Gabriella Andraghetti

Effects of biliopanceratic diversion on type 2 diabetes in patients with BMI 25 to 35.

Objective:Biliopancreatic diversion (BPD) resolves type 2 diabetes in near totality of morbidly obeses [BMI (body mass index) ≥35 kg/m2]. However, studies of BPD effect in BMI range 25.0 to 34.9 kg/m2, including about 90% of diabetic patients, are lacking. Materials and Methods:If BPD effects are independent of weight changes, they should be maintained in patients who, being mildly obese or overweight, will lose little or no weight after operation. Thirty type 2 diabetic patients with BMI 25 to 34.9 were submitted to BPD and monitored 12 months. Thirty-eight diabetic patients selected from a large database, kept 1 year on medical therapy, served as controls. Results:Nineteen male and 11 female. Mean age 56.4 ± 7.4 years, weight 84.8 ± 11.1 kg, BMI 30.6 ± 2.9 kg/m2, waist circumference 104 ± 9.4 cm, diabetes duration 11.2 ± 6.9 years, HbA1c 9.3±1.5. Twelve patients on insulin. Fifteen (2 F) with BMI < 30 (mean: 28.1). No mortality or major adverse events occurred. BMI progressively decreased, stabilizing around 25 since the fourth month, without excessive weight loss. One year after BPD, mean HbA1c was 6.3%±0.8, with 25 patients (83%) controlled (HbA1c⩽7%) on free diet, without antidiabetics, and the remaining improved. Acute insulin response to intravenous glucose had increased from 1.2 ± 2.9 to 4.2 ± 4.4 &mgr;IU/mL. Diabetes resolution correlated positively with BMI. HbA1c decreased at 1 year in the control group, along with an overall increased amount of antidiabetic therapy. Conclusions:BPD improves or resolves diabetes in BMI 25 to 35 without causing excessive weight loss, its action being on insulin sensitivity and beta-cell function. The strikingly different response between morbidly obese and low BMI patients might depend on different beta-cell defect. ClinicalTrials.gov Identifier: NCT00996294

The effects of biliopancreatic diversion on type 2 diabetes mellitus in patients with mild obesity (BMI 30-35 kg/m2) and simple overweight (BMI 25-30 kg/m2): a prospective controlled study.

BackgroundBeneficial effects of BPD on T2DM in BMI >35xa0kg/m2 patients are far better than those in patients with BMI 25–35. This study was aimed at investigating if a similar difference exists between patients with mild obesity (OB, BMI 30–35) or simple overweight (OW, BMI 25–30).MethodsFifteen OB (six M) and 15 OW (13 M), diabetic for ≥3xa0years, with HbA1c ≥7.5% despite medical therapy, underwent BPD. OB/OW: age 55.1u2009±u20098.0/57.8u2009±u20096.7xa0years, BMI 33.1u2009±u20091.5/28.0u2009±u20091.3xa0kg/m2, diabetes duration 11.6u2009±u20098.0/11.1u2009±u20096.1xa0years, insulin therapy 4/8 p. FSG and HbA1c were determined preoperatively and up to 2xa0years. Insulin resistance and beta-cell function were explored by means of HOMA-IR and IVGTT (AIR). Thirty-eight diabetic patients on medical therapy served as controls.ResultsMean BMI stabilized around 27 since the 4th month in OB, and 24 since 1st month in OW. FSG in OB/OW preop, 1, 12, 24xa0months: 234u2009±u200976/206u2009±u200962xa0mg/dL, 154u2009±u200949/176u2009±u200975, 131u2009±u200932/167u2009±u200948, 134u2009±u200941/154u2009±u200941 (cross-sectional n.s. at all times); HbA1c: 9.5u2009±u20091.6/9.1u2009±u20091.3, 7.3u2009±u20091.1/7.3u2009±u20091.2, 5.9u2009±u20090.6/7.1u2009±u20091.1 (pu2009<u20090.01), 5.9u2009±u20090.9/6.9u2009±u20091.1 (pu2009<u20090.01). HOMA-IR, preoperatively 10.7u2009±u20095.8/7.5u2009±u20095.4, went below 3.0 at 1xa0month and remained such until 2xa0years in both groups. AIR, preoperatively 1.11u2009±u20093.17/1.27u2009±u20092.68xa0μIU/mL, in OB significantly increased at 4xa0months to 7.63u2009±u20095.79, maintained up to 2xa0years with 6.95u2009±u20093.19, whereas in OW, statistical significance was reached only at 2xa0years with 5.02u2009±u20094.87.ConclusionsSignificantly different BPD effect, thus biological severity of T2DM, also exists between mildly obese and simply overweight patients. The rise of AIR allows hoping that an increase of beta-cell mass may occur in the long run.ClinicalTrials.gov Identifier: NCT00996294

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.

