Insufficient Insulin Production Research Articles

Potential efficacy of Lactobacillus casei IBRC_M10711 on expression and activity of insulin degrading enzyme but not insulin degradation.

Type 2 diabetes (T2D) is a condition with insufficient insulin production or in the setting of insulin resistance with many origins including intestinal microbiota-related molecular mechanism. Insulin-degrading enzyme (IDE) is responsible for insulin breakdown in various tissues and is known as a potential drug target for T2D. Here, we assessed the effects of cell-free supernatant (CFS) and UV-killed Lactobacillus casei IBRC_M10711 on IDE expression, IDE activity, and insulin degradation in Caco-2 cell line. It was found that CFS and UV-killed L. casei IBRC_M10711 led to lower expression of IDE. UV-killed L. casei IBRC_M10711 significantly inhibited IDE activity but CFS did not. Insulin degradation was affected with none of them. In conclusion, L. casei IBRC_M10711 is effective on IDE expression and its activity, but not on insulin degradation. Future studies are recommended to explore the effect of this probiotic on other substrates of IDE.

Macroporous biohybrid cryogels for co-housing pancreatic islets with mesenchymal stromal cells.

Intrahepatic transplantation of allogeneic pancreatic islets offers a promising therapy for type 1 diabetes. However, long-term insulin independency is often not achieved due to severe islet loss shortly after transplantation. To improve islet survival and function, extrahepatic biomaterial-assisted transplantation of pancreatic islets to alternative sites has been suggested. Herein, we present macroporous, star-shaped poly(ethylene glycol) (starPEG)-heparin cryogel scaffolds, covalently modified with adhesion peptides, for the housing of pancreatic islets in three-dimensional (3D) co-culture with adherent mesenchymal stromal cells (MSC) as accessory cells. The implantable biohybrid scaffolds provide efficient transport properties, mechanical protection, and a supportive extracellular environment as a desirable niche for the islets. MSC colonized the cryogel scaffolds and produced extracellular matrix proteins that are important components of the natural islet microenvironment known to facilitate matrix-cell interactions and to prevent cellular stress. Islets survived the seeding procedure into the cryogel scaffolds and secreted insulin after glucose stimulation in vitro. In a rodent model, intact islets and MSC could be visualized within the scaffolds seven days after subcutaneous transplantation. Overall, this demonstrates the potential of customized macroporous starPEG-heparin cryogel scaffolds in combination with MSC to serve as a multifunctional islet supportive carrier for transplantation applications. Diabetes results in the insufficient production of insulin by the pancreatic β-cells in the islets of Langerhans. Transplantation of pancreatic islets offers valuable options for treating the disease; however, many transplanted islets often do not survive the transplantation or die shortly thereafter. Co-transplanted, supporting cells and biomaterials can be instrumental for improving islet survival, function and protection from the immune system. In the present study, islet supportive hydrogel sponges were explored for the co-transplantation of islets and mesenchymal stromal cells. Survival and continued function of the supported islets were demonstrated in vitro. The in vivo feasibility of the approach was shown by transplantation in a mouse model.

Obese mice on a high-fat alternate-day fasting regimen lose weight and improve glucose tolerance.

Alternate-day fasting (ADF) causes body weight (BW) loss in humans and rodents. However, it is not clear that ADF while maintaining a high-fat (HF) diet results in weight loss and the accompanying improvement in control of circulating glucose. We tested the hypotheses that a high-fat ADF protocol in obese mice would result in (i) BW loss, (ii) improved glucose control, (iii) fluctuating phenotypes on 'fasted' days when compared to 'fed' days and (iv) induction of torpor on 'fasted days'. We evaluated the physiological effects of ADF in diet-induced obese mice for BW, heart rate (HR), body temperature (Tb ), glucose tolerance, insulin responsiveness, blood parameters (leptin, insulin, free fatty acids) and hepatic gene expression. Diet-induced obese male C57BL/6J mice lost one-third of their pre-diet BW while on an ADF diet for 10weeks consisting of HF food. The ADF protocol improved glucose tolerance and insulin sensitivity, although mice on a fast day were less glucose tolerant than the same mice on a fed day. ADF mice on a fast day had low circulating insulin, but had an enhanced response to an insulin-assisted glucose tolerance test, suggesting the impaired glucose tolerance may be a result of insufficient insulin production. On fed days, ADF mice were the warmest, had a high HR and displayed hepatic gene expression and circulating leptin that closely mimicked that of mice fed an ad lib HF diet. ADF mice never entered torpor as assessed by HR and Tb . However, on fast days, they were the coolest, had the slowest HR, and displayed hepatic gene expression and circulating leptin that closely mimicked that of Chow-Fed mice. Collectively, the ADF regimen with a HF diet in obese mice results in weight loss, improved blood glucose control, and daily fluctuations in selected physiological and biochemical parameters in the mouse.

