The role of Th1/Th2 disbalanced immune response in the determination of clinical features of autoimmune diabetes mellitus

Aim. To elucidate the role of Th1/Th2 polarization of immune response in LADA patients in the realization of the clinical phenotype of the disease. Materials and methods. 70 patients aged 21-61 (mean 41.3?1.0 yr) with DM diagnosed based on WHO criteria (1999). Groups 1 and 2 included 13 DM1and 57 DM2 patients (34.6?7.2 and 43.6?7.6 yr respectively). 27 DM2 patients (41.2?1.6 yr) presumably had LADA (P. Zimmet's criteria).Serum anti-GAD65, ICA, and IAA antibodies along with C-peptide were measured in fasting sera and 120 min after GTT by solid phase immunoenzymeassays following manufacturer's instructions with the use of a photometer for Multiscan EX microplates (ThermoLabSystems, Finland) at405 nm (for GAG and ICA) and 450 nm (for IAA and C-peptide). GAD, IAA, and C-peptides levels were calculated automatically from calibrationcurves. Mononuclear leukocytes were isolated by centrifugation in the ficoll-verographin density gradient. The cells thus obtained were resuspendedin the complete nutritient medium reducing their concentration to 2.0x10^6/ml. Phytohemagglutinin (Difco, Germany) was added (10 mcg/1 ml) tothe samples to stimulate mononuclear leukocytes; cell suspensions were further incubated for 24 hr. Initial and PGA-induced levels of IL-2, 4, 10 insupernatants of cell cultures were measured by solid phase immunoassay at 450 nm. Results. At least one type of autoantibodies (GAD, ICA or IAA) was identified in 24.3% of all DM patients (17/70) and in 18% of the DM2 patients(10/57). The level of anti-GAD and ICA ABs and percentage of AB-positive patients were higher in the LADA group while that of anti-IAA ABs amongDM1 patients without LADA. Two AB types at a time were found in 17% (4/23) of the patients with autoimmune DM in the absence of significantdifference between LADA and DM1. Patients with LADA had a significantly lower basal C-peptide level than DM2 patients. The was a tendencytoward lower level of stimulated C-peptide secretion in LADA patients compared with DM2 ones. It suggests impairment of beta-cell secretory functionaffected by the autoimmune process. We observed enhanced basal production of IFN-y by blood mononuclear leukocytes in all DM patients in theabsence of significant difference between the groups. Mitogen-activated production in all CD patients was lower than normal without inter-groupdifferences. Patients with DM2 had the inverted type of IL-2 secretion unlike those with autoimmune diabetes. In both cases it was significantly differentfrom normal values. There was a tendency toward higher basal production of IL-4 by mononuclear leukocytes in LADA and DM2 comparedwith CD1 which reflects pathogenetic peculiarities of beta-cell function in LADA differing from those in DM1 and responsible for slower impairment ofbeta-cell function in this condition. Basal and PGA- induced production of IL-10 was higher in LADA and DM2 than in DM1. It suggests enhancedsuppressor activity of leukocytes that may protect beta-cells from autoimmune destruction and determines gradual development of clinical symptoms ofinsulin deficiency. In contrast, low production of IL-10 in DM1 gives evidence of polarization of the immune response. Conclusion. The loss of functional parenchyma and manifestation of insulin deficiency in LADA occur at a relatively low rate due to the peculiarcharacter of cytokine-mediated cell interactions. It suggests the necessity of an active and careful diagnostic strategy with the use of immunologicalmethods for examination of elder patients presenting with a variety of pathogenetic variants of DM.

