Okinawa-Based Nordic Diet Decreases Plasma Levels of IAPP and IgA against IAPP Oligomers in Type 2 Diabetes Patients.

Pancreas-derived islet amyloid polypeptide (IAPP) aggregates and deposits in the pancreas and periphery of Type 2 Diabetes (T2D) patients, contributing to diabetic complications. The excess IAPP can be removed by autoantibodies, and increased levels of immunoglobulin (Ig) G against IAPP have been reported in T2D patients. However, whether other Ig classes are also affected and if the levels can be managed is less known. This pre-post study examines IgA levels against IAPP oligomers (IAPPO-IgA) in T2D patients and assesses the impact of the Okinawa-based Nordic (O-BN) diet-a low-carbohydrate, high-fiber diet-on these levels after following the diet for 3 months. IAPP, IAPPO-IgA, and total IgA levels were measured in plasma and fecal samples from n = 30 T2D patients collected at baseline, after 3 months of diet, and after additional 4 months of unrestricted diets (a clinical follow-up). The IAPP and IAPPO-IgA levels were significantly lower after 3 months, with the latter also being significantly reduced at the clinical follow-up. The reduction in plasma IAPP and IAPPO-IgA levels correlated with reductions in plasma levels of metabolic and inflammatory markers. Hence, following the O-BN diet for at least 3 months is sufficient to reduce circulating IAPP and IAPPO-IgA levels, which may be principal in managing T2D.

Exploring the Role of Metabolic Hormones in Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive loss of motor neurons. Emerging evidence suggests a potential link between metabolic dysregulation and ALS pathogenesis. This study aimed to investigate the relationship between metabolic hormones and disease progression in ALS patients. A cross-sectional study was conducted involving 44 ALS patients recruited from a tertiary care center. Serum levels of insulin, total amylin, C-peptide, active ghrelin, GIP (gastric inhibitory peptide), GLP-1 active (glucagon-like peptide-1), glucagon, PYY (peptide YY), PP (pancreatic polypeptide), leptin, interleukin-6, MCP-1 (monocyte chemoattractant protein-1), and TNFα (tumor necrosis factor alpha) were measured, and correlations with ALSFRS-R, evolution scores, and biomarkers were analyzed using Spearman correlation coefficients. Subgroup analyses based on ALS subtypes, progression pattern of disease, and disease progression rate patterns were performed. Significant correlations were observed between metabolic hormones and ALS evolution scores. Insulin and amylin exhibited strong correlations with disease progression and clinical functional outcomes, with insulin showing particularly robust associations. Other hormones such as C-peptide, leptin, and GLP-1 also showed correlations with ALS progression and functional status. Subgroup analyses revealed differences in hormone levels based on sex and disease evolution patterns, with male patients showing higher amylin and glucagon levels. ALS patients with slower disease progression exhibited elevated levels of amylin and insulin. Our findings suggest a potential role for metabolic hormones in modulating ALS progression and functional outcomes. Further research is needed to elucidate the underlying mechanisms and explore the therapeutic implications of targeting metabolic pathways in ALS management.

Plasma IAPP-Autoantibody Levels in Alzheimer's Disease Patients Are Affected by APOE4 Status.

Pancreas-derived islet amyloid polypeptide (IAPP) crosses the blood-brain barrier and co-deposits with amyloid beta (Aß) in brains of type 2 diabetes (T2D) and Alzheimer's disease (AD) patients. Depositions might be related to the circulating IAPP levels, but it warrants further investigation. Autoantibodies recognizing toxic IAPP oligomers (IAPPO) but not monomers (IAPPM) or fibrils have been found in T2D, but studies on AD are lacking. In this study, we have analyzed plasma from two cohorts and found that levels of neither immunoglobulin (Ig) M, nor IgG or IgA against IAPPM or IAPPO were altered in AD patients compared with controls. However, our results show significantly lower IAPPO-IgA levels in apolipoprotein E (APOE) 4 carriers compared with non-carriers in an allele dose-dependent manner, and the decrease is linked to the AD pathology. Furthermore, plasma IAPP-Ig levels, especially IAPP-IgA, correlated with cognitive decline, C-reactive protein, cerebrospinal fluid Aß and tau, neurofibrillary tangles, and brain IAPP exclusively in APOE4 non-carriers. We speculate that the reduction in IAPPO-IgA levels may be caused by increased plasma IAPPO levels or masked epitopes in APOE4 carriers and propose that IgA and APOE4 status play a specific role in clearance of circulatory IAPPO, which may influence the amount of IAPP deposition in the AD brain.

