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Liver fat accumulation is associated with reduced hepatic insulin extraction and beta cell dysfunction in healthy older individuals.

Finucane FM, Sharp SJ, Hatunic M, Sleigh A, De Lucia Rolfe E, Aihie Sayer A, Cooper C, Griffin SJ, Wareham NJ - Diabetol Metab Syndr (2014)

Bottom Line: There was no difference in IGI or DI between the groups.Further studies quantifying pancreatic fat content directly and its influence on beta cell function are warranted.ISRCTN60986572.

View Article: PubMed Central - HTML - PubMed

Affiliation: MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Box 285, Hills Road, Cambridge CB20QQ, UK. francis.finucane@mrc-epid.cam.ac.uk.

ABSTRACT

Background: There is a well-established association between type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) secondary to excess accumulation of intrahepatic lipid (IHL), but the mechanistic basis for this association is unclear. Emerging evidence suggests that in addition to being associated with insulin resistance, NAFLD may be associated with relative beta-cell dysfunction. We sought to determine the influence of liver fat on hepatic insulin extraction and indices of beta-cell function in a cohort of apparently healthy older white adults.

Methods: We performed a cross-sectional analysis of 70 healthy participants in the Hertfordshire Physical Activity Trial (39 males, age 71.3 ± 2.4 years) who underwent oral glucose tolerance testing with glucose, insulin and C-Peptide levels measured every 30 minutes over two hours. The areas under the concentration curve for glucose, insulin and C-Peptide were used to quantify hepatic insulin extraction (HIE), the insulinogenic index (IGI), the C-Peptide increment (CGI), the Disposition Index (DI) and Adaptation Index (AI). Visceral fat was quantified with magnetic resonance (MR) imaging and IHL with MR spectroscopy. Insulin sensitivity was measured with the Oral Glucose Insulin Sensitivity (OGIS) model.

Results: 29 of 70 participants (41%) exceeded our arbitrary threshold for NAFLD, i.e. IHL >5.5%. Compared to those with normal IHL, those with NAFLD had higher weight, BMI, waist and MR visceral fat, with lower insulin sensitivity and hepatic insulin extraction. Alcohol consumption, age, HbA1c and alanine aminotransferase (ALT) levels were similar in both groups. Insulin and C-Peptide excursions after oral glucose loading were higher in the NAFLD group, but the CGI and AI were significantly lower, indicating a relative defect in beta-cell function that is only apparent when C-Peptide is measured and when dynamic changes in glucose levels and also insulin sensitivity are taken into account. There was no difference in IGI or DI between the groups.

Conclusions: Although increased IHL was associated with greater insulin secretion, modelled parameters suggested relative beta-cell dysfunction with NAFLD in apparently healthy older adults, which may be obscured by reduced hepatic insulin extraction. Further studies quantifying pancreatic fat content directly and its influence on beta cell function are warranted.

Trial registration: ISRCTN60986572.

No MeSH data available.


Related in: MedlinePlus

(A-D): OGTT-derived indices of beta-cell function. Data are presented as means ± SEM. Dashed bars represent participants with IHL ≤ 5.5%. Solid bars represent participants with IHL > 5.5%, i.e. NAFLD. P values are derived from linear regression modelling with the exposure IHL treated as a continuous variable, adjusted for age, sex, visceral fat area and alcohol consumption.
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Figure 2: (A-D): OGTT-derived indices of beta-cell function. Data are presented as means ± SEM. Dashed bars represent participants with IHL ≤ 5.5%. Solid bars represent participants with IHL > 5.5%, i.e. NAFLD. P values are derived from linear regression modelling with the exposure IHL treated as a continuous variable, adjusted for age, sex, visceral fat area and alcohol consumption.

Mentions: Increased IHL was associated with greater areas under the curve (AUCs) for glucose, insulin and C-Peptide during the OGTT, as shown in Figure 1 (A-C). There was a relatively small but nonetheless statistically significant inverse association between IHL and HIE (mean HIE 88.1 ± 0.5 v 85.6 ± 0.9% in those with normal IHL and elevated IHL, respectively: adjusted β = -0.2 [-0.3, -0.06], p < 0.006). Put another way, every 1% rise in IHL was associated with a 0.2% reduction in HIE. Although there was an absolute increase in insulin secretion with higher IHL, there were no significant associations between IHL and insulin-derived indices of beta-cell function (insulinogenic index and disposition index – IGI, DI) as shown in Figure 2 (A and C). However, there were inverse associations between IHL and C-Peptide derived measures of beta-cell function (C-Peptide-genic index and adaptation index – CGI and AI), as shown in Figure 2 (B and D), such that higher levels of liver fat accumulation were associated with less beta-cell C-Peptide secretion. After adjusting for insulin sensitivity measured by OGIS, the strength of evidence for this association was slightly diminished (beta = -11.5 [-23.7, 0.59], p = 0.062).


