Possible Long-Term Efficacy of Sitagliptin, a Dipeptidyl Peptidase-4 Inhibitor, for Slowly Progressive Type 1 Diabetes (SPIDDM) in the Stage of Non-Insulin-Dependency: An Open-Label Randomized Controlled Pilot Trial (SPAN-S)

<p><strong>Article full text</strong></p> <p><br> The full text of this article can be found <a href="https://link.springer.com/article/10.1007/s13300-017-0299-7"><b>here</b>.</a><br> <br> <strong>Provide enhanced content for this article</strong><br> If you are an author of this publication and would like to provide additional enhanced content for your article then please contact <u>[email protected]</u>.<br> <br> The journal offers a range of additional features designed to increase visibility and readership. All features will be thoroughly peer reviewed to ensure the content is of the highest scientific standard and all features are marked as ‘peer reviewed’ to ensure readers are aware that the content has been reviewed to the same level as the articles they are being presented alongside. Moreover, all sponsorship and disclosure information is included to provide complete transparency and adherence to good publication practices. This ensures that however the content is reached the reader has a full understanding of its origin. No fees are charged for hosting additional open access content.<br> <br> Other enhanced features include, but are not limited to:<br> • Slide decks<br> • Videos and animations<br> • Audio abstracts<br> • Audio slides</p> <p> </p

Clinical and Genetic Characteristics of Non-Insulin-Requiring Glutamic Acid Decarboxylase (GAD) Autoantibody-Positive Diabetes: A Nationwide Survey in Japan

<div><p>Aims</p><p>Glutamic acid decarboxylase autoantibodies (GADAb) differentiate slowly progressive insulin-dependent (type 1) diabetes mellitus (SPIDDM) from phenotypic type 2 diabetes, but many GADAb-positive patients with diabetes do not progress to insulin-requiring diabetes. To characterize GADAb-positive patients with adult-onset diabetes who do not require insulin therapy for >5 years (NIR-SPIDDM), we conducted a nationwide cross-sectional survey in Japan.</p><p>Methods</p><p>We collected 82 GADAb-positive patients who did not require insulin therapy for >5 years (NIR-SPIDDM) and compared them with 63 patients with insulin-requiring SPIDDM (IR-SPIDDM). Clinical and biochemical characteristics, HLA-DRB1-DQB1 haplotypes, and predictive markers for progression to insulin therapy were investigated.</p><p>Results</p><p>Compared with the IR-SPIDDM group, the NIR-SPIDDM patients showed later diabetes onset, higher body mass index, longer duration before diagnosis, and less frequent hyperglycemic symptoms at onset. In addition, C-peptide, LDL-cholesterol, and TG were significantly higher in the NIR-SPIDDM compared to IR-SPIDDM patients. The NIR-SPIDDM group had lower frequency of susceptible HLA-DRB1*04:05-DQB1*04:01 and a higher frequency of resistant HLA-DRB1*15:01-DQB1*06:02 haplotype compared to IR-SPIDDM. A multivariable analysis showed that age at diabetes onset (OR = 0.82), duration before diagnosis of GADAb-positive diabetes (OR = 0.82), higher GADAb level (≥10.0 U/ml) (OR = 20.41), and fasting C-peptide at diagnosis (OR = 0.07) were independent predictive markers for progression to insulin-requiring diabetes. An ROC curve analysis showed that the optimal cut-off points for discriminating two groups was the GADAb level of 13.6 U/ml, age of diabetes onset of 47 years, duration before diagnosis of 5 years, and fasting C-peptide of 0.65 ng/ml.</p><p>Conclusions</p><p>Clinical, biochemical and genetic characteristics of patients with NIR-SPIDDM are different from those of IR-SPIDDM patients. Age of diabetes onset, duration before GADAb-positivity, GADAb level, and fasting C-peptide at diagnosis must be carefully considered in planning prevention trials for SPIDDM.</p></div

Frequency of the HLA DRB1-DQB1 haplotype in NIR-SPIDDM, IR-SPIDDM, and healthy controls.

