unknown mechanism during the amyloidogenic process. The study provides evidence that an increased beta cell storage of IAPP independent of insulin may be an important factor in the early phase of the development of islet amyloid in this form of diabetes.

Amyloid↗
PubMed1997

Systemic AA amyloidosis in captive cheetahs (Acinonyx jubatus).

Ongoing disease surveillance of necropsied captive cheetahs (Acinonyx jubatus) (n = 141) revealed a high prevalence of renal amyloidosis (n = 54 [38%]; age 1 to 16 years). The prevalence increased from 20% in pre- 1990 necropsies to 70% of cheetahs necropsied in 1995. In 74% of the cheetahs with amyloidosis, renal failure was determined to be the sole or partial cause of death. Papillary necrosis was seen only in affected cheetahs and involved 25% of these animals. Amyloid was present predominantly in the medullary interstitium, with minimal glomerular involvement. The amyloid deposits were immunohistochemically identified as AA type using antisera to both human and canine protein AA. A high percentage (52%) of animals with renal amyloid also had subsinusoidal hepatic AA amyloid deposits. Inflammatory diseases were identified in 100% of affected cheetahs. The most common inflammatory disease was chronic lymphoplasmacytic gastritis. The prevalence and severity of gastritis was higher in cheetahs with amyloidosis, and the prevalence of severe gastritis increased from 16% to 43%, coinciding with the increase in prevalence of amyloidosis. These findings suggest that cheetahs have a high prevalence of systemic amyloidosis in response to inflammation and that renal amyloidosis is an increasingly significant cause of morbidity and mortality in captive cheetah populations. Factors of potential importance in the apparent high prevalence of AA amyloidosis in cheetahs are currently being investigated in our laboratories.

Acinonyx↗
PubMed1996

Gray-scale sonographic characterization of aminoglycoside-induced nephrotoxicosis in a canine model.

RATIONALE AND OBJECTIVES: The diagnostic usefulness of gray-scale sonography was evaluated in a canine model of aminoglycoside-induced nephrotoxicosis. METHODS: Sonography was performed before and during the onset and progression of nephrotoxicosis induced by administration of a toxic dosage of gentamicin. Subjective visualization of increased renal cortex echogenicity (IRCE) was objectified with digital image analysis methods. Results of both subjective and objective evaluation were correlated with clinicopathologic tests and renal cortex biopsy obtained concurrently. RESULTS: Subjective visualization of IRCE was associated with significant nephrotoxicosis and was superior to serum creatinine elevation in nephrotoxicity detection. Objective detection of IRCE improved nephrotoxicity detection sensitivity to that of increased urine enzymuria. CONCLUSIONS: Based on the above results, subjective visualization of IRCE in patients with aminoglycoside-induced nephrotoxicity may occur before azotemia and is suggestive of significant renal dysfunction; application of digital image analysis methods may lead to earlier sonographic recognition of nephrotoxicity.

Animals↗
PubMed1996

Islet amyloid and islet amyloid polypeptide in cynomolgus macaques (Macaca fascicularis): an animal model of human non-insulin-dependent diabetes mellitus.

To further characterize spontaneous diabetes mellitus in cynomolgus macaques (Macaca fascicularis) as a model for human non-insulin-dependent diabetes mellitus (NIDDM), we evaluated the morphologic characteristics of the endocrine pancreas of 4 diabetic and 12 age-matched nondiabetic cynomolgus macaques. In addition, the cDNA-predicted amino acid sequence for islet amyloid polypeptide (IAPP) of this species was determined. Islet amyloid deposits exhibiting typical congophilia and green birefringence were found in 4/4 diabetic animals and in 8/12 nondiabetics. Islet amyloid deposits were significantly more extensive in the diabetic macaques (P = 0.001), in which they occupied a mean of 60% of the islet area. In contrast, in the nondiabetic group the maximum islet area occupied by amyloid was 24% (group mean = 6.8%), with four animals having no detectable islet amyloid. Amyloid deposits consistently showed immunoreactivity for IAPP but not for insulin. Comparisons between group means for diabetic versus nondiabetic macaques showed significantly greater islet area (P = 0.01, 85,390 versus 36,540 microns 2) and significantly greater islet area fraction (P = 0.02, 0.065 versus 0.032) for the diabetic group. The cDNA-predicted amino acid sequence for cynomolgus IAPP was identical to that previously reported for pig-tail macaques (M. nemestrina) and had 92%, 86%, and 84% amino acid sequence identity with human, domestic cat, and murine IAPPs, respectively. These findings support the use of cynomolgus macaques as an animal model of human NIDDM.

