Diabetes mellitus in patients with type 1 autoimmune pancreatitis at diagnosis and after corticosteroid therapy

Background:A high prevalence of diabetes mellitus(DM)coexisting with autoimmune pancreatitis(AIP)is observed.However,evidence on the circumstances under which corticosteroid therapy(CST)for AIP improves or worsens DM is scarce.This study aimed to demonstrate and identify predictors of DM control under the influence of CST.Methods:Patients diagnosed with type 1 AIP were enrolled from a prospectively maintained cohort and were classified into three groups according to the chronology in which AIP and DM were diagnosed:pre-existing DM(pDM),concurrent DM(cDM),and non-DM(nDM).The responses of DM to CST were assessed when corticosteroid was ceased or tapered to a maintenance dose and classified as‘improvement’and‘non-improvement’(including‘no change’and‘exacerbation’).Results:Among 101 patients with type 1 AIP,52(51.5%)patients were complicated with DM at the time of AIP diagnosis,with 36 patients in the cDM group and 16 patients in the pDM group.The incidences of diffuse pancreatic swelling(72.2%)and pancreatic body/tail involvement(91.7%)were significantly higher in the cDM group than in both the pDM and nDM groups.Of the 52 patients with DM,CST was administered in 48 cases.Multivariate logistic analysis identified that elevated serum gamma-glutamyl transferase(GGT)level at AIP diagnosis[odds ratio(OR)=0.032,95%confidence interval(CI):0.003-0.412,P=0.008]and pancreatic atrophy after CST(OR=0.027,95%CI:0.003-0.295,P=0.003)were negatively associated with DM control improvement.Conclusions:Patients with diffuse pancreatic swelling and pancreatic body/tail involvement in pancreatitis tended to be complicated with cDM at AIP diagnosis.CST exerted a beneficial effect on the clinical course of DM in nearly half of the AIP patients complicated with DM at diagnosis,particularly in those without elevated serum GGT levels at diagnosis and who did not experience pancreatic atrophy after CST.

Interleukin-35: A key player managing pre-diabetes and chronic inflammatory type 1 autoimmune diabetes

Interleukin-35(IL-35)is a novel protein comprising IL-12αand IL-27βchains.The IL12A and EBI3 genes are responsible for its production.The study of IL-35 has experienced a substantial increase in interest in recent years,as demonstrated by many research papers.Recent clinical studies have shown that individuals who do not have a C-peptide have notably reduced amounts of IL-35 in their blood serum.This is accompanied by a drop in the percentage of IL-35+Treg cells,regulatory B cells,and CD8+FOXP3+cells that produce IL-35.This article em-phasizes the potential significance of IL-35 expression in governing the immune response and its involvement in chronic inflammatory autoimmune diabetes in pancreatic inflammation.It demonstrates IL-35's ability to regulate cytokine proportions,modulate B cells,and protect against autoimmune diabetes.However,further investigation is necessary to ascertain the precise mechanism of IL-35,and meticulous planning is essential for clinical studies.

Maturity-onset diabetes of the young type 9 or latent autoimmune diabetes in adults:A case report and review of literature

BACKGROUND Maturity-onset diabetes of the young(MODY)is a monogenic genetic disease often clinically misdiagnosed as type 1 or type 2 diabetes.MODY type 9(MODY9)is a rare subtype caused by mutations in the PAX4 gene.Currently,there are limited reports on PAX4-MODY,and its clinical characteristics and treatments are still unclear.In this report,we described a Chinese patient with high autoimmune antibodies,hyperglycemia and a site mutation in the PAX4 gene.CASE SUMMARY A 42-year-old obese woman suffered diabetes ketoacidosis after consuming substantial amounts of beverages.She had never had diabetes before,and no one in her family had it.However,her autoantibody tested positive,and she managed her blood glucose within the normal range for 6 mo through lifestyle interventions.Later,her blood glucose gradually increased.Next-generation sequencing and Sanger sequencing were performed on her family.The results revealed that she and her mother had a heterozygous mutation in the PAX4 gene(c.314G>A,p.R105H),but her daughter did not.The patient is currently taking liraglutide(1.8 mg/d),and her blood glucose levels are under control.Previous cases were retrieved from PubMed to investigate the relationship between PAX4 gene mutations and diabetes.CONCLUSION We reported the first case of a PAX4 gene heterozygous mutation site(c.314G>A,p.R105H),which does not appear pathogenic to MODY9 but may facilitate the progression of latent autoimmune diabetes in adults.

