Ill discuss mody this month, and some interesting clinical issues. Mody 2 is due to any of several mutations in the gck gene on chromosome 7 for glucokinase. The mutationinduced structural alterations in the protein were analyzed by molecular modeling. Changes in the gck gene can lead to increases in blood glucose and affected people may be diagnosed with diabetes although this rise in blood glucose is mild and usually does not need treatment. Approximately 2% range 06% of women with a diagnosis of gestational diabetes mellitus have a heterozygous gck gene mutation 23,34,4653. If there is a change in the gck gene this means that it works slightly differently so. The influence of dietary carbohydrate content on glycaemia in patients with glucokinase maturityonset diabetes of the young t k lupa 1,2, i solecka 2, n n owak 1, m szopa 1,2,3, b k iecw ilk 1,2, j skupien 4, i t rybul1,2, b m atejko 1, w m lynarski5and mt m alecki1,2 1department of metabolic diseases, and 3department of medical education. The most common types of monogenic diabetes are the autosomal dominant forms known as maturityonset diabetes of the young mody. Mody is a form of niddm characterized by monogenic autosomal dominant transmission and early age of onset. It is estimated to be the underlying cause of diabetes in 12% of patients diagnosed with diabetes, but prevalence estimates will not be accurate until large population screening studies are performed. Moreover, there are likely to be additional mody genes since there are families in which mody does not cosegregate with markers tightly linked to the three. Chinese children with glucokinasematurityonset diabetes of the young gckmody xiuzhen li1, tzer hwu ting2, huiying sheng1, cui li liang1, yongxian shao1, minyan jiang1, aijing xu1, yunting lin1 and li liu1 abstract background. The influence of dietary carbohydrate content on glycaemia. What does maturityonset diabetes of the young mody look like determining which type of diabetes a patient has is critical in providing the proper care and treatment.
Glucokinase is predominantly expressed in pancreatic beta cells and catalyzes the phosphorylation of glucose to glucose6phosphate. Recognition and management of individuals with hyperglycemia. Glucokinase diabetes is one of the familial diabetes types that together are often called mody maturity onset diabetes of the young. Oct 19, 2011 maturity onset diabetes of the young mody comprises a heterogeneous group of monogenic disorders characterised by. Maturity onset diabetes of the young mody is a monogenic form of diabetes characterized by autosomal dominant inheritance, an early clinical onset and a primary defect in. Glucokinase is an enzyme present in the beta cells of the pancreas. Out of fourteen, up to date discovered, mody genes omim, 2016 the most often affected ones include gck gene encoding glucokinase enzyme and. New hope for glucokinase activators in type 2 diabetes.
Maturityonset diabetes of the young mody canadian journal of. Optimal glucose control in patients with type 2 diabetes remains challenging, particularly because a progressive decline in. Backgroundmaturity onset diabetes of the young type 2 or gck mody is a genetic form of diabetes mellitus provoked by mutations in the glucokinase gene gck. Discuss the major characteristics of mody and list the 3 most common types. Maturityonset diabetes of the young mody is a rare kind of diabetes that runs in families. This is characterized by mild, stable, usually asymptomatic, fasting hyperglycemia that rarely requires pharmacological intervention. Missense glucokinase mutation in maturityonset diabetes of.
Gck encodes for the enzyme glucokinase, which has a central role in the regulation of blood glucose and acts as a glucose sensor in pancreatic. Demystifying maturityonset diabetes of the young mody. Newcastle hospitals maturity onset diabetes of the young mody. One differential diagnosis is maturity onset diabetes of the young mody which.
Maturityonset diabetes of the young mody caused by a. Identification of maturityonset diabetes of the young caused by. Prevalence, characteristics and clinical diagnosis of. Jul 08, 2019 mody is a rare condition, accounting for 15% of all cases of diabetes12, and 16% of pediatric cases of diabetes. Maturity onset diabetes of the young due to glucokinase, hnf1a. Matureonset diabetes of the young, type 2 mody2 is associated with mutations in the glucokinase gck gene that result in impaired glucokinase. Therefore, numerous attempts have been made to find drugs that are able to stimulate insulin secretion in a glucosedependent manner and protect. Mody is much more common than ndm and usually first occurs in adolescence or early adulthood. Please click here to download a pdf version of this information. Glucokinase maturityonset diabetes of the young gckmody represents a distinct subgroup of mody that. Genetic and clinical characteristics of chinese children with. When to consider a diagnosis of mody at the presentation.
