IGF-IR Internalizes with Caveolin-1 and PTRF/Cavin in Hacat Cells

BACKGROUND: Insulin-like growth factor-I receptor (IGF-IR) is a tyrosine kinase receptor (RTK) associated with caveolae, invaginations of the plasma membrane that regulate vesicular transport, endocytosis and intracellular signaling. IGF-IR internalization represents a key mechanism of down-modulation of receptors number on plasma membrane. IGF-IR interacts directly with Caveolin-1 (Cav-1), the most relevant protein of caveolae. Recently it has been demonstrated that the Polymerase I and Transcript Release Factor I (PTRF/Cavin) is required for caveolae biogenesis and function. The role of Cav-1 and PTRF/Cavin in IGF-IR internalization is still to be clarified. METHODOLOGY/PRINCIPAL FINDINGS: We have investigated the interaction of IGF-IR with Cav-1 and PTRF/Cavin in the presence of IGF1in human Hacat cells. We show that IGF-IR internalization triggers Cav-1 and PTRF/Cavin translocation from plasma membrane to cytosol and increases IGF-IR interaction with these proteins. In fact, Cav-1 and PTRF/Cavin co-immunoprecipitate with IGF-IR during receptor internalization. We found a different time course of co-immunoprecipitation between IGF-IR and Cav-1 compared to IGF-IR and PTRF/Cavin. Cav-1 and PTRF/Cavin silencing by siRNA differently affect surface IGF-IR levels following IGF1 treatment: Cav-1 and PTRF/Cavin silencing significantly affect IGF-IR rate of internalization, while PTRF/Cavin silencing also decreases IGF-IR plasma membrane recovery. Since Cav-1 phosphorylation could have a role in IGF-IR internalization, the mutant Cav-1Y14F lacking Tyr14 was transfected. Cav-1Y14F transfected cells showed a reduced internalization of IGF-IR compared with cells expressing wild type Cav-1. Receptor internalization was not impaired by Clathrin silencing. These findings support a critical role of caveolae in IGF-IR intracellular traveling. CONCLUSIONS/SIGNIFICANCE: These data indicate that Caveolae play a role in IGF-IR internalization. Based on these findings, Cav-1 and PTRF/Cavin could represent two relevant and distinct targets to modulate IGF-IR function

Restoration of acute insulin response in T2DM subjects 1 month after biliopancreatic diversion

objective: Biliopancreatic diversion (BPD) restores normal glucose tolerance in a few weeks in morbid obese subjects with type 2 diabetes, improving insulin sensitivity. However, there is less known about the effects of BPD on insulin secretion. We tested the early effects of BPD on insulin secretion in obese subjects with and without type 2 diabetes. Methods and Procedures: Twenty-one consecutive morbid obese subjects, 9 with type 2 diabetes (T2DM) and 12 with normal fasting glucose (NFG) were evaluated, just before and 1 month after BPD, by measuring body weight (BW), glucose, adipocitokines, homeostasis model assessment of insulin resistance (HOMA-IR), acute insulin response (AIR) to e.v. glucose and the insulinogenic index adjusted for insulin resistance ([∆I5/∆G5]/HOMA-IR). Results: Preoperatively, those with T2DM differed from those with NFG in showing higher levels of fasting glucose, reduced AIR (57.9 ± 29.5 vs. 644.9 ± 143.1 pmol/l, P < 0.01) and reduced adjusted insulinogenic index (1.0 ± 0.5 vs. 17.6 ± 3.9 1/mmol 2 , P < 0.001). One month following BPD, in both groups BW was reduced (by ~11%), but all subjects were still severely obese; HOMA-IR and leptin decreased significanlty, while high-molecular weight (HMW) adiponectin and adjusted insulinogenic index increased. In the T2DM group, fasting glucose returned to non-diabetic values. AIR did not change in the NFG group, while in the T2DM group it showed a significant increase (from 58.0 ± 29.5 to 273.8 ± 47.2 pmol/l, P < 0.01). In the T2DM group, the AIR percentage variation from baseline was significantly related to changes in fasting glucose (r = 0.70, P = 0.02), suggesting an important relationship exists between impaired AIR and hyperglycaemia. Discussion: BPD is able to restore AIR in T2DM even just 1 month after surgery. AIR restoration is associated with normalization of fasting glucose concentrations

Clinical Features, Cardiovascular Risk Profile, and Therapeutic Trajectories of Patients with Type 2 Diabetes Candidate for Oral Semaglutide Therapy in the Italian Specialist Care

Introduction: This study aimed to address therapeutic inertia in the management of type 2 diabetes (T2D) by investigating the potential of early treatment with oral semaglutide. Methods: A cross-sectional survey was conducted between October 2021 and April 2022 among specialists treating individuals with T2D. A scientific committee designed a data collection form covering demographics, cardiovascular risk, glucose control metrics, ongoing therapies, and physician judgments on treatment appropriateness. Participants completed anonymous patient questionnaires reflecting routine clinical encounters. The preferred therapeutic regimen for each patient was also identified. Results: The analysis was conducted on 4449 patients initiating oral semaglutide. The population had a relatively short disease duration (42%  60% of patients, and more often than sitagliptin or empagliflozin. Conclusion: The study supports the potential of early implementation of oral semaglutide as a strategy to overcome therapeutic inertia and enhance T2D management

Type 2 diabetes and weight loss following biliopancreatic diversion for obesity.

