Second-phase Insulin Secretion Research Articles

The relationships between hemoglobin and insulin resistance, glucose effectiveness, and first- and second-phase insulin secretion in adult Chinese.

We denote the four major factors related to the development of type 2 diabetes (T2D) as "diabetes factor" (DF); increased insulin resistance (IR); decreased glucose effectiveness (GE); and the first-and-second-phase of insulin secretion (FPIS, SPIS). The level of hemoglobin (Hb) was found to be related to IR and FPIS, but no-known studies focused on its role in relation to SPIS and GE. In this study, we aim to evaluate the relationships between Hb and all four DFs in the same individual. We randomly enrolled 24,407 men and 24,889 women between 30 and 59 years old. IR, FPIS, SPIS and GE were measured according to equations published in our previous studies. To compare the slopes between Hb and the four DFs with different units, we converted their units to percent of change per unit of increased Hb. Age, HDL-cholesterol and GE were higher in women; BMI, blood pressure, LDL-cholesterol, TG, Hb, FPIS, SPIS and IR were higher in men. After they were converted into percentage, the closeness of their relationships to Hb, from the highest to the lowest, were GE, IR, FPIS and SPIS for women and IR, GE, FPIS and SPIS for men. GE was the only one negatively related to Hb. Our data showed that IR, FPIS and SPIS were both positively and, GE negatively, related to the Hb in adult Chinese. For women, GE had the closest association with Hb; for men, it was IR. Both phases of insulin secretion had relatively weaker relationships than IR and GE.

Pathophysiological characteristics in patients with latent autoimmune diabetes in adults using clamp tests: evidence of a continuous disease spectrum of diabetes.

This study aimed to assess islet insulin secretion and insulin resistance in Chinese patients with latent autoimmune diabetes in adults (LADA). Twelve patients with LADA, 10 with type 1 diabetes mellitus (T1DM), 10 with type 2 diabetes mellitus (T2DM), and 10 nondiabetic healthy controls (HCs) were included. Patients with LADA were subtyped according to the glutamic acid decarboxylase antibody (GADA) titer (LADA1, GADA titer ≥ 180 U/mL; LADA2, GADA titer 18-180 U/mL). Insulin secretion and sensitivity were assessed using hyperglycemic and hyperinsulinemic-euglycemic clamp tests, respectively. The first-phase insulin secretion gradually increased in patients with T1DM, LADA1, LADA2, and T2DM to HCs (29.32 ± 6.00mU/L vs. 68.71 ± 4.50mU/L vs. 87.60 ± 11.60mU/L vs. 138.27 ± 13.18mU/L vs. 248.49 ± 21.97mU/L; P < 0.05). The second-phase insulin secretion (2ph) and maximum insulin secretion (MIS) were significantly lower in patients with LADA2 and T2DM than in HCs, but higher in those with LADA1 and T1DM. No significant differences in 2ph and MIS were observed between patients with LADA1 and T1DM, and between those with LADA2 and T2DM. The levels of insulin sensitivity index (ISI) during hyperinsulinemic-euglycemic clamps were lower in patients with LADA and T2DM than in those with T1DM. Patients with T1DM displayed lower ISI compared with HCs. Chinese patients with LADA and T1DM had impaired insulin sensitivity and β-cell function. Furthermore, the hypothesis that diabetes is a continuous spectrum from T1DM, LADA1, LADA2 to T2DM was confirmed in this study.

1756-P: ß-Cell Glucose Sensitivity and Intrapancreatic Adipose Tissue as Predictors of Diabetes Onset

