To summarize the pharmacology of the calcitonin peptide family of receptors and explore their relationship to migraine and current migraine therapies.
Therapeutics that dampen calcitonin gene-related peptide (CGRP) signaling are now in clinical use to prevent or treat migraine. However, CGRP belongs to a broader peptide family, including the peptides amylin and adrenomedullin. Receptors for this family are complex, displaying overlapping pharmacologic profiles. Despite the focus on CGRP and the CGRP receptor in migraine research, recent evidence implicates related peptides and receptors in migraine.
This narrative review summarizes literature encompassing the current pharmacologic understanding of the calcitonin peptide family, and the evidence that links specific members of this family to migraine and migraine-like behaviors.
Recent work links amylin and adrenomedullin to migraine-like behavior in rodent models and migraine-like attacks in individuals with migraine. We collate novel information that suggests females may be more sensitive to amylin and CGRP in the context of migraine-like behaviors. We report that drugs designed to antagonize the canonical CGRP receptor also antagonize a second CGRP-responsive receptor and speculate as to whether this influences therapeutic efficacy. We also discuss the specificity of current drugs with regards to CGRP isoforms and how this may influence therapeutic profiles. Lastly, we emphasize that receptors related to, but distinct from, the canonical CGRP receptor may represent underappreciated and novel drug targets.
Multiple peptides within the calcitonin family have been linked to migraine. The current focus on CGRP and its canonical receptor may be obscuring pathways to further therapeutics. Drug discovery schemes that take a wider view of the receptor family may lead to the development of new anti-migraine drugs with favorable clinical profiles. We also propose that understanding these related peptides and receptors may improve our interpretation regarding the mechanism of action of current drugs.

Inside and outside the brain, accumulation of amyloid fibrils plays key roles in the pathogenesis of fatal age-related diseases such as Alzheimer\'s and Parkinson\'s diseases and wild-type transthyretin amyloidosis. Although the incidence of all amyloidoses increases with age, for some types of amyloidosis aging is known as the main direct risk factor, and these types are typically diseases of elderly people. More than 10 different precursor proteins are known to cause age-associated amyloidosis; these proteins include amyloid β protein, α-synuclein, transthyretin, islet amyloid polypeptide, atrial natriuretic factor, and the newly discovered epidermal growth factor-containing fibulin-like extracellular matrix protein 1. Except for intracerebral amyloidoses, most age-related amyloidoses have been little studied. Indeed, in view of the increasing life expectancy in our societies, understanding how aging is involved in the process of amyloid fibril accumulation and the effects of amyloid deposits on the aging body is extremely important. In this review, we summarize current knowledge about the nature of amyloid precursor proteins, the prevalence, clinical manifestations, and pathogenesis of amyloidosis, and recent advances in our understanding of age-related amyloidoses outside the brain.

A large proportion of persons with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) do not reach the glycosylated haemoglobin (HbA1c) target of < 7% (53 mmol/- mol), with an increasing proportion of them being overweight or obese. In both T1DM and T2DM, there is accelerated gastric emptying and postprandial hyperglucagonemia. Furthermore, insulin therapy itself is associated with risk of hypoglycemia and weight-gain both of which are barriers to achieving good control. Medications which can achieve significant HbA1c and weight reduction associated with an ability to delay gastric emptying and suppress the glucagon secretion with minimal/ no hypoglycemia are of particular interest as an adjuvant to insulin. A synthetic amylin analogue, pramlintide is a drug with above mentioned properties. Other medications with similar properties are glucagon-like peptide-1 receptor agonists (GLP-1 RAs). In this article, we will review the efficacy of pramlintide when given with insulin in improving HbA1c, weight, and cognition with- /without GLP-1 RAs as well as its cardiovascular (CV) safety.

The development of drugs possessing anti-diabetic activities is a long pursued goal in drug discovery. It has been shown that deregulated insulin mediated signaling, oxidative stress, obesity, and β-cell dysfunction are the main factors responsible for the disease. With the advent of new and more powerful screening assays and prediction tools, the idea of a drug that can effectively treat diabetes by targeting different pathways has re-bloomed. Current anti-diabetic therapy is based on synthetic drugs that very often have side effects. For this reason, there is an instantaneous need to develop or search new alternatives. Recently, more attention is being paid to the study of natural products. Their huge advantage is that they can be ingested in everyday diet. Here, we discuss various causes, putative targets, and treatment strategies, mechanistic aspects as well as structural features with a particular focus on naturally occurring flavonoids as promising starting points for anti-diabetic led development.

Human islet amyloid polypeptide (hIAPP) is a naturally occurring, intrinsically disordered protein whose abnormal aggregation into amyloid fibrils is a pathological feature in type 2 diabetes, and its cross-aggregation with amyloid beta has been linked to an increased risk of Alzheimer\'s disease. The soluble, oligomeric forms of hIAPP are the most toxic to β-cells in the pancreas. However, the structure of these oligomeric forms is difficult to characterise because of their intrinsic disorder and their tendency to rapidly aggregate into insoluble fibrils. Experimental studies of hIAPP have generally used non-physiological conditions to prevent aggregation, and they have been unable to describe its soluble monomeric and oligomeric structure at physiological conditions. Molecular dynamics (MD) simulations offer an alternative for the detailed characterisation of the monomeric structure of hIAPP and its aggregation in aqueous solution. This paper reviews the knowledge that has been gained by the use of MD simulations, and its relationship to experimental data for both hIAPP and rat IAPP. In particular, the influence of the choice of force field and water models, the choice of initial structure, and the configurational sampling method used, are discussed in detail. Characterisation of the solution structure of hIAPP and its mechanism of oligomerisation is important to understanding its cellular toxicity and its role in disease states, and may ultimately offer new opportunities for therapeutic interventions.