Amino Acid Sequence↗
PubMed1996

Diabetes mellitus in cystic fibrosis is characterized by islet amyloidosis.

A high proportion of patients with cystic fibrosis (CF) develop diabetes mellitus. In common with type II diabetes mellitus, diabetes mellitus in CF is characterized by a progressive decline in beta-cell function and an approximately 50% decline in beta-cell mass. It is not known whether islet amyloidosis (characteristic of type II diabetes mellitus) is present in diabetes mellitus complicating CF. To address this, pancreatic samples were obtained at autopsy from 9 control cases (without CF) and 41 cases of CF that were, in turn, subdivided into 13 nondiabetic, 12 borderline diabetic, and 16 diabetic cases based on clinical criteria. Islet amyloid was detected by light microscopy in 69% cases of CF with diabetes mellitus, 17% of cases with borderline diabetes mellitus, and none of the nondiabetic cases. Islet amyloid was not present in any of the control cases. Islet amyloidosis derived from islet amyloid polypeptide is a characteristic feature of diabetes mellitus in CF as well as type II diabetes mellitus.

Adolescent↗
PubMed1996

Treatment with growth hormone and dexamethasone in mice transgenic for human islet amyloid polypeptide causes islet amyloidosis and beta-cell dysfunction.

Islet amyloid derived from islet amyloid polypeptide (IAPP) is a well-recognized feature of type II diabetes. However, the mechanism of islet amyloidogenesis is unknown. In vitro studies suggest that amino acid residues 20-29 in human, but not mouse, IAPP confer amyloidogenicity consistent with the absence of spontaneous islet amyloidosis in mice. Several clinical and in vitro studies suggest that increased synthetic rates of IAPP predispose to IAPP-amyloidosis. In the present study, we sought to test the hypothesis that pharmacological induction of insulin resistance in a mouse transgenic (TG) for human IAPP would induce islet amyloid and beta-cell dysfunction. TG and non-transgenic (N-TG) control mice were treated with both rat growth hormone (12 micrograms/day) and dexamethasone (0.24 mg/day) (dex/GH) or received no treatment for 4 weeks, after which animals were killed to examine islet morphology. Treatment with dex/GH caused hyperglycemia (7.3 +/- 0.4 vs. 5.2 +/- 0.1 mmol/l, TG vs. N-TG, P < 0.001) associated with a decreased plasma insulin concentration (595 +/- 51 vs. 996 +/- 100 pmol/l, TG vs. N-TG, P < 0.05) in TG versus control mice. Islet amyloid was induced in treated TG mice but not in control mice. Islet amyloid was identified in both intra- and extracellular deposits, the former being associated with evidence of beta-cell degeneration. We conclude that dex/GH treatment in mice TG for human IAPP induces IAPP-derived islet amyloid, hyperglycemia, and islet dysfunction. The present model recapitulates the islet morphology and phenotype of type II diabetes.

Amyloid↗
PubMed1996

Diabetes mellitus and islet amyloidosis in cynomolgus monkeys.

