Sulfonylurea Sensitivity and MODY

MODY is a relatively rare form of familial diabetes and is part of the differential diagnosis of diabetes presenting in the first three decades of life. MODY is now known to differ fundamentally from type 2 DM in its etiology and is classified separately as type 3A. The key characteristics of this condition are an young age of onset (often before the age of 25 years), noninsulin dependence (absence of features of type 1 DM, with C-peptide positiv-ity and no requirement for insulin within five years of diagnosis), and an autosomal-dominant mode of inheritance (46). At least two consecutive generations are affected with a family member diagnosed (before the age of 25). This is very much a heterogeneous group of disorders with wide variability in the severity of the hyperglycemia and the age at which it becomes clinically manifest. Several genetic subtypes of MODY have now been described, and these are all characterized by mild fasting hyperglycemia in otherwise normal individuals (Table 3) (47). Mutations in six genes have been shown to cause MODY, with two different types of monogenic mutation (48). Glucokinase MODY is caused by mutations in the gene for the glycolytic enzyme glucokinase, and transcription factor MODY is caused by mutations in transcription factors (such as hepatocyte nuclear factor genes HNF-1a, HNF-4a, and HNF-1b and insulin promoter factor-1) (49). There are clear clinical differences between these two different types of MODY, reflecting quantitative and qualitative differences in pancreatic b-cell dysfunction. Glucokinase MODY is relatively mild and characterized by nonprogressive hyperglycemia, which is caused by a stable defect and resetting of the pancreatic glucose sensor. It can be treated with diet alone, and complications are rare. In contrast, MODY caused by mutations in the transcription factors lead to a progressive b-cell defect in insulin secretion, an increasing requirement for treatment, and all the complications usually associated with type 2 DM (50). Diagnostic molecular testing is available for the more common genes involved, although approximately 15% to 20% of the families fitting MODY criteria do not have mutations in any of the known genes (48). A stepwise approach to the etiological investigation of young adults with DM is recommended (51,52). Alternative molecular tests may also be appropriate to identify these patients, with markers downstream of the genetic defect. For example, the haploinsufficiency of the gene coding for HNF-1a is associated with reduced serum apolipoprotein M levels, which may be a useful marker for MODY3 patients (53).

Heterozygous mutations in the HNF-1 a gene are the most common cause of MODY accounting for between 1% and 2% of all cases of DM (57). Isolated case reports have suggested that patients with HNF-1 a MODY (MODY3) are more sensitive to the hypoglycemic effects of sulfonylureas, compared with the patients with type 2 DM (58-61). Hyperexcitability of the pancreas to sulfonylureas has been described in one healthy glucose-tolerant person with an HNF-1 a mutation who showed a greater response to intravenous tolbutamide than healthy controls (62). This has subsequently been demonstrated in a randomized cross-over trial comparing the response to a sulfonylurea and metformin in patients with diabetes caused by either HNF-1 a mutations or type 2 DM (63). Patients

Table 3 Most Common Maturity-Onset Diabetes of the Young Subtypes






End result






Impaired pancreatic b-cell function






Defect in glucose sensing






Impaired pancreatic b-cell function


with diabetes caused by mutations in the HNF-1a gene showed a greater improvement in glycemia in response to treatment with the sulfonylurea gliclazide, in comparison with matched (for body-mass index and degree of glycaemia) patients with type 2 DM. This was not attributable to changes in the hepatic metabolism of the drug but reflects preserved B-cell function and a preserved insulin secretory response to sulfonylureas in patients with MODY. This has important implications for the management of such patients—the increased sensitivity to sulfonylureas would suggest that this class of drug should be used, alongside an appropriate diet, as initial treatment, instead of a biguanide, or even insulin therapy, and at a reduced dosage to improve glycemic control (63). Hypoglycemia may be more common in these patients, and thus the use of very low doses of sulfonylureas is important. Pearson et al. (63) recommend a starting dose of 20-40 mg gliclazide (or equivalent) in this subgroup of patients. Furthermore, cessation of sulfonylureas should be undertaken cautiously as there may be a marked deterioration in glycemic control.

The effects of sulfonylureas are initiated by the drug binding to ATP-sensitive K+ (Katp) channels, inducing membrane depolarization, activation of voltage-gated Ca2+ channels, and subsequent degranulation of insulin-containing vesicles (64). Mice lacking the HNF-1a gene have a dramatic reduction in insulin secretory response to glucose (65,66) and a good insulin secretory response to glibenclamide. Although this has been demonstrated to be accompanied by impaired hepatic clearance and elevated plasma concentrations of the drug (67), the expression of the glycolytic enzymes, gluco-kinase and liver pyruvate kinase, is also reduced in the pancreatic islets of HNF-1a-deficient mice compared with the wild-type mice (68,69). This suggests that the glucose metabolism pathway is a key site of action on HNF-1a, and that in HNF-1a deficiency, the genetic B-cell defect is upstream of the sulfonylurea receptor. Therefore, it is proposed that the good insulin secretory response to sulfonylureas in spite of the poor response to glucose in MODY3 diabetes is the result of a bypass in a severe defect in glucose metabolism and that the signaling pathway downstream of the sulfonylurea receptor is preserved (63). This is illustrated in Figure 1. The challenge for pharmacogenetics in the future is to assist in the identification of a larger group of patients who will respond to specific treatments depending on the predominant underlying pathophysiology.

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  • Karin
    Why is mody sulphonylurea?
    26 days ago

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