Dapagliflozin-Induced Myocardial Flow Reserve Improvement is not Associated with HDL Ability to Stimulate Endothelial Nitric Oxide Production.

BACKGROUND: Sodium-glucose cotransporter-2 (SGLT2) inhibitors have shown controversial results in modulating plasma lipids in clinical trials. Most studies found slight increases in high-density lipoprotein (HDL) cholesterol but few have provided evidence on HDL functionality with disappointing results. However, there is broad agreement that these drugs provide cardiovascular protection through several mechanisms. Our group demonstrated that dapagliflozin improves myocardial flow reserve (MFR) in patients with type 2 diabetes (T2D) with coronary artery disease (CAD). The underlying mechanisms are still unknown, although in vitro studies have suggested the involvement of nitric oxide (NO). AIM: To investigate changes in HDL-mediated modulation of NO production with dapagliflozin and whether there is an association with MFR. METHODS: Sixteen patients with CAD-T2D were enrolled and randomized 1:1 to dapagliflozin or placebo for 4 weeks. Blood samples were collected before and after treatment for each group. The ability of HDL to stimulate NO production in endothelial cells was tested in vitro by incubating human umbilical vein endothelial cells (HUVEC) with apoB-depleted (apoB-D) serum of these patients. The production of NO was assessed by fluorescent assay, and results were expressed as fold versus untreated cells. RESULTS: Change in HDL-mediated NO production remained similar in dapagliflozin and placebo group, even after adjustment for confounders. There were no significant correlations between HDL-mediated NO production and MFR either at baseline or after treatment. No changes were found in HDL cholesterol in either group, while low-density lipoprotein cholesterol (LDL cholesterol) significantly decreased compared to baseline only in treatment group (p = 0.043). CONCLUSIONS: In patients with T2D-CAD, beneficial effects of dapagliflozin on coronary microcirculation seem to be unrelated to HDL functions. However, HDL capacity to stimulate NO production is not impaired at baseline; thus, the effect of drug treatments would be negligible. To conclude, we can assume that HDL-independent molecular pathways are involved in the improvement of MFR in this population. TRIAL REGISTRATION: EudraCT No. 2016-003614-27; ClinicalTrials.gov Identifier: NCT03313752.

Lysophosphatidylinositols Are Upregulated After Human ß-Cell Loss and Potentiate Insulin Release.

In this study, we identified new lipid species associated with the loss of pancreatic ß-cells triggering diabetes. We performed lipidomics measurements on serum from prediabetic mice lacking ß-cell prohibitin-2 (a model of monogenic diabetes) patients without previous history of diabetes but scheduled for pancreaticoduodenectomy resulting in the acute reduction of their ß-cell mass (∼50%), and patients with type 2 diabetes (T2D). We found lysophosphatidylinositols (lysoPIs) were the main circulating lipid species altered in prediabetic mice. The changes were confirmed in the patients with acute reduction of their ß-cell mass and in those with T2D. Increased lysoPIs significantly correlated with HbA1c (reflecting glycemic control), fasting glycemia, and disposition index, and did not correlate with insulin resistance or obesity in human patients with T2D. INS-1E ß-cells as well as pancreatic islets isolated from nondiabetic mice and human donors exposed to exogenous lysoPIs showed potentiated glucose-stimulated and basal insulin secretion. Finally, addition of exogenous lysoPIs partially rescued impaired glucose-stimulated insulin secretion in islets from mice and humans in the diabetic state. Overall, lysoPIs appear to be lipid species upregulated in the prediabetic stage associated with the loss of ß-cells and that support the secretory function of the remaining ß-cells. ARTICLE HIGHLIGHTS: Circulating lysophosphatidylinositols (lysoPIs) are increased in situations associated with ß-cell loss in mice and humans such as (pre-)diabetes, and hemipancreatectomy. Pancreatic islets isolated from nondiabetic mice and human donors, as well as INS-1E ß-cells, exposed to exogenous lysoPIs exhibited potentiated glucose-stimulated and basal insulin secretion. Addition of exogenous lysoPIs partially rescued impaired glucose-stimulated insulin secretion in islets from mice and humans in the diabetic state. LysoPIs appear as lipid species being upregulated already in the prediabetic stage associated with the loss of ß-cells and supporting the function of the remaining ß-cells.

