Β-cell Response Research Articles

Duodeno-jejunal bypass restores β-cell hypersecretion and islet hypertrophy in western diet obese rats.

Duodeno-jejunal bypass (DJB) operation improves glucose homeostasis in morbid obesity, independently of weight loss or reductions in adiposity, through mechanisms not yet fully elucidated. Herein, we evaluated the effects of DJB upon glucose homeostasis, endocrine pancreatic morphology, and β-cell responsiveness to potentiating agents of cholinergic and cAMP pathways, in western diet (WD) obese rats, at 2 months after operation. From 8 to 18 weeks of age male Wistar rats fed on a WD. After this period, a sham (WD Sham group) or DJB (WD DJB) operations were performed. At 2 months after operation glucose homeostasis was verified. Body weight was similar between WD DJB and WD Sham rats, but WD DJB rats showed a decrease in Lee index, retroperitoneal and perigonadal fat pads. Also, WD DJB rats displayed reduced fasting glycemia and insulinemia, and increased insulin-induced Akt activation in the gastrocnemius. Islets from WD DJB rats secreted less amounts of insulin, in response to activators of the cholinergic (carbachol and phorbol 12-myristate 13-acetate) and cAMP (forskolin and 3-isobutyl-1-methyl-xantine) pathways. Islets of WD DJB rats had higher sintaxin-1 protein content than WD Sham, but without modification in muscarinic-3 receptor, protein kinase (PK)-Cα, and (PK)-Aα protein amounts. In addition, islets of WD DJB animals showed reduction in islets and β-cell masses. DJB surgery improves fasting glycemia and insulin action in skeletal muscle. Better endocrine pancreatic morphofunction was associated, at least in part, with the regulation of the cholinergic and cAMP pathways, and improvements in syntaxin-1 islet protein content induced by DJB.

Role of Protein Phosphatase 1 and Inhibitor of Protein Phosphatase 1 in Nitric Oxide-Dependent Inhibition of the DNA Damage Response in Pancreatic β-Cells.

Nitric oxide is produced at micromolar levels by pancreatic β-cells during exposure to proinflammatory cytokines. While classically viewed as damaging, nitric oxide also activates pathways that promote β-cell survival. We have shown that nitric oxide, in a cell type-selective manner, inhibits the DNA damage response (DDR) and, in doing so, protects β-cells from DNA damage-induced apoptosis. This study explores potential mechanisms by which nitric oxide inhibits DDR signaling. We show that inhibition of DDR signaling (measured by γH2AX formation and the phosphorylation of KAP1) is selective for nitric oxide, as other forms of reactive oxygen/nitrogen species do not impair DDR signaling. The kinetics and broad range of DDR substrates that are inhibited suggest that protein phosphatase activation may be one mechanism by which nitric oxide attenuates DDR signaling in β-cells. While protein phosphatase 1 (PP1) is a primary regulator of DDR signaling and an inhibitor of PP1 (IPP1) is selectively expressed only in β-cells, disruption of either IPP1 or PP1 does not modify the inhibitory actions of nitric oxide on DDR signaling in β-cells. These findings support a PP1-independent mechanism by which nitric oxide selectively impairs DDR signaling and protects β-cells from DNA damage-induced apoptosis.

Blockade of cannabinoid 1 receptor improves glucose responsiveness in pancreatic beta cells

Cannabinoid 1 receptors (CB1Rs) are expressed in peripheral tissues, including islets of Langerhans, where their function(s) is under scrutiny. Using mouse β‐cell lines, human islets and CB1R‐null (CB1R −/−) mice, we have now investigated the role of CB1Rs in modulating β‐cell function and glucose responsiveness. Synthetic CB1R agonists diminished GLP‐1‐mediated cAMP accumulation and insulin secretion as well as glucose‐stimulated insulin secretion in mouse β‐cell lines and human islets. In addition, silencing CB1R in mouse β cells resulted in an increased expression of pro‐insulin, glucokinase (GCK) and glucose transporter 2 (GLUT2), but this increase was lost in β cells lacking insulin receptor. Furthermore, CB1R −/− mice had increased pro‐insulin, GCK and GLUT2 expression in β cells. Our results suggest that CB1R signalling in pancreatic islets may be harnessed to improve β‐cell glucose responsiveness and preserve their function. Thus, our findings further support that blocking peripheral CB1Rs would be beneficial to β‐cell function in type 2 diabetes.