Glucagon-like peptide-1 and cholecystokinin production and signaling in the pancreatic islet as an adaptive response to obesity.

Precise control of blood glucose is dependent on adequate β‐cell mass and function. Thus, reductions in β‐cell mass and function lead to insufficient insulin production to meet demand, and result in diabetes. Recent evidence suggests that paracrine signaling in the islet might be important in obesity, and disruption of this signaling could play a role in the pathogenesis of diabetes. For example, we recently discovered a novel islet incretin axis where glucagon‐like peptide‐1 regulates β‐cell production of another classic gut hormone, cholecystokinin. This axis is stimulated by obesity, and plays a role in enhancing β‐cell survival. In the present review, we place our observations in the wider context of the literature on incretin regulation in the islet, and discuss the potential for therapeutic targeting of these pathways.

Plasmonic chip tackles type 1 diabetes diagnosis.

Diabetes mellitus is a group of metabolic disorders of carbohydrate metabolism in which patients develop hyperglycemia. Type 1 diabetes results from cellular-mediated autoimmune destruction of the insulin-producing pancreatic β-cells 1. Patients with type 1 diabetes frequently present with acute symptoms, including life-threatening ketoacidosis, and all patients require lifelong insulin therapy. Type 2 diabetes, which accounts for approximately 90% of all diabetes, has an insidious onset due to combined insulin resistance and insufficient insulin production. In many patients, type 2 diabetes can be controlled with diet, exercise, and oral agents. The worldwide incidence of diabetes has been increasing dramatically. Although most of the rise has been for type 2 diabetes, type 1 has climbed by 2.8% to 4.0% per annum, rising 21% in US youth between 2001 and 2009. At disease onset, most type 1 diabetes patients have autoantibodies to 1 or more of the following: islet cell cytoplasm, insulin [insulin autoantibodies (IAAs)],3 the 65-kDa isoform of glutamic acid decarboxylase (GAD65), insulinoma-associated antigen 2 (IA-2), and zinc transporter 8 (ZnT8) (these are collectively termed islet autoantibodies). Moreover, the presence of islet autoantibodies predicts the development of type 1 diabetes. A recent prospective study measured IAA, GAD65, and IA-2 in 13uu377 children who were at high risk for type 1 diabetes and followed them for 15 years 2. Virtually all the children who had multiple islet autoantibodies developed type 1 diabetes, whereas approximately 15% with a single islet autoantibody progressed to type 1 diabetes. Quantification of islet autoantibodies has proved difficult. Islet cell antibodies were the first autoantibodies identified in type 1 diabetes and are measured on frozen sections of human pancreas by indirect immunofluorescence. The method is technically demanding, labor intensive, difficult to standardize, and currently performed by few laboratories. The other antibodies are most frequently measured by …

Insulin exerts direct, IGF-1 independent actions in growth plate chondrocytes.

Insufficient insulin production or action in diabetic states is associated with growth retardation and impaired bone healing, while the underling mechanisms are unknown. In this study, we sought to define the role of insulin signaling in the growth plate. Insulin treatment of embryonic metatarsal bones from wild-type mice increased chondrocyte proliferation. Mice lacking insulin receptor (IR) selectively in chondrocytes (CartIR−/−) had no discernable differences in total femoral length compared to control littermates. However, CartIR−/− mice exhibited an increase in chondrocyte numbers in the growth plate than that of the controls. Chondrocytes lacking IR had elevated insulin-like growth factor (IGF)-1R mRNA and protein levels. Subsequently, IGF-1 induced phosphorylation of Akt and ERK was enhanced, while this action was eliminated when the cells were treated with IGF-1R inhibitor Picropodophyllin. Deletion of the IR impaired chondrogenic differentiation, and the effect could not be restored by treatment of insulin, but partially rescued by IGF-1 treatment. Intriguingly, the size of hypertrophic chondrocytes was smaller in CartIR−/− mice when compared with that of the control littermates, which was associated with upregulation of tuberous sclerosis complex 2 (TSC2). These results suggest that deletion of the IR in chondrocytes sensitizes IGF-1R signaling and action, IR and IGF-1R coordinate to regulate the proliferation, differentiation and hypertrophy of growth plate chondrocytes.