Six 15- to 20-year-old obese cynomolgus monkeys were determined to have diabetes mellitus. These monkeys were hyperglycemic and hypertriglyceridemic, yet remained nonketotic for several years before requiring clinical intervention. A significant decrease in glucose disappearance and an increased area under the glucose disappearance curve were found in response to intravenous glucose tolerance testing. Basal hyperinsulinemia was found in three animals that, in response to glucose stimulation, had a blunted insulin response, resulting in an overall decrease in the area under the insulin curve. Two animals died during the study and had extensive amyloid infiltration of pancreatic islets. The combined findings of old age, obesity, hyperinsulinemia, improvement in response to caloric restriction, and islet amyloidosis are consistent with type 2 diabetes mellitus.

Adipose Tissue↗
PubMed1996

Estimation of arcuate artery resistive index as a diagnostic tool for aminoglycoside-induced acute renal failure in dogs.

OBJECTIVE: To determine the potential clinical usefulness of duplex Doppler estimation of arcuate artery resistive index (a measure of intrarenal blood flow impedance) for diagnosis of aminoglycoside-induced nephrotoxicosis. ANIMALS: 30 adult, female, mixed-breed dogs, allotted to 3 groups of 10 dogs each as: toxic dosage of gentamicin, therapeutic dosage of gentamicin, and saline solution sham equivalent in volume to that of the toxic dosage of gentamicin. PROCEDURE: After baseline screening to establish normalcy (serum biochemical analysis, endogenous creatinine clearance determination, urinalysis, urine protein-to-creatinine ratio, urine culture, gray-scale sonography, and percutaneous ultrasound-guided renal biopsy), results of arcuate artery resistive index determination were compared with serum creatinine and urine specific gravity values on a Monday-Wednesday-Friday data collection schedule for 10 days. Endogenous creatinine clearance determination, ultrasound-guided renal biopsy, and urine culture were repeated at the end of data collection in all 3 groups. RESULTS: Significant differences in resistive index measurements were not observed, despite clinicopathologic and renal biopsy results compatible with severe acute tubular necrosis in dogs of the toxic dosage group. CONCLUSIONS: Duplex Doppler sonography of arcuate artery blood flow impedance, expressed as the resistive index, appears to have poor clinical usefulness as a diagnostic tool in this disorder. CLINICAL RELEVANCE: Normal arcuate artery resistive index values obtained in dogs for which aminoglycoside-induced nephrotoxicosis is suspected do not exclude the disorder. If abnormal arcuate artery resistive index values are obtained for such dogs, further evaluation for nephropathies other than aminoglycoside-induced nephrotoxicosis may be considered.

Acute Kidney Injury↗
PubMed1995

Assignment of islet amyloid polypeptide (IAPP) gene to feline chromosome B4 using the polymerase chain reaction technique on feline-rodent hybrid cell lines.

The most characteristic morphologic features of the pancreatic islets of human non-insulin-dependent diabetes mellitus (NIDDM, or type 2 diabetes mellitus) and of similar forms of diabetes in cats and macaques are the deposition of amyloid (islet amyloid) and the loss of beta cells. Islet amyloid is derived from islet amyloid polypeptide (IAPP), which is a normal secretory product of the beta cells. Therefore, knowledge of the IAPP gene is of potential importance in defining the pathogenesis of NIDDM. To identify the feline chromosome(s) on which the IAPP gene is located, we screened genomic DNA obtained from 38 feline-rodent hybrid cell lines that have a known feline chromosome content. Feline IAPP DNA was amplified and detected using the polymerase chain reaction technique. Discordancy analysis for each feline chromosome showed that chromosome B4 had the lowest discordancy (P < 0.0001). Feline chromosome B4 shows an extensive conserved syntenic relationship with human chromosome 12, on which the human IAPP gene is located. This study therefore extends and confirms the homology between human chromosome 12 and feline chromosome B4 and provides an additional genetic marker for feline chromosome B4.

Amyloid↗
PubMed1995

Apolipoprotein AI-derived pulmonary vascular amyloid in aged dogs.

