Maturity-onset Diabetes Of Young Research Articles

Maturity Onset Diabetes of the Young – An Overview of Common Types. A Review

Abstract Background and aims: Maturity Onset diabetes in Young (MODY) is an autosomal dominant disease and according to an estimate, the MODY cases are 2% of all the diabetic cases. The objective was to review the common types of MODY reported in literature in context to their geographical areas. Material and method: For literature search, PubMed data base was used. The key word was “Maturity onset diabetes of the young”. The articles were reviewed by titles and if found relevant, the abstract and full article (if available) were retrieved. The studies that were published in English, presented original data and describe type of MODY were included. The information related to author, year of publication and type of MODY was extracted in excel sheet. Results: A total of 1135 studies resulted which were reviewed, and 206 articles were finally selected. The studies were grouped according to the regions i.e. Asia, Europe, America, Africa and Australia & Oceania. The MODY 2 was most prevalent in regions i.e. Asia, Europe, America and Australia & Oceania followed by MODY 3. When analysed according to countries, MODY 2 was found prevalent in India, Korea, UK, Italy, Spain, Czech Republic, Canada and Brazil while MODY 3 was common in Japan, China, France Norway and Germany. Conclusion: The MODY 2 was most common. The data from south Asian countries including Pakistan is lacking. As there is a huge burden of diabetes in the country so there is a dire need to do large scale studies on MODY in the country.

A rare case of Diabetic ketoacidosis (DKA) in a patient with genetically confirmed maturity onset diabetes of young (MODY)

A rare case of Diabetic ketoacidosis (DKA) in a patient with genetically confirmed maturity onset diabetes of young (MODY)

Type 1 Diabetes Genetic Risk Score: A Novel Tool to Discriminate Monogenic and Type 1 Diabetes.

Distinguishing patients with monogenic diabetes from those with type 1 diabetes (T1D) is important for correct diagnosis, treatment, and selection of patients for gene discovery studies. We assessed whether a T1D genetic risk score (T1D-GRS) generated from T1D-associated common genetic variants provides a novel way to discriminate monogenic diabetes from T1D. The T1D-GRS was highly discriminative of proven maturity-onset diabetes of young (MODY) (n = 805) and T1D (n = 1,963) (receiver operating characteristic area under the curve 0.87). A T1D-GRS of >0.280 (>50th T1D centile) was indicative of T1D (94% specificity, 50% sensitivity). We then analyzed the T1D-GRS of 242 white European patients with neonatal diabetes (NDM) who had been tested for all known NDM genes. Monogenic NDM was confirmed in 90, 59, and 8% of patients with GRS <5th T1D centile, 50-75th T1D centile, and >75th T1D centile, respectively. Applying a GRS 50th T1D centile cutoff in 48 NDM patients with no known genetic cause identified those most likely to have a novel monogenic etiology by highlighting patients with probable early-onset T1D (GRS >50th T1D centile) who were diagnosed later and had less syndromic presentation but additional autoimmune features compared with those with proven monogenic NDM. The T1D-GRS is a novel tool to improve the use of biomarkers in the discrimination of monogenic diabetes from T1D.

A new compound heterozygosis for inactivating mutations in the glucokinase gene as cause of permanent neonatal diabetes mellitus (PNDM) in double-first cousins.

BackgroundPermanent neonatal diabetes mellitus (PNDM) is a rare disorder, characterized by uncontrolled hyperglycemia diagnosed during the first 6 months of life. In general, PNDM has a genetic origin and most frequently it results from heterozygous mutations in KCNJ11, INS and ABCC8 genes. Homozygous or compound heterozygous inactivating mutations in GCK gene as cause of PNDM are rare. In contrast, heterozygosis for GCK inactivating mutations is frequent and results in the maturity-onset diabetes of young (MODY), manifested by a mild fasting hyperglycemia usually detected later in life. Therefore, as an autosomal recessive disorder, GCK-PNDM should be considered in families with history of glucose intolerance or MODY in first relatives, especially when consanguinity is suspected.ResultsHere we describe two patients born from non-consanguineous parents within a family. They presented low birth weight with persistent hyperglycemia during the first month of life. Molecular analyses for KCNJ11,INS, ABCC8 did not show any mutation. GCK gene sequencing, however, revealed that both patients were compound heterozygous for two missense combined in a novel GCK-PNDM genotype. The p.Asn254His and p.Arg447Gly mutations had been inherited from their mothers and fathers, respectively, as their mothers are sisters and their fathers are brothers. Parents had been later diagnosed as having GCK-MODY.ConclusionsMutations’ in silico analysis was carried out to elucidate the role of the amino acid changes on the enzyme structure. Both p.Asn254His and p.Arg447Gly mutations appeared to be quite damaging. This is the first report of GCK-PNDM in a Brazilian family.

