Early predictors of GDM identified in women with PCOS

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Early predictors of GDM identified in women with PCOS

BOSTON – A prospective cohort study of women with polycystic ovarian syndrome who developed gestational diabetes mellitus during pregnancy has implicated fasting blood glucose, non–high density lipoprotein, and sex hormone–binding globulin as significant predictive factors for the development of GDM.

“Polycystic ovarian syndrome [PCOS] is the most common reproductive disorder in women of reproductive age and is commonly associated with metabolic disorders including diabetes and obesity. In women with GDM, a history of PCOS is associated with higher incidence of complications and postpregnancy glucose intolerance. Risk factors during early pregnancy in women with PCOS for development of GDM have not been well characterized,” said Dr. Wenyu Huang of Northwestern University, Chicago.

Dr. Wenyu Huang

To provide some clarity, Dr. Huang and his colleagues conducted a prospective cohort study. Inclusion criteria were age 18-45 years, diagnosis of PCOS prior to conception, singlet pregnancy, and enrollment during the first trimester. Preexisting chronic disease including diabetes, hypertension, and thyroid, kidney, or cardiovascular disease was grounds for exclusion. The findings were presented at the annual meeting of the Endocrine Society.

The 248 women with PCOS enrolled from 2011 to 2013 from a screened population of 25,000 pregnant women were followed from their first prenatal visit (before week 18) to delivery. Blood was collected at the first visit for analysis of metabolic hormones. A 75-g oral glucose tolerance test (OGTT) was carried out at week 24-28 and diagnosis of GDM was according to 2013 American Diabetes Association OGTT criteria.

Of the 248 women, 75 (30.2%) developed GDM, and 173 (69.8%) women had normal OGTT results. Examination over the same time period early in pregnancy revealed a higher incidence of GDM in women with PCOS.

In a univariate analysis, PCOS patients who developed GDM had higher fasting blood glucose (FBG), Homeostasis Model Assessment-Insulin resistance (HOMA-IR) score, total cholesterol, low-density lipoprotein cholesterol, non-HDL cholesterol, systolic and diastolic blood pressures, and free testosterone index. These patients also had lower levels of sex hormone–binding globulin (SHBG) and higher likelihood of family history of diabetes and earlier delivery.

Multiple logistic regression revealed associations between increased incidence of GDM and FBG greater than or equal to 4.86 mmol/L, non-HDL cholesterol greater than or equal to 2.84 mmol/L, and SHBG greater than or equal to 222 nmol/L. The predictive power of the three factors for the development of GDM in PCOS was relatively strong.

Future studies could aim to validate the prediction model and clarify the pathogenic basis of GDM in PCOS women, according to the researchers .

The study was funded by the Beijing Science Committee. Dr. Huang had no disclosures.

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BOSTON – A prospective cohort study of women with polycystic ovarian syndrome who developed gestational diabetes mellitus during pregnancy has implicated fasting blood glucose, non–high density lipoprotein, and sex hormone–binding globulin as significant predictive factors for the development of GDM.

“Polycystic ovarian syndrome [PCOS] is the most common reproductive disorder in women of reproductive age and is commonly associated with metabolic disorders including diabetes and obesity. In women with GDM, a history of PCOS is associated with higher incidence of complications and postpregnancy glucose intolerance. Risk factors during early pregnancy in women with PCOS for development of GDM have not been well characterized,” said Dr. Wenyu Huang of Northwestern University, Chicago.

Dr. Wenyu Huang

To provide some clarity, Dr. Huang and his colleagues conducted a prospective cohort study. Inclusion criteria were age 18-45 years, diagnosis of PCOS prior to conception, singlet pregnancy, and enrollment during the first trimester. Preexisting chronic disease including diabetes, hypertension, and thyroid, kidney, or cardiovascular disease was grounds for exclusion. The findings were presented at the annual meeting of the Endocrine Society.

The 248 women with PCOS enrolled from 2011 to 2013 from a screened population of 25,000 pregnant women were followed from their first prenatal visit (before week 18) to delivery. Blood was collected at the first visit for analysis of metabolic hormones. A 75-g oral glucose tolerance test (OGTT) was carried out at week 24-28 and diagnosis of GDM was according to 2013 American Diabetes Association OGTT criteria.

Of the 248 women, 75 (30.2%) developed GDM, and 173 (69.8%) women had normal OGTT results. Examination over the same time period early in pregnancy revealed a higher incidence of GDM in women with PCOS.

In a univariate analysis, PCOS patients who developed GDM had higher fasting blood glucose (FBG), Homeostasis Model Assessment-Insulin resistance (HOMA-IR) score, total cholesterol, low-density lipoprotein cholesterol, non-HDL cholesterol, systolic and diastolic blood pressures, and free testosterone index. These patients also had lower levels of sex hormone–binding globulin (SHBG) and higher likelihood of family history of diabetes and earlier delivery.

Multiple logistic regression revealed associations between increased incidence of GDM and FBG greater than or equal to 4.86 mmol/L, non-HDL cholesterol greater than or equal to 2.84 mmol/L, and SHBG greater than or equal to 222 nmol/L. The predictive power of the three factors for the development of GDM in PCOS was relatively strong.

Future studies could aim to validate the prediction model and clarify the pathogenic basis of GDM in PCOS women, according to the researchers .

The study was funded by the Beijing Science Committee. Dr. Huang had no disclosures.

BOSTON – A prospective cohort study of women with polycystic ovarian syndrome who developed gestational diabetes mellitus during pregnancy has implicated fasting blood glucose, non–high density lipoprotein, and sex hormone–binding globulin as significant predictive factors for the development of GDM.

“Polycystic ovarian syndrome [PCOS] is the most common reproductive disorder in women of reproductive age and is commonly associated with metabolic disorders including diabetes and obesity. In women with GDM, a history of PCOS is associated with higher incidence of complications and postpregnancy glucose intolerance. Risk factors during early pregnancy in women with PCOS for development of GDM have not been well characterized,” said Dr. Wenyu Huang of Northwestern University, Chicago.

Dr. Wenyu Huang

To provide some clarity, Dr. Huang and his colleagues conducted a prospective cohort study. Inclusion criteria were age 18-45 years, diagnosis of PCOS prior to conception, singlet pregnancy, and enrollment during the first trimester. Preexisting chronic disease including diabetes, hypertension, and thyroid, kidney, or cardiovascular disease was grounds for exclusion. The findings were presented at the annual meeting of the Endocrine Society.

The 248 women with PCOS enrolled from 2011 to 2013 from a screened population of 25,000 pregnant women were followed from their first prenatal visit (before week 18) to delivery. Blood was collected at the first visit for analysis of metabolic hormones. A 75-g oral glucose tolerance test (OGTT) was carried out at week 24-28 and diagnosis of GDM was according to 2013 American Diabetes Association OGTT criteria.

Of the 248 women, 75 (30.2%) developed GDM, and 173 (69.8%) women had normal OGTT results. Examination over the same time period early in pregnancy revealed a higher incidence of GDM in women with PCOS.

In a univariate analysis, PCOS patients who developed GDM had higher fasting blood glucose (FBG), Homeostasis Model Assessment-Insulin resistance (HOMA-IR) score, total cholesterol, low-density lipoprotein cholesterol, non-HDL cholesterol, systolic and diastolic blood pressures, and free testosterone index. These patients also had lower levels of sex hormone–binding globulin (SHBG) and higher likelihood of family history of diabetes and earlier delivery.

Multiple logistic regression revealed associations between increased incidence of GDM and FBG greater than or equal to 4.86 mmol/L, non-HDL cholesterol greater than or equal to 2.84 mmol/L, and SHBG greater than or equal to 222 nmol/L. The predictive power of the three factors for the development of GDM in PCOS was relatively strong.

Future studies could aim to validate the prediction model and clarify the pathogenic basis of GDM in PCOS women, according to the researchers .

The study was funded by the Beijing Science Committee. Dr. Huang had no disclosures.

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Early predictors of GDM identified in women with PCOS
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Key clinical point: Several factors may be predictive of early development of gestational diabetes mellitus in pregnant women with polycystic ovarian syndrome.

Major finding: Multiple logistic regression revealed associations between increased incidence of gestational diabetes mellitus and fasting blood glucose greater than or equal to 4.86 mmol/L, non-HDL cholesterol greater than or equal to 2.84 mmol/L, and sex hormone–binding globulin greater than or equal to 222 nmol/L.

Data source: Prospective cohort study involving 248 women.

Disclosures: The study was funded by the Beijing Science Committee. Dr. Huang had no disclosures.

VIDEO: More routine use of unilateral thyroidectomy advocated for papillary thyroid microcarcinoma

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VIDEO: More routine use of unilateral thyroidectomy advocated for papillary thyroid microcarcinoma

BOSTON – A study of over 60 years of patient data from the Mayo Clinic suggests a reconsideration of the routine use of unilateral thyroid lobectomy (UL) as the initial treatment for papillary thyroid microcarcinoma.