Our studies confirm the common occurrence of a unique form of apolipoprotein AI (apoAI)-derived vascular amyloidosis in dogs that appears to be unrelated to other disease conditions, but is associated with aging. Vascular amyloid deposits were most frequently located within the intima and media of medium-sized pulmonary arteries, and were not confirmed in any other tissues. Pulmonary vascular amyloid immunoreactive with antiserum to purified N-terminal (1-71) canine apoAI amyloid protein was demonstrated retrospectively in 12.8% of necropsied dogs (N = 243) 10 years of age or older. In a subsequent expanded 1-year prospective study of necropsied dogs (N = 231) of all ages, apoAI-derived pulmonary vascular amyloid deposits were demonstrated in 0.7% of dogs < 10 years of age and in 22% of dogs 10 years of age or older. The incidence of this form of amyloid in dogs 10 years of age or older was significantly associated with advancing age (P < 0.00001). However, significant differences regarding gender, breed, or the frequency of selected common disease conditions were not observed when the dogs with apoAI-derived amyloid were compared with control dogs. The possibility that this new form of senile apoAI-derived amyloidosis is a manifestation of an age-associated aberration in apoAI metabolism or is related to a mutant form of apoAI is the subject of ongoing investigations.

Aging↗
PubMed1995

Human islet amyloid polypeptide expression in COS-1 cells. A model of intracellular amyloidogenesis.

Non-insulin-dependent diabetes mellitus is characterized by concurrent loss of beta-cells and deposition of islet amyloid derived from islet amyloid polypeptide (IAPP). We have previously demonstrated that IAPP-derived amyloid forms intracellularly in humans with chronic excess insulin expression (eg, insulinoma and insulin receptor antibody-induced insulin resistance). To determine whether overexpression of IAPP results in intracellular amyloid in mammalian cells, we transfected COS cells with vectors expressing amyloidogenic human IAPP or non-amyloidogenic rat IAPP. Transfected COS-1 cells secreted comparable amounts of human IAPP and rat IAPP (2.1 to 2.8 nmol/L/48 hours). After 96 hours, 90% of cells expressing human IAPP contained amyloid fibrils and were degenerating or dead, whereas cells transfected with rat IAPP lacked amyloid and were viable. Thus, overexpression of human IAPP can result in intracellular amyloid formation that is associated with cell death, suggesting that intracellular amyloid may play a role in beta-cell loss in non-insulin-dependent diabetes mellitus.

Amyloid↗
PubMed1994

Islet amyloid polypeptide in human insulinomas. Evidence for intracellular amyloidogenesis.

Amyloid deposits that characteristically form in the pancreatic islets of patients with non-insulin-dependent diabetes mellitus (NIDDM) and in insulinomas are both derived from islet amyloid polypeptide (IAPP). Evidence from previous studies has suggested that deposition of IAPP-derived amyloid is related to inherent amyloidogenic sequences present within normal human IAPP, together with an increased production and local concentration of IAPP. However, whether the aggregation of IAPP to form amyloid fibrils is primarily an intra- or extracellular event is not clear. To address this question, we studied 20 human insulinomas by light and electron microscopy. By light microscopy, amyloid deposits were demonstrated in 13 of 20 (65%) human insulinomas. Furthermore, evaluation of Congo red-stained tumor sections showed small, globular or irregular, congophilic amyloid deposits within the cytoplasm of many tumor cells in 10 of 13 (77%) amyloid-containing insulinomas. Dense, punctate areas of IAPP immunoreactivity within tumor cells corresponded with the congophilic intracellular deposits. Ubiquitin immunoreactivity also was observed as punctate intracellular labeling and within large extracellular amyloid deposits. Among the 10 insulinomas available for electron microscopic evaluation, pathological IAPP-immunoreactive (immunogold) deposits were found in 3 of 5 insulinomas in which amyloid was demonstrated by light microscopy and in none of 5 tumors found negative for amyloid by light microscopy. Morphology of IAPP-immunoreactive deposits varied from those with the classical distinct 7- to 10-nm diameter nonbranching fibrils to those with distinct but faint fibrillarity to those without discernable fibrils.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Influence of dietary protein/calorie intake on renal morphology and function in cats with 5/6 nephrectomy.

