Amylin

The Link between Type 2 Diabetes and Neurodegeneration: Roles for Amyloid-beta, Amylin, and Tau Proteins.[Pubmed:28269785]

J Alzheimers Dis. 2017;59(2):421-432.

A wealth of evidence indicates a strong link between type 2 diabetes (T2D) and neurodegenerative diseases such as Alzheimer's disease (AD). Although the precise mechanism remains unclear, T2D can exacerbate neurodegenerative processes. Brain atrophy, reduced cerebral glucose metabolism, and central nervous system insulin resistance are features of both AD and T2D. The T2D phenotype (glucose dyshomeostasis, insulin resistance, impaired insulin signaling) also promotes AD pathology, namely accumulation of amyloid-beta (Abeta) and hyperphosphorylated tau and can induce other aspects of neuronal degeneration including inflammatory and oxidative processes. Abeta and hyperphosphorylated tau may also have roles in pancreatic beta-cell dysfunction and in reducing insulin sensitivity and glucose uptake by peripheral tissues such as liver, skeletal muscle, and adipose tissue. This suggests a role for these AD-related proteins in promoting T2D. The accumulation of the islet amyloid polypeptide (IAPP, or Amylin) within islet beta-cells is a major pathological feature of the pancreas in patients with chronic T2D. Co-secreted with insulin, Amylin accumulates over time and contributes to beta-cell toxicity, ultimately leading to reduced insulin secretion and onset of overt (insulin dependent) diabetes. Recent evidence also suggests that this protein accumulates in the brain of AD patients and may interact with Abeta to exacerbate the neurodegenerative process. In this review, we highlight evidence indicating T2D in promoting Abeta and tau mediated neurodegeneration and the potential contributions of Abeta and tau in promoting a diabetic phenotype that could further exacerbate neurodegeneration. We also discuss underlying mechanisms by which Amylin can contribute to the neurodegenerative processes.

Amylin receptor ligands reduce the pathological cascade of Alzheimer's disease.[Pubmed:28363773]

Neuropharmacology. 2017 Jun;119:170-181.

Amylin is an important gut-brain axis hormone. Since Amylin and amyloid-beta peptide (Abeta) share similar beta sheet secondary structure despite not having the same primary sequences, we hypothesized that the accumulation of Abeta in the brains of subjects with Alzheimer's disease (AD) might compete with Amylin for binding to the Amylin receptor (AmR). If true, adding exogenous Amylin type peptides would compete with Abeta and reduce the AD pathological cascade, improving cognition. Here we report that a 10-week course of peripheral treatment with human Amylin significantly reduced multiple different markers associated with AD pathology, including reducing levels of phospho-tau, insoluble tau, two inflammatory markers (Iba1 and CD68), as well as cerebral Abeta. Amylin treatment also led to improvements in learning and memory in two AD mouse models. Mechanistic studies showed that an Amylin receptor antagonist successfully antagonized some protective effects of Amylin in vivo, suggesting that the protective effects of Amylin require interaction with its cognate receptor. Comparison of signaling cascades emanating from AmR suggest that Amylin electively suppresses activation of the CDK5 pathway by Abeta. Treatment with Amylin significantly reduced CDK5 signaling in a receptor dependent manner, dramatically decreasing the levels of p25, the active form of CDK5 with a corresponding reduction in tau phosphorylation. This is the first report documenting the ability of Amylin treatment to reduce tauopathy and inflammation in animal models of AD. The data suggest that the clinical analog of Amylin, pramlintide, might exhibit utility as a therapeutic agent for AD and other neurodegenerative diseases.

Optimization of tolerability and efficacy of the novel dual amylin and calcitonin receptor agonist KBP-089 through dose escalation and combination with a GLP-1 analog.[Pubmed:28292761]

Am J Physiol Endocrinol Metab. 2017 Nov 1;313(5):E598-E607.