An In Vivo Zebrafish Model for Interrogating ROS-Mediated Pancreatic β-Cell Injury, Response, and Prevention.

It is well known that a chronic state of elevated reactive oxygen species (ROS) in pancreatic β-cells impairs their ability to release insulin in response to elevated plasma glucose. Moreover, at its extreme, unmitigated ROS drives regulated cell death. This dysfunctional state of ROS buildup can result both from genetic predisposition and environmental factors such as obesity and overnutrition. Importantly, excessive ROS buildup may underlie metabolic pathologies such as type 2 diabetes mellitus. The ability to monitor ROS dynamics in β-cells in situ and to manipulate it via genetic, pharmacological, and environmental means would accelerate the development of novel therapeutics that could abate this pathology. Currently, there is a lack of models with these attributes that are available to the field. In this study, we use a zebrafish model to demonstrate that ROS can be generated in a β-cell-specific manner using a hybrid chemical genetic approach. Using a transgenic nitroreductase-expressing zebrafish line, Tg(ins:Flag-NTR)s950, treated with the prodrug metronidazole (MTZ), we found that ROS is rapidly and explicitly generated in β-cells. Furthermore, the level of ROS generated was proportional to the dosage of prodrug added to the system. At high doses of MTZ, caspase 3 was rapidly cleaved, β-cells underwent regulated cell death, and macrophages were recruited to the islet to phagocytose the debris. Based on our findings, we propose a model for the mechanism of NTR/MTZ action in transgenic eukaryotic cells and demonstrate the robust utility of this system to model ROS-related disease pathology.

Regulation of compensatory β-cell proliferation by inter-organ networks from the liver to pancreatic β-cells.

In insulin-resistant states such as obesity, pancreatic β-cells proliferate to prevent blood glucose elevations. However, the mechanism(s) by which obesity induces compensatory β-cell responses is not fully understood. Recently, several studies have shown that signals from the liver, such as neuronal signals or humoral factors, regulate β-cell proliferation during obesity development. We previously reported a liver-brain-pancreas neuronal relay, consisting of afferent splanchnic nerves, the central nervous system and efferent vagal nerves, to promote this compensatory β-cell proliferation. Furthermore, we recently clarified the molecular mechanisms by which efferent vagal signals induce β-cell proliferation in this inter-organ neuronal network system. Herein, these liver-β-cell inter-organ networks are reviewed, focusing mainly on the neuronal network. The significance of the neuronal network system in the maintenance of glucose homeostasis is also discussed with reference to the relevant literature.

Hydrogen Sulfide Donor NaHS Improves Metabolism and Reduces Muscle Atrophy in Type 2 Diabetes: Implication for Understanding Sarcopenic Pathophysiology

Sarcopenia, a loss of muscle mass and functionality, constitutes a major contributor to disability in diabetes. Hydrogen sulfide (H2S) dynamics and muscle mass regulatory signaling were studied in GK rats, a model for type 2 diabetes (T2D). GK rats exhibited a number of features that are consistent with sarcopenia and T2D including loss of muscle mass and strength, in addition to glucose intolerance, insulin resistance, and impaired β-cell responsiveness to glucose. Mechanistically, activation levels of Akt, a key modulator of protein balance, were decreased in T2D. Consequently, we confirmed reduced activity of mTOR signaling components and higher expression of atrophy-related markers typified by FoxO1/atrogin-1/MuRF1 and myostatin-Smad2/3 signaling during the course of diabetes. We observed in GK rat reduced antioxidant capacity (↓GSH/GSSG) and increased expression and activity of NADPH oxidase in connection with augmented rate of oxidation of lipids, proteins, and DNA. H2S bioavailability and the expression of key enzymes involved in its synthesis were suppressed as a function of diabetes. Interestingly, GK rats receiving NaHS displayed increased muscle Akt/mTOR signaling and decreased expression of myostatin and the FoxO1/MuRF1/atrogin-dependent pathway. Moreover, diabetes-induced heightened state of oxidative stress was also ameliorated in response to NaHS therapy. Overall, the current data support the notion that a relationship exists between sarcopenia, heightened state of oxidative stress, and H2S deficiency at least in the context of diabetes. Moreover, treatment with a potent H2S donor at an early stage of diabetes is likely to mitigate the development of sarcopenia/frailty and predictably reduces its devastating sequelae of amputation.