Change of plasma amylin after bariatric surgery challenged by oral glucose is associated with remission of type 2 diabetes mellitus.

BACKGROUND: Gastric bypass (GB) and sleeve gastrectomy (SG) were found to achieve different remission rates in the treatment of type 2 diabetes (T2DM). The alteration in several gut hormones after bariatric surgery has been demonstrated to play a key role for T2DM remission. Nevertheless, amylin, one of the diabetes-associated peptides, so far has an undetermined position on T2DM remission after bariatric surgery. METHODS: Sixty eligible patients with T2DM (GB, 30; SG, 30) were initially enrolled in the hospital-based randomized trial. Twenty patients (GB, 10; SG, 10) who met the inclusion criteria and agreed to undergo 75-g oral glucose tolerance test (OGTT) were recruited. The recruited subjects underwent anthropometric measurements, routine laboratory tests, and 75-g OGTT before and 1 year after bariatric surgery. Enzyme immunoassays for plasma amylin were analyzed. RESULTS: All subjects that underwent GB and half of those who underwent SG achieved T2DM remission. Plasma amylin levels significantly decreased 60-90 min after OGTT in the GB group (p < 0.05) and 30-60 minutes after OGTT in the SG group (p < 0.05). Significantly decreased plasma amylin levels were observed at 30-90 minutes after OGTT in the noncomplete remitters of the GB group (p < 0.05). Plasma amylin levels initially increased (p < 0.05) within 30 minutes after OGTT and then decreased (p < 0.05) in the next 30-minute interval in the nonremitters of the SG group. CONCLUSION: Postoral glucose challenge amylin levels could be as one of the parameters to evaluate T2DM remission after bariatric surgery, especially in those after SG.

Amylin Dyshomeostasis Hypothesis: Small Vessel-Type Ischemic Stroke in the Setting of Type-2 Diabetes.

Recent histological analyses of human brains show that small vessel-type injuries in the setting of type-2 diabetes colocalize with deposits of amylin, an amyloid-forming hormone secreted by the pancreas. Amylin inclusions are also identified in circulating red blood cells in people with type-2 diabetes and stroke or cardiovascular disease. In laboratory models of type-2 diabetes, accumulation of aggregated amylin in blood and the cerebral microvasculature induces brain microhemorrhages and reduces cerebral blood flow leading to white matter ischemia and neurological deficits. At the cellular level, aggregated amylin causes cell membrane lipid peroxidation injury, downregulation of tight junction proteins, and activation of proinflammatory signaling pathways which, in turn, induces macrophage activation and macrophage infiltration in vascular areas positive for amylin deposition. We review each step of this cascade based on experimental and clinical evidence and propose the hypothesis that systemic amylin dyshomeostasis may underlie the disparity between glycemic control and stroke risk and may be a therapeutic target to reduce the risk of small vessel ischemic stroke in patients with type-2 diabetes.

Acute Nutritional Ketosis and Its Implications for Plasma Glucose and Glucoregulatory Peptides in Adults with Prediabetes: A Crossover Placebo-Controlled Randomized Trial.

