Gunilla T. Westermark

Per Westermark

Importance of Aggregated Islet Amyloid Polypeptide for the Progressive Beta-Cell Failure in Type 2 Diabetes and in Transplanted Human Islets

Following the encouraging report of the Edmonton group, there was a rejuvenation of the islet transplantation field. After that, more pessimistic views spread when long-term results of the clinical outcome were published. A progressive loss of the <svg     style="vertical-align:-3.56265pt;width:10px;" id="M1" height="16.6625" version="1.1" viewBox="0 0 10 16.6625" width="10"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,12.162)"><path id="x1D6FD" d="M558 587q0 -32 -14 -61t-40 -53.5t-48.5 -41t-54.5 -36.5q144 -51 144 -174q0 -55 -43.5 -108t-104.5 -87q-77 -42 -131 -42q-31 0 -54 20t-31 47l11 18q48 -29 108 -29q79 0 119.5 43t40.5 109t-44.5 107.5t-119.5 50.5l22 47q34 1 65 21q96 61 96 157q0 42 -24 67.5&#xA;t-62 25.5q-24 0 -43.5 -9t-35 -29.5t-27 -44t-22.5 -63t-19.5 -75.5t-18.5 -91q-57 -294 -68 -380q-26 -190 -35 -200q-26 -31 -97 -37l-4 26q19 9 48 170l77 413q23 121 52.5 187.5t83.5 114.5q70 62 148 62q51 0 88.5 -34t37.5 -91z" /></g>

		
	
</svg>-cell function meant that almost all patients were back on insulin therapy after 5 years. More than 10 years ago, we demonstrated that amyloid deposits rapidly formed in human islets and in mouse islets transgenic for human IAPP when grafted into nude mice. It is, therefore, conceivable to consider amyloid formation as one potential candidate for the long-term failure. The present paper reviews attempts in our laboratories to elucidate the dynamics of and mechanisms behind the formation of amyloid in transplanted islets with special emphasis on the impact of long-term hyperglycemia.

Arne Andersson

Sara Bohman

L. A. Håkan Borg

Johan F. Paulsson

Sebastian W. Schultz

Amyloid Deposition in Transplanted Human Pancreatic Islets: A Conceivable Cause of Their Long-Term Failure

Transthyretin (TTR) is a major amyloid fibril protein in certain systemic forms of amyloidosis. It is a plasma protein, mainly synthesized by the liver but expression occurs also at certain minor locations, including the endocrine cells in the islets of Langerhans. With the use of immunohistochemistry and in situ hybridization, we have studied the distribution of transthyretin-containing cells in islets of Langerhans in type-2 diabetic and nondiabetic individuals. TTR expression was particularly seen in alpha (glucagon) cells. Islets from type-2 diabetic patients had proportionally more transthyretin-reactive islet cells, including beta cells. A weak transthyretin immunoreaction in IAPP-derived amyloid occurred in some specimens. In seeding experiments in vitro, we found that TTR fibrils did not seed IAPP while IAPP fibrils seeded TTR. It is suggested that islet expression of transthyretin may be altered in type-2 diabetes.

Transthyretin and Amyloid in the Islets of Langerhans in Type-2 Diabetes

Exogenous administration of islet amyloid polypeptide (IAPP) has been shown to inhibit both insulin and glucagon secretion. This study examined <svg     style="vertical-align:-0.1638pt;width:9.7749996px;" id="M3" height="7.9499998" version="1.1" viewBox="0 0 9.7749996 7.9499998" width="9.7749996"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,7.675)"><path id="x1D6FC" d="M545 106q-67 -118 -134 -118q-24 0 -40 37.5t-30 129.5h-2q-47 -72 -103 -119.5t-108 -47.5q-47 0 -76 45.5t-29 119.5q0 113 85 204t174 91q47 0 70 -33.5t43 -119.5h3q32 47 80 140l55 13l10 -9q-47 -80 -138 -201q17 -99 27.5 -136t22.5 -37q23 0 69 61zM333 204&#xA;q-14 98 -31 149.5t-50 51.5q-49 0 -94 -70t-45 -164q0 -55 15.5 -86t40.5 -31q70 0 164 150z" /></g>