Nutrient regulation of pancreatic β-cell proliferation

Excess consumption of energy-dense foods combined with a sedentary lifestyle is driving an obesity epidemic. Although obesity is closely associated with insulin resistance, most individuals meet the insulin demand by increasing their functional β-cell mass. Those who eventually develop type 2 diabetes are distinguished by a failure in this compensatory process. Although a causal role of insulin resistance in compensatory β-cell responses has received considerable experimental support, precisely how the β cell senses changes in the metabolic environment is still unknown. As metabolism of glucose, lipids and amino acids is profoundly altered in obesity, it is not surprising that these nutrients are conspicuous among the factors proposed to contribute. In this review we summarise our understanding of the role of nutrients, in particular glucose, fatty acids and amino acids in β-cell compensation with a particular emphasis on their relation to insulin resistance-induced factors and their underlying mechanism of action. Finally, we describe the concept of epigenetic programming and review recent studies illustrating how the status of the β cell epigenome is a product of its nutrient environment, and how metabolic programming of the β cell contributes to diabetes risk.

S-Equol Activates cAMP Signaling at the Plasma Membrane of INS-1 Pancreatic β-Cells and Protects against Streptozotocin-Induced Hyperglycemia by Increasing β-Cell Function in Male Mice

Background:S-equol, which is enantioselectively produced from daidzein by gut microbiota, has been suggested as a chemopreventive agent against type 2 diabetes mellitus (T2DM), but the underlying mechanisms remain unclear.Objective: We investigated the effects of S-equol on pancreatic β-cell function.Methods: β-Cell growth and insulin secretion were evaluated with male Institute of Cancer Research mice and isolated pancreatic islets from the mice, respectively. The mechanisms by which S-equol stimulated β-cell response were examined in INS-1 β-cells. The effect of S-equol treatment on β-cell function was assessed in low-dose streptozotocin-treated mice. S-equol was used at 10 μmol/L for in vitro and ex vivo studies and was administered by oral gavage (20 mg/kg, 2 times/d throughout the experimental period) for in vivo studies.Results:S-equol administration for 7 d increased Ki67-positive β-cells by 27% (P < 0.01) in mice. S-equol enantioselectively enhanced glucose-stimulated insulin secretion in mouse pancreatic islets by 41% (P < 0.001). In INS-1 cells, S-equol exerted stronger effects than daidzein on cell growth, insulin secretion, and cAMP-response element (CRE)-mediated transcription. These S-equol effects were diminished by inhibiting protein kinase A. The effective concentration of S-equol for stimulating cAMP production at the plasma membrane was lower than that for phosphodiesterase inhibition. S-equol-stimulated CRE activation was negatively controlled by the knockdown of G-protein α subunit group S (stimulatory) and positively controlled by that of G-protein-coupled receptor kinase-3 and -6. Compared with vehicle-treated controls, S-equol gavage treatment resulted in an increase in β-cell mass of 104% (P < 0.05), a trend toward high plasma insulin concentrations (by 118%; P = 0.06), and resistance to hyperglycemia after streptozotocin treatment (78% of AUC after glucose challenge; P < 0.01). S-equol administration significantly increased the number of Ki67-positive proliferating β-cells by 62% (P < 0.01) and decreased that of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive apoptotic β-cells by 75% (P < 0.05).Conclusions: Our results show that S-equol boosts β-cell function and prevents hypoglycemia in mice, suggesting its potential for T2DM prevention.

Relationship Between β-cell Response and Insulin Sensitivity in Horses based on the Oral Sugar Test and the Euglycemic Hyperinsulinemic Clamp.

BackgroundA hyperbolic relationship between β‐cell response and insulin sensitivity (IS) has been described in several species including rodents, dogs, and humans. This relationship has not been elucidated in the horse.Hypothesis/ObjectivesTo determine whether the hyperbolic relationship between β‐cell response and IS exists in horses by using indices of β‐cell response from the oral sugar test (OST) and IS measurements from the euglycemic hyperinsulinemic clamp (EHC). A second aim was to compare how well IS estimates from the OST and EHC correlate.AnimalsForty‐nine horses with different degrees of insulin regulation (normal‐to‐severe insulin dysregulation).MethodsCross‐sectional study. Horses were examined with an OST and an EHC.ResultsDecreased IS was associated with increased β‐cell response in the horses. Nine of 12 comparisons between indices of β‐cell response and IS measures fulfilled the criteria for a hyperbolic relationship. Indices of IS calculated from the OST correlated highly with the insulin‐dependent glucose disposal rate (M) and the insulin‐dependent glucose disposal rate per unit of insulin (M/I) determined from the EHC (r = 0.81–0.87).Conclusions and Clinical ImportanceA hyperbolic relationship between β‐cell response and IS exists in horses, which suggest that horses with insulin dysregulation respond not only with postprandial hyperinsulinemia but are also insulin resistant. The OST is primarily a test for β‐cell response rather than a test for IS, but calculated indices of IS from the OST may be useful to estimate IS in horses, especially when the horse is insulin resistant.