Several evidences suggest that the functional β cell defects anticipate the onset of hyperglycemia and the reduction of mass. To assess whether the β-cell deterioration corresponds to a loss of β-cell mass, we performed glucose oral tolerance test (OGTT) and hyperglycemic clamp (HC) followed by arginine stimulation, in 16 nondiabetic patients who underwent pancreatoduodenectomy (PD), pre and post-surgery. Based on the post-operative OGTT, the subjects were divided into 3 glucose tolerance groups: normal (NGT, n = 5), altered (IGT, n = 4) or diabetes (DM, n = 7) (8F/8M, 51 ± 15 years). To evaluate β cell function, βcell glucose sensitivity (GS) was calculated during HC, as a ratio between insulin secretion and glucose increase. On surgical pancreas samples, the% of intraparenchymal white adipose tissue (WATi score) was measured. Before surgery, insulin secretion after arginine (AIS) was similar between groups, while GS was lower in IGT and DM compared to NGT subjects (62.9 ± 23.1 and 45.5 ± 11.2 vs. 90.6 ± 18.7 pmol • min-1 • m-2, respectively). After 50% PD, the GS decreased in all patients (p &amp;lt;0.01 for all groups), but the reduction was greater in DM than in patients with IGT and NGT (ΔGS: NGT -0.20 ± 0, 19 vs. IGT -0.27 ± 0.11 vs. DM 0.37 ± 0.08, p &amp;lt;0.003). A similar reduction was observed in ΔAIS (NGT -0.38 ± 0.13 vs. IGT -0.76 ± 0.06 vs. DM -0.90 ± 0.04; p &amp;lt;0.01) and in the second phase of insulin secretion. WAT score was significantly higher in IGT and DM than in NGT (WATi score IGT 37.75 ± 11.07%, DM 44.46 ± 31.83%, NGT 5.8 ± 2.35%, p &amp;lt;0.01 and p &amp;lt;0.05 respectively). The loss of GS is the most sensitive predictive parameter of diabetes onset after a 50% reduction in mass. The accumulation of WATi could in turn predict the loss of GS and represent a new potential target for the preservation of the function. Disclosure F. Cinti: None. T. Mezza: None. C. Cefalo: None. G. Sorice: None. S. Moffa: None. I. Severi: None. S. Cinti: None. A. Giaccari: Advisory Panel; Self; Sanofi. Board Member; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Amgen Inc., AstraZeneca, Merck Sharp &amp; Dohme Corp., Sanofi.

2492-PUB: KCNK16 Deficiency Protects Mice against High-Fat Diet-Induced Weight Gain

Potassium Channel, Two Pore Domain Subfamily K, Member 16 (TALK-1/KCNK16) is a K+ channel protein expressed in human and murine pancreas. Recent research by Vierra et al suggested a regulatory function of KCNK16 in mice for glucose-dependent β-cell second-phase insulin and δ-cell somatostatin secretion and a protective effect on fasting glycemia during 3 weeks high-fat diet (HFD). We tested the hypothesis, that deletion of KCNK16 affects body weight and glucose metabolism in vivo during prolonged HFD feeding. Therefore, we analyzed KCNK16-deficient knockout mice (KCNK16-/-) during HFD up to 21 weeks investigating body weight and composition, insulin sensitivity as well as insulin secretion. In HFD-fed KCNK16-/-, we observed a reduced body weight gain. Both, fat and lean mass were reduced and notably body-length was also significantly shorter. KCNK16-/- mice showed reduced food intake, an elevated oxygen consumption and energy expenditure. KCNK16-/- islets showed enhanced insulin secretion under glucose and GIP-1 simulation, but we did not reveal significant changes in fasting or fed plasma glucose or insulin. We found a moderate decrease in blood glucose during an ipITT. However, we did not observe an enhanced insulin sensitivity assessed by hyperinsulinemic-euglycemic clamps nor a beneficial effect of KCNK16 deficiency on the modulation of in vivo insulin secretion during hyperglycemic clamps in HFD-fed mice. In conclusion, we observed a reduced body weight gain, but also shorter body-length in the KCNK16-deficient mouse model during prolonged HFD feeding. Notably, food intake was reduced while energy expenditure was increased. Disclosure S. Brachs: Employee; Spouse/Partner; Treamid Therapeutics GmbH. Research Support; Self; Sanofi-Aventis Deutschland GmbH. U. Schwahn: Employee; Self; Sanofi-Aventis Deutschland GmbH. K. Steinmeyer: Employee; Self; Sanofi-Aventis Deutschland GmbH. M. Schäfer: Employee; Self; Sanofi-Aventis Deutschland GmbH. J. Gassenhuber: Employee; Self; Sanofi-Aventis Deutschland GmbH. Employee; Spouse/Partner; Sanofi-Aventis Deutschland GmbH. J. Spranger: None. Funding Sanofi Aventis Deutschland GmbH