High-molecular weight adiponectin isoforms increase after biliopancreatic diversion in obese subjects.

Objective: Our objective was to test the effect of biliopancreatic diversion (BDP) in adiponectin multimerization. Adiponectin, the major protein secreted by adipose tissue, circulates in plasma in different isoforms. The most clinically relevant oligomers are high‐molecular weight (HMW) multimers and low‐molecular weight (LMW) trimers. Contrasting data on the effect of weight loss on adiponectin isoforms have been reported.

The plant hormone abscisic acid increases in human plasma after hyperglycemia and stimulates glucose consumption by adipocytes and myoblasts

The plant hormone abscisic acid (ABA) is released from glucose‐challenged human pancreatic β cells and stimulates insulin secretion. We investigated whether plasma ABA increased during oral and intravenous glucose tolerance tests (OGTTs and IVGTTs) in healthy human subjects. In all subjects undergoing OGTTs (n=8), plasma ABA increased over basal values (in a range from 2‐ to 9‐fold). A positive correlation was found between the ABA area under the curve (AUC) and the glucose AUC. In 4 out of 6 IVGTTs, little or no increase of ABA levels was observed. In the remaining subjects, the ABA increase was similar to that recorded during OGTTs. GLP‐1 stimulated ABA release from an insulinoma cell line and from human islets, by ~10‐ and 2‐fold in low and high glucose, respectively. Human adipose tissue also released ABA in response to high glucose. Nanomolar ABA stimulated glucose uptake, similarly to insulin, in rat L6 myoblasts and in murine 3T3‐L1 cells differentiated to adipocytes, by increasing GLUT‐4 translocation to the plasma membrane. Demonstration that a glucose load in humans is followed by a physiological rise of plasma ABA, which can enhance glucose uptake by adipose tissues and muscle cells, identifies ABA as a new mammalian hormone involved in glucose metabolism.—Bruzzone, S., Ameri, P., Briatore, L., Mannino, E., Basile, G., Andraghetti, G., Grozio, A., Magnone, M., Guida, L., Scarfì, S., Salis, A., Damonte, G., Sturla, L., Nencioni, A., Fenoglio, D., Fiory, F., Miele, C., Beguinot, F., Ruvolo, V., Bormioli, M., Colombo, G., Maggi, D., Murialdo, G., Cordera, R., De Flora, A., Zocchi, E. The plant hormone abscisic acid increases in human plasma after hyperglycemia and stimulates glucose consumption by adipocytes and myoblasts. FASEB J. 26, 1251‐1260 (2012). www.fasebj.org

Plasma Ghrelin Concentratin in the Short-Term following Biliopancreatic Diversion

Background: Ghrelin is a hormone that increases food intake in rodents and in humans. After gastric bypass surgery, a marked decrease in circulating ghrelin levels has been observed, and it was suggested that this may contribute to the weight-reducing effect of gastric bypass. In this study, the changes in circulating ghrelin levels following biliopancreatic diversion (BPD) were investigated. Materials and Methods: Serum ghrelin concentration was measured in obese patients prior to and 5 days and 2 months following BPD. Results: At the short-term following BPD, marked reduction of serum ghrelin was observed, while thereafter the values returned to initial levels. Conclusion: Unlike following reducing diet or gastric bypass, following BPD only an initial reduction of serum ghrelin concentration was observed, while at 2 months following the operation, when food intake had nearly completely resumed, the values returned to the preoperative levels. This is consistent with the hypothesis that ghrelin production from the stomach is greatly influenced by the direct contact of ingested food with the gastric cells.

Direct modulation of insulin receptor protein tyrosine kinase by vanadate and anti-insulin receptor monoclonal antibodies

Sodium vanadate activates in vitro insulin receptor autophosphorylation and protein tyrosine kinase in a dose-dependent manner. Insulin receptor protein tyrosine kinase is directly activated also by the anti-insulin receptor beta subunit monoclonal antibody 18-44. We previously demonstrated that the anti-insulin receptor monoclonal antibody MA-10 decreases insulin-stimulated receptor protein tyrosine kinase activity in vitro, without inhibiting insulin receptor binding. In this report we show that insulin receptor protein tyrosine kinase, activated by sodium vanadate or by monoclonal antibody 18-44, is inhibited by MA-10 antibody. These data suggest that insulin receptor protein tyrosine kinase activity can be either activated and inhibited through mechanisms different from insulin binding.

