38 HOW TO TREAT : MATURITY-ONSET DIABETES OF THE YOUNG
38 HOW TO TREAT : MATURITY-ONSET DIABETES OF THE YOUNG
8 NOVEMBER 2024 ausdoc . com . au
Box 1 . Consider testing for MODY in individuals with early-onset diabetes with atypical features ( ie , not clearly type 1 or type 2 )
• No history of diabetic ketoacidosis .
• Preserved beta cell function ( ie , the lack of need for insulin treatment or a serum C-peptide level of greater than 200pmol / L even after five or more years of insulin treatment ( ie , a presumptive diagnosis of type 1 diabetes ).
• Absence of clinical features of insulin resistance .
• Non-obese subjects with hyperglycaemia .
• No dyslipidaemia .
• No hypertension .
• No polycystic ovary syndrome .
• A strong family history of a similar type of ( early onset ) diabetes among first-degree relatives or across several generations .
• If MODY is suspected , assess risk using the calculator available at the UK site ( Exeter Diabetes MODY Probability Calculator ). A high probability ( greater than a 25 % chance ) of MODY using an online risk calculator . 8
Source : Adapted from RACGP . Genomics in General Practice 2022 20 Figure 3 . Pancreatic anatomy .
PAGE 36 the same time , de novo mutation of MODY genes may occur sporadically , meaning that a family history is not mandatory .
MODY may sometimes first present in women with the onset of diabetes during pregnancy . In women with mutations in MODY-causing genes , insulin resistance associated with pregnancy places a burden on insulin production , which cannot be adequately compensated for , resulting in an increased risk and severity of gestational diabetes . This is particularly the case with individuals with MODY2 that is caused by a loss of function mutation in the GCK gene . GCK is an enzyme that acts as a sensor for glucose levels to co-ordinate proportionate insulin release in response to a meal . Reduced GCK activity in MODY2 means a higher set-point for insulin secretion from beta cells ( see figure 5 ). Affected individuals with GCK mutations will often have only mild stable hyperglycaemia , at worst , and are usually asymptomatic . However , that changes when a woman with MODY2 becomes pregnant , making it more likely she will develop gestational diabetes .
MODY2 presenting in pregnancy can be difficult to recognise , as gestational diabetes is already common in Australian women . Beyond the deleterious effects of fetal hyperglycaemia on organogenesis , MODY2 also has implications for fetal development .
If the fetus has not inherited the mutated GCK gene from their mother with MODY2 , it will grow large ( with macrosomia , increased abdominal circumference on prenatal ultrasound ) because of excess fetal insulin production , increasing the risk of serious complications during delivery .
If the fetus has the same mutation as its mother , it will also sense glucose in the same way and have
Table 1 . The five most common subtypes of MODY are associated with mutations in different genes that influence the presentation , treatment and prognosis
MODY subtype
MODY1
MODY2
MODY3
MODY4
MODY5
MODY6
Mutated gene Dysfunction Phenotype / prognosis
Hepatocyte nuclear factor-4-alpha ( HNF4A )
Glucokinase ( GCK )
Hepatocyte nuclear factor-1- alpha ( HNF1A )
Insulin promoter factor 1 ( PDX1 )
Hepatocyte nuclear factor-1- beta ( HNF1B )
Neurogenic differentiation factor 1 ( NEUROD1 )
Source : Bonnefond A et al 2023 4
normal growth ( once maternal glucose levels are controlled ). 21
DIAGNOSIS
THE diagnostic criteria for diabetes appear in box 2 .
Once a diagnosis of diabetes is made , it is important to determine the type of diabetes . Patients with MODY are often misdiagnosed as having type 1 or type 2 diabetes . As detailed earlier , it is often difficult to identify those most likely to have MODY compared with other forms of diabetes on clinical criteria alone .
Reduced insulin secretory response to glucose
A higher threshold for glucose-stimulated insulin secretion
Abnormal insulin secretion
Reduced activation of insulin gene in response to hyperglycaemia
Abnormal development of endocrine pancreas
Abnormal development of endocrine pancreas
Progressive insulin deficiency Patients typically present with diabetes in adolescence or early childhood
Mild stable hyperglycaemia Often managed with diet alone Implications during pregnancy , dependent on fetal genotype
Progressive insulin deficiency Lowered renal threshold for glucose causes glycosuria even before diabetes , but some variants are associated with adult onset diabetes Patients typically present with diabetes in adolescence or early childhood Increased sensitivity to insulin and sulfonylureas
Progressive insulin deficiency Patients typically present with diabetes in adolescence or early childhood , but some variants are associated with adult onset diabetes
Progressive insulin deficiency Patients typically present with diabetes in adolescence or early childhood May also be associated with hypomagnesaemia , pancreatic atrophy , kidney dysplasia and cysts , and genital abnormalities
Progressive insulin deficiency Patients typically present with diabetes in adolescence or early childhood
There are several online risk calculators that can assist with identifying some patients with an increased likelihood of MODY ( see box 3 ). However , none of these risk calculators provide the accuracy required to detected unrecognised cases of MODY . In addition , rapidly rising rates of type 2 diabetes in adolescents and young adults has made clinical differentiation from MODY more difficult over the past few decades .
Most patients with type 1 diabetes have autoantibodies at diagnosis . 3 In
young individuals presenting with what seems like type 1 diabetes , consider a diagnosis of MODY in those negative for autoantibodies directed against beta cell antigens ( for example , glutamic acid decarboxylase [ anti-GAD ], insulin autoantibodies [ anti-IAA ], insulinoma-associated protein [ anti-IA-2 ] and zinc transporter T8 [ anti-ZnT8 ]).
This is not a perfect discriminator , as recent data suggest that 5-10 % of adults with type 1 diabetes may have negative islet antibodies but still have type 1 diabetes . 10
Box 2 . Diagnostic criteria for diabetes
• A diagnosis of diabetes is made in any symptomatic patient with :
— A fasting venous plasma glucose concentration 7.0mmol / L or greater .
— A random plasma glucose level greater than 11.0mmol / L .
— A haemoglobin A1c ( HbA1c ) of 6.5 % ( 48mmol / mol ) or greater .
Source : RACGP Diabetes guidelines . 22
Equally , recent reports suggest that some people with MODY and some with type 2 diabetes have autoantibodies , although multiple positive autoantibodies occur less frequently in MODY compared with type 1 diabetes . 23
In autoantibody-negative young individuals , additional testing for plasma C-peptide may be performed ( with a concurrent plasma glucose measurement ) within five hours of eating . Insulin is co-secreted with C-peptide from beta cells . If insulin production is completely destroyed ( as occurs in type 1 diabetes ) circulating C-peptide levels will also be decreased . Most patients with type 1 diabetes will have a C-peptide value of less than 200pmol / L , consistent with beta cell failure , and necessitating the requirement for insulin therapy .
However , about one in every three adults with type 1 diabetes retain at least some insulin and C-peptide secretion , at least initially at diagnosis . Ultimately , both insulin and C-peptide production are lost in those with type 1 diabetes .
After three or more years of diabetes , consider those with PAGE 40