Onset Of Insulin-dependent Diabetes Research Articles

THU278 Hidden In The Immune System: Exogenous Insulin Antibody Syndrome In A Patient With Latent Autoimmune Diabetes In Adults

Abstract Disclosure: H.L. King: None. R. Nagappan: None. A. Sliwinska: None. Hidden in the Immune System: Exogenous Insulin Antibody Syndrome in a Patient with Latent Autoimmune Diabetes in Adults Background: Exogenous insulin antibody syndrome (EIAS) is a rare syndrome associated with insulin antibodies induced by exogenous insulin, found predominantly in patients with type 2 diabetes using various insulin formulations. Here, we present a case of young man previously diagnosed with type 2 diabetes, who was found to have severe refractory diabetic ketoacidosis (DKA) due to EIAS. Clinical Case: A 46-year-old man with a history of type 2 diabetes presented to an outside hospital for one week of fever and malaise. Laboratory studies were notable for serum glucose of 600 mg/dL (70-90mg/dL), HCO3 3 mmol/L (22-28mmol/L), and creatinine of 3.9 mg/dL (0.7-1.3mg/dL). He was diagnosed with DKA, shock and renal failure. During hospital stay, he remained on an insulin drip due to multiple unsuccessful attempts of transitioning to subcutaneous insulin, requiring over 1000 Units of insulin daily. This prompted insulin antibody testing that resulted elevated at >50U/mL (0-0.4U/mL), concerning for EIAS. Treatment was initiated with 5 days of IVIG and mycophenolate mofetil. During this treatment, his baseline insulin infusion rate of 30 Units/hr declined to 18 Units/hr, however at day 3, insulin requirements again increased. For better evaluation, quantitative insulin antibody values were requested and resulted as 362.5U/mL, followed by 350.9U/mL post IVIG treatment. After no significant improvement, patient was transferred to our hospital for further management of EIAS. Plasmapheresis was initiated followed by rituximab with plans for long term maintenance therapy. Dexamethasone was trialed but shortly after discontinued due concern of increased insulin resistance and hyperglycemia. Metformin was also started but discontinued due to concern of worsening acidosis in the setting of acute renal failure requiring CRRT. Ultimately, the patient was transitioned to subcutaneous U500 BID 75-150 Units based on scale. At discharge, metformin and pioglitazone were started. Due to the history of early onset insulin-dependent diabetes at age 30, he was tested for GAD-65 which resulted as positive at 0.28 nmol/L (<=0.02 nmol/L) and C peptide of 0.9ng/mL (0.8 - 3.9 ng/mL) consistent with LADA. Conclusion: EIAS is a rare and very challenging entity, increasing risks of severe ketoacidosis, hypoglycemic episodes and numerous other complications. Although mostly reported in type 2 diabetes, EIAS can occur in patients with LADA suggesting that autoimmunity may play a role. There is no FDA approved treatment, however attempts focus on eliminating antibodies by plasmapheresis, IVIG and immunotherapeutic agents. Presentation: Thursday, June 15, 2023

Wolfram syndrome: a case report with severe polyuria and secondary urological abnormalities

Wolfram syndrome is the condition characterized by juvenile onset diabetes mellitus and optic atrophy, which is also known as DIDMOAD. Classical Wolfram syndrome is a rare autosomal recessive disorder caused by mutations in WFS1, a gene involved in endoplasmic reticulum and mitochondrial function. Patients present with type 1 diabetes mellitus followed by optic atrophy in the first decade, diabetes insipidus and sensorineural deafness in the second decade, dilated renal outflow tracts as early as in the third decade, and various neurological abnormalities in the early fourth decade. We describe a case report of 14-year-old male child diagnosed as wolfram syndrome with type 1 diabetes mellitus, diabetes insipidus, deafness, optic atrophy and severe urological abnormalities. Patients who present with early onset insulin-dependent diabetes mellitus and optic atrophy together should be evaluated with respect to Wolfram Syndrome. If a patient, who is a known case of diabetes mellitus, presents with persistent polyuria or neurogenic bladder despite good glycemic control, suspicion of wolfram syndrome and further evaluation regarding the same must be made. Recognizing and timely management of this condition will help to improve the quality of life in the patient.