From kinetic data (k, T) we calculated the thermodynamic parameters for various processes (nucleation, elongation, fibrillization, etc.) of proteinaceous diseases that are related to the β-amyloid protein (Alzheimer\'s), to tau protein (Alzheimer\'s, Pick\'s), to α-synuclein (Parkinson\'s), prion, amylin (type II diabetes), and to α-crystallin (cataract). Our calculations led to ΔG≠ values that vary in the range 92.8-127 kJ mol-1 at 310 K. A value of ∼10-30 kJ mol-1 is the activation energy for the diffusion of reactants, depending on the reaction and the medium. The energy needed for the excitation of O2 from the ground to the first excited state (1Δg, singlet oxygen) is equal to 92 kJ mol-1 So, the ΔG≠ is equal to the energy needed for the excitation of ground state oxygen to the singlet oxygen (1Δg first excited) state. The similarity of the ΔG≠ values is an indication that a common mechanism in the above disorders may be taking place. We attribute this common mechanism to the (same) role of the oxidative stress and specifically of singlet oxygen, (1Δg), to the above-mentioned processes: excitation of ground state oxygen to the singlet oxygen, 1Δg, state (92 kJ mol-1), and reaction of the empty π* orbital with high electron density regions of biomolecules (∼10-30 kJ mol-1 for their diffusion). The ΔG≠ for cases of heat-induced cell killing (cancer) lie also in the above range at 310 K. The present paper is a review and meta-analysis of literature data referring to neurodegenerative and other disorders.

Amylin is primarily responsible for classifying type II diabetes as an amyloid (protein misfolding) disease as it has great potential to aggregate into toxic nanoparticles, thereby resulting in loss of pancreatic β-cells. Although type II diabetes is on the increase each year, possibly due to bad eating habits of modern society, research on the culprit for this disease is still in its early days. In addition, unlike the culprit for Alzheimer\'s disease, amyloid β-peptide, amylin has failed to receive attention worthy of being featured in an abundance of review articles. Thus, the aim of this paper is to shine the spotlight on amylin in an attempt to put it onto the top of researchers\' to-do list since the secondary complications of type II diabetes have far-reaching and severe consequences on public health both in developing and fully developed countries alike. This paper will cover characteristics of the amylin aggregates, mechanisms of toxicity, and a particular focus on inhibitors of toxicity and techniques used to assess these inhibitors.

BACKGROUND: Postprandial glucose excursions negatively affect glycemic control and markers of cardiovascular health. Pramlintide, an amylinomimetic, is approved for treatment of elevated postprandial glucose levels in type 1 and type 2 diabetes mellitus.
METHODS: A literature search of PubMed was conducted to locate articles (up to January 2011) pertaining to original preclinical and clinical research and reviews of amylin and pramlintide. Additional sources were selected from reference lists within articles obtained through the original literature search and from the internet. This article describes the known effects of endogenous amylin and the pharmacodynamics, pharmacokinetics and clinical efficacy of pramlintide. Drug-drug interactions and safety and tolerability are also reviewed.
CONCLUSIONS: Pramlintide significantly reduces hemoglobin A(1c) and body weight in patients with type 1 and type 2 diabetes mellitus. Newer research is focusing on weight loss effects of pramlintide and pramlintide plus metreleptin in nondiabetic obese individuals. Preliminary results of these studies are discussed.

OBJECTIVE: the objective of this systematic review and meta-analysis was to assess the effect of pramlintide on glycemic control, weight and incidence of nausea and hypoglycaemia in patients with type 2 diabetes mellitus (T2DM) and in obese patients without diabetes (OBP).
METHODS: eight randomized, clinical trials were identified from multiple databases. Qualitative assessments and quantitative analyses were performed.
RESULTS: in four T2DM studies (N = 930,duration of studies 16-52 weeks,120-150 mcg/dose BID-TID), all patients received insulin therapy. In four obesity studies (N = 686,duration of studies 6-24 weeks,120-360 mcg/dose BID-TID), equivalent volumes of placebo were administered before major meals. Pramlintide significantly reduced haemoglobin A1c (HbA1c) (-0.33% [95% CI -0.51, -0.14], p = 0.004) and weight (-2.57 kg, [95% CI -3.44, -1.70], p < 0.00001) versus the control group. More patients in the control group reported hypoglycaemia of any severity versus the pramlintide group (risk ratio 0.84 [95% CI 0.69, 10.3], p = 0.09). In OBP, pramlintide caused a reduction in weight (-2.27 kg [95% CI -2.88, -1.66], p < 0.00001). When event data from both populations were combined, patients randomized to pramlintide were 1.8 times more likely to report nausea of any severity versus control (p = 0.0005).
CONCLUSIONS: pramlintide was associated with a small reduction in HbA1c, and a modest reduction in weight in patients with T2DM or OBP. There was increased incidence of nausea but not hypoglycaemia at any time during therapy. Studies about the long-term effect of pramlintide on diabetes- and cardiovascular-related complications and cost-effectiveness analyses are needed.

The incidence of diabetes mellitus has increased dramatically in the United States over the last 40 years. In 2006, reported cases of diabetes mellitus increased by 6.0%. The vast majority of these increased cases involve Type 2 diabetes, which is becoming much more common in children, adolescents, and young adults. This article reviews the pharmacological treatments available for Type 1 diabetes, the monitoring necessary for diabetes patients, the regimens of intensive insulin therapy that have replaced conventional therapy, and the complications of insulin therapy. Alternate methods of insulin delivery and options for patients are discussed.