HCV-Induced Beta Cell Dysfunction Contributes to HCV-Associated Type-2 Diabetes

Chronic hepatitis C virus (HCV) infection has a close association with type 2 diabetes mellitus (T2DM). Although the mechanisms of insulin resistant in hepatitis C (CHC) patients have been extensively studied, little attention has been given to the role of beta cell function in HCV-associated diabetes. Here, we found HCV could infected the beta cell directly and impair pancreatic beta cell function in CHC and mouse model. Both first-phase and second-phase insulin secretion was impaired, at least partially due to the reduction of exocytosis of secretory insulin-containing granules following HCV infection. Upregulated p38δ in HCV-infected beta cells resulted in inactivation of protein kinase D (PKD), which was responsible for impaired insulin secretory capacity of beta cells. These findings provided a new perspective into mechanism of HCV induced type 2 diabetes and a new inspiration for the important prognostic and therapeutic implications in the management of CHC patients with glucose intolerance. Funding Statement: This work was supported by grants from the National Natural Sciences Foundation of China [grant number 81770859, 81271828, 81471079, 31271268], the National Basic Research Program of China [grant number 2015CB554304], the Youth Innovation Promotion Association, Open Research Fund Program of the State Key Laboratory of Virology of China (grant number 2018IOV003) Declaration of Interests: The authors have declared that no conflict of interest exists. Ethics Approval Statement: Human studies were approved by the Ethics Committee of the First Hospital of Jilin University and the First Affiliated Hospital of Xinjiang Medical University. The written informed consents were received from participants prior to inclusion in the study. All animal experiments were approved by the Institutional Animal Ethical Committee of Wuhan Institute of Virology, Chinese Academy of Sciences (WIV, CAS).

Dynamic changes in insulin and glucagon during disease progression in rhesus monkeys with obesity-related type 2 diabetes mellitus.

To investigate the progression of obesity-related type 2 diabetes mellitus (T2DM) in rhesus monkeys, especially dynamic changes in insulin and glucagon. We followed a cohort of 52 rhesus monkeys for 7 years throughout the progression of obesity-related T2DM. Intravenous glucose tolerance tests were performed every 6 months to evaluate dynamic changes in glucose, insulin and glucagon levels. Obesity in rhesus monkeys increased the overall mortality and T2DM morbidity. During the progression of T2DM, glucagon remained consistently elevated, while insulin initially increased in compensation but then dropped to below normal levels when the monkeys developed overt T2DM. After a glucose challenge, both the first and second phases of insulin secretion increased during the early stage of T2DM; in later stages the first phase was delayed and the second phase was diminished. Our findings showed that, beside the decreased insulin level, hyperglucagonaemia also plays an important role in the development of T2DM.

Postprandial Reactive Hypoglycemia.

Reactive hypoglycemia (RH) is the condition of postprandially hypoglycemia occurring 2-5 hours after food intake. RH is clinically seen in three different forms as follows: idiopathic RH (at 180 min), alimentary (within 120 min), and late RH (at 240–300 min). When the first-phase insulin response decreases, firstly, blood glucose starts to rise after the meal. This leads to late but excessive secretion of the second-phase insulin secretion. Thus, late reactive hypoglycemia occurs. Elevated insulin levels also cause down-regulation of the insulin post-receptor on the muscle and fat cells, thus decreasing insulin sensitivity. The cause of the increase in insulin sensitivity in IRH at 3 h is not completely clear. However, there is a decrease in insulin sensitivity in late reactive hypoglycaemia at 4 or 5 hours. Thus, patients with hypoglycemia at 4 or 5 h who have a family history of diabetes and obesity may be more susceptible to diabetes than patients with hypoglycemia at 3 h. We believe that some cases with normal glucose tolerance in OGTT should be considered as prediabetes at <55 or 60 mg/dl after 4-5 hours after OGTT. Metformin and AGI therapy may be recommended if there is late RH with IFG. Also Metformin, AGİ, TZD, DPP-IVInhibitors, GLP1RA therapy may be recommended if there is late RH with IGT. As a result, postprandial RH (<55 or 60 mg/dl), especially after 4 hours may predict diabetes. Therefore, people with RH along with weight gain and with diabetes history in the family will benefit from a lifestyle modification as well as the appropriate antidiabetic approach in the prevention of diabetes.

Evaluation and Management of Youth-Onset Type 2 Diabetes: A Position Statement by the American Diabetes Association.