Amylin and GLP-1 agonism induce a well-known anorexic effect at dose initiation, which is managed by dose escalation. In this study we investigated how to optimize tolerability while maintaining efficacy of a novel, highly potent dual Amylin and calcitonin receptor agonist (DACRA), KBP-089. Furthermore, we tested the GLP-1 add-on potential of KBP-089 in high-fat diet (HFD)-fed rats. KBP-089 potently activated both the Amylin and calcitonin receptors in vitro and demonstrated a prolonged receptor activation as well as a potent reduction of acute food intake. HFD rats dosed every day or every second day obtained equal weight loss at study end, albeit with an uneven reduction in both food intake and body weight in rats dosed every second day. In a 4-fold dose escalation, KBP-089 induced a transient reduction in food intake at every escalation step, with reducing magnitude over time, and the following treatment with 2.5, 10, and 40 microg/kg resulted in an ~15% vehicle-corrected weight loss, a corresponding reduction in adipose tissue (AT), and, in all treatment groups, improved oral glucose tolerance (P < 0.01). Twofold and linear escalations suppressed body weight evenly with no significant reduction in food intake at either escalation step. KBP-089 (1.25 microg/kg) and liraglutide (50 microg/kg) reduced 24-h food intake by 29% and 37% compared with vehicle, respectively; however, when they were combined, 24-h food intake was reduced by 87%. Chronically, KBP-089 (1.25 microg/kg) and liraglutide (50 microg/kg) lowered body weight 8% and 2% in HFD rats, respectively, whereas the combination resulted in a 12% body weight reduction. Moreover, the combination improved glucose tolerance (P < 0.05). In conclusion, DACRAs act complementarily with GLP-1 on food intake and body weight. Furthermore, on escalation, KBP-089 was well tolerated and induced and sustained a significant weight loss and a reduction in AT in lean and HFD rats, underscoring the potential of KBP-089 as an anti-obesity agent.

Amylin Acts in the Lateral Dorsal Tegmental Nucleus to Regulate Energy Balance Through Gamma-Aminobutyric Acid Signaling.[Pubmed:28237459]

Biol Psychiatry. 2017 Dec 1;82(11):828-838.

BACKGROUND: The pancreatic- and brain-derived hormone Amylin promotes negative energy balance and is receiving increasing attention as a promising obesity therapeutic. However, the neurobiological substrates mediating Amylin's effects are not fully characterized. We postulated that Amylin acts in the lateral dorsal tegmental nucleus (LDTg), an understudied neural processing hub for reward and homeostatic feeding signals. METHODS: We used immunohistochemical and quantitative polymerase chain reaction analyses to examine expression of the Amylin receptor complex in rat LDTg tissue. Behavioral experiments were performed to examine the mechanisms underlying the hypophagic effects of Amylin receptor activation in the LDTg. RESULTS: Immunohistochemical and quantitative polymerase chain reaction analyses show expression of the Amylin receptor complex in the LDTg. Activation of LDTg Amylin receptors by the agonist salmon calcitonin dose-dependently reduces body weight, food intake, and motivated feeding behaviors. Acute pharmacological studies and longer-term adeno-associated viral knockdown experiments indicate that LDTg Amylin receptor signaling is physiologically and potentially preclinically relevant for energy balance control. Finally, immunohistochemical data indicate that LDTg Amylin receptors are expressed on gamma-aminobutyric acidergic neurons, and behavioral results suggest that local gamma-aminobutyric acid receptor signaling mediates the hypophagia after LDTg Amylin receptor activation. CONCLUSIONS: These findings identify the LDTg as a novel nucleus with therapeutic potential in mediating Amylin's effects on energy balance through gamma-aminobutyric acid receptor signaling.

Pramlintide, the synthetic analogue of amylin: physiology, pathophysiology, and effects on glycemic control, body weight, and selected biomarkers of vascular risk.[Pubmed:18561511]

Vasc Health Risk Manag. 2008;4(2):355-62.