		
	
</svg>-cell function in mice with <svg     style="vertical-align:-3.56265pt;width:10px;" id="M4" height="16.6625" version="1.1" viewBox="0 0 10 16.6625" width="10"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,12.162)"><path id="x1D6FD" d="M558 587q0 -32 -14 -61t-40 -53.5t-48.5 -41t-54.5 -36.5q144 -51 144 -174q0 -55 -43.5 -108t-104.5 -87q-77 -42 -131 -42q-31 0 -54 20t-31 47l11 18q48 -29 108 -29q79 0 119.5 43t40.5 109t-44.5 107.5t-119.5 50.5l22 47q34 1 65 21q96 61 96 157q0 42 -24 67.5&#xA;t-62 25.5q-24 0 -43.5 -9t-35 -29.5t-27 -44t-22.5 -63t-19.5 -75.5t-18.5 -91q-57 -294 -68 -380q-26 -190 -35 -200q-26 -31 -97 -37l-4 26q19 9 48 170l77 413q23 121 52.5 187.5t83.5 114.5q70 62 148 62q51 0 88.5 -34t37.5 -91z" /></g>

		
	
</svg>-cell specific overexpression of human IAPP (hIAPP) after an oral protein gavage (75&#x2009;mg whey protein/mouse). Baseline glucagon levels were higher in transgenic mice (41<svg     style="vertical-align:-0.3003pt;width:10.1px;" id="M5" height="9.5625" version="1.1" viewBox="0 0 10.1 9.5625" width="10.1"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,9.125)"><path id="xB1" d="M535 290h-212v-206h-58v206h-213v50h213v193h58v-193h212v-50zM535 -22h-483v50h483v-50z" /></g>

		
	
</svg>4.0&#x2009;pg/mL, <svg     style="vertical-align:-0.1638pt;width:36.237499px;" id="M6" height="11.225" version="1.1" viewBox="0 0 36.237499 11.225" width="36.237499"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,10.963)"><path id="x1D45B" d="M495 86q-46 -47 -87 -72.5t-63 -25.5q-43 0 -16 107l49 210q7 34 8 50.5t-3 21t-13 4.5q-35 0 -109.5 -72.5t-115.5 -140.5q-21 -75 -38 -159q-50 -10 -76 -21l-6 8l84 340q8 35 -4 35q-17 0 -67 -46l-15 26q44 44 85.5 70.5t64.5 26.5q35 0 10 -103l-24 -98h2&#xA;q42 56 97 103.5t96 71.5q46 26 74 26q9 0 16 -2.5t14 -11.5t9.5 -24.5t-1 -44t-13.5 -68.5q-30 -117 -47 -200q-4 -19 -3.5 -25t6.5 -6q21 0 70 48z" /></g><g transform="matrix(.017,-0,0,-.017,13.305,10.963)"><path id="x3D" d="M535 323h-483v50h483v-50zM535 138h-483v50h483v-50z" /></g><g transform="matrix(.017,-0,0,-.017,28.008,10.963)"><path id="x36" d="M137 343l67 33q37 17 63 17q79 0 129.5 -53t50.5 -131q0 -92 -58 -156.5t-147 -64.5t-147 68t-58 182q0 63 17 119t43 95.5t61.5 72t69 52t67.5 31.5q62 22 128 33l6 -32q-56 -11 -108 -35q-149 -71 -184 -231zM227 337q-47 0 -95 -27q-6 -23 -6 -70q0 -93 36 -155.5&#xA;t96 -62.5q53 0 78 45.5t25 105.5q0 68 -35 116t-99 48z" /></g>

		
	
</svg>) than in wildtype animals (19<svg     style="vertical-align:-0.3003pt;width:10.1px;" id="M7" height="9.5625" version="1.1" viewBox="0 0 10.1 9.5625" width="10.1"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,9.125)"><use xlink:href="#xB1"/></g>

		
	
