Juvenile-onset Insulin-dependent Diabetes Research Articles

A novel ALMS1 splice mutation in a non-obese juvenile-onset insulin-dependent syndromic diabetic patient

Insulin-dependent juvenile-onset diabetes may occur in the context of rare syndromic presentations suggesting monogenic inheritance rather than common multifactorial autoimmune type 1 diabetes. Here, we report the case of a Lebanese patient diagnosed with juvenile-onset insulin-dependent diabetes presenting ketoacidosis, early-onset retinopathy with optic atrophy, hearing loss, diabetes insipidus, epilepsy, and normal weight and stature, who later developed insulin resistance. Despite similarities with Wolfram syndrome, we excluded the WFS1 gene as responsible for this disease. Using combined linkage and candidate gene study, we selected ALMS1, responsible for Alström syndrome, as a candidate gene. We identified a novel splice mutation in intron 18 located 3 bp before the intron-exon junction (IVS18-3T>G), resulting in exon 19 skipping and consequent frameshift generating a truncated protein (V3958fs3964X). The clinical presentation of the patient significantly differed from typical Alström syndrome by the absence of truncal obesity and short stature, and by the presence of ketoacidotic insulin-dependent diabetes, optic atrophy and diabetes insipidus. Our observation broadens the clinical spectrum of Alström syndrome and suggests that ALMS1 mutations may be considered in patients who initially present with an acute onset of insulin-dependent diabetes.

A Case of Insulin-Dependent Diabetes Associated With Enteroviral Infections

Enteroviruses have been reported to be a potential trigger of the development of type 1 diabetes by inducing β-cell autoantibodies and by directly destroying β-cells (1). Although the precise underlying mechanisms for enterovirus-mediated development of diabetes remain unknown, the systematic review and meta-analysis of observational molecular studies demonstrates a clinically significant association between enteroviral infections detected by molecular methods and type 1 diabetes (2). Here we report a case of juvenile-onset insulin-dependent diabetes resulting from various enteroviral infections. A 20-year-old man was referred and admitted to our hospital because of a penile inflammation, suffering from general fatigue, and body weight loss for 2 weeks in March 2011. He had a high fever (38–39°C) at 2 weeks before the admission. …

Endocrine and metabolic aspects of the Wolfram syndrome

Wolfram syndrome (WS), also known as DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy and Deafness), is a neurodegenerative disease with autosomal recessive inheritance with incomplete penetrance. DIDMOAD is a very rare disease with an estimated prevalence of 1 in 770,000 and it is believed to occur in 1 of 150 patients with juvenile-onset insulin-dependent diabetes mellitus. Additionally, WS may also present with different endocrine and metabolic abnormalities such as anterior and posterior pituitary gland dysfunction. This mini-review summarizes the variable presentation of WS and the need of screening for other metabolic and hormonal abnormalities, coexisting in this rare syndrome.

Wolfram syndrome 1 gene (WFS1) product localizes to secretory granules and determines granule acidification in pancreatic -cells

Wolfram syndrome is an autosomal recessive disorder characterized by juvenile-onset insulin-dependent diabetes mellitus and optic atrophy. The gene responsible for the syndrome (WFS1) encodes an endoplasmic reticulum (ER) resident transmembrane protein. The Wfs1-null mouse exhibits progressive insulin deficiency causing diabetes. Previous work suggested that the function of the WFS1 protein is connected to unfolded protein response and to intracellular Ca(2+) homeostasis. However, its precise molecular function in pancreatic β-cells remains elusive. In our present study, immunofluorescent and electron-microscopic analyses revealed that WFS1 localizes not only to ER but also to secretory granules in pancreatic β-cells. Intragranular acidification was assessed by measuring intracellular fluorescence intensity raised by the acidotrophic agent, 3-[2,4-dinitroanilino]-3'-amino-N-methyldipropyramine. Compared with wild-type β-cells, there was a 32% reduction in the intensity in WFS1-deficient β-cells, indicating the impairment of granular acidification. This phenotype may, at least partly, account for the evidence that Wfs1-null islets have impaired proinsulin processing, resulting in an increased circulating proinsulin level. Morphometric analysis using electron microscopy evidenced that the density of secretory granules attached to the plasma membrane was significantly reduced in Wfs1-null β-cells relative to that in wild-type β-cells. This may be relevant to the recent finding that granular acidification is required for the priming of secretory granules preceding exocytosis and may partly explain the fact that glucose-induced insulin secretion is profoundly impaired in young prediabetic Wfs1-null mice. These results thus provide new insights into the molecular mechanisms of β-cell dysfunction in patients with Wolfram syndrome.