Liver fat accumulation is associated with reduced hepatic insulin extraction and beta cell dysfunction in healthy older individuals.

Finucane FM, Sharp SJ, Hatunic M, Sleigh A, De Lucia Rolfe E, Aihie Sayer A, Cooper C, Griffin SJ, Wareham NJ - Diabetol Metab Syndr (2014)

(A-D): OGTT-derived indices of beta-cell function. Data are presented as means ± SEM. Dashed bars represent participants with IHL ≤ 5.5%. Solid bars represent participants with IHL > 5.5%, i.e. NAFLD. P values are derived from linear regression modelling with the exposure IHL treated as a continuous variable, adjusted for age, sex, visceral fat area and alcohol consumption.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3974597&req=5

Figure 2: (A-D): OGTT-derived indices of beta-cell function. Data are presented as means ± SEM. Dashed bars represent participants with IHL ≤ 5.5%. Solid bars represent participants with IHL > 5.5%, i.e. NAFLD. P values are derived from linear regression modelling with the exposure IHL treated as a continuous variable, adjusted for age, sex, visceral fat area and alcohol consumption.
Mentions: Increased IHL was associated with greater areas under the curve (AUCs) for glucose, insulin and C-Peptide during the OGTT, as shown in Figure 1 (A-C). There was a relatively small but nonetheless statistically significant inverse association between IHL and HIE (mean HIE 88.1 ± 0.5 v 85.6 ± 0.9% in those with normal IHL and elevated IHL, respectively: adjusted β = -0.2 [-0.3, -0.06], p < 0.006). Put another way, every 1% rise in IHL was associated with a 0.2% reduction in HIE. Although there was an absolute increase in insulin secretion with higher IHL, there were no significant associations between IHL and insulin-derived indices of beta-cell function (insulinogenic index and disposition index – IGI, DI) as shown in Figure 2 (A and C). However, there were inverse associations between IHL and C-Peptide derived measures of beta-cell function (C-Peptide-genic index and adaptation index – CGI and AI), as shown in Figure 2 (B and D), such that higher levels of liver fat accumulation were associated with less beta-cell C-Peptide secretion. After adjusting for insulin sensitivity measured by OGIS, the strength of evidence for this association was slightly diminished (beta = -11.5 [-23.7, 0.59], p = 0.062).

Bottom Line: There was no difference in IGI or DI between the groups.Further studies quantifying pancreatic fat content directly and its influence on beta cell function are warranted.ISRCTN60986572.

View Article: PubMed Central - HTML - PubMed

Affiliation: MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Box 285, Hills Road, Cambridge CB20QQ, UK. francis.finucane@mrc-epid.cam.ac.uk.

ABSTRACT

Background: There is a well-established association between type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) secondary to excess accumulation of intrahepatic lipid (IHL), but the mechanistic basis for this association is unclear. Emerging evidence suggests that in addition to being associated with insulin resistance, NAFLD may be associated with relative beta-cell dysfunction. We sought to determine the influence of liver fat on hepatic insulin extraction and indices of beta-cell function in a cohort of apparently healthy older white adults.

Methods: We performed a cross-sectional analysis of 70 healthy participants in the Hertfordshire Physical Activity Trial (39 males, age 71.3 ± 2.4 years) who underwent oral glucose tolerance testing with glucose, insulin and C-Peptide levels measured every 30 minutes over two hours. The areas under the concentration curve for glucose, insulin and C-Peptide were used to quantify hepatic insulin extraction (HIE), the insulinogenic index (IGI), the C-Peptide increment (CGI), the Disposition Index (DI) and Adaptation Index (AI). Visceral fat was quantified with magnetic resonance (MR) imaging and IHL with MR spectroscopy. Insulin sensitivity was measured with the Oral Glucose Insulin Sensitivity (OGIS) model.

Results: 29 of 70 participants (41%) exceeded our arbitrary threshold for NAFLD, i.e. IHL >5.5%. Compared to those with normal IHL, those with NAFLD had higher weight, BMI, waist and MR visceral fat, with lower insulin sensitivity and hepatic insulin extraction. Alcohol consumption, age, HbA1c and alanine aminotransferase (ALT) levels were similar in both groups. Insulin and C-Peptide excursions after oral glucose loading were higher in the NAFLD group, but the CGI and AI were significantly lower, indicating a relative defect in beta-cell function that is only apparent when C-Peptide is measured and when dynamic changes in glucose levels and also insulin sensitivity are taken into account. There was no difference in IGI or DI between the groups.

Conclusions: Although increased IHL was associated with greater insulin secretion, modelled parameters suggested relative beta-cell dysfunction with NAFLD in apparently healthy older adults, which may be obscured by reduced hepatic insulin extraction. Further studies quantifying pancreatic fat content directly and its influence on beta cell function are warranted.

Trial registration: ISRCTN60986572.

No MeSH data available.


Related in: MedlinePlus