Islet amyloid polypeptide (IAPP, or amylin) is one of the major secretory products of β-cells of the pancreatic islets of Langerhans. It is a regulatory peptide with putative function both locally in the islets, where it inhibits insulin and glucagon secretion, and at distant targets. It has binding sites in the brain, possibly contributing also to satiety regulation and inhibits gastric emptying. Effects on several other organs have also been described. IAPP was discovered through its ability to aggregate into pancreatic islet amyloid deposits, which are seen particularly in association with type 2 diabetes in humans and with diabetes in a few other mammalian species, especially monkeys and cats. Aggregated IAPP has cytotoxic properties and is believed to be of critical importance for the loss of β-cells in type 2 diabetes and also in pancreatic islets transplanted into individuals with type 1 diabetes. This review deals both with physiological aspects of IAPP and with the pathophysiological role of aggregated forms of IAPP, including mechanisms whereby human IAPP forms toxic aggregates and amyloid fibrils.

Islet Amyloid Polypeptide, Islet Amyloid, and Diabetes Mellitus

The pancreatic islet displays diverse patterns of endocrine cell arrangement. The prototypic islet, with insulin-secreting β-cells forming the core surrounded by other endocrine cells in the periphery, is largely based on studies of normal rodent islets. Recent reports on large animals, including humans, show a difference in islet architecture, in which the endocrine cells are randomly distributed throughout the islet. This particular species difference has raised concerns regarding the interpretation of data based on rodent studies to humans. On the other hand, further variations have been reported in marsupials and some nonhuman primates, which possess an inverted ratio of β-cells to other endocrine cells. This review discusses the striking plasticity of islet architecture and cellular composition among various species including changes in response to metabolic states within a single species. We propose that this plasticity reflects evolutionary acquired adaptation induced by altered physiological conditions, rather than inherent disparities between species.

Pancreatic islet plasticity: Interspecies comparison of islet architecture and composition

Onset of Type 2 diabetes occurs when the pancreatic beta-cell fails to adapt to the increased insulin demand caused by insulin resistance. Morphological and therapeutic intervention studies have uncovered an inflammatory process in islets of patients with Type 2 diabetes characterized by the presence of cytokines, immune cells, beta-cell apoptosis, amyloid deposits, and fibrosis. This insulitis is due to a pathological activation of the innate immune system by metabolic stress and governed by IL-1 signaling. We propose that this insulitis contributes to the decrease in beta-cell mass and the impaired insulin secretion observed in patients with Type 2 diabetes.

https://www.zora.uzh.ch/id/eprint/26504/1/Islet_Inflammation_impairs_in_the_pancreatic.pdf

Islet Inflammation Impairs the Pancreatic β-Cell in Type 2 Diabetes

Amyloid deposition and reduced β-cell mass are pathological hallmarks of the pancreatic islet in type 2 diabetes; however, whether the extent of amyloid deposition is associated with decreased β-cell mass is debated. We investigated the possible relationship and, for the first time, determined whether increased islet amyloid and/or decreased β-cell area quantified on histological sections is correlated with increased β-cell apoptosis. Formalin-fixed, paraffin-embedded human pancreas sections from subjects with (n = 29) and without (n = 39) diabetes were obtained at autopsy (64 ± 2 and 70 ± 4 islets/subject, respectively). Amyloid and β cells were visualized by thioflavin S and insulin immunolabeling. Apoptotic β cells were detected by colabeling for insulin and by TUNEL. Diabetes was associated with increased amyloid deposition, decreased β-cell area, and increased β-cell apoptosis, as expected. There was a strong inverse correlation between β-cell area and amyloid deposition (r = -0.42, P < 0.001). β-Cell area was selectively reduced in individual amyloid-containing islets from diabetic subjects, compared with control subjects, but amyloid-free islets had β-cell area equivalent to islets from control subjects. Increased amyloid deposition was associated with β-cell apoptosis (r = 0.56, P < 0.01). Thus, islet amyloid is associated with decreased β-cell area and increased β-cell apoptosis, suggesting that islet amyloid deposition contributes to the decreased β-cell mass that characterizes type 2 diabetes.

β-Cell Loss and β-Cell Apoptosis in Human Type 2 Diabetes Are Related to Islet Amyloid Deposition

