Amyloid Deposits In Pancreatic Islets Research Articles

On the importance of being amidated: Analysis of the role of the conserved C-terminal amide of amylin in amyloid formation and cytotoxicity

The polypeptide hormone Amylin (also known as islet amyloid polypeptide) plays a role in regulation of glucose metabolism, but forms pancreatic islet amyloid deposits in type 2 diabetes. The process of islet amyloid formation contributes to β-cell dysfunction and the development of the disease. Amylin is produced as a pro-from and undergoes processing prior to secretion. The mature hormone contains an amidated C-terminus. Analysis of an alignment of vertebrate amylin sequences reveals that the processing signal for amidation is strictly conserved. Furthermore, the enzyme responsible for C-terminal amidation is found in all of these organisms. Comparison of the physiologically relevant amidated form to a variant with a free C-terminus (Amylin-COO−) shows that replacement of the C-terminal amide with a carboxylate slows, but does not prevent amyloid formation. Pre-fibrillar species produced by both variants are toxic to cultured β-cells, although hAmylin-COO− is moderately less so. Amyloid fibrils produced by either peptide are not toxic. Prior work (ACS Pharmacol. Translational. Sci. 1, 132–49 (2018)) shows that Amylin- COO− exhibits a 58-fold reduction in activation of the Amylin1 receptor and 20-fold reduction in activation of the Amylin3 receptor. Thus, hAmylin-COO− exhibits significant toxicity, but significantly reduced activity and offers a reagent for studies which aim to decouple hAmylin's toxic effects from its activity. The different behaviours of free and C-terminal amidated Amylin should be considered when designing systems to produce the polypeptide recombinantly.

Creating the amylin story

This paper is based on a presentation given at the Annual Meeting of the Society for the Study of Ingestive Behavior in July 2021 and provides a personal view on some of the milestones in the discovery of amylin as a constituent of pancreatic islet amyloid deposits, as a pancreatic beta-cell hormone, and on its role in physiology and pathophysiology. Only selected effects of amylin are discussed here because we recently published extensive reviews on the physiology and pathophysiology of amylin. Amylin was discovered as the main constituent of islet amyloid that is predominantly found in pancreatic islets in type 2 diabetics. These deposits, and in particular small oligomer aggregates of amylin seem to contribute to the progressive beta-cell damage seen in type 2 diabetics. Amylin is also a physiologically relevant circulating hormone with diverse metabolic functions, e.g. inhibition of eating, of pancreatic glucagon secretion and of gastric emptying. Knowledge of these types of functions and amylin's mechanisms of action lead to the development of amylin analogues that are now among the most promising anti-obesity targets in clinical testing. With this review, I want to give a short overview of 35 exciting years of amylin research.

4-Phenylbutyrate (PBA) treatment reduces hyperglycemia and islet amyloid in a mouse model of type 2 diabetes and obesity

Amyloid deposits in pancreatic islets, mainly formed by human islet amyloid polypeptide (hIAPP) aggregation, have been associated with loss of β-cell mass and function, and are a pathological hallmark of type 2 diabetes (T2D). Treatment with chaperones has been associated with a decrease in endoplasmic reticulum stress leading to improved glucose metabolism. The aim of this work was to investigate whether the chemical chaperone 4-phenylbutyrate (PBA) prevents glucose metabolism abnormalities and amyloid deposition in obese agouti viable yellow (Avy) mice that overexpress hIAPP in β cells (Avy hIAPP mice), which exhibit overt diabetes. Oral PBA treatment started at 8 weeks of age, when Avy hIAPP mice already presented fasting hyperglycemia, glucose intolerance, and impaired insulin secretion. PBA treatment strongly reduced the severe hyperglycemia observed in obese Avy hIAPP mice in fasting and fed conditions throughout the study. This effect was paralleled by a decrease in hyperinsulinemia. Importantly, PBA treatment reduced the prevalence and the severity of islet amyloid deposition in Avy hIAPP mice. Collectively, these results show that PBA treatment elicits a marked reduction of hyperglycemia and reduces amyloid deposits in obese and diabetic mice, highlighting the potential of chaperones for T2D treatment.

