PAS: Getting a grip on glucokinase MODY

SAN DIEGO – The two main things to understand about maturity-onset diabetes of the young due to mutations in the glucokinase gene are that this form of diabetes is far more common than you probably realize, and – unique in the world of diabetes – no treatment is warranted, according to Dr. Siri Atma W. Greeley, a pediatric endocrinologist at the University of Chicago.

He cited what he called “a great study” by investigators at the University of Exeter (England), who showed that very, very few patients with glucokinase maturity-onset diabetes of the young (GCK MODY) develop micro- or macrovascular complications. Despite a median 48.6 years of follow-up of 99 patients with GCK MODY, also known as MODY 2, the prevalence and severity of retinopathy, nephropathy, peripheral neuropathy, cardiovascular disease, and peripheral vascular disease weren’t significantly different from controls (JAMA 2014;311:279-86).

“Just remember – these patients do not get diabetes-related complications. And we think that if they do, it might be because they later go on to develop type 2 diabetes; for instance, if they become obese and have a genetic predisposition in addition to having their GCK mutation,” Dr. Greeley said at the annual meeting of the Pediatric Academic Societies.

There’s another reason to spare patients with GCK MODY from lifelong diabetes therapy, besides the facts that treatment is costly, has side effects, and does nothing to minimize their risk of vascular complications because their risk isn’t increased: Namely, pharmacotherapy doesn’t alter glycemic control in these patients. The Exeter group has shown that HbA_1c in patients with GCK MODY isn’t affected by treatment with insulin or oral hypoglycemic agents (Diabetologia 2014;57:54-6). That’s because the GCK gene acts as a blood glucose sensor for the pancreas, and a mutation causes the gene to reset blood glucose at a slightly higher than normal level. Treatment is ineffective because the body will relentlessly strive to maintain blood glucose at the reset level, he explained.

Typically, however, patients with GCK MODY are treated – inappropriately – with insulin or oral hypoglycemic agents because they have been misdiagnosed as having type 2 or less commonly type 1 diabetes. Indeed, roughly half of patients with GCK MODY have been on drug therapy for more than 3 months at the time they enroll in the U.S. Monogenic Diabetes Registry maintained by Dr. Greeley and coworkers at the University of Chicago. Some are actually on an insulin pump.

“There’s a lot of unnecessary treatment going on with these patients,” he said.

The only time treatment of GCK MODY is appropriate, the endocrinologist added, is in some affected women during pregnancy in order to control fetal growth.

How common is GCK MODY in pregnancy? The Exeter group has estimated the population prevalence at 1.2 cases per 1,000 pregnancies, or 0.1%, based on genetic testing of participants in the Atlantic Diabetes in Pregnancy Study (Diabetes Care 2014;37:1230-6). However, among more than 61,000 unrelated individuals who have participated in various large-scale gene sequencing projects under the umbrella of the Exome Aggregation Consortium, GCK mutation rates were higher, ranging from 2.71 cases per 1,000 non-Finnish Europeans to 4.93 per 1,000 among Latinos and 5.74 per 1,000 Africans.

More than 90% of all cases of MODY with a known cause are due to mutations in one of four genes: GCK, hepatocyte nuclear factor homeobox 1-alpha (HNF1A), HNF1 homeobox 1B, or HNF4 alpha. Investigators in the U.S. multicenter SEARCH for Diabetes in Youth Study performed gene-sequencing studies in 586 study participants and found the prevalence of mutations in GCK, HNF1A, or HNF4 alpha was 1.2% among the pediatric diabetes population (J. Clin. Endocrinol. Metab. 2013;98:4055-62). That finding has clear implications for clinical practice: “All of you, if you’re seeing any number of diabetes patients, should have at least a handful of cases of MODY,” Dr. Greeley observed.

The hallmark of GCK MODY is mild fasting hyperglycemia present from birth, with a stable HbA_1c below 7.8% throughout life. But Dr. Greeley emphasized that there is no set of clinical features that make the diagnosis of GCK MODY or other forms of MODY with 100% certainty. The only way to firmly establish the diagnosis is through genetic testing, which in Dr. Greeley’s view is vastly underutilized. He was coinvestigator in a study that demonstrated that genetic testing for causative mutations in the big-four genes is cost effective in selected circumstances. And at least one major insurer, he added, is starting to come around to that point of view.

Dr. Greeley’s research is funded by the National Institutes of Health, the American Diabetes Association, and the Kovler Family Foundation. He reported having no financial conflicts.