Deterioration of insulin release rate response to glucose during oral glucose tolerance test is associated with an increased risk of incident diabetes in normal glucose tolerance subjects.

β-Cell dedifferentiation, characterized by loss of glucose sensitivity (β-cell glucose sensitivity [βCGS]), has been reported to play an important role in the development of type 2 diabetes (T2D). Traditionally, βCGS was derived from C-peptide-based method. However, C-peptide was not routinely examined in normal subjects and diabetes never treated with insulin. Thus, the aim of the study was to evaluate the use of insulin in oral glucose tolerance test (OGTT) in estimation of β-cell glucose response ability. A total of 1,599 subjects including normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and T2D were included in the study. A subgroup of NGT subjects (n=591) were followed up for an average duration of 56.88 ± 20.76 months. Insulin release rate (IRRINS ) in the function of glucose (IRRINS response to glucose [IRRG]) during OGTT was compared with βCGS. Both βCGS derived from C-peptide by deconvolution approach and IRRG by insulin release progressively declined from NGT to IGT and T2D. Both βCGS and IRRG were associated with deposit of first-phase insulin secretion (DI1st ). After 56.88 ± 20.76 months, 32 (5.41%) NGT subjects had developed T2D. NGT subjects who progressed to diabetes after follow-up had lower IRRG and DI1st levels than those who did not (P < 0.01). Furthermore, multiple logistic regression analyses showed that decreased IRRG was a significant independent risk predictor for future diabetes after adjustment of age, body mass index (BMI), homeostasis model assessment (HOMA)-insulin resistance, DI1st and family history. NGT subjects with decreased IRRG during OGTT had defective early insulin secretion and were at higher risk of developing diabetes. IRRG could be a useful T2D predictor in NGT subjects. © 2017 IUBMB Life, 69(9):756-766, 2017.

The rs7903146 Variant in the TCF7L2 Gene Increases the Risk of Prediabetes/Type 2 Diabetes in Obese Adolescents by Impairing β-Cell Function and Hepatic Insulin Sensitivity

OBJECTIVEIn this study, we aimed to explore the mechanism by which TCF7L2 rs7903146 risk allele confers susceptibility to impaired glucose tolerance (IGT) or type 2 diabetes (T2D) in obese adolescents.RESEARCH DESIGN AND METHODSThe rs7903146 variant in the TCF7L2 gene was genotyped in a multiethnic cohort of 955 youths. All subjects underwent an oral glucose tolerance test with the use of the Oral Minimal Model to assess insulin secretion, and 33 subjects underwent a hyperinsulinemic-euglycemic clamp. In 307 subjects, a follow-up oral glucose tolerance test was repeated after 3.11 ± 2.36 years.RESULTSThe TCF7L2 rs7903146 risk allele was associated with higher 2-h glucose levels in Caucasians (P = 0.006) and African Americans (P = 0.009), and a trend was seen also in Hispanics (P = 0.072). Also, the T allele was associated with decreased β-cell responsivity and IGT (P < 0.05). Suppression of endogenous hepatic glucose production was lower in subjects with the risk variant (P = 0.006). Finally, the odds of showing IGT/T2D at follow-up were higher in subjects carrying the minor allele (odds ratio 2.224; 95% CI 1.370–3.612; P = 0.0012).CONCLUSIONSThe rs7903146 variant in the TCF7L2 gene increases the risk of IGT/T2D in obese adolescents by impairing β-cell function, and hepatic insulin sensitivity predicts the development of IGT/T2D over time.

Genetic Disruption of Adenosine Kinase in Mouse Pancreatic β-Cells Protects Against High-Fat Diet-Induced Glucose Intolerance.