Erythrocyte membrane fluidity: A novel biomarker of residual cardiovascular risk in type 2 diabetes.

AIMS: Improving the composition of circulating fatty acids (FA) leads to a reduction in cardiovascular diseases (CVD) in high-risk individuals. The membrane fluidity of red blood cells (RBC), which reflects circulating FA status, may be a valid biomarker of cardiovascular (CV) risk in type 2 diabetes (T2D). METHODS: Red blood cell membrane fluidity, quantified as general polarization (GP), was assessed in 234 subjects with T2D, 86 with prior major CVD. Based on GP distribution, a cut-off of .445 was used to divide the study cohort into two groups: the first with higher GP, called GEL, and the second, defined as lower GP (LGP). Lipidomic analysis was performed to evaluate FA composition of RBC membranes. RESULTS: Although with comparable CV risk factors, the LGP group had a greater percentage of patients with major CVD than the GEL group (40% vs 24%, respectively, p < .05). Moreover, in a logistic regression analysis, a lower GP value was independently associated with the presence of macrovascular complications. Lipidomic analysis showed a clear shift of LGP membranes towards a pro-inflammatory condition due to higher content of arachidonic acid and increased omega 6/omega 3 index. CONCLUSIONS: Increased membrane fluidity is associated with a higher CV risk in subjects with T2D. If confirmed in prospective studies, membrane fluidity could be a new biomarker for residual CV risk assessment in T2D.

Dapagliflozin treatment is associated with a reduction of epicardial adipose tissue thickness and epicardial glucose uptake in human type 2 diabetes.

OBJECTIVE: We recently demonstrated that treatment with sodium-glucose cotransporter-2 inhibitors (SGLT-2i) leads to an increase in myocardial flow reserve in patients with type 2 diabetes (T2D) with stable coronary artery disease (CAD). The mechanism by which this occurs is, however, unclear. One of the risk factors for cardiovascular disease is inflammation of epicardial adipose tissue (EAT). Since the latter is often increased in type 2 diabetes patients, it could play a role in coronary microvascular dysfunction. It is also well known that SGLT-2i modify adipose tissue metabolism. We aimed to investigate the effects of the SGLT-2i dapagliflozin on metabolism and visceral and subcutaneous adipose tissue thickness in T2D patients with stable coronary artery disease and to verify whether these changes could explain observed changes in myocardial flow. METHODS: We performed a single-center, prospective, randomized, double-blind, controlled clinical trial with 14 T2D patients randomized 1:1 to SGLT-2i dapagliflozin (10 mg daily) or placebo. The thickness of visceral (epicardial, mediastinal, perirenal) and subcutaneous adipose tissue and glucose uptake were assessed at baseline and 4 weeks after treatment initiation by 2-deoxy-2-[18F]fluoro-D-glucose Positron Emission Tomography/Computed Tomography during hyperinsulinemic euglycemic clamp. RESULTS: The two groups were well-matched for baseline characteristics (age, diabetes duration, HbA1c, BMI, renal and heart function). Dapagliflozin treatment significantly reduced EAT thickness by 19% (p = 0.03). There was a significant 21.6% reduction in EAT glucose uptake during euglycemic hyperinsulinemic clamp in the dapagliflozin group compared with the placebo group (p = 0.014). There were no significant effects on adipose tissue thickness/metabolism in the other depots explored. CONCLUSIONS: SGLT-2 inhibition selectively reduces EAT thickness and EAT glucose uptake in T2D patients, suggesting a reduction of EAT inflammation. This could explain the observed increase in myocardial flow reserve, providing new insights into SGLT-2i cardiovascular benefits.

Drug-Induced Acute Pancreatitis in Adults: Focus on Antimicrobial and Antiviral Drugs, a Narrative Review.