BACKGROUND: The potential of a ketone monoester (ß-hydroxybutyrate; KEßHB) supplement to rapidly mimic a state of nutritional ketosis offers a new therapeutic possibility for diabetes prevention and management. While KEßHB supplementation has a glucose-lowering effect in adults with obesity, its impact on glucose control in other insulin-resistant states is unknown. OBJECTIVES: The primary objective was to investigate the effect of KEßHB-supplemented drink on plasma glucose in adults with prediabetes. The secondary objective was to determine its impact on plasma glucoregulatory peptides. METHODS: This randomized controlled trial [called CETUS (Cross-over randomizEd Trial of ß-hydroxybUtyrate in prediabeteS)] included 18 adults [67% men, mean age = 55 y, mean BMI (kg/m2) = 28.4] with prediabetes (glycated hemoglobin between 5.7% and 6.4% and/or fasting plasma glucose between 100 and 125 mg/dL). Participants were randomly assigned to receive KEßHB-supplemented and placebo drinks in a crossover sequence (washout period of 7-10 d between the drinks). Blood samples were collected from 0 to 150 min, at intervals of 30 min. Paired-samples t tests were used to investigate the change in the outcome variables [ß-hydroxybutyrate (ßHB), glucose, and glucoregulatory peptides] after both drinks. Repeated measures analyses were conducted to determine the change in concentrations of the prespecified outcomes over time. RESULTS: Blood ßHB concentrations increased to 3.5 mmol/L within 30 minutes after KEßHB supplementation. Plasma glucose AUC was significantly lower after KEßHB supplementation than after the placebo [mean difference (95% CI): -59 (-85.3, -32.3) mmol/L × min]. Compared with the placebo, KEßHB supplementation led to significantly greater AUCs for plasma insulin [0.237 (0.044, 0.429) nmol/L × min], C-peptide [0.259 (0.114, 0.403) nmol/L × min], and glucose-dependent insulinotropic peptide [0.243 (0.085, 0.401) nmol/L × min], with no significant differences in the AUCs for amylin, glucagon, and glucagon-like peptide 1. CONCLUSIONS: Ingestion of the KEßHB-supplemented drink acutely increased the blood ßHB concentrations and lowered the plasma glucose concentrations in adults with prediabetes. Further research is needed to investigate the dynamics of repeated ingestions of a KEßHB supplement by individuals with prediabetes, with a view to preventing new-onset diabetes. This trial was registered at www.clinicaltrials.gov as NCT03889210.

Testing the effects of the GLP-1 receptor agonist exenatide on cocaine self-administration and subjective responses in humans with cocaine use disorder.

BACKGROUND: Preclinical rodent studies have demonstrated reduced cocaine taking after administration of glucagon-like peptide 1 (GLP-1) analogues. We investigated effects of a GLP-1 analogue (exenatide) on behavioral and subjective effects of cocaine in individuals with cocaine use disorder (CUD). METHODS: Non-treatment-seeking CUD subjects underwent two human laboratory cocaine self-administration test sessions following an acute 3 -h pre-treatment with exenatide (5 mcg; subcutaneously) or placebo. Primary outcomes consisted of infusions of cocaine and visual analog scale self-ratings of euphoria and wanting cocaine. Secondary outcomes consisted of pertinent hormone levels (GLP-1, insulin, and amylin). RESULTS: Thirteen individuals completed the study. Acute pretreatment with exenatide versus placebo did not change cocaine infusions (8.5 ± 1.2 vs. 9.1 ± 1.2; p = 0.39), self-reported euphoria (4.4 ± 0.8 vs. 4.1 ± 0.8; p = 0.21), or wanting of cocaine (5.6 ± 0.9 vs. 5.4 ± 0.9; p = 0.46). Exenatide vs. placebo reduced levels of GLP-1 (p = 0.03) and insulin (p = 0.02). Self-administered cocaine also reduced levels of GLP-1 (p < 0.0001), insulin (p < 0.0001), and amylin (p < 0.0001). CONCLUSIONS: We did not find evidence that low dose exenatide alters cocaine self-administration or the subjective effects of cocaine in people with CUD. Limitations such as single acute rather than chronic pre-treatment, as well as evaluation of only one dose, preclude drawing firm conclusions about the efficacy of exenatide. Exenatide and cocaine independently reduced levels of GLP-1 and insulin, while cocaine also reduced levels of amylin.

Amyloidogenesis of feline amylin and plasma levels in cats with diabetes mellitus or pancreatitis.

Amylin is a pancreatic hormone cosecreted along with insulin and involved in pancreatic amyloidosis and ß-cell apoptosis in diabetic cats and humans. Amylin is usually elevated in early stages of type 2 diabetes but recently was found to be increased in acute and chronic pancreatitis in humans. Currently, there are little data about feline amylin propensity to fibrillate and no information on circulating levels of this hormone during feline pancreatitis. We compared 4 amylin analogues and found cat amylin to be more prone to amyloid fibrillation than human amylin, the triple-proline analogue pramlintide and rat amylin. We also measured plasma amylin levels in healthy lean cats, diabetic cats, and cats with pancreatitis. Plasma amylin was higher in diabetic cats compared with healthy lean cats (P < 0.001). Interestingly, amylin levels during pancreatitis were higher than those of both lean cats (P < 0.0001) and diabetic cats without pancreatitis (P < 0.005). These data support evidence of feline amylin being more prone to aggregation than human amylin in vitro, which may influence diabetes mellitus progression and ß-cell failure in vivo. Furthermore, our data show an increase in amylin levels during feline pancreatitis and the need for future research on the role of this hormone in the pathogenesis of pancreatic inflammation associated to feline diabetes mellitus.