Although all types of diabetes result in hyperglycemia, the pathophysiology of each type of diabetes is different. These guidelines summarize available data specific to the comprehensive care of youth with type 2 diabetes. The objective is to enrich the recognition of type 2 diabetes in youth, its risk factors, its pathophysiology, its management, and the prevention of associated complications. Glucose homeostasis is maintained by a balance between insulin secretion from the pancreatic β-cells and sensitivity to insulin in skeletal muscle, adipose tissue, and liver (1). When insulin sensitivity declines, insulin secretion must increase to maintain glucose tolerance, and, in most youth, decreased insulin sensitivity due to puberty and/or obesity is compensated by increased insulin secretion. However, when β-cells cannot secrete sufficient insulin to compensate for insulin resistance, abnormalities in glucose homeostasis ensue, potentially progressing to prediabetes and type 2 diabetes as β-cell function deteriorates further (2–9). The relationship between β-cell function and insulin sensitivity in adults and youth has been demonstrated to be a hyperbolic function and can be described mathematically as the product of insulin sensitivity and β-cell function, called the disposition index (DI) (1). The DI essentially expresses the amount of insulin being secreted relative to the degree of insulin resistance and is a constant for a given degree of glucose tolerance in any one individual. Overweight and obesity are major acquired contributors to the development of insulin resistance, particularly in the face of the physiologic insulin resistance characteristic of puberty. Robust pancreatic β-cell compensatory insulin secretion maintains normal glucose homeostasis. However, in adolescents with obesity who develop type 2 diabetes, there is severe peripheral and hepatic insulin resistance, with ∼50% lower peripheral insulin sensitivity than peers with obesity without diabetes, along with increased fasting hepatic glucose production and inadequate first- and second-phase insulin secretion, resulting …

In Vivo Deletion of β-Cell Drp1 Impairs Insulin Secretion Without Affecting Islet Oxygen Consumption.

Mitochondria are dynamic organelles that undergo frequent fission and fusion events. Mitochondrial fission is required for ATP production, the tricarboxylic acid cycle, and processes beyond metabolism in a cell-type specific manner. Ex vivo and cell line studies have demonstrated that Drp1, a central regulator of mitochondrial fission, is required for glucose-stimulated insulin secretion (GSIS) in pancreatic β cells. Herein, we set out to interrogate the role of Drp1 in β-cell insulin secretion in vivo. We generated β-cell-specific Drp1 knockout (KO) mice (Drp1β-KO) by crossing a conditional allele of Drp1 to Ins1cre mice, in which Cre recombinase replaces the coding region of the Ins1 gene. Drp1β-KO mice were glucose intolerant due to impaired GSIS but did not progress to fasting hyperglycemia as adults. Despite markedly abnormal mitochondrial morphology, Drp1β-KO islets exhibited normal oxygen consumption rates and an unchanged glucose threshold for intracellular calcium mobilization. Instead, the most profound consequences of β-cell Drp1 deletion were impaired second-phase insulin secretion and impaired glucose-stimulated amplification of insulin secretion. Our data establish Drp1 as an important regulator of insulin secretion in vivo and demonstrate a role for Drp1 in metabolic amplification and calcium handling without affecting oxygen consumption.

The Relationships Between Hemoglobin and Diabetes Factors (Insulin Resistance, Glucose Effectiveness, First- and Second-Phase Insulin Secretion) in Old Chinese

Summary Background Diabetes is characterized by increased insulin resistance (IR) and decreased insulin secretion. The roles of glucose effectiveness (GE), first- and second-phase insulin secretion (FPIS, SPIS) are often overlooked. We denote these factors as diabetic factors (DF). Hemoglobin (Hb) has been shown to be related to IR and FPIS, but not to SPIS and GE. The aims of this study are to investigate the relationships between Hb and DFs and to compare which one has the tightest correlation with Hb in old Chinese. Methods We randomly enrolled 5109 men and 5851 women, whose age were over 65 years old. Subjects, who were obese or on medications, were excluded. Simple correlation was applied to evaluate the relationships between Hb and 4 DFs. To compare the relative tightness between each correlation lines, all the units of the DFs were transformed into percentage. Results All the biochemistry data were higher in subjects with metabolic syndrome (MetS) in both genders, except for GE and HDL. Similar trends were also noted when dividing subjects into quartiles of Hb. The results of simple correlation showed that all the DFs are significantly related to Hb except for FPIS in women. The association between Hb and GE is negative. After transforming the different units into percentage, the relationships with Hb, from the highest to lowest, were IR, SPIS, GE and FPIS in both genders. Conclusion Our data show that all DFs are almost related to Hb. IR has the tightest correlation with Hb in old Chinese.