Juvenile, insulin‐dependent diabetes mellitus, type 1‐related dermatoses

Juvenile insulin-dependent diabetes mellitus type 1 (IDDM) is a well-recognized worldwide entity, the significance of which has increased because of its recent upsurging trends, warranting attention on variety of its clinical expressions, in particular, pertaining to skin, an aspect seldom taken cognizance of. Hence an endeavour to recap the related dermatoses, such as limited joint mobility syndrome including sclerodermoid (scleroderma-like) changes, xerosis, necrobiosis lipoidica diabeticorum, granuloma annulare, diabetic foot syndrome, has been made. Complexities relating to the recently explored issues of atopic dermatitis and drug hypersensitivity syndrome have also been covered adequately. In addition, the current concepts of the physiopathology of type 1 diabetes-related dermatoses are briefly recapitulated for clarity.

Relationship among psychopathological dimensions, coping mechanisms, and glycemic control in a Croatian sample of adolescents with diabetes mellitus type 1

Psychopathological factors associated with metabolic control in juvenile insulin-dependent diabetes mellitus (IDDM) deserve further investigation. This study assessed the relationship among specific psychopathological dimensions, coping mechanisms, and metabolic control in a Croatian clinical sample of adolescents with IDDM. One-hundred and one adolescents (aged 11-18) with IDDM filled out the youth self report (YSR) assessing psychopathological dimension and the scale of coping with stress (SCS). Glycemic control was estimated by the percentage of glycated hemoglobin (HbA1c). Subjects were divided into three groups according to HbA1C values: "optimal", "suboptimal control", and "at high risk". Subjects in optimal glycemic control presented with significantly lower scores in most of YSR scales compared to subjects at high risk. Moreover, they had significantly lower scores in avoidance and emotional reactivity and significantly higher scores in cognitive restructuring and problem solving SCS subscales. Regression models revealed that both internalizing and externalizing YSR scores, as well as emotional reactivity coping scores, independently contributed to explain variability of HbA1C values. Both internalizing and externalizing psychopathological dimensions, as well as emotion-oriented coping strategies, are independently associated with poor metabolic control in both boys and girls with IDDM, thus representing potential interest targets of psychotherapeutic interventions aimed at improving glycemic control in this population.

Rapid and persistent regression of severe new vessels on the disc in proliferative diabetic retinopathy after a single intravitreal injection of pegaptanib

Rapid and persistent regression of severe new vessels on the disc in proliferative diabetic retinopathy after a single intravitreal injection of pegaptanib

Current Developments in Wolfram Syndrome

Wolfram syndrome (WS), an infrequent cause of diabetes mellitus, derives its name from the physician who first reported the combination of juvenile-onset diabetes mellitus and optic atrophy. Also referred to as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy and deafness), it is an autosomal recessive neurodegenerative disease characterized by various clinical manifestations, such as diabetes mellitus, optic atrophy, diabetes insipidus, deafness, neurological symptoms, renal tract abnormalities, psychiatric manifestations and gonadal disorders. The condition is very rare with an estimated prevalence of one in 770,000 of the normal population, one out of 150 cases of juvenile-onset insulin-dependent diabetes mellitus, and with a carrier frequency of one in 354. This progressive neurodegenerative disease usually results in death before the age of 50 years and many patients lead a morbid life. The pathogenesis of the disorder although unknown is ascribed to mutation of a gene on chromosome 4p encoding a transmembrane protein of undetermined function called wolframin. This review summarizes the variable presentation of the disorder, its widespread complications, poor quality of life in affected individuals, and the problems in diagnosis and treatment of the syndrome.