https://escholarship.org/content/qt2sm515rz/qt2sm515rz.pdf?t=o0h70o

Type 2 diabetes as a protein misfolding disease

beta-Cell dysfunction is an important factor in the development of hyperglycemia of type-2 diabetes mellitus, and pancreatic islet amyloidosis (IA) has been postulated to be one of the main contributors to impaired insulin secretion. The aim of this study was to evaluate the correlation of IA with metabolic parameters and its effect on islets of Langerhans remodeling and relative endocrine-cell volume in baboons. We sequenced the amylin peptide, determined the fibrillogenic propensities, and evaluated pancreatic histology, clinical and biochemical characteristics, and endocrine cell proliferation and apoptosis in 150 baboons with different metabolic status. Amylin sequence in the baboon was 92% similar to humans and showed superimposable fibrillogenic propensities. IA severity correlated with fasting plasma glucose (FPG) (r = 0.662, P < 0.001) and HbA1c (r = 0.726, P < 0.001), as well as with free fatty acid, glucagon values, decreased homeostasis model assessment (HOMA) insulin resistance, and HOMA-B. IA severity was associated with a decreased relative beta-cell volume, and increased relative alpha-cell volume and hyperglucagonemia. These results strongly support the concept that IA and beta-cell apoptosis in concert with alpha-cell proliferation and hypertrophy are key determinants of islets of Langerhans "dysfunctional remodeling" and hyperglycemia in the baboon, a nonhuman primate model of type-2 diabetes mellitus. The most important determinants of IA were age and FPG (R(2) = 0.519, P < 0.0001), and different FPG levels were sensitive and specific to predict IA severity. Finally, a predictive model for islet amyloid severity was generated with age and FPG as required variables.

https://www.pnas.org/content/pnas/106/33/13992.full.pdf

Pancreatic islet amyloidosis, β-cell apoptosis, and α-cell proliferation are determinants of islet remodeling in type-2 diabetic baboons

Introduction. This study evaluated the association between obesity and the K109R, Q223R, and K656N polymorphisms of the leptin receptor (LEPR) locus. Such polymorphisms cause changes in the extracellular extreme of the LEPR gene product and appear to be related to signal transduction toward the cell. Subjects and methods. A total of 128 participants between 6 and 17 years of age from a Mexican Mestizo population were included in the study. Individuals were classified as overweight–obese (n = 76) and normal (n = 52), based on anthropomorphic measurements. The K109R, Q223R, and K656N polymorphisms of the LEPR were determined by the size of restriction fragments obtained from polymorphic fragment amplification (polymerase chain reaction-restriction fragment length polymorphism) obtained from genomic DNA. Allele frequency was compared using the chi-square test. Odds ratio was calculated to determine allele obesity risk factor. Results. Variant allele frequency was 109R = 0.35, 223R = 0.49, and 656N = 0.11 for...

Leptin Receptor Gene K656N Polymorphism Is Associated with Low Body Fat Levels and Elevated High-Density Cholesterol Levels in Mexican Children and Adolescents

Objetivo: Identificar si existen diferencias significativas en los grados de desalineamiento del eje mecanico de rodillas comparando dos metodos de medicion, uno tradicional y un metodo alterno. Material y metodos: Se tomaron 100 ejes mecanicos de rodillas en pacientes de ambos sexos, los cuales fueron sometidos a la evaluacion tradicional para medir los grados de desviacion de los mismos y posteriormente fueron sometidos a la evaluacion con el metodo de correccion que proponemos para medir dichos grados de desviacion y se compararon los resultados obtenidos. Se estandarizo el metodo para control de la variable de medicion colocando a los pacientes para la toma de los ejes en un mismo punto durante la toma radiografica. Para evaluar el grado de desviacion en el alineamiento de los miembros pelvicos, utilizamos una regla de madera con marcas metalicas a cada centimetro y numerada cada 10 cm, que fue usada como referencia para la correccion del eje mecanico de acuerdo con las caracteristicas de cada paciente. Resultados: De 100 ejes mecanicos evaluados por el metodo tradicional y por el metodo alterno, respectivamente, los resultados obtenidos fueron los siguientes: la deformidad de varo para el miembro pelvico derecho fue de 21° + 16° vs. 7 + 6°; para el miembro pelvico izquierdo fue de 22 + 17° vs. 8 + 5°; la deformidad en valgo para el miembro pelvico derecho fue de 21 + 15° vs. 8 + 6; y finalmente, para el miembro pelvico izquierdo fue de 16 + 11 vs. 6 + 5°. Conclusiones: Nuestros resultados sugieren que el metodo propuesto permite obtener una mejor medicion del eje mecanico y la correccion tiene un comportamiento exponencial, es decir, mientras mayor sea el angulo de medicion con el metodo tradicional mayor es la correccion con nuestra propuesta. Palabras clave: Eje mecanico, rodillas, miembros pelvicos, Genu varo, Genu valgo.

/pdf/metodo-alterno-para-medicion-del-eje-mecanico-de-rodillas-2fs6pl25ho.pdf

Método alterno para medición del eje mecánico de rodillas

/pdf/resistencia-a-la-insulina-y-efecto-sobre-la-excitabilidad-y-4ebs256mck.pdf

Resistencia a la insulina y efecto sobre la excitabilidad y contracción del músculo esquelético en rata Insulin resistance and its effect on excitability and contraction of the skeletal muscle in rats

Carlos Enrique Tene-Pérez

Papers

Pancreatic islet amyloidosis, β-cell apoptosis, and α-cell proliferation are determinants of islet remodeling in type-2 diabetic baboons

Leptin Receptor Gene K656N Polymorphism Is Associated with Low Body Fat Levels and Elevated High-Density Cholesterol Levels in Mexican Children and Adolescents

Método alterno para medición del eje mecánico de rodillas

Resistencia a la insulina y efecto sobre la excitabilidad y contracción del músculo esquelético en rata Insulin resistance and its effect on excitability and contraction of the skeletal muscle in rats