Causal Association of Overall Obesity and Abdominal Obesity with Type 2 Diabetes: A Mendelian Randomization Analysis.

This study aimed to compare the causal effect of overall obesity and abdominal obesity on type 2 diabetes among Chinese Han individuals. The causal relationship of BMI and waist-to-hip ratio (WHR) with the risk of glucose deterioration and glycemic traits was compared using two different genetic instruments based on 30 BMI loci and 6 WHR loci with Mendelian randomization (MR) in three prospective cohorts (n = 6,476). Each 1-SD genetically instrumented higher WHR was associated with a 65.7% higher risk of glucose deterioration (95% CI = 1.069-2.569, P = 0.024), whereas no significant association of BMI with glucose deterioration was observed. Furthermore, a causal relationship was found only between BMI and homeostatic model assessment β-cell function (HOMA-B) (β = 0.143, P = 0.001), and there was a nominal association with Stumvoll second-phase insulin secretion traits (β = 0.074, P = 0.022). The significance level did not persist in sensitivity analyses, except in the causal estimate of WHR on the Gutt index in MR-Egger (β = -0.379, P = 0.022) and the causal estimate of BMI on homeostatic model assessment β-cell function in weighted median MR (β = 0.128, P = 0.017). The data from this study support the potential causal relationship between abdominal obesity and hyperglycemia, which may be driven by aggravated insulin resistance, in contrast with the potential causal relationship between overall obesity and insulin secretion.

Deletion of the RabGAP TBC1D1 Leads to Enhanced Insulin Secretion and Fatty Acid Oxidation in Islets From Male Mice.

The Rab guanosine triphosphatase-activating protein (RabGAP) TBC1D1 has been shown to be a key regulator of glucose and lipid metabolism in skeletal muscle. Its function in pancreatic islets, however, is not yet fully understood. Here, we aimed to clarify the specific impact of TBC1D1 on insulin secretion and substrate use in pancreatic islets. We analyzed the dynamics of glucose-stimulated insulin secretion (GSIS) and lipid metabolism in isolated islets from Tbc1d1-deficient (D1KO) mice. To further investigate the underlying cellular mechanisms, we conducted pharmacological studies in these islets. In addition, we determined morphology and number of both pancreatic islets and insulin vesicles in β-cells using light and transmission electron microscopy. Isolated pancreatic islets from D1KO mice exhibited substantially increased GSIS compared with wild-type (WT) controls. This was attributed to both enhanced first and second phase of insulin secretion, and this enhanced secretion persisted during repetitive glucose stimuli. Studies with sulfonylureas or KCl in isolated islets demonstrated that TBC1D1 exerts its function via a signaling pathway at the level of membrane depolarization. In line, ultrastructural analysis of isolated pancreatic islets revealed both higher insulin-granule density and number of docked granules in β-cells from D1KO mice compared with WT controls. Like in skeletal muscle, lipid use in isolated islets was enhanced upon D1KO, presumably as a result of a higher mitochondrial fission rate and/or higher mitochondrial activity. Our results clearly demonstrate a dual role of TBC1D1 in controlling substrate metabolism of the pancreatic islet.

Effect of body mass index on diabetogenesis factors at a fixed fasting plasma glucose level.