</svg>5.1&#x2009;pg/mL, <svg     style="vertical-align:-0.1638pt;width:36.237499px;" id="M8" height="10.925" version="1.1" viewBox="0 0 36.237499 10.925" width="36.237499"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,10.65)"><use xlink:href="#x1D45B"/></g><g transform="matrix(.017,-0,0,-.017,13.305,10.65)"><use xlink:href="#x3D"/></g><g transform="matrix(.017,-0,0,-.017,28.008,10.65)"><path id="x35" d="M153 550l-26 -186q79 31 111 31q90 0 141.5 -51t51.5 -119q0 -93 -89 -166q-85 -69 -173 -71q-32 0 -61.5 11.5t-41.5 23.5q-18 17 -17 34q2 16 22 33q14 9 26 -1q61 -50 124 -50q60 0 93 43.5t33 104.5q0 69 -41.5 110t-121.5 41q-53 0 -102 -20l38 305h286l6 -8&#xA;l-26 -65h-233z" /></g>

		
	
</svg>, <svg     style="vertical-align:-0.1638pt;width:58.712502px;" id="M9" height="11.375" version="1.1" viewBox="0 0 58.712502 11.375" width="58.712502"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,11.112)"><path id="x1D443" d="M619 482q0 -69 -40.5 -119t-96 -72.5t-118.5 -26.5h-44l-70 20l-31 -151q-14 -67 0.5 -83t89.5 -22l-5 -28h-287l8 28q65 7 81.5 22t29.5 83l79 398q12 56 0.5 70.5t-78.5 20.5l7 28h255q108 0 164 -43t56 -125zM524 478q0 141 -146 141q-25 0 -47 -8q-16 -6 -20.5 -13.5&#xA;t-10.5 -39.5l-43 -241q37 -13 83 -13q67 0 125.5 45t58.5 129z" /></g><g transform="matrix(.017,-0,0,-.017,15.582,11.112)"><use xlink:href="#x3D"/></g><g transform="matrix(.017,-0,0,-.017,30.286,11.112)"><path id="x2E" d="M113 -12q-24 0 -39.5 16t-15.5 42q0 24 16 40.5t40 16.5t40 -16.5t16 -40.5q0 -26 -16 -42t-41 -16z" /></g><g transform="matrix(.017,-0,0,-.017,34.162,11.112)"><path id="x30" d="M241 635q53 0 94 -28.5t63.5 -76t33.5 -102.5t11 -116q0 -58 -11 -112.5t-34 -103.5t-63.5 -78.5t-94.5 -29.5t-95 28t-64.5 75t-34.5 102.5t-11 118.5q0 58 11.5 112.5t34.5 103t64.5 78t95.5 29.5zM238 602q-32 0 -55.5 -25t-35.5 -68t-17.5 -91t-5.5 -105&#xA;q0 -76 10 -138.5t37 -107.5t69 -45q32 0 55.5 25t35.5 68.5t17.5 91.5t5.5 105t-5.5 105.5t-18 92t-36 68t-56.5 24.5z" /></g><g transform="matrix(.017,-0,0,-.017,42.321,11.112)"><path id="x31" d="M384 0h-275v27q67 5 81.5 18.5t14.5 68.5v385q0 38 -7.5 47.5t-40.5 10.5l-48 2v24q85 15 178 52v-521q0 -55 14.5 -68.5t82.5 -18.5v-27z" /></g><g transform="matrix(.017,-0,0,-.017,50.481,11.112)"><use xlink:href="#x35"/></g>

		
	
</svg>). In contrast, the glucagon response to protein was impaired in transgenic animals (21<svg     style="vertical-align:-0.3003pt;width:10.1px;" id="M10" height="9.5625" version="1.1" viewBox="0 0 10.1 9.5625" width="10.1"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,9.125)"><use xlink:href="#xB1"/></g>

		
	
</svg>2.7&#x2009;pg/mL in transgenic mice versus 38<svg     style="vertical-align:-0.3003pt;width:10.1px;" id="M11" height="9.5625" version="1.1" viewBox="0 0 10.1 9.5625" width="10.1"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,9.125)"><use xlink:href="#xB1"/></g>