Association of autoimmune thyroid disease with type 1 diabetes mellitus and its ultrasonic diagnosis and management

As a common hyperglycemic disease,type 1 diabetes mellitus(T1DM)is a complicated disorder that requires a lifelong insulin supply due to the immunemediated destruction of pancreaticβcells.Although it is an organ-specific autoimmune disorder,T1DM is often associated with multiple other autoimmune disorders.The most prevalent concomitant autoimmune disorder occurring in T1DM is autoimmune thyroid disease(AITD),which mainly exhibits two extremes of phenotypes:hyperthyroidism[Graves'disease(GD)]and hypothyroidism[Hashimoto's thyroiditis,(HT)].However,the presence of comorbid AITD may negatively affect metabolic management in T1DM patients and thereby may increase the risk for potential diabetes-related complications.Thus,routine screening of thyroid function has been recommended when T1DM is diagnosed.Here,first,we summarize current knowledge regarding the etiology and pathogenesis mechanisms of both diseases.Subsequently,an updated review of the association between T1DM and AITD is offered.Finally,we provide a relatively detailed review focusing on the application of thyroid ultrasonography in diagnosing and managing HT and GD,suggesting its critical role in the timely and accurate diagnosis of AITD in T1DM.

Pembrolizumab autoimmune related diabetes:Moving forward,keep learning

Immune checkpoint inhibitors(and more specifically programmed cell death 1/programmed cell death ligand 1 inhibitors as Pembrolizumab)initiated a revolution in the field of melanoma and have now expanded to several tumor subtypes and in increasingly broader clinical contexts,including the adjuvant and neoadjuvant setting,with potentially curable patients and prolonged survival.The side effects related to these drugs include a wide spectrum of manifestations,with endocrinological adverse events being some of the most frequent.Pembrolizumab-induced type 1 diabetes mellitus is an infrequent but potentially serious and not clearly reversible side effect that possesses characteristic clinical features and has high morbidity and mortality,with a chronic impact on quality of life.The etiopathogenesis of this phenomenom needs to be further investigated and a collaborative effort through the involvement of oncologists and other medical specialists is necessary for the correct identification and management of patients at risk.

Six-year follow-up of pancreatic β cell function in adults with latent autoimmune diabetes

AIM: To investigate the characteristics of the progression of islet β cell function in Chinese latent autoimmune diabetes in adult (LADA) patients with glutamic acid decarboxylase antibody (GAD-Ab) positivity, and to explore the prognostic factors for β cell function. METHODS: Forty-five LADA patients with GAD-Ab positivity screened from phenotypic type 2 diabetic (T2DM) patients and 45 T2DM patients without GAD-Ab matched as controls were followed-up every 6 mo. Sixteen patients in LADA1 and T2DM1 groups respectively have been followed-up for 6 years, while 29 patients in LADA2 and T2DM2 groups respectively for only 1.5 years. GAD-Ab was determined by radioligand assay, and C-peptides (CP) by radioimmune assay.RESULTS: The percentage of patients whose fasting CP(FCP) decreased more than 50% compared with thebaseline reached to 25.0% at 1.5th year in LADA1 group, and FCP level decreased (395.8±71.5 vs 572.8±72.3 pmol/L, P＜0.05) at 2.5th year and continuously went down to the end of follow-up. No significant changes of the above parameters were found in T2DM1 group. The average decreased percentages of FCP per year in LADA and T2DM patients were 15.8% (4.0-91.0%) and 5.2% (-3.5 to 35.5%, P= 0.000) respectively. The index of GAD-Ab was negatively correlated with the FCP in LADA patients (rs= -0.483, P = 0.000). The decreased percentage of FCP per year in LADA patients were correlated with GAD-Ab index, body mass index (BMI) and age at onset (rs = 0.408, -0.301 and -0.523 respectively, P＜0.05). Moreover, GAD-Ab wasthe only risk factor for predicting βcell failure in LADA patients (B = 1.455, EXP (B) = 4.283, P = 0.023). CONCLUSION: The decreasing rate of islet β cell function in LADA, being highly heterogeneous, is three times that of T2DM patients. The titer of GAD-Ab is an important predictor for the progression of islet β cell function, and age at onset and BMI could also act as the predictors.