Photodegradation of porphyrin-bound hIAPP(1–37) fibrils

Amyloid deposits in pancreatic islets of type 2 diabetes mellitus (T2DM) are mainly comprised of human islet amyloid polypeptide (hIAPP), the degradation of hIAPP fibrils by photoactive porphyrin could be a preventive strategy against T2DM.

Use of the PET ligand florbetapir for in vivo imaging of pancreatic islet amyloid deposits in hIAPP transgenic mice.

Islet amyloid deposits contribute to beta cell dysfunction and death in most individuals with type 2 diabetes but non-invasive methods to determine the presence of these pathological protein aggregates are currently not available. Therefore, we examined whether florbetapir, a radiopharmaceutical agent used for detection of amyloid-β deposits in the brain, also allows identification of islet amyloid in the pancreas. Saturation binding assays were used to determine the affinity of florbetapir for human islet amyloid polypeptide (hIAPP) aggregates in vitro. Islet amyloid-prone transgenic mice that express hIAPP in their beta cells and amyloid-free non-transgenic control mice were used to examine the ability of florbetapir to detect islet amyloid deposits in vitro, in vivo and ex vivo. Mice or mouse pancreases were subjected to autoradiographic, histochemical and/or positron emission tomography (PET) analyses to assess the utility of florbetapir in identifying islet amyloid. In vitro, florbetapir bound synthetic hIAPP fibrils with a dissociation constant of 7.9nmol/l. Additionally, florbetapir bound preferentially to amyloid-containing hIAPP transgenic vs amyloid-free non-transgenic mouse pancreas sections in vitro, as determined by autoradiography (16,475 ± 5581 vs 5762 ± 575 density/unit area, p < 0.05). In hIAPP transgenic and non-transgenic mice fed a high-fat diet for 1year, intravenous administration of florbetapir followed by PET scanning showed that the florbetapir signal was significantly higher in amyloid-laden hIAPP transgenic vs amyloid-free non-transgenic pancreases in vivo during the first 5min of the scan (36.83 ± 2.22 vs 29.34 ± 2.03 standardised uptake value × min, p < 0.05). Following PET, pancreases were excised and florbetapir uptake was determined ex vivo by γ counting. Pancreatic uptake of florbetapir was significantly correlated with the degree of islet amyloid deposition, the latter assessed by histochemistry (r = 0.74, p < 0.001). Florbetapir binds to islet amyloid deposits in a specific and quantitative manner. In the future, florbetapir may be useful as a non-invasive tool to identify islet amyloid deposits in humans.

Characterization of Dog, Cat, Guinea Pig, and Human IAPP toxicity in HeLa cells

Type 2 diabetes is one of the leading causes of death in the U.S. Type 2 Diabetes is the most generic form of diabetes, where your body suffers from insulin resistance. Islet Amyloid Polypeptide (IAPP) is a regulatory peptide which inhibits glucagon and insulin secretion. The aggregation of IAPP is present in pancreatic islet amyloid deposits seen especially in Type 2 diabetes in humans and other mammalian species. Our objective was to see how the changes in IAPP sequence correlates to the toxicity of IAPP on mammalian cells. Here, we focus on dog, cat, and guinea pig IAPP. Molecular techniques such as MTT assay and LDH Cytotoxicity assay were used to test the effect animal IAPP has on HeLa cells. As well as to see the effect mixing human and animal IAPP has on the HeLa cells. MTT assay results showed that the animal IAPP volumes had no significant effect on mammalian cell viability while the human IAPP was consistently toxic to the cells. Cell viability percentages stayed relatively constant despite increasing IAPP volume. In comparison, human IAPP showed a decreasing cell viability trend with increasing IAPP volume. However, when dog IAPP and human IAPP were mixed, cell viability was increased. The same effect occurred with the mixing of cat IAPP and human IAPP. LDH Cytotoxicity assay results showed that percent toxicity increased with increasing IAPP volumes for human, cat and guinea pig. Dog IAPP cell toxicity stayed constant as IAPP volume increased. When dog IAPP and cat IAPP were separately mixed with human IAPP, a decrease in cell toxicity is seen. Mixing guinea pig IAPP with human IAPP had no effect on cell viability or cell toxicity. Further experiments are necessary to determine a correlation between these specific animal IAPPs and cell toxicity.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The IAPP Toxicity on Rats, Raccoons and Degus in HeLa Cells