Acute pancreatitis (AP) is an acute inflammation of the pancreas caused by the activation of digestive enzymes in the pancreatic tissue. The main causes of AP are cholelithiasis and alcohol abuse; less commonly, it can be caused by drugs, with a prevalence of up to 5%. Causal associations between drugs and pancreatitis are largely based on case reports or case series with limited evidence. We reviewed the available data on drug-induced AP, focusing on antimicrobial drugs and antivirals, and discussed the current evidence in relation to the classification systems available in the literature. We found 51 suspected associations between antimicrobial and antiviral drugs and AP. The drugs with the most evidence of correlation are didanosine, protease inhibitors, and metronidazole. In addition, other drugs have been described in case reports demonstrating positive rechallenge. However, there are major differences between the various classifications available, where the same drug being assigned to different probability classes. It is likely that the presence in multiple case reports of an association between acute pancreatitis and a drug should serve as a basis for conducting prospective randomized controlled trials to improve the quality of the evidence.

Physical Activity and Type 2 Diabetes: In Search of a Personalized Approach to Improving ß-Cell Function.

Type 2 diabetes mellitus (T2DM) is one of the most widespread diseases worldwide. Lifestyle interventions, including diet and physical activity (PA), are fundamental non-pharmacological components of T2DM therapy. Exercise interventions are strongly recommended for people with or at risk of developing or already with overt diabetes, but adherence to PA guidelines in this population is still challenging. Furthermore, the heterogeneity of T2DM patients, driven by differing residual ß-cell functionality, as well as the possibility of practicing different types and intensities of PA, has led to the need to develop tailored exercise and training plans. Investigations on blood glucose variation in response to exercise could help to clarify why individuals do not respond in the same way to PA, and to guide the prescription of personalized treatments. The aim of this review is to offer an updated overview of the current evidence on the effects of different regimens and modalities of PA regarding glucose sensing and ß-cell secretory dynamics in individuals with prediabetes or T2DM, with a special focus on ß-cell function.

Antibiotic Utilization in Acute Pancreatitis: A Narrative Review.

Acute pancreatitis is a complex inflammatory disease with significant morbidity and mortality. Despite advances in its management, the role of antibiotics in the prophylaxis and treatment of acute pancreatitis remains controversial. The aim of this comprehensive review is to analyze current evidence on the use of antibiotics in acute pancreatitis, focusing on prophylactic and therapeutic strategies. Prophylactic use aims to prevent local and systemic infections. However, recent studies have questioned the routine use of antibiotics for prophylaxis and highlighted the potential risks of antibiotic resistance and adverse effects. In selected high-risk cases, such as infected necrotizing pancreatitis, prophylactic antibiotic therapy may still be beneficial. As for therapeutic use, antibiotics are usually used to treat infected pancreatic necrosis and extrapancreatic infections. When selecting an antibiotic, the microbiologic profile and local resistance patterns should be considered. Combination therapy with broad-spectrum antibiotics is often recommended to cover both Gram-positive and Gram-negative pathogens. Recent research has highlighted the importance of individualized approaches to antibiotic use in acute pancreatitis and underscored the need for a tailored approach based on patient-specific factors. This review also highlights the potential role of new antimicrobial agents and alternative strategies, such as probiotics, in the management of acute pancreatitis.

An update on pancreatic regeneration mechanisms: Searching for paths to a cure for type 2 diabetes.

BACKGROUND: Over the last decades, various approaches have been explored to restore sufficient ß-cell mass in diabetic patients. Stem cells are certainly an attractive source of new ß-cells, but an alternative option is to induce the endogenous regeneration of these cells. SCOPE OF REVIEW: Since the exocrine and endocrine pancreatic glands have a common origin and a continuous crosstalk unites the two, we believe that analyzing the mechanisms that induce pancreatic regeneration in different conditions could further advance our knowledge in the field. In this review, we summarize the latest evidence on physiological and pathological conditions associated with the regulation of pancreas regeneration and proliferation, as well as the complex and coordinated signaling cascade mediating cell growth. MAJOR CONCLUSIONS: Unraveling the mechanisms involved in intracellular signaling and regulation of pancreatic cell proliferation and regeneration may inspire future investigations to discover potential strategies to cure diabetes.

