Insulin Secretion Rate Research Articles

Long-term Metabolic and Socioeducational Outcomes of Transient Neonatal Diabetes: A Longitudinal and Cross-sectional Study.

Transient neonatal diabetes mellitus (TNDM) occurs during the 1st year of life and remits during childhood. We investigated glucose metabolism and socioeducational outcomes in adults. We included 27 participants with a history of TNDM currently with (n = 24) or without (n = 3) relapse of diabetes and 16 non-TNDM relatives known to be carriers of causal genetic defects and currently with (n = 9) or without (n = 7) diabetes. Insulin sensitivity and secretion were assessed by hyperinsulinemic-euglycemic clamp and arginine-stimulation testing in a subset of 8 TNDM participants and 7 relatives carrying genetic abnormalities, with and without diabetes, compared with 17 unrelated control subjects without diabetes. In TNDM participants, age at relapse correlated positively with age at puberty (P = 0.019). The mean insulin secretion rate and acute insulin response to arginine were significantly lower in TNDM participants and relatives of participants with diabetes than in control subjects (median 4.7 [interquartile range 3.7-5.7] vs. 13.4 [11.8-16.1] pmol/kg/min, P < 0.0001; and 84.4 [33.0-178.8] vs. 399.6 [222.9-514.9] µIU/mL, P = 0.0011), but were not different between participants without diabetes (12.7 [10.4-14.3] pmol/kg/min and 396.3 [303.3-559.3] µIU/mL, respectively) and control subjects. Socioeducational attainment was lower in TNDM participants than in the general population, regardless of diabetes duration. Relapse of diabetes occurred earlier in TNDM participants compared with relatives and was associated with puberty. Both groups had decreased educational attainment, and those with diabetes had lower insulin secretion capacity; however, there was no difference in insulin resistance in adulthood. These forms of diabetes should be included in maturity-onset diabetes of the young testing panels, and relatives of TNDM patients should be screened for underlying defects, as they may be treated with drugs other than insulin.

Free fatty acid receptor 3 differentially contributes to β-cell compensation under high-fat diet and streptozotocin stress.

The free fatty acid receptor 3 (FFA3) is a nutrient sensor of gut microbiota-generated nutrients, the short-chain fatty acids. Previously, we have shown that FFA3 is expressed in β-cells and inhibits islet insulin secretion ex vivo. Here, we determined the physiological relevance of the above observation by challenging wild-type (WT) and FFA3 knockout (KO) male mice with 1) hyperglycemia and monitoring insulin response via highly sensitive hyperglycemic clamps, 2) dietary high fat (HF), and 3) chemical-induced diabetes. As expected, FFA3 KO mice exhibited significantly higher insulin secretion and glucose infusion rate in hyperglycemic clamps. Predictably, under metabolic stress induced by HF-diet feeding, FFA3 KO mice exhibited less glucose intolerance compared with the WT mice. Moreover, similar islet architecture and β-cell area in HF diet-fed FFA3 KO and WT mice was observed. Upon challenge with streptozotocin (STZ), FFA3 KO mice initially exhibited a tendency for an accelerated incidence of diabetes compared with the WT mice. However, this difference was not maintained. Similar glycemia and β-cell mass loss was observed in both genotypes 10 days post-STZ challenge. Higher resistance to STZ-induced diabetes in WT mice could be due to higher basal islet autophagy. However, this difference was not protective because in response to STZ, similar autophagy induction was observed in both WT and FFA3 KO islets. These data demonstrate that FFA3 plays a role in modulating insulin secretion and β-cell response to stressors. The β-cell FFA3 and autophagy link warrant further research.

Time Course of Normalization of Functional β-Cell Capacity in the Diabetes Remission Clinical Trial After Weight Loss in Type 2 Diabetes.

To assess functional β-cell capacity in type 2 diabetes during 2 years of remission induced by dietary weight loss. A Stepped Insulin Secretion Test with Arginine was used to quantify functional β-cell capacity by hyperglycemia and arginine stimulation. Thirty-nine of 57 participants initially achieved remission (HbA1c <6.5% [<48 mmol/mol] and fasting plasma glucose <7 mmol/L on no antidiabetic drug therapy) with a 16.4 ± 7.7 kg weight loss and were followed up with supportive advice on avoidance of weight regain. At 2 years, 20 participants remained in remission in the study. A nondiabetic control (NDC) group, matched for age, sex, and weight after weight loss with the intervention group, was studied once. During remission, median (interquartile range) maximal rate of insulin secretion increased from 581 (480-811) pmol/min/m2 at baseline to 736 (542-998) pmol/min/m2 at 5 months, 942 (565-1,240) pmol/min/m2 at 12 months (P = 0.028 from baseline), and 936 (635-1,435) pmol/min/m2 at 24 months (P = 0.023 from baseline; n = 20 of 39 of those initially in remission). This was comparable to the NDC group (1,016 [857-1,507] pmol/min/m2) by 12 (P = 0.064) and 24 (P = 0.244) months. Median first-phase insulin response increased from baseline to 5 months (42 [4-67] to 107 [59-163] pmol/min/m2; P < 0.0001) and then remained stable at 12 and 24 months (110 [59-201] and 125 [65-166] pmol/min/m2, respectively; P < 0.0001 vs. baseline) but lower than that of the NDC group (250 [226-429] pmol/min/m2; P < 0.0001). A gradual increase in assessed functional β-cell capacity occurred after weight loss, becoming similar to that of NDC group participants by 12 months. This result was unchanged at 2 years with continuing remission of type 2 diabetes.

