Pramlintide in the Treatment of Diabetes Mellitus

Edelman, Steve; Maier, Holly; Wilhelm, Ken

doi:10.2165/0063030-200822060-00004

Cited by 54 publications

(39 citation statements)

References 26 publications

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“…2 In insulin-treated patients with diabetes, pramlintide, a synthetic and equipotent analog of human amylin, 3,4 reduces postprandial glucose excursions by suppressing inappropriately elevated postprandial glucagon secretion and by slowing gastric emptying. [5][6][7] Amylin also reliably reduces food intake and body weight in rodents. Peripheral administration decreases food intake, 8 and among systemically administered anorexigenic molecules (amylin, salmon calcitonin, peptide YY 3-36, cholecystokinin-8, glucagon-like peptide-1, CGRP, adrenomedullin, leptin, the melanocortin agonist MTII, the cannabinoid receptor antagonist AM251 and naloxone), amylin receptor agonism demonstrates the greatest potency to inhibit consumption.…”

Section: Introductionmentioning

confidence: 99%

Davalintide (AC2307), a novel amylin-mimetic peptide: enhanced pharmacological properties over native amylin to reduce food intake and body weight

Mack¹,

Soares²,

Wilson³

et al. 2009

Int J Obes

105

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Objective: The current set of studies describe the in vivo metabolic actions of the novel amylin-mimetic peptide davalintide (AC2307) in rodents and compares these effects with those of the native peptide. Research design and methods: The anti-obesity effects of davalintide were examined after intraperitoneal injection or sustained peripheral infusion through subcutaneously implanted osmotic pumps. The effect of davalintide on food intake after lesioning of the area postrema (AP) and neuronal activation as measured by c-Fos, were also investigated. Results: Similar to amylin, davalintide bound with high affinity to amylin, calcitonin and calcitonin gene-related peptide receptors. Acutely, davalintide displayed greater suppression of dark-cycle feeding and an extended duration of action compared with amylin (23 versus 6 h). Davalintide had no effect on locomotor activity or kaolin consumption at doses that decreased food intake. Davalintide-induced weight loss through infusion was dose dependent, durable up to 8 weeks, fat-specific and lean-sparing, and was associated with a shift in food preference away from high-fat (palatable) chow. Metabolic rate was maintained during active weight loss. Both davalintide and amylin failed to suppress food intake after lesioning of the AP and activated similar brain nuclei, with davalintide displaying an extended duration of c-Fos expression compared with amylin (8 versus 2 h). Conclusion: Davalintide displayed enhanced in vivo metabolic activity over amylin while retaining the beneficial properties possessed by the native molecule. In vitro receptor binding, c-Fos expression and AP lesion studies suggest that the metabolic actions of davalintide and amylin occur through activation of similar neuronal pathways.

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Section: Introductionmentioning

confidence: 99%

Davalintide (AC2307), a novel amylin-mimetic peptide: enhanced pharmacological properties over native amylin to reduce food intake and body weight

Mack¹,

Soares²,

Wilson³

et al. 2009

Int J Obes

105

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“…IAPP mediated inhibition of glycolysis induces metabolic stress due to nutrient deprivation resulting in accumulation of intra-cellular ROS and the induction of apoptosis in p53 deficient tumors and cancer cells. Importantly, a synthetic analog of amylin called pramlintide 30 is an FDA approved drug used to treat type I and II diabetic patients. Treatment of p53-deficient tumors and p53 altered human cancer cell lines with pramlintide resulted in glycolytic inhibition within the tumor and marker tumor regression.…”

Section: Introductionmentioning

confidence: 99%

Novel therapeutic interventions for p53-altered tumors through manipulation of its family members, p63 and p73

