Impact of tirzepatide in a patient with type 1 diabetes and obesity: A case report.

BACKGROUND: The purpose of this case report is to describe the use of tirzepatide, a glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonist, in a patient with type 1 diabetes mellitus (T1DM) and obesity. CASE SUMMARY: A 23-year-old female with T1DM since the age of 10 years was referred to an endocrinology clinic for specialized diabetes care with a pharmacist owing to increasing insulin requirements and resistance. At baseline, the patient weighed 195 pounds (86.64 kg), which had increased significantly by approximately 40 pounds in the last year, and had a body mass index of 38 kg/m2 and hemoglobin A1c (HbA1c) level of 7.4%. She used hybrid closed loop insulin pump technology with continuous glucose monitoring in 100% automation mode. The patient used on average 55.4 units of basal insulin and 26.5 units of bolus per day (total daily dose, 81.9 units) with a time in range (TIR) of 31%. The patient was started on tirzepatide 2.5 mg weekly and titrated to 7.5 mg weekly with 4-week dose titrations. After 12 weeks, the patient's TIR had doubled to 61% with improvements in glucose variability, insulin requirements had decreased to 57.6 units per day, HbA1c had decreased to 6.9%, daily carbohydrates had decreased by approximately 24%, and weight had decreased to 188 pounds (-7 lbs). PRACTICE IMPLICATIONS: With additional studies, tirzepatide may be a safe and effective option for patients with T1DM and obesity to improve glycemic control, reduce insulin requirements, and promote weight loss.

Peroxynitrite nitration of Tyr 56 in Hsp90 induces PC12 cell death through P2X7R-dependent PTEN activation.

The diffusion-limited reaction of nitric oxide (NO) and superoxide (O2-) produces peroxynitrite (ONOO-), a biological oxidant that has been implicated in a number of pathological conditions, including neurodegenerative disorders. We previously reported that incubation of PC12 cells with peroxynitrite triggers apoptosis by simultaneously inhibiting the PI3K/Akt survival pathway, and activating the p38 and JNK MAP kinase pathways. We also reported that peroxynitrite-treated Heat Shock Protein 90 (Hsp90) stimulates PC12 cell death. Here, we show that nitrated Hsp90 mediates peroxynitrite-induced apoptosis by regulating specific signaling pathways triggered by activation of the purine receptor P2X7 (P2X7R) and downstream activation of PTEN. Intracellular delivery of peroxynitrite-treated Hsp90 was sufficient to stimulate PC12 cell death. In contrast, intracellular delivery of peroxynitrite-treated Hsp90 in which the five tyrosine (Tyr) residues susceptible to nitration were replaced by nitration-resistant phenylalanine had no effect on PC12 cell survival. Further, only nitration of Hsp90 at Tyr 56 was necessary and sufficient to stimulate PC12 cell apoptosis, and incubation of PC12 cells with peroxynitrite resulted in Hsp90 nitration at Tyr 56. Inhibition of P2X7R or downstream inhibition of PTEN prevented PC12 cell death stimulated by both incubation with peroxynitrite and nitrated Hsp90 (Hsp90NY). Peroxynitrite, Hsp90NY, and P2X7R activation all increased p38 and JNK MAP kinases activity, while inhibiting the Akt survival pathway. These results suggest that, in undifferentiated PC12 cells, peroxynitrite triggers apoptosis via nitration of Hsp90 at Tyr 56, which in turn activates P2X7R and PTEN. These results contrast with observations in motor neurons where the nitration of either Tyr 33 or Tyr 56 in Hsp90 stimulates apoptosis, suggesting that the targets of peroxynitrite may be different in different cell types. However, uncovering the pathways through which peroxynitrite triggers cell death in neurodegenerative conditions will provide new potential targets for therapeutic treatment.

Venous Biomechanics of Angioplasty and Stent Placement: Implications of the Poisson Effect.

PURPOSE: To characterize the Poisson effect in response to angioplasty and stent placement in veins and identify potential implications for guiding future venous-specific device design. MATERIALS AND METHODS: In vivo angioplasty and stent placement were performed in 3 adult swine by using an established venous stenosis model. Iron particle endothelium labeling was performed for real-time fluoroscopic tracking of the vessel wall during intervention. A finite-element computational model of a vessel was created with ADINA software (version 9.5) with arterial and venous biomechanical properties obtained from the literature to compare the response to radial expansion. RESULTS: In vivo angioplasty and stent placement in a venous stenosis animal model with iron particle endothelium labeling demonstrated longitudinal foreshortening that correlated with distance from the center of the balloon (R2 = 0.87) as well as adjacent segment narrowing that correlated with the increase in diameter of the treated stenotic segment (R2 = 0.89). Finite-element computational analysis demonstrated increased Poisson effect in veins relative to arteries (linear regression coefficient slope comparison, arterial slope 0.033, R2 = 0.9789; venous slope 0.204, R2 = 0.9975; P < .0001) as a result of greater longitudinal Young modulus in veins compared with arteries. CONCLUSIONS: Clinically observed adjacent segment narrowing during venous angioplasty and stent placement is a result of the Poisson effect, with redistribution of radially applied force to the longitudinal direction. The Poisson effect is increased in veins relative to arteries as a result of unique venous biomechanical properties, which may be relevant to consider in the design of future venous interventional devices.