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 ß 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.

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/m]. However, studies of BPD effect in BMI range 25.0 to 34.9 kg/m, 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/m, 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 µIU/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.

Insulin analogues: fears, facts and fantasies.

IGF-I and insulin, acting through both IGF-I and insulin receptors, have been studied widely to evaluate their oncogenic and teratogenic properties. These two properties need to be studied for each new insulin analogue, in addition to measurements of their metabolic and pharmacodynamic features. This editorial critiques a study in this issue of the journal of several insulin analogues in their action in vitro on several cancer-related cell lines. The conclusions and limitations of these studies are highlighted, especially as they influence guidelines for using these analogues patients.

Caveolin-1 down-regulation inhibits insulin-like growth factor-I receptor signal transduction in H9C2 rat cardiomyoblasts.

Caveolin (Cav)-1, the major caveolar protein, directly interacts with IGF-I receptor (IGF-IR) and its intracellular substrates. To determine the role of Cav-1 in IGF-IR signaling, we transfected H9C2 cells with small interfering RNA specific for Cav-1-siRNA. The selective down-regulation of Cav-1 (90%) was associated with a smaller reduction of Cav-2, whereas Cav-3 expression was unaffected. A significant reduction of IGF-IR tyrosine phosphorylation in Cav-1-siRNA H9C2 cells was found compared with H9C2 control cells (Ctr-siRNA). The reduced IGF-IR autophosphorylation resulted in a decrease of insulin receptor substrate-1, Shc, and Akt activation. In addition, in Cav-1-siRNA H9C2 cells, IGF-I did not prevent apoptosis, suggesting that Cav-1 is required to mediate the antiapoptotic effect of IGF-I in cardiomyoblasts. The down-regulation of Cav-1 decreased IGF-IR activation and affected the ability of IGF-I to prevent apoptosis after serum withdrawal also in human umbilical vein endothelial cells. These results demonstrate that: 1) Cav-1 down-regulation negatively affects IGF-IR tyrosine phosphorylation; 2) this effect causes a reduced activation of insulin receptor substrate-1, Shc, and Akt; and 3) Cav-1 is involved in IGF-IR antiapoptotic signaling after serum deprivation.

Pregnancy in formerly type 2 diabetes obese women following biliopancreatic diversion for obesity.

BACKGROUND: This study describes the pregnancy of previously obese women with type 2 diabetic who reduced body weight and normalized serum glucose level following biliopancreatic diversion (BPD) for obesity. METHODS: A subset of ten women who had type 2 diabetes prior to BPD and who developed pregnancy after the operation was retrospectively identified. RESULTS: All pregnancies were completely normal, and serum glucose levels remained within the physiological range throughout all the pregnancy. These post-diabetic women delivered 13 infants in good health with a normal birth weight and no case of macrosomia. CONCLUSIONS: These data are a clinical confirmation of the post-BPD improvement of beta-cell response to increased functional demand in obese patients with preoperative type 2 diabetes.

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' care and quality of life.

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.

Effect of two fasting periods of different duration on ghrelin response to a mixed meal.

BACKGROUND AND AIM: The inhibitory effect of food on ghrelin secretion is reduced in several eating disorders such as restricting type anorexia nervosa, bulimia and obesity. These conditions are frequently characterised by irregular distribution of meals during the day. It is unknown whether two short fasting periods different duration affect ghrelin response to a mixed meal. Aim of the present study was to examine, in healthy volunteers, the effects of two fasting periods of different duration on pre- and post-prandial ghrelin concentrations after a standard mixed meal. METHODS AND RESULTS: Nine healthy men (mean age+/-S.E.M., 25.1+/-0.2 years; mean body mass index+/-S.E.M., 22.6+/-0.3kg/m2) were studied in 2 days after 12h of fasting (12F) and 17h of fasting (17F) with a within-subject repeated measure design. On both days they ate a standardized mixed meal. Before each meal hunger rating was evaluated with a visual analogue score. Blood samples for ghrelin, insulin, and glucose were collected at 0, 45, 60, 90, 120, 150 and 180min after meal. Comparing fasting values of 17F with 12F there was a significant increase in plasma ghrelin (160+/-20 vs. 146+/-18fmol/mL, P=0.015) and hunger rating (evaluated with a visual analogue scores) (7.0+/-0.3 vs. 5.1+/-0.4, P<0.003). A positive correlation between fasting ghrelin and hunger rating (r=0.52, P<0.01) was found. Circulating ghrelin decreased after both meals without any significant difference in relation with the previous length of fasting. Also postmeal ghrelin AUC as well as fasting and postmeal concentrations of insulin and glucose were similar after 12F and 17F. CONCLUSIONS: In healthy subjects a longer fasting period increases ghrelin concentration but did not affect post-prandial ghrelin response to a mixed meal.

Impaired increase of plasma abscisic Acid in response to oral glucose load in type 2 diabetes and in gestational diabetes.

The plant hormone abscisic acid (ABA) is present and active in humans, regulating glucose homeostasis. In normal glucose tolerant (NGT) human subjects, plasma ABA (ABAp) increases 5-fold after an oral glucose load. The aim of this study was to assess the effect of an oral glucose load on ABAp in type 2 diabetes (T2D) subjects. We chose two sub-groups of patients who underwent an oral glucose load for diagnostic purposes: i) 9 treatment-naive T2D subjects, and ii) 9 pregnant women with gestational diabetes (GDM), who underwent the glucose load before and 8-12 weeks after childbirth. Each group was compared with matched NGT controls. The increase of ABAp in response to glucose was found to be abrogated in T2D patients compared to NGT controls. A similar result was observed in the women with GDM compared to pregnant NGT controls; 8-12 weeks after childbirth, however, fasting ABAp and ABAp response to glucose were restored to normal in the GDM subjects, along with glucose tolerance. We also retrospectively compared fasting ABAp before and after bilio-pancreatic diversion (BPD) in obese, but not diabetic subjects, and in obese T2D patients, in which BPD resulted in the resolution of diabetes. Compared to pre-BPD values, basal ABAp significantly increased 1 month after BPD in T2D as well as in NGT subjects, in parallel with a reduction of fasting plasma glucose. These results indicate an impaired hyperglycemia-induced ABAp increase in T2D and in GDM and suggest a beneficial effect of elevated ABAp on glycemic control.

