Effect of Age on Diabetogenicity of Alloxan in Ossabaw Miniature Swine

According to a single study in dogs that was conducted in 1949, the diabetic effects of the β-cell toxin alloxan are dependent on age. The current study examined whether this age-dependence of alloxan is present in the clinically relevant Ossabaw miniature swine (Sus scrofa domestica) model of metabolic syndrome. Juvenile swine (n = 8; age, 4.3 ± 0.2 mo) and adult swine (n = 8; age, 7.4 ± 0.2 mo) received alloxan (average dosage, 140 mg/kg IV) and were placed on a hypercaloric, atherogenic diet for 6 mo. The metabolic syndrome profile was confirmed by measuring body weight, cholesterol, and triglycerides. Intravenous glucose tolerance testing was used to assess glucose clearance and peripheral plasma insulin levels. The β-cell mass was calculated by immunohistochemical staining of pancreatic tissue. Although juvenile and adult swine exhibited comparable severity of metabolic syndrome, adult swine developed impaired glucose clearance and elevated fasting blood glucose levels at 6 mo after alloxan administration on the atherogenic diet. Peripheral plasma insulin levels in juvenile and adult swine were comparable at all time points and lower than in nonalloxan-treated age-matched controls, which is reflected in the lower pancreatic β-cell mass of the 2 treated groups. However, compared with adult pigs, juvenile swine exhibited greater insulin response recovery (complete or partial restoration of peripheral insulin levels to reference values) at 6 mo after alloxan administration. Overall, these results indicate that youth can confer some protection against the diabetogenic effects of alloxan in swine, potentially due in part to the greater insulin response recovery of young pigs. This study supports previous research that the effects of alloxan are dependent on the developmental maturity of the animal

Effect of Age on Diabetogenicity of Alloxan in Ossabaw Miniature Swine

According to a single study in dogs that was conducted in 1949, the diabetic effects of the β-cell toxin alloxan are dependent on age. The current study examined whether this age-dependence of alloxan is present in the clinically relevant Ossabaw miniature swine (Sus scrofa domestica) model of metabolic syndrome. Juvenile swine (n = 8; age, 4.3 ± 0.2 mo) and adult swine (n = 8; age, 7.4 ± 0.2 mo) received alloxan (average dosage, 140 mg/kg IV) and were placed on a hypercaloric, atherogenic diet for 6 mo. The metabolic syndrome profile was confirmed by measuring body weight, cholesterol, and triglycerides. Intravenous glucose tolerance testing was used to assess glucose clearance and peripheral plasma insulin levels. The β-cell mass was calculated by immunohistochemical staining of pancreatic tissue. Although juvenile and adult swine exhibited comparable severity of metabolic syndrome, adult swine developed impaired glucose clearance and elevated fasting blood glucose levels at 6 mo after alloxan administration on the atherogenic diet. Peripheral plasma insulin levels in juvenile and adult swine were comparable at all time points and lower than in nonalloxan-treated age-matched controls, which is reflected in the lower pancreatic β-cell mass of the 2 treated groups. However, compared with adult pigs, juvenile swine exhibited greater insulin response recovery (complete or partial restoration of peripheral insulin levels to reference values) at 6 mo after alloxan administration. Overall, these results indicate that youth can confer some protection against the diabetogenic effects of alloxan in swine, potentially due in part to the greater insulin response recovery of young pigs. This study supports previous research that the effects of alloxan are dependent on the developmental maturity of the animal

Alloxan-induced diabetes exacerbates coronary atherosclerosis and calcification in Ossabaw miniature swine with metabolic syndrome

Abstract Background There is a preponderance of evidence implicating diabetes with increased coronary artery disease (CAD) and calcification (CAC) in human patients with metabolic syndrome (MetS), but the effect of diabetes on CAD severity in animal models remains controversial. We investigated whether diabetes exacerbates CAD/CAC and intracellular free calcium ([Ca2+]i) dysregulation in the clinically relevant Ossabaw miniature swine model of MetS. Methods Sixteen swine, eight with alloxan-induced diabetes, were fed a hypercaloric, atherogenic diet for 6 months. Alloxan-induced pancreatic beta cell damage was examined by immunohistochemical staining of insulin. The metabolic profile was confirmed by body weight, complete blood panel, intravenous glucose tolerance test (IVGTT), and meal tolerance test. CAD severity was assessed with intravascular ultrasound and histology. [Ca2+]i handling in coronary smooth muscle (CSM) cells was assessed with fura-2 ratiometric imaging. Results Fasting and post-prandial blood glucose, total cholesterol, and serum triglycerides were elevated in MetS-diabetic swine. This group also exhibited hypoinsulinemia during IVGTT and less pancreatic beta cell mass when compared to lean and MetS-nondiabetic swine. IVUS analysis revealed that MetS-diabetic swine had greater percent wall coverage, percent plaque burden, and calcium index when compared to lean and MetS-nondiabetic swine. Fura-2 imaging of CSM [Ca2+]i revealed that MetS-nondiabetic swine exhibited increased sarcoplasmic reticulum Ca2+ store release and Ca2+ influx through voltage-gated Ca2+ channels compared to lean swine. MetS-diabetic swine exhibited impaired Ca2+ efflux. Conclusions Diabetes exacerbates coronary atherosclerosis and calcification in Ossabaw miniature swine with MetS, accompanied by progression of [Ca2+]i dysregulation in advanced CAD/CAC. These results recapitulate increased CAD in humans with diabetes and establish Ossabaw miniature swine as an animal model for future MetS/diabetes comorbidity studies

Targeted Drug Delivery for the Treatment of Abdominal Pain in Chronic Pancreatitis: A Retrospective Case Series

Summary: Abdominal pain secondary to chronic pancreatitis (CP) is difficult to manage and often requires chronic oral opioid therapy (OOT). Targeted drug delivery (TDD) allows for a diminished dose of opioid intake and improved pain levels. TDD has been used in different pain syndromes with only limited reports in CP. Objective: The objective of this article is to perform a retrospective review of CP patients treated with TDD versus OOT to compare chronic pain control and consumed morphine-equivalent doses. Methods: Patients receiving TDD between September 2011 and August 2018 were included. All patients were weaned off oral opioids one week before intrathecal trial and pump implantation. Patients with intrathecal trials providing at least 50% pain relief underwent pump implantation. Data were collected while on OOT and at two weeks, three months, and nine months post-implant. Data were analyzed with Microsoft Excel 365 MSO using means and standard deviations. P-values were calculated using a two-tailed student’s t-test with paired two-sample means. Results: Twenty-three patients were analyzed. Pre-trial average pain score was 6.5/10 with a mean improvement with trials greater than 71%. The mean chronic baseline oral morphine milligram equivalents (MME) was 188. The mean MME on TDD at two weeks (0.36), three months (1.39), and nine months (2.47) were significantly lower than OOT. Mean pain scores were 6, 4.9, and 5.6 at two weeks, three months, and nine months, respectively, compared to 6.5 on OOT. Discussion: The results of this study indicate that TDD provides improved pain control with significantly lower opioid doses