Why do some glucose-lowering agents improve non-alcoholic fatty liver disease whereas others do not? A narrative review in search of a unifying hypothesis.

Non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D) are metabolic disorders connected by common pathophysiological mechanisms. Since insulin resistance (IR) and metabolic alterations are common to both conditions, almost all glucose-lowering agents which improve IR have also been studied in patients with NAFLD. Some have shown great efficacy, others none. Thus, the mechanisms behind the efficacy of these drugs in improving hepatic steatosis, steatohepatitis, and eventually fibrosis remain controversial. Glycaemic control improves T2D, but probably has limited effects on NAFLD, as all glucose-lowering agents ameliorate glucose control but only a few improve NAFLD features. In contrast, drugs that either improve adipose tissue function, reduce lipid ingestion, or increase lipid oxidation are particularly effective in NAFLD. We therefore hypothesise that improved free fatty acid metabolism may be the unifying mechanism behind the efficacy of some glucose-lowering agents on NAFLD and may represent the key to NAFLD treatment.

Effects of PCSK9 inhibition on glucose metabolism and ß-cell function in humans: a pilot study.

Background: Anti-PCSK9 monoclonal antibodies are effective in reducing LDL-C and cardiovascular events by neutralizing circulating PCSK9. PCSK9, however, is also expressed in tissues, including the pancreas, and studies on PCSK9 KO mice have shown impaired insulin secretion. Statin treatment is already known to affect insulin secretion. Our aim was to conduct a pilot study to evaluate the effect of anti-PCSK9 mAb on glucose metabolism and ß-cell function in humans. Methods: Fifteen non-diabetic subjects, candidates for anti-PCSK9 mAb therapy, were enrolled. All underwent OGTT at baseline and after 6 months of therapy. During OGTT, insulin secretion parameters were derived from C-peptide by deconvolution (ß cell glucose sensitivity). Surrogate insulin sensitivity indices were also obtained from OGTT (Matsuda). Results: Glucose levels during OGTT were unchanged after 6 months of anti-PCSK9 mAb treatment, as well as insulin and C-peptide levels. The Matsuda index remained unchanged, while ß-cell glucose sensitivity improved post-therapy (before: 85.3 ± 65.4; after: 118.6 ± 70.9 pmol min-1m-2mM-1; p<0.05). Using linear regression, we found a significant correlation between ßCGS changes and BMI (p=0.004). Thus, we compared subjects with values above and below the median (27.6 kg/m2) and found that those with higher BMI had a greater increase in ßCGS after therapy (before: 85.37 ± 24.73; after: 118.62 ± 26.83 pmol min-1m-2mM-1; p=0.007). There was also a significant correlation between ßCGS change and Matsuda index through linear regression (p=0.04), so we analyzed subjects who had values above and below the median (3.8). This subgroup analysis showed a slight though not significant improvement in ßCGS in more insulin resistant patients, (before: 131.4 ± 69.8; after: 170.8 ± 92.7 pmol min-1m-2mM-1; p=0.066). Conclusions: Our pilot study demonstrates that six-month treatment with anti-PCSK9 mAb improves ß-cell function, and does not alter glucose tolerance. This improvement is more evident in patients with greater insulin-resistance (low Matsuda) and higher BMI.

Nutrition in Acute Pancreatitis: From the Old Paradigm to the New Evidence.

The nutritional management of acute pancreatitis (AP) patients has widely changed over time. The "pancreatic rest" was the cornerstone of the old paradigm, and nutritional support was not even included in AP management. Traditional management of AP was based on intestinal rest, with or without complete parenteral feeding. Recently, evidence-based data underlined the superiority of early oral or enteral feeding with significantly decreased multiple-organ failure, systemic infections, surgery need, and mortality rate. Despite the current recommendations, experts still debate the best route for enteral nutritional support and the best enteral formula. The aim of this work is to collect and analyze evidence over the nutritional aspects of AP management to investigate its impact. Moreover, the role of immunonutrition and probiotics in modulating inflammatory response and gut dysbiosis during AP was extensively studied. However, we have no significant data for their use in clinical practice. This is the first work to move beyond the mere opposition between the old and the new paradigm, including an analysis of several topics still under debate in order to provide a comprehensive overview of nutritional management of AP.