“Papillary thyroid microcarcinoma [PTM] patients have a normal life expectancy and typically are cured by adequate tumor resection. More than 99% of PTM patients are not at risk of either distant spread or mortality from cancer,” said Dr. Ian D. Hay of the Mayo Clinic, Rochester, Minn. Unilateral thyroid lobectomy is one treatment option for papillary thyroid microcarcinoma along with conventional bilateral nodal resection approaches of near-total thyroidectomy (NT) or total thyroidectomy (TT), or selective radioactive iodine remnant ablation (RRA).

Dr. Ian D. Hay

Awareness of PTM is not new; examination of thyroid glands at autopsy going back decades has revealed their presence in 6%-36% of samples. A more recent development is the use of high-resolution ultrasound-guided biopsies of papillary thyroid carcinoma (PTC) lesions as small as 3 cm. For example, at the Mayo Clinic the diagnosis of PTM was about one annually from 1935 to 1944, while from 2005 to 2014 the average was close to one per day. “At Mayo, 34% of PTCs seen since 1995 are PTMs,” Dr. Hay said at the annual meeting of the Endocrine Society.

The best initial management of PTMs is disputed, with observation favored by some, TT and RRA favored by others, and ethanol ablation having been found to be effective by institutions including the Mayo Clinic. UL has been deemphasized, despite the 2015 American Thyroid Association Guidelines recommendation of UL as the usual surgical procedure for adults with PTM.

Dr. Hay and his colleagues sought to provide some clarity to the issue by taking advantage of the institute’s database of adult (18+ years) PTM patients who were consecutively treated from 1935 to 2014. The decades of data allowed a long-term look at patient outcomes. They examined data from 1,345 patients, 954 women and 391 men with a median age at surgery of 48 years. The mean follow-up was 15.4 years, representing almost 21,000 patient years. Data on tumor recurrence and cause-specific mortality were derived from a data base of over 4,300 PTC patients representing over 66,000 patient-years of observation.

Median tumor size was 7 mm (range, 0.08-1.0 cm). Extrathyroid invasion was evident in 18 (1.3%) cases and 298 tumors (26%) were multifocal. There were 399 (30%) node-positive tumors at diagnosis and 4 (0.3%) cases featuring initial distant metastases.

The mean MACIS (metastasis, age at presentation, completeness of surgical resection, invasion [extrathyroidal], size) score was 4.25 with little variation in score over time. Almost all (96%) patients had a MACIS score of under 6. Bilateral lobar resection was done in 1,132 (95%) patients, with NT or TT comprising 80% of the cases. UL was done in only 202 (15%) cases. The use of TT skyrocketed from 3% of the cases done in the first 2 decades to 40% in the last 2 decades. Regional nodes were removed at surgery in 743 (55%) cases, either by “node picking” (23%) or compartmental dissection (32%).

Overall survival following surgery in PTM patients was similar to age- and gender-matched controls (397 deaths observed, 431 deaths expected; P = .16). Only four (0.3%) patients died of PTM. The rates of locoregional recurrence were similar for the unilateral and bilateral approaches (P = .90). In 1,148 patients with potentially curable PTM, defined as the absence of metastasis at diagnosis and no gross residual disease, the rates of tumor recurrence 10, 20, and 40 years after surgery were 6%, 7%, and 10%, respectively. In these 1,148 patients, the 30-year locoregional recurrence rates after UL alone were similar to those seen after NT or TT followed by RRA (P = .99).

UL did not result in permanent unilateral vocal cord paresis or permanent hypoparathyroidism. These adversities were more likely to develop following bilateral lobectomy.

“Since [UL] produces comparable recurrence results when compared to bilateral surgery and is not associated with either cord paresis or hypoparathyroidism, then perhaps it is overdue for institutions like Mayo to individualize our treatment policies and more often employ UL when surgery, and not observation or ultrasound-guided percutaneous ethanol ablation, is chosen to treat PTM,” said Dr. Hay.

Dr. Hay was adamant on the overuse of ultrasound in the detection of small-diameter carcinomas in the decision for bilateral surgery. “It’s embarrassing how much we are wasting resources and doing too much ultrasound too often,” he said in an interview.

Dr. Hay had no disclosures.

 

 

The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
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BOSTON – A study of over 60 years of patient data from the Mayo Clinic suggests a reconsideration of the routine use of unilateral thyroid lobectomy (UL) as the initial treatment for papillary thyroid microcarcinoma.

“Papillary thyroid microcarcinoma [PTM] patients have a normal life expectancy and typically are cured by adequate tumor resection. More than 99% of PTM patients are not at risk of either distant spread or mortality from cancer,” said Dr. Ian D. Hay of the Mayo Clinic, Rochester, Minn. Unilateral thyroid lobectomy is one treatment option for papillary thyroid microcarcinoma along with conventional bilateral nodal resection approaches of near-total thyroidectomy (NT) or total thyroidectomy (TT), or selective radioactive iodine remnant ablation (RRA).

Dr. Ian D. Hay

Awareness of PTM is not new; examination of thyroid glands at autopsy going back decades has revealed their presence in 6%-36% of samples. A more recent development is the use of high-resolution ultrasound-guided biopsies of papillary thyroid carcinoma (PTC) lesions as small as 3 cm. For example, at the Mayo Clinic the diagnosis of PTM was about one annually from 1935 to 1944, while from 2005 to 2014 the average was close to one per day. “At Mayo, 34% of PTCs seen since 1995 are PTMs,” Dr. Hay said at the annual meeting of the Endocrine Society.

The best initial management of PTMs is disputed, with observation favored by some, TT and RRA favored by others, and ethanol ablation having been found to be effective by institutions including the Mayo Clinic. UL has been deemphasized, despite the 2015 American Thyroid Association Guidelines recommendation of UL as the usual surgical procedure for adults with PTM.

Dr. Hay and his colleagues sought to provide some clarity to the issue by taking advantage of the institute’s database of adult (18+ years) PTM patients who were consecutively treated from 1935 to 2014. The decades of data allowed a long-term look at patient outcomes. They examined data from 1,345 patients, 954 women and 391 men with a median age at surgery of 48 years. The mean follow-up was 15.4 years, representing almost 21,000 patient years. Data on tumor recurrence and cause-specific mortality were derived from a data base of over 4,300 PTC patients representing over 66,000 patient-years of observation.

Median tumor size was 7 mm (range, 0.08-1.0 cm). Extrathyroid invasion was evident in 18 (1.3%) cases and 298 tumors (26%) were multifocal. There were 399 (30%) node-positive tumors at diagnosis and 4 (0.3%) cases featuring initial distant metastases.

The mean MACIS (metastasis, age at presentation, completeness of surgical resection, invasion [extrathyroidal], size) score was 4.25 with little variation in score over time. Almost all (96%) patients had a MACIS score of under 6. Bilateral lobar resection was done in 1,132 (95%) patients, with NT or TT comprising 80% of the cases. UL was done in only 202 (15%) cases. The use of TT skyrocketed from 3% of the cases done in the first 2 decades to 40% in the last 2 decades. Regional nodes were removed at surgery in 743 (55%) cases, either by “node picking” (23%) or compartmental dissection (32%).

Overall survival following surgery in PTM patients was similar to age- and gender-matched controls (397 deaths observed, 431 deaths expected; P = .16). Only four (0.3%) patients died of PTM. The rates of locoregional recurrence were similar for the unilateral and bilateral approaches (P = .90). In 1,148 patients with potentially curable PTM, defined as the absence of metastasis at diagnosis and no gross residual disease, the rates of tumor recurrence 10, 20, and 40 years after surgery were 6%, 7%, and 10%, respectively. In these 1,148 patients, the 30-year locoregional recurrence rates after UL alone were similar to those seen after NT or TT followed by RRA (P = .99).

UL did not result in permanent unilateral vocal cord paresis or permanent hypoparathyroidism. These adversities were more likely to develop following bilateral lobectomy.

“Since [UL] produces comparable recurrence results when compared to bilateral surgery and is not associated with either cord paresis or hypoparathyroidism, then perhaps it is overdue for institutions like Mayo to individualize our treatment policies and more often employ UL when surgery, and not observation or ultrasound-guided percutaneous ethanol ablation, is chosen to treat PTM,” said Dr. Hay.

Dr. Hay was adamant on the overuse of ultrasound in the detection of small-diameter carcinomas in the decision for bilateral surgery. “It’s embarrassing how much we are wasting resources and doing too much ultrasound too often,” he said in an interview.

Dr. Hay had no disclosures.

 

 

The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel

BOSTON – A study of over 60 years of patient data from the Mayo Clinic suggests a reconsideration of the routine use of unilateral thyroid lobectomy (UL) as the initial treatment for papillary thyroid microcarcinoma.

“Papillary thyroid microcarcinoma [PTM] patients have a normal life expectancy and typically are cured by adequate tumor resection. More than 99% of PTM patients are not at risk of either distant spread or mortality from cancer,” said Dr. Ian D. Hay of the Mayo Clinic, Rochester, Minn. Unilateral thyroid lobectomy is one treatment option for papillary thyroid microcarcinoma along with conventional bilateral nodal resection approaches of near-total thyroidectomy (NT) or total thyroidectomy (TT), or selective radioactive iodine remnant ablation (RRA).