Characterization of Inhibitory Effectiveness in Hyperpolarization-Activated Cation Currents by a Group of ent-Kaurane-Type Diterpenoids from Croton tonkinensis.

Croton is an extensive flowering plant genus in the spurge family, Euphorbiaceae. Three croton compounds with the common ent-kaurane skeleton have been purified from Croton tonkinensis. Methods: We examined any modifications of croton components (i.e., croton-01 [ent-18-acetoxy-7α-hydroxykaur-16-en-15-one], croton-02 [ent-7α,14β-dihydroxykaur-16-en-15-one] and croton-03 [ent-1β-acetoxy-7α,14β-dihydroxykaur-16-en-15-one] on either hyperpolarization-activated cation current (Ih) or erg-mediated K+ current identified in pituitary tumor (GH3) cells and in rat insulin-secreting (INS-1) cells via patch-clamp methods. Results: Addition of croton-01, croton-02, or croton-03 effectively and differentially depressed Ih amplitude. Croton-03 (3 μM) shifted the activation curve of Ih to a more negative potential by approximately 11 mV. The voltage-dependent hysteresis of Ih was also diminished by croton-03 administration. Croton-03-induced depression of Ih could not be attenuated by SQ-22536 (10 μM), an inhibitor of adenylate cyclase, but indeed reversed by oxaliplatin (10 μM). The Ih in INS-1 cells was also depressed effectively by croton-03. Conclusion: Our study highlights the evidence that these ent-kaurane diterpenoids might conceivably perturb these ionic currents through which they have high influence on the functional activities of endocrine or neuroendocrine cells.

Impaired counterregulatory responses to hypoglycaemia following oral glucose in adults with cystic fibrosis.

The aim of this study was to determine the mechanism(s) for hypoglycaemia occurring late following oral glucose loading in patients with cystic fibrosis (CF). A 3h 75g OGTT was performed in 27 non-diabetic adults with CF who were classified based on this test as experiencing hypoglycaemia (glucose <3.3mmol/l with or without symptoms or glucose <3.9mmol/l with symptoms, n = 14) or not (n = 13). Beta cell function, incretin (glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic peptide [GIP]) and counterregulatory hormone responses (glucagon, catecholamines, growth hormone and cortisol) were assessed. The two groups did not differ in age, weight or BMI. There were more male participants and individuals with pancreatic exocrine insufficiency in the hypoglycaemia group. Fasting plasma glucose did not differ between the two groups (5.3 ± 0.16 vs 5.3 ± 0.10mmol/l). Both fasting insulin (20.7 ± 2.9 vs 36.5 ± 4.8pmol/l; p = 0.009) and C-peptide (0.38 ± 0.03 vs 0.56 ± 0.05nmol/l; p = 0.002) were lower in those who experienced hypoglycaemia. Following glucose ingestion, glucose concentrations were significantly lower in the hypoglycaemia group from 135min onwards, with a nadir of 3.2 ± 0.2 vs 4.8 ± 0.3mmol/l at 180min (p < 0.001). The test was terminated early in three participants because of a glucose level <2.5mmol/l. Insulin and C-peptide concentrations were also lower in the hypoglycaemia group, while incretin hormone responses were not different. Modelling demonstrated that those experiencing hypoglycaemia were more insulin sensitive (439 ± 17.3 vs 398 ± 13.1mlmin-1m-2, p = 0.074 based on values until 120min [n = 14]; 512 ± 18.9 vs 438 ± 15.5mlmin-1m-2, p = 0.006 based on values until 180min [n = 11]). In line with their better insulin sensitivity, those experiencing hypoglycaemia had lower insulin secretion rates (ISRfasting: 50.8 ± 3.2 vs 74.0 ± 5.9pmolmin-1m-2, p = 0.002; ISROGTT: 44.9 ± 5.0 vs 63.4 ± 5.2nmol/m2, p = 0.018) and beta cell glucose sensitivity (47.4 ± 4.5 vs 79.2 ± 7.5pmolmin-1m-2 [mmol/l]-1, p = 0.001). Despite the difference in glucose concentrations, there were no significant increases in glucagon, noradrenaline, cortisol or growth hormone levels. Adrenaline increased by only 66% and 61% above baseline at 165 and 180min when glucose concentrations were 3.8 ± 0.2 and 3.2 ± 0.2mmol/l, respectively. Hypoglycaemia occurring late during an OGTT in people with CF was not associated with the expected counterregulatory hormone response, which may be a consequence of more advanced pancreatic dysfunction/destruction.

Measurement of bioactive osteocalcin in humans using a novel immunoassay reveals association with glucose metabolism and β-cell function.