Interictal amylin levels in chronic migraine patients: A case-control study.

BACKGROUND: Recently, amylin and its receptors were found in different structures involved in migraine pathophysiology. Here, we evaluate interictal concentrations of amylin and calcitonin gene-related peptide in peripheral blood as biomarkers for chronic migraine. METHODS: We prospectively recruited patients with episodic migraine, chronic migraine and healthy controls. Interictal amylin and calcitonin gene-related peptide levels were assessed in blood samples using enzyme linked immunosorbent assay. RESULTS: We assessed plasma samples from 58 patients with episodic migraine (mean age 37.71 ± 10.47, 87.9% female), 191 with chronic migraine (mean age 46.03 ± 11.93, 95% female), and on 68 healthy controls (mean age 43.58 ± 11.08 years, 86% female). Body mass index was 25.94 ± 4.53 kg/m2 for migraine patients and 25.13 ± 4.92 kg/m2 for healthy controls (p = 0.0683). Interictal plasma amylin levels were higher in chronic migraine patients (47.1 pg/mL) than in the episodic migraine patients (28.84 pg/mL, p < 0.0001) and healthy controls (24.74 pg/mL, p < 0.0001). Plasma calcitonin gene-related peptide levels were increased (20.01 pg/mL) in chronic migraine patients when compared to healthy controls (11.37 pg/mL, p = 0.0016), but not to episodic migraine patients (18.89 pg/mL, p = 0.4369). Applying a cut-off concentration of 39.68 pg/mL plasma amylin, the sensitivity to differentiate chronic migraine from healthy controls was 57.6% and the specificity was 88.2%. Variables such as age, analgesic overuse, depression, allodynia, use of preventive medication or a history of aura did not influence the plasma concentrations of amylin or calcitonin gene-related peptide. CONCLUSION: Interictal plasma amylin levels are higher in patients with chronic migraine and may serve as a diagnostic biomarker for chronic migraine.

First-Phase Insulin and Amylin after Bariatric Surgery: A Prospective Randomized Trial on Patients with Insulin Resistance or Diabetes after Gastric Bypass or Sleeve Gastrectomy.

BACKGROUND: Most patients with severe obesity show glucose intolerance. Early after sleeve gastrectomy (LSG) or gastric bypass (LRYGB), a marked amelioration in glycemic control occurs. The underlying mechanism is not yet clear. OBJECTIVE: To determine whether the improvement in glycemic control on the level of endocrine pancreatic function is due to an increased first-phase insulin secretion comparing LRYGB to LSG. SETTING: University of Basel Hospital and St. Clara Research Ltd., Basel, Switzerland. METHODS: Sixteen morbidly obese patients with severe obesity and different degrees of insulin resistance were randomized to LSG or LRYGB, and islet cell functions were tested by intravenous glucose and intravenous arginine administration before and 4 weeks after surgery. RESULTS: Fasting insulin and glucose levels and homeostasis model assessment insulin resistance were significantly lower in both groups after surgery compared to baseline, while no change was seen in fasting C-peptide, amylin, and glucagon. After intravenous glucose stimulation, no statistically significant pre- to postoperative change in area under the curve (AUC 0-60 min) was seen for insulin, glucagon, amylin, and C-peptide. No statistically significant pre- to postoperative change in incremental AUC for first-phase insulin release (AUC 0-10 min), second-phase insulin secretion (AUC 10-60 min), and insulin/glucose ratio could be shown in either group. Arginine-stimulated insulin and glucagon release showed no pre- to postoperative change. CONCLUSION: Intravenous glucose and arginine administrations show no pre- to postoperative changes of insulin release, amylin, glucagon, or C-peptide concentrations, and no differences between LRYGB and LSG were found. The postoperative improvement in glycemic control is not caused by changes in endocrine pancreatic hormone secretion.

Peripheral insulin and amylin levels in Parkinson's disease.

