HOW TO TREAT 41 titrated SU therapy in any patient suspected to have MODY . 26
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HOW TO TREAT 41 titrated SU therapy in any patient suspected to have MODY . 26
However , other agents may also effectively control the often modestly elevated glucose levels in individuals with MODY without the additional burden of hypoglycaemia or weight gain associated with SUs .
In addition , patients with MODY3 may have an increased risk of diabetic complications , including retinopathy and kidney disease . 27 This necessitates a more aggressive approach to management that potentially prioritises organ-protective agents such as SGLT2 inhibitors and GLP-1 receptor agonists , which are both effective glucose-lowering agents in this setting . As progressive beta cell failure is central to the pathogenesis of diabetes in most forms of MODY ( except GCK-dependent MODY2 ), insulin therapy may ultimately be needed to maintain adequate blood glucose control .
Achieving and maintaining optimal glucose control is associated with improved clinical outcomes . 28 , 29 What is ‘ optimal ’ may be different for different individuals ; consider individual factors such as a patient ’ s daily activity , history of hypoglycaemia , occupation , comorbidities and personal goals .
HbA1c is routinely measured on blood tests and reflects the average plasma glucose level over the previous 10-12 weeks , such that the average plasma glucose level approximates to [ 2 x HbA1c (%)] – 6 .
HbA1c testing is subsidised by Medicare every three months , but in those with stable therapy and glucose levels , biannual testing is appropriate . Most adults with MODY can safely target an HbA1c less than 53mmol / mol ( less than 7.0 %), with lower targets of 48mmol / mol ( 6.5 %) for those who can safely achieve this control once they achieve less than 7 %.
Some adults with MODY , or their carers , assess the adequacy of treatment by undertaking regular and frequent monitoring of plasma glucose levels . This may be more important in individuals on SU or insulin therapy to reduce the risk of hypoglycaemia . Blood glucose testing is generally performed on capillary glucose ( obtained by finger prick ) 4-6 times daily , typically before meals and before bed .
Individuals with poor glycaemic control or frequent hypoglycaemic events may require more frequent monitoring , especially if they have impaired hypoglycaemia awareness , or they are undertaking highrisk activities . Additional monitoring may also be appropriate to reduce the risk of hypoglycaemia with exercise , as a legal requirement for driving , during periods of illness , and when an insulin regimen has been recently changed
Adults with MODY registered on the National Diabetes Service Scheme ( NDSS ) are eligible to receive significantly subsidised glucose testing strips . Continuous glucose monitors are not currently subsidised under the NDSS for patients with MODY . These devices can have advantages over a glucometer , particularly as they avoid the need for regular capillary glucose monitoring and increase the frequency of glucose level readings , especially at night . Safe targets for most adults with MODY appear in box 4 .
However , the benefits of aiming for these targets must be weighed against the risk of hypoglycaemia and the challenges of adherence with treatment personalised for each individual .
Diet and lifestyle , and its co-ordination with drug therapy , play an important role in achieving and maintaining optimal glucose control in patients with MODY . At first , this may be very confusing to patients , as their diabetes is not caused by their diet or lifestyle . Many patients can be managed with diet / lifestyle alone ( especially those with MODY2 ), and glycaemic control in all other types of MODY benefits from an individual optimising their diet and lifestyle .
Encourage all adults with
Figure 6 . A systematic approach to the diagnosis of MODY .
High BMI , insulin resistance
• Metabolic syndrome
• Acanthosis nigricans
T2DM
Treat GCK-MODY
GAD-65 : glutamic acid decarboxylase-65 autoantibodies ; IAA : insulin autoantibodies ; IA-2A : tyrosine phosphatase-related islet antigen-2 autoantibodies ; OADs : oral antidiabetic drugs ; ZnT8 : zinc transporter 8 autoantibodies ; HNF1B : hepatocyte nuclear factor-1 beta ; GCK-MODY : glucokinase-MODY ; HNF4A-MODY : hepatic nuclear factor 4 alpha-MODY ; HNF1A-MODY : hepatic nuclear factor 1 alpha-MODY
Insidious onset
• No ketoacidosis
• Autoantibody negative
• Serum C-peptide greater than 200pmol / L at diagnosis
• Stimulated C-peptide greater than 200pmol / L at least three years after diagnosis
Non-progressive hyperglycaemia
• Asymptomatic
• Fasting plasma glucose less than 8.0mmol / L
• HbA1c less than 8 %
• Impaired glucose tolerance — Small increase in OGTT
Genetic testing for GCK-MODY
• Serial single gene testing or
• Multigene panel
Insulin production
MODY highly suspected
Clinical assessment
• Measure fasting plasma glucose , OGTT , HbA1c , ketones , autoantibodies ( IA-2 , GAD-65 , ZN-T8 ), C-peptide , lipids and BMI if : ‐ Onset of hyperglycaemia before age 30 ‐ Clinical features not compatible with either type 1 or type 2 diabetes ‐ Family history ( at least one first-degree relative ) of diabetes
Normal BMI , occasional insulin resistance
• Family history of diabetes
Low HDL , low triglyceride , high HDL
• Absence of glycosuria
Set-point
Progressive hyperglycaemia
• Symptomatic
• Occasionally overweight
• Impaired glucose tolerance
Genetic testing for HNF4A-MODY
• Serial single gene testing or
• Multigene panel
Treat HNF4A-MODY
Blood glucose
Insulin production
Figure 5 . The production of insulin is balanced with blood glucose levels , such that higher blood glucose levels result in a rise in insulin production . In MODY2 , the set-point for glucose-triggered insulin production is shifted so that higher blood glucose levels are required to trigger comparable insulin secretion .
Acute onset
• Episodes of ketoacidosis
• Autoantibody positive ( IA-2 , GAD-65 and / or ZN-T8 )
• Serum C-peptide less than 200pmol / L at diagnosis
• Stimulated C-peptide less than 200pmol / L at least three years after diagnosis
T1DM
Renal cysts and diabetes syndrome
• Pancreatic and extrapancreatic features — Renal cysts — Hypomagnesemia — Hyperuricemia and early-onset gout — Genital tract abnormalities — Pancreatic hypoplasia — Pancreatic exocrine insufficiency — Abnormal LFTs
• HNF1B score equal to or greater than 8
Genetic testing for HNF1B-MODY
• Serial single gene testing or
• Multigene panel
Treat HNF1B-MODY
High HDL
• Presence of glycosuria
Genetic testing for HNF1A-MODY
• Serial single gene testing or
• Multigene panel
Treat HNF1A-MODY
Higher set-point
Blood glucose
Based on Nkonge KM et al 2020 10 , Faguer S et al 2014 23A