Study of Tripterygium Associated with Nicotinamide in Treating Late-onset Autoimmune Diabetes Mellitus in Adults

Objective: To explore the effect of Tripterygium polyglycoside (TP) associated with nicotinamide on the islet cell function, immune parameters and lipoperoxide (LPO) in adult patients with late-onset autoimmune diabetes mellitus (LADA). Methods: Thirty-six cases of LADA were randomly divided into three groups: TP group (n=12), treated with TP plus orally taken metformin; combined treatment group (n= 12), treated with TP combined with nicotinamide and metformin, and control group (n=12) treated with metformin alone. They were followed-up for 18 months. Results: (1) Compared with the control group after 9 months of treatment, postprandial plasma glucose and LPO in combined treatment group were decreased (P <0.05), and the postprandial C-peptide was higher (P<0.05). At the 18th month, the value of postprandial C-peptide in the TP and combined treatment group was higher than that in the control group. The slL-2R level of both TP and combined treatment groups were lowered (P<0.01); (2) Islet cell antibody (ICA) positive of 5 cases in the TP group and 6 cases in the combined treatment group got converted to the negative respectively , while only one in the control group at the time (P<0.05); (3) The level of LPO in the combined treatment group was significantly lower than that in the TP group at the 18th month of treatment (P<0. 05). Conclusion: TP combined with nicotinamide played a role in immunity regulation, decreasing the titer of islet cell antibody and slL-2R, which also reduced the production of LPO and had a tendency to improve islet cell function in early LADA patients.

Gestational diabetes mellitus combined with fulminant type 1 diabetes mellitus, four cases of double diabetes: A case report

BACKGROUND Fulminant type 1 diabetes mellitus(FT1DM)that occurs during pregnancy or the perinatal period is known as pregnancy-related FT1DM(PF),always without history of abnormal glucose metabolism.Here,we present four patients who developed FT1DM during treatment but were first diagnosed with gestational diabetes mellitus(GDM).CASE SUMMARY The clinical data of four patients with GDM combined with FT1DM admitted to our hospital between July 2018 and April 2021 were collected,and the patients and their infants were followed up.All patients were diagnosed with GDM during the second trimester and were treated.The blood glucose level elevated suddenly during the third trimester and then were diagnosed with FT1DM.Two patients had an insulin allergy,and two had symptoms of upper respiratory tract infection before onset.One patient developed ketoacidosis,and three developed ketosis.Two patients had cesarean section deliveries,and two had vaginal deliveries.The growth and development of the infants were normal.C-peptide levels were lower than those at onset,suggesting progressive impairment of islet function.The frequencies of the DRB109:01,DQB103:03,DQA103:02,DPA101:03,DPA102:02,DPB105:01,DRB401:03,G 01:01,and G 01:04 human leukocyte antigen(HLA)-G alleles were high in the present study.CONCLUSION In comparison with pregnancy-associated FT1DM(PF),patients with GDM combined with FT1DM had an older age of onset,higher body mass index,slower onset,fewer prodromal symptoms,and less acidosis.The pathogenesis may be due to various factors affecting the already fragileβ-cells of GDM patients with genetically susceptible class II HLA genotypes.We speculate that GDM combined with FT1DM during pregnancy,referred to as“double diabetes,”is a subtype of PF with its own unique characteristics that should be investigated further.