Islet β-cells adapt to insulin resistance through increased insulin secretion and expansion. Type 2 diabetes typically occurs when prolonged insulin resistance exceeds the adaptive capacity of β-cells. Our prior screening efforts led to the discovery that adenosine kinase (ADK) inhibitors stimulate β-cell replication. Here, we evaluated whether ADK disruption in mouse β-cells affects β-cell mass and/or protects against high-fat diet (HFD)-induced glucose dysregulation. Mice targeted at the Adk locus were bred to Rip-Cre and Ins1-Cre/ERT1Lphi mice to enable constitutive (βADKO) and conditional (iβADKO) disruption of ADK expression in β-cells, respectively. Weight gain, glucose tolerance, insulin sensitivity, and glucose-stimulated insulin secretion (GSIS) were longitudinally monitored in normal chow (NC)-fed and HFD-fed mice. In addition, β-cell mass and replication were measured by immunofluorescence-based islet morphometry. NC-fed adult βADKO and iβADKO mice displayed glucose tolerance, insulin tolerance and β-cell mass comparable to control animals. By contrast, HFD-fed βADKO and iβADKO animals had improved glucose tolerance and increased in vivo GSIS. Improved glucose handling was associated with increased β-cell replication and mass. We conclude that ADK expression negatively regulates the adaptive β-cell response to HFD challenge. Therefore, modulation of ADK activity is a potential strategy for enhancing the adaptive β-cell response.

IVGTT-based simple assessment of glucose tolerance in the Zucker fatty rat: Validation against minimal models.

For the assessment of glucose tolerance from IVGTT data in Zucker rat, minimal model methodology is reliable but time- and money-consuming. This study aimed to validate for the first time in Zucker rat, simple surrogate indexes of insulin sensitivity and secretion against the glucose-minimal-model insulin sensitivity index (SI) and against first- (Φ1) and second-phase (Φ2) β-cell responsiveness indexes provided by C-peptide minimal model. Validation of the surrogate insulin sensitivity index (ISI) and of two sets of coupled insulin-based indexes for insulin secretion, differing from the cut-off point between phases (FPIR3-SPIR3, t = 3 min and FPIR5-SPIR5, t = 5 min), was carried out in a population of ten Zucker fatty rats (ZFR) and ten Zucker lean rats (ZLR). Considering the whole rat population (ZLR+ZFR), ISI showed a significant strong correlation with SI (Spearman’s correlation coefficient, r = 0.88; P<0.001). Both FPIR3 and FPIR5 showed a significant (P<0.001) strong correlation with Φ1 (r = 0.76 and r = 0.75, respectively). Both SPIR3 and SPIR5 showed a significant (P<0.001) strong correlation with Φ2 (r = 0.85 and r = 0.83, respectively). ISI is able to detect (P<0.001) the well-recognized reduction in insulin sensitivity in ZFRs, compared to ZLRs. The insulin-based indexes of insulin secretion are able to detect in ZFRs (P<0.001) the compensatory increase of first- and second-phase secretion, associated to the insulin-resistant state. The ability of the surrogate indexes in describing glucose tolerance in the ZFRs was confirmed by the Disposition Index analysis. The model-based validation performed in the present study supports the utilization of low-cost, insulin-based indexes for the assessment of glucose tolerance in Zucker rat, reliable animal model of human metabolic syndrome.

DPP-4 inhibitor treatment: β-cell response but not HbA1c reduction is dependent on the duration of diabetes.

IntroductionDipeptidyl peptidase-4 (DPP-4) inhibitors reduce hyperglycemia in patients with type 2 diabetes mellitus (T2DM) by enhancing insulin and suppressing glucagon secretion. Since T2DM is associated with progressive loss of β-cell function, we hypothesized that the DPP-4 inhibitor action to improve β-cell function would be attenuated with longer duration of T2DM.MethodsData from six randomized, placebo-controlled trials of 24 weeks duration, where β-cell response to vildagliptin 50 mg twice daily was assessed, were pooled. In each study, the insulin secretory rate relative to glucose (ISR/G 0–2h) during glucose load (standard meal or oral glucose tolerance test) was assessed at baseline and end of study. The mean placebo-subtracted difference (PSD) in the change in ISR/G 0–2h from baseline for each study was evaluated as a function of age, duration of T2DM, baseline ISR/G 0–2h, glycated hemoglobin (HbA1c), fasting plasma glucose, body mass index, and mean PSD in the change in HbA1c from baseline, using univariate model.ResultsThere was a strong negative association between the PSD in the change from baseline in ISR/G 0–2h and duration of T2DM (r= −0.89, p<0.02). However, there was no association between the PSD in the change from baseline in ISR/G 0–2h and the PSD in the change from baseline in HbA1c (r=0.33, p=0.52). None of the other characteristics were significantly associated with mean PSD change in ISR/G 0–2h.ConclusionThese findings indicate that the response of the β-cell, but not the HbA1c reduction, with vildagliptin is dependent on duration of T2DM. Further, it can be speculated that glucagon suppression may become the predominant mechanism via which glycemic control is improved when treatment with a DPP-4 inhibitor, such as vildagliptin, is initiated late in the natural course of T2DM.

