Type 1 diabetes occurs in young diabetes mellitus, by contrast, is a disease of the middle These are the typical pictures, but type 2 diabetes can …
JOURNAL
OF
THE
ROYAL
SOCIETY
OF
MEDICINE
Volume 94
February 2001
H U Rehman MRCP
J R Soc Med 2001;94:6567
Type 1 diabetes occurs in young people and is of rapid onset Autoimmune destruction of the insulin-secreting b-cells of the pancreas is the major cause, marked by the presence of islet cell antibodies1 and glutamic acid decarboxylase antibodies2 in 7080 of patients3 Type 2 diabetes mellitus, by contrast, is a disease of the middle aged or elderly and usually begins insidiously Insulin resistance and a strong family history are the hallmarks These are the typical pictures, but type 2 diabetes can develop in early adulthood and type 1 diabetes in the middle aged or elderly In this paper I review the variants to be considered in a young adult 545 years with diabetes mellitus of slowly progressive onset
MATURITY ONSET DIABETES OF THE YOUNG MODY
MODY is early-onset type 2 diabetes, usually beginning under the age of 25 years Those affected are seldom obese The condition is inherited in autosomal dominant fashion and accounts for some 25 of type 2 diabetes4 GAD autoantibodies are not found Five subtypes have so far been identied, due to different gene defects5 MODY due to
HNF4a mutations on chromosome 20q MODY 1 closely resembles classic type 2 diabetes Several HNF4a mutations have been described Q268X, F75fsdelT, K99fsdelAA, R127W, R154X, and E276Q6 Under the age of 10 years most individuals who carry these mutations have a normal fasting blood glucose and normal glucose tolerance Thereafter, glycaemic control deteriorates and diabetes is usually diagnosed between 12 and 35 years of age The prevalence of microvascular and macrovascular complications is similar to that in classic type 2 diabetes Impaired b-cell function seems to be the main reason for abnormal glucose control, insulin resistance being unimportant MODY due to mutations in the glucokinase GCK gene on chromosome 7 MODY 2 is a milder form of diabetes More than 45 GCK mutations have been described7 All patients have modest fasting hyperglycaemia from birth 68 mmol/L and there is only slight deterioration over time8 Usually there are no symptoms and diagnosis is typically made on routine screening in a young person with
Department of Medicine, Hull Royal Inrmary, Hull HU3 2JZ, UK E-mail: habibrehman@lineonenet
a family history of type 2 diabetes mellitus in two or more generations The
main defect is in b-cell glucose sensing, caused by mutations in the glucokinase gene9; thus, fasting glucose is set at a higher baseline b-cell function is otherwise normal and the response to a glucose challenge is good Patients with MODY 2 are highly sensitive to sulphonylurea medication and seldom get microvascular complications10 MODY due to HNF1a mutations on chromosome 12q MODY 3 is similar to MODY 1 in its clinical presentation11 More than 45 HNF-1a mutations have been described12 MODY due to mutations in insulin promoter factor 1 MODY 4 seems similar to MODY 1 and MODY 3 in phenotype but clinical details are limited It arises when the mutated gene is present in the heterozygous state; homozygosity results in pancreatic agenesis13 The average age of onset is 35 years Most patients require dietary management or oral hypoglycaemic agents14 MODY 5, due to HNF1b mutations, is the most recently discovered subtype and presents between 12 and 28 years of age Initial data suggest a clinical course similar to MODY 3 and MODY 4 Cystic renal disease and chronic renal failure appear to be associated with it15 Subtypes of MODY are outlined in Table 1
EARLY ONSET TYPE 2 DIABETES
EOD
With EOD the age of onset is between 25 and 40 years Most patients are obese and commonly they are hypertensive and dyslipidaemic as well Usually both parents are diabetic or have impaired glucose tolerance16, the mode of inheritance being autosomal dominant Glutamic acid decarboxylase autoantibodies GAD are not usually found but about 10 of patients are positive for b-cell antibodies At least in the early years, insulin is not needed The insulin response to an oral glucose load is much more heterogeneous than in MODY3 diabetes17, and the primary defect seems to be a decrease in the response of peripheral tissues to insulin A combination of early onset, hypertension, and dyslipidaemia puts these individuals at high risk of microvascular and macrovascular complications Table 2 summarizes the differences between EOD and MODY