Monogenic diabetes in children:An underdiagnosed and poorly managed clinical dilemma

Monogenic diabetes,constituting 1%-2%of global diabetes cases,arises from single gene defects with distinctive inheritance patterns.Despite over 50 associated genetic disorders,accurate diagnoses and management of monogenic diabetes remain inadequate,underscoring insufficient clinician awareness.The disease spectrum encompasses maturity-onset diabetes of the young(MODY),characterized by distinct genetic mutations affecting insulin secretion,and neonatal diabetes mellitus(NDM)-a heterogeneous group of severe hyperglycemic disorders in infants.Mitochondrial diabetes,autoimmune monogenic diabetes,genetic insulin resistance and lipodystrophy syndromes further diversify the monogenic diabetes landscape.A tailored approach based on phenotypic and biochemical factors to identify candidates for genetic screening is recommended for suspected cases of MODY.NDM diagnosis warrants immediate molecular genetic testing for infants under six months.Identifying these genetic defects presents a unique opportunity for precision medicine.Ongoing research aimed to develop cost-effective genetic testing methods and gene-based therapy can facilitate appropriate identification and optimize clinical outcomes.Identification and study of new genes offer a valuable opportunity to gain deeper insights into pancreatic cell biology and the pathogenic mechanisms underlying common forms of diabetes.The clinical review published in the recent issue of World Journal of Diabetes is such an attempt to fill-in our knowledge gap about this enigmatic disease.

Role of cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes pathway in diabetes and its complications

Diabetes mellitus(DM)is one of the major causes of mortality worldwide,with inflammation being an important factor in its onset and development.This review summarizes the specific mechanisms of the cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS)-stimulator of interferon genes(STING)pathway in mediating inflammatory responses.Furthermore,it compre-hensively presents related research progress and the subsequent involvement of this pathway in the pathogenesis of early-stage DM,diabetic gastroenteropathy,diabetic cardiomyopathy,non-alcoholic fatty liver disease,and other complic-ations.Additionally,the role of cGAS-STING in autonomic dysfunction and intes-tinal dysregulation,which can lead to digestive complications,has been discuss-ed.Altogether,this study provides a comprehensive analysis of the research advances regarding the cGAS-STING pathway-targeted therapeutic agents and the prospects for their application in the precision treatment of DM.

WJD 5^(th) Anniversary Special Issues(3): Type 1 diabetes Distinct clinical and laboratory characteristics of latent autoimmune diabetes in adults in relation to type 1 and type 2 diabetes mellitus

Ever since its first appearance among the multiple forms of diabetes,latent autoimmune diabetes in adults(LADA),has been the focus of endless discussions concerning mainly its existence as a special type of diabetes.In this mini-review,through browsing important peer-reviewed publications,(original articles and reviews),we will attempt to refresh our knowledge regarding LADA hoping to enhance our understanding of this controversial diabetes entity.A unique combination of immunological,clinical and metabolic characteristics has been identified in this group of patients,namely persistent islet cell antibodies,high frequency of thyroid and gastric autoimmunity,DR3 and DR4 human leukocyte antigen haplotypes,progressive loss of beta cells,adult disease onset,normal weight,defective glycaemic control,and without tendency to ketoacidosis.Although anthropomorphic measurements are useful as a first line screening,the detection of C-peptide levels and the presence of glutamic acid decarboxylase(GAD)autoantibodies is undoubtedly the sine qua non condi-tion for a confirmatory LADA diagnosis.In point of fact,GAD autoantibodies are far from being solely a biomarker and the specific role of these autoantibodies in disease pathogenesis is still to be thoroughly studied.Nevertheless,the lack of diagnostic criteria and guidelines still puzzle the physicians,who struggle between early diagnosis and correct timing for insulin treatment.

