Improved Β-cell Function Research Articles

Evidence-Based Consensus on Positioning of SGLT2i in Type 2 Diabetes Mellitus in Indians.

The current diabetes management strategies not only aim at controlling glycaemic parameters but also necessitate continuous medical care along with multifactorial risk reduction through a comprehensive management concept. The sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a group of evolving antidiabetic agents that have the potential to play a pivotal role in the comprehensive management of patients with diabetes due to their diverse beneficial effects. SGLT2i provide moderate glycaemic control, considerable body weight and blood pressure reduction, and thus have the ability to lower the risk of macrovascular and microvascular complications. Some of the unique characteristics associated with SGLT2i, such as reduction in body weight (more visceral fat mass loss than subcutaneous fat loss), reduction in insulin resistance and improvement in β-cell function, as measured by homeostatic model assessment-β (HOMA-β) could be potentially beneficial and help in overcoming some of the challenges faced by Indian patients with diabetes. In addition, a patient-centric approach with individualised treatment during SGLT2i therapy is inevitable in order to reduce diabetic complications and improve quality of life. Despite their broad benefits profile, the risk of genital tract infections, volume depletion, amputations and diabetic ketoacidosis associated with SGLT2i should be carefully monitored. In this compendium, we systematically reviewed the literature from Medline, Cochrane Library, and other relevant databases and attempted to provide evidence-based recommendations for the positioning of SGLT2i in the management of diabetes in the Indian population.Funding: AstraZeneca Pharma India Limited.

Central role of the β-cell in driving regression of diabetes after liver transplantation in cirrhotic patients

Diabetes occurring as a direct consequence of loss of liver function is usually characterized by non-diabetic fasting plasma glucose (FPG) and haemoglobin A1c (HbA1c) levels and should regress after orthotopic liver transplantation (OLT). This observational, longitudinal study investigated the relationship between the time-courses of changes in all 3 direct determinants of glucose regulation, i.e., β-cell function, insulin clearance and insulin sensitivity, and diabetes regression after OLT. Eighty cirrhotic patients with non-diabetic FPG and HbA1c levels underwent an extended oral glucose tolerance test (OGTT) before and 3, 6, 12 and 24 months after OLT. The OGTT data were analysed with a mathematical model to estimate derivative control (DC) and proportional control (PC) of β-cell function and insulin clearance (which determine insulin bioavailability), and with the Oral Glucose Insulin Sensitivity (OGIS)-2 h index to estimate insulin sensitivity. At baseline, 36 patients were diabetic (45%) and 44 were non-diabetic (55%). Over the 2-year follow-up, 23 diabetic patients (63.9%) regressed to non-diabetic glucose regulation, whereas 13 did not (36.1%); moreover, 4 non-diabetic individuals progressed to diabetes (9.1%), whereas 40 did not (90.9%). Both DC and PC increased in regressors (from month 3 and 24, respectively) and decreased in progressors, whereas they remained stable in non-regressors and only PC decreased in non-progressors. Insulin clearance increased in all groups, apart from progressors. Likewise, OGIS-2 h improved at month 3 in all groups, but thereafter it continued to improve only in regressors, whereas it returned to baseline values in the other groups. Increased insulin bioavailability driven by improved β-cell function plays a central role in favouring diabetes regression after OLT, in the presence of a sustained improvement of insulin sensitivity. Diabetes occurring in cirrhosis as a direct consequence of loss of liver function should regress after transplantation of a new functioning liver, though the pathophysiological mechanisms are unclear. This is the first study evaluating the contribution of all 3 direct determinants of insulin-dependent glucose regulation using a sophisticated mathematical model. Results show that β-cell function is the key process governing favourable or detrimental changes in glucose regulation in cirrhotic patients undergoing transplantation, pointing to the need to develop therapies to sustain β-cell function in these individuals. ClinicalTrials.gov, NCT02038517.

Predictors of Long-Term Glycemic Remission After 2-Week Intensive Insulin Treatment in Newly Diagnosed Type 2 Diabetes.