MON-LB121 New Onset Insulin Dependent Diabetes Mellitus Secondary to Treatment With Immune Checkpoint Inhibitor

Background: Checkpoint inhibitors, immunomodulatory antibodies that are used to enhance the immune system, have substantially improved the prognosis for patients with advanced malignancy like melanoma and lung cancer. Despite important clinical benefits, checkpoint inhibition is associated with a unique spectrum of side effects termed immune-related adverse events (irAEs). IrAEs include dermatologic, gastrointestinal, hepatic, endocrine, and other less common inflammatory events. Among them is endocrine toxicity, most commonly targeting the thyroid, pituitary, or adrenal glands. New-onset diabetes mellitus has been reported in only around 1% of patients in a recent study.Although rare, fulminant and even fatal toxicities may occur with immune checkpoint inhibitors, and therefore, prompt recognition and management is important. Here we are going to present a patient with new onset Insulin dependent Diabetes mellitus secondary to immunotherapy.It usually presents with diabetic ketoacidosis (DKA) and follows a rapid course. Awareness and prompt management are therefore key. History and investigations:62 year old lady diagnosed with Right Uveal melanoma more than 2 years ago and was treated with Enucleation followed by Rt prosthetic eye. Subsequently patient developed metastatic melanoma with subcutaneous lesion in right paravertebral region, right humoral head and right gluteal muscle. It was unclear whether patient had metastatic uveal or cutaneous melanoma. Other PMH includes were Hypertension and Anxiety.Patient was started on Ipilimumab (CTLA-4 inhibitor) and Nivolumab (PD1 inhibitor) 6 months ago, and Ipilimumab was stopped 8 weeks ago due to side effects but continued with Nivolumab. Other current medications were Amlodipine 10 mg once daily and AmitriptylinePatient was complaining of extreme fatigue last one week and was diagnosed with Hypothyroidism with TSH >100 mIU/L (Normal 0.27-4.2) and FT4 5.4 pmol/L (Normal 12.0-22.0), subsequently patient was started on Levothyroxine 50 mcg once daily.Patient presented to emergency department with polyuria and polydipsia last 5 days and also blurred vision for last 3 weeks. Patient did not notice any recent weight loss and had widespread pain, worse on skin lesions and hip joints but did not had any other specific complaints.Patient was current smoker with more than 40 pack year history and was taking 25 units of Alcohol per week for many years. Patient did not had any significant family history including any history diabetes in the family.On examination, patient was clinically dry with capillary refill time was 5 seconds.Investigations showed-Venous blood gas-Blood Glucose - Hi (mmol/L out of range), later 22.7 mmol/LPh- 7.291, PCO2 6.14 kPa, HCO3 19.3 mmol/L, Lactate 2.2 mmol/LBlood ketones- Hi (mmol/L out of range), later >7 mmol/LOther investigations showed-Na 131 mmol/L (Normal 135-145), K 5.4 mmol/L (Normal 3.5-5.1), Urea 7.1 mmol/L (Normal 1.7-8.3)Creatinine 139 umol/L (Normal 49-92)Bilirubin 12 umol/L (Normal 0-20), ALT 56 IU/L (Normal 10-35), ALP 157 IU/L (Normal 35-104)Amylase 59 IU/L (Normal 28-100), Albumin 48 g/L (Normal 34-50), Adjusted Calcium 2.56 mmol/L (Normal 2.2-2.6)9 am Cortisol 826 nmol/L (Normal 133-537), ACTH 28 ng/l (Normal 7.2-63.3)FSH 78.7 IU/L (Normal 25.8-134.8), LH 37.6 IU/L (Normal 7.7-58.5)IGF1 9.6 nmol/L (Normal 3.5-32.0), Prolactin 476 mIU/L (Normal 102-496)HbA1C 10.6% / 93 mmol/mmol (Normal 20-42)Serum Anti-GAD titre- 5 IU/L (Normal 0-10)Patient was started on treatment for Diabetic Ketoacidosis (DKA) with intravenous fluid and also fixed rate Insulin infusion according to protocol. Patient responded well to treatment and biochemical profile improved with initial treatment, subsequently patient was started on regular basal bolus Insulin regime with the help from the diabetes team. Discussion:Here we have presented a case with new onset Insulin dependent Diabetes Mellitus induced by immune checkpoint inhibitor. This kind of Diabetes progress rapidly to severe insulin deficiency compared to spontaneous Type 1 Diabetes, frequently patient present with DKA and do not go into remission. As this condition can develop rapidly, it is suggested that glucose level is to be monitored regularly and also to check HbA1C prior to initiating the immunotherapy. Their management requires complex Insulin regime to get good glycaemic control and add significant comorbidity along with the underlying cancer. The exact pathophysiologic mechanism and predictive biomarkers have not yet been established. The end result is permanent Insulin dependence. In future better characterization and further study is required to improve diagnosis and management, also to follow the natural history of this condition.Reference:1) Kotwal A, Haddox C, Block M, et alImmune checkpoint inhibitors: an emerging cause of insulin-dependent diabetesBMJ Open Diabetes Research and Care 2019;7:e000591. doi: 10.1136/bmjdrc-2018-0005912) Immune checkpoint inhibitors and type 1 diabetes mellitus: a case report and systematic review.de Filette JMK1, Pen JJ2, Decoster L3, Vissers T4, Bravenboer B1, Van der Auwera BJ5, Gorus FK5, Roep BO6,7, Aspeslagh S3, Neyns B3, Velkeniers B1, Kharagjitsingh AV1,