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Role of C-Peptide in the Regulation of Microvascular Blood Flow

Experimental Diabetes Research ◽

10.1155/2008/176245 ◽

2008 ◽

Vol 2008 ◽

pp. 1-8 ◽

Cited By ~ 7

Author(s):

T. Forst ◽

T. Kunt ◽

B. Wilhelm ◽

M. M. Weber ◽

A. Pfützner

Keyword(s):

Blood Flow ◽

Beta Cell ◽

Cell Function ◽

Pancreatic Beta Cell ◽

Microvascular Blood Flow ◽

Diabetic Patients ◽

C Peptide ◽

Glucose Levels ◽

Peptide Secretion

During the recent years, the role of C-peptide, released from the pancreatic beta cell, in regulating microvascular blood flow, has received increasing attention. In type 1 diabetic patients, intravenous application of C-peptide in physiological concentrations was shown to increase microvascular blood flow, and to improve microvascular endothelial function and the endothelial release of NO. C-peptide was shown to impact microvascular blood flow by several interactive pathways, like stimulatingNa+K+ATPase or the endothelial release of NO. There is increasing evidence, that in patients with declining beta cell function, the lack of C-peptide secretion might play a putative role in the development of microvascular blood flow abnormalities, which go beyond the effects of declining insulin secretion or increased blood glucose levels.

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SAT-667 Partial Beta-Cell Destruction: An Atypical Case of Immune Checkpoint Inhibitor Diabetes Mellitus

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.1563 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Zoe Quandt ◽

Katy K Tsai ◽

Victoria C Hsiao

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Beta Cell ◽

Immune Checkpoint ◽

Beta Cell Function ◽

Cell Function ◽

Autoimmune Diabetes ◽

Insulin Production ◽

C Peptide

Abstract Background: Autoimmune diabetes mellitus (CPI-DM) caused by immune checkpoint inhibitors (CPIs) is rare- occurring in approximately one percent of patients exposed to this form of cancer immunotherapy. Typically, this immune related adverse event occurs after treatment with PD-1/PD-L1 inhibitors. It is characterized by abrupt insulinopenia leading to acute hyperglycemia. Beta cell autoantibodies are positive in approximately half the cases. DKA is common at the time of diagnosis. Recovery of beta cell function has been reported in only two case reports. In one case, spontaneous resolution occurred following cessation of CPI therapy and in the other the patient was treated with infliximab for concurrent inflammatory arthritis prior to resolution of CPI-DM. Clinical Case: A 50-year-old woman was started on adjuvant pembrolizumab for stage IIIC melanoma following surgery. She had no prior history of diabetes mellitus, thyroid disease, or other autoimmune disease. Pre-infusion random blood glucoses (RBG) were 84 - 105 mg/dL. After 36 weeks, she developed hypothyroidism (TSH 17.5 (0.5-4.1 mIU/L), FT4 6 (10-18 ug/dL)) and started levothyroxine. Pembrolizumab was continued. For nine weeks following her diagnosis with CPI- hypothyroidism, her pre-infusion RBG ranged from 102-133. At 45 weeks (15 cycles) after initiating pembrolizumab, her RBG was 260. She was not on glucocorticoids and had no other signs of inflammation or stress. Pembrolizumab was continued. Just prior to her 17th cycle, 48 weeks after initiating adjuvant pembrolizumab, her RBG was 482 with a normal anion gap and HCO3, and her A1c was 8.9%. Her last dose of pembrolizumab was held. She started metformin and liraglutide. In just three weeks, a random c-peptide was inadequate at 1.7 (0.8-3.5 ng/mL) with a recent RBG of 220 and A1c of 10.3%, showing the acuity and extremity of her hyperglycemia. Over the course of the year, she has achieved excellent glucose control (A1c 6.3-7.1) on this regimen with preservation of insulin production (c-peptides 1.4-1.8 with matched RBG 92-129). She never required insulin. Her beta cell autoantibodies are negative. Clinical Lessons: This is a case of CPI-DM in which the patient did not have complete loss of beta-cell function. The acuity of her hyperglycemia is not consistent with new onset type 2 diabetes. At diagnosis, her c-peptide was inadequate suggesting insufficient insulin production rather than insulin resistance. Therefore, her hyperglycemia is more consistent with CPI-DM than type 2 diabetes. Atypically, she did not progress to fulminant beta cell failure, which could have been due to cessation of pembrolizumab (which is not unique to this case), initiation of liraglutide and metformin, or other unknown immunologic responses that inhibited full beta cell loss. This case raises the possibility of preventing fully insulin dependent CPI-DM if hyperglycemia is caught and treated early.

