Pancreatic Lipomatosis Is a Structural Marker in Nondiabetic Children With Mutations in Carboxyl-Ester Lipase

Abstract

Both pancreatic volume reduction and lipomatosis have been observed in subjects with diabetes. The underlying molecular and pathological mechanisms are, however, poorly known, and it has been speculated that both features are secondary to diabetes. We have recently described pancreatic atrophy and lipomatosis in diabetic subjects of two Norwegian families with a novel syndrome of diabetes and exocrine pancreatic dysfunction caused by heterozygous carboxyl-ester lipase (CEL) mutations. To explore the early pathological events in this syndrome, we performed radiological examinations of the pancreas in nondiabetic mutation carriers with signs of exocrine dysfunction. In a case series study at a tertiary hospital, we evaluated 11 nondiabetic and mutation-positive children with fecal elastase deficiency and 11 age-and sex-matched control subjects using ultrasound and magnetic resonance imaging (MRI) to estimate pancreatic fat content. The pancreata of nondiabetic mutation carriers exhibited increased reflectivity on ultrasound and had MRI findings indicative of lipomatosis. Apparently, carriers of heterozygous CEL mutations accumulate fat in their pancreas before the anticipated development of diabetes. Our findings suggest that lipomatosis of the pancreas reflects early events involved in the pathogenesis of diabetes and exocrine pancreatic dysfunction syndrome. Diabetes 56: 444 -449, 2007 T he pancreas consists of acinar and ductal cells with the islets of Langerhans scattered within the exocrine tissue. ␤-Cells, which are central in the development of diabetes, constitute the major part of the islets (1). There are reports in diabetic subjects of pathological changes involving not only the islets but the entire pancreatic gland, such as pancreatic volume reduction (2-8) and lipomatosis (fatty infiltration) of the pancreas (9,10). The lipomatosis reported in autopsy studies has been described as patchy intralobular or perilobular areas of fat replacement of pancreatic parenchyma (9,10). Pancreatic size reduction and lipomatosis have been discussed as possible secondary events involved in atrophy and lipomatosis related to diabetes due to a reduced insulinotropic effect on the acinar cells (11-13). The underlying molecular and pathophysiological mechanisms are, however, poorly known. Monogenic pancreatic diseases could cast important light on early pathological events and provide the opportunity to study subjects before the development of diabetes.We recently described pancreatic atrophy and lipomatosis in diabetic subjects of two Norwegian families with a novel syndrome of diabetes and pancreatic exocrine dysfunction (MODY8; OMIM [Online Mendelian Inheritance in Man] no. 609812) caused by heterozygous carboxyl-ester lipase (CEL) mutations (14). In that report, computerized tomography of the pancreas was performed in adult mutation carriers, and most of the studied subjects were already diabetic. We hypothesized that the morphologic abnormalities of the pancreas that were identified, particularly the lipomatosis,...

Pancreatic Fat Content and β-Cell Function in Men With and Without Type 2 Diabetes

“…The latter mechanism may, in addition to glycotoxic cell injury, be one of the explanations why the diabetic subjects had more pancreatic fat than those without diabetes (19,20). Recently, evidence for a possible association between pancreatic lipomatosis and ␤-cell function was demonstrated (22). Using magnetic resonance imaging in 11 nondiabetic nonobese children with heterozygous carboxyl-ester lipase mutation, i.e., a rare mutation that causes diabetes and exocrine pancreatic dysfunction in association with pancreatic lipomatosis in adults, the authors found increased pancreatic fat content and a significant reduction of the first-phase insulin response to intravenous glucose in the mutation carriers.…”

Monogenic diabetes mellitus in Norway

“…In the future, we expect that more detailed phenotyping using radiological imaging and physiological characterization will improve the value of the registry, enabling us to diagnose monogenic diabetes more efficiently (32). An example is the use of ultrasound examination to diagnose HNF1B-MODY and CEL-MODY (13,33). In the near future, we think tailored hybridization capture for selected genes of interest and very high-coverage sequencing of specific gene panels will replace the traditional Sanger sequencing.…”

Стеатоз Підшлункової Залози В Дітей. Частина 1. Етіологія, Епідеміологія Та Патогенез

“…Ліпоматоз паренхіми підшлункової залози в носіїв мутації в гені карбоксилестерліпази спостері-гається вже на ранніх стадіях діабету, що пояснює на-явність екзокринної панкреатичної недостатності при синдромі MODY (maturity-onset diabetes of the young -цукровий діабет дорослого типу в молодих). MODY є рідкісною, сімейною, клінічно і генетично гетеро-генною формою діабету, що характеризується почат-ком у молодому віці (як правило, 10-45 років) зі збе-реженням секреції ендогенного інсуліну, із відсутністю автоімунного ураження В-клітин підшлункової залози, відсутністю ожиріння та резистентності до інсуліну з можливістю екстрапанкреатичних проявів [19,20].…”