Dr. Ian D. Hay

Awareness of PTM is not new; examination of thyroid glands at autopsy going back decades has revealed their presence in 6%-36% of samples. A more recent development is the use of high-resolution ultrasound-guided biopsies of papillary thyroid carcinoma (PTC) lesions as small as 3 cm. For example, at the Mayo Clinic the diagnosis of PTM was about one annually from 1935 to 1944, while from 2005 to 2014 the average was close to one per day. “At Mayo, 34% of PTCs seen since 1995 are PTMs,” Dr. Hay said at the annual meeting of the Endocrine Society.

The best initial management of PTMs is disputed, with observation favored by some, TT and RRA favored by others, and ethanol ablation having been found to be effective by institutions including the Mayo Clinic. UL has been deemphasized, despite the 2015 American Thyroid Association Guidelines recommendation of UL as the usual surgical procedure for adults with PTM.

Dr. Hay and his colleagues sought to provide some clarity to the issue by taking advantage of the institute’s database of adult (18+ years) PTM patients who were consecutively treated from 1935 to 2014. The decades of data allowed a long-term look at patient outcomes. They examined data from 1,345 patients, 954 women and 391 men with a median age at surgery of 48 years. The mean follow-up was 15.4 years, representing almost 21,000 patient years. Data on tumor recurrence and cause-specific mortality were derived from a data base of over 4,300 PTC patients representing over 66,000 patient-years of observation.

Median tumor size was 7 mm (range, 0.08-1.0 cm). Extrathyroid invasion was evident in 18 (1.3%) cases and 298 tumors (26%) were multifocal. There were 399 (30%) node-positive tumors at diagnosis and 4 (0.3%) cases featuring initial distant metastases.

The mean MACIS (metastasis, age at presentation, completeness of surgical resection, invasion [extrathyroidal], size) score was 4.25 with little variation in score over time. Almost all (96%) patients had a MACIS score of under 6. Bilateral lobar resection was done in 1,132 (95%) patients, with NT or TT comprising 80% of the cases. UL was done in only 202 (15%) cases. The use of TT skyrocketed from 3% of the cases done in the first 2 decades to 40% in the last 2 decades. Regional nodes were removed at surgery in 743 (55%) cases, either by “node picking” (23%) or compartmental dissection (32%).

Overall survival following surgery in PTM patients was similar to age- and gender-matched controls (397 deaths observed, 431 deaths expected; P = .16). Only four (0.3%) patients died of PTM. The rates of locoregional recurrence were similar for the unilateral and bilateral approaches (P = .90). In 1,148 patients with potentially curable PTM, defined as the absence of metastasis at diagnosis and no gross residual disease, the rates of tumor recurrence 10, 20, and 40 years after surgery were 6%, 7%, and 10%, respectively. In these 1,148 patients, the 30-year locoregional recurrence rates after UL alone were similar to those seen after NT or TT followed by RRA (P = .99).

UL did not result in permanent unilateral vocal cord paresis or permanent hypoparathyroidism. These adversities were more likely to develop following bilateral lobectomy.

“Since [UL] produces comparable recurrence results when compared to bilateral surgery and is not associated with either cord paresis or hypoparathyroidism, then perhaps it is overdue for institutions like Mayo to individualize our treatment policies and more often employ UL when surgery, and not observation or ultrasound-guided percutaneous ethanol ablation, is chosen to treat PTM,” said Dr. Hay.

Dr. Hay was adamant on the overuse of ultrasound in the detection of small-diameter carcinomas in the decision for bilateral surgery. “It’s embarrassing how much we are wasting resources and doing too much ultrasound too often,” he said in an interview.

Dr. Hay had no disclosures.

 

 

The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
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VIDEO: More routine use of unilateral thyroidectomy advocated for papillary thyroid microcarcinoma
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Key clinical point: Unilateral thryoidectomy should be reconsidered as a routine strategy in treatment of papillary thyroid microcarcinoma.

Major finding: Data compiled from over 80 years at a single institution indicates the value of unilateral thyroidectomy in terms of recurrence and morbidity.

Data source: Retrospective analysis of data from 1,153 adult patients.

Disclosures: Dr. Hay had no disclosures.

Morning cortisol rules out adrenal insufficiency

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Morning cortisol rules out adrenal insufficiency

BOSTON – A random morning serum cortisol above 11.1 mcg/dL safely rules out adrenal insufficiency in both inpatients and outpatients, according to a review of 3,300 adrenal insufficiency work-ups at the Edinburgh Centre for Endocrinology and Diabetes.

The finding could help eliminate the cost and hassle of unnecessary adrenocorticotropic hormone (ACTH) stimulation tests; the investigators estimated that the cut point would eliminate almost half of them without any ill effects. “You can be very confident that patients aren’t insufficient if they are above that line,” with more than 99% sensitivity. If they are below it, “they may be normal, and they may be abnormal.” Below 1.8 mcg/dL, adrenal insufficiency is almost certain, but between the cutoffs, ACTH stimulation is necessary, said lead investigator Dr. Scott Mackenzie, a trainee at the center.

Dr. Scott Mackenzie

In short, “basal serum cortisol as a screening test ... offers a convenient and accessible means of identifying patients who require further assessment,” he said at the annual meeting of the Endocrine Society.

Similar cut points have been suggested by previous studies, but the Scottish investigation is the first to validate its findings both inside and outside of the hospital.

The team arrived at the 11.1 mcg/dL morning cortisol cut point by comparing basal cortisol levels and synacthen results in 1,628 outpatients. They predefined a sensitivity of more than 99% for adrenal sufficiency to avoid missing anyone with true disease. The cut point’s predictive power was then validated in 875 outpatients and 797 inpatients. Morning basal cortisol levels proved superior to afternoon levels.

The investigators were thinking about cost-effectiveness, but they also wanted to increase screening. “We may be able to reduce the number of adrenal insufficiency cases we are missing because [primary care is] reluctant to send people to the clinic for synacthen tests” due to the cost and inconvenience. As with many locations in the United States, “our practice is to do [ACTH on] everyone.” If there was “a quick and easy 9 a.m. blood test” instead, it would help, Dr. Mackenzie said.

Adrenal insufficiency was on the differential for a wide variety of reasons, including hypogonadism, pituitary issues, prolactinemia, fatigue, hypoglycemia, postural hypotension, and hyponatremia. Most of the patients were middle aged, and they were about evenly split between men and women.

There was no outside funding for the work, and the investigators had no disclosures.

aotto@frontlinemedcom.com

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BOSTON – A random morning serum cortisol above 11.1 mcg/dL safely rules out adrenal insufficiency in both inpatients and outpatients, according to a review of 3,300 adrenal insufficiency work-ups at the Edinburgh Centre for Endocrinology and Diabetes.

The finding could help eliminate the cost and hassle of unnecessary adrenocorticotropic hormone (ACTH) stimulation tests; the investigators estimated that the cut point would eliminate almost half of them without any ill effects. “You can be very confident that patients aren’t insufficient if they are above that line,” with more than 99% sensitivity. If they are below it, “they may be normal, and they may be abnormal.” Below 1.8 mcg/dL, adrenal insufficiency is almost certain, but between the cutoffs, ACTH stimulation is necessary, said lead investigator Dr. Scott Mackenzie, a trainee at the center.

Dr. Scott Mackenzie

In short, “basal serum cortisol as a screening test ... offers a convenient and accessible means of identifying patients who require further assessment,” he said at the annual meeting of the Endocrine Society.

Similar cut points have been suggested by previous studies, but the Scottish investigation is the first to validate its findings both inside and outside of the hospital.

The team arrived at the 11.1 mcg/dL morning cortisol cut point by comparing basal cortisol levels and synacthen results in 1,628 outpatients. They predefined a sensitivity of more than 99% for adrenal sufficiency to avoid missing anyone with true disease. The cut point’s predictive power was then validated in 875 outpatients and 797 inpatients. Morning basal cortisol levels proved superior to afternoon levels.

The investigators were thinking about cost-effectiveness, but they also wanted to increase screening. “We may be able to reduce the number of adrenal insufficiency cases we are missing because [primary care is] reluctant to send people to the clinic for synacthen tests” due to the cost and inconvenience. As with many locations in the United States, “our practice is to do [ACTH on] everyone.” If there was “a quick and easy 9 a.m. blood test” instead, it would help, Dr. Mackenzie said.

Adrenal insufficiency was on the differential for a wide variety of reasons, including hypogonadism, pituitary issues, prolactinemia, fatigue, hypoglycemia, postural hypotension, and hyponatremia. Most of the patients were middle aged, and they were about evenly split between men and women.

There was no outside funding for the work, and the investigators had no disclosures.

aotto@frontlinemedcom.com

BOSTON – A random morning serum cortisol above 11.1 mcg/dL safely rules out adrenal insufficiency in both inpatients and outpatients, according to a review of 3,300 adrenal insufficiency work-ups at the Edinburgh Centre for Endocrinology and Diabetes.