[email protected]

SAN DIEGO – The two main things to understand about maturity-onset diabetes of the young due to mutations in the glucokinase gene are that this form of diabetes is far more common than you probably realize, and – unique in the world of diabetes – no treatment is warranted, according to Dr. Siri Atma W. Greeley, a pediatric endocrinologist at the University of Chicago.

He cited what he called “a great study” by investigators at the University of Exeter (England), who showed that very, very few patients with glucokinase maturity-onset diabetes of the young (GCK MODY) develop micro- or macrovascular complications. Despite a median 48.6 years of follow-up of 99 patients with GCK MODY, also known as MODY 2, the prevalence and severity of retinopathy, nephropathy, peripheral neuropathy, cardiovascular disease, and peripheral vascular disease weren’t significantly different from controls (JAMA 2014;311:279-86).

“Just remember – these patients do not get diabetes-related complications. And we think that if they do, it might be because they later go on to develop type 2 diabetes; for instance, if they become obese and have a genetic predisposition in addition to having their GCK mutation,” Dr. Greeley said at the annual meeting of the Pediatric Academic Societies.

There’s another reason to spare patients with GCK MODY from lifelong diabetes therapy, besides the facts that treatment is costly, has side effects, and does nothing to minimize their risk of vascular complications because their risk isn’t increased: Namely, pharmacotherapy doesn’t alter glycemic control in these patients. The Exeter group has shown that HbA_1c in patients with GCK MODY isn’t affected by treatment with insulin or oral hypoglycemic agents (Diabetologia 2014;57:54-6). That’s because the GCK gene acts as a blood glucose sensor for the pancreas, and a mutation causes the gene to reset blood glucose at a slightly higher than normal level. Treatment is ineffective because the body will relentlessly strive to maintain blood glucose at the reset level, he explained.

Typically, however, patients with GCK MODY are treated – inappropriately – with insulin or oral hypoglycemic agents because they have been misdiagnosed as having type 2 or less commonly type 1 diabetes. Indeed, roughly half of patients with GCK MODY have been on drug therapy for more than 3 months at the time they enroll in the U.S. Monogenic Diabetes Registry maintained by Dr. Greeley and coworkers at the University of Chicago. Some are actually on an insulin pump.

“There’s a lot of unnecessary treatment going on with these patients,” he said.

The only time treatment of GCK MODY is appropriate, the endocrinologist added, is in some affected women during pregnancy in order to control fetal growth.

How common is GCK MODY in pregnancy? The Exeter group has estimated the population prevalence at 1.2 cases per 1,000 pregnancies, or 0.1%, based on genetic testing of participants in the Atlantic Diabetes in Pregnancy Study (Diabetes Care 2014;37:1230-6). However, among more than 61,000 unrelated individuals who have participated in various large-scale gene sequencing projects under the umbrella of the Exome Aggregation Consortium, GCK mutation rates were higher, ranging from 2.71 cases per 1,000 non-Finnish Europeans to 4.93 per 1,000 among Latinos and 5.74 per 1,000 Africans.

More than 90% of all cases of MODY with a known cause are due to mutations in one of four genes: GCK, hepatocyte nuclear factor homeobox 1-alpha (HNF1A), HNF1 homeobox 1B, or HNF4 alpha. Investigators in the U.S. multicenter SEARCH for Diabetes in Youth Study performed gene-sequencing studies in 586 study participants and found the prevalence of mutations in GCK, HNF1A, or HNF4 alpha was 1.2% among the pediatric diabetes population (J. Clin. Endocrinol. Metab. 2013;98:4055-62). That finding has clear implications for clinical practice: “All of you, if you’re seeing any number of diabetes patients, should have at least a handful of cases of MODY,” Dr. Greeley observed.

The hallmark of GCK MODY is mild fasting hyperglycemia present from birth, with a stable HbA_1c below 7.8% throughout life. But Dr. Greeley emphasized that there is no set of clinical features that make the diagnosis of GCK MODY or other forms of MODY with 100% certainty. The only way to firmly establish the diagnosis is through genetic testing, which in Dr. Greeley’s view is vastly underutilized. He was coinvestigator in a study that demonstrated that genetic testing for causative mutations in the big-four genes is cost effective in selected circumstances. And at least one major insurer, he added, is starting to come around to that point of view.

Dr. Greeley’s research is funded by the National Institutes of Health, the American Diabetes Association, and the Kovler Family Foundation. He reported having no financial conflicts.