Although several studies suggest that improved β-cell function is a key determinant of glycemic remission in type 2 diabetes, other predictors remain unclear. The aim of this clamp-based study was to identify predictors of 2-year glycemic remission after short-term intensive insulin treatment. A 2-year follow-up was planned in 124 drug-naive patients with type 2 diabetes who received continuous subcutaneous insulin infusion (CSII) for 2 weeks. Euglycemic-hyperinsulinemic clamps and IV glucose tolerance tests were performed to assess the insulin sensitivity [glucose infusion rate (GIR)] and acute insulin response (AIR) before and after CSII. First-phase insulin secretion was restored, and the GIR was significantly improved (P < 0.0001) after the 2-week CSII. Glycemic remission rates were 47.6% and 30.7% after 12 and 24 months of follow-up, respectively. Cox analysis revealed that a higher post-CSII glucose level [hazard ratio (HR), 1.38; 95% CI, 1.15 to 1.66; P = 0.0005] and older age at diabetes diagnosis (HR, 1.34; 95% CI, 1.05 to 1.72; P = 0.02) accounted for an increased risk of hyperglycemic relapse. A 1 SD increase in the AIR (HR, 0.75; 95% CI, 0.57 to 0.99; P = 0.04), GIR (HR, 0.67; 95% CI, 0.48 to 0.93; P = 0.016) after CSII, and baseline GIR (HR, 0.71; 95% CI, 0.51 to 0.99; P = 0.047) was inversely associated with this risk. Younger age at diabetes diagnosis, higher baseline insulin sensitivity, and lower glucose levels after insulin treatment significantly favored a 2-year glycemic remission. This long-term remission was attributed to both improved insulin sensitivity and enhanced β-cell function after short-term intensive insulin treatment.

Short-term insulin therapy at the time of diagnosis of Type 2 diabetes leads to better glycemic control and improved beta cell function

Background: Impaired insulin secretion and insulin resistance are the underlying pathophysiological defects in Type 2 diabetes (T2DM) that lead to hyperglycaemia. The β-cell defect in T2DM is usually progressive, leading to eventual β-cell exhaustion and dependence on insulin. It is known that glucotoxicity and lipotoxicity contribute to the initial decreased insulin secretion at the time of diagnosis of T2DM. Therefore, an aggressive approach early in the course of the disease to correct these defects could possibly alter the natural history of T2DM. Objectives: Our aim was to study the effect of administration of a short course of insulin therapy at the onset of T2DM on glycaemic parameters and pancreatic β-cell function as assessed by C-peptide estimation. Materials and Methods: Treatment-naive T2DM patients (n = 426) with known duration of diabetes of <3 months were recruited from Dr. Mohan’s Diabetes Specialities Centre at Chennai. All patients were treated initially with short-term insulin therapy (4–6 weeks) along with oral hypoglycaemic agents (OHAs), usually metformin alone or sometimes in combination with sulphonylurea. Subsequently, they were continued on diet, exercise and OHA, wherever required. The baseline characteristics, fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) and glycated haemoglobin (HbA1c), were compared after (an initial) a mean follow-up period of 2.6 months. Patients were then followed up for another 2 years to evaluate their long-term glycaemic control. Fasting and stimulated C-peptide levels were measured in a subset of patients at baseline and at follow-up at 2–3 months, 1 year and 2 years. Results: There was a significant reduction in both FPG and PPG levels. The mean FPG decreased from 214 ± 82 to 111 ± 29mg/dl (P < 0.001), whereas the PPG decreased from 332 ± 120 to 158 ± 54mg/dl (P < 0.001). The HbA1c decreased from 11.8% ± 1.9% to 6.8% ± 1.1% (P < 0.001). There was a significant improvement in the serum C-peptide levels, indicating an improvement in β-cell function. The fasting C-peptide levels improved from a mean of 0.85 ± 0.3 to 1.09 ± 0.4 pmol/ml, whereas the stimulated C-peptide value increased from a mean of 1.63 ± 0.8 to 2.09 ± 1.0 pmol/ml even at the end of 2 years after the insulin was discontinued. There was also a favourable change in lipid profile of the patients. Conclusion: Our study demonstrates that, in newly diagnosed T2DM, a short course of insulin therapy given for 4–6 weeks can lead to long-term good glycaemic control and beneficial effects on pancreatic β-cell function, which is sustained up to 2 years.