First-phase insulin secretion: can its evaluation direct therapeutic approaches?

Our work is aimed at unraveling the role of the first-phase insulin secretion in the natural history of type 2 diabetes mellitus (T2DM) and its interrelationship with insulin resistance and with ß cell function and mass. Starting from pathophysiology, we investigate the impact of impaired secretion on glucose homeostasis and explore postmeal hyperglycemia as the main clinical feature, underlining its relevance in the management of the disease. We also review dietary and pharmacological approaches aimed at improving early secretory defects and restoring residual ß cell function. Furthermore, we discuss possible approaches to detect early secretory defects in clinical practice. By providing a journey through human and animal data, we attempt a unification of the recent evidence in an effort to offer a new outlook on ß cell secretion.

Pancreatic Cancer Resistance to Treatment: The Role of Microbiota.

Pancreatic cancer (PC) is an aggressive malignancy and the fourth leading cause of cancer death in the United States and Europe. It is estimated that PC will be the second leading cause of cancer death by 2030. In addition to late diagnosis, treatment resistance is a major cause of shortened survival in pancreatic cancer. In this context, there is growing evidence that microbes play a regulatory role, particularly in therapy resistance and in creating a microenvironment in the tumor, that favors cancer progression. The presence of certain bacteria belonging to the gamma-proteobacteria or mycoplasmas appears to be associated with both pharmacokinetic and pharmacodynamic changes. Recent evidence suggests that the microbiota may also play a role in resistance mechanisms to immunotherapy and radiotherapy. However, the interactions between microbiota and therapy are bilateral and modulate therapy tolerance. Future perspectives are increasingly focused on elucidating the role of the microbiota in tumorigenesis and processes of therapy resistance, and a better understanding of these mechanisms may provide important opportunities to improve survival in these patients.

Intra-islet insulin synthesis defects are associated with endoplasmic reticulum stress and loss of beta cell identity in human diabetes.

AIMS/HYPOTHESIS: Endoplasmic reticulum (ER) stress and beta cell dedifferentiation both play leading roles in impaired insulin secretion in overt type 2 diabetes. Whether and how these factors are related in the natural history of the disease remains, however, unclear. METHODS: In this study, we analysed pancreas biopsies from a cohort of metabolically characterised living donors to identify defects in in situ insulin synthesis and intra-islet expression of ER stress and beta cell phenotype markers. RESULTS: We provide evidence that in situ altered insulin processing is closely connected to in vivo worsening of beta cell function. Further, activation of ER stress genes reflects the alteration of insulin processing in situ. Using a combination of 17 different markers, we characterised individual pancreatic islets from normal glucose tolerant, impaired glucose tolerant and type 2 diabetic participants and reconstructed disease progression. CONCLUSIONS/INTERPRETATION: Our study suggests that increased beta cell workload is accompanied by a progressive increase in ER stress with defects in insulin synthesis and loss of beta cell identity.

Dapagliflozin improves myocardial flow reserve in patients with type 2 diabetes: the DAPAHEART Trial: a preliminary report.