Advancements and challenges in generating accurate animal models of gestational diabetes mellitus

The maintenance of glucose homeostasis during pregnancy is critical to the health and well-being of both the mother and the developing fetus. Strikingly, approximately 7% of human pregnancies are characterized by insufficient insulin production or signaling, resulting in gestational diabetes mellitus (GDM). In addition to the acute health concerns of hyperglycemia, women diagnosed with GDM during pregnancy have an increased incidence of complications during pregnancy as well as an increased risk of developing type 2 diabetes (T2D) later in life. Furthermore, children born to mothers diagnosed with GDM have increased incidence of perinatal complications, including hypoglycemia, respiratory distress syndrome, and macrosomia, as well as an increased risk of being obese or developing T2D as adults. No single environmental or genetic factor is solely responsible for the disease; instead, a variety of risk factors, including weight, ethnicity, genetics, and family history, contribute to the likelihood of developing GDM, making the generation of animal models that fully recapitulate the disease difficult. Here, we discuss and critique the various animal models that have been generated to better understand the etiology of diabetes during pregnancy and its physiological impacts on both the mother and the fetus. Strategies utilized are diverse in nature and include the use of surgical manipulation, pharmacological treatment, nutritional manipulation, and genetic approaches in a variety of animal models. Continued development of animal models of GDM is essential for understanding the consequences of this disease as well as providing insights into potential treatments and preventative measures.

Small‐molecule inhibition of inflammatory β‐cell death

With the worldwide increase in diabetes prevalence there is a pressing unmet need for novel antidiabetic therapies. Insufficient insulin production due to impaired β-cell function and apoptotic reduction of β-cell mass is a common denominator in the pathogenesis of diabetes. Current treatments are directed at improving insulin sensitivity, and stimulating insulin secretion or replacing the hormone, but do not target progressive apoptotic β-cell loss. Here we review the current development of small-molecule inhibitors designed to rescue β-cells from apoptosis. Several distinct classes of small molecules have been identified that protect β-cells from inflammatory, oxidative and/or metabolically induced apoptosis. Although none of these have yet reached the clinic, β-cell protective small molecules alone or in combination with current therapies provide exciting opportunities for the development of novel treatments for diabetes.

Peripheral Pathways in the Food-Intake Control towards the Adipose-Intestinal Missing Link

In the physiological state a multitude of gut hormones are released into the circulation at the same time depending on the quality and quantity of the diet. These hormones interact with receptors at various points in the “gut-brain axis” to affect short-term and intermediate-term feelings of hunger and satiety. The combined effects of macronutrients on the predominant gut hormone secretion are still poorly understood. Besides, adipokines form an important part of an “adipoinsular axis” dysregulation which may contribute to β-cell failure and hence to type 2 diabetes mellitus (T2DM). Even more, gestational diabetes mellitus (GDM) and T2DM seem to share a genetic basis. In susceptible individuals, chronic exaggerated stimulation of the proximal gut with fat and carbohydrates may induce overproduction of an unknown factor that causes impairment of incretin production and/or action, leading to insufficient or untimely production of insulin, so that glucose intolerance develops. The bypass of the duodenum and jejunum might avoid a putative hormone overproduction in the proximal foregut in diabetic patients that might counteract the action of insulin, while the early presentation of undigested or incompletely digested food to the ileum may anticipate the production of hormones such as GLP1, further improving insulin action.