Osteocalcin (OCN) is a bone-derived hormone involved in the regulation of glucose metabolism. In serum, OCN exists in carboxylated and uncarboxylated forms (ucOCN), and studies in rodents suggest that ucOCN is the bioactive form of this hormone. Whether this is also the case in humans is unclear, because a reliable assay to measure ucOCN is not available. Here, we established and validated a new immunoassay (ELISA) measuring human ucOCN and used it to determine the level of bioactive OCN in two cohorts of overweight or obese subjects, with or without type 2 diabetes (T2D). The ELISA could specifically detect ucOCN concentrations ranging from 0.037 to 1.8 ng/mL. In a first cohort of overweight or obese postmenopausal women without diabetes (n = 132), ucOCN correlated negatively with fasting glucose (r = -0.18, P = 0.042) and insulin resistance assessed by the homeostatic model assessment of insulin resistance (r = -0.18, P = 0.038) and positively with insulin sensitivity assessed by a hyperinsulinemic-euglycemic clamp (r = 0.18, P = 0.043) or insulin sensitivity index derived from an oral glucose tolerance test (r = 0.26, P = 0.003). In a second cohort of subjects with severe obesity (n = 16), ucOCN was found to be lower in subjects with T2D compared with those without T2D (2.76 ± 0.38 versus 4.52 ± 0.06 ng/mL, P = 0.009) and to negatively correlate with fasting glucose (r = -0.50, P = 0.046) and glycated hemoglobin (r = -0.57, P = 0.021). Moreover, the subjects with ucOCN levels below 3 ng/mL had a reduced insulin secretion rate during a hyperglycemic clamp (P = 0.03). In conclusion, ucOCN measured with this novel and specific assay is inversely associated with insulin resistance and β-cell dysfunction in humans.

The jejunum is the key factor in insulin resistance.

Biliopancreatic diversion (BPD) is more effective than Roux-en-Y gastric bypass (RYGB) on both insulin resistance and diabetes. Because the major difference between the 2 procedures resides in the length of jejunal bypass, we investigated the role of the jejunum in insulin resistance. University hospital in Italy. Insulin sensitivity (IS) and secretion were measured before and 4 weeks after RYGB or BPD in 16 patients. A translational study was also conducted in 6 pigs, by isolating a jejunal loop with its vascular and nerve supply (Thiry-Vella loop [TVL]). TVL was doubly stomatized and bowel continuity restored by a side-to-side jejuno-jejunostomy. At baseline and 4 weeks postoperatively a glucose bolus was injected either in the stomach or in the TVL. Whole-body IS and jejunal heat shock proteins (HSPs) were measured. Primary porcine hepatocyte cultures were incubated with plasma or individual HSPs. Whole-body IS increased from 353.5 ± 26.7 to 442.0 ± 37.4 (P < .05) after RYGB and from 312.4 ± 14.9 to 441.2 ± 15.9 mL/m-2/min-1 (P < .001) after BPD. Hepatic IS was unchanged after RYGB, while it increased from .3 ± .01 to .4 ± .1 (μM/pM) - 1 (P < .01) after BPD. Total insulin secretion rate remained unchanged after RYGB but decreased (from 58.3 ± 23.6 to 33.1 ± 7.8 nmol/m-2, P<.05) after BPD. Jejunectomy in pigs enhanced IS (.3 ± .01 versus .2 ± .01 mM/pM, P < .001), while injection of glucose into TVL reduced it (.1 ± .01 versus .3 ± .01 mM/pM, P < .0001). The jejunum secreted HSPs, Hsp70, and GRP78, which impaired insulin signaling in hepatocyte cultures. This study shows that jejunal bypass in both humans and pigs improves IS. Injection of glucose into the TVL in pigs determines insulin resistance. In response to glucose, the jejunum secretes HSPs that impair insulin signaling.

Effect of exercise training on insulin sensitivity, hyperinsulinemia and ectopic fat in black South African women: a randomized controlled trial.

We investigated the effects of a 12-week exercise intervention on insulin sensitivity (SI) and hyperinsulinemia and associated changes in regional and ectopic fat. Healthy, black South African women with obesity (mean age 23 ± 3.5 years) and of isiXhosa ancestry were randomised into a 12-week aerobic and resistance exercise training group (n = 23) and a no exercise group (control, n = 22). Pre and post-intervention testing included assessment of SI, insulin response to glucose (AIRg), insulin secretion rate (ISR), hepatic insulin extraction (FEL) and disposition index (DI) (AIRg × SI) (frequently sampled i.v. glucose tolerance test); fat mass and regional adiposity (dual-energy X-ray absorptiometry); hepatic, pancreatic and skeletal muscle fat content and abdominal s.c. and visceral adipose tissue volumes (MRI). Exercise training increased VO2peak (mean ± s.d.: 24.9 ± 2.42 to 27.6 ± 3.39 mL/kg/min, P < 0.001), SI (2.0 (1.2-2.8) to 2.2 (1.5-3.7) (mU/l)-1 min-1, P = 0.005) and DI (median (interquartile range): 6.1 (3.6-7.1) to 6.5 (5.6-9.2) × 103 arbitrary units, P = 0.028), and decreased gynoid fat mass (18.5 ± 1.7 to 18.2 ± 1.6%, P < 0.001) and body weight (84.1 ± 8.7 to 83.3 ± .9.7 kg, P = 0.038). None of these changes were observed in the control group, but body weight increased (P = 0.030). AIRg, ISR and FEL, VAT, SAT and ectopic fat were unaltered after exercise training. The increase in SI and DI were not associated with changes in regional or ectopic fat. Exercise training increased SI independent from changes in hyperinsulinemia and ectopic fat, suggesting that ectopic fat might not be a principal determinant of insulin resistance in this cohort.

Effects of treatment with metformin and/or sitagliptin on beta-cell function and insulin resistance in prediabetic women with previous gestational diabetes.