Improved β-cell Function and Prolonged Remission of Diabetes Type 1 by GLP-1 Agonist Treatment in Newly Diagnosed Adolescences

Improved β-cell Function and Prolonged Remission of Diabetes Type 1 by GLP-1 Agonist Treatment in Newly Diagnosed Adolescences

Cell Type-Selective Expression of Circular RNAs in Human Pancreatic Islets

Understanding distinct cell-type specific gene expression in human pancreatic islets is important for developing islet regeneration strategies and therapies to improve β-cell function in type 1 diabetes (T1D). While numerous transcriptome-wide studies on human islet cell-types have focused on protein-coding genes, the non-coding repertoire, such as long non-coding RNA, including circular RNAs, remains mostly unexplored. Here, we explored transcriptional landscape of human α-, β-, and exocrine cells from published total RNA sequencing (RNA-seq) datasets to identify circular RNAs (circRNAs). Our analysis revealed that circRNAs are highly abundant in both α- and β-cells. We identified 10,830 high-confidence circRNAs expressed in human α-, β-, and exocrine cells. The most highly expressed candidates were MAN1A2, RMST, and HIPK3 across the three cell-types. Alternate circular isoforms were observed for circRNAs in the three cell-types, indicative of potential distinct functions. Highly selective α- and β-cell circRNAs were identified, which is suggestive of their potential role in regulating β-cell function.

TLR4 triggered complex inflammation in human pancreatic islets

Type 2 Diabetes (T2D) is strongly associated with obesity and inflammation. Toll-like receptor-4 (TLR-4) is the major pro-inflammatory pathway with its ligands and downstream products increased systemically in T2D and in at-risk individuals. Detailed mechanisms of the complex proinflammatory response in pancreatic islets remain unknown.In isolated human islets LPS induced IL-1β, IL-6, IL-8 and TNF production in a TLR4-dependent manner and severely impaired β-cell survival and function. IL-6 antagonism improved β-cell function. IL-8, which was identified specifically in α-cells, initiated monocyte migration, a process fully blocked by IL-8 neutralization. The TLR4 response was potentiated in obese donors; with higher IL-1β, IL-6 and IL-8 expression than in non-obese donors.TLR4 activation leads to a complex multi-cellular inflammatory response in human islets, which involves β-cell failure, cytokine production and macrophage recruitment to islets. In obesity, the amplified TLR4 response may potentiate β-cell damage and accelerate diabetes progression.

Chemical chaperone-conjugated exendin-4 as a cytoprotective agent for pancreatic β-cells.

Endoplasmic reticulum stress has been considered a major cause of pancreatic β-cell dysfunction and apoptosis leading to diabetes. Glucagon-like peptide-1 receptor activation and chemical chaperones have been known to reduce endoplasmic reticulum stress and improve β-cell function and survival. The purpose of this study was to prepare and evaluate the chemical chaperone tauroursodeoxycholic acid-conjugated exendin-4 as a protective agent for pancreatic β-cells. Mono-tauroursodeoxycholic acid-Lys27-exendin-4 conjugate (TUM1-Ex4) showed better receptor binding affinity than other conjugates with strong in vitro insulinotropic activity in rat pancreatic β-cells and in vivo hypoglycemic activity in type 2 diabetic db/db mice. In INS-1 cells under endoplasmic reticulum stress induced by thapsigargin, TUM1-Ex4 promoted cell survival in a dose-dependent manner. In western blot analysis, TUM1-Ex4 reduced the expression of the endoplasmic reticulum stress marker GRP78 and phosphorylation of the translation initiation factor eIF2α. These results reveal that TUM1-Ex4 accelerates translational recovery and contributes to β-cell protection and survival. The present study indicates that the chemical chaperone-coupled glucagon-like peptide-1 receptor agonist is a feasible therapeutic strategy to enhance β-cell function and survival.