Autoimmune Endocrine Dysfunctions Associated with Cancer Immunotherapies.

Immune checkpoint inhibitors block the checkpoint molecules. Different types of cancer immune checkpoint inhibitors have been approved recently: CTLA-4 monoclonal antibodies (as ipilimumab); anti-PD-1 monoclonal antibodies (as pembrolizumab and nivolumab); and anti-PD-L1 monoclonal antibodies (as atezolizumab, avelumab, and durmalumab). We collect recent published results about autoimmune endocrine dysfunctions associated with cancer antibody immunotherapies. These agents cause a raised immune response leading to immune-related adverse events (irAEs), varying from mild to fatal, based on the organ system and severity. Immune-related endocrine toxicities are usually irreversible in 50% of cases, and include hypophysitis, thyroid dysfunctions, type 1 diabetes mellitus, and adrenal insufficiency. Anti-PD-1-antibodies are more frequently associated with thyroid dysfunctions (including painless thyroiditis, hypothyroidism, thyrotoxicosis, or thyroid storm), while the most frequent irAE related to anti-CTLA-4-antibodies is hypophysitis. The combination of anti-CTLA-4 and anti-PD-1 antibodies is associated with a 30% chance of irAEs. Symptoms and clinical signs vary depending on the target organ. IrAEs are usually managed by an oncological therapist, but in more challenging circumstances (i.e., for new onset insulin–dependent diabetes, hypoadrenalism, gonadal hormones dysfunctions, or durable hypophysitis) an endocrinologist is needed.

Neonatal hypoglycemia, early-onset diabetes and hypopituitarism due to the mutation in EIF2S3 gene causing MEHMO syndrome

Recently, the genetic cause of several syndromic forms of glycemia dysregulation has been described. One of them, MEHMO syndrome, is a rare X-linked syndrome recently linked to the EIF2S3 gene mutations. MEHMO is characterized by Mental retardation, Epilepsy, Hypogonadism/hypogenitalism, Microcephaly, and Obesity. Moreover, patients with MEHMO had also diabetes and endocrine phenotype, but detailed information is missing. We aimed to provide more details on the endocrine phenotype in two previously reported male probands with MEHMO carrying a frame-shift mutation (I465fs) in the EIF2S3 gene. Both probands had a neonatal hypoglycemia, early onset insulin-dependent diabetes, and hypopituitarism due to dysregulation and gradual decline of peptide hormone secretion. Based on the clinical course in our two probands and also in previously published patients, neonatal hypoglycemia followed by early-onset diabetes and hypopituitarism may be a consistent part of the MEHMO phenotype.