OBJECTIVE: Cardiovascular (CV) outcome trials have shown that in patients with type 2 diabetes (T2D), treatment with sodium-glucose cotransporter-2 inhibitors (SGLT-2i) reduces CV mortality and hospital admission rates for heart failure (HF). However, the mechanisms behind these benefits are not fully understood. This study was performed to investigate the effects of the SGLT-2i dapagliflozin on myocardial perfusion and glucose metabolism in patients with T2D and stable coronary artery disease (coronary stenosis ≥ 30% and < 80%), with or without previous percutaneous coronary intervention (> 6 months) but no HF. METHODS: This was a single-center, prospective, randomized, double-blind, controlled clinical trial including 16 patients with T2D randomized to SGLT-2i dapagliflozin (10 mg daily) or placebo. The primary outcome was to detect changes in myocardial glucose uptake (MGU) from baseline to 4 weeks after treatment initiation by [(18)F]2-deoxy-2-fluoro-D-glucose (FDG) PET/CT during hyperinsulinemic euglycemic clamp. The main secondary outcome was to assess whether the hypothetical changes in MGU were associated with changes in myocardial blood flow (MBF) and myocardial flow reserve (MFR) measured by 13N-ammonia PET/CT. The study was registered at eudract.ema.europa.eu (EudraCT No. 2016-003614-27) and ClinicalTrials.gov (NCT03313752). RESULTS: 16 patients were randomized to dapagliflozin (n = 8) or placebo (n = 8). The groups were well-matched for baseline characteristics (age, diabetes duration, HbA1c, renal and heart function). There was no significant change in MGU during euglycemic hyperinsulinemic clamp in the dapagliflozin group (2.22 ± 0.59 vs 1.92 ± 0.42 µmol/100 g/min, p = 0.41) compared with the placebo group (2.00 ± 0.55 vs 1.60 ± 0.45 µmol/100 g/min, p = 0.5). Dapagliflozin significantly improved MFR (2.56 ± 0.26 vs 3.59 ± 0.35 p = 0.006 compared with the placebo group 2.34 ± 0.21 vs 2.38 ± 0.24 p = 0.81; pint = 0.001) associated with a reduction in resting MBF corrected for cardiac workload (p = 0.005; pint = 0.045). A trend toward an increase in stress MBF was also detected (p = 0.054). CONCLUSIONS: SGLT-2 inhibition increases MFR in T2D patients. We provide new insight into SGLT-2i CV benefits, as our data show that patients on SGLT-2i are more resistant to the detrimental effects of obstructive coronary atherosclerosis due to increased MFR, probably caused by an improvement in coronary microvascular dysfunction. Trial registration EudraCT No. 2016-003614-27; ClinicalTrials.gov Identifier: NCT03313752.

Circulating 1,5-Anhydroglucitol as a Biomarker of ß-cell Mass Independent of a Diabetes Phenotype in Human Subjects.

CONTEXT: During an asymptomatic prediabetic state, the functional ß-cell mass decreases to a critical threshold, triggering diabetes and related symptoms. To date, there are no reliable readouts able to capture in vivo a potential drop of the ß-cell mass. OBJECTIVE: Beside its use as a short-term marker of glycemic control, the deoxyhexose 1,5-anhydroglucitol was identified in rodents as a circulating biomarker of the functional ß-cell mass already in the asymptomatic prediabetic stage. The present study investigated the putative corresponding relevance of circulating 1,5-anhydroglucitol in different human cohorts. METHODS: We analyzed clinical and blood parameters in patients with established type 2 diabetes and subjects considered at high risk of developing diabetes, as well as patients with no history of diabetes scheduled for pancreaticoduodenectomy. RESULTS: Circulating 1,5-anhydroglucitol was reduced in type 2 diabetic patients, negatively correlating with fasting plasma glucose (P < 0.0001) and hemoglobin A1c (P < 0.0001). In healthy subjects, 1,5-AG levels positively correlated with body mass index (P = 0.004) and Homeostatic Model Assessment of Insulin Resistance %S (P < 0.03) and was particularly high in nondiabetic obese individuals, potentially accounting for compensatory ß-cell expansion. Patients with no history of diabetes undergoing pancreaticoduodenectomy exhibited a 50% reduction of circulating 1,5-anhydroglucitol levels following surgery leading to an acute loss of their ß-cell mass (P = 0.002), regardless their glucose tolerance status. CONCLUSION: In summary, plasma concentration of 1,5-anhydroglucitol follows the ß-cell mass and its noninvasive monitoring may alert about the loss of ß cells in subjects at risk for diabetes, an event that cannot be captured by other clinical parameters of glycemic control.

Insulin regulates arginine-stimulated insulin secretion in humans.