The finding could help eliminate the cost and hassle of unnecessary adrenocorticotropic hormone (ACTH) stimulation tests; the investigators estimated that the cut point would eliminate almost half of them without any ill effects. “You can be very confident that patients aren’t insufficient if they are above that line,” with more than 99% sensitivity. If they are below it, “they may be normal, and they may be abnormal.” Below 1.8 mcg/dL, adrenal insufficiency is almost certain, but between the cutoffs, ACTH stimulation is necessary, said lead investigator Dr. Scott Mackenzie, a trainee at the center.

Dr. Scott Mackenzie

In short, “basal serum cortisol as a screening test ... offers a convenient and accessible means of identifying patients who require further assessment,” he said at the annual meeting of the Endocrine Society.

Similar cut points have been suggested by previous studies, but the Scottish investigation is the first to validate its findings both inside and outside of the hospital.

The team arrived at the 11.1 mcg/dL morning cortisol cut point by comparing basal cortisol levels and synacthen results in 1,628 outpatients. They predefined a sensitivity of more than 99% for adrenal sufficiency to avoid missing anyone with true disease. The cut point’s predictive power was then validated in 875 outpatients and 797 inpatients. Morning basal cortisol levels proved superior to afternoon levels.

The investigators were thinking about cost-effectiveness, but they also wanted to increase screening. “We may be able to reduce the number of adrenal insufficiency cases we are missing because [primary care is] reluctant to send people to the clinic for synacthen tests” due to the cost and inconvenience. As with many locations in the United States, “our practice is to do [ACTH on] everyone.” If there was “a quick and easy 9 a.m. blood test” instead, it would help, Dr. Mackenzie said.

Adrenal insufficiency was on the differential for a wide variety of reasons, including hypogonadism, pituitary issues, prolactinemia, fatigue, hypoglycemia, postural hypotension, and hyponatremia. Most of the patients were middle aged, and they were about evenly split between men and women.

There was no outside funding for the work, and the investigators had no disclosures.

aotto@frontlinemedcom.com

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Key clinical point: Skip ACTH stimulation if morning serum cortisol is above 11.1 mcg/dL.

Major finding: A morning serum cortisol above 11.1 mcg/dL is a test of adrenal function with 99% sensitivity.

Data source: Review of 3,300 adrenal insufficiency work-ups.

Disclosures: There was no outside funding for the work, and the investigators had no disclosures.

Low Thyroid Function Increases Odds of Type 2 Diabetes

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BOSTON – Results of a population-based study involving more than 8,000 adults from the Netherlands who were diabetes free at baseline has implicated low thyroid function with a 13% increased likelihood of developing type 2 diabetes, and up to 40% higher in individuals with prediabetes.

The heightened risk exists even for individuals with subclinical hypothyroidism, in whom thyroid-stimulating hormone (TSH) in the blood is still in the normal concentration range.

“These findings suggest we should consider screening people with prediabetes for low thyroid function,” Dr. Layal Chaker of Erasmus Medical Center, Rotterdam, the Netherlands, said at the annual meeting of the Endocrine Society.

Thyroid screening is recommended for patients with type 1 diabetes, since they are at increased risk of thyroid disease. An association between thyroid dysfunction in the form of hypothyroidism and type 2 diabetes has been surmised, since type 2 diabetes and hypothyroidism tend to be more prevalent in older adults, and since hypothyroidism has been linked with weight gain and reduced sensitivity to insulin.

To further study the link between thyroid function and diabetes, Dr. Chaker and her colleagues studied data from 8,452 participants aged 45 years and above (mean age 62 years, 58% female) from the Rotterdam Study, a prospective, longitudinal cohort study in the Ommoord district of Rotterdam that was undertaken to investigate the risk factors of cardiovascular, neurological, ophthalmologic, and endocrine diseases in the elderly. The cohort was considered representative of the general population in the Netherlands. All participants had blood tests to measure blood glucose, TSH, and free thyroxine (FT4). Normal blood glucose was considered to be under 5.9 mmol/L, prediabetes as over 5.9 to less than 7.0 mmol/L glucose, and diabetes as above 7.0 mmol/L.

Prediabetes and type 2 diabetes developed in 1,100 and 798 subjects, respectively, during a mean follow-up of 7.9 years. Higher TSH levels increased the risk of development of type 2 diabetes risk (hazard ratio [HR] 1.13, 95% confidence interval [CI], 1.08-1.18, per logTSH). This risk held even for subjects whose TSH levels were at the lower end of the reference range of thyroid function (HR 1.24, CI, 1.06-1.45). The risk of diabetes was reduced in subjects with FT4 levels that were elevated (HR 0.96, CI, 0.93-0.99, per pmol/L) and for those whose FT4 levels were in the reference range (HR 0.96, CI, 0.92-0.99). Low thyroid function, even within the normal range, was associated with a 1.4 times risk of progression from prediabetes to type 2 diabetes (P = .002).

“Low and, surprisingly, low-normal thyroid function are risk factors for incident diabetes, especially in individuals with prediabetes,” said Dr. Chaker.

The data point to the need to clarify whether screening for and treatment of subclinical hypothyroidism can help curb the development of diabetes, she added.

Dr. Chaker had no disclosures.

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BOSTON – Results of a population-based study involving more than 8,000 adults from the Netherlands who were diabetes free at baseline has implicated low thyroid function with a 13% increased likelihood of developing type 2 diabetes, and up to 40% higher in individuals with prediabetes.

The heightened risk exists even for individuals with subclinical hypothyroidism, in whom thyroid-stimulating hormone (TSH) in the blood is still in the normal concentration range.

“These findings suggest we should consider screening people with prediabetes for low thyroid function,” Dr. Layal Chaker of Erasmus Medical Center, Rotterdam, the Netherlands, said at the annual meeting of the Endocrine Society.

Thyroid screening is recommended for patients with type 1 diabetes, since they are at increased risk of thyroid disease. An association between thyroid dysfunction in the form of hypothyroidism and type 2 diabetes has been surmised, since type 2 diabetes and hypothyroidism tend to be more prevalent in older adults, and since hypothyroidism has been linked with weight gain and reduced sensitivity to insulin.

To further study the link between thyroid function and diabetes, Dr. Chaker and her colleagues studied data from 8,452 participants aged 45 years and above (mean age 62 years, 58% female) from the Rotterdam Study, a prospective, longitudinal cohort study in the Ommoord district of Rotterdam that was undertaken to investigate the risk factors of cardiovascular, neurological, ophthalmologic, and endocrine diseases in the elderly. The cohort was considered representative of the general population in the Netherlands. All participants had blood tests to measure blood glucose, TSH, and free thyroxine (FT4). Normal blood glucose was considered to be under 5.9 mmol/L, prediabetes as over 5.9 to less than 7.0 mmol/L glucose, and diabetes as above 7.0 mmol/L.

Prediabetes and type 2 diabetes developed in 1,100 and 798 subjects, respectively, during a mean follow-up of 7.9 years. Higher TSH levels increased the risk of development of type 2 diabetes risk (hazard ratio [HR] 1.13, 95% confidence interval [CI], 1.08-1.18, per logTSH). This risk held even for subjects whose TSH levels were at the lower end of the reference range of thyroid function (HR 1.24, CI, 1.06-1.45). The risk of diabetes was reduced in subjects with FT4 levels that were elevated (HR 0.96, CI, 0.93-0.99, per pmol/L) and for those whose FT4 levels were in the reference range (HR 0.96, CI, 0.92-0.99). Low thyroid function, even within the normal range, was associated with a 1.4 times risk of progression from prediabetes to type 2 diabetes (P = .002).

“Low and, surprisingly, low-normal thyroid function are risk factors for incident diabetes, especially in individuals with prediabetes,” said Dr. Chaker.

The data point to the need to clarify whether screening for and treatment of subclinical hypothyroidism can help curb the development of diabetes, she added.

Dr. Chaker had no disclosures.

Vidyard Video

BOSTON – Results of a population-based study involving more than 8,000 adults from the Netherlands who were diabetes free at baseline has implicated low thyroid function with a 13% increased likelihood of developing type 2 diabetes, and up to 40% higher in individuals with prediabetes.

The heightened risk exists even for individuals with subclinical hypothyroidism, in whom thyroid-stimulating hormone (TSH) in the blood is still in the normal concentration range.

“These findings suggest we should consider screening people with prediabetes for low thyroid function,” Dr. Layal Chaker of Erasmus Medical Center, Rotterdam, the Netherlands, said at the annual meeting of the Endocrine Society.

Thyroid screening is recommended for patients with type 1 diabetes, since they are at increased risk of thyroid disease. An association between thyroid dysfunction in the form of hypothyroidism and type 2 diabetes has been surmised, since type 2 diabetes and hypothyroidism tend to be more prevalent in older adults, and since hypothyroidism has been linked with weight gain and reduced sensitivity to insulin.