Type 1 Diabetes Candidate Genes Linked to Pancreatic Islet Cell Inflammation and Beta-Cell Apoptosis.

Type 1 diabetes (T1D) is a chronic immune-mediated disease resulting from the selective destruction of the insulin-producing pancreatic islet β-cells. Susceptibility to the disease is the result of complex interactions between environmental and genetic risk factors. Genome-wide association studies (GWAS) have identified more than 50 genetic regions that affect the risk of developing T1D. Most of these susceptibility loci, however, harbor several genes, and the causal variant(s) and gene(s) for most of the loci remain to be established. A significant part of the genes located in the T1D susceptibility loci are expressed in human islets and β cells and mounting evidence suggests that some of these genes modulate the β-cell response to the immune system and viral infection and regulate apoptotic β-cell death. Here, we discuss the current status of T1D susceptibility loci and candidate genes with focus on pancreatic islet cell inflammation and β-cell apoptosis.

Prevention of type 2 diabetes mellitus in women with previous gestational diabetes mellitus.

Gestational diabetes mellitus (GDM), defined as any degree of glucose intolerance with onset or first recognition during pregnancy, is characterized by underlying maternal defects in the β-cell response to insulin during pregnancy. Women with a previous history of GDM have a greater than 7-fold higher risk of developing postpartum diabetes compared with women without GDM. Various risk factors for postpartum diabetes have been identified, including maternal age, glucose levels in pregnancy, family history of diabetes, pre-pregnancy and postpartum body mass index, dietary patterns, physical activity, and breastfeeding. Genetic studies revealed that GDM shares common genetic variants with type 2 diabetes. A number of lifestyle interventional trials that aimed to ameliorate modifiable risk factors, including diet, exercise, and breastfeeding, succeeded in reducing the incidence of postpartum diabetes, weight retention, and other obesity-related morbidities. The present review summarizes the findings of previous studies on the incidence and risk factors of postpartum diabetes and discusses recent lifestyle interventional trials that attempted to prevent postpartum diabetes.

Toward Connecting Metabolism to the Exocytotic Site.

Within cells the regulated exocytosis of secretory granules controls multiple physiological functions, including endocrine hormone secretion. Release of the glucose-regulating hormone insulin from pancreatic islet β cells is critical for whole-body metabolic homeostasis. Impaired insulin secretion appears early in the progression to type 2 diabetes (T2D). Key mechanisms that control the β-cell exocytotic response, mediating the long-known but little understood metabolic amplification of insulin secretion, are becoming clearer. Recent insights indicate a convergence of metabolism-driven signals, such as lipid-derived messengers and redox-dependent deSUMOylation, at the plasma membrane to augment Ca2+-dependent insulin exocytosis. These pathways have important implications for the metabolic control of hormone secretion, for the functional compensation that occurs in obesity, and for impaired insulin secretion in diabetes.

Islet adaptations in fetal sheep persist following chronic exposure to high norepinephrine.