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Inheritance of Mildly Activating ABCC8 Mutation From a Mother With MODY Causes Permanent Neonatal Diabetes Mellitus (NDM) in Two Siblings Who Also Carry a Second Inactivating Mutation: Genetic Testing Allows for Improved Treatment With Sulfonylureas (SU)

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.923 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A452-A452

Author(s):

Maria Victoria Salguero Bermonth ◽

Lisa Letourneau-Freiberg ◽

Nancy Devine ◽

Siri Atma W Greeley

Keyword(s):

Genetic Testing ◽

Beta Cell ◽

Beta Cell Function ◽

Cell Function ◽

Family Members ◽

Neonatal Diabetes ◽

Cell Surface Expression ◽

High Dose ◽

C Peptide ◽

Significant Difference

Abstract Background: Heterozygous activating mutations in KCNJ11 or ABCC8 are the most common cause of neonatal diabetes (NDM). ABCC8 (SUR1) mutations more often cause transient NDM. Inactivating ABCC8 mutations can cause congenital hyperinsulinism (HI), but very rarely will such mutations be inherited together. Mildly activating KATP mutations can also be a cause of MODY, but even if genetic testing is considered, many commercial testing panels do not include these genes, despite the significant difference in treatment that can result due to sulfonylurea (SU) responsiveness. Clinical Case: The proband was diagnosed with DM at 11 months old and fortuitously treated with SU for 3 years. He was switched to insulin and had poor DM control thereafter. Sister was diagnosed at 3.5 months old and had poor DM control on insulin. Mother was diagnosed with DM at 27 years old and treated with various medications including insulin. Genetic testing revealed that mother carried ABCC8 mutation R1380C previously described to cause transient NDM and/or later-onset DM consistent with her phenotype. Both children inherited this mutation from her and inherited a variant (L1148R) from their father without diabetes that has been reported in association with HI. The L1148R allele may reduce cell surface expression thereby increasing the relative expression and pathogenic effect of the R1380C allele that has not previously been described to cause permanent NDM. We assessed SU responsiveness by measuring maximal beta-cell function through combined mixed meal and arginine testing. Mother exhibited easily detectable C-peptide levels at baseline that improved by SU treatment. In contrast, the children displayed almost undetectable baseline beta-cell function with variable response to SU: the sister who had been chronically poorly controlled on insulin therapy displayed barely improved C-peptide production, while her brother who had previously been treated with SU as an infant had markedly improved beta-cell function on SU. Within two months of continued treatment with high doses of SU only, he was able to start lowering his SU dose with improved glycemia. His sister was started on high-dose SU in addition to insulin, but continued to have difficulty adhering to her treatment regimen. Her blood sugar improved after the addition of long-acting GLP-1 agonist (liraglutide) but she later became pregnant and returned to insulin only. Her glycemic control improved when re-started on SU after pregnancy. The mother exhibited excellent DM on a lower dose of exclusive SU therapy. Clinical Lesson: Genetic testing can dramatically alter management and must be pursued in both NDM and family members with diabetes later in life. Careful assessment of clinical characteristics along with genetic testing for segregation patterns in family members can greatly improve understanding of the causality of previous uncharacterized variants.

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Imaging Beta-Cell Function in the Pancreas of Non-Human Primates Using a Zinc-Sensitive MRI Contrast Agent

Frontiers in Endocrinology ◽

10.3389/fendo.2021.641722 ◽

2021 ◽

Vol 12 ◽

Author(s):

Veronica Clavijo Jordan ◽

Catherine D. G. Hines ◽

Liza T. Gantert ◽

Shubing Wang ◽

Stacey Conarello ◽

...

