Beta Cells

Diabetes mellitus is a disease characterized by a range of metabolic complications involving an individual's blood glucose levels, and its main regulator, insulin. These complications can vary largely from person to person depending on their current biophysical state. Biomedical research day-by-day makes strides to impact the lives of patients of a variety of diseases, including diabetes. One large stride that is being made is the generation of techniques to assist physicians to ``personalize medicine''. From available physiological data, biological understanding of the system, and dimensional analysis, a differential equation-based mathematical model was built in a sequential matter, to be able to elucidate clearly how each parameter correlates to the patient's current physiological state. We developed a simple mathematical model that accurately simulates the dynamics between glucose, insulin, and pancreatic $\beta$-cells throughout disease progression with constraints to maintain biological relevance. The current framework is clearly capable of tracking the patient's current progress through the disease, dependent on factors such as latent insulin resistance or an attrite $\beta$-cell population. Further interests would be to develop tools that allow the direct and feasible testing of how effective a given plan of treatment would be at returning the patient to a desirable biophysical state.

Background and aim
The islets of Langerhans is an important endocrine gland which regulate the blood glucose level. The micro anatomic studies in human fetal pancreatic islets were significant since there were controversies regarding their origin and time of appearance. The role of maternal insulin in the development of fetal pancreatic islet cells  and their significance in the fetal period is clinically important. Pregnant mothers with diabetes seems to protect their children from diabetes by the early stimulation of beta cells. So the incidence of diabetes in children of diabetic mothers  were less when compared to diabetic fathers.
Materials and Methods
Thirty five autopsy specimens were collected from the department of pathology medical college, Trivandrum, Kerala. The gestational age of the fetuses range from 10-40 weeks. The histological examination of the specimens were done is the department of anatomy, Govt. Medical College, Trivandrum.
Result
According to the present study both acini and islets were developed  from the endodermal secretary tubules. Acini and islets were appeared by 12 weeks, and beta cells appeared by 14 weeks. At 28 weeks alpha cells appeared and the cytoplasm of beta cells contained granules. At 32 weeks well defined islets and the granules appeared in the  cytoplasm of alpha cells.
Conclusions
The fetal pancreatic islets and acini had a common endoderimal origin- the secretary tubules. The islets and acini appeared by 12 weeks, the beta cells by 14 weeks. A diabetic mother  can protect their children from diabetes to some extend than a diabetic father.

Key words:
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Aims/hypothesis Chronic exposure of pancreatic beta cells to high glucose and fatty acids has been proposed to induce glucolipotoxicity. However, contradictory results suggest adaptations of the beta cells, which might be instrumental for partial preservation of the secretory response. In this context, we delineated the expression pattern of genes related to lipid pathways along with fat storage/mobilisation during glucose-stimulated insulin secretion. Methods Insulin-secreting cells were cultured for 3 days at different glucose concentrations (5.5, 11.1, 25 mmol/l) without or with BSA-complexed 0.4 mmol/l palmitate and oleate. Then, transcriptomic analyses of lipid pathways were performed in human islets by RNA-Seq and in INS-1E cells and rat islets by quantitative RT-PCR. Storage of fat was assessed in INS-1E cells by electron microscopy and Bodipy staining, which was also used for measuring lipid mobilisation rate. The secretory response was monitored during acute 15 mmol/l glucose stimulation using online luminescence assay for INS-1E cells and by radioimmunoassay for rat islets. Results In human islets, chronic exposure to palmitate and oleate modified expression of a panel of genes involved in lipid handling. Culture at 25 mmol/l glucose upregulated genes encoding for enzymes of the glycerolipid/NEFA cycle and downregulated receptors implicated in fatty acid signalling. Similar results were obtained in INS-1E cells, indicating enhanced capacity of the glycerolipid/NEFA cycle under glucotoxic conditions. Exposure to unsaturated C18:1 fatty acid favoured intracellular lipid accumulation in a glucose-dependent way, an effect also observed with saturated C16:0 fatty acid when combined with the panlipase inhibitor Orlistat. After the glucolipotoxic culture, intracellular fat mobilisation was required for acute glucosestimulated secretion, particularly in oleate-treated cells under glucotoxic culture conditions. The lipid mobilisation rate was governed chiefly by the levels of stored fat as a direct consequence of the culture conditions rather than energetic demands, except in palmitate-loaded cells. Conclusions/interpretation Glucolipotoxic conditions promote the capacity of the glycerolipid/NEFA cycle thereby preserving part of the secretory response. The cycle of fat storage/mobilisation emerges as a mechanism helping the beta cell to cope with glucotoxic conditions.

The enzyme phosphatidylinositol 3-kinase (PI3-kinase) exerts an important role in the transduction of the anorexigenic and thermogenic signals delivered by insulin and leptin to first-order neurons of the arcuate nucleus in the hypothalamus. The termination of the intracellular signals generated by the activation of PI3-kinase depends on the coordinated activity of specific inositol phosphatases. Here we show that phosphoinositide-specific inositol polyphosphate 5-phosphatase IV (5ptase IV) is highly expressed in neurons of the arcuate and lateral nuclei of the hypothalamus. Upon intracerebroventricular (ICV) treatment with insulin, 5ptase IV undergoes a time-dependent tyrosine phosphorylation, which follows the same patterns of canonical insulin signaling through the insulin receptor, insulin receptor substrate-2, and PI3-kinase. To evaluate the participation of 5ptase IV in insulin action in hypothalamus, we used a phosphorthioate-modified antisense oligonucleotide specific for th...