Type 2 diabetes is the most common form of diabetes, where the body suffers from insulin resistance. The islet amyloid polypeptide (IAPP) is a secretory product of beta cells in pancreatic islets of Langerhans that also inhibits glucagon and insulin secretion. The aggregation of IAPP is present in pancreatic islet amyloid deposits seen especially in Type 2 diabetes, in humans and other mammalian species. The objective of this study was to determine the effects of the animal toxicity on mammalian cells. In this work, the human IAPP sequence and the effect on mammalian cells was compared to the IAPP from degu, rat, and raccoon. Molecular techniques such as MTT and LDH Cytotoxicity assay were used to test the effect of human and animal IAPP on HeLa cells. The MTT results show a consistent drop in cell viability as the concentration of IAPP from a human, degu, rat and raccoon increases. LDH cytotoxicity shows the highest toxicity in human IAPP compared to the rest of the studied animals. Although when mixing both the human and animal IAPPs, the toxicity of the human IAPP decreased whereas the viability had no significant effect. Further molecular analysis is necessary to determine the correlation between animal IAPP toxicity and the incidence of Type 2 diabetes.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Intraneuronal Amylin Deposition, Peroxidative Membrane Injury and Increased IL-1β Synthesis in Brains of Alzheimer's Disease Patients with Type-2 Diabetes and in Diabetic HIP Rats.

Amylin is a hormone synthesized and co-secreted with insulin by pancreatic β-cells that crosses the blood-brain barrier and regulates satiety. Amylin from humans (but not rodents) has an increased propensity to aggregate into pancreatic islet amyloid deposits that contribute to β-cell mass depletion and development of type-2 diabetes by inducing oxidative stress and inflammation. Recent studies demonstrated that aggregated amylin also accumulates in brains of Alzheimer's disease (AD) patients, preponderantly those with type-2 diabetes. Here, we report that, in addition to amylin plaques and mixed amylin-Aβ deposits, brains of diabetic patients with AD show amylin immunoreactive deposits inside the neurons. Neuronal amylin formed adducts with 4-hydroxynonenal (4-HNE), a marker of peroxidative membrane injury, and increased synthesis of the proinflammatory cytokine interleukin (IL)-1β. These pathological changes were mirrored in rats expressing human amylin in pancreatic islets (HIP rats) and mice intravenously injected with aggregated human amylin, but not in hyperglycemic rats secreting wild-type non-amyloidogenic rat amylin. In cultured primary hippocampal rat neurons, aggregated amylin increased IL-1β synthesis via membrane destabilization and subsequent generation of 4-HNE. These effects were blocked by membrane stabilizers and lipid peroxidation inhibitors. Thus, elevated circulating levels of aggregated amylin negatively affect the neurons causing peroxidative membrane injury and aberrant inflammatory responses independent of other confounding factors of diabetes. The present results are consistent with the pathological role of aggregated amylin in the pancreas, demonstrate a novel contributing mechanism to neurodegeneration, and suggest a direct, potentially treatable link of type-2 diabetes with AD.

Discovery of ethyl urea derivatives as inhibitors of islet amyloid polypeptide fibrillization and cytotoxicity

Islet amyloid polypeptide (IAPP) has been shown to form amyloid deposits in pancreatic islets, thereby furthering type 2 diabetes disease progression. Further discovery of new molecules is needed to create a diverse set of molecules that impede pancreatic amyloidosis. We have recently designed and synthesized N-phenyl-N'-(2-ethyl)ureas (EU) that are non-cytotoxic small molecules, to evaluate the role of the aryl-substituted moiety on the inhibition of hIAPP fibrillization. Several EUs were tested in vitro for their anti-amyloidogenic activity using the fluorometric ThT assay, the photo-induced cross-linking (PIUCP) assay, and cell survival assay in pancreatic MIN-6 cells. EU-362 and EU-418 were able to significantly inhibit the formation of hIAPP fibrils and protected cells from amyloid cytotoxic effects. Our results suggest that increasing the nucleophilic potency of the aryl moiety significantly enhances the anti-amyloidogenic activity of the molecules.