Oral Therapy in a Diabetic Patient With History of Infantile Hyperinsulinism

Dear editor, Hyperinsulinism is the most common cause of persistent hypoglycemia in early infancy (1). Loss of function mutation in HNF4A gene is an unusual cause of this disease (2). HNF4A protein is a homodimer nuclear transcription factor with 474 amino acids which plays a role in 22 identified pathways. Mutations in this gene cause deficiency in regulation of beta-cell development and nuclear receptors transcription pathways, associated with maturity onset diabetes of Young (MODY) and HNF4A-related hyperinsulinism (3, 4). Association of hyperinsulinemia in infancy and diabetes in adolescence has been reported only in patients with HNF4A mutations (4). We present a patient with hyperinsulinmia in infancy and diabetes in adolescence without HNF4A mutation and with good response to oral hypoglycemic agents. In infancy, this patient presented with persistent hyperinsulinemic hypoglycemia. He was on oral diazoxide until 3 years of age when this drug was tapered and discontinued. Genetic study was not performed at that time due to limitation of facilities. After that time, his blood sugar was normal until 15 years of age when he presented with diabetes mellitus. Starting HbA1c was 9.5%. In addition, fasting triglyceride level and cholesterol level was 66 mg/dL and 168 mg/dL, respectively. Other routine laboratory studies were within the normal range. Pancreas anatomy was also normal in ultrasonography. At the time of manifestation of diabetes, he was 162 cm tall (about 25th percentile for sex and age) and 51 kg (about 25th percentile for sex and age). He did not have any family history of diabetes. Insulin therapy associated with oral sylfonylurea (Glibenclamid) was started with impression of monogenic diabetes. As he responded, insulin dose was gradually tapered and discontinued, and an α-glucodisase inhibitor (Acarbose) was started to improve his mild postprandial hyperglycemia. The treatment was continued with 0.1 mg/kg/day Glibenclamid and 50 mg Acarbose before each meal. Self-monitoring of blood glucose by the patient and most of the measurements were in the target range (70-130 mg/dL). After 4 months of treatment, HbA1c was 6.7%. He tolerated the medications well without any side effect. According to previous history of the patient, the most probable diagnosis was HNF4ɑ mutation. However, the results of HNF4ɑ gene study by DNA sequencing method revealed no mutation and only a previously reported variant rs745975 C > T determined in nucleotide 5 of intron 1 (5). This variant was associated with Stearoyl-CoA desaturase 1 activity (6) and with type 2 diabetes mellitus (7). History of hyperinsulinism in infancy, diabetes mellitus in adolescence, low plasma triglyceride level, and good response to oral hypoglycemic agents has been reported in previous cases of MODY type 1 with HNF4A mutation (8). Mutation in HNF4A was not found in the presented case and due to shortage of facilities, more genetic study was not performed, however, his clinical course is in favor of a type of monogenic diabetes. This case showed that some adolescent diabetic patients, even without family history of diabetes, and without clinical characteristics of type 2 diabetes may have good response to oral hypoglycemic agents. Further studies are needed to find more cases of monogenic diabetes in adolescents, and to determine which diabetic adolescent can be treated with oral agents. Also, it is recommended that in every patient whose diabetes commences in adolescence, a precise history about hypoglycemia of infancy should be obtained.