In patients with nonsyndromic diabetes, greater than 99% of mody with a known genetic etiology results from mutations in hepatocyte nuclear factor hnf1a formerly mody3, glucokinase gck mody2, or hnf4a mody1. It is worth being aware that those with mody 3 tend to have glycosuria at quite normal blood sugar levels and can develop kidney disease before a diagnosis of diabetes is finally made. Mody maturity onset diabetes of the young is a specific type of diabetes caused by mutation in a single gene, involved in the development and function of the. Molecular and clinical characterization of glucokinase.
If a child does inherit the mutation they will generally go on to develop mody before theyre 25, whatever their. Diabetes caused by mutations in the glucokinase gck gene. Objective the posttranslational regulation of glucokinase gk differs in hepatocytes and pancreatic. However, a rise in childhood obesity has made distinguishing between type 1 and type 2 diabetes increasingly more challenging. Inactivating heterozygous mutations in the glucokinase gene gck cause a form of monogenic diabetes with autosomal dominant inheritance gck matureonset diabetes of the young mody 1,2. The influence of dietary carbohydrate content on glycaemia in. Diagnosis and management of glucokinase monogenic diabetes. This means that the blood glucose does not become too high if glucokinase is functioning normally. We describe a codon 299 mutation in the glucokinase gene in a british pedigree with maturityonset diabetes of the young mody resulting in a substitution of glycine to arginine. Furthermore, both mody and type 2 diabetes are associated with a strong family. Its unique kinetic properties result in the rate of glucose phosphorylation being proportional to the physiologic glucose concentration. The majority of mody cases are due to mutations in one of four genes.
We screened members of 35 families with features of maturityonset diabetes of the young for mutations in the glucokinase gene and found 16 different mutations. Clinical management of women with monogenic diabetes. Gckmody is one the most common mody subtypes, affecting 0. It has a vital role in enabling the pancreatic beta cells to accurately detect circulating blood glucose levels and adjust insulin secretion accordingly to keep blood sugar levels at a homeostatic set point of approximately 5mmoll. While diabetes associated complications are rare, about 2% of pts with all forms of mody require insulin treatment. The enzymatic activity and thermal stability of wildtype wt gk and several mutant forms associated with maturityonset diabetes of the young type 2 mody2 were determined by a steadystate kinetic analysis of the purified expressed proteins. Diagnosis and management of glucokinase monogenic diabetes in. Mody is quite rare its estimated to comprise 12% of those with dm. Phenotype heterogeneity in glucokinasematurityonset. There is scarcity of information on the clinical features and genetics of glucokinasematurityonset. Neonatal diabetes is a rare disorder with an estimated incidence of 1 in 400,000 live births. Victoria l rudland 1,2 1 department of diabetes and endocrinology, westmead hospital, sydney, nsw, australia. Gckmody has generally been considered a phenotypically homogenous mild form of diabetes, which does not lead to marked hyperglycemia or diabetes complications and does not need.
Mody is caused by a mutation or change in a single gene. Gene mutations in glucokinase gck account for 30% to 60% of the cases of mody. Like type 1 and type 2 diabetes, mody affects the way your body uses and stores sugar from food. Normal glucokinase triggers insulin secretion as the glucose exceeds about 90 mgdl 5. Patients are often misdiagnosed with t1 or t2dm, and the diagnosis of mody is often delayed. Spyer g, hattersley at, sykes je, sturley rh, macleod km. Mody is a rare condition, accounting for 15% of all cases of diabetes12, and 16% of pediatric cases of diabetes. These mody genes encode the enzymes glucokinase gck mody 2 that is liable. Identification of 14 new glucokinase mutations and. Pdf clinical heterogeneity in monogenic diabetes caused by. Glucokinasematurityonset diabetes of the young gckmody, also known as mody2, is caused by heterozygous inactivating mutations in the gck gene. Pdf maturity onset diabetes of the young type 2 or gck mody is a genetic form of diabetes mellitus provoked by mutations in the glucokinase gene. Management in patients with diabetes due a mutations of.