β‐Cell Function Improvement After Biliopancreatic Diversion in Subjects With Type 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 (AIRbasal) was reduced but insulin response at 14 mmol/l of plasma glucose (AIR14) was increased. Therefore, after BPD any statistical difference in AIR14 between NFG and T2DM disappeared (1,032 ± 123 for NFG and 665 ± 236 pmol/l for T2DM, P = ns). The same was observed for SlopeAIR, a measure of glucose potentiation, reduced in T2DM before BPD but increased after surgery, when no statistically significant difference resulted compared with NFG (SlopeAIR 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.

Microgram amounts of abscisic acid in fruit extracts improve glucose tolerance and reduce insulinemia in rats and in humans

2‐Cis,4‐trans‐abscisic acid (ABA) is a plant hormone that is present also in animals. Several lines of evidence suggest that ABA contributes to the regulation of glycemia in mammals: nanomolar ABA stimulates insulin release from β‐pancreatic cells and glucose transporter‐4‐mediated glucose uptake by myoblasts and adipocytes in vitro; plasma ABA increases in normal human subjects, but not in diabetic patients, after a glucose load for an oral glucose tolerance test (OGTT). The presence of ABA in fruits prompted an exploration of the bioavailability of dietary ABA and the effect of ABA‐rich fruit extracts on glucose tolerance. Rats underwent an OGTT, with or without 1 μg/kg ABA, either synthetic or present in a fruit extract. Human volunteers underwent an OGTT or a standard breakfast and lunch, with or without a fruit extract, yielding an ABA dose of 0.85 or 0.5 μg/kg, respectively. Plasma glucose, insulin, and ABA were measured at different time points. Oral ABA at 0.5–1 μg/kg significantly lowered glycemia and insulinemia in rats and in humans. Thus, the glycemia‐lowering effect of low‐dose ABA in vivo does not depend on an increased insulin release. Low‐dose ABA intake may be proposed as an aid to improving glucose tolerance in patients with diabetes who are deficient in or resistant to insulin.—Magnone, M., Ameri, P., Salis, A., Andraghetti, G., Emionite, L., Murialdo, G., De Flora, A., Zocchi, E. Microgram amounts of abscisic acid in fruit extracts improve glucose tolerance and reduce insulinemia in rats and in humans. FASEB J. 29, 4783–4793 (2015). www.fasebj.org

Effects of Gastric Bypass on Type 2 Diabetes in Patients with BMI 30 to 35

BackgroundThis study aims to investigate if the benefits on glycemic control following Roux-en-Y gastric bypass (RYGB) in morbidly obese type 2 diabetes (T2DM) patients are maintained in the 30–35xa0kg/m2 BMI (body mass index) range, comparing results with those in literature.MethodsThe study participants were twenty T2DM patients aging 35–70xa0years, BMI 30.0–34.9xa0kg/m2, minimum diabetes duration 3xa0years, glycosylated haemoglobin (HbA1c) ≥7.5xa0% despite good clinical practice medical therapy, submitted to laparoscopic RYGB, and monitored during 36xa0months. Twenty-seven matched diabetic patients as controls.ResultsFive females, mean age 57 (42–69)u2009years, weight 96.0 (70–111)u2009kg, BMI 32.9 (30.3–34.9)u2009kg/m2, waist circumference 112 (100–128)u2009cm, diabetes duration 14 (3–28)u2009years, HbA1c 9.5 (7.5–14.2)u2009%, and C-peptide 3.2 (1,6–9.1)u2009mcg/l. Ten patients were on insulin. There was no mortality, and there were two major late complications. BMI and waist decreased stabilizing around 25xa0kg/m2 and 92xa0cm. Fasting serum glucose and HbA1c reached values around 150xa0mg/dl and 7xa0%, which subsequently maintained. There was remission in 25xa0% of cases, control 45xa0%, and all the others improved. HOMA-IR and insulin sensitivity index normalized at 1xa0month, then maintained. AIR and insulinogenic index showed no postoperative changes. Diabetes remission correlated negatively with duration (pu2009<u20090.05; r2u2009=u20090.61), while control positively with C-peptide (pu2009<u20090.05; r2u2009=u20090.19). In the control group, FSG, HbA1c, serum triglyceride, and cholesterol significantly decreased with considerable progressive increase of antidiabetic/antihyperlipemic therapy. All patients had HbA1c >7xa0% at 2–3xa0years.ConclusionsGlycemic control obtained by RYGB in this study was less good than that reported by others, apparently due to different patient selection criteria. Our results do not support RYGB weight loss-independent effect on beta-cell function in the T2DM patients with BMI 30–35xa0kg/m2.