BACKGROUND: The authors investigated the weight loss and maintenance in type 2 diabetic obese patients undergoing biliopancreatic diversion (BPD). METHODS: Two series of diabetic and non-diabetic obese patients matched for gender, age and baseline body mass index (BMI) were evaluated prior to BPD, on the occasion of the regular follow-up visit at 1, 2 and 3 years following the operation, and at the fifth postoperative year. At each follow-up point, body weight (BW), BMI, and serum glucose concentration were measured. RESULTS: In all type 2 diabetic patients, the serum glucose level fell to within the normal range at the first postoperative year and remained within normal limits without any medication throughout all the follow-up period. In preoperatively diabetic subjects, mean values of BW and BMI were closely similar to those of non-diabetic subjects at all follow-up points, and the stabilization weight was independently related to age and to initial BW values. CONCLUSIONS: In obese patients with type 2 diabetes, the glucose level steadily normalized in every case following BPD, and values remained unchanged throughout the follow-up period. After the operation, the type 2 diabetic obese patients experienced the same stable weight reduction as their non-diabetic counterparts

The interplay between diabetes, depression and affective temperaments: A structural equation model

Background Diabetes and depression are reciprocally linked, but few studies modeled their interplay considering the influence of affective temperaments (AT) and demographic factors. Methods Participants with type 1 and type 2 diabetes (T1DM and T2DM, n=279) recruited from Diabetes Units were assessed with the Beck Depression Inventory (BDI), Temperament Evaluation of Memphis, Pisa, Paris and San Diego-autoquestionnaire version (TEMPS-A), Morisky Medication Adherence Scale (MMAS), Diabetes Distress Scale (DDS) and Cumulative Illness Rating Scales (CIRS). Glycosylated hemoglobin levels (HBA1C) was used as index of glycemic control. The bi-directional association between glycemic control, depression and candidate mediators was examined with Structural Equation Modeling, testing the impact of moderator variables (AT, diabetes type, age and gender) with multigroup comparison. Results The association between HBA1C and depressive symptoms was mediated by diabetes-related distress, while there was no definite evidence of depression influencing HBA1C through changes of adherence, tiredness, appetite, alcohol intake or smoking. Among individuals with AT, distress was unrelated to HBA1C and had a higher impact on depression; adherence was inversely association with HBA1C. Moreover, physical comorbidities impacted on depression. While diabetes type had a moderation role, age and gender did not affect the model. Limitations Cross sectional design, lack of objective measures of diet and physical activity. Conclusions Glycemic control seem to influence the severity of depressive symptoms, but the reciprocal association seems non-significant. AT and diabetes type may shape this relationship influencing distress and adherence to medications. Findings may aid interventions aimed at improving patients\u2019 care and quality of life

Beta-cell function improvement after biliopancreatic diversion in subjects withtype 2 diabetes and morbid obesity.

In subjects with obesity and type 2 diabetes mellitus (T2DM), biliopancreatic diversion (BPD) improves glucose stimulated insulin secretion, whereas the effects on other secretion mechanisms are still unknown. Our objective was to evaluate the early effects of BPD on nonglucose-stimulated insulin secretion. In 16 morbid obese subjects (9 with T2DM and 7 with normal fasting glucose (NFG)), we measured insulin secretion after glucose-dependent arginine stimulation test and after intravenous glucose tolerance test (IVGTT) before and 1 month after BPD. After surgery the mean weight lost was 13% in both groups. The acute insulin response during IVGTT was improved in T2DM after BDP (from 55 +/- 10 to 277 +/- 91 pmol/l, P = 0.03). A reduction of insulin response to arginine was observed in NFG, whereas opposite was found in T2DM. In particular, acute insulin response to arginine at basal glucose concentrations (AIR(basal)) was reduced but insulin response at 14 mmol/l of plasma glucose (AIR(14)) was increased. Therefore, after BPD any statistical difference in AIR(14) between NFG and T2DM disappeared (1,032 +/- 123 for NFG and 665 +/- 236 pmol/l for T2DM, P = ns). The same was observed for Slope(AIR), a measure of glucose potentiation, reduced in T2DM before BPD but increased after surgery, when no statistically significant difference resulted compared with NFG (Slope(AIR) after BPD: 78 +/- 11 in NFG and 56 +/- 18 pmol/l in T2DM, P = ns). In conclusion, in obese T2DM subjects 1 month after BPD we observed a great improvement of both glucose- and nonglucose-stimulated insulin secretions. The mechanisms by which BDP improve insulin secretion are still unknown