AimThe present study evaluated the relative influence of body mass index (BMI) on insulin resistance (IR), first-phase insulin secretion (FPIS), second-phase insulin secretion (SPIS), and glucose effectiveness (GE) at a fixed fasting plasma glucose level in an older ethnic Chinese population.MethodsIn total, 265 individuals aged 60 years with a fasting plasma glucose level of 5.56 mmol/L were enrolled. Participants had BMIs of 20.0–34.2 kg/m2. IR, FPIS, SPIS, and GE were estimated using our previously developed equations. Pearson correlation analysis was conducted to assess the correlations between the four diabetogenesis factors and BMI. A general linear model was used to determine the differences in the percentage of change among the four factor slopes against BMI.ResultsSignificant correlations were observed between BMI and FPIS, SPIS, IR, and GE in both women and men, which were higher than those reported previously. In men, BMI had the most profound effect on SPIS, followed by IR, FPIS, and GE, whereas in women, the order was slightly different: IR, followed by FPIS, SPIS, and GE. Significant differences were observed among all these slopes, except for the slopes between FPIS and SPIS in women (p = 0.856) and IR and FPIS in men (p = 0.258).ConclusionsThe contribution of obesity to all diabetes factors, except GE, was higher than that reported previously. BMI had the most profound effect on insulin secretion in men and on IR in women in this 60-year-old cohort, suggesting that lifestyle modifications for obesity reduction in women remain the most important method for improving glucose metabolism and preventing future type 2 diabetes mellitus.

The Second Phase of Insulin Secretion in Nondiabetic Islet-Grafted Recipients Is Altered and Can Predict Graft Outcome.

Islet transplantation (IT) can treat patients with severely unstable type 1 diabetes. Prehepatic kinetics of insulin secretion (ISec) in two phases can be calculated by C-peptide levels during meal tests. We proposed to describe the ISec profile after a mixed-meal tolerance test (MMTT) in IT recipients and to determine whether the calculated ISec indexes can predict graft outcome. We analyzed 34 MMTT among 11 patients who underwent IT between 2011 and 2016 and compared them with healthy controls and patients with type 2 diabetes (T2D). ISec indexes and insulin sensitivity were calculated from models of Van Cauter, Breda, and Mari after MMTT. Graft success was defined by total insulin independence without any criteria for diabetes. In patients with successful IT, the first- and second-phase ISec indexes were lower than those of controls (P < 0.001) and did not differ from those of the T2D group. Nevertheless, insulin sensitivity of IT recipients was similar to that of the control group and higher than that of the T2D group. The index of the second phase of ISec ɸS was correlated with total infused islet equivalents (IEQs), was a good predictor of diabetes (re)occurrence, and allowed us to calculate 9500 IEQ/kg as the minimum needed to reach insulin independence. We showed that indexes from the first and second phases of ISec are altered in insulin-independent IT recipients. Higher sensitivity distinguishes them from patients with T2D. Even in insulin-independent patients, IT remains a marginal mass model. Moreover, ɸS can estimate transplanted islet mass and predict IT recipient outcomes.

Adiposity and family history of type 2 diabetes in an admixed population of adolescents: Associations with insulin sensitivity, beta-cell function, and hepatic insulin extraction in BRAMS study

AimsInsulin resistance and beta-cell dysfunction manifest differently across racial/ethnic groups, and there is a lack of knowledge regarding the pathophysiology of type 2 diabetes mellitus (T2DM) for ethnically admixed adolescents. This study aimed to investigate the influence of adiposity and family history (FH) of T2DM on aspects of insulin sensitivity, beta-cell function, and hepatic insulin extraction in Brazilian adolescents. MethodsA total of 82 normoglycemic adolescents were assessed. The positive FH of T2DM was defined as the presence of at least one known family member with T2DM. The hyperglycemic clamp test consisted of a 120-min protocol. Insulin secretion and beta-cell function were obtained from C-peptide deconvolution. Analysis of covariance considered pubertal stage as a covariate. ResultsBoth lean and overweight/obese adolescents had similar glycemic profiles and disposition indexes. Overweight/obese adolescents had about 1/3 the insulin sensitivity of lean adolescents (1.1 ± 0.2 vs. 3.4 ± 0.3 mg·kg·min·pmol ∗ 1000), which was compensated by an increase around 2.5 times in basal (130 ± 7 vs. 52 ± 10 pmol·l·min) and total insulin secretion (130,091 ± 12,230 vs. 59,010 ± 17,522 pmol·l·min), and in the first and second phases of insulin secretion; respectively (p < 0.001). This increase was accompanied by a mean reduction in hepatic insulin extraction of 35%, and a 2.7-time increase in beta-cell glucose sensitivity (p < 0.05). The positive FH of T2DM was not associated with derangements in insulin sensitivity, beta-cell function, and hepatic insulin extraction. ConclusionsIn an admixed sample of adolescents, the hyperglycemic clamp test demonstrated that adiposity had a strong influence, and FH of T2DM had no direct influence, in different aspects of glucose metabolism.