		
	
</svg>5.7&#x2009;pg/mL in wildtype mice at 15 minutes; <svg     style="vertical-align:-0.1638pt;width:58.712502px;" id="M12" height="11.375" version="1.1" viewBox="0 0 58.712502 11.375" width="58.712502"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,11.112)"><use xlink:href="#x1D443"/></g><g transform="matrix(.017,-0,0,-.017,15.582,11.112)"><use xlink:href="#x3D"/></g><g transform="matrix(.017,-0,0,-.017,30.286,11.112)"><use xlink:href="#x2E"/></g><g transform="matrix(.017,-0,0,-.017,34.162,11.112)"><use xlink:href="#x30"/></g><g transform="matrix(.017,-0,0,-.017,42.321,11.112)"><path id="x32" d="M412 140l28 -9q0 -2 -35 -131h-373v23q112 112 161 170q59 70 92 127t33 115q0 63 -31 98t-86 35q-75 0 -137 -93l-22 20l57 81q55 59 135 59q69 0 118.5 -46.5t49.5 -122.5q0 -62 -29.5 -114t-102.5 -130l-141 -149h186q42 0 58.5 10.5t38.5 56.5z" /></g><g transform="matrix(.017,-0,0,-.017,50.481,11.112)"><path id="x37" d="M447 623l8 -12l-283 -613l-74 -10l-7 11q174 283 297 551h-216q-48 0 -62.5 -12t-33.5 -63h-29q10 60 18 148h382z" /></g>

		
	
</svg>). Baseline insulin levels did not differ between the groups, while the insulin response, as the glucagon response, was impaired after protein challenge (<svg     style="vertical-align:-0.1638pt;width:58.712502px;" id="M13" height="11.375" version="1.1" viewBox="0 0 58.712502 11.375" width="58.712502"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,11.112)"><use xlink:href="#x1D443"/></g><g transform="matrix(.017,-0,0,-.017,15.582,11.112)"><use xlink:href="#x3D"/></g><g transform="matrix(.017,-0,0,-.017,30.286,11.112)"><use xlink:href="#x2E"/></g><g transform="matrix(.017,-0,0,-.017,34.162,11.112)"><use xlink:href="#x30"/></g><g transform="matrix(.017,-0,0,-.017,42.321,11.112)"><use xlink:href="#x31"/></g><g transform="matrix(.017,-0,0,-.017,50.481,11.112)"><path id="x38" d="M249 635q70 0 116 -43t46 -105q0 -46 -28 -80q-22 -25 -80 -64q62 -35 97 -75t35 -99q0 -81 -63 -131t-135 -50q-83 0 -137.5 45.5t-54.5 123.5q0 52 45 95q29 28 89 64q-109 62 -109 155q0 66 50.5 115t128.5 49zM238 603q-42 0 -67.5 -31t-25.5 -72q0 -50 32.5 -79.5&#xA;t98.5 -62.5q61 48 61 124q0 59 -29.5 90t-69.5 31zM248 20q46 0 76.5 33.5t30.5 89.5q0 50 -39 85.5t-110 71.5q-81 -54 -81 -137q0 -67 35.5 -105t87.5 -38z" /></g>

		
	
</svg>). Glucose levels were not different between the groups and did not change significantly after protein gavage. Acetaminophen was given through gavage to the animals (2&#x2009;mg/mouse) to estimate gastric emptying. The plasma acetaminophen profile was similar in the two groups of mice. We conclude that disturbances in glucagon secretion exist in mice with <svg     style="vertical-align:-3.56265pt;width:10px;" id="M14" height="16.6625" version="1.1" viewBox="0 0 10 16.6625" width="10"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,12.162)"><use xlink:href="#x1D6FD"/></g>

		
	
</svg>-cell specific overexpression of human IAPP, which are not secondary to changes in gastric emptying. The reduced glucagon response to protein challenge may reflect a direct inhibitory influence of hIAPP on glucagon secretion.