Generation of mature pancreatic β-cells from embryonic stem (ES) cells in vitro could provide a therapy for insulin-dependent diabetes mellitus. Recent ES cell differentiation protocols have improved the differentiation efficiency toward β-cells by recapitulating in vivo pancreatic development. Toward this end, there is a large number of developmental and β-cell functional studies that could guide the design of more efficient differentiation protocols, predominantly during the late stages. In this review, I have classified these studies according to the intracellular signaling pathways they relate to—phosphatidylinositol 3-kinase, Hedgehog, Calcineurin/NFAT, Epac, and bone morphogenetic protein.

Nos travaux proposent un lien fonctionnel entre les horloges moleculaires du pancreas endocrine, sa fonction en condition physiologique et la pathogenese du diabete type 2 (DT2) chez l’etre humain. Nos experiences demontrent que la perturbation des horloges dans les cellules α- et β- des ilots humains altere l’accumulation et l’exocytose des granules d’insuline et de glucagon. Nous avons egalement observe que les ilots de donneurs atteints de DT2 possedent des horloges dont l’amplitude circadienne est diminuee et dont la capacite de synchronisation in vitro est affaiblie. De maniere interessante, le modulateur d’horloges, Nobiletine, stimule l’amplitude des oscillations circadiennes ainsi que la secretion de l’insuline de ces ilots pathologiques. Enfin, nous rapportons que le mecanisme de regeneration des cellules β chez les souris diabetiques est sous l’influence des horloges moleculaires via le role essentiel du composant cle BMAL1 dans ce mecanisme.

Chronic exposure to elevated levels of glucose and free fatty acids impairs beta-cell function, leading to insulin secretion defects and eventually beta-cell failure. Using a semi-high throughput approach applied to INS-1E beta-cells, we tested multiple conditions of chronic exposure to basal, intermediate and high glucose, combined with saturated versus mono-and polyunsaturated fatty acids in order to assess cell integrity, lipid metabolism, mi-tochondrial function, glucose-stimulated calcium rise and secretory kinetics. INS-1E beta-cells were cultured for 3 days at different glucose concentrations (5.5, 11.1, 25 mM) without or with BSA-complexed 0.4 mM saturated (C16:0 palmitate), monounsaturated (C18:1 oleate) or polyunsaturated (C18:2 linoleate, C18:3 linolenate) fatty acids, resulting in 0.1-0.5 μM unbound fatty acids. Accumulation of triglycerides in cells exposed to fatty acids was glucose-dependent, oleate inducing the strongest lipid storage and protecting against glucose-induced cy-totoxicity. The combined chronic exposure to both high glucose and either palmitate or oleate altered mi-tochondrial function as well as glucose-induced calcium rise. This pattern did not directly translate at the se-cretory level since palmitate and oleate exhibited distinct effects on the first and the second phases of glucose-stimulated exocytosis. Both fatty acids changed the activity of kinases, such as the MODY-associated BLK. Additionally, chronic exposure to fatty acids modified membrane physicochemical properties by increasing membrane fluidity, oleate exhibiting larger effects compared to palmitate. Chronic fatty acids differentially and specifically exacerbated some of the glucotoxic effects, without promoting cytotoxicity on their own. Each of the tested fatty acids functionally modified INS-1E beta-cell, oleate inducing the strongest effects.

Conclusion: Diabetic human islet-engrafted immunodeficient mice treated with lixisenatide show improved restoration of normoglycemia, human plasma insulin, and glucose tolerance compared to vehicle-treated mice engrafted with the same donor islets.

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We examined the transcriptional expression and functional effects of receptors for the extracellular pyrimidines uridine triphosphate (UTP) and uridine diphosphate (UDP), on insulin and glucagon secretion in isolated mouse pancreatic islets and purified b-cells. Using real-time PCR, the UDP receptor P2Y 6 was found to be highly expressed in both whole islets and b-cells purified by repeated counter-flow elutriation, whereas no mRNA expression for UTP receptors P2Y 4 and P2Y 2 could be detected. Functional in vitro experiments revealed that the P2Y 6 agonist UDPbS dose-dependently enhanced insulin and glucagon release during short-term incubation (1 h), while P2Y 6 activation during a longer period (24 h), selectively increased insulin release, especially at high glucose levels. The corresponding EC 50 value for UDPbS ranged from 3.2 Â 10 À8 M to 1.6 Â 10 À8 M for both glucose concentrations. The P2Y 6 antagonist MRS2578 inhibited the effects of UDPbS, supporting a P2Y 6 specific effect. In addition to negative RT-PCR results, the lack of response to UTPcS a selective P2Y 2/4 agonist further rule out the involvement of P2Y 2/4 receptors in the islet hormone release. Our results suggest a modulatory role for UDP via a functional active P2Y 6 receptor in the regulation of islet hormone release.