Amylin replacement with pramlintide as an adjunct to insulin therapy improves long‐term glycaemic and weight control in Type 1 diabetes mellitus: a 1‐year, randomized controlled trial

Ratner, Robert E.; Dickey, Richard A.; Fineman, Mark; Maggs, David; Shen, Larry Z.; Strobel, Susan; Weyer, Christian; Kolterman, Orville G.

doi:10.1111/j.1464-5491.2004.01319.x

Cited by 274 publications

(271 citation statements)

References 41 publications

Supporting

Mentioning

259

Contrasting

Order By: Relevance

“…rIAPP, which is nontoxic and does not form amyloid in vivo or in vitro, differs from hIAPP at six sites, including three proline residues at positions 25, 28, and 29 and the replacement of H18 by R. These substitutions significantly influence the aggregation behavior of the polypeptide, whereas the others are more conservative: F23 in the human peptide is replaced by L, and I26 by V. We used the following series of mutations to test the role of specific residues in membrane interactions: First, pramlintide (PM) is an analog of hIAPP, which contains the three proline substitutions found in rIAPP. The molecule does not form amyloid in dilute solution, is not toxic, and has been approved as a complement to insulin therapy for the treatment of diabetes (32). Comparison of hIAPP and PM allows us to probe the role of the three prolines.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Islet amyloid polypeptide toxicity and membrane interactions

Cao

Abedini

Wang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

131

143

View full text Add to dashboard Cite

Islet amyloid polypeptide (IAPP) is responsible for amyloid formation in type 2 diabetes and contributes to the failure of islet cell transplants, however the mechanisms of IAPP-induced cytotoxicity are not known. Interactions with model anionic membranes are known to catalyze IAPP amyloid formation in vitro. Human IAPP damages anionic membranes, promoting vesicle leakage, but the features that control IAPP-membrane interactions and the connection with cellular toxicity are not clear. Kinetic studies with wildtype IAPP and IAPP mutants demonstrate that membrane leakage is induced by prefibrillar IAPP species and continues over the course of amyloid formation, correlating additional membrane disruption with fibril growth. Analyses of a set of designed mutants reveal that membrane leakage does not require the formation of β-sheet or α-helical structures. A His-18 to Arg substitution enhances leakage, whereas replacement of all of the aromatic residues via a triple leucine mutant has no effect. Biophysical measurements in conjunction with cytotoxicity studies show that nonamyloidogenic rat IAPP is as effective as human IAPP at disrupting standard anionic model membranes under conditions where rat IAPP does not induce cellular toxicity. Similar results are obtained with more complex model membranes, including ternary systems that contain cholesterol and are capable of forming lipid rafts. A designed point mutant, I26P-IAPP; a designed double mutant, G24P, I26P-IAPP; a double N-methylated variant; and pramlintide, a US Food and Drug Administration-approved IAPP variant all induce membrane leakage, but are not cytotoxic, showing that there is no one-to-one relationship between disruption of model membranes and induction of cellular toxicity.

show abstract

Section: Resultsmentioning

confidence: 99%

“…PM, N-methyl-IAPP, and rIAPP have been reported to be nontoxic (32,34,36). We tested the cytotoxicity of I26P-IAPP, DM-IAPP, rIAPP, and N-methyl-IAPP using rat insulinoma-1 (INS-1) β cells.…”

Section: Toxic and Nontoxic Variants Of Iapp Induce Model Membranementioning

confidence: 99%

Islet amyloid polypeptide toxicity and membrane interactions

Cao

Abedini

Wang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

131

143

View full text Add to dashboard Cite

show abstract

“…Side effects of pramlintide administration are a likely reason; nausea, anorexia, vomiting and hypoglycemia are commonly reported adverse events (Whitehouse et al 2002, Ratner et al 2004, Edelman et al 2006) and appear to be worse in T1D than in T2D or obese individuals. The anorexia and nausea induced by pramlintide may also be factors in sustained weight loss and long-term improvements in glycemia.…”

Section: Journal Of Molecular Endocrinologymentioning

confidence: 99%

IAPP and type 1 diabetes: implications for immunity, metabolism and islet transplants

Denroche

Verchere

2018

Journal of Molecular Endocrinology

View full text Add to dashboard Cite

Islet amyloid polypeptide (IAPP), the main component of islet amyloid in type 2 diabetes and islet transplants, is now recognized as a contributor to beta cell dysfunction. Increasingly, evidence warrants its investigation in type 1 diabetes owing to both its immunomodulatory and metabolic actions. Autoreactive T cells to IAPP-derived epitopes have been described in humans, suggesting that IAPP is an islet autoantigen in type 1 diabetes. In addition, although aggregates of IAPP have not been implicated in type 1 diabetes, they are potent pro-inflammatory stimuli to innate immune cells, and thus, could influence autoimmunity. IAPP aggregates also occur rapidly in transplanted islets and likely contribute to islet transplant failure in type 1 diabetes through sterile inflammation. In addition, since type 1 diabetes is a disease of both insulin and IAPP deficiency, clinical trials have examined the potential benefits of IAPP replacement in type 1 diabetes with the injectable IAPP analogue, pramlintide. Pramlintide limits postprandial hyperglycemia by delaying gastric emptying and suppressing hyperglucagonemia, underlining the possible role of IAPP in postprandial glucose metabolism. Here, we review IAPP in the context of type 1 diabetes: from its potential involvement in type 1 diabetes pathogenesis, through its role in glucose metabolism and use of IAPP analogues as therapeutics, to its potential role in clinical islet transplant failure and considerations in this regard for future beta cell replacement strategies.

show abstract

“…Pramlintide can significantly decrease post-meal glucagon levels in type 1 diabetes mellitus and trials have also shown that pramlintide reduces glucose variability by delaying gastric emptying. [51][52][53][54][55] …”

Section: Amylinmentioning

confidence: 99%

Alpha cell function in type 1 diabetes

Hughes

Narendran

2014

Br J Diabetes

View full text Add to dashboard Cite

Our understanding of the pathogenesis of type 1 diabetes mellitus has traditionally revolved around the insulin deficiency that follows pancreatic beta cell loss. However, there is an increasing appreciation of defects in other glucoregulatory cells in type 1 diabetes mellitus. Oversecretion of glucagon from pancreatic alpha cells is characteristic of type 1 diabetes mellitus, and modulating these glucagon levels reduces hyperglycaemia. This article reviews alpha cell function in type 1 diabetes mellitus. We examine how its function is controlled and compromised, and review studies that target alpha cell function. Finally, we explore potential approaches to modulating alpha cell function in type 1 diabetes mellitus. Br J Diabetes Vasc Dis 2014;14:45-51

show abstract

Amylin replacement with pramlintide as an adjunct to insulin therapy improves long‐term glycaemic and weight control in Type 1 diabetes mellitus: a 1‐year, randomized controlled trial

Abstract: These results show that mealtime amylin replacement with pramlintide, as an adjunct to insulin therapy, improves long-term glycaemic and weight control in patients with Type 1 diabetes.

Cited by 274 publications

References 41 publications

Islet amyloid polypeptide toxicity and membrane interactions

Islet amyloid polypeptide toxicity and membrane interactions

IAPP and type 1 diabetes: implications for immunity, metabolism and islet transplants

Alpha cell function in type 1 diabetes

Contact Info

Product

Resources

About