Successful treatment of prediabetes in clinical practice using physiological assessment (STOP DIABETES)

Of the 84 million American adults with prediabetes, over 5 to 7 years, about 28 million progress to type 2 diabetes. We aimed to assess whether a real-world, pathophysiology-based, therapeutic approach could prevent development of type 2 diabetes in high-risk individuals. We did a retrospective observational study of people at increased risk of type 2 diabetes from a community practice in southern California, USA. Participants had an oral glucose tolerance test and were assigned a risk stratification on the basis of presence and severity of insulin resistance, impaired β-cell function, and glycaemia (ie, 1-h plasma glucose concentration of more than 8·6 mmol/L during an oral glucose tolerance test). Treatment was recommended on the basis of risk: metformin, pioglitazone, glucagon-like peptide-1 (GLP-1) receptor agonist, and lifestyle therapy for participants at high risk of diabetes, and metformin, pioglitazone, and lifestyle therapy for those at intermediate risk. Individuals who refused pharmacological therapy were assigned to lifestyle therapy only. Participants were followed up every 6 months and oral glucose tolerance tests were repeated at 6 months and subsequently every 2 years or sooner. The primary outcome of our analysis was incidence of type 2 diabetes according to the American Diabetes Association criteria, within the study period (2009-16). This study is registered with ClinicalTrials.gov, number NCT03308773. Between Jan 1, 2009 and Dec 31, 2016, we assessed 1769 people at increased risk of diabetes, of which 747 (42%) were identified at high or intermediate risk and were recommended pharmacological treatment. Of 422 participants analysed, 28 (7%) progressed to type 2 diabetes (seven [5%] of 141 participants who received metformin, pioglitazone, and lifestyle therapy, none [0%] of 81 who received metformin, pioglitazone, GLP-1 receptor agonist, and lifestyle therapy, and 21 [11%] of 200 who received lifestyle therapy only) after mean follow-up of 32·09 months (SEM 1·24). Compared with participants who received lifestyle therapy only, the adjusted hazard ratio for progression to type 2 diabetes was 0·29 (95% CI 0·11-0·78, p=0·0009) in participants who received metformin and pioglitazone, and 0·12 (95% CI 0·02-0·94, p=0·04) in participants who received metformin, pioglitazone, and GLP-1 receptor agonist. Improved β-cell function was the strongest predictor of type 2 diabetes prevention. Progression to type 2 diabetes in people at high risk of diabetes can be markedly reduced with interventions designed to correct underlying pathophysiological disturbances (ie, impaired insulin secretion and resistance) in a real-world setting. None.

Whole-Organism Chemical Screening Identifies Modulators of Pancreatic β-Cell Function

β-Cell loss and dysfunction play a critical role in the progression of type 1 and type 2 diabetes. Identifying new molecules and/or molecular pathways that improve β-cell function and/or increase β-cell mass should significantly contribute to the development of new therapies for diabetes. Using the zebrafish model, we screened 4,640 small molecules to identify modulators of β-cell function. This in vivo strategy identified 84 stimulators of insulin expression, which simultaneously reduced glucose levels. The insulin promoter activation kinetics for 32 of these stimulators were consistent with a direct mode of action. A subset of insulin stimulators, including the antidiabetic drug pioglitazone, induced the coordinated upregulation of gluconeogenic pck1 expression, suggesting functional response to increased insulin action in peripheral tissues. Notably, Kv1.3 inhibitors increased β-cell mass in larval zebrafish and stimulated β-cell function in adult zebrafish and in the streptozotocin-induced hyperglycemic mouse model. In addition, our data indicate that cytoplasmic Kv1.3 regulates β-cell function. Thus, using whole-organism screening, we have identified new small-molecule modulators of β-cell function and glucose metabolism.

