Diabetes-related Amylin Dyshomeostasis: a Contributing Factor to Cerebrovascular Pathology and Dementia

Type 2 diabetes (T2D) increases the risk for cerebrovascular disease (CVD) and dementia. The underlying molecular mechanisms remain elusive, which hampers the development of treatment or/and effective prevention strategies. Recent studies suggest that dyshomeostasis of amylin, a satiety hormone that forms pancreatic amyloid in patients with T2D, promotes accumulation of amylin in cerebral small blood vessels and interaction with Alzheimer's disease (AD) pathology. Overexpression of human amylin in rodents (rodent amylin does not form amyloid) leads to late-life onset T2D and neurologic deficits. In this Review, we discuss clinical evidence of amylin pathology in CVD and AD and identify critical characteristics of animal models that could help to better understand molecular mechanisms underlying the increased risk of CVD and AD in patients with prediabetes or T2D.

Novel Molecules Regulating Energy Homeostasis: Physiology and Regulation by Macronutrient Intake and Weight Loss

Excess energy intake, without a compensatory increase of energy expenditure, leads to obesity. Several molecules are involved in energy homeostasis regulation and new ones are being discovered constantly. Appetite regulating hormones such as ghrelin, peptide tyrosine-tyrosine and amylin or incretins such as the gastric inhibitory polypeptide have been studied extensively while other molecules such as fibroblast growth factor 21, chemerin, irisin, secreted frizzle-related protein-4, total bile acids, and heme oxygenase-1 have been linked to energy homeostasis regulation more recently and the specific role of each one of them has not been fully elucidated. This mini review focuses on the above mentioned molecules and discusses them in relation to their regulation by the macronutrient composition of the diet as well as diet-induced weight loss.

Computational Approach for Protein Structure Prediction / 대한의료정보학회지

OBJECTIVES: To predict the structure of protein, which dictates the function it performs, a newly designed algorithm is developed which blends the concept of self-organization and the genetic algorithm. METHODS: Among many other approaches, genetic algorithm is found to be a promising cooperative computational method to solve protein structure prediction in a reasonable time. To automate the right choice of parameter values the influence of self-organization is adopted to design a new genetic operator to optimize the process of prediction. Torsion angles, the local structural parameters which define the backbone of protein are considered to encode the chromosome that enhances the quality of the confirmation. Newly designed self-configured genetic operators are used to develop self-organizing genetic algorithm to facilitate the accurate structure prediction. RESULTS: Peptides are used to gauge the validity of the proposed algorithm. As a result, the structure predicted shows clear improvements in the root mean square deviation on overlapping the native indicates the overall performance of the algorithm. In addition, the Ramachandran plot results implies that the conformations of phi-psi angles in the predicted structure are better as compared to native and also free from steric hindrances. CONCLUSIONS: The proposed algorithm is promising which contributes to the prediction of a native-like structure by eliminating the time constraint and effort demand. In addition, the energy of the predicted structure is minimized to a greater extent, which proves the stability of protein.

Roles of calcitonin gene-related peptide family in pain and opioid tolerance / 生理学报

The calcitonin gene-related peptide (CGRP) family mainly includes CGRPα, CGRPβ, adrenomedullin, calcitonin and amylin. The members of CGRP family and their receptors are widely distributed in the central and peripheral nervous systems. Studies show that members of CGRP family such as CGRP and adrenomedullin play important roles in the transmission of nociceptive information. At spinal level, CGRP promotes the transmission of nociceptive information, spinal morphine tolerance, migraine, inflammatory pain and neuropathic pain. At superspinal level, CGRP suppresses the transmission of nociceptive information. Adrenomedullin is a pain-related neuropeptide which has recently been demonstrated. It facilitates the transmission of nociceptive information and is involved in the development and maintenance of opioid tolerance. The involvement of amylin and calcitonin in pain is not clear yet.

Leptin, Neuropeptide Y and Islet Amyloid Polypeptide Levels in Obese Children / 대한소아소화기영양학회지

PURPOSE: The aim of this study was to compare serum leptin, neuropeptide Y (NPY), and islet amyloid polypeptide (amylin) levels in obese and normal weight children, and to investigate their correlations with anthropometric parameters and metabolic bio-marker levels. METHODS: Body mass index (BMI), waist and hip circumference, blood pressure (systolic/diastolic), lipid profile, fasting glucose, and serum insulin, leptin, NPY, and amylin levels were measured in 56 children (24 obese children and 32 non-obese controls). Homeostatic model assessment-insulin resistance (HOMA-IR) values were calculated and the relationships between anthropometric variables, metabolic biomarkers, and diet-regulating factors (leptin, NPY, and amylin levels) were examined. RESULTS: BMI, hip circumference, waist circumference, and systolic and diastolic pressure were significantly higher in the obese group than in the non-obese group (p<0.0001). Total cholesterol, triglyceride, low-density lipoprotein-cholesterol, glucose, and insulin levels were also significantly higher in the obese group (p<0.05). On the other hand, high-density lipoprotein-cholesterol levels were higher in the non-obese group , but this was not significant. Serum leptin, NPY, and amylin levels were significantly higher in the obese group (p<0.05). Furthermore, in the obese group, leptin levels were found to be significantly correlated with BMI (r=0.379, p=0.043), and NPY levels (r=0.377, p=0.044), and amylin levels were found to be significantly correlated with insulin levels (r=0.400, p=0.048), and HOMA-IR (r=0.459, p=0.028). CONCLUSION: Metabolic risk factor alterations are present in obese children, and these children show abnormalities in the diet regulatory system caused by leptin, NPY, and amylin resistance. Of particular note, amylin was found to be positively correlated with insulin resistance.