BACKGROUND: Type-2-diabetes (T2D) has surfaced as a potential risk factor for Parkinson's disease (PD) in some epidemiological studies. Evidence of glucose metabolism alterations in PD from molecular studies remains conflicting. Amylin, the T2D amyloid protein, has been implicated in PD in pathological studies. We aimed to assess peripheral levels of amylin and insulin in PD patients and control subjects (Cs). METHODS: We conducted an observational cross-sectional study of 111 participants: 73 PD and 38 Cs, similar in age, sex and body mass index. All underwent motor (UPDRS-MDS-III), non-motor (NMSS) and cognitive (MDRS) scales as well as determination of four parameters: fasting glycaemia, glycated haemoglobin, fasting plasma insulin (FPI) and fasting plasma amylin (FPA). RESULTS: FPI was significantly lower in PD than Cs (p = 0.034). In participants with age above cohort-median-age, FPA was higher in PD than Cs (p = 0.046). The FPA/FPI ratio (FPAIR) was significantly higher in PD than Cs (p = 0.024). In PD, modest correlation was found between higher insulin-resistance and NMSS scores. CONCLUSIONS: PD patients had lower FPI and increased FPAIR. In older PD subgroup, FPA was increased. The more the insulin resistance, the higher the non-motor scores. These findings provide an additional link between pathophysiology of diabetes and PD. This might be related to a dissociated insulin and amylin secretion in PD, in line with recent evidence of endocrine pancreas role in PD pathogeny.

Protein-conformational diseases in childhood: Naturally-occurring hIAPP amyloid-oligomers and early ß-cell damage in obesity and diabetes.

BACKGROUND AND AIMS: This is the first time that obesity and diabetes mellitus (DM) as protein conformational diseases (PCD) are reported in children and they are typically diagnosed too late, when ß-cell damage is evident. Here we wanted to investigate the level of naturally-ocurring or real (not synthetic) oligomeric aggregates of the human islet amyloid polypeptide (hIAPP) that we called RIAO in sera of pediatric patients with obesity and diabetes. We aimed to reduce the gap between basic biomedical research, clinical practice-health decision making and to explore whether RIAO work as a potential biomarker of early ß-cell damage. MATERIALS AND METHODS: We performed a multicentric collaborative, cross-sectional, analytical, ambispective and blinded study; the RIAO from pretreated samples (PTS) of sera of 146 pediatric patients with obesity or DM and 16 healthy children, were isolated, measured by sound indirect ELISA with novel anti-hIAPP cytotoxic oligomers polyclonal antibody (MEX1). We carried out morphological and functional studied and cluster-clinical data driven analysis. RESULTS: We demonstrated by western blot, Transmission Electron Microscopy and cell viability experiments that RIAO circulate in the blood and can be measured by ELISA; are elevated in serum of childhood obesity and diabetes; are neurotoxics and works as biomarkers of early ß-cell failure. We explored the range of evidence-based medicine clusters that included the RIAO level, which allowed us to classify and stratify the obesity patients with high cardiometabolic risk. CONCLUSIONS: RIAO level increases as the number of complications rises; RIAOs > 3.35 µg/ml is a predictor of changes in the current indicators of ß-cell damage. We proposed a novel physio-pathological pathway and shows that PCD affect not only elderly patients but also children. Here we reduced the gap between basic biomedical research, clinical practice and health decision making.

Acute zoster plasma contains elevated amyloid, correlating with Aß42 and amylin levels, and is amyloidogenic.

Herpes zoster is associated with an increased dementia and neovascular macular degeneration risk and a decline in glycemic control in diabetes mellitus. Because amyloid is present and pathogenic in these diseases, we quantified amyloid, Aß40, Aß42, and amylin in 14 zoster and 10 control plasmas. Compared with controls, zoster plasma had significantly elevated amyloid that correlated with Aß42 and amylin levels and increased amyloid aggregation with addition of exogenous Aß42 or amylin. These results suggest that zoster plasma contains factor(s) that promotes aggregation of amyloidogenic peptides, potentially contributing to the toxic amyloid burden and explaining accelerated disease progression following zoster.

Fast screening method for molecular recognition of islet amyloid polypeptide from whole blood samples collected from diabetic patients with disposable stochastic sensors obtained by nanolayer, and nanolayer by nanolayer deposition using cold plasma.