Keyword(s):

Beta Cell ◽

Contrast Agent ◽

Contrast Enhancement ◽

Beta Cells ◽

Beta Cell Function ◽

Pancreatic Beta Cells ◽

Cell Function ◽

Mri Contrast Agent ◽

C Peptide

Non-invasive beta cell function measurements may provide valuable information for improving diabetes diagnostics and disease management as the integrity and function of pancreatic beta cells have been found to be compromised in Type-1 and Type-2 diabetes. Currently, available diabetes assays either lack functional information or spatial identification of beta cells. In this work, we introduce a method to assess the function of beta cells in the non-human primate pancreas non-invasively with MRI using a Gd-based zinc(II) sensor as a contrast agent, Gd-CP027. Additionally, we highlight the role of zinc(II) ions in the paracrine signaling of the endocrine pancreas via serological measurements of insulin and c-peptide. Non-human primates underwent MRI exams with simultaneous blood sampling during a Graded Glucose Infusion (GGI) with Gd-CP027 or with a non-zinc(II) sensitive contrast agent, gadofosveset. Contrast enhancement of the pancreas resulting from co-release of zinc(II) ion with insulin was observed focally when using the zinc(II)-specific agent, Gd-CP027, whereas little enhancement was detected when using gadofosveset. The contrast enhancement detected by Gd-CP027 increased in parallel with an increased dose of infused glucose. Serological measurements of C-peptide and insulin indicate that Gd-CP027, a high affinity zinc(II) contrast agent, potentiates their secretion only as a function of glucose stimulation. Taken in concert, this assay offers the possibility of detecting beta cell function in vivo non-invasively with MRI and underscores the role of zinc(II) in endocrine glucose metabolism.

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Decline Pattern of Beta-cell Function in Adult-onset Latent Autoimmune Diabetes: an 8-year Prospective Study

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa205 ◽

2020 ◽

Vol 105 (7) ◽

pp. 2331-2340 ◽

Cited By ~ 1

Author(s):

Xia Li ◽

Yan Chen ◽

Yuting Xie ◽

Yufei Xiang ◽

Xiang Yan ◽

...

Keyword(s):

Beta Cell ◽

Prospective Study ◽

Beta Cell Function ◽

Cell Function ◽

Autoimmune Diabetes ◽

Dropout Rate ◽

Acid Decarboxylase ◽

Stable Mode ◽

C Peptide

Abstract Objective To explore the decline pattern and possible determinants of beta-cell function progression in patients with latent-onset autoimmune diabetes in adults (LADA). Research Design and Methods In this 8-year prospective study, 106 LADA individuals underwent annual follow-up and their pattern of beta-cell function progression was assessed. Beta-cell function failure was defined by fasting C-peptide (FCP) < 75 pmol/L. Other clinical characteristics, including age of onset, body mass index (BMI), and glutamic acid decarboxylase autoantibody (GADA) titer, were analyzed to find out possible determinants of beta-cell function progression. Results The dropout rate was 4.7%. During the 8-year follow-up period, 29 (28.7%) of the 101 subjects developed beta-cell function failure. The decline pattern of C-peptide in LADA was biphasic, showing an initial rapid linear progression and then followed by a stable mode. The declination speed of FCP was 55.19 pmol/L/year (95% CI, −62.54 to −47.84, P < 0.001) during the first 5 years and 4.62 pmol/L/year (95% CI, −69.83 to 60.60, P = 0.790) thereafter. Further analysis showed that GADA titer was the most valuable discriminatory parameter related to a higher risk of development of beta-cell function failure (GADA titer of 173.5 WHO units/mL; area under the curve [AUC], 0.824). Beta-cell function failure occurred in 71.3% of high-GADA titer patients while only 6.2% of low-titer patients. Conclusions The decline pattern of C-peptide was a fast-followed-by-slow biphasic mode, with about a quarter of LADA patients developing beta-cell function failure during the first 8 years. GADA titer less than 173.5 WHO units /mL was propitious for the preservation of beta-cell function.

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Glycemia, Beta-Cell Function and Sensitivity to Insulin in Mildly to Critically Ill Covid-19 Patients

Medicina ◽

10.3390/medicina57010068 ◽

2021 ◽

Vol 57 (1) ◽

pp. 68 ◽

Cited By ~ 1

Author(s):

Ioannis Ilias ◽

Aristidis Diamantopoulos ◽

Maria Pratikaki ◽

Efthymia Botoula ◽

Edison Jahaj ◽

...