Type 1 diabetes and polyglandular autoimmune syndrome: A review

Type 1 diabetes(T1D) is an autoimmune disorder caused by inflammatory destruction of the pancreatic tissue. The etiopathogenesis and characteristics of the pathologic process of pancreatic destruction are well described. In addition, the putative susceptibility genes for T1 D as a monoglandular disease and the relation to polyglandular autoimmune syndrome(PAS) have also been wellexplored. The incidence of T1 D has steadily increased in most parts of the world, especially in industrialized nations. T1 D is frequently associated with autoimmune endocrine and non-endocrine diseases and patients with T1 D are at a higher risk for developing several glandular autoimmune diseases. Familial clustering is observed, which suggests that there is a genetic predisposition. Various hypotheses pertaining to viral- and bacterialinduced pancreatic autoimmunity have been proposed, however a definitive delineation of the autoimmune pathomechanism is still lacking. In patients with PAS, pancreatic and endocrine autoantigens either colocalize on one antigen-presenting cell or are expressed on two/various target cells sharing a common amino acid, which facilitates binding to and activation of T cells. The most prevalent PAS phenotype is the adult type 3 variant or PAS type Ⅲ, which encompasses T1 D and autoimmune thyroid disease. This review discusses the findings of recent studies showing noticeable differences in the genetic background and clinical phenotype of T1 D either as an isolated autoimmune endocrinopathy or within the scope of polyglandular autoimmune syndrome.

Latent autoimmune diabetes in adults:A distinct but heterogeneous clinical entity

Latent autoimmune diabetes in adults(LADA) accounts for 2-12 of all cases of diabetes.Patients are typically diagnosed after 35 years of age and are often misdiagnosed as type Ⅱ Diabetes Mellitus(DM).Glycemic control is initially achieved with sulfonylureas but patients eventually become insulin dependent more rapidly than with type Ⅱ DM patients.Although they have a type Ⅱ DM phenotype,patients have circulating beta(β) cell autoantibodies,a hallmark of type Ⅰ DM.Alternative terms that have been used to describe this condition include type 1.5 diabetes,latent type Ⅰ diabetes,slowly progressive Insulin Dependent Diabetes Mellitus,or youth onset diabetes of maturity.With regards to its autoimmune basis and rapid requirement for insulin,it has been suggested that LADA is a slowly progressive form of type Ⅰ DM.However,recent work has revealed genetic and immunological differences between LADA and type Ⅰ DM.The heterogeneity of LADA has also led to the proposal of criteria for its diagnosis by the Immunology of Diabetes Society.Although many workers have advocated a clinically oriented approach for screening of LADA,there are no universally accepted criteria for autoantibody testing in adult onset diabetes.Following recent advances in immunomodulatory therapies in type Ⅰ DM,the same strategy is being explored in LADA.This review deals with the contribution of the genetic,immunological and metabolic components involved in the pathophysiology of LADA and recent approaches in screening of this distinct but heterogeneous clinical entity.

Sintilimab-induced autoimmune diabetes:A case report and review of the literature

BACKGROUND With the widespread application of immune checkpoint inhibitor(ICI)therapy,the number of immune-related adverse effects(irAEs)has increased over the years.Autoimmune diabetes mellitus(DM)is a rare irAEs of ICIs and can be troublesome and life threatening.CASE SUMMARY We report a 78-year-old woman with no history of diabetes who presented with hyperglycemia up to 23.4 mmol/L(random blood glucose level)after 14 courses of sintilimab.Hemoglobin A1c was 8.2%,fasting insulin was 0.29 mIU/mL,and fasting C-peptide was decreased to a level with negative autoantibodies.Combing her medical history and laboratory examination,she was diagnosed with programmed cell death(PD)-1-inhibitor-induced,new-onset autoimmune DM.After controlling her blood glucose,she was treated with daily insulin by subcutaneous injection.She was allowed to continue anti-PD-1 therapy and she still obtained some therapeutic efficacy.We also reviewed some published cases(n=36)of PD-1/PD-ligand 1(PD-L1)inhibitor-induced DM.We also discuss potential pathogenic mechanisms,clinical features,prognostic markers(βcell antibodies,human leukocyte antigen type,PD-L1 Level)of this rare adverse effect.CONCLUSION It is important for all clinicians to be aware of DM as an irAEs of ICIs.