Association of weight gain and fifteen adipokines with declining beta-cell function in Mexican Americans.

Obesity and adipokines are associated with development of type 2 diabetes. However, limited longitudinal studies have examined their roles on declining β-cell function over time. This report assessed three adiposity measures (BMI, percent body fat, trunk fat), insulin resistance, and fifteen adipokines in relationship to longitudinal change in β-cell function measured by disposition index (DI) from frequently-sampled-intravenous-glucose-tolerance testing. The results showed that three factors were significantly and independently associated with rate of change in DI over time: rate of change in BMI (negative), rate of change in IL-6 (negative), and baseline adiponectin (positive). The association was the strongest for changing BMI and was largely explained by changing insulin resistance; the association with changing IL-6 was also largely explained by changing insulin resistance. Baseline adiponectin remained positively associated after adjustment for changing insulin resistance, suggesting an independent effect of adiponectin to preserve or improve β-cell function. These findings provide evidence and potential mechanisms for the role of obesity in promoting β-cell dysfunction, highlighting the potential importance of mitigating obesity and its metabolic effects in preventing and treating type 2 diabetes.

Peptide-based sequestration of the adaptor protein Nck1 in pancreatic β cells enhances insulin biogenesis and protects against diabetogenic stresses

One feature of diabetes is the failure of pancreatic β cells to produce insulin, but the molecular mechanisms leading to this failure remain unclear. Increasing evidence supports a role for protein kinase R-like endoplasmic reticulum kinase (PERK) in the development and function of healthy pancreatic β cells. Previously, our group identified the adaptor protein Nck1 as a negative regulator of PERK. Indeed, we demonstrated that Nck1, by directly binding PERK autophosphorylated on Tyr561, limits PERK activation and signaling. Accordingly, we found that stable depletion of Nck1 in β cells promotes PERK activation and signaling, increases insulin biosynthesis, and improves cell viability in response to diabetes-related stresses. Herein, we explored the therapeutic potential of abrogating the interaction between Nck and PERK to improve β-cell function and survival. To do so, we designed and used a peptide containing the minimal PERK sequence involved in binding Nck1 conjugated to the cell-permeable protein transduction domain from the HIV protein TAT. In the current study, we confirm that the synthetic TAT-Tyr(P)561 phosphopeptide specifically binds the SH2 domain of Nck and prevents Nck interaction with PERK, thereby promoting basal PERK activation. Moreover, we report that treatment of β cells with TAT-Tyr(P)561 inhibits glucolipotoxicity-induced apoptosis, whereas it enhances insulin production and secretion. Taken together, our results support the potential of sequestering Nck using a synthetic peptide to enhance basal PERK activation and create more robust β cells.

Liver blood dynamics after bariatric surgery: the effects of mixed-meal test and incretin infusions.

Aims/hypothesisThe mechanisms for improved glycemic control after bariatric surgery in subjects with type 2 diabetes (T2D) are not fully known. We hypothesized that dynamic hepatic blood responses to a mixed-meal are changed after bariatric surgery in parallel with an improvement in glucose tolerance.MethodsA total of ten morbidly obese subjects with T2D were recruited to receive a mixed-meal and a glucose-dependent insulinotropic polypeptide (GIP) infusion before and early after (within a median of less than three months) bariatric surgery, and hepatic blood flow and volume (HBV) were measured repeatedly with combined positron emission tomography/MRI. Ten lean non-diabetic individuals served as controls.ResultsBariatric surgery leads to a significant decrease in weight, accompanied with an improved β-cell function and glucagon-like peptide 1 (GLP-1) secretion, and a reduction in liver volume. Blood flow in portal vein (PV) was increased by 1.65-fold (P = 0.026) in response to a mixed-meal in subjects after surgery, while HBV decreased in all groups (P < 0.001). When the effect of GIP infusion was tested separately, no change in hepatic arterial and PV flow was observed, but HBV decreased as seen during the mixed-meal test.Conclusions/interpretationEarly after bariatric surgery, PV flow response to a mixed-meal is augmented, improving digestion and nutrient absorption. GIP influences the post-prandial reduction in HBV thereby diverting blood to the extrahepatic sites.