Keyword(s):

Insulin Secretion ◽

Beta Cell ◽

Critically Ill ◽

Beta Cell Function ◽

Cell Function ◽

Model Assessment ◽

Secondary Diabetes ◽

C Peptide ◽

Number Of Patients ◽

Patients With Diabetes

Background and objectives: Critically and non-critically ill patients with SARS-CoV-2 infection (Covid-19) may present with higher-than-expected glycemia, even in the absence of diabetes. With this study we aimed to assess glucose, glycemic gap (GlyG) and insulin secretion/sensitivity measures in patients with Covid-19. Materials and Methods: We studied, upon admission, 157 patients with Covid-19 (84: in wards and 73: in intensive care units; ICU); 135 had no history of diabetes. We measured blood glucose upon admission as well as glycated hemoglobin (A1c), plasma insulin and C-peptide. We calculated the GlyG and the Homeostasis Model Assessment 2 (HOMA2) estimates of steady state beta cell function (HOMA2%B) and insulin sensitivity (HOMA2%S). Statistical assessment was done with analysis or the Kruskal-Wallis test. Results: Compared to patients in the wards without diabetes, patients with diabetes in the wards, as well as patients in the ICU (without or with diabetes) had higher admission glycemia. The GlyG was significantly higher in patients without diabetes in the ICU compared to patients without diabetes in the wards, while HOMA2%B based on glucose and insulin was significantly higher in the ICU patients compared to patients in the wards. Of all the parameters, HOMA2%S based on C-peptide/glucose was higher in survivors (n = 133). Conclusions: In our series of patients with Covid-19, a substantial number of patients with and without diabetes had admission hyperglycemia and those who were critically ill may have had compromised insulin secretion and lowered sensitivity to insulin. These findings lend credence to reports of association between Covid-19 and hyperglycemia/secondary diabetes.

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Pancreatic beta-cell function and glucose metabolism in human segmental pancreas and kidney transplantation

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1993.264.3.e441 ◽

1993 ◽

Vol 264 (3) ◽

pp. E441-E449 ◽

Cited By ~ 2

Author(s):

E. Christiansen ◽

H. B. Andersen ◽

K. Rasmussen ◽

N. J. Christensen ◽

K. Olgaard ◽

...

Keyword(s):

Insulin Secretion ◽

Glucose Metabolism ◽

Beta Cell ◽

Kidney Transplant ◽

Beta Cell Function ◽

Cell Function ◽

Pancreatic Beta Cell ◽

Secretion Rate ◽

C Peptide ◽

Insulin Secretion Rate

beta-Cell function and glucose metabolism were studied in eight insulin-dependent diabetic recipients of combined segmental pancreas and kidney transplant with peripheral insulin delivery (Px), in eight nondiabetic kidney-transplant individuals (Kx), and in eight normal subjects (Ns) after three consecutive mixed meals. All subjects had normal fasting plasma glucose, but increased basal levels of C-peptide were demonstrated in the transplant groups (P < 0.05 relative to Ns). Postprandial hyperglycemia was increased 14% in Kx and 32% in Px (P < 0.05), whereas compared with Ns postprandial C-peptide levels were increased three- and twofold, respectively, in Kx and Px (P < 0.05). Compared with Ns basal insulin secretion rate (combined model) was increased 2-fold in Kx and 1.4-fold in Px (P < 0.05). Maximal insulin secretion rate was reduced 25% in Px compared with Kx (P < 0.05) but not different from that of Ns (P NS). Also, maximal insulin secretion rate occurred later in Px than in controls (Tmax: Px 50 min, Kx 30 min, and Ns 32 min; P < 0.05). The total integrated insulin secretion was increased 1.4-fold in Px compared with Ns (P < 0.05) but decreased 1.4-fold compared with Kx (P < 0.05). Fasting and postprandial proinsulin-to-C-peptide molar ratios were inappropriately increased in Px compared with Kx and Ns. Basal hepatic glucose production was increased 43% in Px and 33% in Kx compared with Ns (P < 0.05). Postprandial total systemic glucose appearance was similar in all three groups, whereas peripheral glucose disposal was 15% reduced in Px (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

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Role of insulin sensitivity and beta cell function in the development of periodontal disease in adults without diabetes

Journal Of Clinical Periodontology ◽

10.1111/jcpe.12162 ◽

2013 ◽

Vol 40 (12) ◽

pp. 1079-1086 ◽

Cited By ~ 15

Author(s):

Petra Timonen ◽

Tuomas Saxlin ◽

Matti Knuuttila ◽

Anna Liisa Suominen ◽

Antti Jula ◽

...