Nursing a patient with latent autoimmune diabetes in adults with insulin-related lipodystrophy,allergy,and exogenous insulin autoimmune syndrome:A case report

BACKGROUND Latent autoimmune diabetes in adults(LADA)is a special type of type 1 diabetes mellitus.During the early stages,patients with LADA are treated with oral antidiabetics.However,insulin treatment is still required as islet function gradually declines.Once patients have developed insulin allergy,clinical treatment and nursing care become very challenging.CASE SUMMARY Here,we report a case of LADA with insulin-related lipodystrophy,allergy,and exogenous insulin autoimmune syndrome during insulin treatment,thus making it very difficult to effectively control glucose levels with insulin.We attempted subcutaneous injection and an insulin pump to desensitize the patient’s response to insulin,and finally assisted the doctor to select the appropriate insulin treatment for the patient.We describe the management of this patient from a nursing viewpoint.CONCLUSION We summarize the nursing experience of a case with complex insulin allergy requiring desensitization treatment.Our approach is very practical and can be applied to similar patients needing insulin desensitization.

Status of autoimmune diabetes 20-year after generation of BDC2.5-TCR transgenic non-obese diabetic mouse

Type 1 diabetes(T1D) is an autoimmune disease that results from the destruction of insulin-producing cells by autoreactive T cells,leading to lifelong dependency on insulin therapy and increased risk of long-term cardiovascular complications.Here we take the opportunity of the 20thanniversary of the generation of the BDC2.5 TCR transgenic non-obese diabetic(NOD) mouse model,to provide a brief overview of the significant progress that has been made in understanding the role of T cells in the disease pathogenesis period.This included development of hundreds of reagents that block or even reverse new-onset disease by directly or indirectly controlling T cells.We also reflect on the sobering fact that none of these strategies has shown significant efficacy in clinical trials and discuss potential reasons hindering translation of the preclinical findings into successful therapeutic strategies and potential ways forward.

DIABETOGENIC T CELLS INDUCE AUTOIMMUNE DIABETES IN BALB/c MICE

Objective To investigate the role of T cell and its subsets in the induction of insulifis and type 1 diabetes mellitus （T1DM） in BALB/c mice. Methods Autoimmune diabetes mellitus was developed by intraperitoneal injection of 40 mg/kg streptozotocin （STZ） daily for 5 consecutive days in BALB/c mice as sources of donor cells. Spleen cells from diabetic mice were then cultured for 7 days in the stimulation of interleukin-2 （IL-2） to harvest diabetogenic T cells, which were subse-quently transferred into normal BALB/c mice recipients. MTT, ELISA, and HE staining were used to analyze the lym- phocyte proliferation, cytokine （ IL-2, interferon-γ, IL-4, and IL-10） levels, and pathological changes in pancreatic is- lets. Results As few as 3×10^6 diabetogenic T cells successfully induced diabetes mellitus in recipients pretreated with STZ twice, whereas transfer of equal amount of normal splenocytes, T cell-depleted diabetogenic splenocytes, or diabe-togenic CD4^＋ T cells alone in recipients receiving STZ twice pretreatment was proved not to induce diabetes mellitus either. A markedly increased lymphocyte proliferation, high levels of interferon-γ/and IL-2 in the supernatants of diabeto-genic T cells were observed. In addition, a markedly enhanced lymphocyte proliferation, a high level of interferon-γ/secretion in serum, and numerous lymphocytes infiltration in pancreatic islets were detected in the diabetic mice induced by diabetogenic T cells transfer. Conclusions A novel T1DM murine model is established in STZ-pretreated BALB/c mice by adoptive transfer of diabetogenic T cells. CD4^＋ T cells with interferon-γ/may promote the onset of diabetes mellitus.