GDF15 Is a Contraction-Induced Myokine That Regulates Pancreatic ß-Cell Function

β-cell dysfunction plays a major role in the onset of type 2 diabetes (T2D). Exercise improves or restores β-cell function in both humans and rodents with T2D. The specific mechanism is unclear. We hypothesized that exercise-induced myokines engage in cross-talk with the pancreas to help regulate β-cell function and mass. To test our hypothesis, differentiated C2C12 myotubes were subjected to electrical pulse stimulation (EPS) to simulate in vivo exercise. EPS-conditioned media from the contracting myotubes significantly elevated glucose-stimulated insulin secretion (GSIS) in β-cells vs. non-EPS control conditions (P&amp;lt;0.05). RNA-sequencing and bioinformatic analysis enabled us to identify Growth Differentiation Factor 15 (GDF15) as a novel contraction-induced myokine that potentially communicates with β-cells. At the cellular level, recombinant GDF15 protein treatment upregulated the GSIS response in β-cells by 55% (P&amp;lt;0.05), with no effect on cellular apoptosis, cytotoxicity or proliferation. Furthermore, qRT-PCR analysis, ELISA, immunoblots, and intracellular assays demonstrated that GDF15 may regulate first-phase insulin secretion by increasing the intracellular ATP/ADP ratio, inhibiting K+ channels and increasing the intracellular Ca2+ without affecting insulin synthesis. Using translational approaches, we found a positive correlation between fasting plasma GDF15 and insulin secretion in prediabetic subjects (R=0.64, P&amp;lt;0.01, n=22). A 6 week supervised functional high-intensity exercise intervention increased fasting plasma GDF15 by 35% in adults with T2D (P&amp;lt;0.01, n=12) and, interestingly, the increase in GDF15 was positively correlated with an increase in the β-cell disposition index (R=0.72, P&amp;lt;0.01, n=12), providing further support that GDF15 may be involved in improving β-cell function. In summary, these findings expand our understanding of skeletal muscle as an endocrine organ and identify GDF15 as a potential myokine for T2D therapy. Disclosure H. Zhang: None. A. Mulya: None. S. Nieuwoudt: None. R. McDowell: None. J.P. Kirwan: None.

Dorzagliatin (HMS5552), a novel dual-acting glucokinase activator, improves glycaemic control and pancreatic β-cell function in patients with type 2 diabetes: A 28-day treatment study using biomarker-guided patient selection.

To investigate the pharmacokinetics and pharmacodynamics of a dual-acting glucokinase activator, dorzagliatin, and its safety, tolerability and effect on pancreatic β-cell function in Chinese patients with type 2 diabetes (T2D). A total of 24 T2D patients were selected, utilizing a set of predefined clinical biomarkers, and were randomized to receive dorzagliatin 75 mg twice or once daily (BID, QD respectively) for 28 days. Changes in HbA1c and glycaemic parameters from baseline to Day 28 were assessed. In addition, changes in β-cell function from baseline to Day 32 were evaluated. Significant reductions in HbA1c were observed in both regimens on Day 28 (-0.79%, 75 mg BID; -1.22%, 75 mg QD). Similar trends were found in the following parameters, including reductions from baseline in fasting plasma glucose by 1.20 mmol/L and 1.51 mmol/L, in 2-hour postprandial glucose by 2.48 mmol/L and 5.03 mmol/L, and in glucose AUC0-24 by 18.59% and 20.98%, for the BID and QD groups, respectively. Both regimens resulted in improvement in β-cell function as measured by steady state HOMA 2 parameter, %B, which increased by 36.31% and 40.59%, and by dynamic state parameter, ΔC30 /ΔG30 , which increased by 24.66% and 167.67%, for the BID and QD groups, respectively. Dorzagliatin was well tolerated in both regimens, with good pharmacokinetic profiles. Dorzagliatin treatment for 28 days in Chinese T2D patients, selected according to predefined biomarkers, resulted in significant improvement in β-cell function and glycaemic control. The safety and pharmacokinetic profile of dorzagliatin supports a subsequent Phase II trial design and continued clinical development.