LONG-TERM IMPROVEMENT OF GLUCOSE HOMEOSTASIS AND BODY COMPOSITION IN PATIENTS UNDERGOING LAPAROSCOPIC SLEEVE GASTRECTOMY.

Laparoscopic sleeve gastrectomy (SG) has gained popularity as a metabolic procedure, but its long-term effectiveness for Romanian patients remains unclear. To assess the long-term efficacy of SG for Romanian patients and to evaluate the differences between 5 years and 1 year follow-up. A longitudinal, prospective analysis of collected data from 68 patients undergoing SG between 2009 and 2014 was performed. Long-term outcomes at 5 years were analyzed in terms of total weight loss (%TWL), excess weight loss (%EWL), body composition and glucose homeostasis. All patients meeting the standard criteria for SG before inclusion were prospectively enrolled in the study. Of the 68 patients, eight were lost to follow-up, therefore, 60 patients (41.7±12.5 years, baseline body mass index [BMI] 44.6±9.9Kg/m2) were analyzed. The BMI decreased at 12 months with 30.7% from the preoperative BMI (p<0.001) and subsequently stabilized at 5 years.TWL and EWL were 30.6% and 83.1%, respectively at 1 year, with a slightly increase at 5 years.Therapeutic success rate (%EWL≥50) and diabetes remission rate (Buchwald criteria) were 93.3% and respectively 63.6% at 5 years. Insulin sensitivity index and metabolic clearance rate of glucose increased with 92.5% and 60.1% respectively, in the third month from baseline (p<0.001), while estimated second phase of insulin secretion decreased with 7.9% in the first month postoperatively (p=0.04), remaining stable afterwards. SG was effective in terms of %EWL, body composition and glucose homeostasis improvement for Romanian patients, the outcomes stabilizing after 1 year follow-up.

Long-term feeding of high-fat plus high-fructose diet induces isolated impaired glucose tolerance and skeletal muscle insulin resistance in miniature pigs

BackgroundDuring the prediabetic development, the changes in β-cell function and tissue-specific insulin resistance have been described. However, there are conflicting views in insulin secretory capacity between early clinical observation and recent proposed mathematical model. On the basis of digestive and metabolic similarities with humans, swine have great potential as an animal model to investigate the progressive mechanisms of prediabetes. The aim of this study was to investigate the insulin secretory response and tissue-specific insulin resistance in a dietary-induced prediabetic porcine model.MethodsAdult male Taiwan Lee-Sung miniature pigs were randomized into two groups: (1) low-fat diet and (2) high-fat plus high-fructose diet (HFHF; 20.9% crude fat and 17.8% fructose). During the 12-month dietary intervention, body weights and blood glucose levels were measured monthly. Intravenous glucose tolerance test was used for measuring glucose tolerance and insulin secretory capacity. At the end of the experiment, liver and soleus muscle specimens were collected for ex vivo insulin sensitivity testing.ResultsThe results showed that the HFHF group had obesity, hyperinsulinemia, and dyslipidemia, but normal fasting glucose levels. The HFHF pigs exhibited enhanced first- and second-phase insulin secretion and high 2-h postload glucose levels in intravenous glucose tolerance test. Furthermore, the skeletal muscle specimens from the HFHF group were desensitized to insulin stimulation as shown by the lack of AKT Ser473 phosphorylation; however, the liver specimens remained a normal response.ConclusionsIn conclusion, the HFHF diet-fed pigs developed isolated impaired glucose tolerance corresponding to prediabetes with an intense insulin secretory response and skeletal muscle insulin resistance.

Association of bone turnover markers with glucose metabolism in Chinese population.