To further study the link between thyroid function and diabetes, Dr. Chaker and her colleagues studied data from 8,452 participants aged 45 years and above (mean age 62 years, 58% female) from the Rotterdam Study, a prospective, longitudinal cohort study in the Ommoord district of Rotterdam that was undertaken to investigate the risk factors of cardiovascular, neurological, ophthalmologic, and endocrine diseases in the elderly. The cohort was considered representative of the general population in the Netherlands. All participants had blood tests to measure blood glucose, TSH, and free thyroxine (FT4). Normal blood glucose was considered to be under 5.9 mmol/L, prediabetes as over 5.9 to less than 7.0 mmol/L glucose, and diabetes as above 7.0 mmol/L.

Prediabetes and type 2 diabetes developed in 1,100 and 798 subjects, respectively, during a mean follow-up of 7.9 years. Higher TSH levels increased the risk of development of type 2 diabetes risk (hazard ratio [HR] 1.13, 95% confidence interval [CI], 1.08-1.18, per logTSH). This risk held even for subjects whose TSH levels were at the lower end of the reference range of thyroid function (HR 1.24, CI, 1.06-1.45). The risk of diabetes was reduced in subjects with FT4 levels that were elevated (HR 0.96, CI, 0.93-0.99, per pmol/L) and for those whose FT4 levels were in the reference range (HR 0.96, CI, 0.92-0.99). Low thyroid function, even within the normal range, was associated with a 1.4 times risk of progression from prediabetes to type 2 diabetes (P = .002).

“Low and, surprisingly, low-normal thyroid function are risk factors for incident diabetes, especially in individuals with prediabetes,” said Dr. Chaker.

The data point to the need to clarify whether screening for and treatment of subclinical hypothyroidism can help curb the development of diabetes, she added.

Dr. Chaker had no disclosures.

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VIDEO: Low thyroid function increases odds of type 2 diabetes

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BOSTON – Results of a population-based study involving more than 8,000 adults from the Netherlands who were diabetes free at baseline has implicated low thyroid function with a 13% increased likelihood of developing type 2 diabetes, and up to 40% higher in individuals with prediabetes.

The heightened risk exists even for individuals with subclinical hypothyroidism, in whom thyroid-stimulating hormone (TSH) in the blood is still in the normal concentration range.

“These findings suggest we should consider screening people with prediabetes for low thyroid function,” Dr. Layal Chaker of Erasmus Medical Center, Rotterdam, the Netherlands, said at the annual meeting of the Endocrine Society.

Thyroid screening is recommended for patients with type 1 diabetes, since they are at increased risk of thyroid disease. An association between thyroid dysfunction in the form of hypothyroidism and type 2 diabetes has been surmised, since type 2 diabetes and hypothyroidism tend to be more prevalent in older adults, and since hypothyroidism has been linked with weight gain and reduced sensitivity to insulin.

To further study the link between thyroid function and diabetes, Dr. Chaker and her colleagues studied data from 8,452 participants aged 45 years and above (mean age 62 years, 58% female) from the Rotterdam Study, a prospective, longitudinal cohort study in the Ommoord district of Rotterdam that was undertaken to investigate the risk factors of cardiovascular, neurological, ophthalmologic, and endocrine diseases in the elderly. The cohort was considered representative of the general population in the Netherlands. All participants had blood tests to measure blood glucose, TSH, and free thyroxine (FT4). Normal blood glucose was considered to be under 5.9 mmol/L, prediabetes as over 5.9 to less than 7.0 mmol/L glucose, and diabetes as above 7.0 mmol/L.

Prediabetes and type 2 diabetes developed in 1,100 and 798 subjects, respectively, during a mean follow-up of 7.9 years. Higher TSH levels increased the risk of development of type 2 diabetes risk (hazard ratio [HR] 1.13, 95% confidence interval [CI], 1.08-1.18, per logTSH). This risk held even for subjects whose TSH levels were at the lower end of the reference range of thyroid function (HR 1.24, CI, 1.06-1.45). The risk of diabetes was reduced in subjects with FT4 levels that were elevated (HR 0.96, CI, 0.93-0.99, per pmol/L) and for those whose FT4 levels were in the reference range (HR 0.96, CI, 0.92-0.99). Low thyroid function, even within the normal range, was associated with a 1.4 times risk of progression from prediabetes to type 2 diabetes (P = .002).

“Low and, surprisingly, low-normal thyroid function are risk factors for incident diabetes, especially in individuals with prediabetes,” said Dr. Chaker.

The data point to the need to clarify whether screening for and treatment of subclinical hypothyroidism can help curb the development of diabetes, she added.

Dr. Chaker had no disclosures.

 

 

 

 

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BOSTON – Results of a population-based study involving more than 8,000 adults from the Netherlands who were diabetes free at baseline has implicated low thyroid function with a 13% increased likelihood of developing type 2 diabetes, and up to 40% higher in individuals with prediabetes.

The heightened risk exists even for individuals with subclinical hypothyroidism, in whom thyroid-stimulating hormone (TSH) in the blood is still in the normal concentration range.

“These findings suggest we should consider screening people with prediabetes for low thyroid function,” Dr. Layal Chaker of Erasmus Medical Center, Rotterdam, the Netherlands, said at the annual meeting of the Endocrine Society.

Thyroid screening is recommended for patients with type 1 diabetes, since they are at increased risk of thyroid disease. An association between thyroid dysfunction in the form of hypothyroidism and type 2 diabetes has been surmised, since type 2 diabetes and hypothyroidism tend to be more prevalent in older adults, and since hypothyroidism has been linked with weight gain and reduced sensitivity to insulin.

To further study the link between thyroid function and diabetes, Dr. Chaker and her colleagues studied data from 8,452 participants aged 45 years and above (mean age 62 years, 58% female) from the Rotterdam Study, a prospective, longitudinal cohort study in the Ommoord district of Rotterdam that was undertaken to investigate the risk factors of cardiovascular, neurological, ophthalmologic, and endocrine diseases in the elderly. The cohort was considered representative of the general population in the Netherlands. All participants had blood tests to measure blood glucose, TSH, and free thyroxine (FT4). Normal blood glucose was considered to be under 5.9 mmol/L, prediabetes as over 5.9 to less than 7.0 mmol/L glucose, and diabetes as above 7.0 mmol/L.

Prediabetes and type 2 diabetes developed in 1,100 and 798 subjects, respectively, during a mean follow-up of 7.9 years. Higher TSH levels increased the risk of development of type 2 diabetes risk (hazard ratio [HR] 1.13, 95% confidence interval [CI], 1.08-1.18, per logTSH). This risk held even for subjects whose TSH levels were at the lower end of the reference range of thyroid function (HR 1.24, CI, 1.06-1.45). The risk of diabetes was reduced in subjects with FT4 levels that were elevated (HR 0.96, CI, 0.93-0.99, per pmol/L) and for those whose FT4 levels were in the reference range (HR 0.96, CI, 0.92-0.99). Low thyroid function, even within the normal range, was associated with a 1.4 times risk of progression from prediabetes to type 2 diabetes (P = .002).

“Low and, surprisingly, low-normal thyroid function are risk factors for incident diabetes, especially in individuals with prediabetes,” said Dr. Chaker.

The data point to the need to clarify whether screening for and treatment of subclinical hypothyroidism can help curb the development of diabetes, she added.

Dr. Chaker had no disclosures.

 

 

 

 

BOSTON – Results of a population-based study involving more than 8,000 adults from the Netherlands who were diabetes free at baseline has implicated low thyroid function with a 13% increased likelihood of developing type 2 diabetes, and up to 40% higher in individuals with prediabetes.

The heightened risk exists even for individuals with subclinical hypothyroidism, in whom thyroid-stimulating hormone (TSH) in the blood is still in the normal concentration range.

“These findings suggest we should consider screening people with prediabetes for low thyroid function,” Dr. Layal Chaker of Erasmus Medical Center, Rotterdam, the Netherlands, said at the annual meeting of the Endocrine Society.

Thyroid screening is recommended for patients with type 1 diabetes, since they are at increased risk of thyroid disease. An association between thyroid dysfunction in the form of hypothyroidism and type 2 diabetes has been surmised, since type 2 diabetes and hypothyroidism tend to be more prevalent in older adults, and since hypothyroidism has been linked with weight gain and reduced sensitivity to insulin.

To further study the link between thyroid function and diabetes, Dr. Chaker and her colleagues studied data from 8,452 participants aged 45 years and above (mean age 62 years, 58% female) from the Rotterdam Study, a prospective, longitudinal cohort study in the Ommoord district of Rotterdam that was undertaken to investigate the risk factors of cardiovascular, neurological, ophthalmologic, and endocrine diseases in the elderly. The cohort was considered representative of the general population in the Netherlands. All participants had blood tests to measure blood glucose, TSH, and free thyroxine (FT4). Normal blood glucose was considered to be under 5.9 mmol/L, prediabetes as over 5.9 to less than 7.0 mmol/L glucose, and diabetes as above 7.0 mmol/L.