Acute plasma glucose increase, but not early insulin response, regulates plasma ghrelin.

OBJECTIVE: The independent role of glucose and insulin in ghrelin regulation is still controversial; this is also because in healthy subjects it is difficult to isolate the increase of glucose from that of insulin. The aim of this study was to discriminate the effect of glucose increase alone and early insulin response on plasma ghrelin, comparing ghrelin variation after i.v. glucose between healthy subjects and type 2 diabetic (T2DM) subjects, in whom the early insulin response to i.v. glucose is abolished. METHODS: Plasma glucose, insulin and ghrelin levels were measured 0, 3, 5, 10, 30, 45 and 60 min after a 5 g glucose i.v. bolus in seven healthy control subjects and eight T2DM subjects. RESULTS: There were no significant differences in body mass index, basal insulin and basal ghrelin between T2DM and healthy subjects. Basal glucose levels were higher in T2DM subjects than in controls. After i.v. glucose administration, plasma glucose increased significantly in both groups and the glucose peak was higher in T2DM subjects than in controls (9.67+/-1.25 (s.d.) vs 6.88+/-1.00 mmol/l, P<0.01). Insulin increased rapidly in controls, while in T2DM subjects, plasma insulin did not rise in the first 10 min. After the glucose bolus, plasma ghrelin showed a significant reduction both in controls and in T2DM subjects after 5 min. CONCLUSION: These findings indicate that a low-dose i.v. glucose bolus reduces ghrelin both in controls and in T2DM subjects and therefore that early insulin response does not affect plasma ghrelin.

Effects of gastric bypass on type 2 diabetes in patients with BMI 30 to 35.

BACKGROUND: This 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 30-35 kg/m(2) BMI (body mass index) range, comparing results with those in literature. METHODS: The study participants were twenty T2DM patients aging 35-70 years, BMI 30.0-34.9 kg/m(2), minimum diabetes duration 3 years, glycosylated haemoglobin (HbA1c) ≥7.5% despite good clinical practice medical therapy, submitted to laparoscopic RYGB, and monitored during 36 months. Twenty-seven matched diabetic patients as controls. RESULTS: Five females, mean age 57 (42-69) years, weight 96.0 (70-111) kg, BMI 32.9 (30.3-34.9) kg/m(2), waist circumference 112 (100-128) cm, diabetes duration 14 (3-28) years, HbA1c 9.5 (7.5-14.2) %, and C-peptide 3.2 (1,6-9.1) mcg/l. Ten patients were on insulin. There was no mortality, and there were two major late complications. BMI and waist decreased stabilizing around 25 kg/m(2) and 92 cm. Fasting serum glucose and HbA1c reached values around 150 mg/dl and 7%, which subsequently maintained. There was remission in 25% of cases, control 45%, and all the others improved. HOMA-IR and insulin sensitivity index normalized at 1 month, then maintained. AIR and insulinogenic index showed no postoperative changes. Diabetes remission correlated negatively with duration (p < 0.05; r (2) = 0.61), while control positively with C-peptide (p < 0.05; r (2) = 0.19). In the control group, FSG, HbA1c, serum triglyceride, and cholesterol significantly decreased with considerable progressive increase of antidiabetic/antihyperlipemic therapy. All patients had HbA1c >7% at 2-3 years. CONCLUSIONS: Glycemic 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 30-35 kg/m(2).

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.

BACKGROUND: Beneficial effects of BPD on T2DM in BMI >35 kg/m(2) 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). METHODS: Fifteen OB (six M) and 15 OW (13 M), diabetic for ≥ 3 years, with HbA1c ≥ 7.5% despite medical therapy, underwent BPD. OB/OW: age 55.1 ± 8.0/57.8 ± 6.7 years, BMI 33.1 ± 1.5/28.0 ± 1.3 kg/m(2), diabetes duration 11.6 ± 8.0/11.1 ± 6.1 years, insulin therapy 4/8 p. FSG and HbA1c were determined preoperatively and up to 2 years. 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. RESULTS: Mean BMI stabilized around 27 since the 4th month in OB, and 24 since 1st month in OW. FSG in OB/OW preop, 1, 12, 24 months: 234 ± 76/206 ± 62 mg/dL, 154 ± 49/176 ± 75, 131 ± 32/167 ± 48, 134 ± 41/154 ± 41 (cross-sectional n.s. at all times); HbA1c: 9.5 ± 1.6/9.1 ± 1.3, 7.3 ± 1.1/7.3 ± 1.2, 5.9 ± 0.6/7.1 ± 1.1 (p < 0.01), 5.9 ± 0.9/6.9 ± 1.1 (p < 0.01). HOMA-IR, preoperatively 10.7 ± 5.8/7.5 ± 5.4, went below 3.0 at 1 month and remained such until 2 years in both groups. AIR, preoperatively 1.11 ± 3.17/1.27 ± 2.68 µIU/mL, in OB significantly increased at 4 months to 7.63 ± 5.79, maintained up to 2 years with 6.95 ± 3.19, whereas in OW, statistical significance was reached only at 2 years with 5.02 ± 4.87. CONCLUSIONS: Significantly 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.

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.

Beta-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 (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.