Euglycemic DKA as an Initial Presentation of Immunotherapy-Induced Insulin-Dependent Diabetes

New onset insulin dependent diabetes (DM) has been reported in cancer patients (pts) receiving immunotherapy (IO). Typically, pts have Grade 3 hyperglycemia (CTCAE) and sometimes DKA. Euglycemic DKA has been reported in pts on empagliflozin (Empa). We present a unique case of euglycemic DKA as initial presentation for immunotherapy induced insulin dependent DM. Pt is a 68 year old man without preexisting DM started on nivolumab for metastatic prostate cancer. Following 2 doses of nivolumab, he developed fatigue, weight loss and Grade 2 hyperglycemia for which he was started on metformin, glipizide, and Empa by his outside physician. His BG levels ranged from 130-200 mg/dL on these therapies. Nivolumab treatment was stopped due to significant adverse effects. On return visit to our clinic, approximately 3 months after initial hyperglycemia, pt complained of persistent fatigue, weight loss and a new fruity odor in his breath. Labs revealed BG of 134mg/dl, bicarb of 19 mEq/L (23-30mEq/L), anion gap (AG) of 17mEq/L (4-14mEq/L). Urine ketones were positive and c-peptide level was 0.3ng/ml (0.8- 3.85ng/ml). Pt was advised to immediately stop Empa and follow-up with local ER. When he presented to local ER, approximately 4 days later, he was hyperglycemic with glucose 316 mg/dL, and labwork consistent with classic DKA. Pt was initiated on basal bolus insulin regimen and had resolution of DKA.IO mediated DM results from immune mediated islet cell destruction leading to rapidly progressive insulin deficiency. When suspected, these pts should be evaluated for beta cell dysfunction and insulin should be used for glycemic control. This case highlights that SGLT2 therapy should be used with caution in patients with hyperglycemia on immunotherapy as it could mask the diagnosis of DKA. In addition, this case shows that patients taken off of immunotherapy may develop delayed glycemic complications and may need long term monitoring. Disclosure P. Iyer: None. S.N. Thosani: Consultant; Spouse/Partner; Boston Scientific Corporation, Medtronic. Speaker's Bureau; Spouse/Partner; AbbVie Inc..

Neonatal hypoglycemia, early-onset diabetes and hypopituitarism due to the mutation in EIF2S3 gene causing MEHMO syndrome.

Recently, the genetic cause of several syndromic forms of glycemia dysregulation has been described. One of them, MEHMO syndrome, is a rare X-linked syndrome recently linked to the EIF2S3 gene mutations. MEHMO is characterized by Mental retardation, Epilepsy, Hypogonadism/hypogenitalism, Microcephaly, and Obesity. Moreover, patients with MEHMO had also diabetes and endocrine phenotype, but detailed information is missing. We aimed to provide more details on the endocrine phenotype in two previously reported male probands with MEHMO carrying a frame-shift mutation (I465fs) in the EIF2S3 gene. Both probands had a neonatal hypoglycemia, early onset insulin-dependent diabetes, and hypopituitarism due to dysregulation and gradual decline of peptide hormone secretion. Based on the clinical course in our two probands and also in previously published patients, neonatal hypoglycemia followed by early-onset diabetes and hypopituitarism may be a consistent part of the MEHMO phenotype.

Enhanced Vascular Collateralization Through the Pancreaticoduodenal Arcade Secondary to Median Arcuate Ligament Compression of the Celiac Axis in the Setting of Pancreatic Body Adenocarcinoma: The Ideal Scenario for the Modified Appleby Procedure

Abstract Background: A modified Appleby procedure for pancreatic body tumors relies upon collateral vessels maintaining blood flow to the proper hepatic artery (PHA) through the pancreaticoduodenal arcade (PDA) off of the superior mesenteric artery (SMA). Compression of the celiac axis by the median arcuate ligament (MAL) promotes the expansion of collateral vessels without preoperative intervention. Case Presentation: A 51-year-old male with asymptomatic compression of the celiac artery presented with new onset insulin-dependent diabetes mellitus. He underwent imaging that demonstrated a locally advanced pancreatic body tumor that encased the superior mesenteric vein and portal vein confluence and involved the common hepatic artery. He had an adequate response to neoadjuvant FOLFIRINOX chemotherapy and underwent an uncomplicated modified Appleby procedure with a margin negative resection. Hepatic blood flow was adequate through the PHA as a result of collateralization of blood flow through the PDA off th...