Nanolayer and nanolayer by nanolayer deposition of nanofilms of Ag and C using cold plasma in sequences (Ag, Ag-C, Ag-Ag-C), on porous paper, were used to design three disposable stochastic sensors for the assay of amyloid polypeptide from whole blood. The nanofilms were modified with α-cyclodextrin. The test developed using the nanofilm-based disposable stochastic sensors is used for early detection of diabetes. The wider linear concentration range (1.00 × 10-6-1.00 ng mL-1) and the lower limit of quantification (1.00 × 10-6ng mL-1) were obtained using the disposable stochastic sensors based on Ag-C and Ag-Ag-C, while the highest sensitivity (3.19 × 104 s-1/µg mL-1) was recorded using the disposable stochastic sensor based on Ag-Ag-C. The screening methods were fully validated using whole blood samples from confirmed patients, when the recovery of the islet amyloid polypeptide was higher than 98.00%. Graphical abstract.

Dietary Supplementation with Curcumin Reduce Circulating Levels of Glycogen Synthase Kinase-3ß and Islet Amyloid Polypeptide in Adults with High Risk of Type 2 Diabetes and Alzheimer's Disease.

Dietary supplementation with curcumin has been previously reported to have beneficial effects in people with insulin resistance, type 2 diabetes (T2D) and Alzheimer's disease (AD). This study investigated the effects of dietary supplementation with curcumin on key peptides implicated in insulin resistance in individuals with high risk of developing T2D. Plasma samples from participants recruited for a randomised controlled trial with curcumin (180 mg/day) for 12 weeks were analysed for circulating glycogen synthase kinase-3 ß (GSK-3ß) and islet amyloid polypeptide (IAPP). Outcome measures were determined using ELISA kits. The homeostasis model for assessment of insulin resistance (HOMA-IR) was measured as parameters of glycaemic control. Curcumin supplementation significantly reduced circulating GSK-3ß (-2.4 ± 0.4 ng/mL vs. -0.3 ± 0.6, p = 0.0068) and IAPP (-2.0 ± 0.7 ng/mL vs. 0.4 ± 0.6, p = 0.0163) levels compared with the placebo group. Curcumin supplementation significantly reduced insulin resistance (-0.3 ± 0.1 vs. 0.01 ± 0.05, p = 0.0142) compared with placebo group. Dietary supplementation with curcumin reduced circulating levels of IAPP and GSK-3ß, thus suggesting a novel mechanism through which curcumin could potentially be used for alleviating insulin resistance related markers for reducing the risk of T2D and AD.

Dietary zinc restriction promotes degeneration of the endocrine pancreas in mice.

Zinc is a key component of several proteins, interacting with the pancreatic hormones insulin and amylin. The role of zinc in insulin oligomerization and crystallinity is well established, although the effects of dietary zinc restriction on both energetic metabolism and ß-pancreatic hormonemia and morphology remain unexplored. Here we report the effects of dietary zinc restriction on the endocrine pancreas and metabolic phenotype of mice. Nontransgenic male Swiss mice were fed a low-zinc or control diet for 4 weeks after weanling. Growth, glycemia, insulinemia and amylinemia were lower and pancreatic islets were smaller in the intervention group despite the preserved insulin crystallinity in secretory granules. We found strong immunostaining for insulin, amylin and oligomers in apoptotic pancreatic islet. High production of ß-pancreatic hormones in zinc-restricted animals counteracted the reduced islet size caused by apoptosis. These data suggest that zinc deficiency is sufficient to promote islet ß-cell hormonal disruption and degeneration.

Effect of amylin on memory and central insulin resistance in a rat model of Alzheimer's disease.

Context: Alzheimer's disease is strongly associated with brain insulin signalling.Objective: Investigating the effect of amylin as a novel treatment in streptozotocin (STZ) rat model of AD.Materials and methods: Alzheimer's disease (AD) was induced in albino rats by intracerebroventricular injection of STZ (3 mg/kg). Rats received either amylin analogue (Pramlintide 200 µg/kg/day) or Metformin (30 mg/kg/day) for 5 weeks.Results: Both Pramlintide and Metformin improve learning and memory through enhancing insulin signalling (p-IR and p-PI3K) which lead to lowering level of CSF glucose, phosphorylated tau proteins, and amyloid-ß peptide (Aß) in hippocampus.Conclusions: Insulin sensitisers as Metformin and Pramlintide can improve learning and memory and decrease the pathological changes in STZ induced rat model of AD. However, Pramlintide is superior to Metformin in some memory tests which related to its action as an amylin analogue. Amylin improves learning and memory through an independent effect other than insulin sensitisation.