The association between type 2 diabetes (T2DM) and bone metabolism has been discussed previously but is controversial. In this study we aimed to evaluate the association of bone turnover markers with glucose metabolism in Chinese population, in which 919 males and 4171 postmenopausal females in a region of Shanghai were recruited. Anthropometric and biochemical traits related to glucose and bone metabolism were analyzed. Participants were classified according to their glucose tolerance as normal glucose tolerance (NGT), impaired glucose regulation (IGR) or T2DM. Males and females were analyzed separately, and then associations between bone turnover markers (BTMs) and glucose metabolism were evaluated. The results showed that in females, the serum levels of N-terminal osteocalcin (N-MID), N-terminal procollagen of type I collagen (PINP) and β-cross-linked C-telopeptide of type I collagen (β-CTX) were significantly decreased in the T2DM group compared to the NGT group (P<0.01). When age, body mass index, serum lipids, fat percentage, visceral fat area, subcutaneous fat area, anti-diabetic medicines, PINP, N-MID and β-CTX were included in one logistic model, N-MID (OR [95% CI]: 0.954 [0.932; 0.976]; P=0.0001) was significantly associated with T2DM in females. In females, N-MID was associated with insulin sensitivity and HOMA-β. PINP was significantly associated with HOMA-β, GUTT-ISI, Stumvoll first-phase insulin secretion index (STU-1) and Stumvoll second-phase insulin secretion index (STU-2), but β-CTX was associated only with HOMA-β (β±SE: 0.1331±0.0311; P=1.95×10-5) and GUTT-ISI (β±SE: 0.0727±0.0229; P=0.0015). In males, N-MID was significantly correlated with HOMA-β (β±SE: 0.3439±0.0633; P=7.75×10-8), GUTT-ISI (β±SE: 0.1601±0.0531; P=0.0027) and STU-1 (β±SE: 0.2529±0.1033; P=0.0146). Significant associations were also detected between β-CTX and HOMA-β (β±SE: 0.2736±0.0812; P=0.0009). This study reveals that BTMs are highly associated with T2DM, insulin sensitivity and beta cell function in both Chinese males and postmenopausal females.

Low-Dose Persistent Organic Pollutants Impair Insulin Secretory Function of Pancreatic β-Cells: Human and In Vitro Evidence.

Low-dose persistent organic pollutants (POPs), especially organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs), have emerged as a new risk factor for type 2 diabetes. We evaluated whether chronic exposure to low-dose POPs affects insulin secretory function of β-cells in humans and in vitro cells. Serum concentrations of OCPs and PCBs were measured in 200 adults without diabetes. Mathematical model-based insulin secretion indices were estimated by using a 2-h seven-sample oral glucose tolerance test. Insulin secretion by INS-1E β-cells was measured after 48 h of treatment with three OCPs or one PCB mixture. Static second-phase insulin secretion significantly decreased with increasing serum concentrations of OCPs. Adjusted means were 63.2, 39.3, 44.1, 39.3, 39.7, and 22.3 across six categories of a summary measure of OCPs (Ptrend = 0.02). Dynamic first-phase insulin secretion remarkably decreased with increasing concentrations of OCPs among only insulin-sensitive individuals (Ptrend = 0.02); the insulin levels among individuals with high OCPs were ∼30% of those with low OCPs. Compared with OCPs, PCBs showed weaker associations. The decreased insulin secretion by INS-1E β-cells was observed for even 1 pmol/L OCP. The data from human and in vitro cell experiments suggest that chronic exposure to low-dose POPs, especially OCPs, can induce pancreatic β-cell dysfunction.

Impact of insulin glargine and lixisenatide on β-cell function in patients with type 2 diabetes mellitus: A randomized open-label study.

It is known that β-cell function can be enhanced by direct stimulation of insulin secretion or by induction of β-cell rest, but whether both strategies can complement each other has not yet been examined. A total of 28 people with type 2 diabetes (glycated haemoglobin 7.8% ± 0.5%) were treated with either lixisenatide or titrated insulin glargine, followed by their combined administration, each over 4 weeks. First- and second-phase insulin secretion during an intravenous glucose challenge were calculated. First- and second-phase insulin secretion were not increased with glargine alone, but increased after addition of lixisenatide ( P < .001). Lixisenatide alone increased first- and second-phase insulin secretion ( P < .01). Addition of insulin glargine tended to further increase first-phase insulin secretion (P = .054), as well as insulin and C-peptide concentrations ( P < .05). Second-phase insulin secretion was not affected by the addition of glargine. The sequence of initiating lixisenatide or glargine had no effect on the final measures of glycaemia or insulin secretion. Thus, lixisenatide and, to a lesser extent, insulin glargine, increase glucose-stimulated insulin secretion in an additive manner.