Implications of False Positive Serology ofToxoplasma gondiiin a Pre-transplant Patient

A 21-year-old white male with cystic fibrosis. Pre-transplant workup in preparation for bilateral lung transplant. Cystic fibrosis diagnosed at age 3, onset of insulin-dependent diabetes around age 20, and multiple hospitalizations for pulmonary and gastrointestinal complications. FAMILY AND SOCIAL HISTORY: The patient lives with his father and stepmother, has a pet bearded dragon, and has multiple tattoos and piercings. His stepmother has a cat, but he does not clean the litter box. The pre-transplant workup included several tests for infectious diseases, tests of organ function, radiology studies, and markers of malignancy. The only significant finding was a positive Toxoplasma gondii (T. gondii) IgM titer (> or = 1:40) (reference values for IgM: negative; < 1:40, positive; > or = 1:40) and IgG (1:2048) (reference values for IgG: negative; < 1:16, equivocal; > or = 1:16 - < 1:256, positive; > or = 1:256). Testing was done by indirect immunofluorescence assay (IFA) in April 2012 in our hospital laboratory. The patient was treated with sulfadiazine, leucovorin, and pyrimethamine. Three months later (July), he returned for follow-up testing. Real-time polymerase chain reaction (PCR) for T. gondii DNA performed by a reference laboratory was negative. One month later (August), Toxoplasma serology was performed by enzyme-linked immunosorbent assay (ELISA) by a different reference laboratory and showed an elevated IgM of 0.95 IU/mL (reference values: negative; < 0.55 IU/mL, equivocal; > or = 0.55- < 0.65 IU/mL, positive; > or = 0.65 IU/mL) and a normal level of IgG (< 4 IU/mL). At this time, PCR was repeated and was negative. An additional month later (September), the patient's serology studies were performed at a third reference laboratory and showed an elevated IgM of 1.32 IU/mL (reference values: negative; 0.89, equivocal; 0.90 - 1.09, positive; > 1.10) and a normal IgG.

The Role of Renal Regulatory Mechanisms in the Evolution and Treatment of Pediatric Diabetic Ketoacidosis

Diabetic ketoacidosis (DKA) is a life threatening complication of diabetes mellitus in pediatric patients with new onset insulin dependent diabetes. Despite advances in therapy mortality from DKA, especially in children less than two years, remains high. This review highlights the role of obligatory renal defense mechanisms in the evolution of DKA and its implication for therapy: to accomplish this goal the review starts with a cursory description of the pathogenesis and pathophysiology of metabolic derangements in DKA as a basis for understanding the renal compensatory mechanisms geared towards restoration of acid-base balance; then, the next section of the review describes how alterations in fluid and electrolyte balance at the onset of DKA and the extent of renal regulatory defense mechanisms geared towards its restoration can predispose to cerebral edema at the beginning of therapy. We conclude by suggesting that restoration of fluid and electrolyte balance should be based on the severity of metabolic acidosis as determined by the extent of renal impairment at the onset and during the course of DKA rather than strictly by protocols.