Inhibition of islet amyloid polypeptide fibril formation by selenium-containing phycocyanin and prevention of beta cell apoptosis

Human islet amyloid polypeptide (hIAPP) fibril is the major constituent of amyloid deposits in pancreatic islets of type 2 diabetes. Misfolding and hIAPP fibril formation are thought to be important in the pathogenesis of diabetes. Studies have showed that selenium-containing phycocyanin (Se-PC) inhibited the fibrillation of hIAPP to form nanoscale particles, which is mainly by interfering with the combination between hIAPP. Small nanoscale oligomers tended to grow into larger nanoparticles and the size of nanoparticles increased with the incubation time. By interfering with the fibrillation of hIAPP and altering the structure, Se-PC alleviated hIAPP-induced cell apoptosis. Meantime, generation of ROS produced during the fibrillation process was inhibited, which was proposed to be the main factor for the hIAPP-cytotoxicity in beta cells. Taken together, Se-PC inhibited hIAPP fibrillation, thus suppressed the formation of ROS to show protective effect on hIAPP mediated cell apoptosis. Our studies provide useful information for our understanding of the interaction mechanisms of Se-PC on hIAPP structure and protective mechanisms on hIAPP cytotoxicity, presenting useful candidate for anti-diabetes drug development.

Acidic pH retards the fibrillization of human islet amyloid polypeptide due to electrostatic repulsion of histidines

The human Islet Amyloid Polypeptide (hIAPP) is the major constituent of amyloid deposits in pancreatic islets of type-II diabetes. IAPP is secreted together with insulin from the acidic secretory granules at a low pH of approximately 5.5 to the extracellular environment at a neutral pH. The increased accumulation of extracellular hIAPP in diabetes indicates that changes in pH may promote amyloid formation. To gain insights and underlying mechanisms of the pH effect on hIAPP fibrillogenesis, all-atom molecular dynamics simulations in explicit solvent model were performed to study the structural properties of five hIAPP protofibrillar oligomers, under acidic and neutral pH, respectively. In consistent with experimental findings, simulation results show that acidic pH is not conducive to the structural stability of these oligomers. This provides a direct evidence for a recent experiment [L. Khemtemourian, E. Domenech, J. P. F. Doux, M. C. Koorengevel, and J. A. Killian, J. Am. Chem. Soc. 133, 15598 (2011)], which suggests that acidic pH inhibits the fibril formation of hIAPP. In addition, a complementary coarse-grained simulation shows the repulsive electrostatic interactions among charged His18 residues slow down the dimerization process of hIAPP by twofold. Besides, our all-atom simulations reveal acidic pH mainly affects the local structure around residue His18 by destroying the surrounding hydrogen-bonding network, due to the repulsive interactions between protonated interchain His18 residues at acidic pH. It is also disclosed that the local interactions nearby His18 operating between adjacent β-strands trigger the structural transition, which gives hints to the experimental findings that the rate of hIAPP fibril formation and the morphologies of the fibrillar structures are strongly pH-dependent.

The role of two natural flavonoids on human amylin aggregation

Misfolded amylin, the human polypeptide hormone, forms amyloid deposits in pancreatic islets. These amyloid deposits contribute to the dysfunction of beta-cells and the loss of beta-cell mass in type 2 diabetes mellitus (T2DM). Inhibition of amylin fibrillization has been regarded as a potential therapeutic approach for T2DM. Using i¬‚uorescence spectroscopic analysis with thioi¬‚avin T, the role of two naturally occurring flavonoids named myricetin and epigallocatechin gallate on human amylin hormone fibrillization and destabilization of fibrillar aggregates were examined under near physiological conditions. The results showed that after 168 h incubation by shaker incubator in 37°C. Myricetin at 10 and 40 µM repressed amylin amyloid formation by 25.3 and 22.4%, respectively (p<0.05), and the similar values of epigallocatechin gallate inhibited the formation of β-sheet structure by 18.1 and 16.7%, respectively (p<0.05). The obtained data also confirmed that amyloidal sheet opening was induced by myricetin and epigallocatechin gallate significantly (p<0.05). Therefore, it was concluded that islet amyloid cytotoxicity to β-cells may be reduced by these two flavonoids, and these compounds should be key molecules for the development of the therapeutics for diabetes mellitus. Key words: Human islet amyloid polypeptide, hyperglycemia, myricetin, epigallocatechin gallate, flavonoids.