Type 1 diabetes and associated autoimmune diseases

BACKGROUND Common autoimmune diseases(AID)tend to occur together in the same individual and families.Type 1 diabetes(T1D)is caused by an autoimmuneinduced inflammatory destruction of the pancreatic tissue and clusters with several other AID.AIM To compare the demographic,clinical,and serological features of patients with single T1D vs those with T1D and associated AID.METHODS From October 1999 to February 2020,a total of 665 patients with T1D and their first-degree relatives were evaluated.RESULTS Compared to patients with isolated T1D,those with T1D+AID were older and had a higher female:male ratio.Average patient age and age at disease onset were higher in T1D+AID vs T1D only.The average time interval between T1D onset and the onset of a second glandular AID was markedly shorter than the time interval between T1D and the occurrence of a non-endocrine AID.T1Dspecific autoantibodies were more frequent in patients with T1D+AID and relatives vs those with T1D only.However,the prevalence of AID and autoantibodies against various tissues were found to be higher in relatives of patients with T1D only compared to relatives of patients with T1D+AID.CONCLUSION Annual serological and subsequent functional screening for AID in patients with T1D and their first-degree relatives is recommended.

The Predictive Value of Biopsy of the Pancreas and Its Therapeutic Impact in Autoimmune Diabetes

Diabetes Mellitus is by definition an end-stage organ failure. Type 1 diabetes mellitus (T1DM) is an autoimmune disease. Auto-inflammatory infiltrate appears to characterize the insulitis associated with T2DM. Recently, in 2013, Eva Corpos and colleagues described a comprehensive composition of peri-islet capsules and their basement membrane (BM). Virtanen I, Otonkoski T and Irving-Rodgers H.F. have reported similar descriptions few years earlier which have not been taken seriously as they deserve. Bluestone JA, Virtanen I and Irving-Rodgers H.F. and other colleagues reported that accumulation of the lymphocytes around the islets without invasion of the BM is the first step in disease induction (non-destructive insulitis phase). Invasion of the BM byleucocytic infiltration (destructive insulitis phase) occurs over a period of several years offering a good window for therapeutic intervention. Clinical symptoms appear only when 70% - 90% of β-cell mass are destroyed. This data emphasize the importance of identification and classification of such pathologic features by performing a biopsy of the pancreas with histoimmunochemistry analysis at the pre-hyperglycemic stage in a high risk genetically predisposed autoimmune suspected patient which may at least in part help to achieve new therapeutic approaches and help in halting the progression to end stage pancreatic disease (ESPD) known as diabetes mellitus. In this review we are going to emphasize the predictive role biopsy of the pancreas can build up a solid gold standard tool in diagnosis, stage and therapeutically follow up autoimmune diabetes mellitus.

Latent Autoimmune Diabetes in Adults Complicated by Persistent Isolated Glucosuria in the Absence of Hyperglycemia

Latent autoimmune diabetes in adults (LADA) is an autoimmune diabetes of adult-onset with the presence of diabetes associated autoantibodies. Familial renal glucosuria (FRG) is an inherited renal tubular disorder that causes persistent isolated glucosuria in the absence of hyperglycemia. We report a novel case of LADA and certain FRG. A 44-year-old man was admitted to our hospital for uncontrolled diabetes. Before admission, he had never suffered from diabetic coma and showed an improvement in HbA1c only with diet therapy. His HbA1c was 11.9% (107 mmol/mol), and anti-glutamic acid decarboxylase antibody was 13.0 U/mL. A glucagon stimulation test showed the decrease of insulin secretion: plasma C-peptide (CPR) 0 min, 0.69 ng/mL;CPR 6 min, 0.90 ng/mL. Analysis of genomic DNA revealed a novel heterozygous mutation in the SGLT2 coding gene, SLC5A2 (c.875G >A, p.Cys292Tyr), which was assessed as probably damaging with a score of 0.998 (sensitivity: 0.27;specificity: 0.99) by an in silico analysis. Therefore, he was diagnosed with LADA and certain FRG. He has not shown any symptoms and his HbA1c improved to 6.4% (46 mmol/mol) three months after the introduction of insulin therapy. Our case clearly implies the clinical effectiveness of SGLT2 inhibition in patients with LADA.