Glutazumab, a novel long-lasting GLP-1/anti-GLP-1R antibody fusion protein, exerts anti-diabetic effects through targeting dual receptor binding sites

AimsGlucagon like-peptide-1 (GLP-1)-based drugs have been proposed as mono- or combined therapy for type 2 diabetes mellitus. Thus we characterized a novel antibody fusion protein engineered by linking the human GLP-1 derivative to a humanized GLP-1 receptor (GLP-1R) antibody via a peptide linker. Materials and methodsGlutazumab was characterized by receptor binding and reporter activation assays, and its specificity was investigated with the aid of the cognate receptor antagonist exendin (9-39) and antibody Ab1. Pharmacokinetics was evaluated in Sprague-Dawley (SD) rats and cynomolgus monkeys, and pharmacodynamics was assessed in normal ICR and spontaneous type 2 diabetic KKAy mice. Hypoglycemic effects were evaluated after acute administration and glucose metabolism and β-cell function were assessed with repeated administrations. Dulaglutide was a positive control in all experiments. ResultsGlutazumab significantly bound and activated GLP-1R, but the receptor antagonist exendin (9-39) did not inhibit the activation except when combined with Ab1. Single injection of glutazumab reduced the blood glucose in ICR mice and KKAy mice, and the half-lives in SD rats and cynomolgus monkeys were 18 h and 33.6 h. Repeated injections of glutazumab controlled glycemic fluctuations and improved β-cell function in KKAy mice. ConclusionsAs a novel GLP-1R agonist, glutazumab may be a potential treatment for T2DM.

LH-21 and abnormal cannabidiol improve β-cell function in isolated human and mouse islets through GPR55-dependent and -independent signalling.

To examine the effects of Abn-CBD (GPR55 agonist) and LH-21 (CB1 antagonist) on human and mouse islet function, and to determine signalling via GPR55 using islets from GPR55-/- mice. Islets isolated from human organ donors and mice were incubated in the absence or presence of Abn-CBD or LH-21, and insulin secretion, [Ca2+ ]i, cAMP, apoptosis, β-cell proliferation and CREB and AKT phosphorylation were examined using standard techniques. Abn-CBD potentiated glucose-stimulated insulin secretion and elevated [Ca2+ ]i in human islets and islets from both GPR55+/+ and GPR55-/- mice. LH-21 also increased insulin secretion and [Ca2+ ]i in human islets and GPR55+/+ mouse islets, but concentrations of LH-21 up to 0.1 μM were ineffective in islets from GPR55-/- mice. Neither ligand affected basal insulin secretion or islet cAMP levels. Abn-CBD and LH-21 reduced cytokine-induced apoptosis in human islets and GPR55+/+ mouse islets, and these effects were suppressed after GPR55 deletion. They also increased β-cell proliferation: the effects of Abn-CBD were preserved in islets from GPR55-/- mice, while those of LH-21 were abolished. Abn-CBD and LH-21 increased AKT phosphorylation in mouse and human islets. This study showed that Abn-CBD and LH-21 improve human and mouse islet β-cell function and viability. Use of islets from GPR55-/- mice suggests that designation of Abn-CBD and LH-21 as a GPR55 agonist and a CB1 antagonist, should be revised.

Deficiency of Sphingosine-1-Phosphate Reduces the Expression of Prohibitin and Causes β-Cell Impairment via Mitochondrial Dysregulation.