Altered degradation of circulating nucleic acids and oligonucleotides in diabetic patients

Foreign, infection-associated or endogenously generated circulating nucleotide motifs may represent the critical determinants for the activation of the Toll-like receptors (TLRs), leading to immune stimulation and cytokine secretion. The importance of circulating nucleases is to destroy nucleic acids and oligonucleotides in the blood stream and during cell entry. Patients with juvenile insulin-dependent diabetes, adult patients with insulin-dependent diabetes and adult patients with type 2 diabetes were allocated to the study, together with the age-matched control subjects. Plasma RNase and nuclease activity were examined, in relation to different substrates-TLRs response modifiers, and circulating RNA and oligonucleotides were isolated. The fall in enzyme activity in plasma was obtained for rRNA, poly(C), poly(U), poly(I:C), poly(A:U) and CpG, especially in juvenile diabetics. In order to test the non-enzymatic glycation, commercial RNase (E.C.3.1.27.5) and control plasma samples were incubated with increasing glucose concentrations (5, 10, 20 and 50 mmol/l). The fall of enzyme activity was expressed more significantly in control plasma samples than for the commercial enzyme. Total amount of purified plasma RNA and oligonucleotides was significantly higher in diabetic patients, especially in juvenile diabetics. The increase in the concentration of nucleotides corresponded to the peak absorbance at 270 nm, similar to polyC. The electrophoretic bands shared similar characteristics between controls and each type of diabetic patients, except that the bands were more expressed in diabetic patients. Decreased RNase activity and related increase of circulating oligonucleotides may favor the increase of nucleic acid “danger motifs”, leading to TLRs activation.

Fibrous Lesions of the Breast: Imaging-Pathologic Correlation

Fibroepithelial lesions of the breast are commonly seen in clinical practice. The masses are composed of a combination of prominent stroma and varying glandular elements. Fibroadenomas, benign lesions that derive from the terminal duct lobular unit, are the most common and are often identified at clinical examination or mammography as circumscribed masses. Benign mesenchymal tumors include focal fibrosis, pseudoangiomatous stromal hyperplasia, and fibromatosis or desmoid tumor. Phyllodes tumor, which is similar to fibroadenoma but has increased cellularity in the stroma, is typically benign but has malignant potential. Diabetic fibrous mastopathy, a stromal proliferation found in patients with juvenile-onset insulin-dependent diabetes, is a reactive fibrous lesion. Most of these lesions manifest as masses at clinical and/or mammographic examination. Some (eg, fibroadenomas) may be associated with calcifications. Except for fibromatosis and phyllodes tumor, fibroepithelial lesions need not be excised if the diagnosis is confirmed by the results of histologic analysis at percutaneous biopsy. To correctly differentiate between fibrous breast lesions that are benign and those that should be resected, the physician must be familiar with the correlated radiologic-pathologic findings in the various lesion types.

Type 1 diabetes mellitus and oral health: assessment of tooth loss and edentulism.

The oral health of an adult population previously diagnosed with juvenile onset insulin dependent-diabetes was comprehensively assessed. The goal of this exploratory cross-sectional evaluation was to described the characteristics related to partial tooth loss edentulism in subjects with Type 1 diabetes mellitus. An adult population of 406 Type 1 diabetes mellitus subjects, who had been monitored for 6-8 years as part of a University of Pittsburgh longitudinal study of medical complications associated with diabetes, received an oral health examination for missing teeth, edentulism, coronal and root caries, periodontal status, and oral health behaviors. Of the 406 subjects evaluated, 204 had no missing teeth, 186 had partial tooth loss (1-27 missing teeth), and 16 were edentulous. Patients who had partial tooth loss or who were edentulous were generally older; had lower incomes and levels of education; and had higher rates of nephropathy, neuropathy, retinopathy, and peripheral vascular disease. A logistic regression model found partial tooth loss to be significantly associated with extensive periodontal disease in remaining teeth (OR = 7.35), a duration of diabetes longer than 24 years (OR = 5.32), not using dental floss (OR = 2.37), diabetic neuropathy (OR = 2.29), household income less than $20,000 (OR = 2.21), multiple coronal caries and fillings (OR = 1.98), and bleeding on probing (OR = 1.82). Although the majority of these adult Type 1 diabetes patients had serious medical complications associated with their diabetes, the possible impact of diabetes mellitus on oral health should be included in their overall management.