Early presentation of gait impairment in Wolfram Syndrome

BackgroundClassically characterized by early onset insulin-dependent diabetes mellitus, optic atrophy, deafness, diabetes insipidus, and neurological abnormalities, Wolfram syndrome (WFS) is also associated with atypical brainstem and cerebellar findings in the first decade of life. As such, we hypothesized that gait differences between individuals with WFS and typically developing (TD) individuals may be detectable across the course of the disease.MethodsGait was assessed for 13 individuals with WFS (min 6.4 yrs, max 25.8 yrs) and 29 age-matched, typically developing individuals (min 5.6 yrs, max 28.5 yrs) using a GAITRite ® walkway system. Velocity, cadence, step length, base of support and double support time were compared between groups.ResultsAcross all tasks, individuals with WFS walked slower (p = 0.03), took shorter (p ≤ 0.001) and wider (p ≤ 0.001) steps and spent a greater proportion of the gait cycle in double support (p = 0.03) compared to TD individuals. Cadence did not differ between groups (p = 0.62). Across all tasks, age was significantly correlated with cadence and double support time in the TD group but only double support time was correlated with age in the WFS group and only during preferred pace forward (rs= 0.564, p = 0.045) and dual task forward walking (rs= 0.720, p = 0.006) tasks. Individuals with WFS also had a greater number of missteps during tandem walking (p ≤ 0.001). Within the WFS group, spatiotemporal measures of gait did not correlate with measures of visual acuity. Balance measures negatively correlated with normalized gait velocity during fast forward walking (rs = −0.59, p = 0.03) and percent of gait cycle in double support during backward walking (rs = −0.64, p = 0.03).ConclusionsQuantifiable gait impairments can be detected in individuals with WFS earlier than previous clinical observations suggested. These impairments are not fully accounted for by the visual or balance deficits associated with WFS, and may be a reflection of early cerebellar and/or brainstem abnormalities. Effective patient-centered treatment paradigms could benefit from a more complete understanding of the progression of motor and other neurological symptom presentation in individuals with WFS.

Reliability and validity of the Wolfram Unified Rating Scale (WURS)

BackgroundWolfram syndrome (WFS) is a rare, neurodegenerative disease that typically presents with childhood onset insulin dependent diabetes mellitus, followed by optic atrophy, diabetes insipidus, deafness, and neurological and psychiatric dysfunction. There is no cure for the disease, but recent advances in research have improved understanding of the disease course. Measuring disease severity and progression with reliable and validated tools is a prerequisite for clinical trials of any new intervention for neurodegenerative conditions. To this end, we developed the Wolfram Unified Rating Scale (WURS) to measure the severity and individual variability of WFS symptoms. The aim of this study is to develop and test the reliability and validity of the Wolfram Unified Rating Scale (WURS).MethodsA rating scale of disease severity in WFS was developed by modifying a standardized assessment for another neurodegenerative condition (Batten disease). WFS experts scored the representativeness of WURS items for the disease. The WURS was administered to 13 individuals with WFS (6-25 years of age). Motor, balance, mood and quality of life were also evaluated with standard instruments. Inter-rater reliability, internal consistency reliability, concurrent, predictive and content validity of the WURS were calculated.ResultsThe WURS had high inter-rater reliability (ICCs>.93), moderate to high internal consistency reliability (Cronbach’s α = 0.78-0.91) and demonstrated good concurrent and predictive validity. There were significant correlations between the WURS Physical Assessment and motor and balance tests (rs>.67, p<.03), between the WURS Behavioral Scale and reports of mood and behavior (rs>.76, p<.04) and between WURS Total scores and quality of life (rs=-.86, p=.001). The WURS demonstrated acceptable content validity (Scale-Content Validity Index=0.83).ConclusionsThese preliminary findings demonstrate that the WURS has acceptable reliability and validity and captures individual differences in disease severity in children and young adults with WFS.