REVIEW ARTICLES
65
Diabetes mellitus in the young
JOURNAL
OF
THE ROYAL
SOCIETY OF
MEDICINE
Volume
94
February 2001
Table 1 Subtypes of maturity onset diabetes of the young MODY
MODY 1 MODY 2 MODY 3 MODY 4 MODY 5
Genetic locus Gene Frequency Age at diagnosis Severity of diabetes Complications
20q NHF-4b 5 Post-pubertal Severe Frequent
7p
Glucokinase 125 Childhood Mild Rare
12q NHF-1a 65 Post-pubertal Severe Frequent
13q IPF-1 Unknown Early adulthood Mild? Unknown
17 HNF-1b Unknown Childhood Severe? Frequent?
LATENT AUTOIMMUNE DIABETES OF ADULTHOOD LADA
About 10 of patients diagnosed with diabetes have latent autoimmune diabetes of adulthood, characterized by the presence of glutaminic acid decarboxylase antibodies18,19 This is a slowly progressive form of type 1 diabetes which usually presents after the age of 25 years The clinical onset tends to be less acute than that of type 1 diabetes, and the initial diagnosis is commonly of type 2 The patients are younger and thinner than those with type 2, and they show some of the classic features of type 1 diabetes including weight loss, low C-peptide concentration, an increased frequency of HLA DR3 and DR4, and positive tests for islet cell and glutamic acid decarboxylase antibodies20 Although insulin secretion is better preserved in the slowly progressing than in the rapidly progressing form of autoimmune diabetes, patients are insulin decient and require insulin treatment early in their clinical course21 They also have some degree of insulin resistance22 There is
an argument for checking for glutamic acid decarboxylase antibody in all newly diagnosed young and thin patients with type 2 diabetes since a positive result almost invariably means that the patient will require insulin23 Despite their lower body mass index, waist-to-hip ratio and C-peptide concentrations and higher HDL2 high-density lipoprotein cholesterol concentrations, LADA patients have about the
Table 2 Differences between EOD early onset diabetes and MODY
maturity onset diabetes of the young EOD MODY
same prevalence of microvascular and macrovascular complications as those with type 2 diabetes24
MATERNALLY INHERITED DIABETES AND DEAFNESS MIDD
of parents abnormal of siblings abnormal Peak age of onset year Obesity Clinical course Insulin required
90 68 2540 Frequent Progressive Often Common
50 50 1520 Rare Slowly progressive Seldom Uncommon
MIDD is type 2 diabetes caused by a mutation in mitochondrial DNA 3243 tRNAleu25 with usual onset before the age of 40 years The same mutation is associated with the syndrome of MELAS mitochondrial myopathy, encephalopathy, lacticacidosis, and stroke-like episodes26 Why some carriers develop MELAS and others diabetes is unclear
Recently another point mutation, characterized by a T?C transition at mtDNA position 14709 within the tRNAGlu gene, has been described27 A sensorineural hearing loss, not always leading to clinically manifest deafness, commonly precedes the onset of diabetes Individuals with MIDD are usually not obese Mitochondrial myopathy, from mild or even silent to severe, can be found in all patients if looked for28 Cardiac disorders, hypertension, nephropathy and spontaneous abortion have been frequently noted but whether these are true diabetic complications or comorbidities of the mutation is not known About half of all diabetic patients who are 3243 carriers were previously diagnosed as having type 1 diabetes, though islet cell antibodies are either absent or very low29 MIDD patients tend to be insulinopenic, and the defect is thought to lie in insulin release rather than the producing capacity of b-cells30 The severity of glucose intolerance varies, manageable by diet and/or oral hypoglycaemic agents in some patients and requiring insulin in others; but ve years after diagnosis most patients will need insulin31
CONCLUSION
66
Microvascular complications
With recognition of new variants,
there have been major changes in the classication and understanding of diabetes Slowly progressive forms of type 1 and type 2 diabetes in adults aged 2540 years present special difculties An understanding of these intermediate types is important
JOURNAL
OF
THE
ROYAL
SOCIETY
OF
MEDICINE
Volume 94
February 2001
because the precise diagnosis has implications for prognoses, treatment and screening of family members
REFERENCES
17 Doria A, Yang Y, Malecki M, Scotti S, Dreyfus J, et al Phenotypic characteristics of early-onset-autosomal-dominant diabetes unlinked to maturity-onset diabetes of the young MODY genes Diabetes Care 1999;22:25361 18 Turner R, Stratton I, Horton V, et al UKPDS 25 Autoantibodies to islet cytoplasm and glutamic acid decarboxylase for prediction of insulin requirement in type 2 diabetes Lancet 1997;350:128893 19 Tuomi T, Groop LC, Zimmet PZ, Rowley MJ, et al Antibodies to glutamic acid decarboxylase reveal latent autoimmune diabetes mellitus in adults with non-insulin dependent onset of disease Diabetes 1993;42: 35862 20 Groop L, Miettinen A, Groop P-H, Meri S, Koskimies S, Bottazzo GF Organ-specic autoimmunity and HLA-DR antigens as markers for