et al. 2016

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TP53 is highly mutated in human cancers, thus targeting this tumor suppressor pathway is highly desirable and will impact many cancer patients.1,2 Therapeutic strategies to reactivate the p53-pathway have been challenging, 3,4 and no effective treatment exists. 5 We utilized the p53-family members, p63 and p73, which are not frequently mutated in cancer, to treat p53-defective cancers. The N-terminal splice variants of p63 and p73 are denoted as the TA and DN isoforms. We recently demonstrated that deletion of either DNp63 or DNp73 in p53-deficient mouse tumors results in tumor regression mediated by metabolic programming. Using this strategy, we identified pramlintide, a synthetic analog of amylin, as an effective treatment for p53 deficient and mutant tumors. Here, we show the utility of using pramlintide, as a potential cancer preventive option for p53-deficient tumors in mouse models. Additionally, we found that in vivo inhibition of both DNp63 and DNp73 in combination accelerates tumor regression and increases survival of p53-deficient mice. We report that inhibition of both DNp63 and DNp73 in combination results in upregulation of 3 key metabolic regulators, IAPP, GLS2, and TIGAR resulting in an increase in apoptosis and tumor regression in DNp63/DNp73/p53 deficient thymic lymphomas. These data highlight the value of generating inhibitors that will simultaneously target DNp63 and DNp73 to treat cancer patients with alterations in p53.

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“…Conceptually, this approach is appealing. The loss of b-cell function leads to the obvious loss of insulin production but also amylin production as well (36). Amylin plays an important role physiologically by suppressing glucagon production, contributing to regulation of gastric emptying, and impacting satiety.…”

Section: Hormones Beyond Glucagonmentioning

confidence: 99%

Pathway to Artificial Pancreas Systems Revisited: Moving Downstream

Kowalski

2015

Diabetes Care

106

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Artificial pancreas (AP) systems, a long-sought quest to replicate mechanically islet physiology that is lost in diabetes, are reaching the clinic, and the potential of automating insulin delivery is about to be realized. Significant progress has been made, and the safety and feasibility of AP systems have been demonstrated in the clinical research center and more recently in outpatient "real-world" environments. An iterative road map to AP system development has guided AP research since 2009, but progress in the field indicates that it needs updating. While it is now clear that AP systems are technically feasible, it remains much less certain that they will be widely adopted by clinicians and patients. Ultimately, the true success of AP systems will be defined by successful integration into the diabetes health care system and by the ultimate metric: improved diabetes outcomes.An electromechanical approach to improve glycemic control and quality of life for people with diabetesdan artificial pancreas (AP) (or an automated insulin-delivery system or bionic pancreas)dhas been a long-sought technological goal of diabetes researchers (1). However, a number of significant challenges needed to be overcome to deliver an AP system to people with diabetes. The past 10 years have seen many of these challenges addressed, and recent studies have demonstrated compelling safety and efficacy of the prototype systems (2). Technical feasibility is only a step toward declaring victory. Research and development efforts will continue to improve upon first-generation AP systems. But, it is clear that resources will need to be deployed to address clinical adoption challengesdincluding device usability and reimbursement.Research and development efforts over the past 10 years have addressed a number of the critical issues facing AP development, and recent studies again signal a move to a new phase and a call for a new road map to AP systems. A number of groups have demonstrated proof of concept with a variety of algorithmic approaches and closed-loop strategies and the data are compelling. In a Bench to Clinic narrative, Cefalu and Tamborlane (3) dive much deeper than this Perspective intends into the "how" of AP systems. They note quite astutely that "it is not the journey, but the destination that matters" (3).It may come as a surprise to many clinicians, but a small and growing group of lay, "do-it-yourself," technically savvy people with diabetes or loved ones of people with diabetes has been using semiautomated closed-loop systems at home for well over 2 years with impressive results (4-6). These systems, similar to systems being studied in academic studies, combine off-the-shelf insulin pumps and continuous glucose monitors with control algorithms (computer software that interprets glucose information and drives the dosing of insulin) powered by cell phone devices. The results from academia and these anecdotal reports are harbingers of a JDRF, New York, NY

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Pramlintide in the Treatment of Diabetes Mellitus

Cited by 54 publications

References 26 publications

Davalintide (AC2307), a novel amylin-mimetic peptide: enhanced pharmacological properties over native amylin to reduce food intake and body weight

Davalintide (AC2307), a novel amylin-mimetic peptide: enhanced pharmacological properties over native amylin to reduce food intake and body weight

Novel therapeutic interventions for p53-altered tumors through manipulation of its family members, p63 and p73

Pathway to Artificial Pancreas Systems Revisited: Moving Downstream

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