Some estimates are that over 90% of mody patients are misdiagnosed as having t2d because many physicians are not aware of the distinctions. However, mody is frequently misdiagnosed as types 1 or 2 diabetes, and studies estimate that as manyas 95% of mody cases in the usa go. Continuous glucose monitoring in patients with glucokinase deficiency patients pt with glucokinas patients pt with glucokinase deficiency gkd, mody 2 have varying degrees of glucose intolerance. Influence of maternal and fetal glucokinase mutations in gestational diabetes. Pregnancy is a time when asymptomatic women are screened for hyperglycemia, and so women with gckmody may be detected as having gestational diabetes mellitus. Research design and methods activity and protein expression of gkmody and persistent hyperinsulinemic. Heterozygous inactivating mutations in the glucokinase gck gene cause a hyperglycemic condition termed maturityonset diabetes of the young mody 2 or gckmody. Mody 2 glucokinase the glucokinase gene regulates the amount of insulin produced by the pancreas in response to blood glucose. Missense glucokinase mutation in maturityonset diabetes. Glucokinase catalyzes the phosphorylation of glucose to glucose6phosphate. This means that the beta cell and hepatocyte can respond appropriately to fluctuations in the degree of glycemia.
Maturity onset diabetes of the young mody comprises a heterogeneous group of monogenic disorders characterised by. Mody 2 is a form of maturity onset diabetes of the young. Identifying glucokinase monogenic diabetes mellitus in a multiethnic. Maturity onset diabetes of the young mody the journal of.
Glucokinase transcription becomes nearly undetectable in prolonged starvation, severe carbohydrate deprivation, or untreated insulindeficient diabetes. Mody has been believed to be rare in asian people, and only a few case reports have been published. Glucokinasematurityonset diabetes of the young gckmody is an autosomal dominant disorder caused by heterozygous inactivating gck gene mutations. For adults who do not need immediate insulin treatment, a default diagnosis of type 2 diabetes is the most common outcome, but a small proportion of patients will actually have maturityonset diabetes of the young mody.
Diabetes, maturity onset in the young mody statpearls ncbi. Clinical heterogeneity in monogenic diabetes caused by. Clinical heterogeneity in monogenic diabetes caused by mutations in the glucokinase gene gckmody article pdf available in diabetes care 332. Mody 2 is a form of maturity onset diabetes of the young mody 2 is due to any of several mutations in the gck gene on chromosome 7 for glucokinase.
Management in patients with diabetes due a mutations of the. Not all children with diabetes have type 1 di abetes. Mody is a rare form of diabetes which is different from both type 1 and type 2 diabetes, and runs strongly in families. Pdf effects of novel maturityonset diabetes of the young mody. Demystifying maturityonset diabetes of the young mody kristine m. Genetic and clinical characteristics of chinese children. Maturityonset diabetes of the young mody was first reported in 1974 as mild familial diabetes with dominant inheritance. Jun 14, 20 the most common types of monogenic diabetes are the autosomal dominant forms known as maturityonset diabetes of the young mody. At the conclusion of this presentation, participants should be able to. Susceptibility of glucokinasemody mutants to inactivation by oxidative stress in pancreatic. Mutations in genes on chromosomes 20, 7 and 12, designated mody1, mody2glucokinase gck and mody3, respectively, can cause this form of diabetes 35.
Neonatal diabetes mellitus due to complete glucokinase deficiency. Maturityonset diabetes of the young mody caused by a glucokinase mutation v62m which results in defective regulation of the enzyme glucokinase italicgckital glucokinase italicgckitalic serves as the pancreatic glucosesensor. Gck analysis for maturity onset diabetes of the young type 2. Methodologyprincipal findingswe screened the gck gene by direct sequencing in 30 patients from south italy with suspected mody. We tested the hypothesis that gk mutants that cause maturityonset diabetes of the young gkmody show compromised activity and posttranslational regulation in. Continuous glucose monitoring in patients with glucokinase. Clinical management of women with monogenic diabetes during. The mechanisms by which insulin induces glucokinase may involve both of the major intracellular pathways of insulin action, the extracellular signalregulated kinase erk 12 cascade, and the. Glucokinase gk is expressed in the pancreatic betacells and liver, and plays a key role in the regulation of glucose homeostasis. The enzymatic activity and thermal stability of wildtype wt gk and several mutant forms associated with maturityonset diabetes of the young type 2 mody 2 were determined by a steadystate kinetic analysis of the purified expressed proteins. Gckmody has generally been considered a phenotypically homogenous mild form of diabetes, which does not lead to marked hyperglycemia or diabetes complications and does not need treatment 2 5. Glucokinase gck is a gene which plays an important role in recognising how high the. When to consider a diagnosis of mody at the presentation of. While diabetesassociated complications are rare, about 2% of.
