MEN 1 Associated with an Increased Prevalence of Diabetes Mellitus
MEN 1 Associated with an Increased Prevalence of Diabetes Mellitus
Objective: Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominant syndrome characterized by primary hyperparathyroidism, pituitary neoplasia and foregut lineage neuroendocrine tumours. It has also been associated with premature cardiovascular death. As diabetes is a risk factor for increased cardiovascular mortality we investigated the prevalence and clinical correlates of glycaemic abnormalities in a large MEN 1 kindred.
Patients and Design: The glycaemic status of 72 MEN 1 affected and 133 unaffected members of a single large MEN 1 pedigree was assessed. Fasting glucose results were categorized and compared using WHO criteria. Associations between glycaemic status and MEN 1 phenotype were assessed.
Results: Thirteen (18·1%) patients with MEN 1 compared to 5 (3·8%) control patients were diabetic (P < 0·001). Six (8·3%) MEN 1 patients had impaired fasting glucose compared to 4 (3%) of controls (P < 0·05). Of patients with MEN 1, uncontrolled hypercalcaemia (P < 0·05) and elevated serum gastrin (P < 0·05) were more common amongst patients diagnosed with abnormal glycaemia than those with normoglycaemia. There was a nonsignificant trend for elevated chromogranin A, pancreatic polypeptide, gastric inhibitory polypeptide (but not glucagon) and history of bronchopulmonary carcinoid in MEN 1 patients with elevated glycaemia.
Conclusions: Diabetes and impaired fasting glucose occur significantly more frequently amongst MEN 1 patients than controls and is associated with uncontrolled hyperparathyroidism and evidence of enteropancreatic hyperstimulation.
Multiple endocrine neoplasia type 1 (MEN 1) is typically associated with hyperplastic and neoplastic lesions of the parathyroid, pituitary and foregut lineage endocrine tissue. Malignant tumours complicating MEN 1 are an important source of morbidity and mortality in individuals inheriting this disorder. Life expectancy in MEN 1 is significantly reduced compared to that of the general population. Whilst improvements in the management of hyperparathyroidism and Zollinger-Ellison syndrome over recent decades have had a beneficial impact on longevity, mean age at death in MEN 1 remains up to two decades below that expected for the general population.
Malignancy, hyperparathyroidism and peptic ulcer disease account for up to 50% of premature death amongst MEN 1 gene carriers. However, the remainder succumb to apparently unrelated conditions. Of note, some studies have identified cardiovascular disease as a cause for premature mortality in MEN 1 patients. The adverse vascular impact of hyperparathyroidism and consequent renal disease is a possible explanation for this observation. A recently published small study found evidence suggestive of insulin resistance in MEN 1 patients compared to unaffected siblings. However, there has not previously been a detailed assessment of conventional cardiovascular risk factors in patients with MEN 1.
Disorders of glucose metabolism and insulin resistance are important risk factors for macrovascular disease in the general population. The pathophysiological basis of insulin resistance is known to be complex, in part mediated by endocrine factors produced in adipose and enteropancreatic tissue. Adipocytokines such as leptin and resistin, as well as gastroduodenal and pancreatic mediators of insulin resistance and energy homeostasis, are known to be involved.
Enteropancreatic tumours in MEN 1 typically produce a broad range of hormones. Secretion of insulin, glucagon, pancreatic polypeptide, gastrin and chromogranin A are well recognized. Whilst clinical syndromes associated with gastrin, glucagon and insulin excess are commonly reported in MEN 1, the potential consequence of hypersecretion of other hormonal species is poorly characterized. Pluri-hormonal immunoreactivity is often observed in enteropancreatic tumour tissue despite in most cases the absence of either a measurable degree of systemic hypersecretion or overt clinical symptoms. It is likely therefore that some of the hormonal species elaborated by neoplastic enteropancreatic tumours in MEN 1 are not routinely measured and may have as yet uncharacterized clinical implications.
A large 1 MEN 1 kindred (Tasman 1) has previously been described. The pedigree spans five generations and consists of more than 2500 descendants of a common founder. Screening has been offered to family members over the past 20 years. More than 160 individuals with MEN 1 have been identified to date. As opposed to institutional case series for MEN 1, which often utilize patients from multiple families with diverse underlying MEN 1 mutations, the Tasman 1 pedigree facilitates assessment of MEN 1 expression in a relatively homogeneous genetic and environmental context. In this study we assessed the prevalence and associations of hyperglycaemia and diabetes mellitus in members of the Tasman 1, MEN 1 kindred.