BackgroundEmerging evidence suggests that sphingolipids may be involved in type 2 diabetes. However, the exact signaling defect through which disordered sphingolipid metabolism induces β-cell dysfunction remains unknown. The current study demonstrated that sphingosine-1-phosphate (S1P), the product of sphingosine kinase (SphK), is an essential factor for maintaining β-cell function and survival via regulation of mitochondrial action, as mediated by prohibitin (PHB).MethodsWe examined β-cell function and viability, as measured by mitochondrial function, in mouse insulinoma 6 (MIN6) cells in response to manipulation of cellular S1P and PHB levels.ResultsLack of S1P induced by sphingosine kinase inhibitor (SphKi) treatment caused β-cell dysfunction and apoptosis, with repression of mitochondrial function shown by decreases in cellular adenosine triphosphate content, the oxygen consumption rate, the expression of oxidative phosphorylation complexes, the mitochondrial membrane potential, and the expression of key regulators of mitochondrial dynamics (mitochondrial dynamin-like GTPase [OPA1] and mitofusin 1 [MFN1]). Supplementation of S1P led to the recovery of mitochondrial function and greatly improved β-cell function and viability. Knockdown of SphK2 using small interfering RNA induced mitochondrial dysfunction, decreased glucose-stimulated insulin secretion (GSIS), and reduced the expression of PHB, an essential regulator of mitochondrial metabolism. PHB deficiency significantly reduced GSIS and induced mitochondrial dysfunction, and co-treatment with S1P did not reverse these trends.ConclusionAltogether, these data suggest that S1P is an essential factor in the maintenance of β-cell function and survival through its regulation of mitochondrial action and PHB expression.

ROLE AND PLACE OF DAPAGLIFLOZIN IN THE MANAGEMENT OF 2nd TYPE DIABETES: FROM THEORY TO PRACTICE

A new approach to the treatment of the Type 2 diabetes mellitus (T2DM) based on drug-induced glycosuria and reduction in renal threshold of glucose, and drugs with a similar mechanism of action belong to an innovative class of antidiabetic drugs: inhibitors of 2nd type sodium-glucose cotransporter (GLT-2). In addition to improving glycemic control SGCT-2 inhibitors promote moderate weight loss and blood pressure (BP), increased sensitivity of tissues to insulin and improve β-cell function. Dapagliflozin an oral SGCT-2 inhibitor, which is due to the insulin independent mechanism of action is characterized by the minimal risk of hypoglycemia compared to traditional antidiabetic drugs, such as sulfonylurea and insulin. For this reason, the drug has the unique ability to combine with other oral hypoglycemic agents (OHGA). In addition, due to its natriuretic effect and ability to reduce body weight and blood pressure dapagliflozin is the drug of choice in patients with T2DM and cardiovascular diseases of atherosclerotic genesis. A combination of advantages, including a favorable safety profile of dapagliflozin allows extensive use of this drug for the initiation and intensification of T2DM treatment.

Effect of sitagliptin on glucose control in type 2 diabetes mellitus after Roux-en-Y gastric bypass surgery.

The present study was a 4-week randomized trial to assess the efficacy and safety of sitagliptin, a dipeptidyl-peptidase-4 inhibitor, in persistent or recurring type 2 diabetes after Roux-en-Y gastric bypass surgery (RYGB). Participants (n = 32) completed a mixed meal test (MMT) and self-monitoring of plasma glucose (SMPG) before and 4 weeks after randomization to either sitagliptin 100 mg daily or placebo daily. Questionnaires were administered to assess gastrointestinal discomfort. Outcome variables were glucose, active glucagon-like peptide-1 and β-cell function during the MMT, and glucose levels during SMPG. Age (56.3 ± 8.2 years), body mass index (34.4 ± 6.7 kg/m2 ), glycated haemoglobin (7.21 ± 0.77%), diabetes duration (12.9 ± 10.0 years), years since RYGB (5.6 ± 3.3 years) and β-cell function did not differ between the placebo and sitagliptin groups at pre-intervention. Sitagliptin was well tolerated, decreased postprandial glucose levels during the MMT (from 8.31 ± 1.92 mmol/L to 7.67 ± 1.59 mmol/L, P = 0.03) and mean SMPG levels, but had no effect on β-cell function. In patients with diabetes and mild hyperglycemia after RYGB, a short course of sitagliptin provided a small but significant glucose-lowering effect, with no identified improvement in β-cell function.