Fatty acids in the portal vein of the rat regulate hepatic insulin clearance.

Svedberg, Jan; Strömblad, G; Wirth, Alfred; Smith, Ulf; Björntorp, Per

doi:10.1172/jci115534

Cited by 112 publications

(62 citation statements)

References 34 publications

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“…An alternative explanation is that the decreased insulin clearance is simply secondary to some other metabolic abnormality in the relatives. Increased NEFA levels have been shown to decrease hepatic insulin clearance [34], and is thought All data are presented as the respective means and the SD of the differences to be the mechanism by which hyperinsulinaemia develops in subjects with abdominal obesity [35]. However, there was no evidence that this mechanism was important in the relatives in the present study.…”

Section: Discussionmentioning

confidence: 59%

Multiple metabolic abnormalities in normal glucose tolerant relatives of NIDDM families

et al. 1997

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Non-insulin-dependent diabetes mellitus (NIDDM) is a complex metabolic condition characterised by both impaired insulin secretion and insulin resistance [1]. It is also recognised that elevated circulating proinsulin levels are an important and consistent feature of NIDDM [2][3][4][5], and may represent a specific defect of pancreatic beta-cell function. There is continuing debate as to whether insulin deficiency or insulin resistance represents the primary abnormality which predisposes to the development of NIDDM [6], although it is clear that comparative insulin deficiency is a sine qua non for NIDDM to develop [7].In an attempt to identify the early fundamental abnormalities, non-diabetic first degree relatives of NIDDM patients have been studied, as they have a 40 % lifetime risk of progressing to diabetes [8]. However, such an approach has so far failed to clarify matters, as some studies have found a principal defect of insulin secretion [9-13], several have suggested that Diabetologia (1997Diabetologia ( ) 40: 1185Diabetologia ( -1190 Multiple metabolic abnormalities in normal glucose tolerant relatives of NIDDM families Summary Non-diabetic first degree relatives of noninsulin-dependent diabetic (NIDDM) families are at increased risk of developing diabetes mellitus, and have been studied to identify early metabolic abnormalities. Hormone concentrations measured by specific enzyme immunoassays were assessed in non-diabetic relatives of North European extraction, and control subjects with no family history of diabetes were matched for age, sex and ethnicity. A 75-g oral glucose tolerance test was conducted and those with newly diagnosed NIDDM were excluded. Basal insulin resistance was determined by homeostasis model assessment (HOMA), and hepatic insulin clearance by C-peptide:insulin molar ratio. Relatives (n = 150) were heavier (BMI: p < 0.0001) than the control subjects (n = 152), and had an increased prevalence of impaired glucose tolerance (15 vs 3 %, p < 0.01). The relatives had increased fasting proinsulin levels and decreased C-peptide levels following the glucose load, while insulin levels were increased at all time points. To examine whether the differences in hormone levels were secondary to the differences in glucose tolerance and adiposity, we studied 100 normal glucose tolerant relatives and control subjects pairmatched for age, sex, waist-hip ratio and BMI. The differences in proinsulin levels were no longer apparent. However, the relatives remained more insulin resistant, and had decreased C-peptide levels and Cpeptide:insulin ratios at all time points. In conclusion, we have identified several metabolic abnormalities in the normal glucose tolerant relatives, and propose that the decreased hepatic insulin clearance helps to maintain normoglycaemia in the face of combined insulin resistance and decreased insulin secretion. [Diabetologie (1997[Diabetologie ( ) 40: 1185[Diabetologie ( -1190

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Section: Discussionmentioning

confidence: 59%

Multiple metabolic abnormalities in normal glucose tolerant relatives of NIDDM families

et al. 1997

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“…It is also possible that elevated circulating NEFA levels contributed to the elevated insulin levels, as high NEFA levels reduce hepatic insulin extraction [41,42]. Indeed, the fasting NEFA concentrations correlated with the fasting insulin levels (r=0.263; p<0.0005).…”

Section: Discussionmentioning

confidence: 99%

Parallel manifestation of insulin resistance and beta cell decompensation is compatible with a common defect in Type 2 diabetes