To investigate the effect of sitagliptin (SITA) and metformin (MET) monotherapy as well as in combination (MET+SITA) on beta-cell function and insulin sensitivity in women with recent gestational diabetes (GDM) and impaired glucose regulation (IGR: impaired fasting glucose and/or impaired glucose tolerance). Forty women were randomly assigned to receive SITA (100 mg qd), MET (850 mg bid) or MET+SITA (50 + 850 mg bid) for 16 weeks. A 75 g oral glucose tolerance test (OGTT) and +125 mg/dL hyperglycaemic clamp followed by 5 g i.v. L-arginine were performed at baseline and end of study. The primary outcome of the study was the mean change in arginine-stimulated insulin secretion rate during the hyperglycaemic clamp test from baseline to 16-week therapy. At week 16, body mass index declined in all groups (-1.2 ± 0.2 kg/m2 ; P < 0.05). MET+SITA gave a greater increase of first phase(2-10 min) insulin secretion and arginine-stimulated response (720.3 ± 299.0 to 995.5 ± 370.3 pmol/L and 3.2 ± 0.6 to 4.8 ± 1.0 pmoL/min, respectively, both P < 0.05) compared with MET and SITA. Similarly, MET+SITA was more effective in increasing OGTT-based glucose sensitivity (55.7 ± 11.3 to 108 ± 56.2 pmol x min-1 m-2 x mM-1 ; P = 0.04) and insulin-stimulated glucose disposal (M/I: 2.2 ± 0.5 to 4.6 ± 1.3 mg/kg/min÷μIU/min/ml; P = 0.04; Matsuda index [SI]: 3.1 ± 0.4 to 5.7 ± 1.1; P = 0.03) compared with either MET or SITA. Disposition index (ISSI-2) increased with MET+SITA and SITA (both P < 0.05), while no significant change was observed in MET. Among MET+SITA women, 33% reverted to normal glucose tolerance (NGT) compared with 14% with MET and 7% with SITA (P < 0.05). This study shows that MET+SITA is superior to SITA and MET monotherapy regarding beta-cell function and insulin sensitivity improvement in IGR women with previous GDM, and may offer a potential pharmacologic intervention to reduce the risk of type 2 diabetes in this high-risk population.

Insulin Sensitivity Measured with the Oral Minimal Model is lower in Obese Subjects Who Report omitting their Breakfast

Introduction: Omitting the breakfast has been reported to promote weight gain and to impair insulin sensitivity. However this latter effect was only assessed with simple surrogates. We thus aimed at verifying if insulin sensitivity is lowered in individuals who omit their breakfast with a more quantitative assessment, using the “Oral Minimal Model” (OMM) i.e., an extension of Bergman’s minimal model to oral glucose tolerance-tests, in a cross-sectional study of a population exhibiting the full range of body mass indices.Materials and methods: We selected on our database of patients, explored for weight and/or eating disorders, 27 individuals omitting their breakfast (defined on the basis of an alimentary standardized questionnaire) and compared them to 103 matched subjects taking a hyperglucidic breakfast. The breakfast was analyzed with the OMM for the assessment of insulin sensitivity. Insulin secretion was assessed with a previously reported procedure, allowing the calculation of the parameters of phase 1 and 2 of insulin secretion of Cobelli and Mari’s models. In addition, it is already known that Mari’s model provides an index of post stimulatory potentiation of insulin secretion. Disposition indices (product of SI and insulin secretion parameters) were also determined.Results: In the 27 subjects omitting their breakfast compared to the 103 matched subjects the difference in insulin sensitivity was not found. No difference in insulin secretion parameters is detected. Homeostasis between insulin secretion and insulin sensitivity appears to be functional. However when splitting the sample in categories of BMI the expected difference appears in the range 30-40. In this subgroup (Omitting (n=9) BMI: 35.4±0.99 vs. non-omitting (n=47) BMI: 34.1±0.37 kg/m²) insulin sensitivity was lower in individuals omitting their breakfast (4.32 10-4 min-1/(μU/ml)± 0.94 vs. 9.33±1.84, p=0.03). Despite a slight increase in insulin levels and in the overall insulin secretion rate, a decrease in potentiation and in disposition index was evidenced in individuals omitting their breakfast. The lowering effect of omitting the breakfast on insulin sensitivity is thus evidenced in obese subjects in this sample (but not in those with a BMI below 30). This impairment in insulin sensitivity resulted in a decrease of glucose tolerance by 34%. This finding, based on a cross-sectional study but using a sophisticated measurement, is in agreement with the previous report that omission of the breakfast may induce resistance to insulin. It suggests that the worsening effect on SI that was experimentally found in an interventional study in healthy women becomes important enough in obese subjects to be detected in a cross-sectional study, and that this effect associates a decrease in SI and an incomplete adaptation of insulin release to this reduction in SI, and thus a decrease in glucose tolerance.

Postnatal β2 adrenergic treatment improves insulin sensitivity in lambs with IUGR but not persistent defects in pancreatic islets or skeletal muscle.