Prediabetes and type 2 diabetes developed in 1,100 and 798 subjects, respectively, during a mean follow-up of 7.9 years. Higher TSH levels increased the risk of development of type 2 diabetes risk (hazard ratio [HR] 1.13, 95% confidence interval [CI], 1.08-1.18, per logTSH). This risk held even for subjects whose TSH levels were at the lower end of the reference range of thyroid function (HR 1.24, CI, 1.06-1.45). The risk of diabetes was reduced in subjects with FT4 levels that were elevated (HR 0.96, CI, 0.93-0.99, per pmol/L) and for those whose FT4 levels were in the reference range (HR 0.96, CI, 0.92-0.99). Low thyroid function, even within the normal range, was associated with a 1.4 times risk of progression from prediabetes to type 2 diabetes (P = .002).

“Low and, surprisingly, low-normal thyroid function are risk factors for incident diabetes, especially in individuals with prediabetes,” said Dr. Chaker.

The data point to the need to clarify whether screening for and treatment of subclinical hypothyroidism can help curb the development of diabetes, she added.

Dr. Chaker had no disclosures.

 

 

 

 

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Key clinical point: Hypothyroidism increases the risk of developing type 2 diabetes.

Major finding: Higher TSH levels increased the risk of development of type 2 diabetes risk (hazard ratio 1.13, 95% confidence interval, 1.08-1.18, per logTSH).

Data source: Population-based study of 8,452 adult from the Netherlands

Disclosures: Dr. Chaker had no disclosures.

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VIDEO: Liraglutide acts on GLP-1 receptors to lessen desire for high-fat foods

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BOSTON – Two related studies of brain structure and the mechanism of the analog of glucagon-like peptide (GLP) hormone liraglutide indicate that the drug works to decrease reward-related activation of brain sites linked to desire for unhealthy foods in patients with type 2 diabetes.

“Our finding suggests that liraglutide may make people more attentive to what they are eating, particularly high-calories or high-fat foods,” said study co-investigator Olivia Farr, PhD, of Beth Israel Deaconess Hospital and Harvard Medical School, Boston.

Liraglutide, which has been approved for weight management for obese patients and those with type 2 diabetes, is known to promote weight loss, but the mechanism by which this occurs has not been fully understood. The investigators undertook two studies, one to examine human brains to identify GLP-1 receptors and the other to examine the impact liraglutide administration may have on neural responses to food cues in patients with type 2 diabetes.

Immunohistochemical examination of 22 human brain samples identified GLP-1 receptors in the hypothalamus, medulla oblongata, and parietal cortex. GLP-1 receptors have previously only been identified in animals. The findings support the role of the receptors in weight loss in patients on liraglutide.

The researchers then performed a second randomized, placebo-controlled, double-blind, cross-over study involving 18 adult patients with type 2 diabetes. The subjects received, in random order, injections of placebo or liraglutide. Liraglutide was titrated to 0.6 mg at visit 1, 1.2 mg at visit 2, and 1.8 mg at visit 3, which were a week apart, with the highest dose maintained in the 3 days between visits 3 and 4. The total period was 17 days. Visit 4 was an overnight stay followed by functional magnetic resonance imaging (fMRI). Then, after a 3-week washout period, the participants received the other treatment on the same schedule, with another fMRI scan.

During the fMRI, participants viewed images of different foods that had been determined in pre-trial testing to be generally perceived as desirable (typically cakes, pastries, fried food, and fast food) and undesirable (typically leafy greens, fruits, vegetables, and other low-calorie food). In addition, non-food images were shown to verify that the brain activation was driven by the food images. The regions of the brain that became active during inspection of the images were determined.

Liraglutide decreased activation of the parietal cortex in response to the highly desirable food images. Additionally, activation in the insula and putamen was reduced; these regions are involved in the brain’s reward system. Increased perception of hunger and appetite by the participants when they viewed images of desirable foods correlated with increased activation of GLP-1 receptors in the parietal and visual cortices during liraglutide treatment. In participants experiencing nausea, decreased brain activation in the cingulate cortex was apparent. Hypothalamus-related activity was not evident.

“This decreased activation means that individuals on liraglutide find highly desirable foods less attention-grabbing and less rewarding than they typically would without liraglutide,” said Dr. Farr.

The researchers suggested that liraglutide could be suited for weight loss in those who opt for high-fat food as a means of pleasure. Further, the data point to a central mechanism contributing to or underlying effects of liraglutide on metabolism/weight loss.

The Harvard researchers are seeking to confirm the findings in a larger study using the 3-mg dose of liraglutide that has been approved for obesity. In addition, they will explore whether the brain response to liraglutide is a general phenomenon or whether individuals differ.

Dr. Farr had no disclosures.

The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
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BOSTON – Two related studies of brain structure and the mechanism of the analog of glucagon-like peptide (GLP) hormone liraglutide indicate that the drug works to decrease reward-related activation of brain sites linked to desire for unhealthy foods in patients with type 2 diabetes.

“Our finding suggests that liraglutide may make people more attentive to what they are eating, particularly high-calories or high-fat foods,” said study co-investigator Olivia Farr, PhD, of Beth Israel Deaconess Hospital and Harvard Medical School, Boston.

Liraglutide, which has been approved for weight management for obese patients and those with type 2 diabetes, is known to promote weight loss, but the mechanism by which this occurs has not been fully understood. The investigators undertook two studies, one to examine human brains to identify GLP-1 receptors and the other to examine the impact liraglutide administration may have on neural responses to food cues in patients with type 2 diabetes.

Immunohistochemical examination of 22 human brain samples identified GLP-1 receptors in the hypothalamus, medulla oblongata, and parietal cortex. GLP-1 receptors have previously only been identified in animals. The findings support the role of the receptors in weight loss in patients on liraglutide.

The researchers then performed a second randomized, placebo-controlled, double-blind, cross-over study involving 18 adult patients with type 2 diabetes. The subjects received, in random order, injections of placebo or liraglutide. Liraglutide was titrated to 0.6 mg at visit 1, 1.2 mg at visit 2, and 1.8 mg at visit 3, which were a week apart, with the highest dose maintained in the 3 days between visits 3 and 4. The total period was 17 days. Visit 4 was an overnight stay followed by functional magnetic resonance imaging (fMRI). Then, after a 3-week washout period, the participants received the other treatment on the same schedule, with another fMRI scan.

During the fMRI, participants viewed images of different foods that had been determined in pre-trial testing to be generally perceived as desirable (typically cakes, pastries, fried food, and fast food) and undesirable (typically leafy greens, fruits, vegetables, and other low-calorie food). In addition, non-food images were shown to verify that the brain activation was driven by the food images. The regions of the brain that became active during inspection of the images were determined.

Liraglutide decreased activation of the parietal cortex in response to the highly desirable food images. Additionally, activation in the insula and putamen was reduced; these regions are involved in the brain’s reward system. Increased perception of hunger and appetite by the participants when they viewed images of desirable foods correlated with increased activation of GLP-1 receptors in the parietal and visual cortices during liraglutide treatment. In participants experiencing nausea, decreased brain activation in the cingulate cortex was apparent. Hypothalamus-related activity was not evident.

“This decreased activation means that individuals on liraglutide find highly desirable foods less attention-grabbing and less rewarding than they typically would without liraglutide,” said Dr. Farr.

The researchers suggested that liraglutide could be suited for weight loss in those who opt for high-fat food as a means of pleasure. Further, the data point to a central mechanism contributing to or underlying effects of liraglutide on metabolism/weight loss.

The Harvard researchers are seeking to confirm the findings in a larger study using the 3-mg dose of liraglutide that has been approved for obesity. In addition, they will explore whether the brain response to liraglutide is a general phenomenon or whether individuals differ.

Dr. Farr had no disclosures.

The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel

BOSTON – Two related studies of brain structure and the mechanism of the analog of glucagon-like peptide (GLP) hormone liraglutide indicate that the drug works to decrease reward-related activation of brain sites linked to desire for unhealthy foods in patients with type 2 diabetes.

“Our finding suggests that liraglutide may make people more attentive to what they are eating, particularly high-calories or high-fat foods,” said study co-investigator Olivia Farr, PhD, of Beth Israel Deaconess Hospital and Harvard Medical School, Boston.

Liraglutide, which has been approved for weight management for obese patients and those with type 2 diabetes, is known to promote weight loss, but the mechanism by which this occurs has not been fully understood. The investigators undertook two studies, one to examine human brains to identify GLP-1 receptors and the other to examine the impact liraglutide administration may have on neural responses to food cues in patients with type 2 diabetes.

Immunohistochemical examination of 22 human brain samples identified GLP-1 receptors in the hypothalamus, medulla oblongata, and parietal cortex. GLP-1 receptors have previously only been identified in animals. The findings support the role of the receptors in weight loss in patients on liraglutide.

The researchers then performed a second randomized, placebo-controlled, double-blind, cross-over study involving 18 adult patients with type 2 diabetes. The subjects received, in random order, injections of placebo or liraglutide. Liraglutide was titrated to 0.6 mg at visit 1, 1.2 mg at visit 2, and 1.8 mg at visit 3, which were a week apart, with the highest dose maintained in the 3 days between visits 3 and 4. The total period was 17 days. Visit 4 was an overnight stay followed by functional magnetic resonance imaging (fMRI). Then, after a 3-week washout period, the participants received the other treatment on the same schedule, with another fMRI scan.

