Pancreatic Steatosis Associates With Impaired Insulin Secretion in Genetically Predisposed Individuals

Róbert Wagner; Benjamin Assad Jaghutriz; Felicia Gerst; Morgana Barroso Oquendo; Jürgen Machann; Fritz Schick; Markus W Löffler; Silvio Nadalin; Falko Fend; Alfred Königsrainer; Andreas Peter; Dorothea Siegel-Axel; Susanne Ullrich; Hans-Ulrich Häring; Andreas Fritsche; Martin Heni

doi:10.1210/clinem/dgaa435

Pancreatic Steatosis Associates With Impaired Insulin Secretion in Genetically Predisposed Individuals

J Clin Endocrinol Metab. 2020 Nov 1;105(11):3518-3525. doi: 10.1210/clinem/dgaa435.

Authors

Róbert Wagner^{1

2

3}, Benjamin Assad Jaghutriz^{1

2

3}, Felicia Gerst^{1

2

3}, Morgana Barroso Oquendo^{1

2

3}, Jürgen Machann^{1

2

4}, Fritz Schick^{1

2

4}, Markus W Löffler^{5

6

7}, Silvio Nadalin⁵, Falko Fend⁸, Alfred Königsrainer⁵, Andreas Peter^{1

2

9}, Dorothea Siegel-Axel^{1

2

3}, Susanne Ullrich^{1

2

3}, Hans-Ulrich Häring^{1

2

3}, Andreas Fritsche^{1

2

3}, Martin Heni^{1

2

3}

Affiliations

¹ Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.
² German Center for Diabetes Research (DZD e.V.).
³ Department of Internal Medicine, Division of Diabetology, Endocrinology and Nephrology, University Hospital Tübingen, Tübingen, Germany.
⁴ Section on Experimental Radiology, University Hospital Tübingen, Tübingen, Germany.
⁵ Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany.
⁶ Interfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany.
⁷ Department of Clinical Pharmacology, University Hospital Tübingen, Tübingen, Germany.
⁸ Institute of Pathology and Neuropathology, University Hospital Tübingen, Tübingen, Germany.
⁹ Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, University Hospital Tübingen, Tübingen, Germany.

Abstract

Context: Pancreatic steatosis leading to beta-cell failure might be involved in type 2 diabetes (T2D) pathogenesis.

Objective: We hypothesized that the genetic background modulates the effect of pancreatic fat on beta-cell function and investigated genotype × pancreatic fat interactions on insulin secretion.

Design: Two observational studies.

Setting: University hospital.

Patients or participants: A total of 360 nondiabetic individuals with elevated risk for T2D (Tuebingen Family Study [TUEF]), and 64 patients undergoing pancreatectomy (Pancreas Biobank [PB], HbA1c <9%, no insulin therapy).

Main outcome measures: Insulin secretion calculated from 5-point oral glucose tolerance test (TUEF) and fasting blood collection before surgery (PB). A genome-wide polygenic score for T2D was computed from 484,788 genotyped variants. The interaction of magnetic resonance imaging-measured and histologically quantified pancreatic fat with the polygenic score was investigated. Partitioned risk scores using genome-wide significant variants were also computed to gain insight into potential mechanisms.

Results: Pancreatic steatosis interacted with genome-wide polygenic score on insulin secretion (P = 0.003), which was similar in the replication cohort with histological measurements (P = 0.03). There was a negative association between pancreatic fat and insulin secretion in participants with high genetic risk, whereas individuals with low genetic risk showed a positive correlation between pancreatic fat and insulin secretion. Consistent interactions were found with insulin resistance-specific and a liver/lipid-specific polygenic scores.

Conclusions: The associations suggest that pancreatic steatosis only impairs beta-cell function in subjects at high genetic risk for diabetes. Genetically determined insulin resistance specifically renders pancreatic fat deleterious for insulin secretion.

Keywords: beta cell function; insulin secretion; non-alcoholic fatty pancreas disease; pancreatic steatosis; prediabetes; type 2 diabetes.

Publication types

Observational Study
Research Support, Non-U.S. Gov't

MeSH terms

Adipose Tissue / diagnostic imaging
Aged
Blood Glucose
Body Mass Index
Diabetes Mellitus, Type 2 / genetics*
Female
Genetic Predisposition to Disease
Glucose Tolerance Test
Humans
Insulin Resistance / genetics*
Insulin Secretion / genetics*
Male
Middle Aged
Pancreas / diagnostic imaging
Pancreas / metabolism*
Pancreatic Diseases / diagnostic imaging
Pancreatic Diseases / genetics
Pancreatic Diseases / metabolism*

Substances

Blood Glucose