Key points Previous studies in fetuses with intrauterine growth restriction (IUGR) have shown that adrenergic dysregulation was associated with low insulin concentrations and greater insulin sensitivity.Although whole‐body glucose clearance is normal, 1‐month‐old lambs with IUGR at birth have higher rates of hindlimb glucose uptake, which may compensate for myocyte deficiencies in glucose oxidation.Impaired glucose‐stimulated insulin secretion in IUGR lambs is due to lower intra‐islet insulin availability and not from glucose sensing.We investigated adrenergic receptor (ADR) β2 desensitization by administering oral ADRβ modifiers for the first month after birth to activate ADRβ2 and antagonize ADRβ1/3. In IUGR lambs ADRβ2 activation increased whole‐body glucose utilization rates and insulin sensitivity but had no effect on isolated islet or myocyte deficiencies.IUGR establishes risk for developing diabetes. In IUGR lambs we identified disparities in key aspects of glucose‐stimulated insulin secretion and insulin‐stimulated glucose oxidation, providing new insights into potential mechanisms for this risk. Placental insufficiency causes intrauterine growth restriction (IUGR) and disturbances in glucose homeostasis with associated β adrenergic receptor (ADRβ) desensitization. Our objectives were to measure insulin‐sensitive glucose metabolism in neonatal lambs with IUGR and to determine whether daily treatment with ADRβ2 agonist and ADRβ1/β3 antagonists for 1 month normalizes their glucose metabolism. Growth, glucose‐stimulated insulin secretion (GSIS) and glucose utilization rates (GURs) were measured in control lambs, IUGR lambs and IUGR lambs treated with adrenergic receptor modifiers: clenbuterol atenolol and SR59230A (IUGR‐AR). In IUGR lambs, islet insulin content and GSIS were less than in controls; however, insulin sensitivity and whole‐body GUR were not different from controls. Of importance, ADRβ2 stimulation with β1/β3 inhibition increases both insulin sensitivity and whole‐body glucose utilization in IUGR lambs. In IUGR and IUGR‐AR lambs, hindlimb GURs were greater but fractional glucose oxidation rates and ex vivo skeletal muscle glucose oxidation rates were lower than controls. Glucose transporter 4 (GLUT4) was lower in IUGR and IUGR‐AR skeletal muscle than in controls but GLUT1 was greater in IUGR‐AR. ADRβ2, insulin receptor, glycogen content and citrate synthase activity were similar among groups. In IUGR and IUGR‐AR lambs heart rates were greater, which was independent of cardiac ADRβ1 activation. We conclude that targeted ADRβ2 stimulation improved whole‐body insulin sensitivity but minimally affected defects in GSIS and skeletal muscle glucose oxidation. We show that risk factors for developing diabetes are independent of postnatal catch‐up growth in IUGR lambs as early as 1 month of age and are inherent to the islets and myocytes.

Deficiency of Urokinase Plasminogen Activator May Impair β Cells Regeneration and Insulin Secretion in Type 2 Diabetes Mellitus.

Background: The relationship between urokinase-type plasminogen activator (uPA) and the development of type 2 diabetes mellitus (T2DM) was investigated in the study by using mice and cell models, as well as patients with T2DM. Methods: In mice models, wild-type and uPA knockout (uPA-/-) BALB/c mice were used for induction of T2DM. In cell models, insulin secretion rate and β cell proliferation were assessed in normal and high glucose after treating uPA siRNA, uPA, or anti-uPA antibody. In our clinical study, patients with T2DM received an oral glucose-tolerance test, and the relationship between uPA and insulin secretion was assessed. Results: Insulin particles and insulin secretion were mildly restored one month after induction in wild-type mice, but not in uPA-/- mice. In cell models, insulin secretion rate and cell proliferation declined in high glucose after uPA silencing either by siRNA or by anti-uPA antibody. After treatment with uPA, β cell proliferation increased in normal glucose. In clinical study, patients with T2DM and higher uPA levels had better ability of insulin secretion than those with lower uPA levels. Conclusion: uPA may play a substantial role in insulin secretion, β cell regeneration, and progressive development of T2DM. Supplementation of uPA might be a novel approach for prevention and treatment of T2DM in the future.

Gluco-metabolic effects of oral and intravenous alcohol administration in men.

BackgroundIngestion of the calorically dense compound alcohol may cause metabolic disturbances including hypoglycaemia, hepatic steatosis and insulin resistance, but the underlying mechanisms are uncertain. The gastrointestinal tract is well recognised as a major influencer on glucose, protein and lipid metabolism, but its role in alcohol metabolism remains unclear.ObjectiveTo examine the effects of oral and intravenous alcohol, respectively, on plasma concentrations of several gluco-regulatory hormones including serum/plasma insulin, C-peptide, glucagon, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP-1) and fibroblast growth factor 21 (FGF21).Design and methodsIn a double-blinded, randomised, crossover design, we subjected 12 healthy men to intragastric ethanol infusion (IGEI) and an isoethanolaemic intravenous ethanol infusion (IVEI) (0.7 g alcohol per kg body weight), respectively, on two separate experimental days.ResultsIsoethanolaemia during the two alcohol administration forms was obtained (P = 0.38). During both interventions, plasma glucose peaked after ~30 min and thereafter fell below baseline concentrations. GIP and GLP-1 concentrations were unaffected by the two interventions. Insulin concentrations were unaffected by IGEI but decreased during IVEI. C-peptide, insulin secretion rate and glucagon concentrations were lowered similarly during IGEI and IVEI. FGF21 concentrations increased dramatically (nine-fold) and similarly during IGEI and IVEI.ConclusionsAlcohol does not seem to affect the secretion of incretin hormones but decreased insulin and glucagon secretion independently of gut-derived factors. IGEI as well as IVEI potently stimulate FGF21 secretion indicating a gut-independent effect of alcohol on FGF21 secretion in humans.

The Effects of Mental Stress on Non-insulin-dependent Diabetes: Determining the Relationship Between Catecholamine and Adrenergic Signals from Stress, Anxiety, and Depression on the Physiological Changes in the Pancreatic Hormone Secretion.