During the fMRI, participants viewed images of different foods that had been determined in pre-trial testing to be generally perceived as desirable (typically cakes, pastries, fried food, and fast food) and undesirable (typically leafy greens, fruits, vegetables, and other low-calorie food). In addition, non-food images were shown to verify that the brain activation was driven by the food images. The regions of the brain that became active during inspection of the images were determined.

Liraglutide decreased activation of the parietal cortex in response to the highly desirable food images. Additionally, activation in the insula and putamen was reduced; these regions are involved in the brain’s reward system. Increased perception of hunger and appetite by the participants when they viewed images of desirable foods correlated with increased activation of GLP-1 receptors in the parietal and visual cortices during liraglutide treatment. In participants experiencing nausea, decreased brain activation in the cingulate cortex was apparent. Hypothalamus-related activity was not evident.

“This decreased activation means that individuals on liraglutide find highly desirable foods less attention-grabbing and less rewarding than they typically would without liraglutide,” said Dr. Farr.

The researchers suggested that liraglutide could be suited for weight loss in those who opt for high-fat food as a means of pleasure. Further, the data point to a central mechanism contributing to or underlying effects of liraglutide on metabolism/weight loss.

The Harvard researchers are seeking to confirm the findings in a larger study using the 3-mg dose of liraglutide that has been approved for obesity. In addition, they will explore whether the brain response to liraglutide is a general phenomenon or whether individuals differ.

Dr. Farr had no disclosures.

The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
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Bionic glucagon delivery improved hypoglycemia control in T1D patients

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BOSTON – A wearable, closed-loop bionic pancreas system that automatically delivers glucagon has been found to improve hypoglycemia control in patients with type 1 diabetes.

A double-blind, randomized, placebo-controlled, cross-over study (NCT02181127) has demonstrated the value of automated injection of glucagon in establishing glycemic regulation in adult patients with type 1 diabetes. “Automated glucagon delivery reduces hypoglycemia and increases time in range without an increase in mean glucose, with no difference in insulin dose,” said Dr. Laya Ekhlaspour of Massachusetts General Hospital, Boston.

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Glycemic regulation can be problematic in young adults with type 1 diabetes, whose blood glucose levels can fall below 70 mg/dL for over 2 hours daily, even with glycemic control using conventional insulin pump therapy. The typical response to hypoglycemia – supplying glucose in a quickly digested form – is a short-term solution and is not effective during sleep.

Dr. Ekhlaspour and her colleagues surmised that a closed-loop system comprising a wearable bionic pancreas system that automatically delivers glucagon could reduce the incidence and severity of hypoglycemia when used along with the conventional insulin therapies of multiple daily injection (MDI) or continuous subcutaneous insulin infusion (CSII).

Of 31 subjects screened, 27 were eligible in terms of the frequency of hypoglycemia, but 5 were excluded because of scheduling problems, leaving 22 patients. The participants, adults with type 1 diabetes, had blood glucose levels below 60 mg/dL on average at least twice a week, and some periods with blood glucose below 50 mg/dL.

In addition to self-administered insulin (CSII or MDI), the subjects also received glucagon or placebo for 24 hours at a time using the automated wearable bionic pancreas system. In the 2-week study, the subjects (mean age 42 years; mean duration of diabetes 25 years) were randomized to receive glucagon or placebo for a total of 7 days each. The subjects were not told which preparation they were receiving.

The primary outcome of area over the curve (AOC) under 60 mg/dL was reduced by 75% on days when glucagon was supplied (851 mg/dL/min), compared with days when placebo was supplied (3,414 mg/dL/min), a significant difference. The difference in AOC was even more pronounced at night (117 vs. 1,309 mg/dL/min).

The percentage of subjects with blood glucose of 70 -180 mg/dL was significantly greater on days when glucagon was administered than when placebo was given (69% versus 62%). Subjects spent 74% less time with blood glucose under 60 mg/dL on days when glucagon was supplied, compared with placebo (1.2% versus 4.7%).

Symptomatic hypoglycemia episodes were significantly fewer for glucagon, compared with placebo (0.6 versus 1.2). The need for oral carbohydrates was reduced when glucagon was provided (1.3 versus 1.9 interventions per day). Nausea severity rankings for glucagon and placebo on the visual analog scale were similar.

Dr. Ekhlaspour had no disclosures.

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BOSTON – A wearable, closed-loop bionic pancreas system that automatically delivers glucagon has been found to improve hypoglycemia control in patients with type 1 diabetes.

A double-blind, randomized, placebo-controlled, cross-over study (NCT02181127) has demonstrated the value of automated injection of glucagon in establishing glycemic regulation in adult patients with type 1 diabetes. “Automated glucagon delivery reduces hypoglycemia and increases time in range without an increase in mean glucose, with no difference in insulin dose,” said Dr. Laya Ekhlaspour of Massachusetts General Hospital, Boston.

©Tashatuvango/Thinkstockphotos.com

Glycemic regulation can be problematic in young adults with type 1 diabetes, whose blood glucose levels can fall below 70 mg/dL for over 2 hours daily, even with glycemic control using conventional insulin pump therapy. The typical response to hypoglycemia – supplying glucose in a quickly digested form – is a short-term solution and is not effective during sleep.

Dr. Ekhlaspour and her colleagues surmised that a closed-loop system comprising a wearable bionic pancreas system that automatically delivers glucagon could reduce the incidence and severity of hypoglycemia when used along with the conventional insulin therapies of multiple daily injection (MDI) or continuous subcutaneous insulin infusion (CSII).

Of 31 subjects screened, 27 were eligible in terms of the frequency of hypoglycemia, but 5 were excluded because of scheduling problems, leaving 22 patients. The participants, adults with type 1 diabetes, had blood glucose levels below 60 mg/dL on average at least twice a week, and some periods with blood glucose below 50 mg/dL.

In addition to self-administered insulin (CSII or MDI), the subjects also received glucagon or placebo for 24 hours at a time using the automated wearable bionic pancreas system. In the 2-week study, the subjects (mean age 42 years; mean duration of diabetes 25 years) were randomized to receive glucagon or placebo for a total of 7 days each. The subjects were not told which preparation they were receiving.

The primary outcome of area over the curve (AOC) under 60 mg/dL was reduced by 75% on days when glucagon was supplied (851 mg/dL/min), compared with days when placebo was supplied (3,414 mg/dL/min), a significant difference. The difference in AOC was even more pronounced at night (117 vs. 1,309 mg/dL/min).

The percentage of subjects with blood glucose of 70 -180 mg/dL was significantly greater on days when glucagon was administered than when placebo was given (69% versus 62%). Subjects spent 74% less time with blood glucose under 60 mg/dL on days when glucagon was supplied, compared with placebo (1.2% versus 4.7%).

Symptomatic hypoglycemia episodes were significantly fewer for glucagon, compared with placebo (0.6 versus 1.2). The need for oral carbohydrates was reduced when glucagon was provided (1.3 versus 1.9 interventions per day). Nausea severity rankings for glucagon and placebo on the visual analog scale were similar.

Dr. Ekhlaspour had no disclosures.

BOSTON – A wearable, closed-loop bionic pancreas system that automatically delivers glucagon has been found to improve hypoglycemia control in patients with type 1 diabetes.

A double-blind, randomized, placebo-controlled, cross-over study (NCT02181127) has demonstrated the value of automated injection of glucagon in establishing glycemic regulation in adult patients with type 1 diabetes. “Automated glucagon delivery reduces hypoglycemia and increases time in range without an increase in mean glucose, with no difference in insulin dose,” said Dr. Laya Ekhlaspour of Massachusetts General Hospital, Boston.

©Tashatuvango/Thinkstockphotos.com

Glycemic regulation can be problematic in young adults with type 1 diabetes, whose blood glucose levels can fall below 70 mg/dL for over 2 hours daily, even with glycemic control using conventional insulin pump therapy. The typical response to hypoglycemia – supplying glucose in a quickly digested form – is a short-term solution and is not effective during sleep.

Dr. Ekhlaspour and her colleagues surmised that a closed-loop system comprising a wearable bionic pancreas system that automatically delivers glucagon could reduce the incidence and severity of hypoglycemia when used along with the conventional insulin therapies of multiple daily injection (MDI) or continuous subcutaneous insulin infusion (CSII).

Of 31 subjects screened, 27 were eligible in terms of the frequency of hypoglycemia, but 5 were excluded because of scheduling problems, leaving 22 patients. The participants, adults with type 1 diabetes, had blood glucose levels below 60 mg/dL on average at least twice a week, and some periods with blood glucose below 50 mg/dL.

In addition to self-administered insulin (CSII or MDI), the subjects also received glucagon or placebo for 24 hours at a time using the automated wearable bionic pancreas system. In the 2-week study, the subjects (mean age 42 years; mean duration of diabetes 25 years) were randomized to receive glucagon or placebo for a total of 7 days each. The subjects were not told which preparation they were receiving.

