Re – print- An Adjunct Treatment Reverses Chronic Insulin-dependent (Type 1) Diabetes in a Teenager

Globally, more than 30 million people suffer from diabetes mellitus type 1 (T1DM) characterized by pancreas producing little or no insulin hormone to facilitate glucose entering cells for energy production. T1DM patients tend to suffer a higher overall rate of atherosclerosis, cancer, and end-stage renal failure. No drug or surgical therapy seems to halt its annual upward trend amongst children and young adults. Consequently, a significant number of sufferers turn to complementary or alternative therapies for help to arrest this chronic endocrine condition. This paper discusses how a well-designed evidence-based dietary and nutritional therapy with some lifestyle modifications might offer a solution for this highly complex autoimmune disorder. The treatment outcome demonstrated a partial regeneration of pancreatic islet beta cells with substantial improvement for all relevant serum and urine markers tested.

Multi-omics profiling of living human pancreatic islet donors reveals heterogeneous beta cell trajectories toward type 2 diabetes

Existing studies do not sufficiently describe the molecular changes of pancreatic islet beta cells leading to their deficient insulin secretion in type 2 diabetes (T2D). Here we address this deficiency with a comprehensive multi-omics analysis of metabolically profiled pancreatectomized living human donors stratified along the glycemic continuum from normoglycemia to T2D. Islet pools isolated from surgical samples by laser-capture microdissection had remarkably heterogeneous transcriptomic and proteomic profiles in diabetics, but not in non-diabetic controls. Transcriptomics analysis of this unique cohort revealed islet genes already dysregulated in prediabetic individuals with impaired glucose tolerance. Our findings demonstrate a progressive but disharmonic remodeling of mature beta cells, challenging current hypotheses of linear trajectories toward precursor or trans-differentiation stages in T2D. Further, integration of islet transcriptomics and pre-operative blood plasma lipidomics data enabled us to define the relative importance of gene co-expression modules and lipids positively or negatively associated with HbA1c levels, pointing to potential prognostic markers.

Potential positive and negative consequences of ZnT8 inhibition

SLC30A8 encodes the zinc transporter ZnT8. SLC30A8 haploinsufficiency protects against type 2 diabetes (T2D), suggesting that ZnT8 inhibitors may prevent T2D. We show here that, while adult chow fed Slc30a8 haploinsufficient and knockout (KO) mice have normal glucose tolerance, they are protected against diet-induced obesity (DIO), resulting in improved glucose tolerance. We hypothesize that this protection against DIO may represent one mechanism whereby SLC30A8 haploinsufficiency protects against T2D in humans and that, while SLC30A8 is predominantly expressed in pancreatic islet beta cells, this may involve a role for ZnT8 in extra-pancreatic tissues. Consistent with this latter concept we show in humans, using electronic health record-derived phenotype analyses, that the ‘C’ allele of the non-synonymous rs13266634 SNP, which confers a gain of ZnT8 function, is associated not only with increased T2D risk and blood glucose, but also with increased risk for hemolytic anemia and decreased mean corpuscular hemoglobin (MCH). In Slc30a8 KO mice, MCH was unchanged but reticulocytes, platelets and lymphocytes were elevated. Both young and adult Slc30a8 KO mice exhibit a delayed rise in insulin after glucose injection, but only the former exhibit increased basal insulin clearance and impaired glucose tolerance. Young Slc30a8 KO mice also exhibit elevated pancreatic G6pc2 gene expression, potentially mediated by decreased islet zinc levels. These data indicate that the absence of ZnT8 results in a transient impairment in some aspects of metabolism during development. These observations in humans and mice suggest the potential for negative effects associated with T2D prevention using ZnT8 inhibitors.

Age matters: Grading granule secretion in beta cells

Insulin is stored in secretory granules to facilitate rapid release in response to rising glucose levels, but the mechanisms by which these granules are identified and prioritized for secretion remains unclear. Using a fluorescent timer and flow cytometry–assisted organelle sorting, Yau et al. develop an elegant approach to assess insulin secretion as a function of granule age in pancreatic islet beta cells. Their findings supply quantitative evidence supporting the age-dependent release of different granule pools and confirm earlier models of preferential release of younger granules.