Bo Ahrén

Maria Sörhede Winzell

Disturbed <svg style="vertical-align:-0.1638pt" height="7.9499998" version="1.1" viewBox="0 0 9.7749996 7.9499998" width="9.7749996" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg"><g transform="matrix(.017,-0,0,-.017,.062,7.675)"><path id="x1D6FC" d="M545 106q-67 -118 -134 -118q-24 0 -40 37.5t-30 129.5h-2q-47 -72 -103 -119.5t-108 -47.5q-47 0 -76 45.5t-29 119.5q0 113 85 204t174 91q47 0 70 -33.5t43 -119.5h3q32 47 80 140l55 13l10 -9q-47 -80 -138 -201q17 -99 27.5 -136t22.5 -37q23 0 69 61zM333 204&#xA;q-14 98 -31 149.5t-50 51.5q-49 0 -94 -70t-45 -164q0 -55 15.5 -86t40.5 -31q70 0 164 150z" /></g></svg>-Cell Function in Mice with <svg style="vertical-align:-3.56265pt" height="16.6625" version="1.1" viewBox="0 0 10 16.6625" width="10" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg"><g transform="matrix(.017,-0,0,-.017,.062,12.162)"><path id="x1D6FD" d="M558 587q0 -32 -14 -61t-40 -53.5t-48.5 -41t-54.5 -36.5q144 -51 144 -174q0 -55 -43.5 -108t-104.5 -87q-77 -42 -131 -42q-31 0 -54 20t-31 47l11 18q48 -29 108 -29q79 0 119.5 43t40.5 109t-44.5 107.5t-119.5 50.5l22 47q34 1 65 21q96 61 96 157q0 42 -24 67.5&#xA;t-62 25.5q-24 0 -43.5 -9t-35 -29.5t-27 -44t-22.5 -63t-19.5 -75.5t-18.5 -91q-57 -294 -68 -380q-26 -190 -35 -200q-26 -31 -97 -37l-4 26q19 9 48 170l77 413q23 121 52.5 187.5t83.5 114.5q70 62 148 62q51 0 88.5 -34t37.5 -91z" /></g></svg>-Cell Specific Overexpression of Human Islet Amyloid Polypeptide

The molecular mechanism of amyloid formation by the islet amyloid polypeptide (IAPP) has been intensively studied since its identification in the late 1980s. The IAPP(20–29) region is considered to be the central amyloidogenic module of the polypeptide. This assumption is mainly based on the amyloidogenic properties of the region and on the large sequence diversity within this region between the human and mouse IAPP, as the mouse IAPP does not form amyloids. A few years ago, another region within IAPP was identified that seems to be at least as important as IAPP(20–29) in facilitation of molecular recognition that leads to amyloid formation. Here, we reinforce our and others' previous findings by analyzing supporting evidence from the recent literature. Moreover, we provide new proofs to our hypothesis by comparing between the amyloidogenic properties of the two regions derived from the IAPP of cats, which is also known to form amyloid fibrils.

Sharon Gilead

Ehud Gazit

The Role of the 14–20 Domain of the Islet Amyloid Polypeptide in Amyloid Formation