Islet amyloid polypeptide in pancreatic islets from type 2 diabetic subjects

Aims/hypothesis: Islet amyloid polypeptide (IAPP) is a chief constituent of amyloid deposits in pancreatic islets, characteristic histopathology for type 2 diabetes. The goal of this study was to analyze islet cell composition in diabetic islets for the process of transforming water-soluble IAPP in β-cells to water-insoluble amyloid deposits by Immunocytochemical staining using different dilutions of anti-IAPP antibody. IAPP in β-cell granules may initiate β-cell necrosis through apoptosis to form interstitial amyloid deposits in type 2 diabetic islets. Results: Control islets revealed twice as much β-cells as α-cells whereas 15 of 18 type 2 diabetic cases (83%) revealed α- cells as major cells in larger islets. Diabetic islets consisted of more larger islets with more σ-cells than β-cells, which contribute to hyperglucagonemia. In control islets, percentage of IAPP-positive cells against β-cells was 40–50% whereas percentage for type 2 diabetic islets was about 25%. Amyloid deposits in diabetic islets were not readily immunostained for IAPP using 1: 800 diluted antibody, however, 1: 400 and 1: 200 diluted solutions provided stronger immunostaining in early stages of islet amyloidogenesis after treating the deparaffinized sections with formic acid. Methods: Using commercially available rabbit antihuman IAPP antibody, immunocytochemical staining was performed on 18 cases of pancreatic tissues from type 2 diabetic subjects by systematically immunostaining for insulin, glucagon, somatostatin (SRIF) and IAPP compared with controls. Sizes of islets were measured by 1 cm scale, mounted in 10X eye piece. Conclusions/Interpretation: α cells were major islet cells in majority of diabetic pancreas (83%) and all diabetic islets contained less IAPP-positive cells than controls, indicating that IAPP deficiency in pancreatic islets is responsible for decreased IAPP in blood. In diabetic islets, water-soluble IAPP disappeared in β-cell granules, which transformed to water-insoluble amyloid deposits. Amyloid deposits were not readily immunostained using IAPP 1: 800 diluted antibody but were stronger immunostained for IAPP in early stages of amyloid deposited islets using less diluted solutions after formic acid treatment. In early islet amyloidogenesis, dying β-cell cytoplasm was adjacently located to fine amyloid fibrils, supporting that IAPP in secretary granules from dying β cells served as nidus for islet β-sheet formation.

Silibinin inhibits the toxic aggregation of human islet amyloid polypeptide

In type 2 diabetes mellitus (T2DM), misfolded human islet amyloid polypeptide (hIAPP) forms amyloid deposits in pancreatic islets. These amyloid deposits contribute to the dysfunction of β-cells and the loss of β-cell mass in T2DM patients. Inhibition of hIAPP fibrillization has been regarded as a potential therapeutic approach for T2DM. Silibinin, a major active flavonoid extracted from herb milk thistle (Silybum marianum), has been used for centuries to treat diabetes in Asia and Europe with unclear mechanisms. In this study, we tested whether silibinin has any effect on the amyloidogenicity of hIAPP. Our results provide first evidence that silibinin inhibits hIAPP fibrillization via suppressing the toxic oligomerization of hIAPP and enhances the viability of pancreatic β-cells, therefore silibinin may serve as a potential therapeutic agent for T2DM.