<p>Frequency of the HLA DRB1-DQB1 haplotype in NIR-SPIDDM, IR-SPIDDM, and healthy controls.</p

Optimal cut-off values of GADAb level, age at diabetes onset, duration before diagnosis of GADAb-positive diabetes, and FCPR for a progression to insulin-requiring diabetes by ROC curve analysis.

<p>Optimal cut-off values of GADAb level, age at diabetes onset, duration before diagnosis of GADAb-positive diabetes, and FCPR for a progression to insulin-requiring diabetes by ROC curve analysis.</p

Multivariate logistic regression analysis for predictive markers of progression to insulin-requiring diabetes.

<p>Multivariate logistic regression analysis for predictive markers of progression to insulin-requiring diabetes.</p

Pathological features of the pancreas affected by fulminant type 1 diabetes (FT1DM).

<p><b>A:</b> CD8 + T cells (red) infiltrate from outside the islet, disrupting vascular BMs (green, arrows) through the interstitial space between the vasculature and islets. Arrowheads indicate BMs (green) of exocrine pancreatic cells. <b>B:</b> BMs and ECM surrounding islets (green) are markedly disrupted and punctuated (arrows) in FT1DM. The vasculatures of the islets show marked dilation, and the vascular BMs have lost the human-specific double membrane profile <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0095110#pone.0095110-Virtanen1" target="_blank">[15]</a> (arrowheads). <b>C:</b> Acinar-like cell cluster touching Langerhans islets with thin interstitial surrounding (ATLANTIS) shows marked expression of REG Iα (green) in FT1DM. BMs (red, arrows) encapsulating the islet beta cells (blue) and ATLANTIS (green) are disrupted and discontinuous in some parts. <b>D:</b> Double immunostaining for amylase (red) and REG Iα (green) shows that amylase expression in the ATLANTIS (in circle) in inflamed FT1DM becomes faint in inverse relation to REG Iα over-expression. I: Islet, PAC: pancreatic acinar cells. <b>E:</b> Triple immunostaining for REG Iα (green), glucagon + somatostatin (SS) + pancreatic polypeptide (PP) (red), and insulin (blue) demonstrates that REG Iα-positive cells are not beta, glucagon, SS, or PP cells. <b>F:</b> Serum levels of REG Iα are increased in the patients with FT1DM of duration less than 2 weeks. **p<0.01 vs. controls.</p

REG Iα-positive cell cluster contacting with beta cell cluster and surrounded by common BMs and ECM.

<p><b>A–D</b>: Immunostaining for REG Iα (green) (<b>A</b>), acinar-like cell marker, amylase (blue). (<b>B</b>), and double immunostaining with insulin (brown) and fibronectin (red) (<b>C</b>). Auto-fluorescence of collagen fiber surrounding islet is observed (<b>A</b>, arrowheads). The merged image (<b>D</b>) shows that amylase-positive acinar-like cells that are in contact with beta cells express REG Iα protein (light blue: arrowheads), and the acinar-like cell cluster is surrounded by BMs/ECM (red, fibronectin). <b>E</b>: Electron-immunostaining with immuno-gold for REG Iα (20 nm: arrowheads) in acinar-like cell touching a beta cell containing insulin (5 nm: arrows). REG Iα is mainly localized in the center of the vesicle that is near the beta cell wall. <b>F</b>: Immuno-electron microscopy with immunogold for REG Iα (25 nm: arrowheads) and insulin (5 nm: arrows). Densely stained REG Iα vesicle (*) is just beside the cell wall touching a beta cell. Dissolved vesicles positive for REG Iα (arrowheads) are observed in insulin-containing beta cells.</p

Cell-cell interaction between acinar-like cells and islet endocrine cells encapsulated by common BMs.