The primary outcome of area over the curve (AOC) under 60 mg/dL was reduced by 75% on days when glucagon was supplied (851 mg/dL/min), compared with days when placebo was supplied (3,414 mg/dL/min), a significant difference. The difference in AOC was even more pronounced at night (117 vs. 1,309 mg/dL/min).

The percentage of subjects with blood glucose of 70 -180 mg/dL was significantly greater on days when glucagon was administered than when placebo was given (69% versus 62%). Subjects spent 74% less time with blood glucose under 60 mg/dL on days when glucagon was supplied, compared with placebo (1.2% versus 4.7%).

Symptomatic hypoglycemia episodes were significantly fewer for glucagon, compared with placebo (0.6 versus 1.2). The need for oral carbohydrates was reduced when glucagon was provided (1.3 versus 1.9 interventions per day). Nausea severity rankings for glucagon and placebo on the visual analog scale were similar.

Dr. Ekhlaspour had no disclosures.

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Faster aspart speeds onset of activity in Type 1 diabetes

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Faster aspart speeds onset of activity in Type 1 diabetes

BOSTON A new formulation of faster-acting insulin aspart (faster aspart) provided more rapid and extensive glucose-lowering activity than did standard insulin aspart, based on results of a randomized, double-blind, crossover study presented at the annual meeting of the Endocrine Society.

Subcutaneous injections of faster aspart of 0.1 (low dose), 0.2 (moderate dose), and 0.4 (high dose) U/kg were associated with an onset of activity that was twice as fast as that of standard insulin aspart and with insulin exposure that was two-fold higher in the first 30 minutes, said Dr. Tim Heise, CEO of finance and administration for Profil Institute for Metabolic Research, Neuss, Germany.

Brian Hoyle/Frontline Medical News
Dr. Tim Heise

“Faster aspart was well tolerated, and no safety issues were identified. No injection site infections were observed, and no serious adverse events were reported,” said Dr. Heise.

Faster aspart consists of insulin aspart along with niacinamide as an absorption modifier and L-arginine as a stabilizer. The aim of a faster-acting mealtime insulin is to mimic more closely the physiologic mealtime insulin response of the healthy pancreas.

What has not been clear is whether the benefits of faster aspart are concentration-dependent and whether the effective concentrations are clinically relevant.

The pharmacokinetic and pharmacodynamic properties of faster aspart were tested at three clinically relevant doses in 46 adults, aged 18 to 64 years, with type 1 diabetes. Study participants had been treated for a year or more with multiple daily injections of insulin or continuous subcutaneous insulin injection; their total insulin dose was less than 1.2 U/kg/day with less than 0.7 U/kg/day as a bolus dose. Body mass index ranged from about 19 to 28 kg/m2. Of the subjects, 76% were men, all were white, and they had diabetes for about 21 years.

At all three doses, onset of activity was about twice as rapid with faster aspart as with standard insulin aspart; 50% of the maximum exposure to the dose was achieved in 8 to 12 minutes with faster aspart. This rapid appearance of activity was especially evident within 30 minutes of injection, with the kinetics becoming more similar to those of standard insulin aspart from 30 to 60 minutes.

Blood glucose was lowered by 0.3 mmol/L from baseline at a rate up to 26% faster with faster aspart. Similar to the exposure data, glucose reduction was especially evident in the first 30 minutes following injection of faster aspart, with the decline in glucose levels being about twice as great compared to insulin aspart.

Further information from a phase 3 study evaluating faster aspart will be reported at the American Diabetes Association meeting to be held this summer, according to Dr. Heise.

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BOSTON A new formulation of faster-acting insulin aspart (faster aspart) provided more rapid and extensive glucose-lowering activity than did standard insulin aspart, based on results of a randomized, double-blind, crossover study presented at the annual meeting of the Endocrine Society.

Subcutaneous injections of faster aspart of 0.1 (low dose), 0.2 (moderate dose), and 0.4 (high dose) U/kg were associated with an onset of activity that was twice as fast as that of standard insulin aspart and with insulin exposure that was two-fold higher in the first 30 minutes, said Dr. Tim Heise, CEO of finance and administration for Profil Institute for Metabolic Research, Neuss, Germany.

Brian Hoyle/Frontline Medical News
Dr. Tim Heise

“Faster aspart was well tolerated, and no safety issues were identified. No injection site infections were observed, and no serious adverse events were reported,” said Dr. Heise.

Faster aspart consists of insulin aspart along with niacinamide as an absorption modifier and L-arginine as a stabilizer. The aim of a faster-acting mealtime insulin is to mimic more closely the physiologic mealtime insulin response of the healthy pancreas.

What has not been clear is whether the benefits of faster aspart are concentration-dependent and whether the effective concentrations are clinically relevant.

The pharmacokinetic and pharmacodynamic properties of faster aspart were tested at three clinically relevant doses in 46 adults, aged 18 to 64 years, with type 1 diabetes. Study participants had been treated for a year or more with multiple daily injections of insulin or continuous subcutaneous insulin injection; their total insulin dose was less than 1.2 U/kg/day with less than 0.7 U/kg/day as a bolus dose. Body mass index ranged from about 19 to 28 kg/m2. Of the subjects, 76% were men, all were white, and they had diabetes for about 21 years.

At all three doses, onset of activity was about twice as rapid with faster aspart as with standard insulin aspart; 50% of the maximum exposure to the dose was achieved in 8 to 12 minutes with faster aspart. This rapid appearance of activity was especially evident within 30 minutes of injection, with the kinetics becoming more similar to those of standard insulin aspart from 30 to 60 minutes.

Blood glucose was lowered by 0.3 mmol/L from baseline at a rate up to 26% faster with faster aspart. Similar to the exposure data, glucose reduction was especially evident in the first 30 minutes following injection of faster aspart, with the decline in glucose levels being about twice as great compared to insulin aspart.

Further information from a phase 3 study evaluating faster aspart will be reported at the American Diabetes Association meeting to be held this summer, according to Dr. Heise.

BOSTON A new formulation of faster-acting insulin aspart (faster aspart) provided more rapid and extensive glucose-lowering activity than did standard insulin aspart, based on results of a randomized, double-blind, crossover study presented at the annual meeting of the Endocrine Society.

Subcutaneous injections of faster aspart of 0.1 (low dose), 0.2 (moderate dose), and 0.4 (high dose) U/kg were associated with an onset of activity that was twice as fast as that of standard insulin aspart and with insulin exposure that was two-fold higher in the first 30 minutes, said Dr. Tim Heise, CEO of finance and administration for Profil Institute for Metabolic Research, Neuss, Germany.

Brian Hoyle/Frontline Medical News
Dr. Tim Heise

“Faster aspart was well tolerated, and no safety issues were identified. No injection site infections were observed, and no serious adverse events were reported,” said Dr. Heise.

Faster aspart consists of insulin aspart along with niacinamide as an absorption modifier and L-arginine as a stabilizer. The aim of a faster-acting mealtime insulin is to mimic more closely the physiologic mealtime insulin response of the healthy pancreas.

What has not been clear is whether the benefits of faster aspart are concentration-dependent and whether the effective concentrations are clinically relevant.

The pharmacokinetic and pharmacodynamic properties of faster aspart were tested at three clinically relevant doses in 46 adults, aged 18 to 64 years, with type 1 diabetes. Study participants had been treated for a year or more with multiple daily injections of insulin or continuous subcutaneous insulin injection; their total insulin dose was less than 1.2 U/kg/day with less than 0.7 U/kg/day as a bolus dose. Body mass index ranged from about 19 to 28 kg/m2. Of the subjects, 76% were men, all were white, and they had diabetes for about 21 years.

At all three doses, onset of activity was about twice as rapid with faster aspart as with standard insulin aspart; 50% of the maximum exposure to the dose was achieved in 8 to 12 minutes with faster aspart. This rapid appearance of activity was especially evident within 30 minutes of injection, with the kinetics becoming more similar to those of standard insulin aspart from 30 to 60 minutes.

Blood glucose was lowered by 0.3 mmol/L from baseline at a rate up to 26% faster with faster aspart. Similar to the exposure data, glucose reduction was especially evident in the first 30 minutes following injection of faster aspart, with the decline in glucose levels being about twice as great compared to insulin aspart.

Further information from a phase 3 study evaluating faster aspart will be reported at the American Diabetes Association meeting to be held this summer, according to Dr. Heise.

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Key clinical point: As a faster-acting mealtime insulin, faster aspart may mimic more closely the physiologic mealtime insulin response of the healthy pancreas.

Major finding: At all three doses, onset of activity was about twice as rapid with faster aspart as with standard insulin aspart; 50% of the maximum exposure to the dose was achieved in 8 to 12 minutes with faster aspart.

Data source: Double-blind, randomized, cross-over study of responses to subcutaneous injections of faster aspart of 0.1 (low dose), 0.2 (moderate dose), and 0.4 (high dose) U/kg in 46 study participants with type 1 diabetes.

Disclosures: The study was funded by Novo Nordisk, the developer of faster-acting insulin aspart. Dr. Heine disclosed a variety of research support from drug companies, including funding from Novo Nordisk.