Involvement of ATP-sensitive Potassium (KATP) Channels in the Loss of Beta-cell Function Induced by Human Islet Amyloid Polypeptide

Islet amyloid polypeptide (IAPP) is a major component of amyloid deposition in pancreatic islets of patients with type 2 diabetes. It is known that IAPP can inhibit glucose-stimulated insulin secretion; however, the mechanisms of action have not yet been established. In the present work, using a rat pancreatic beta-cell line, INS1E, we have created an in vitro model that stably expressed human IAPP gene (hIAPP cells). These cells showed intracellular oligomers and a strong alteration of glucose-stimulated insulin and IAPP secretion. Taking advantage of this model, we investigated the mechanism by which IAPP altered beta-cell secretory response and contributed to the development of type 2 diabetes. We have measured the intracellular Ca(2+) mobilization in response to different secretagogues as well as mitochondrial metabolism. The study of calcium signals in hIAPP cells demonstrated an absence of response to glucose and also to tolbutamide, indicating a defect in ATP-sensitive potassium (K(ATP)) channels. Interestingly, hIAPP showed a greater maximal respiratory capacity than control cells. These data were confirmed by an increased mitochondrial membrane potential in hIAPP cells under glucose stimulation, leading to an elevated reactive oxygen species level as compared with control cells. We concluded that the hIAPP overexpression inhibits insulin and IAPP secretion in response to glucose affecting the activity of K(ATP) channels and that the increased mitochondrial metabolism is a compensatory response to counteract the secretory defect of beta-cells.

Islet Amyloid Polypeptide, Islet Amyloid, and Diabetes Mellitus

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.

Interaction of hIAPP with Model Raft Membranes and Pancreatic β‐Cells: Cytotoxicity of hIAPP Oligomers

Type II diabetes mellitus (T2DM) is associated with beta-cell failure, which correlates with the formation of pancreatic islet amyloid deposits. The human islet amyloid polypeptide (hIAPP) is the major component of islet amyloid and undergoes structural changes followed by self-association and pathological tissue deposition during aggregation in T2DM. There is clear evidence that the aggregation process is accelerated in the presence of particular lipid membranes. Whereas hIAPP aggregation has been extensively studied in homogeneous model membrane systems, especially negatively charged lipid bilayers, information on the interaction of hIAPP with heterogeneous model raft membranes has been missing until now. In the present study, we focus on the principles of aggregation and amyloid formation of hIAPP in the presence of model raft membranes. Time-lapse tapping mode AFM and confocal fluorescence microscopy experiments followed membrane permeabilization and localization of hIAPP in the raft membrane. Together with the ThT and WST-1 assay, the data revealed elevated cytotoxicity of hIAPP oligomers on INS-1E cells.

Amyloidosis of pancreatic islets in primary amyloidosis (AL type)

Seven cases of primary amyloidosis (AL-type) were studied immunocytochemically for the possible involvement of pancreatic islets. The two cases with extensive organ involvement by AL-amyloidosis revealed amyloid deposits in pancreatic islets by routine HE and Congo red staining, which were positive for amyloid p and amyloid a, but were only focally positive for light chains kappa and lambda. Positive staining for amyloid p and amyloid a was also noted in the scattered pancreatic acinar tissues, and this positive staining was not specifically located in pancreatic islets as seen in type 2 diabetes mellitus. It is concluded that amyloid deposits in pancreatic islets occur in systemic AL-amyloidosis by a different mechanism from type 2 diabetes. Islet amyloidosis in AL-amyloidosis appears to deposit via circulation, depositing in both pancreatic islets and acinar tissue through blood vessels. In type 2 diabetes, beta islet cells die by cytotoxic effects of smaller amylin (islet amyloid polypeptide, IAPP) aggregates, and the interstitial space created by the necrotic beta cells is replaced by larger IAPP aggregates, to form complex, polymerized islet amyloid. In AL-amyloidosis, the amount of amyloid and light chain deposits in pancreatic islets is much less than that of the other organs and appears to have no connection to type 2 diabetes because the patients did not present diabetes or hyperglycemia. However, considerable islet amyloidosis can be seen in severe AL-type amyloidosis.