Balance impairment in individuals with Wolfram syndrome

AimWolfram syndrome (WFS), a rare neurodegenerative disorder, is characterized by early onset insulin-dependent diabetes mellitus, optic atrophy, deafness, diabetes insipidus, and neurological abnormalities. Although previously unreported, we hypothesized that neurological complications may be detectable in relatively early stages of the disease. As the cerebellum and brainstem seem particularly vulnerable in WFS, we focused on balance functions critically dependent on these regions. The primary goal of this investigation was to compare balance in young individuals with WFS, in relatively early stages of the disease, to an age-matched cohort using a clinically applicable test. MethodBalance was assessed via the mini-BESTest in 13 children, adolescents and young adults with WFS and 30 typically developing age-matched individuals. ResultsA significant difference was observed between groups in balance as well as in three of four subcomponents of the mini-BESTest and in two timed tasks related to balance. Mini-BESTest scores were correlated with age among typically developing individuals. In the WFS group, mini-BESTest scores were related to overall motor dysfunction, but not age. InterpretationImpairments in balance in WFS may occur earlier in the disease process than previously recognized and appear to be related to overall neurological progression rather than chronological age. Recognizing balance impairments and understanding which balance systems contribute to balance deficits in those with WFS may allow for development of effective patient-centered treatment paradigms.

Microcephaly with Simplified Gyration, Epilepsy, and Infantile Diabetes Linked to Inappropriate Apoptosis of Neural Progenitors

We describe a syndrome of primary microcephaly with simplified gyral pattern in combination with severe infantile epileptic encephalopathy and early-onset permanent diabetes in two unrelated consanguineous families with at least three affected children. Linkage analysis revealed a region on chromosome 18 with a significant LOD score of 4.3. In this area, two homozygous nonconserved missense mutations in immediate early response 3 interacting protein 1 (IER3IP1) were found in patients from both families. IER3IP1 is highly expressed in the fetal brain cortex and fetal pancreas and is thought to be involved in endoplasmic reticulum stress response. We reported one of these families previously in a paper on Wolcott-Rallison syndrome (WRS). WRS is characterized by increased apoptotic cell death as part of an uncontrolled unfolded protein response. Increased apoptosis has been shown to be a cause of microcephaly inanimal models. An autopsy specimen from one patient showed increased apoptosis in the cerebral cortex and pancreas beta cells, implicating premature cell death as the pathogenetic mechanism. Both patient fibroblasts and control fibroblasts treated with siRNA specific for IER3IP1 showed an increased susceptibility to apoptotic cell death under stress conditions in comparison to controls. This directly implicates IER3IP1 in the regulation of cell survival. Identification of IER3IP1 mutations sheds light on the mechanisms of brain development and on the pathogenesis of infantile epilepsy and early-onset permanent diabetes.

Clinico-pathological findings in a patient with progressive cerebellar ataxia, autoimmune polyendocrine syndrome, hepatocellular carcinoma and anti-GAD autoantibodies

Objective To report clinical and pathological findings of a patient with late onset insulin-dependent diabetes mellitus (IDDM), progressive cerebellar ataxia (PCA) and hepatocellular carcinoma (HCC). Patient A 64-year-old woman, with a long lasting IDDM, progressively developed a severe cerebellar syndrome and died 2 years after the onset of the symptoms for a systemic infection. Autoantibodies to antigastric parietal cell and anti-pancreatic islet cell resulted positive. Autopsy showed a selective loss of Purkinje cells in the cerebellum, with an increase of Bergmann glia and variable microglial proliferation; furthermore, it disclosed an HCC. GAD-Abs were detected both in serum and CSF. Conclusions Clinical and experimental reports suggest a possible role of neoplastic cells in producing GAD-Abs. We postulate, in our case, that HCC could have been responsible for an overproduction of GAD-Abs, leading to the onset of PCA. Thus, GAD-Abs could be considered as a paraneoplastic marker in a subgroup of patients with PCA.

Wolfram Syndrome presenting with optic atrophy and diabetes mellitus: two case reports

Wolfram syndrome is the constellation of juvenile onset diabetes mellitus and optic atrophy, known as DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness).Patients demonstrate diabetes mellitus followed by optic atrophy in the first decade, diabetes insipidus and sensorineural deafness in the second decade, dilated renal outflow tracts early in the third decade, and multiple neurological abnormalities early in the fourth decade.This study reports two siblings with late diagnosed wolfram syndrome with diabetes insipidus, diabetes mellitus, optic atrophy, deafness and severe urological abnormalities.In conclusion, cases having early onset insulin-dependent diabetes mellitus and optic atrophy together need to be evaluated with respect to Wolfram.