Non-insulin-dependent diabetes or type II diabetes is prevalent around the world. A high-fat diet and chronic inactivity are often responsible for this chronic ailment. However, it is suspected that a high level of stress can also exacerbate diabetes. High anxiety can result in the release of sympathetic hormones that can elevate both cortisol and glucose levels, decrease insulin release, or affect the sensitivity and resistant of the insulin hormone. We have analyzed three research articles to see how stress and anxiety can affect non-insulin-dependent diabetes. In the first article, we selected participants with type II diabetes and injected them with saline or norepinephrine. The results indicated that participants with norepinephrine had experienced a decrease in glucose disposal and reduction in insulin secretion rate. Our second article utilizes African-American adults with type II diabetes. We provide them with a survey to determine how stress, anxiety, and depression can affect adherence to lifestyle modifications such as exercise and eating a proper diet. We find that subjects with higher stress levels tend to have lower compliance with their lifestyle regimes. Our third article focuses on female participants and divides them into two categories which are high chronic stress (HCS) and low chronic stress (LCS). We use an MRI to observe their brain activity while they stare at a picture of high-caloric type food. Our results indicate that there are different responses in various brain structure activities between subjects with HCS and LCS group. With these analyses, it can improve on the way healthcare providers can consult with their patients who have exacerbated type II diabetes despite proper medication and lifestyle modification.

Joint and separate exposure to alcohol and \u22069-tetrahydrocannabinol produced distinct effects on glucose and insulin homeostasis in male rats

Cannabis and alcohol co-use is common, and the trend may increase further given the current popularity of cannabis legalization. However, the metabolic consequences of such co-use are unclear. Here, we investigated how co-administration of alcohol and ∆9-tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, affects body weight and visceral adiposity, and glucose and insulin homeostasis in rats. For 16 consecutive days during adolescence, male rats drank saccharin or alcohol after receiving subcutaneous oil or THC injections in Experiment 1 and voluntarily consumed alcohol, THC edible, or both drugs in Experiment 2. Experiment 1 showed that following abstinence, drug co-exposure reduced visceral fat and the amount of insulin required to clear glucose during an oral glucose tolerance test (OGTT). In Experiment 2, rats received a high-fat diet (HFD) after 3-week abstinence. Although adolescent drug use did not interact with the HFD to worsen hyperglycemia and hyperinsulinemia during an OGTT, HFD-fed rats that co-used alcohol and THC had the lowest insulin levels 75 min after an insulin injection, suggesting an altered rate of insulin secretion and degradation. These results suggest that THC and alcohol co-exposure can distinctly alter the physiology of glucose and insulin homeostasis in a rodent model.

Acute Changes of Bile Acids and FGF19 After Sleeve Gastrectomy and Roux-en-Y Gastric Bypass.

Gastric bypass (GBP) and sleeve gastrectomy (SG) are both effective bariatric treatments that cause sustained weight loss as well as improvement of type 2 diabetes mellitus (T2DM). The underlying mechanisms are under investigation, including the contribution of alterations in bile acids (BAs) in achieving or maintaining the beneficial metabolic effects after bariatric surgery. The aim of this study is to investigate the acute and short-term effects of GBP and SG on BA compositions and fibroblast growth factor 19 (FGF19) in obese individuals with T2DM and to evaluate any correlations between changes in these measures with glucose metabolic improvements. The levels of both fasting and postprandial plasma BA compositions after oral glucose tolerance test (OGTT), fasting FGF19 and various metabolic indices were measured 1day before and at 3days and 3months after GBP and SG in 19 obese patients (GBP = 8, SG = 11) with T2DM. Body weight loss was observed after both GBP and SG 3months post-operatively, with no significant difference between the two intervention groups (15.0 ± 3.1% vs. 13.9 ± 5.2%, P = 0.761). At 3days post-operation, FGF19 levels increased significantly in both surgery groups (GBP, 118.3 ± 57.3 vs. 363.6 ± 131.0pgmL-1, post-operation P = 0.008; SG, 173.2 ± 127.8 vs. 422.0 ± 243.6pgmL-1, post-operation P = 0.001). Fasting and postprandial increases from pre-operative values in secondary (r = 0.57, P = 0.02; r = 0.58, P = 0.01), conjugated (r = 0.50, P = 0.01; r = 0.48, P = 0.04), glycine-conjugated (r = 0.52, P = 0.05; r = 0.46, P = 0.05) and secondary-conjugated (r = 0.53, P = 0.02; r = 0.60, P = 0.01) BAs correlated with decreases in the postprandial states of glucose (defined by area under the curve (AUC) over 120min (AUC0-120min)). Increases in postprandial primary-conjugated BAs were found to be associated with decreases in HOMA-IR (r = 0.45, P = 0.05). However, increases in fasting and postprandial taurine-conjugated BA correlated with decreases in both basal insulin secretion rate (r = 0.47, P = 0.04; r = 0.48, P = 0.04) and C-peptide level (r = 0.45, P = 0.05; r = 0.47, P = 0.04). After 3months, fasting and postprandial increases in secondary (r = 0.51, P = 0.03; r = 0.48, P = 0.04), secondary-conjugated (r = 0.52, P = 0.02; r = 0.51, P = 0.03) and non-12α-OH (r = 0.51, P = 0.02; r = 0.58, P = 0.01) BAs were found to correlate with increases in Stumvoll Insulin Sensitivity Index. Increases in both fasting and postprandial 12α-OH BAs were correlated with the decreases in glucose AUC (r = 0.46, P = 0.05; r = 0.41, P = 0.04). Both GBP and SG achieve increases in many BA species as early as 3days post-operation, which are sustained at 3months post-operation. Rises in secondary BA and conjugated forms are correlated with early improvements in glucose metabolism at 3days post-operation. These along with 12α-OH BA correlated with improved glucose metabolism at 3months post-operation, suggesting they may contribute to the observed T2DM remission after bariatric surgery.