et al. 2004

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Aims/hypothesis. The aim of the study was to evaluate the relationship between insulin sensitivity, beta cell function and glucose tolerance, and its dependence on variants in the newly identified Type 2 diabetes susceptibility gene, calpain-10 (CAPN10). Methods. We studied 203 men of the same age but with varying degrees of glucose tolerance. These men participated in (i) an oral glucose tolerance test, (ii) a euglycaemic clamp combined with indirect calorimetry and infusion of [3-3 H]-glucose and (iii) a stepwise assessment of acute insulin response to arginine (AIR) at three different glucose concentrations (fasting, 14 and 28 mmol/l).Results. There was a linear increase in NEFA levels (p<0.0005) and WHR (p<0.0005) and decrease in glucose uptake due to a reduction in glucose storage over the entire range of glucose tolerance (r=−0.404; p<0.005). No increase in endogenous glucose production (EGP) was seen until patients had manifest diabetes. However, when EGP was expressed relative to fasting insulin concentrations, there was a linear deterioration of basal hepatic insulin sensitivity (r= −0.514; p<0.005). The AIR followed a bell-shaped curve with an initial rise and subsequent decrease. However, AIR adjusted for insulin sensitivity (disposition index) showed a linear decrease with increasing glucose concentrations (r=−0.563; p<0.001) starting already in subjects with normal glucose tolerance. There was an inverse correlation between increase in WHR and NEFA and peripheral as well as hepatic insulin sensitivity. Subjects with the genotype combination of CAPN10 consisting of SNP44 TT and SNP43 GG genotypes had significantly lower insulin-stimulated glucose uptake than carriers of the other genotype combinations (5.3±0.4 vs 7.2±0.4 mg·ffm kg −1 min −1 ·mU·l −1 ; p<0.005). Conclusions/interpretation. We conclude that the prediabetic state is characterised by a similar linear deterioration of peripheral and hepatic insulin sensitivity as beta cell function and that variants in the CAPN10 gene modify this relationship. These findings are compatible with a common defect in muscle, liver and beta cells in the pathogenesis of Type 2 diabetes.

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“…39 ± 41 Patients with`early NIDDM' have increased rates of gastric emptying according to one study, 42 while others have demonstrated correlations between gastric emptying and serum glucose and insulin in normal subjects and patients with NIDDM. 43 Alone or in conjunction with rapid absorption of lipid, 38,44 glucose and insulin increases may lead to insulin resistance 9,45 and the metabolic syndrome with centralavisceral fat distribution and dyslipidemia. Indeed, in a recent study normalizing glycemia in type II diabetics, plasma glucose was shown to be a prime determinant of hepatic insulin action in the presence of a decrease in serum FFA.…”

Section: Discussionmentioning

confidence: 99%

Metabolic correlates of eating behavior in severe obesity

et al. 2001

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BACKGROUND:The bene®t of spreading energy intake over many small meals (`nibbling') rather than few large ones (`gorging') for control of blood glucose, serum lipids and body fat accretion has been known for 60 y, but the mechanisms are poorly understood. Men exhibit more of a gorging eating pattern than women and are also more prone to the metabolic complications of obesity, as are women with a`male', central distribution of adipose tissue. We have shown correlations between central fat distribution, and other components of the metabolic`Syndrome X' and fatty in®ltration of the liver. Here we study relationships between eating rate and fat distribution and test the hypothesis that gorging might be associated with fatty liver. SUBJECTS AND METHODS:In 30 non-alcoholic, non-diabetic, severely obese women (body mass index, BMI 47 AE 1 kgam 2 ; mean AE s.e.m.) with a mean age of 36 AE 1 y and 16 men (BMI: 52 AE 3) age 38 AE 2 y, who were candidates for anti-obesity surgery, we measured eating rate using an eating monitor, and fat distribution by the waist ± hip circumference ratio (WHR). In addition in the 17 women and 11 men who had surgery, serum lipids were analyzed and routine liver biopsies were evaluated for steatosis by a pathologist blinded to the conditions of the study. RESULTS: Men ate signi®cantly faster than women (188 AE 28 vs 123 AE 9 gamin; P`0.01), and had more liver fat (score: 2.7 AE 03 vs 1.5 AE 0.3; P`0.01), with no statistically signi®cant sex differences in s-cholesterol or s-triglycerides. Eating rate correlated with WHR (r 0.46; P`0.01, n 46), liver fat (r 0.55; P`0.01), and s-triglycerides (r 0.42; P`0.05) adjusting for sex. Liver fat correlated with WHR (r 0.50; P`0.05), s-triglycerides (r 0.70; P`0.01) and s-cholesterol (r 0.50; P`0.05), while there were no signi®cant correlations with BMI or body weight. In multivariate analysis eating rate (32%), meal size (8%) and WHR (6%) contributed 46% of the variance in liver fat. CONCLUSION: We showed increased eating rates in severely obese men and women with central fat distribution. Furthermore, increased eating rates were associated with fatty liver and elevated serum lipids. Eating rate in severely obese women and men may be a determinant of the metabolic syndrome.

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Fatty acids in the portal vein of the rat regulate hepatic insulin clearance.

Cited by 112 publications

References 34 publications

Multiple metabolic abnormalities in normal glucose tolerant relatives of NIDDM families

Multiple metabolic abnormalities in normal glucose tolerant relatives of NIDDM families

Parallel manifestation of insulin resistance and beta cell decompensation is compatible with a common defect in Type 2 diabetes

Metabolic correlates of eating behavior in severe obesity

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