Complications in pregnancy elevate fetal norepinephrine (NE) concentrations. Previous studies in NE-infused sheep fetuses revealed that sustained exposure to high NE resulted in lower expression of α2-adrenergic receptors in islets and increased insulin secretion responsiveness after acutely terminating the NE infusion. In this study, we determined if the compensatory increase in insulin secretion after chronic elevation of NE is independent of hyperglycemia in sheep fetuses and whether it is persistent in conjunction with islet desensitization to NE. After an initial assessment of glucose-stimulated insulin secretion (GSIS) at 129 ± 1 days of gestation, fetuses were continuously infused for seven days with NE and maintained at euglycemia with a maternal insulin infusion. Fetal GSIS studies were performed again on days 8 and 12. Adrenergic sensitivity was determined in pancreatic islets collected at day 12. NE infusion increased (P < 0.01) fetal plasma NE concentrations and lowered (P < 0.01) basal insulin concentrations compared to vehicle-infused controls. GSIS was 1.8-fold greater (P < 0.05) in NE-infused fetuses compared to controls at both one and five days after discontinuing the infusion. Glucose-potentiated arginine-induced insulin secretion was also enhanced (P < 0.01) in NE-infused fetuses. Maximum GSIS in islets isolated from NE-infused fetuses was 1.6-fold greater (P < 0.05) than controls, but islet insulin content and intracellular calcium signaling were not different between treatments. The half-maximal inhibitory concentration for NE was 2.6-fold greater (P < 0.05) in NE-infused islets compared to controls. These findings show that chronic NE exposure and not hyperglycemia produce persistent adaptations in pancreatic islets that augment β-cell responsiveness in part through decreased adrenergic sensitivity.

The variability in beta-cell function in placebo-treated subjects with type 2 diabetes: application of the weight-HbA1c-insulin-glucose (WHIG) model.

The weight-glycosylated haemoglobin (HbA1C)-insulin-glucose (WHIG) model describes the effects of changes in weight on insulin sensitivity (IS) in newly diagnosed, obese subjects receiving placebo treatment. This model was applied to a wider population of placebo-treated subjects, to investigate factors influencing the variability in IS and β-cell function. The WHIG model was applied to the WHIG dataset (Study 1) and two other placebo datasets (Studies 2 and 3). Studies 2 and 3 consisted of nonobese subjects and subjects with advanced type 2 diabetes mellitus (T2DM). Body weight, fasting serum insulin (FSI), fasting plasma glucose (FPG) and HbA1c were used for nonlinear mixed-effects modelling (using NONMEM v7.2 software). Sources of interstudy variability (ISV) and potential covariates (age, gender, diabetes duration, ethnicity, compliance) were investigated. An ISV for baseline parameters (body weight and β-cell function) was required. The baseline β-cell function was significantly lower in subjects with advanced T2DM (median difference: Study 2: 15.6%, P < 0.001; Study 3: 22.7%, P < 0.001) than in subjects with newly diagnosed T2DM (Study 1). A reduction in the estimated insulin secretory response in subjects with advanced T2DM was observed but diabetes duration was not a significant covariate. The WHIG model can be used to describe the changes in weight, IS and β-cell function in the diabetic population. IS remained relatively stable between subjects but a large ISV in β-cell function was observed. There was a trend towards decreasing β-cell responsiveness with diabetes duration, and further studies, incorporating subjects with a longer history of diabetes, are required.

Effect of Insulin Resistance on Monounsaturated Fatty Acid Levels: A Multi-cohort Non-targeted Metabolomics and Mendelian Randomization Study.

Insulin resistance (IR) and impaired insulin secretion contribute to type 2 diabetes and cardiovascular disease. Both are associated with changes in the circulating metabolome, but causal directions have been difficult to disentangle. We combined untargeted plasma metabolomics by liquid chromatography/mass spectrometry in three non-diabetic cohorts with Mendelian Randomization (MR) analysis to obtain new insights into early metabolic alterations in IR and impaired insulin secretion. In up to 910 elderly men we found associations of 52 metabolites with hyperinsulinemic-euglycemic clamp-measured IR and/or β-cell responsiveness (disposition index) during an oral glucose tolerance test. These implicated bile acid, glycerophospholipid and caffeine metabolism for IR and fatty acid biosynthesis for impaired insulin secretion. In MR analysis in two separate cohorts (n = 2,613) followed by replication in three independent studies profiled on different metabolomics platforms (n = 7,824 / 8,961 / 8,330), we discovered and replicated causal effects of IR on lower levels of palmitoleic acid and oleic acid. A trend for a causal effect of IR on higher levels of tyrosine reached significance only in meta-analysis. In one of the largest studies combining “gold standard” measures for insulin responsiveness with non-targeted metabolomics, we found distinct metabolic profiles related to IR or impaired insulin secretion. We speculate that the causal effects on monounsaturated fatty acid levels could explain parts of the raised cardiovascular disease risk in IR that is independent of diabetes development.