UKPDS 25: autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylase for prediction of insulin requirement in type 2 diabetes

Autoantibodies to islet-cell cytoplasm (ICA) and glutamic acid decarboxylase (GADA) can occur in apparently typical, non-insulin dependent diabetes mellitus (type 2). We investigated whether the presence of either or both antibodies characterises a subtype of diabetes and provides better prediction of requirement for insulin therapy by 6 years' follow-up than clinical variables. We measured ICA and GADA at diagnosis of diabetes in a representative population of 3672 white patients with type 2 diabetes, aged between 25 and 65 years. The phenotype was assessed by age of onset, body-mass index, percentage haemoglobin A1c (HbA1c), and islet beta-cell function. We investigated the need for insulin therapy among 1538 patients not assigned insulin and followed up for 6 years from diagnosis. The proportion of patients with ICA and GADA decreased with increasing age at diagnosis (from 33 [21%] of 157 patients aged 25-34 [corrected] to 66 [4%] of 1769 aged 55-65 for ICA; from 53 [34%] to 122 [7%] for GADA). Among patients younger than 35 at diagnosis, those with ICA or GADA had lower body-mass index than those without (mean 24.9 [SD 6.0] vs 31.7 [7.3] kg/m2; p < 0.0001 and had higher percentage of HbA1c (9.7 vs 8.7%, p < 0.05). 94% of patients with ICA and 84% of those with GADA required insulin therapy by 6 years, compared with 14% of those without the antibodies (p < 0.0001). Among patients older than 55 at diagnosis, the difference between those with and without antibodies in body-mass index was smaller (27.2 [5.4] vs 28.6 [4.8] kg/m2, p < 0.001); 44% of those with ICA, 34% of those with GADA, and 5% with neither antibody required insulin therapy by 6 years (p < 0.0001). Among patients older than 45 years, body-mass index and HbA1c provided little predictive information for insulin requirement, whereas the positive predictive values of GADA (> or = 60 U/L) alone, or both GADA (> or = 20 U/L) and ICA (> 5 U/L), for insulin therapy were 52% and 68%. Among young adults with type 2 diabetes, the phenotype of those with ICA or GADA antibodies was similar to that of classic juvenile-onset insulin-dependent diabetes, and either phenotype or antibodies predicted insulin requirement. In older adults, the phenotype was closer to that of patients without antibodies and only the presence of antibodies predicted an increased likelihood of insulin requirement.

Urinary biotinidase and alanine excretion in patients with insulin-dependent diabetes mellitus.

Twenty-four-hour urine specimens from 21 juvenile insulin-dependent diabetics and 10 healthy controls were compared with respect to biotinidase activity and alanine content. Urinary biotinidase activity was analysed by a newly developed high-performance liquid chromatography (HPLC) method. It was found that the excretion of biotinidase in urine was elevated in diabetics (7.02 mU/d; p < 0.005) as compared with controls (not detectable). Alanine excretion was also found to increase (p < 0.01) in diabetics. Biotinidase excretion in diabetics was correlated with alanine excretion (rS = 0.667; p < 0.01), but not with protein, albumin or N-acetyl-beta-glucosaminidase excretion. The simultaneous elevation of urinary biotinidase and alanine excretion in juvenile diabetics suggests that changes in kidney metabolism arise in the early stages of diabetes.