Amyloid formation is cytotoxic and can activate the caspase cascade. Here, we monitor caspase-3-like activity as reduction of fluorescence resonance energy transfer (FRET)  using the contstruct  pFRET2-DEVD containing enhanced cyan fluorescent protin (EYFP) linked by the caspase-3 specific cleavage site residues DEVD. Beta-TC-6 cells were transfected, and  the fluoorescence was measured at 440&#x2009;nm excitation and 535&#x2009;nm (EYFP) and 480&#x2009;nm (ECFP) emission wavelength. Cells were incubated with recombinant pro lset Amyloid Polypeptide (<i>rec</i> prolAPP) or the processing metabolites of prolAPP;   the N-terminal flanking peptide withIAPP (<i>rec</i>N+IAPP); IAPP with the C-terminal flanking peptied (<i>rec</i>IAPP+C) and lslet Amyloid  Polypeptide (<i>rec</i>IAPP) . Peptides were added in solubilized from (50&#x2009;<svg style="vertical-align:-3.56265pt;width:9.5625px;" id="M1" height="12.175" version="1.1" viewBox="0 0 9.5625 12.175" width="9.5625" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
				<g transform="matrix(.017,-0,0,-.017,.062,7.675)">
					<path id="x1D707" d="M538 96q-38 -45 -84 -76.5t-71 -31.5q-44 0 -15 117q12 49 18 89h-2q-99 -128 -163 -178q-36 -28 -70 -28q-26 0 -44 38h-2q-16 -69 -16 -129q0 -43 11 -75.5t24 -42.5l1 -6q-7 -12 -24.5 -23t-37.5 -11q-40 0 -40 76q0 52 35 202l94 407l78 24l5 -5q-32 -122 -72 -310&#xA;q-7 -33 0 -55t25 -22q36 0 105.5 75t107.5 145l32 146l75 26h10q-50 -197 -78 -347q-7 -38 6 -38q7 0 31 17t47 39z" />
				</g>
			</svg>M) or as performed amyloid-like fibrils, or as a combination of these. FRET was measured and incubation with a mixture of solubilized peptide and performed fibrils resulted in loss of  FRET and apoptosis was determined to occure in cells incubated with <i>rec</i>proIAPP (49&#x25;), <i>rec</i>N+IAPP (46&#x25;), <i>rec</i>IAPP (72&#x25;) and <i>rec</i>IAPP+C  (59&#x25;). These results show that proIAPP and the processing intermediates reside the same cell toxic capacity as IAPP, and they can all have a central role in the reduction of beta-cell number in type 2 diabetes.

Martin Köhler

Ingo Leibiger

Per-Olof Berggren

Real-Time Monitoring of Apoptosis by Caspase-3-Like Protease Induced FRET Reduction Triggered by Amyloid Aggregation

Human islet amyloid polypeptide (hIAPP), a pancreatic islet protein of 37 amino acids, is the main component of islet amyloid, seen at autopsy in patients with type 2 diabetes mellitus (DM2). To investigate the roles of hIAPP and islet amyloid in DM2, we generated transgenic mice expressing hIAPP in their islet beta cells. In this study, we found that after a long-term, high-fat diet challenge islet amyloid was observed in only 4 of 19 hIAPP transgenic mice. hIAPP transgenic females exhibited severe glucose intolerance, which was associated with a downregulation of GLUT-2 mRNA expression. In isolated islets from hIAPP males cultured for 3 weeks on high-glucose medium, the percentage of amyloid containing islets increased from 5.5% to 70%. This ex vivo system will allow a more rapid, convenient, and specific study of factors influencing islet amyloidosis as well as of therapeutic strategies to interfere with this pathological process.

J. W. M. Höppener

H. M. Jacobs

N. Wierup

G. Sotthewes

M. Sprong

P. de Vos

R. Berger

F. Sundler

B. Ahrén

Human Islet Amyloid Polypeptide Transgenic Mice: In Vivo and Ex Vivo Models for the Role of hIAPP in Type 2 Diabetes Mellitus