Keyword(s):

Insulin Sensitivity ◽

Periodontal Disease ◽

Beta Cell ◽

Beta Cell Function ◽

Cell Function

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A Triple Threat? The Role of Diet, Nutrition, and the Microbiota in T1D Pathogenesis

Frontiers in Nutrition ◽

10.3389/fnut.2021.600756 ◽

2021 ◽

Vol 8 ◽

Author(s):

Emma E. Hamilton-Williams ◽

Graciela L. Lorca ◽

Jill M. Norris ◽

Jessica L. Dunne

Keyword(s):

Beta Cell ◽

Intestinal Microbiota ◽

Beta Cell Function ◽

Cell Function ◽

The Body ◽

Islet Autoimmunity ◽

Potential Mechanism ◽

Modifiable Factors ◽

And Function

In recent years the role of the intestinal microbiota in health and disease has come to the forefront of medical research. Alterations in the intestinal microbiota and several of its features have been linked to numerous diseases, including type 1 diabetes (T1D). To date, studies in animal models of T1D, as well as studies in human subjects, have linked several intestinal microbiota alterations with T1D pathogenesis. Features that are most often linked with T1D pathogenesis include decreased microbial diversity, the relative abundance of specific strains of individual microbes, and altered metabolite production. Alterations in these features as well as others have provided insight into T1D pathogenesis and shed light on the potential mechanism by which the microbiota plays a role in T1D pathogenesis, yet the underlying factors leading to these alterations remains unknown. One potential mechanism for alteration of the microbiota is through diet and nutrition. Previous studies have shown associations of diet with islet autoimmunity, but a direct contributing factor has yet to be identified. Diet, through introduction of antigens and alteration of the composition and function of the microbiota, may elicit the immune system to produce autoreactive responses that result in the destruction of the beta cells. Here, we review the evidence associating diet induced changes in the intestinal microbiota and their contribution to T1D pathogenesis. We further provide a roadmap for determining the effect of diet and other modifiable factors on the entire microbiota ecosystem, including its impact on both immune and beta cell function, as it relates to T1D. A greater understanding of the complex interactions between the intestinal microbiota and several interacting systems in the body (immune, intestinal integrity and function, metabolism, beta cell function, etc.) may provide scientifically rational approaches to prevent development of T1D and other childhood immune and allergic diseases and biomarkers to evaluate the efficacy of interventions.

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Multi-Organ Crosstalk with Endocrine Pancreas: A Focus on How Gut Microbiota Shapes Pancreatic Beta-Cells

Biomolecules ◽

10.3390/biom12010104 ◽

2022 ◽

Vol 12 (1) ◽

pp. 104

Author(s):

Elisa Fernández-Millán ◽

Carlos Guillén

Keyword(s):

Beta Cell ◽

Beta Cells ◽

Cell Biology ◽

Pancreatic Beta Cells ◽

Metabolic Diseases ◽

Cell Function ◽

Cell Mass ◽

Beta Cell Mass ◽

Short Chain Fatty Acids

Type 2 diabetes (T2D) results from impaired beta-cell function and insufficient beta-cell mass compensation in the setting of insulin resistance. Current therapeutic strategies focus their efforts on promoting the maintenance of functional beta-cell mass to ensure appropriate glycemic control. Thus, understanding how beta-cells communicate with metabolic and non-metabolic tissues provides a novel area for investigation and implicates the importance of inter-organ communication in the pathology of metabolic diseases such as T2D. In this review, we provide an overview of secreted factors from diverse organs and tissues that have been shown to impact beta-cell biology. Specifically, we discuss experimental and clinical evidence in support for a role of gut to beta-cell crosstalk, paying particular attention to bacteria-derived factors including short-chain fatty acids, lipopolysaccharide, and factors contained within extracellular vesicles that influence the function and/or the survival of beta cells under normal or diabetogenic conditions.

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