Molecular modeling and identification of novel glucokinase activators through stepwise virtual screening

The glucose phosphorylating enzyme glucokinase (GK) is a 50kD monomeric protein having 465 amino acids. It maintains glucose homeostasis inside cells, acts as a glucose sensor in pancreatic β-cells and as a rate controlling enzyme for hepatic glucose clearance and glycogen synthesis. It has two binding sites, one for binding d-glucose and the other for a putative allosteric activator named glucokinase activator (GKA). The GKAs interact with the same region of the GK enzyme that is commonly affected by naturally occurring mutations in humans. However, many GKAs do not bind to GK in the absence of glucose. Recently, it has been reported that GKAs are highly effective in patients with type 2 diabetes mellitus.In this milieu a molecular modeling study has been carried out on three natural variants of GK that lie in the GKA binding site and are known to cause maturity onset diabetes of young (MODY). Additionally, a 10ns molecular dynamics simulation was done on each of the modeled variant in order to explore the flexibility of this site. Subsequently, a systematic virtual screening study was done to identify compounds which can bind with high affinity at GKA binding site of mutant GK.

An analysis of diet and nutrition status of Uyghur families with maturity onset diabetes of young

To study the status of diet and nutrition in Uyghur families with maturity onset diabetes of young (MODY).Four MODY families were composed of four generations of Uyghur with 50 members collected from Kashgar,Shanshan,and Ili regions of Xinjiang Uyghur Autonomous Region.A dietary survey with a semi-quantitative food frequency questionnaire was conducted.According to the sex and different intensities of physical activity,the nutrient intake was calculated by nutrition calculator software,and the results were compared with recommended nutrients intake(RNI).Cereals,livestock,and poultry meat,being the main food stuff in Uyghur MODY families,accounted for 54.11％ and 13.87％ of total energy respectively,while fruit,fish,and shrimps were seldom taken,and accounted for 0.41％ and 0.26％ of total energy respectively.Carbohydrate,protein,and fat accounted for 55.0％,16.7％,and 28.4％ of total energy intake respectively,within the scope of the RNI for diabetes suggested by both Chinese Diabetes Society and the American Diabetes Association.The total energy and all three major nutrients were excessively taken by subjects of different genders and different intensities physical activity from Uyghur MODY families in Xinjiang.Uyghur diets lead to excessive calorie intake in the Uyghur MODY family members.The Health education of Uyghur language and text should be strengthened,so as to improve the scientific dietary knowledge. Key words: Maturity onset diabetes of young; Semi-quantitative food frequency questionnaire; Dietary survey

HNF-1beta mutation affects PKD2 and SOCS3 expression causing renal cysts and diabetes in MODY5 kindred

Maturity onset diabetes of young (MODY) type 5 is a form of non-insulin-dependent diabetes mellitus associated with renal cysts. It is an autosomal dominant disorder caused by mutations in the gene encoding hepatocyte nuclear factor-1β (HNF-1β). We performed molecular screening of HNF-1β in a 13-year-old patient and his affected father, and analyzed polycystic kidney disease 2 (PKD2) gene and suppressor of cytokine signaling 3 (SOCS3) expression in lymphoblastoid cell lines and lymphocytes from both patients. We found a novel HNF-1β frameshift mutation (c.C1304del) that results in a truncated protein (p.I434IfsX1). The genetic change is localized in the transactivated protein domain. We demonstrated that this novel HNF-1β mutation strongly influences the expression of both PKD2, responsible for the formation of the renal cysts, and SOCS3, which is associated with early diabetes onset.

MOLECULAR GENETICS AND CLINICAL ASPECTS OF MONOGENIC DIABETES MELLITUS

The paper is dedicated to clinical and laboratory aspects of Diabetes Mellitus non-immune forms, such as neonatal Diabetes Mellitus, Maturity Onset Diabetes of young (MODY), DIDMOAD-syndrome, Wolframe syndrome, Alstrom syndrome and its determinating genes. The analysis of proper clinical results are present in this paper.