The presence of fibrillar protein deposits (amyloid) of human islet amyloid polypeptide (hIAPP) in the pancreatic islets of Langerhans is thought to be related to death of the insulin-producing islet <svg style="vertical-align:-2.29482pt;width:8.8500004px;" id="M2" height="13.425" version="1.1" viewBox="0 0 8.8500004 13.425" width="8.8500004"  xmlns="http://www.w3.org/2000/svg"><g transform="matrix(1.25,0,0,-1.25,0,13.425)"><g transform="translate(72,-61.26)"><text transform="matrix(1,0,0,-1,-71.95,63.6)"><tspan style="font-size: 12.50px; " x="0" y="0">𝛽</tspan></text></g></g></svg>-cells in type 2 diabetes mellitus (DM2). The mechanism of hIAPP-induced <svg style="vertical-align:-2.29482pt;width:8.8500004px;" id="M3" height="13.425" version="1.1" viewBox="0 0 8.8500004 13.425" width="8.8500004"  xmlns="http://www.w3.org/2000/svg"><g transform="matrix(1.25,0,0,-1.25,0,13.425)"><g transform="translate(72,-61.26)"><text transform="matrix(1,0,0,-1,-71.95,63.6)"><tspan style="font-size: 12.50px; " x="0" y="0"></tspan></text></g></g></svg>-cell death is not understood. However, there is growing evidence that hIAPP-induced disruption of <svg style="vertical-align:-2.29482pt;width:8.8500004px;" id="M4" height="13.425" version="1.1" viewBox="0 0 8.8500004 13.425" width="8.8500004"  xmlns="http://www.w3.org/2000/svg"><g transform="matrix(1.25,0,0,-1.25,0,13.425)"><g transform="translate(72,-61.26)"><text transform="matrix(1,0,0,-1,-71.95,63.6)"><tspan style="font-size: 12.50px; " x="0" y="0">𝛽</tspan></text></g></g></svg>-cell membranes is the cause of hIAPP cytotoxicity. Amyloid cytotoxicity by membrane damage has not only been suggested for hIAPP, but also for peptides and proteins related to other misfolding diseases, like Alzheimer&#x2019;s disease, Parkinson&#x2019;s disease, and prion diseases. Here we review the interaction of hIAPP with membranes, and discuss recent progress in the field, with a focus on hIAPP structure and on the proposed mechanisms of hIAPP-induced membrane damage in relation to <svg style="vertical-align:-2.29482pt;width:8.8500004px;" id="M5" height="13.425" version="1.1" viewBox="0 0 8.8500004 13.425" width="8.8500004"  xmlns="http://www.w3.org/2000/svg"><g transform="matrix(1.25,0,0,-1.25,0,13.425)"><g transform="translate(72,-61.26)"><text transform="matrix(1,0,0,-1,-71.95,63.6)"><tspan style="font-size: 12.50px; " x="0" y="0">𝛽</tspan></text></g></g></svg>-cell death in DM2.

Lucie Khemtémourian

J. Antoinette Killian

Jo W. M. Höppener

Maarten F. M. Engel

Recent Insights in Islet Amyloid Polypeptide-Induced Membrane Disruption and Its Role in <svg style="vertical-align:-3.56265pt" height="16.6625" version="1.1" viewBox="0 0 10 16.6625" width="10" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg"><g transform="matrix(.017,-0,0,-.017,.062,12.162)"><path id="x1D6FD" d="M558 587q0 -32 -14 -61t-40 -53.5t-48.5 -41t-54.5 -36.5q144 -51 144 -174q0 -55 -43.5 -108t-104.5 -87q-77 -42 -131 -42q-31 0 -54 20t-31 47l11 18q48 -29 108 -29q79 0 119.5 43t40.5 109t-44.5 107.5t-119.5 50.5l22 47q34 1 65 21q96 61 96 157q0 42 -24 67.5&#xA;t-62 25.5q-24 0 -43.5 -9t-35 -29.5t-27 -44t-22.5 -63t-19.5 -75.5t-18.5 -91q-57 -294 -68 -380q-26 -190 -35 -200q-26 -31 -97 -37l-4 26q19 9 48 170l77 413q23 121 52.5 187.5t83.5 114.5q70 62 148 62q51 0 88.5 -34t37.5 -91z" /></g></svg>-Cell Death  in Type 2 Diabetes Mellitus

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<p><em>Journal of Diabetes Research</em> publishes articles related to type 1 and type 2 diabetes. Topics include etiology, pathogenesis, management, and prevention of diabetes, as well as associated complications such as nephropathy.</p>


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<p>Chief Editor Dr Mark Yorek, from the University of Iowa, is currently researching vascular and neural disease related to obesity and diabetes. His active research studies focus on etiology, treatment and prevention of nerve damage.</p>


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Journal of Diabetes Research publishes articles related to type 1 and type 2 diabetes. Topics include etiology, pathogenesis, management, and prevention of diabetes, as well as associated complications such as nephropathy.

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Journal of Diabetes Research | Hindawi

Journal of Diabetes Research

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