Pramlintide is a synthetic version of the naturally occurring pancreatic peptide called Amylin. Amylin and pramlintide have similar effects on lowering postprandial glucose, lowering postprandial glucagon and delaying gastric emptying. Pramlintide use in type 1 and insulin requiring type 2 diabetes mellitus (DM) is associated with modest reductions in HbAlc often accompanied by weight loss. Limited data show a neutral effect on blood pressure. Small studies suggest small reductions in LDL-cholesterol in type 2 DM and modest reductions in triglycerides in type 1 DM. Markers of oxidation are also reduced in conjunction with reductions in postprandial glucose. Nausea is the most common side effect. These data indicate that pramlintide has a role in glycemic control of both type 1 and type 2 DM. Pramlintide use is associated with favorable effects on weight, lipids and other biomarkers for atherosclerotic disease.

Amylin agonists: a novel approach in the treatment of diabetes.[Pubmed:15561917]

Diabetes. 2004 Dec;53 Suppl 3:S233-8.

Amylin is a peptide hormone that is cosecreted with insulin from the pancreatic beta-cell and is thus deficient in diabetic people. It inhibits glucagon secretion, delays gastric emptying, and acts as a satiety agent. Amylin replacement could therefore possibly improve glycemic control in some people with diabetes. However, human Amylin exhibits physicochemical properties predisposing the peptide hormone to aggregate and form amyloid fibers, which may play a part in beta-cell destruction in type 2 diabetes. This obviously makes it unsuitable for pharmacological use. A stable analog, pramlintide, which has actions and pharmacokinetic and pharmacodynamic properties similar to the native peptide, has been developed. The efficacy and safety of pramlintide administration has been tested in a vast number of clinical trials. Approximately 5,000 insulin-treated patients have received pramlintide and approximately 250 for > or =2 years. The aims of this review are to 1) briefly describe actions of Amylin as demonstrated in animal and human models and 2) primarily review results from clinical trials with the Amylin analog pramlintide.

Amylin/islet amyloid polypeptide: biochemistry, physiology, patho-physiology.[Pubmed:7781840]

Diabete Metab. 1995 Feb;21(1):3-25.

Amylin is a 37 amino-acid peptide mainly produced by the islet beta-cell. Aggregation of Amylin is partly responsible for amyloid formation. Amyloid deposits occur both extracellularly and intracellularly and may contribute to beta-cell degeneration. Amylin is packed in beta-cell granules and cosecreted with insulin in response to the same stimuli but, unlike other beta-cell products, it is produced from specific a gene on chromosome 12. Basal, plasma Amylin concentrations are around 5 pM, and increase fourfold after meals or glucose. Higher levels are found in cases of insulin resistance, obesity, gestational diabetes and in some patients with NIDDM. Low or absent levels are found in insulin-dependent diabetic patients. There are similarities between Amylin and non beta-cell peptides such as calcitonin gene related peptides (CGRP). They may bind to the same receptor, determine similar post-receptor phenomena and qualitatively similar actions but with different degree of potency. The actions of Amylin are multiple and mostly exerted in the regulation of fuel metabolism. In muscle, Amylin opposes glycogen synthesis, activates glycogenolysis and glycolysis (increasing lactate production). Consequently, Amylin increases lactate output by muscle and increases the plasma lactate concentration. In fasting conditions, this lactate may serve as a gluconeogenic substrate for the liver, contributing to replenish depleted glycogen stores and to increase glucose production. In non-fasting conditions, lactate can be transformed by liver in triglycerides. It is not clear at present whether Amylin actions on the liver are direct or mediated by changes in circulating metabolites. A probably indirect effect of Amylin in muscle is to decrease insulin- (or glucose)-induced glucose uptake, which may contribute to insulin resistance. Other actions include inhibition of glucose-stimulated insulin secretion and, in general, actions mimicking CGRP effects. Some of these actions are seen at supraphysiological concentrations. The physiopathological consequences of Amylin deficiency, or excess are under active by investigated.

Amylin, amide, human, a 37-amino acid polypeptide, is a pancreatic hormone cosecreted with insulin that exerts unique roles in metabolism and glucose homeostasis. Amylin, amide, human inhibits glucagon secretion, delays gastric emptying, and acts as a satiety agent.

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