Serum Metabonomic Study of 2 Uyghur Probable MODY Families Based on 1H NMR

Objective: To study the characteristics of changes in serum metabolites in two Uyghur families with probable maturity-onset diabetes of young (MODY). Method: We gathered two probable MODY families composed of four generations of Uyghurs from Kashgar region, Xinjiang Uyghur Autonomous Region, China. A total of 52 family members were gathered. Their general information, measured blood glucose levels, blood lipid levels, and blood pressure were analyzed. Using 1H Nuclear Magnetic Resonance (1H NMR) spectroscopy, serum metabolites were measured for each study participants. After having conducted data pretreatment on the spectrogram, orthogonal partial least squares discriminant analysis (OPLS-DA) was used to interpret data. We divided subjects into two groups according to blood glucose (norrmal and high), blood pressure, body mass index (BMI) levels, and compared the metabolites. We determined differences of metabolism components between each group's serum using pearson correlation coefficients with significant difference detection and two-dimensional spectrum technology. Results: ?Isoleucine and tyrosine levels were decreased significantly (p<0.05) and ?-glucose, ?-glucose levels were increased obviously(p<0.05), when high blood glucose group compared with normal blood glucose group ?Citrate, phaseomannite, 1-methyl histidine and tyrosine levels were all decreased significantly(p<0.05), When comparing serum metabolites between hypertension group and norrmal blood pressure group in probable MODY family members ?No significant metabonomic changes were observed when comparing norrmal BMI group and high BMI group. Conclusion: The metabolites in the serum of Uyghur probable MODY family members were very different in different groups. Isoleucine, citrate, inositol, 1-methylhistidine and tyrosine are the differential metabolites, these metabolites can be considered as candidate biomarkers for predicting probable MODY. Differences of the metabolits in serum of probable MODY families suggested that the TCA cycle metabolic disorder and the obstruction of fat metabolism in the patients of the probable MODY families.

Role of transglutaminase 2 in glucose tolerance: knockout mice studies and a putative mutation in a MODY patient.

Transglutaminase 2 (TGase 2) is a Ca+2-dependent enzyme that catalyzes both intracellular and extracellular cross-linking reactions by transamidation of specific glutamine residues. TGase 2 is known to be involved in the membrane-mediated events required for glucose-stimulated insulin release from the pancreatic beta cells. Here we show that targeted disruption of TGase 2 impairs glucose-stimulated insulin secretion. TGase 2-/- mice show glucose intolerance after intraperitoneal glucose loading. TGase 2-/- mice manifest a tendency to develop hypoglycemia after administration of exogenous insulin as a consequence of enhanced insulin receptor substrate 2 (IRS-2) phosphorylation. We suggest that the increased peripheral sensitivity to insulin partially compensates for the defective secretion in this animal model. TGase 2-/- mouse phenotype resembles that of the maturity-onset diabetes of young (MODY) patients. In the course of screening for human TGase 2 gene in Italian subjects with the clinical features of MODY, we detected a missense mutation (N333S) in the active site of the enzyme. Collectively, these results identify TGase 2 as a potential candidate gene in type 2 diabetes.

SRC-1 and GRIP1 Coactivate Transcription with Hepatocyte Nuclear Factor 4

Hepatocyte nuclear factor-4 (HNF4), a member of the nuclear receptor superfamily, plays an important role in tissue-specific gene expression, including genes involved in hepatic glucose metabolism. In this study, we show that SRC-1 and GRIP1, which act as coactivators for various nuclear receptors, associate with HNF4 in vivo and enhance its transactivation potential. The AF-2 domain of HNF4 is required for this interaction and for the potentiation of transcriptional activity by these coactivators. p300 can also serve as a coactivator with HNF4, and it synergizes with SRC-1 to further augment the activity of HNF4. HNF4 is also a key regulator of the expression of hepatocyte nuclear factor-1 (HNF1). The overexpression of SRC-1 or GRIP1 enhances expression from a HNF1 gene promoter-reporter in HepG2 hepatoma cells, and this requires an intact HNF4-binding site in the HNF1 gene promoter. Type 1 maturity onset diabetes of young (MODY), which is characterized by abnormal glucose-mediated insulin secretion, is caused by mutations of the HNF4 gene. A mutation of the HNF4-binding site in the HNF1 gene promoter has also been associated with MODY. Thus, HNF4 is involved in the regulation of glucose homeostasis at several levels and along with the SRC-1, GRIP1, and p300 may play an important role in the pathophysiology of non-insulin-dependent diabetes mellitus.