Endocrine effects of the novel ghrelin receptor inverse agonist PF-5190457: Results from a placebo-controlled human laboratory alcohol co-administration study in heavy drinkers.

Both animal and human work suggests that the ghrelin system may be involved in the mechanisms that regulate the development and maintenance of alcohol use disorder. Previously, in a Phase 1b study, we tested pharmacological blockade of the growth hormone secretagogue receptor 1a (GHS-R1a, also known as the ghrelin receptor), in heavy drinking individuals with PF-5190457, an orally bioavailable, potent and selective GHS-R1a inverse agonist. We report here the effects of PF-5190457 on endocrine blood concentrations of amylin, gastric inhibitory polypeptide, glucagon-like peptide 1, insulin, leptin, pancreatic polypeptide, peptide YY, thyroid stimulating hormone, free triiodothyronine (T3), thyroxine (T4), cortisol, prolactin, and glucose during PF-5190457 dosing, as compared to placebo, in absence of alcohol as well as during an alcohol challenge when PF-5190457 was on steady-state. Blood hormone levels were largely unaffected by PF-5190457, both during dosing and in the context of alcohol challenge. The safety-related relevance of these findings to further develop PF-5190547 in alcohol use disorder is discussed. CLINICALTRIALS.GOV: NCT02039349. This article is part of the special issue on 'Neuropeptides'.

Unpacking the aggregation-oligomerization-fibrillization process of naturally-occurring hIAPP amyloid oligomers isolated directly from sera of children with obesity or diabetes mellitus.

The formation of amyloid oligomers and fibrils of the human islet amyloid polypeptide (hIAPP) has been linked with ß- cell failure and death which causes the onset, progression, and comorbidities of diabetes. We begin to unpack the aggregation-oligomerization-fibrillization process of these oligomers taken from sera of pediatric patients. The naturally occurring or real hIAPP (not synthetic) amyloid oligomers (RIAO) were successfully isolated, we demonstrated the presence of homo (dodecamers, hexamers, and trimers) and hetero-RIAO, as well as several biophysical characterizations which allow us to learn from the real phenomenon taking place. We found that the aggregation/oligomerization process is active in the sera and showed that it happens very fast. The RIAO can form fibers and react with anti-hIAPP and anti-amyloid oligomers antibodies. Our results opens the epistemic horizon and reveal real differences between the four groups (Controls vs obesity, T1DM or T2DM) accelerating the process of understanding and discovering novel and more efficient prevention, diagnostic, transmission and therapeutic pathways.

Effect of diabetes-specific nutrition formulas on satiety and hunger hormones in patients with type 2 diabetes.

OBJECTIVES: Diabetes-specific nutritional formulas (DSNFs) are frequently used by patients with type 2 diabetes (T2D) as part of nutrition therapy to improve glycemic control and reduce body weight. However, their effects on hunger and satiety hormones when compared to an isocaloric standardized breakfast are not fully understood. This study aims to evaluate the postprandial effects of two DSNFs-Glucerna (GL) and Ultra Glucose Control (UGC)-versus oatmeal on selected satiety and hunger hormones. METHOD: After an overnight fast, 22 patients with T2D (mean age 62.3 ± 6.8 years, A1C 6.8 ± 0.7%, body weight 97.4 ± 21.3 kg, and BMI 33.2 ± 5.9 kg/m²) were given 200 kcal of each meal on three separate days. Blood samples for amylin, cholecystokinin (CCK), ghrelin, glucagon, leptin, and peptide-YY (PYY) were collected at baseline and 30, 60, 90, 120, 180, and 240 min after the start of each meal. Incremental area under the curve (iAUC0-240) for each hormone was calculated. RESULTS: iAUC0-240 for glucagon and PYY were significantly higher after GL and UGC than after oatmeal (p < 0.001 for both). No difference was observed between the three meals on postprandial amylin, CCK, ghrelin, and leptin hormones. CONCLUSIONS: Intake of DSNFs significantly increases secretion of PYY and glucagon, two important satiety hormones. While subjective satiety was not directly evaluated, the increased effect on satiety hormones may partially explain the mechanism of body weight loss associated with DSNF use.