[email protected]

SAN DIEGO – The two main things to understand about maturity-onset diabetes of the young due to mutations in the glucokinase gene are that this form of diabetes is far more common than you probably realize, and – unique in the world of diabetes – no treatment is warranted, according to Dr. Siri Atma W. Greeley, a pediatric endocrinologist at the University of Chicago.

He cited what he called “a great study” by investigators at the University of Exeter (England), who showed that very, very few patients with glucokinase maturity-onset diabetes of the young (GCK MODY) develop micro- or macrovascular complications. Despite a median 48.6 years of follow-up of 99 patients with GCK MODY, also known as MODY 2, the prevalence and severity of retinopathy, nephropathy, peripheral neuropathy, cardiovascular disease, and peripheral vascular disease weren’t significantly different from controls (JAMA 2014;311:279-86).

“Just remember – these patients do not get diabetes-related complications. And we think that if they do, it might be because they later go on to develop type 2 diabetes; for instance, if they become obese and have a genetic predisposition in addition to having their GCK mutation,” Dr. Greeley said at the annual meeting of the Pediatric Academic Societies.

There’s another reason to spare patients with GCK MODY from lifelong diabetes therapy, besides the facts that treatment is costly, has side effects, and does nothing to minimize their risk of vascular complications because their risk isn’t increased: Namely, pharmacotherapy doesn’t alter glycemic control in these patients. The Exeter group has shown that HbA_1c in patients with GCK MODY isn’t affected by treatment with insulin or oral hypoglycemic agents (Diabetologia 2014;57:54-6). That’s because the GCK gene acts as a blood glucose sensor for the pancreas, and a mutation causes the gene to reset blood glucose at a slightly higher than normal level. Treatment is ineffective because the body will relentlessly strive to maintain blood glucose at the reset level, he explained.

Typically, however, patients with GCK MODY are treated – inappropriately – with insulin or oral hypoglycemic agents because they have been misdiagnosed as having type 2 or less commonly type 1 diabetes. Indeed, roughly half of patients with GCK MODY have been on drug therapy for more than 3 months at the time they enroll in the U.S. Monogenic Diabetes Registry maintained by Dr. Greeley and coworkers at the University of Chicago. Some are actually on an insulin pump.

“There’s a lot of unnecessary treatment going on with these patients,” he said.

The only time treatment of GCK MODY is appropriate, the endocrinologist added, is in some affected women during pregnancy in order to control fetal growth.

How common is GCK MODY in pregnancy? The Exeter group has estimated the population prevalence at 1.2 cases per 1,000 pregnancies, or 0.1%, based on genetic testing of participants in the Atlantic Diabetes in Pregnancy Study (Diabetes Care 2014;37:1230-6). However, among more than 61,000 unrelated individuals who have participated in various large-scale gene sequencing projects under the umbrella of the Exome Aggregation Consortium, GCK mutation rates were higher, ranging from 2.71 cases per 1,000 non-Finnish Europeans to 4.93 per 1,000 among Latinos and 5.74 per 1,000 Africans.

More than 90% of all cases of MODY with a known cause are due to mutations in one of four genes: GCK, hepatocyte nuclear factor homeobox 1-alpha (HNF1A), HNF1 homeobox 1B, or HNF4 alpha. Investigators in the U.S. multicenter SEARCH for Diabetes in Youth Study performed gene-sequencing studies in 586 study participants and found the prevalence of mutations in GCK, HNF1A, or HNF4 alpha was 1.2% among the pediatric diabetes population (J. Clin. Endocrinol. Metab. 2013;98:4055-62). That finding has clear implications for clinical practice: “All of you, if you’re seeing any number of diabetes patients, should have at least a handful of cases of MODY,” Dr. Greeley observed.

The hallmark of GCK MODY is mild fasting hyperglycemia present from birth, with a stable HbA_1c below 7.8% throughout life. But Dr. Greeley emphasized that there is no set of clinical features that make the diagnosis of GCK MODY or other forms of MODY with 100% certainty. The only way to firmly establish the diagnosis is through genetic testing, which in Dr. Greeley’s view is vastly underutilized. He was coinvestigator in a study that demonstrated that genetic testing for causative mutations in the big-four genes is cost effective in selected circumstances. And at least one major insurer, he added, is starting to come around to that point of view.

Dr. Greeley’s research is funded by the National Institutes of Health, the American Diabetes Association, and the Kovler Family Foundation. He reported having no financial conflicts.

[email protected]