Exocrine pancreatic insufficiency combined with insulin‐dependent diabetes mellitus in a juvenile German shepherd dog

Canine juvenile-onset insulin-dependent diabetes mellitus is a rare disease. While pancreatic acinar atrophy is a well known picture in the dog, the simultaneous occurrence with an endocrine insufficiency has never been clearly established. The clinical, pathological and immunohistochemical findings of a three-month-old German shepherd dog with insulin-dependent diabetes mellitus concurrent with exocrine pancreatic insufficiency are described.

Diabetes in the operating room: Metabolic challenges for the anesthesiologist

IABETES MELLITUS is the most commonly occurring metabolic disorder in humans today. The term encompasses a heterogeneous group of diseases that have common characteristics of chronic hyperglycemia and other disturbances of carbohydrate and lipid metabolism. All are associated with medical complications such as microvascular complications of the eye and kidney, peripheral vascular disease, and coronary artery disease. The majority of diabetics are in age categories where the incidence of surgery is high, and many disorders associated with diabetes, such as cholelithiasis, cataracts, vascular disease, and infections require surgical care. It is estimated that more than 50% of diabetics will have one or more surgeries in their lifetime. 1,2 Classically, the attention of the anesthesiologist in managing the care of diabetic patients has centered around prevention of acute complications of abnormal blood glucose levels and ketosis during the surgery itself, but intraoperative glucose level management may influence perioperative events as diverse as wound healing, infection response, and neurological function. To understand perioperative problems of patients with diabetes, it is useful to consider differences between two major diabetic groups: type I diabetics, also called juvenile-onset diabetics or insulin-dependent diabetics, and type II diabetics, also known as maturity-onset or noninsulin-dependent diabetics. Although these two classifications are not always strictly distinct from one another and do not include all diabetic disorders, they contrast some important epidemiological and metabolic differences among diabetic patients.

HLA, ESD, GLOI, C3 and HP polymorphisms and juvenile insulin dependent diabetes mellitus in Tamil Nadu (South India)

Fifty juvenile insulin dependent diabetes mellitus (JIDDM) patients of Tamil Nadu (South India) were typed for HLA-A, -B, -C, -DR, and -DQ, ESD, GLOI, C3 and HP polymorphisms. The frequencies of B8, DR3, DR4, DR53 and DQ2 antigens of the HLA system were significantly higher in the patients than in controls (relative risk, RR = 4.81; 5.14; 3.98; 3.36 and 2.53, respectively). However HLA-DR2, -DR5 and -DQ1, observed less frequently in the patient group, appear to play a role of protection against the disease (RR = 0.32; 0.30 and 0.20 respectively). HLA haplotype analysis demonstrated very high relative risk associated with two hitherto unreported haplotypes namely A3, DR1 and Cw3, DR4 (RR = 27.30 and 20.00, respectively) and also scanty distribution of the haplotypes A1, B17 and DR2, DQ1 (RR = 0.39 and 0.36 respectively) in the patient group. Among other genetic markers tested, GLOI is informative with its phenotype GLOI 2-1 showing positive association with JIDDM (RR = 4.06).

Optic Disk Risk Factors for Nonarteritic Anterior Ischemic Optic Neuropathy

The anatomic characteristics of a relatively small optic nerve head, absent to small physiologic cup, abnormal branching pattern of central retinal vessels, and a lush nerve-fiber bundle layer elevating the disk margins are associated with the occurrence of certain ischemic disease states. These diseases include the following: (1) nonarteritic anterior ischemic optic neuropathy, (2) anterior ischemic optic neuropathy of the young, (3) the papillopathy in patients with juvenile insulin-dependent diabetes mellitus, and (4) Leber's hereditary optic neuropathy. The finding of such a disk at risk should signal the possible later development of visual dysfunction. Ordinarily, when an ophthalmologist discusses risk factors in relationship to the optic disk, the topic is that of open-angle glaucoma and the predictability of the ultimate development of visual field loss. In the early 1980s, Hoyt suggested that certain disk characteristics may predispose an individual to the development of nonarteritic anterior ischemic optic neuropathy (Hoyt, W. F., unpublished data, presented at the Rocky Mountain Neuro-Ophthalmologic Society Meeting, February 1982). Specifically, in these cases he noted that the unaffected eye has a small or absent physiologic cup. Several investigators went on to confirm Hoyt's observation that these crowded disks are at risk for developing nonarteritic anterior ischemic optic neuropathy.! The hallmarks of the disk at risk are as follows: (1) relatively small optic nerve head, (2) absent to small physiologic cup, (3) increased number of branches of the central retinal vessels within the disk, and (4) a normal, healthy-appearing nerve-fiber bundle layer with heaping up of at least the superior, nasal, and inferior fibers (Fig. 1). These disks are similar in many ways to those described by Rosenberg, Savino, and GlaserS,6 as being characteristic of pseudopapilledema. Presumably, a small physiologic cup is the