BACKGROUND: Although still controversial, several studies in humans have suggested That dietary protein restriction may slow the rate of progression of chronic renal failure. Thus, the influence of dietary protein on renal function and progression of renal failure has been the subject of numerous studies in several animal models of chronic renal failure, including rodents, dogs, and baboons. Because of the high incidence of chronic renal failure in aged cats, and the high dietary protein requirements of cats, we studied the effects of dietary protein intake on renal function, proteinuria, and renal morphology in cats with reduced renal mass. EXPERIMENTAL DESIGN: Partial (5/6) nephrectomy was performed in 14 young adult female cats. Sham surgical procedures were performed in eight control cats. Control cats and cats with 5/6 nephrectomy were randomly assigned to diets containing either 27.6% (low) or 51.7% (high) protein and studied for 1 year. RESULTS: Renal mass reduction by 5/6 decreased glomerular filtration rate by 2/3 and significantly increased proteinuria. Cats with remnant kidneys had significantly higher systolic and mean blood pressures than control cats. Increased dietary protein/calorie intake significantly increased glomerular filtration rate and proteinuria in all cats. Glomerular filtration rates remained stable in all cats over the year of study. However, high protein/calorie intake resulted in significant renal morphologic injury in remnant kidney cats that was prevented by dietary protein/calorie restriction. Light and electron microscopic glomerular changes in remnant kidney cats fed the high protein diet were similar to changes previously reported in rats and dogs with remnant kidneys. CONCLUSIONS: Dietary protein/calorie restriction limits proteinuria and glomerular injury in cats with remnant kidneys in a fashion similar to that reported in rats. However, the remnant kidney model in the cat appeared to be associated with a slower rate of progression compared with kidney model in the cat appeared to be associated with a slower rate of progression compared with rats.

Animals↗
PubMed1993

Islet amyloid polypeptide: a review of its biology and potential roles in the pathogenesis of diabetes mellitus.

Islet amyloidosis (IA) is the principal lesion in the endocrine pancreas of human beings with non-insulin-dependent diabetes mellitus (NIDDM) and in the similar forms of diabetes mellitus in domestic cats and macaques. As such, the delineation of the pathogenesis of this form of amyloidosis may be crucial to the understanding of the development and progression of NIDDM. Islet amyloid polypeptide (IAPP) is a recently discovered polypeptide that is the principal constituent of IA in human beings, cats, and macaques. IAPP is produced by the pancreatic beta-cells and is co-packaged with insulin in the beta-cell secretory vesicles. Immunohistochemical and physiologic evidence supports the notion that the beta-cells are heterogenous with respect to their relative contents of insulin and IAPP. Therefore, although IAPP is co-secreted with insulin in response to a variety of well-known insulin secretagogues, the molar ratio of these two proteins that is released from the islets may vary, depending upon the glucose concentration and prevailing metabolic milieu. IAPP is highly conserved among mammalian species and has about 45% homology to another neuropeptide, calcitonin gene-related peptide. IAPP is encoded by a single-copy gene located, in the human being, on chromosome 12. IAPP is expressed as a 93 (murine)-89 (human)-amino acid prepropolypeptide that is processed enzymatically, resulting in the removal of amino- and carboxy-terminal propeptide segments. The 20-29 region of the IAPP molecule is most important in the ability of IAPP to form amyloid fibrils. The role of IAPP and IA in the pathogenesis of human NIDDM and similar forms of diabetes mellitus in cats and macaques may involve several possible mechanisms, including 1) direct physical/chemical damage to beta-cells, resulting in necrosis and loss of functional islet tissue, 2) biologic activities of IAPP that oppose those of insulin or abnormally suppress insulin secretion, and 3) interference by IA deposits of passage of insulin out of beta-cells and/or entrance of glucose and other secretogogues into the islet. The roles of each of these possible mechanisms have yet to be demonstrated. In addition, the physiological significance of the apparent IAPP deficiency in both insulin-dependent diabetes mellitus and NIDDM is currently unknown.

Amino Acid Sequence↗