<p><b>A:</b> A desmosomal junction (arrowhead) is observed between acinar-like cells (AC) and alpha cells (A), which are encapsulated by common BMs and ECM. <b>B</b>: Coated-pit-like structure is observed between an acinar-like cell (AC) and an alpha cell (A) touching directly and covered by common BMs (arrows). Inset shows a magnified view of the coated-pit-like structure. <b>C</b>: Excretion of vesicles from acinar-like cells (AC) to a beta cell (B). Note the vesicular membrane of the AC is dissolved (arrow), and the vesicular content is released to the beta cell (B) touching it. <b>D1</b>: Exocytotic features of vesicles in acinar-like cells (AC) to beta cells (B), which are in contact with each other. Arrowhead indicates BMs/ECM encapsulating acinar-like cells and beta cells, V: vasculature. <b>D2:</b> Higher magnified view of D1. The vesicle is internalized to the beta cell. AC: acinar-like cell, B: beta cell. <b>E:</b> Vesicles of acinar-like cells (AC) are internalized to touching alpha cells (A) and beta cell (B) shown by arrows. Arrowheads indicate BMs/ECM surrounding beta cell (B), alpha cell (A), and acinar-like cell (AC). Inset shows magnified view of (E). LB: lipofuscin body, ER: endoplasmic reticulum.</p

Replicating islet cells in fulminant type 1 diabetes (FT1DM).

<p><b>A</b>: Ki67-positive cells are increased in the pancreas of FT1DM. The cell composition of increased Ki67⁺ cells (red nuclei) is mainly REG Iα positive cells (green: arrowheads), islet non-beta cells (arrows), and islet beta cells (*, blue). <b>B</b>: The percentage of islets positive for Ki67 is increased in the pancreas of FT1DM. The number in parentheses indicates the total number of islets studied in FT1DM and control. See the detailed characterization of the subjects in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0095110#s2" target="_blank">Research Design and Methods</a>. **P<0.0001 vs. controls, mean ± SEM. <b>C</b>: The number of islets positive for Ki67 in non-beta islet cells is increased in FT1DM. Non-beta islet cells were stained by mixed antisera for glucagon, somatostatin, and pancreatic polypeptide, and the values are expressed as percentage of islets positive for Ki67. The number in parentheses indicates the total number of islets studied in FT1DM and controls. **P = 0.02 vs. controls, mean ± SEM. <b>D</b>: The number of islets positive for Ki67 in beta cells tends to increase, but it is not significant due to the markedly decreased number of beta cells in individual islets in FT1DM. The number in parentheses indicates the total number of islets studied in FT1DM and controls. <b>E</b>: The number of Ki67-positive beta cells is increased in FT1DM. The numbers in parentheses indicate the total number of beta cells counted in the islets of FT1DM and controls. See a detailed characterization in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0095110#s2" target="_blank">Research Design and Methods</a>. *P = 0.043 vs. controls, mean ± SEM.</p

Reconstructed feature of islet cell cluster, acinar-like cell cluster, and BMs and ECM.

<p><b>A–H</b>: Overview of the architecture reconstructed by serial pancreatic beta cell clusters (insulin: blue) and acinar-like cell clusters (amylase: red) surrounded by continuous BMs and ECM (fibronectin: green). <b>I, J</b>: Relationship between the beta cell area (X-axis) and the capsular area (Y-axis), which contains the beta cell area and the acinar-like cell area. A clear linear correlation between beta cell area and capsular area was observed (p<0.001, n = 517). See the schematic definition in (J). <b>J 1–3</b>: Schematic definition of capsular area and acinar-like cell area. The capsular area (b: dashed line) is composed of the acinar-like cell area (red in the dashed line) and the islet cell area (a: blue) (mostly beta cell area). A good correlation between the capsular area and islet cell area (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0095110#pone-0095110-g003" target="_blank">Figure 3-I</a>) indicates that a constant proportion of islet cell clusters are accompanied by acinar-like cell clusters irrespective of the size of beta cell clusters.</p