Functional coupling reactions of human amylin receptor and nicotinic acetylcholine receptors in rat brain neurons / 生理学报

Human amylin (hAmylin) is co-released with insulin from pancreatic B-cells and the actions of this peptide on its target tissues maintain the cell excitability and glucose homeostasis. Inappropriate control of hAmylin secretion may result in human disease, particularly Alzheimer's disease (AD). It's unknown that which kind of receptor is activated by human amylin, leading to the neurotoxicity in neurons of brain. Nicotinic acetylcholine receptors (nAChRs) are known to play a critical role in a variety of nervous diseases. In the present study, we sought to determine the inter-relationships between these two receptors by examining the actions of hAmylin and nicotine on whole-cell currents and membrane potential in basal forebrain neurons. Whole cell patch-clamp recordings were performed on enzymatically dissociated neurons of the diagonal band of Broca (DBB), a cholinergic basal forebrain nucleus. The results showed that either hAmylin or nicotine individually caused a dose-dependent (1 nmol/L-20 µmol/L) membrane depolarization and an increase in firing frequency of DBB neurons. Application of AC253, an amylin receptor antagonist, blocked the excitatory effects of not only hAmylin but also nicotine; dihydro-β-erythroidine (DHβE), a nAChR antagonist, also blocked the effects of nicotine and hAmylin. These electrophysiological results suggest that hAmylin receptor and nAChRs on DBB neurons are coupled and may function in a co-operative manner to influence the excitability of DBB neurons. This finding is important for us to understand the cause and mechanisms of AD.

Delayed Response of Amylin Levels after an Oral Glucose Challenge in Children with Prader-Willi Syndrome

PURPOSE: Amylin secretion is increased parallel to insulin in obese subjects. Despite their marked obesity, a state of relative hypoinsulinemia occurs in children with Prader-Willi syndrome (PWS). Based on the hypothesis that amylin levels may be relatively low in PWS children, contributing to their excessive appetite, we studied amylin levels after oral glucose loading in children with PWS and overweight controls. MATERIALS AND METHODS: Plasma levels of amylin, glucagon, insulin, and glucose were measured at 0, 30, 60, 90, and 120 min after a glucose challenge in children with PWS (n = 18) and overweight controls (n = 25); the relationships among the variables were investigated in these two groups. RESULTS: Amylin levels were significantly correlated with insulin during fasting and during the oral glucose tolerance test in both groups. Amylin levels between 0 and 60 min after glucose loading were statistically different between the two groups. They were lower in children with PWS than in the controls between 0 and 30 min after glucose loading. CONCLUSION: The relatively low levels of amylin, compared to those in overweight controls, during the early phase of glucose loading in patients with PWS, may contribute, in part, to the excessive appetite of PWS patients as compared to the overweight controls.

Novel Therapies for Type 2 Diabetes Mellitus / 대한소아내분비학회지

Type 2 diabetes mellitus (T2DM) is a progressive disorder caused by a combination of insulin resistance and betacell dysfunction. The role of new hormones and systems in maintaining blood glucose homeostasis has recently been recognized. This recognition has led to the development of several novel classes of medications, including the incretin mimetic agents (glucagon like polypeptide-1 analogs and dipeptidyl peptidase IV inhibitors), the amylin analog and the endocannabinoid-1 receptor blocker. This review looks at these new agents in terms of their mode of action, pharmacokinetics and use in clinical practice. The new agents offer treatment options in select adult patients now, however, the efficacy and the safety has to be evaluated thoroughly by long term studies before the application to pediatric patients.

New and emerging drugs in type 2 diabetes / 대한내과학회지

Recent advances in understanding insulin secretion, action and signaling have led to the development of new pharmacological agents. Several new emerging drugs and drug classes for the management of diabetes are under development, including the incretin mimetic agents (exenatide, dipeptidyl peptidase 4 inhibitors, and glucagon-like peptide 1 analogues), the amylin analogue pramlintide, the cannabinoid-1 receptor antagonist rimonabant, the mixed peroxisome proliferator-activated receptor agonists muraglitazar and the inhaled insulin preparation Exubera. New drugs and technologic advances being made available will help achieve the goals of treating patients with diabetes to all the appropriate metabolic targets. Longer term studies will help providers weigh the benefits, adverse effects, cost, and unknown long-term risks of these medications.

Immunocytochemical Expression of Amylin in Pancreatic Islets of Man, Rabbit and Guinea Pig / 대한해부학회지

A putative polypeptide hormone identified as amylin[islet amyloid polypeptide] is synthesized and co-localized with insulin in B cells of pancreatic islets in several animal species including man. However, there is growing evidence that somatostatin cells are also expressed and contained amylin in the pancreatic islets of the rat The aim of the present study was to investigate the immunocytochemical expression of the amylin within the endocrine pancreas of the man, rabbit and guinea pig, with special reference to the possible ability of islet cells other than insulin cells to synthesize amylin. For this purpose serial sections of the pancreatic islets were stainedimmunocytochemically using anti-amylin, anti-insulin, anti-glucagon, anti-somatostatin antisera. In serial sections of pancreatic islets of the man and rabbit, it was shown that amylin immunoreactivity occurred in insulin-reactive B cells predominantly located in interior of the islets. In contrast, amylin immunoreacivity appeared in glucagon-reactive A cells peripherally located in the islets of the guinea pig. These results suggest that in both the man and rabbit, amylin is synthesized by B cells for subsequent co-secretion with insulin, and that in guinea pig, amylin is synthesized by A cells for co-secretion with glucagon. It thus appears that amylin release may be mediated by different secretory mechanisms according to animal species.