beta-cell destruction in patients with type II diabetes Diabetes 1998;37: 99103 21 Groop LC, Bottazzo GF, Doniach D Islet cell antibodies identify latent type I diabetes in patients aged 3575 at diagnosis Diabetes 1986;35:23741 Ê 22 Carlsson A, Sundkvist G, Groop L, Tuomi T Insulin and glucagons secretion in patients with slowly progressing autoimmue diabetes LADA J Clin Endocrinol Metab 2000;85:7680 23 Tuomi T, Groop LC, Zimmet PZ, Rowley MJ, Knowles W, Mackay IR Antibodies to glutamic acid decarboxylase reveal latent autoimmune diabetes mellitus in adults with non-insulin-dependent onset of disease Diabetes 1993;42:35962 24 Isomaa B, Almgren P, Henricsson M, et al Chronic complications in patients with slowly progressing autoimmune type 1 diabetes LADA Diabetes Care 1999;22:134753 25 Maasen JA, Kadowaki T Maternally inherited diabetes and deafness: a new diabetes subtype Diabetologia 1996;39:37582 26 Goto Y, Nonaka I, Horai S A mutation in the tRNALeu UUR gene associated with the MELAS subgroup of mitochondrial encephalomyopathies Nature 1990;348:6513 27 Hao H, Bonilla E, Manfredi G, Di Mauro S, Moraes CT Segregation patterns of a novel mutation in the mitochondrial tRNA glutamic
acid gene associated with myopathy and diabetes mellitus Am J Hum Genet 1995;56:101725 28 Vialettes BH, Paquis-Flucklinger V, Pelissier JF, et al Phenotypic expression of diabetes secondary to a T14709C mutation of mitochondrial DNA Diabetes Care 1997;20:17317 29 Oka Y, Katagiri H, Yazaki Y, Murase T, Kabayashi T Mitochondrial gene mutation in islet cell antibody positive patients who were initially non-insulin-dependent diabetes Lancet 1993;342:5278 30 Velho G, Byrne MM, Clement K, et al Clinical phenotypes, insulin secretion, and insulin sensitivity in kindreds with maternally inherited diabetes and deafness due to mitochondrial tRNA Leu, UUR gene mutation Diabetes 1996;45:47887 31 Maasen JA, van den Ouweland JMW, tHart LM, Lemkes HHPJ Maternally inherited diabetes and deafness; a diabetic subtype associated with a mutation in mitochondrial DNA Horm Metab Res 1997;29:505
1 Bottazzo GF, Florin-Christensen A, Doniach D Islet cell antibodies in diabetes mellitus with autoimmune polyendocrine deciencies Lancet 1974;ii:127983 2 Baekkeskov V, Aanstoot HJ, Christgau S, et al Identication of the 64k autoantigen in insulin-dependent diabetes as the GABA synthesizing enzyme glutamic acid
decarboxylase Nature 1990;347:1526 3 Verge CF, Howard NJ, Rowley MJ, et al Antiglutamate decarboxylase and other antibodies at the onset of childhood IDDM: a population based study Diabetologia 1994;37:11320 4 Ledermann HM Is maturity onset diabetes at young age MODY more common in Europe than previously assumed? Lancet 1995; 345:648 5 Winter WE, Nakamura M, House DV Monogenic diabetes mellitus in youth The MODY syndromes Endocrinol Metab Clin NA 1999;28: 76585 6 Yamagata K, Ruruta H, Oda N, et al Mutations in the hepatocyte nuclear factor-4a gene in maturity-onset diabetes of the young MODY1 Nature 1996;384:458 7 Froguel P, Zoulai H, Vionnet N, et al Familial hyperglycaemia due to mutations in glucokinase: denition of a subtype of diabetes mellitus N Engl J Med 1993;328:676702 8 Page RC, Hattersley AT, Levy JC, et al Clinical characteristics of subjects with a missense mutation in glucokinase Diabet Med 1995;12: 20917 9 Hattersley AT Maturity-onset diabetes of the young: clinical heterogeneity explained by genetic heterogeneity Diabet Med 1998;15:1524 10 Velho G, Blanche H, Vaxillaire M, et al Identication of 14 new glucokinase mutations and description of the clinical prole of 42
MODY-2 families Diabetologia 1997;40:21724 11 Appleton M, Ellard S, Bulman M, Frayling T, Page R, Hattersley AT Clinical characteristics of the HNF1a MODY3 and glucokinase mutations [Abstract] Diabetologia 1997;40:A161 12 Yamagata K, Oda N, Kaisaki PJ, et al Mutations in the hepatocyte nuclear factor-1a gene in maturity-onset diabetes of the young MODY3 Nature 1996;384:455 13 Stoffers DA, Zinkin NT, Stanojevic V, et al Pancreatic agenesis attributable to a single nucleotide deletion in the human IPFI gene coding sequence Nat Genet 1997;15:106 14 Stoffers DA, Ferrer J, Clarke WL, Habener JF Early-onset type II diabetes mellitus MODY4 linked to IPF1 Nat Genet 1997;17:384 15 Horikawa Y, Iwasaki N, Hara M, et al Mutation in hepatocyte factor1b gene TCF2 associated with MODY Nat Genet 1997;17:384 16 ORahilly S, Spivey RS, Holman RR, Nugent Z, et al Type II diabetes of early onset: a distinct clinical and genetic syndrome? BMJ 1987;294: 9238
67
Source:ndhcri.org