Summary and Introduction
Summary
Objective: Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominant syndrome characterized by primary hyperparathyroidism, pituitary neoplasia and foregut lineage neuroendocrine tumours. It has also been associated with premature cardiovascular death. As diabetes is a risk factor for increased cardiovascular mortality we investigated the prevalence and clinical correlates of glycaemic abnormalities in a large MEN 1 kindred.
Patients and Design: The glycaemic status of 72 MEN 1 affected and 133 unaffected members of a single large MEN 1 pedigree was assessed. Fasting glucose results were categorized and compared using WHO criteria. Associations between glycaemic status and MEN 1 phenotype were assessed.
Results: Thirteen (18·1%) patients with MEN 1 compared to 5 (3·8%) control patients were diabetic (P < 0·001). Six (8·3%) MEN 1 patients had impaired fasting glucose compared to 4 (3%) of controls (P < 0·05). Of patients with MEN 1, uncontrolled hypercalcaemia (P < 0·05) and elevated serum gastrin (P < 0·05) were more common amongst patients diagnosed with abnormal glycaemia than those with normoglycaemia. There was a nonsignificant trend for elevated chromogranin A, pancreatic polypeptide, gastric inhibitory polypeptide (but not glucagon) and history of bronchopulmonary carcinoid in MEN 1 patients with elevated glycaemia.
Conclusions: Diabetes and impaired fasting glucose occur significantly more frequently amongst MEN 1 patients than controls and is associated with uncontrolled hyperparathyroidism and evidence of enteropancreatic hyperstimulation.
Introduction
Multiple endocrine neoplasia type 1 (MEN 1) is typically associated with hyperplastic and neoplastic lesions of the parathyroid, pituitary and foregut lineage endocrine tissue. Malignant tumours complicating MEN 1 are an important source of morbidity and mortality in individuals inheriting this disorder. Life expectancy in MEN 1 is significantly reduced compared to that of the general population. Whilst improvements in the management of hyperparathyroidism and Zollinger-Ellison syndrome over recent decades have had a beneficial impact on longevity, mean age at death in MEN 1 remains up to two decades below that expected for the general population.
Malignancy, hyperparathyroidism and peptic ulcer disease account for up to 50% of premature death amongst MEN 1 gene carriers. However, the remainder succumb to apparently unrelated conditions. Of note, some studies have identified cardiovascular disease as a cause for premature mortality in MEN 1 patients. The adverse vascular impact of hyperparathyroidism and consequent renal disease is a possible explanation for this observation. A recently published small study found evidence suggestive of insulin resistance in MEN 1 patients compared to unaffected siblings. However, there has not previously been a detailed assessment of conventional cardiovascular risk factors in patients with MEN 1.
Disorders of glucose metabolism and insulin resistance are important risk factors for macrovascular disease in the general population. The pathophysiological basis of insulin resistance is known to be complex, in part mediated by endocrine factors produced in adipose and enteropancreatic tissue. Adipocytokines such as leptin and resistin, as well as gastroduodenal and pancreatic mediators of insulin resistance and energy homeostasis, are known to be involved.
Enteropancreatic tumours in MEN 1 typically produce a broad range of hormones. Secretion of insulin, glucagon, pancreatic polypeptide, gastrin and chromogranin A are well recognized. Whilst clinical syndromes associated with gastrin, glucagon and insulin excess are commonly reported in MEN 1, the potential consequence of hypersecretion of other hormonal species is poorly characterized. Pluri-hormonal immunoreactivity is often observed in enteropancreatic tumour tissue despite in most cases the absence of either a measurable degree of systemic hypersecretion or overt clinical symptoms. It is likely therefore that some of the hormonal species elaborated by neoplastic enteropancreatic tumours in MEN 1 are not routinely measured and may have as yet uncharacterized clinical implications.
A large 1 MEN 1 kindred (Tasman 1) has previously been described. The pedigree spans five generations and consists of more than 2500 descendants of a common founder. Screening has been offered to family members over the past 20 years. More than 160 individuals with MEN 1 have been identified to date. As opposed to institutional case series for MEN 1, which often utilize patients from multiple families with diverse underlying MEN 1 mutations, the Tasman 1 pedigree facilitates assessment of MEN 1 expression in a relatively homogeneous genetic and environmental context. In this study we assessed the prevalence and associations of hyperglycaemia and diabetes mellitus in members of the Tasman 1, MEN 1 kindred.
Source...