Optic Disk Risk Factors for Nonarteritic Anterior Ischemic Optic Neuropathy

The anatomic characteristics of a relatively small optic nerve head, absent to small physiologic cup, abnormal branching pattern of central retinal vessels, and a lush nerve-fiber bundle layer elevating the disk margins are associated with the occurrence of certain ischemic disease states. These diseases include the following: (1) nonarteritic anterior ischemic optic neuropathy, (2) anterior ischemic optic neuropathy of the young, (3) the papillopathy in patients with juvenile insulin-dependent diabetes mellitus, and (4) Leber's hereditary optic neuropathy. The finding of such a disk at risk should signal the possible later development of visual dysfunction. Ordinarily, when an ophthalmologist discusses risk factors in relationship to the optic disk, the topic is that of open-angle glaucoma and the predictability of the ultimate development of visual field loss. In the early 1980s, Hoyt suggested that certain disk characteristics may predispose an individual to the development of nonarteritic anterior ischemic optic neuropathy (Hoyt, W. F., unpublished data, presented at the Rocky Mountain Neuro-Ophthalmologic Society Meeting, February 1982). Specifically, in these cases he noted that the unaffected eye has a small or absent physiologic cup. Several investigators went on to confirm Hoyt's observation that these crowded disks are at risk for developing nonarteritic anterior ischemic optic neuropathy.! The hallmarks of the disk at risk are as follows: (1) relatively small optic nerve head, (2) absent to small physiologic cup, (3) increased number of branches of the central retinal vessels within the disk, and (4) a normal, healthy-appearing nerve-fiber bundle layer with heaping up of at least the superior, nasal, and inferior fibers (Fig. 1). These disks are similar in many ways to those described by Rosenberg, Savino, and GlaserS,6 as being characteristic of pseudopapilledema. Presumably, a small physiologic cup is the

The possible link between insulin dependent (juvenile) diabetes mellitus and dietary cow milk

The possible link between insulin dependent (juvenile) diabetes mellitus and dietary cow milk

HLA-DQB1 typing of north east Italian IDDM patients using amplified DNA, oligonucleotide probes and a rapid DNA-enzyme immunoassay (DEIA)

We report on HLA-DQB1 typing in IDDM patients of north east Italian region using an enzymatic method based on the detection of hybridization reaction between PCR amplified DNA from whole blood and allele specific oligonucleotides by an antibody directed against double stranded DNA (DNA-enzyme immunoassay or DEIA). The method is reliable, simple and sensitive as the classical radioactive method with the advantage of using a universal non radioactive detection reagent. Nineteen families, each including one subject with juvenile insulin-dependent diabetes mellitus (IDDM) were analyzed. A strong association between absence of an aspartic acid (Asp) in position 57 of DQB1β chain in homozygous conditions and susceptibility to IDDM was found. In contrast with some previous observations, however, no significant association was found between Asp/non-Asp heterozygous genotype and IDDM. No patients were found with an homozygous Asp/Asp genotype, known to be protective in caucasoid population. Of particular interest was the DQB1 alleli distribution in our population sample. The non-Asp allele most frequently found in IDDM subjects was the DQB1 0201 allele and this finding was statistically significant (Pc value <0.05, relative risk = 5.01). No significant association was found for any other allele including the DQB1 0302 (Pc value = not significant although with relative risk = 3.28) previously reported as the most frequent allele in IDDM caucasoid patients.