Phenotype heterogeneity in glucokinasematurityonset diabetes. Frontiers hidden modylooking for a needle in a haystack. If a parent has this gene mutation, any child they have, has a 50% chance of inheriting it from them. Maturity onset diabetes of the young mody mody affects 12% of people with diabetes but often goes unrecognised. Monogenic glucokinasematurityonset diabetes of the young gckmody is the second most common type of diabetes mellitus dm after. Mody may be misdiagnosed as type 1 or type 2 diabetes mellitus 1, 2. Diagnosis and management of maturity onset diabetes of the.
Heterozygous mutations leading to partial deficiency of glucokinase are associated with mody, and homozygous mutations resulting in complete deficiency of this enzyme lead to permanent neonatal diabetes mellitus. If there is a change in the gck gene this means that it works slightly differently so that the blood glucose is reset at a higher level than in. Maturityonset diabetes of the young or mody is considered by many physicians and researchers to be a subset of type 2 diabetes t2d and is often misdiagnosed as t2d. There was statistically significant evidence of genetic heterogeneity, with an estimated 45 to 95% of the 16 families showing linkage to glucokinase. This gene contains the blueprint for an enzyme that is important in for the normal regulation of insulin production. Matschinsky, loranne agius, catherine arden diabetes dec 2011, 60 12 31753185. Most cases of monogenic diabetes are incorrectly diagnosed. Maturityonset diabetes mody is a subgroup if this form. Mutations in glucokinase are associated with defects in insulin secretion and hepatic glycogen synthesis resulting in mild chronic hyperglycaemia, impaired glucose tolerance or diabetes mellitus. The university of chicago medicine kovler diabetes center.
Glucokinase serves as the glucose sensor for the pancreatic beta cell. Heterozygous inactivating mutations in the glucokinase gck gene cause a hyperglycemic condition termed maturityonset diabetes of the young mody 2 or gck mody. Gckmody carriers were found in a frequency of 3% among 1043 diabetes mellitus dm patients and constituted the second most numerous group of dm patients, following type 1 dm, in our centre. Glucokinase gene mutations mody 2 in asian indians. It is a dominantly inherited genetic condition, therefore children of an affected parent with mody have a 50% chance of inheriting the gene and developing mody themselves. Neonatal diabetes mellitus due to complete glucokinase. Welsh, rn, msn, cpnp nemours aiduponthospital for children objectives. Maturity onset diabetes of the young mody diabetes uk. A gp will often be the first health professional involved in making a diagnosis of diabetes. Pregnancy outcome of japanese patients with glucokinase. Normal glucokinase triggers insulin secretion as the glucose exceeds about 90 mgdl 5 mm.
According to the 2011 american diabetes association ada guidelines. What does it mean if there is a change in the gck gene. Genetic testing for glucokinase mutations in clinically selected. Pdf glucokinase acts as the pancreatic glucose sensor and plays a critical role in the regulation of insulin secretion by the betacell. Gck analysis for maturity onset diabetes of the young type. Pdf clinical heterogeneity in monogenic diabetes caused. Maturityonset diabetes of the young mody is a suspected diagnosis in young nonobese patients who lack an autoimmune cause for diabetes and who have a family history of diabetes in successive generations. The most common form of monogenic diabetes is mody, which is estimated to account for 12% of all diabetes worldwide 2. Neonatal diabetes mellitus ndm and maturityonset diabetes of the young mody are the two main forms of monogenic diabetes. Mutations in gck associated with gckmody typically result in a modest decrease in glucokinase activity, which in turn leads to mild fasting hyperglycemia 4.
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