Candidate gene studies reveal that the WFS1 gene joins the expanding list of novel type 2 diabetes genes

Wolfram syndrome, originally described in 1938, is a rare, autosomal recessive disease that is characterised by young onset insulin-dependent diabetes, progressive sensorineural deafness, diabetes insipidus, autonomic nervous system dysfunction and, ultimately, brainstem atrophy and premature death [1]. The Wolfram gene (WFS1), which encodes wolframin, was mapped to chromosome 4p in families with multiple affected individuals [2], and cloned in 1998 [3]. Wolframin is a protein of 890 amino acids that is produced in a wide variety of tissues, most prominently in pancreatic beta cells and brain. Over 100 missense and non-sense mutations have been described patients. As these mutations are associated with a non-immune loss of beta cells and diabetes, the gene was subsequently evaluated in more common forms of diabetes.

Microcephaly and simplified gyral pattern of the brain associated with early onset insulin-dependent diabetes mellitus

Two families are presented with a child suffering from microcephaly with a simplified gyral pattern of the brain (SGP) and early onset insulin dependent diabetes mellitus (IDDM). The first patient was diagnosed postmortally with Wolcott-Rallison syndrome, after her younger brother developed IDDM, and a homozygous mutation in the eukaryotic translation initiation factor 2-alpha kinase 3 was found. The younger brother did not undergo magnetic resonance imaging (MRI). The patient from the second family has no EIF2AK3 mutation. SGP is considered to arise from decreased neuronal proliferation or increased apoptosis at an early stage of embryonal development, but insight into the pathways involved is minimal. EIF2AK3 is involved in translation initiation. It has been proposed that loss of function mutations reduce the ability of the cell to respond to endoplasmic reticulum stress, resulting in apoptosis of pancreatic Langerhans cells. Our findings suggest that in some cases, early onset IDDM and SGP can arise from common mechanisms leading to increased apoptosis.

Low protein diet confers resistance to the inhibitory effects of interleukin 1β on insulin secretion in pancreatic islets☆

High protein content in the diet during childhood and adolescence has been associated to the onset insulin-dependent diabetes mellitus. We investigated the effect of interleukin-1β (IL-1β) on insulin secretion, glucose metabolism, and nitrite formation by islets isolated from rats fed with normal protein (NP, 17%) or low protein (LP, 6%) after weaning. Pretreatment of islets with IL-1β for 1 h or 24 h inhibited the insulin secretion induced by glucose in both groups, but it was less marked in LP than in NP group. Islets from LP rats exhibited a decreased IL-1β-induced nitric oxide (NO) production, lower inhibition of D-[U 14C]-glucose oxidation to 14CO 2 and less pronounced effect of IL-1β on α-ketoisocaproic acid-induced insulin secretion than NP islets. However, when the islets were stimulated by high concentrations of K + the inhibitory effect of IL-1β on insulin secretion was not different between groups. In conclusion, protein restriction protects β-cells of the deleterious effect of IL-1β, apparently, by decreasing NO production. The lower NO generation in islets from protein deprived rats may be due to increased free fatty acids oxidation and consequent alteration in Ca 2+ homeostasis.

$34 m for juvenile diabetes

The largest ever statistical study of the genetics of type 1 diabetes has been funded by the Wellcome Trust (London, UK) and the Juvenile Diabetes Research Foundation. Over the course of five years, a $34 (£20) million grant will be used to identify the genes involved in juvenile onset (insulin dependent) diabetes, using 10 000 diabetic and 10 000 healthy subjects. The research, which will be based at the Wellcome Trust Centre for Molecular Mechanisms in Disease (University of Cambridge, UK), will also incorporate analysis of non-obese diabetic (NOD) mice. This follows on from a recently published Korean–Canadian study, in which juvenile diabetes was eliminated in NOD mice by insulin gene therapy. Ahyun Chul Lee and colleagues (Yonsei University Medical School, Seoul, South Korea) used a recombinant adeno-associated virus that expressed an insulin analogue, and prompted long-term remission from diabetes. These data hold great promise for treatment in humans, which currently requires several insulin injections per day. AR