The usefulness and limitations of the diabetic macaque model in evaluating long‐term porcine islet xenograft survival

Various groups have reported prolonged diabetes reversal and graft function after porcine islet transplantation into diabetic macaques using different experimental designs (macaque source, islet source, type of immunosuppression): subsequently, the International Xenotransplantation Association has published recommendations for entering a clinical trial. Our experiments showed limitations that affected consistent achievement of long-term survival. We aimed to identify these limitations and underlying causes to emphasize the translational value of this highly relevant type 1 diabetic macaque model. We reviewed data from our institution and literature data on long-term porcine islet xenograft survival in the diabetic macaque model, especially focusing on aspects of incomplete diabetes reversal relative to macaque normal values. This phenomenon was compared with diabetes reversal in an allo-islet transplant model in macaques and with chronic insulin treatment of diabetic macaques, all with 180-day follow-up. This comparison enabled to identify potential model limitations and underlying causative factors. Especially in the xenograft model, the achievement of long-term graft survival revealed limitations including chronic, mild hyperglycemia and absence of body weight (BW) gain or even progressive BW loss. Metabolic incompatibilities in glycemic control (i.e., insulin kinetics) between the pig and macaque species underlie chronic, mild hyperglycemia. This phenomenon might not bear relevance for the pig-to-human species combination because the glycemic control in pigs and humans is similar and differs from that in nonhuman primates (NHP). Weight loss could be related to changes in the gastrointestinal tract related with local high exposure to orally administered immunosuppressants; these must be given at higher dose levels because of low bioavailability in macaques to achieve systemic exposure at therapeutic levels. This is aggravated by insufficient graft insulin production in proportion to the needs of macaques: this model limitation has no translational value to the pig-to-human setting. Nutritional deficits can result in incorrect interpretation of blood glucose levels and C-peptide levels regarding graft function. Likewise, nutritional status alters physiologic responses, influencing susceptibility to infectious and noninfectious complications. THE model-induced confounding described interferes with accurate interpretation of safety and efficacy studies, which affects the translational value of pig-to-NHP islet cell transplant studies to the pig-to-human transplant condition.

FORMULATION AND IN-VITRO EVALUATION OF SUSTAINED RELEASE MATRIX TABLETS OF GLIPIZIDE

Diabetes mellitus is a metabolic disorder caused by insufficient production of endogenous insulin, with or without resistance to insulin action, resulting in hyperglycaemia. In type 1 diabetes mellitus, there is a failure in production of insulin as a result of destruction of the cells of the pancreas, and patients require treatment with insulin whereas type 2 diabetes can be characterised by defects in both insulin action (i.e. insulin resistance) and insulin secretion, and is associated with elevated basal hepatic glucose production. Glipizide is a second-generation sulfonylurea that can acutely lower the blood glucose level in humans by stimulating the release of insulin from the pancreas and is typically prescribed to treat type II diabetes. Different formulations were prepared by varying the concentration of HPMC used as polymers. The effect of varying concentration of hydrophilic polymers (HPMC 5cps and 15 cps) was studied on the release pattern of glipizide. Sustained release glipizide matrix tablets were prepared by wet granulation and compression of hydroxypropylmethyl cellulose (5 cps and 15 cps), drug and other excipients mixture. The promising formulation was compared with the marketed sample of suatained release glynase in terms of release pattern. The release rate of a glipizide from matrix tablet was decreased with increasing the concentration as well as viscosity polymer. This might be probably due to increased swelling and reduced erosion rate of matrix tablet. The formulation 13 (F13) showed the similar result as marketed sample of sustained release glynase tablets in terms of release rate. Key Words: Glipizide, Hydroxy propyl methyl cellulose (HPMC), Viscosity grades

Maturation of Human Embryonic Stem Cell–Derived Pancreatic Progenitors Into Functional Islets Capable of Treating Pre-existing Diabetes in Mice

Diabetes is a chronic debilitating disease that results from insufficient production of insulin from pancreatic β-cells. Islet cell replacement can effectively treat diabetes but is currently severely limited by the reliance upon cadaveric donor tissue. We have developed a protocol to efficiently differentiate commercially available human embryonic stem cells (hESCs) in vitro into a highly enriched PDX1+ pancreatic progenitor cell population that further develops in vivo to mature pancreatic endocrine cells. Immature pancreatic precursor cells were transplanted into immunodeficient mice with streptozotocin-induced diabetes, and glycemia was initially controlled with exogenous insulin. As graft-derived insulin levels increased over time, diabetic mice were weaned from exogenous insulin and human C-peptide secretion was eventually regulated by meal and glucose challenges. Similar differentiation of pancreatic precursor cells was observed after transplant in immunodeficient rats. Throughout the in vivo maturation period hESC-derived endocrine cells exhibited gene and protein expression profiles that were remarkably similar to the developing human fetal pancreas. Our findings support the feasibility of using differentiated hESCs as an alternative to cadaveric islets for treating patients with diabetes.