Diabetes mellitus, tuberculosis and the mycobacteria: Two millenia of enigma

The thought that tuberculosis and the mycobacteria could cause diabetes seems farfetched, but is not. The peculiar relationship and frequent association of diabetes mellitus and tuberculosis has been observed for more than 2000 years, yet the reason for this correlation is, to this day, not known. Before the discovery of insulin, a diagnosis of diabetes was a death sentence within 5 years, and the usual cause of that death was tuberculosis. Despite this, in the 5th century, tuberculosis was already being portrayed as a "complication" of diabetes, a view little changed to this day, parroting Root's original 1934 description of "a one-sided relationship": tuberculosis still seen as a common complication of diabetes, while diabetes is thought to be no more common among TB patients than in the population at large. To Nichol's, this was "not logically tenable" and in his study of 178 otherwise healthy, non-diabetic military men with tuberculosis at Fitzsimmons Army Hospital, one-third had abnormal glucose screening tests. But despite his findings and those of Reaud in New York and others, this was not being recognized elsewhere, and Nichols wanted to know why. Nichols concluded that the incidence of diabetes among tuberculosis patients was considerably underestimated and that in tuberculosis patients, diabetes develops quite commonly. Diabetes was easy to detect. Tuberculosis and the mycobacteria were not. The evidence for a mycobacterial cause of diabetes is mounting rapidly. Schwartz and Haas both linked Type-2 diabetes to tuberculosis. And the pancreatic islet amyloid deposits that they found as a by-product of systemic tubercular infection have recently been dissolved by rifampicin, a first line drug against tuberculosis. Engelbach spoke of "transitory" diabetes in TB and Karachunskii noted changes in carbohydrate metabolism in patients with tuberculosis which commonly led to insulin deficiency with persistent hyperglycemia. Furthermore, mycobacterial elements have been shown recently not only to cause "autoimmune" Type-1 diabetes in NOD (non-obese diabetic) mice, but act as a vaccine to stop the inevitable diabetes that would otherwise materialize. The documentation of patient cases where TB has preceded and come before the development of diabetes is extensive yet underplayed and both Lin's and Tsai's studies speak of tuberculosis complicated by diabetes. Diabetes has been around since the first century AD, in a perpetual state of coping and managing. It is time, it is long past time, to cure diabetes. But current models as to its cause are not equipping us to do so.

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The thought that tuberculosis and the mycobacteria could cause diabetes seems farfetched, but is not. The peculiar relationship and frequent association of diabetes mellitus and tuberculosis has been observed for more than 2000 years, yet the reason for this correlation is, to this day, not known. Before the discovery of insulin, a diagnosis of diabetes was a death sentence within 5 years, and the usual cause of that death was tuberculosis. Despite this, in the 5th century, tuberculosis was already being portrayed as a “complication” of diabetes, a view little changed to this day, parroting Root’s original 1934 description of “a one-sided relationship”: tuberculosis still seen as a common complication of diabetes, while diabetes is thought to be no more common among TB patients than in the population at large. To Nichol’s, this was “not logically tenable” and in his study of 178 otherwise healthy, non-diabetic military men with tuberculosis at Fitzsimmons Army Hospital, one-third had abnormal glucose screening tests. But despite his findings and those of Reaud in New York and others, this was not being recognized elsewhere, and Nichols wanted to know why. Nichols concluded that the incidence of diabetes among tuberculosis patients was considerably underestimated and that in tuberculosis patients, diabetes develops quite commonly. Diabetes was easy to detect. Tuberculosis and the mycobacteria were not.The evidence for a mycobacterial cause of diabetes is mounting rapidly. Schwartz and Haas both linked Type-2 diabetes to tuberculosis. And the pancreatic islet amyloid deposits that they found as a by-product of systemic tubercular infection have recently been dissolved by rifampicin, a first line drug against tuberculosis. Engelbach spoke of “transitory” diabetes in TB and Karachunskii noted changes in carbohydrate metabolism in patients with tuberculosis which commonly led to insulin deficiency with persistent hyperglycemia. Furthermore, mycobacterial elements have been shown recently not only to cause “autoimmune” Type-1 diabetes in NOD (non-obese diabetic) mice, but act as a vaccine to stop the inevitable diabetes that would otherwise materialize. The documentation of patient cases where TB has preceded and come before the development of diabetes is extensive yet underplayed and both Lin’s and Tsai’s studies speak of tuberculosis complicated by diabetes. Diabetes has been around since the first century AD, in a perpetual state of coping and managing. It is time, it is long past time, to cure diabetes. But current models as to its cause are not equipping us to do so.