124-OR: Comparison of OGTT Model-Derived Measures of ß-Cell Function between Youth and Adults

Results from hyperglycemic clamps in the Restoring Insulin Secretion (RISE) Study found that youth (10-19 y) with impaired glucose tolerance (IGT) or early type 2 diabetes (T2D) are more insulin resistant and secrete more insulin than adults (20-65 y), despite similar BMI. Here we use Mari modeling of RISE 3-h OGTT data to explore differences in β-cell function between youth and adults. The Mari model describes the relationship between insulin secretion rate (ISR) and glucose concentration. The slope of the relationship is β-cell glucose sensitivity (GS); ISR at a fixed glucose is also calculated. Derived terms include the 3-h to baseline potentiation factor ratio (PFR; a relative insulin secretion increase during the OGTT) and rate sensitivity (RS; the dependence of ISR on the glucose rate of change). Analysis of covariance was used to compare youth vs. adults, with secretion measures adjusted for insulin sensitivity (M/I) from hyperglycemic clamps. Adjusted GS was significantly higher in youth vs. adults with IGT but not in those with T2D. Adjusted RS and ISR at plasma glucose of 5 and 7 mmol/L were higher in youth vs. adults for both IGT and T2D. The PFR was lower in youth than adults, suggesting possible differences in either incretin effects or glucose potentiation. Our OGTT findings provide additional evidence that β-cells in youth are more responsive to glucose than adults, with reduced secretion parameters in those with T2D. Disclosure K. Utzschneider: Consultant; Self; Novo Nordisk Inc. A. Mari: Consultant; Self; Eli Lilly and Company. Research Support; Self; Boehringer Ingelheim International GmbH. M. Tripputi: None. K.J. Mather: Advisory Panel; Self; Roche Diabetes Care. Research Support; Self; Abbott, Merck &amp; Co., Inc., Novo Nordisk A/S, Sanofi. K.J. Nadeau: None. S. Edelstein: None. T.S. Hannon: Advisory Panel; Self; Eli Lilly and Company. S.A. Arslanian: None. M. Cree-Green: None. T.A. Buchanan: Research Support; Self; Allergan, Apollo EndoSurgery. S. Caprio: None. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., Novo Nordisk A/S. Consultant; Self; Neurimmune. Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Merck &amp; Co., Inc., Novo Nordisk A/S. R. Consortium: None. Funding American Diabetes Association (1-14-RISE-01 to S.E.K.); National Institute of Diabetes and Digestive and Kidney Diseases

1840-P: Pioglitazone Increases Metabolic Insulin Clearance (MCRI) in IGT Subjects: The ACT NOW Study

Recent studies have documented that the MCRI plays a major role in determining the plasma insulin response to ingested glucose. We evaluated the long-term effect of pioglitazone (PIO) on MCRI in 441 IGT subjects (ACT NOW study) who were randomized to PIO (45 mg/day) or placebo and followed for an average of 2.4 years. OGTT was performed at baseline and study end. 50 placebo-treated subjects developed type 2 diabetes versus 15 PIO-treated subjects (p&amp;lt;0.005). Insulin secretion rate (ISR) was measured from deconvolution of plasma C-peptide curve. MCRI was measured as ISR/mean insulin conc during OGTT. Data were correlated with changes in liver enzymes and peripheral insulin sensitivity measured with the Matsuda index (MI). Results: PIO improved MI from to 3.9 ±1 to 7.5 ±3 (p&amp;lt;0.0001), glucose tolerance (mean glucose OGTT from 172±2to 148±1mg/dl, p&amp;lt;0.0001) and reduced ALT(from 30±1 to 24±1, p&amp;lt;0.0001). Fasting insulin secretion increased in the placebo group (420 ±14 to 558 ±21 pmol/min, p &amp;lt; 0.0001 vs. baseline) and did not change in the PIO group (411 ±14 to 446 ± 19; p &amp;lt;0.0001, PIO vs. placebo). During the OGTT (0- 120 min) ISR increased in both groups (PIO, 165 ±3 to 189 ± 5 nmol; placebo, 167 ±3 to 202 ±6; p &amp;lt; 0.0001 vs. baseline in both groups; p = NS, PIO vs. placebo).The MCRI increased in both groups but the increase was much greater in PIO (3.5 ± 0.2 to 6.0±0.2 ml/min; placebo, 3.5 ± 0.1 to 4.7±0.2; p &amp;lt; 0.0001 vs. baseline in both groups; p &amp;lt;0.0001, PIO vs. placebo). In the whole dataset the improvement in insulin clearance was associated with improvement in peripheral insulin sensitivity (r=0.62, p&amp;lt;0.0001), the reduction in mean plasma glucose concentration during OGTT (r=-0.31, p&amp;lt;0.0001) and decrease in ALT (r=-0.14, p&amp;lt;0.009). Conclusion: PIO treatment results in an increase in MCRI that is associated with improved hepatic function, glucose metabolism and peripheral insulin sensitivity. Disclosure A. Gastaldelli: Consultant; Self; A. Menarini Diagnostics, Eli Lilly and Company, Genentech, Inc., Gilead Sciences, Inc., Inventiva Pharma. D. Tripathy: None. R.A. DeFronzo: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc.

