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

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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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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Glutamic acid decarboxylase (GAD65) autoantibodies in prediction of beta-cell function and remission in recent-onset IDDM after cyclosporin treatment. The Canadian-European Randomized Control Trial Group

Diabetes ◽

10.2337/diabetes.43.11.1291 ◽

1994 ◽

Vol 43 (11) ◽

pp. 1291-1296 ◽

Cited By ~ 9

Author(s):

J. S. Petersen ◽

T. Dyrberg ◽

A. E. Karlsen ◽

J. Molvig ◽

B. Michelsen ◽

...

Keyword(s):

Beta Cell ◽

Glutamic Acid Decarboxylase ◽

Randomized Control Trial ◽

Beta Cell Function ◽

Cell Function ◽

Acid Decarboxylase ◽

Trial Group ◽

Recent Onset ◽

Cyclosporin Treatment ◽

Randomized Control

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Autoantigen Treatment in Type 1 Diabetes: Unsolved Questions on How to Select Autoantigen and Administration Route

International Journal of Molecular Sciences ◽

10.3390/ijms21051598 ◽

2020 ◽

Vol 21 (5) ◽

pp. 1598 ◽

Cited By ~ 3

Author(s):

Johnny Ludvigsson

Keyword(s):

Type 1 Diabetes ◽

Beta Cell ◽

Beta Cell Function ◽

Cell Function ◽

Human Subjects ◽

Subcutaneous Administration ◽

Acid Decarboxylase ◽

Recent Onset ◽

Prevention Trials

Autoantigen treatment has been tried for the prevention of type 1 diabetes (T1D) and to preserve residual beta-cell function in patients with a recent onset of the disease. In experimental animal models, efficacy was good, but was insufficient in human subjects. Besides the possible minor efficacy of peroral insulin in high-risk individuals to prevent T1D, autoantigen prevention trials have failed. Other studies on autoantigen prevention and intervention at diagnosis are ongoing. One problem is to select autoantigen/s; others are dose and route. Oral administration may be improved by using different vehicles. Proinsulin peptide therapy in patients with T1D has shown possible minor efficacy. In patients with newly diagnosed T1D, subcutaneous injection of glutamic acid decarboxylase (GAD) bound to alum hydroxide (GAD-alum) can likely preserve beta-cell function, but the therapeutic effect needs to be improved. Intra-lymphatic administration may be a better alternative than subcutaneous administration, and combination therapy might improve efficacy. This review elucidates some actual problems of autoantigen therapy in the prevention and/or early intervention of type 1 diabetes.

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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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Four-Year Follow-Up of Glucose Tolerance and Beta-Cell Function in Nondiabetic Cystic Fibrosis Patients

Hormone Research ◽

10.1159/000184591 ◽

1995 ◽

Vol 44 (2) ◽

pp. 45-50 ◽

Cited By ~ 13

Author(s):

F. De Luca ◽

T. Arrigo ◽

A. Di Benedetto ◽

A. Tedeschi ◽

C. Sferlazzas ◽

...

Keyword(s):

Cystic Fibrosis ◽

Glucose Tolerance ◽

Beta Cell ◽

Beta Cell Function ◽

Cell Function

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

Diabetes Mellitus ◽

10.14341/2072-0351-5628 ◽

2011 ◽

Vol 14 (2) ◽

pp. 12-17 ◽

Cited By ~ 2

Author(s):

Tatiana Vladimirovna Saprina ◽

F E Lazarenko ◽

T S Prokhorenko ◽

N V Ryazantseva ◽

Irina Nikolaevna Vorozhtsova

Keyword(s):

Immune Response ◽

Beta Cell ◽

Cell Function ◽

Solid Phase ◽

Autoimmune Diabetes ◽

Mononuclear Leukocytes ◽

Diagnostic Strategy ◽

C Peptide ◽

Significant Difference

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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Circulating C-Peptide: Measurement and Clinical Application

Annals of Clinical Biochemistry International Journal of Laboratory Medicine ◽

10.1177/000456328101800301 ◽

1981 ◽

Vol 18 (3) ◽

pp. 125-130 ◽

Cited By ~ 28

Author(s):

J Peter Ashby ◽

Brian M Frier

Keyword(s):

Beta Cell ◽

Beta Cell Function ◽

Plasma Insulin ◽

Cell Function ◽

Pancreatic Beta Cell ◽

Plasma Insulin Concentration ◽

C Peptide ◽

Clinical Disorders ◽

Pancreatic Beta Cell Function ◽

Secretory Capacity

Pancreatic beta-cell function is usually assessed by the measurement of plasma insulin concentration in various clinical situations. However, the advent of an assay for the measurement of connecting-peptide (C-peptide) concentration in plasma has provided a further method for the assessment of the secretory capacity of the pancreatic beta cell in clinical disorders, particularly in the investigation of hypoglycaemia. The metabolism and immunoassay methodology of C-peptide are reviewed, and its application in clinical practice is outlined.

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