Purification of age-distinct insulin secretory granules through antigen restriction using the CLIP-tag

Pancreatic islet beta cells employ secretory granules for the storage and glucose-stimulated release of the hormone insulin. The competence of an insulin granule for exocytosis depends on spatial and temporal variables such as its proximity to the plasma membrane as well as its age, with newly-generated granules being preferentially released. The molecular underpinnings for the control of these variables remain largely unknown and their uncovering is of high relevance for the study of diabetes, which results from deficient insulin secretion. However, we still lack a comprehensive view about the molecular composition of the insulin granules and how this may change over their lifetime. Here we report a strategy for the background-free purification of insulin secretory granules of distinct age from insulinoma INS-1 cells. We show that utilization of an immuno-based affinity approach for pulse-chase labeled insulin secretory granules, produces a highly enriched granular fraction. Our approach precludes typical contaminants from the solid phase and may be designed to purify secretory granules of a distinct age.

Recent advances in understanding the role of glucagon-like peptide 1

The discovery that glucagon-like peptide 1 (GLP-1) mediates a significant proportion of the incretin effect during the postprandial period and the subsequent observation that GLP-1 bioactivity is retained in type 2 diabetes (T2D) led to new therapeutic strategies being developed for T2D treatment based on GLP-1 action. Although owing to its short half-life exogenous GLP-1 has no use therapeutically, GLP-1 mimetics, which have a much longer half-life than native GLP-1, have proven to be effective for T2D treatment since they prolong the incretin effect in patients. These GLP-1 mimetics are a desirable therapeutic option for T2D since they do not provoke hypoglycaemia or weight gain and have simple modes of administration and monitoring. Additionally, over more recent years, GLP-1 action has been found to mediate systemic physiological beneficial effects and this has high clinical relevance due to the post-diagnosis complications of T2D. Indeed, recent studies have found that certain GLP-1 analogue therapies improve the cardiovascular outcomes for people with diabetes. Furthermore, GLP-1–based therapies may enable new therapeutic strategies for diseases that can also arise independently of the clinical manifestation of T2D, such as dementia and Parkinson’s disease. GLP-1 functions by binding to its receptor (GLP-1R), which expresses mainly in pancreatic islet beta cells. A better understanding of the mechanisms and signalling pathways by which acute and chronic GLP-1R activation alleviates disease phenotypes and induces desirable physiological responses during healthy conditions will likely lead to the development of new therapeutic GLP-1 mimetic–based therapies, which improve prognosis to a greater extent than current therapies for an array of diseases.

The rs10229583 polymorphism near paired box gene 4 is associated with gestational diabetes mellitus in Chinese women

Objective The rs10229583 polymorphism near paired box gene 4 ( PAX4) is associated with insulin resistance and type 2 diabetes. Mutations in the PAX4 gene may be associated with impaired differentiation/development of pancreatic islet beta cells during fetal development and, consequently, a compromised insulin response to high blood glucose. To ascertain whether this polymorphism plays a role in gestational diabetes mellitus (GDM), we investigated the genotypic and allele frequency differences between GDM and normal pregnancies. Methods A total of 310 GDM and 440 normal pregnancies were evaluated. Allele and genotype frequencies of rs10229583 were determined for all participants with Sanger sequencing and SNaPshot. Association of the allele and genotypes of the single nucleotide polymorphism with the disease was analyzed using Pearson’s χ2 test and OR (odds ratio). Results The G allele was more frequent in patients with GDM compared with controls (OR = 1.47, 95% confidence interval (CI): 1.12–1.939). The GG genotype frequency of rs10229583 was significantly different between subjects with GDM and normal controls (OR = 1.411, 95% CI: 1.032–1.928). The OR of the GA + GG genotype was 3.182 (95% CI: 1.294–7.826) for patients with GDM compared with controls. Conclusion The present study suggests that rs10229583 is associated with GDM.