66-OR: Remission of Type 2 Diabetes for Two Years Is Associated with Full Recovery of Beta-Cell Functional Mass in the Diabetes Remission Clinical Trial (DiRECT)

Aims: Observational studies have suggested that beta cell functional mass inevitably decreases over time. We assessed this after 2 years in a geographically defined subgroup of DiRECT who achieved initial remission after diet-induced weight loss. Methods: A Stepped Insulin Secretion Test with Arginine (SISTA) was used to quantify functional beta cell mass (maximum insulin secretory response during hyperglycemia). Insulin secretion rates were estimated by de-convolution; 40 subjects initially achieved remission (HbA1c&amp;lt;6.5% and FPG &amp;lt;126mg/dl on no antidiabetic drug therapy). At 2 years 20 subjects (13M/7F) remained in remission, 13 gained weight and relapsed, and 7 lost to follow-up. A nondiabetic Comparator (NDC) group, matched for age/gender of DiRECT intervention group participants after weight loss, was studied. Results: In the responder group, median (IQ range) maximum rate of insulin secretion increased from 0.58 (0.48 to 0.81) at baseline to 0.74 (0.54 to 1.00) at 5 months, 0.94 (0.57 to 1.24) (p=0.017 from baseline) at 12 months, and 0.94(0.64 to 1.44) (p=0.030 from baseline) nmol/min/m2 at 24 months. This was comparable to NDC (1.02(0.86 to 1.51) nmol/min/m2) by 12 (p=0.064) and 24 months (p=0.244). Median first phase insulin response increased in responders from 0.042 (0.004 to 0.0637) at baseline to 0.108 (0.058 to 0.163) nmol/min/m2 (p&amp;lt;0.0001) at 5 months, to (0.110(0.059 to 0.201) then 0.125(0.066 to 0.166) nmol/min/m2; p&amp;lt;0.0001)] at 12 and 24 months. Those who failed to maintain remission were characterized by more weight regain 5-24 months (11. 3±1.9 vs. 6.6±1.0 kg, p=0.036). In responders mean HBA1C was 6.0±0.0% at 24 months. Conclusion: Provided weight regain is minimized, remission of type 2 diabetes is durable over 2 years, with a gradual increase to normal beta cell functional mass. Disclosure S.V. Zhyzhneuskaya: None. A. Al-Mrabeh: None. A.C. Barnes: None. B. Aribisala: None. K.G. Hollingsworth: None. H. Pilkington: None. N. Sattar: Advisory Panel; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk A/S. Consultant; Self; NAPP Pharmaceuticals Limited. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. Speaker's Bureau; Self; Amgen Inc., Eli Lilly and Company, Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Roche Diagnostics France, Sanofi. M.E. Lean: Consultant; Self; Counterweight Ltd., Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S. R. Taylor: Advisory Panel; Self; Wilmington Healthcare. Speaker's Bureau; Self; Lilly Diabetes, Novartis AG. Funding Diabetes UK

1827-P: Higher Glucagon-Like Peptide-1 Response and Lower Beta-Cell Glucose Sensitivity Are Associated with Increased Glycemic Variability among Individuals with Prediabetes

Background: Increased glycemic variability (GV) is thought to represent abnormalities of glucose homeostasis in the progression from prediabetes to diabetes. We evaluated the association between GV, beta-cell function and glucagon-like peptide 1 (GLP-1) response among individuals with prediabetes. Methods: 61 individuals with prediabetes (age Mean±SD 56±9 years, 31 male) each wore a blinded continuous glucose monitor (Medtronic iPro2) for 72 hours. Standard deviation (SD) and coefficient of variation (CV) were calculated from CGM glucose. Participants underwent a 2-hour mixed-meal tolerance test with measurement of insulin, C-peptide, GLP-1 for modelling of beta-cell function. Results: Early and late GLP-1/glucose ratio were positively correlated with CGM sensor glucose SD (r = 0.29, p=0.02 and r= 0.28 p = 0.048 respectively). Beta-cell glucose sensitivity (βCGS) was negatively correlated with SD (r = -0.28, p = 0.03). In multivariate analyses, only βCGS and GLP-1 response were significant predictors of SD, while early phase insulin and insulin secretion rate predicted average sensor glucose but not indices of GV. Conclusions: Higher GLP-1 response and reduced βCGS are associated with greater glucose fluctuations in the prediabetic range. Disclosure E. Chow: Research Support; Self; Powder Pharmaceuticals Inc., Sanofi-Aventis. A. Luk: None. J. Ling: None. A.P. Kong: Advisory Panel; Self; Lilly Diabetes. Research Support; Self; AstraZeneca, Lilly Diabetes. Speaker's Bureau; Self; Abbott. Other Relationship; Self; AstraZeneca, Novartis Pharmaceuticals Corporation, Sanofi. R.C. Ma: Advisory Panel; Self; Boehringer Ingelheim International GmbH. Research Support; Self; AstraZeneca, Bayer AG, Pfizer Inc. Stock/Shareholder; Self; GemVCare. Other Relationship; Self; AstraZeneca. E. Ferrannini: None. J.C. Chan: Board Member; Self; Asia Diabetes Foundation. Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Medtronic, Merck Sharp &amp; Dohme Corp., Sanofi-Aventis. Research Support; Self; Amgen Inc., AstraZeneca, Lee Powder, Lilly Diabetes, Pfizer Inc., Sanofi-Aventis. Speaker's Bureau; Self; Ascensia Diabetes Care. Stock/Shareholder; Self; GemVCare.