Discovery of Novel Glucose-Regulated Proteins in Isolated Human Pancreatic Islets Using LC–MS/MS-Based Proteomics

The prevalence of diabetes mellitus is increasing dramatically throughout the world, and the disease has become a major public health issue. The most common form of the disease, type 2 diabetes, is characterized by insulin resistance and insufficient insulin production from the pancreatic beta-cell. Since glucose is the most potent regulator of beta-cell function under physiological conditions, identification of the insulin secretory defect underlying type 2 diabetes requires a better understanding of glucose regulation of human beta-cell function. To this aim, a bottom-up LC-MS/MS-based proteomics approach was used to profile pooled islets from multiple donors under basal (5 mM) or high (15 mM) glucose conditions. Our analysis discovered 256 differentially abundant proteins (∼p < 0.05) after 24 h of high glucose exposure from more than 4500 identified in total. Several novel glucose-regulated proteins were elevated under high glucose conditions, including regulators of mRNA splicing (pleiotropic regulator 1), processing (retinoblastoma binding protein 6), and function (nuclear RNA export factor 1), in addition to neuron navigator 1 and plasminogen activator inhibitor 1. Proteins whose abundances markedly decreased during incubation at 15 mM glucose included Bax inhibitor 1 and synaptotagmin-17. Up-regulation of dicer 1 and SLC27A2 and down-regulation of phospholipase Cβ4 were confirmed by Western blots. Many proteins found to be differentially abundant after high glucose stimulation are annotated as uncharacterized or hypothetical. These findings expand our knowledge of glucose regulation of the human islet proteome and suggest many hitherto unknown responses to glucose that require additional studies to explore novel functional roles.

Nonhuman primates and other animal models in diabetes research.

Animal models are important for determining the pathogenesis of and potential treatments for obesity and diabetes. Nonhuman primates (NHPs) are particularly useful for studying these disorders. As in humans, type 2 diabetes mellitus is the most common form of diabetes in NHPs and occurs more often in older obese animals, with a metabolic progression from insulin resistance (IR) and impaired glucose tolerance to overt diabetes. Histopathologic changes in pancreatic islets are also similar to those seen in humans with diabetes. Initially, there is islet hyperplasia with abundant insulin production to compensate for IR, followed by insufficient insulin production with replacement of islets with islet-associated amyloid. Diabetic NHPs also have adverse changes in plasma lipid and lipoprotein concentrations, biomarkers of obesity, inflammation, and oxidative stress, and protein glycation that contribute to the numerous complications of the disease. Furthermore, sex hormones, pregnancy, and environmental factors (e.g., diet and stress) affect IR and can also contribute to diabetes progression in NHPs. Additionally, due to their similar clinical and pathologic characteristics, NHPs have been used in many pharmacological studies to assess new therapeutic agents. For these reasons, NHPs are particularly valuable animal models of obesity and diabetes for studying disease pathogenesis, risk factors, comorbidities, and therapeutic interventions.

Essay for the 2011 CIHR/CMAJ award: glucagon-like peptides for metabolic and gastrointestinal disorders

See related articles by Kelsall at [www.cmaj.ca/lookup/doi/10.1503/cmaj.112129][1], and by Koren and colleagues at [www.cmaj.ca/lookup/doi/10.1503/cmaj.112128][2] Type 2 diabetes arises as a result of insufficient insulin production, commonly in the setting of impaired insulin action. Type 2

Innovative Treatments in Diabetes Type 1

Type 1 diabetes mellitus (T1DM) is a metabolic disease caused by autoimmune destruction of beta cells in the pancreas leading to insufficient production of insulin. The standard treatment of diabetes relies on multiple injections of insulin. One of the main drawbacks of this treatment is the inability to replicate timing and action on endogenous insulin secretion when beta cells are intact. Resulting hyper- and hypoglycemias cause long term and acute side effects of the disease. There are multiple approaches to overcome this problem: insulin pumps, oral insulin preparations, immunomodulatory treatments and transplantation of beta cells. This review summarizes recent advances in the treatment of diabetes.