AIMS: Insulin potentiates glucose-stimulated insulin secretion. These effects are attenuated in beta cell-specific insulin receptor knockout mice and insulin resistant humans. This investigation examines whether short duration insulin exposure regulates beta cell responsiveness to arginine, a non-glucose secretagogue, in healthy humans. MATERIALS AND METHODS: Arginine-stimulated insulin secretion was studied in 10 healthy humans. In each subject arginine was administered as a bolus followed by continuous infusion on two occasions one month apart, after sham/saline or hyperinsulinemic-isoglycemic clamp, respectively providing low and high insulin pre-exposure conditions. Arginine-stimulated insulin secretion was measured by C-peptide deconvolution, and by a selective immunogenic (DAKO) assay for direct measurement of endogenous but not exogenous insulin. RESULTS: Pre-exposure to exogenous insulin augmented arginine-stimulated insulin secretion. The effect was seen acutely following arginine bolus (endogenous DAKO insulin incremental AUC240-255min 311.6 ±â€¯208.1 (post-insulin exposure) versus 120.6 ±â€¯42.2 µU/ml•min (sham/saline) (t-test P = 0.021)), as well as in response to continuous arginine infusion (DAKO insulin incremental AUC260-290min 1095.3 ±â€¯592.1 (sham/saline) versus 564.8 ±â€¯207.1 µU/ml•min (high insulin)(P = 0.009)). Findings were similar when beta cell response was assessed using C-peptide, insulin secretion rates by deconvolution, and the C-peptide to glucose ratio. CONCLUSIONS: We demonstrate a physiologic role of insulin in regulation of the beta cell secretory response to arginine.

Alpha-Lipoic Acid and Glucose Metabolism: A Comprehensive Update on Biochemical and Therapeutic Features.

Alpha-lipoic acid (ALA) is a natural compound with antioxidant and pro-oxidant properties which has effects on the regulation of insulin sensitivity and insulin secretion. ALA is widely prescribed in patients with diabetic polyneuropathy due to its positive effects on nerve conduction and alleviation of symptoms. It is, moreover, also prescribed in other insulin resistance conditions such as metabolic syndrome (SM), polycystic ovary syndrome (PCOS) and obesity. However, several cases of Insulin Autoimmune Syndrome (IAS) have been reported in subjects taking ALA. The aim of the present review is to describe the main chemical and biological functions of ALA in glucose metabolism, focusing on its antioxidant activity, its role in modulating insulin sensitivity and secretion and in symptomatic peripheral diabetic polyneuropathy. We also provide a potential explanation for increased risk for the development of IAS.

Prediabetes: how pathophysiology drives potential intervention on a subclinical disease with feared clinical consequences.

INTRODUCTION: Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder whose rising incidence suggests the epidemic proportions of the disease. Impaired fasting glucose (IFG) and Impaired Glucose Tolerance (IGT) - alone or combined - represent two intermediate metabolic condition between Normal Glucose Tolerance (NGT) and overt T2DM. EVIDENCE ACQUISITION: Databases were systematically screened using the following MeSH terms combination as follows: 1. prediabetes, 2. prediabetic state, 3. prevention, 4. lifestyle, 5. diet, 6. nutrition, 7. pharmacotherapy, 8. metformin, 9. thiazolidinediones, 10. sodium glucose cotransporter 2 inhibitors, 11. GLP 1 receptor agonists, 12. alpha glucosidase inhibitors, 13. insulin, 14. DPP IV inhibitors. EVIDENCE SYNTHESIS: Several studies have demonstrated that insulin resistance and beta-cell impairment can be identified even in normoglycemic prediabetic individuals. Worsening of these two conditions may lead to progression of IGT and/or IFG status to overt diabetes. Starting from these assumptions, it seems logical to suppose that interventions aimed at improving metabolic conditions, even in prediabetes, could represent an effective target to halt transition from IGT/IFG to manifest T2DM. Starting from pathophysiological knowledge, in this review we evaluate two possible interventions (lifestyle modifications and pharmacological agents) eligible as prediabetes therapy since they have been demonstrated to improve insulin resistance and beta-cell impairment. CONCLUSIONS: Detecting high-risk people and treating them could represent an effective strategy to slow down progression to overt diabetes, normalize glucose tolerance, and even prevent micro- and macrovascular complications.