Emerging utility of once-weekly exenatide in patients with type 2 diabetes

Goud, Aditya; Zhong, Jixin; Rajagopalan, Sanjay

doi:10.2147/dmso.s69354

Cited by 3 publications

(2 citation statements)

References 34 publications

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“…It shares 53% homology with the human GLP-1 [237] and avidly binds to the GLP-1 receptor on the surface of pancreatic β cells [283]; it is largely resistant to the action of serine protease Dipeptidyl peptidase-4 (DPP-4) [284]. The greater stability of the peptide exendin-4 sparked its rapid development and it is currently used for the treatment of T2D, because this compound reduces both fasting and prandial glucose levels [285]. In addition, it has been demonstrated that this compound limits food intake and increases satiety in normal glycemic and hyperglycemic individuals, with a consequent reduction in body weight [286,287,288].…”

Section: Antidiabetic Agent From Lizard Venom: Exenaidementioning

confidence: 99%

Insulin Release Mechanism Modulated by Toxins Isolated from Animal Venoms: From Basic Research to Drug Development Prospects

2019

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Venom from mammals, amphibians, snakes, arachnids, sea anemones and insects provides diverse sources of peptides with different potential medical applications. Several of these peptides have already been converted into drugs and some are still in the clinical phase. Diabetes type 2 is one of the diseases with the highest mortality rate worldwide, requiring specific attention. Diverse drugs are available (e.g., Sulfonylureas) for effective treatment, but with several adverse secondary effects, most of them related to the low specificity of these compounds to the target. In this context, the search for specific and high-affinity compounds for the management of this metabolic disease is growing. Toxins isolated from animal venom have high specificity and affinity for different molecular targets, of which the most important are ion channels. This review will present an overview about the electrical activity of the ion channels present in pancreatic β cells that are involved in the insulin secretion process, in addition to the diversity of peptides that can interact and modulate the electrical activity of pancreatic β cells. The importance of prospecting bioactive peptides for therapeutic use is also reinforced.

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Section: Antidiabetic Agent From Lizard Venom: Exenaidementioning

confidence: 99%

Insulin Release Mechanism Modulated by Toxins Isolated from Animal Venoms: From Basic Research to Drug Development Prospects

2019

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“…Eptifibatide extracted from venom of Sistrurus miliarius barbourin is effectively used for treatment of acute coronary syndromes (Tcheng and O’Shea, 1999; Zambelli et al, 2016). Exenatide, a peptide from lizard Heloderma suspectum , is currently used for treatment of type 2 diabetes (Goud et al, 2015). Spider venom contains peptide toxins targeting ion channels, making it a valuable resource for several potential therapeutic applications (Peng et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

JZTX-V Targets the Voltage Sensor in Kv4.2 to Inhibit Ito Potassium Channels in Cardiomyocytes

Zhang

Luo

et al. 2019

Front. Pharmacol.

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Kv4 potassium channels are responsible for transient outward K + currents in the cardiac action potential (AP). Previous experiments by our group demonstrated that Jingzhaotoxin-V (JZTX-V) selectively inhibits A-type potassium channels. However, the specific effects of JZTX-V on the transient outward (I to ) current of cardiomyocytes and underlying mechanism of action remain unclear. In the current study, 100 nM JZTX-V effectively inhibited the I to current and extended the action potential duration (APD) of neonatal rat ventricular myocytes (NRVM). We further analyzed the effects of JZTX-V on Kv4.2, a cloned channel believed to underlie the I to current in rat cardiomyocytes. JZTX-V inhibited the Kv4.2 current with a half-maximal inhibitory concentration (IC 50 ) of 13 ± 1.7 nM. To establish the molecular mechanism underlying the inhibitory action of JZTX-V on Kv4.2, we performed alanine scanning mutagenesis of Kv4.2 and JZTX-V and assessed the effects of the mutations on binding activities of the proteins. Interestingly, the Kv4.2 mutations V285A, F289A, and V290A reduced the affinity for JZTX-V while I275A and L277A increased the affinity for JZTX-V. Moreover, mutation of positively charged residues (R20 and K22) of JZTX-V and the hydrophobic patch (formed by W5, M6, and W7) led to a significant reduction in toxin sensitivity, indicating that the hydrophobic patch and electrostatic interactions played key roles in the binding of JZTX-V with Kv4.2. Data from our study have shed light on the specific roles and molecular mechanisms of JZTX-V in the regulation of I to potassium channels and supported its utility as a potential novel antiarrhythmic drug.

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Diabetes and the Small Intestine

Gotfried

Priest

Schey

2017

Curr Treat Options Gastro

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Diabetes mellitus (DM) and its associated complications are becoming increasingly prevalent. Gastrointestinal symptoms associated with diabetes is known as diabetic enteropathy (DE) and may manifest as either diarrhea, fecal incontinence, constipation, dyspepsia, nausea, and vomiting or a combination of symptoms. The long-held belief that vagal autonomic neuropathy is the primary cause of DE has recently been challenged by newer theories of disease development. Specifically, hyperglycemia and the resulting oxidative stress on neural networks, including the nitrergic neurons and interstitial cells of Cajal (ICC), are now believed to play a central role in the development of DE. DE occurs in the majority of patients with diabetes; however, tools for early diagnosis and targeted therapy to counter the detrimental and potentially irreversible effects on the small bowel are lacking. Delay in diagnosis is further compounded by the fact that DE symptoms overlap with those of gastroparesis or can be confused with side effects from diabetes medications. Still, early recognition of the presence of DE is essential to mitigating symptoms and preventing further progression of complications including dysmotility and malabsorption. Current diagnostic modalities include manometry, wireless motility capsule (SmartPill™), and scintigraphy; however, these are not regularly utilized in clinical practice due to limited availability. Several medications are available for symptom relief in DE patients including rifaximin for small intestinal bacterial overgrowth (SIBO) and somatostatin analogues for diarrhea. While rodent models on stem cell therapy and alteration of the microbiome are promising, there is still a great need for further research on the pathologic underpinnings and development of novel treatment modalities for DE.

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Emerging utility of once-weekly exenatide in patients with type 2 diabetes

Cited by 3 publications

References 34 publications

Insulin Release Mechanism Modulated by Toxins Isolated from Animal Venoms: From Basic Research to Drug Development Prospects

Insulin Release Mechanism Modulated by Toxins Isolated from Animal Venoms: From Basic Research to Drug Development Prospects

JZTX-V Targets the Voltage Sensor in Kv4.2 to Inhibit Ito Potassium Channels in Cardiomyocytes

Diabetes and the Small Intestine

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