Endoplasmic Reticulum Stress-Associated Lipid Droplet Formation and Type II Diabetes.

Diabetes mellitus (DM), a metabolic disorder characterized by hyperglycemia, is caused by insufficient insulin production due to excessive loss of pancreatic β cells (type I diabetes) or impaired insulin signaling due to peripheral insulin resistance (type II diabetes). Pancreatic β cell is the only insulin-secreting cell type that has highly developed endoplasmic reticulum (ER) to cope with high demands of insulin synthesis and secretion. Therefore, ER homeostasis is crucial to the proper function of insulin signaling. Accumulating evidence suggests that deleterious ER stress and excessive intracellular lipids in nonadipose tissues, such as myocyte, cardiomyocyte, and hepatocyte, cause pancreatic β-cell dysfunction and peripheral insulin resistance, leading to type II diabetes. The excessive deposition of lipid droplets (LDs) in specialized cell types, such as adipocytes, hepatocytes, and macrophages, has been found as a hallmark in ER stress-associated metabolic diseases, including obesity, diabetes, fatty liver disease, and atherosclerosis. However, much work remains to be done in understanding the mechanism by which ER stress response regulates LD formation and the pathophysiologic role of ER stress-associated LD in metabolic disease. This paper briefly summarizes the recent advances in ER stress-associated LD formation and its involvement in type II diabetes.

Pharmacogenetics of insulin secretagogue antidiabetics

Type 2 diabetes is making up to 90% of the all diabetic cases. In addition to insulin resistance, insufficient B-cell function also plays an important role in the pathogenesis of the disease. The insufficient production and secretion of insulin can be increased by secretagogue drugs, like sulfonylureas and incretin mimetics/enhancers. In recent years growing number of genetic failures of the B-cells has been detected. These genetic variants can influence the efficacy of secretagogue drugs. Some of these gene polymorphisms were identified in the genes encoding the KATP channel (KCNJ11 and ABCC8). These mutations are able either to reduce or increase the insulin secretion and can modify the insulin response to sulfonylurea treatment. Other polymorphisms were found on genes encoding enzymes or transcription factors. In recent years, the genetic variants of TCF7L2 and its clinical importance have been intensely studied. Authors give a summary of the above gene polymorphisms and their role in insulin secretion.

Dosage planning for diabetes patients using data mining methods

Abstract The condition of high blood sugar (glucose) level is called as diabetes mellitus. Cause of this disease can be either insufficient insulin production or improper response of body cell to insulin. Diabetes patients should use different drugs in order to keep their blood sugar level within normal range values. The purpose of this study is to develop a data mining model for which will predict a suitable dosage planning for diabetes patients. Medical records of 89 different patient records were used in this study. 318 diabetes assays were extracted using these patient records. ANFIS and Rough Set methods were used for dosage planning objective. According to the results of ANFIS and Rough Set methods, ANFIS is a more successful and reliable method for diabetes drug planning objective when compared to Rough Set method.

Human being needs a revolution on diabetes therapy

Diabetes mellitus (DM) is a group of metabolic diseases associated with hyperglycemia. The main problem is insufficient insulin production in pancreas β-cells (Type 1 DM) or insensitivity (or resistance) of the tissues to insulin (Type 2 DM). Type 2 DM (T2DM) is the most common type of DM. T2DM is typically associated with obesity, sedentary lifestyle, old age, family history of diabetes, and ethnicity. Diabetes mellitus is the most common endocrine disorder currently affecting over 170 million people worldwide. In 2030, it is predicted that 360 million people will suffer from this disease. Especially T2DM is rapidly emerging as one of the greatest global health problems of the 21st Century. As a consequence, it is expected that a rise in the complications associated with diabetes, such as ischemic heart disease, stroke, neuropathy, retinopathy, and nephropathy, will be triggered. Chronically-elevated blood glucose is not only important in diabetes but also several other chronic diseases including metabolic syndrome, obesity, and cardiovascular disorders. Therefore, ...