Effects of a single 10mg dose of empagliflozin on postprandial insulin kinetics in patients with postbariatric hypoglycaemia

Introduction: Postbariatric hypoglycaemia (PBH) is an increasingly recognized late metabolic complication of Roux-en-Y gastric bypass (GB) surgery. PBH typically manifests with a fact occurring post-meal hyperglycaemic peak, followed by a disproportionately exaggerated insulin response leading to low glucose levels. On this basis, we evaluated the effect of a single dose of empagliflozin 10mg vs. placebo on parameters of insulin kinetics. Materials and methods: Insulin secretion, hepatic insulin extraction and total insulin clearance were evaluated after a single of empagliflozin 10mg vs. placebo followed by a standardized liquid mixed meal were evaluated in 11 subjects with confirmed PBH after GB over 3h. Parameters of interest were calculated using established mathematical models. Indices were compared between the groups using the Wilcoxon signed-rank test. Results Total beta-cell responsiveness tends to be lower with empagliflozin vs. placebo (24.83±11.00 vs. 27.15±9.68 [10-9 min-1], p=0.150). Total first-pass hepatic insulin extraction increased after empagliflozin compared to placebo (49.6±14.2 vs. 39.7±12.1 %, p=0.006), while no significant effect of empaglizflozin on basal first-pass hepatic insulin extraction was observed (79.7±7.1 vs. 81.1±6.6 %, p=0.521). Total insulin clearance resulted to be significantly lower after empagliflozin compared to placebo (3.91±1.58 vs. 3.00±1.27 l/min, p=0.002). Conclusion The present analysis suggests that the hypoglycaemia-attenuating effect of SGLT2-inhibition in patients with PBH is mainly mediated by an increment in insulin clearance, with also a tendency to a reduction in insulin secretion.

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β-Cell “rest” accompanies reduced first-pass hepatic insulin extraction in the insulin-resistant, fat-fed canine model

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00351.2006 ◽

2007 ◽

Vol 292 (6) ◽

pp. E1581-E1589 ◽

Cited By ~ 45

Author(s):

Stella P. Kim ◽

Martin Ellmerer ◽

Erlinda L. Kirkman ◽

Richard N. Bergman

Keyword(s):

Insulin Resistance ◽

Insulin Secretion ◽

Insulin Sensitivity ◽

Cell Function ◽

Physiological Mechanism ◽

Initial Increase ◽

Β Cell ◽

Euglycemic Hyperinsulinemic Clamp ◽

First Pass ◽

Hepatic Insulin Extraction

During insulin resistance, glucose homeostasis is maintained by an increase in plasma insulin via increased secretion and/or decreased first-pass hepatic insulin extraction. However, the relative importance of insulin secretion vs. clearance to compensate for insulin resistance in obesity has yet to be determined. This study utilizes the fat-fed dog model to examine longitudinal changes in insulin secretion and first-pass hepatic insulin extraction during development of obesity and insulin resistance. Six dogs were fed an isocaloric diet with an ∼8% increase in fat calories for 12 wk and evaluated at weeks 0, 6, and 12 for changes in 1) insulin sensitivity by euglycemic-hyperinsulinemic clamp, 2) first-pass hepatic insulin extraction by direct assessment, and 3) glucose-stimulated insulin secretory response by hyperglycemic clamp. We found that 12 wk of a fat diet increased subcutaneous and visceral fat as assessed by MR imaging. Consistent with increased body fat, the dogs exhibited a ∼30% decrease in insulin sensitivity and fasting hyperinsulinemia. Although insulin secretion was substantially increased at week 6, β-cell sensitivity returned to prediet levels by week 12. However, peripheral hyperinsulinemia was maintained because of a significant decrease in first-pass hepatic insulin extraction, thus maintaining hyperinsulinemia, despite changes in insulin release. Our results indicate that when obesity and insulin resistance are induced by an isocaloric, increased-fat diet, an initial increase in insulin secretion by the β-cells is followed by a decrease in first-pass hepatic insulin extraction. This may provide a secondary physiological mechanism to preserve pancreatic β-cell function during insulin resistance.

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Effects of glucose load and/or arginine on insulin and growth hormone secretion in hyperprolactinemia and obesity

Acta Endocrinologica ◽

10.1530/eje.0.1350205 ◽

1996 ◽

Vol 135 (2) ◽

pp. 205-210 ◽

Cited By ~ 12

Author(s):

Mauro Maccario ◽

Silvia Grottoli ◽

Paola Razzore ◽

Massimo Procopio ◽

Salvatore Endrio Oleandri ◽

...

Keyword(s):

Body Mass Index ◽

Growth Hormone ◽

Insulin Secretion ◽

Body Mass ◽

Hormone Secretion ◽

Growth Hormone Secretion ◽

Insulin Response ◽

Glucose Load ◽

Gh Secretion ◽

Glucose Levels

Maccario M, Grottoli S, Razzore P, Procopio M, Oleandri SE, Ciccarelli E, Camanni F, Ghigo E. Effects of glucose load and/or arginine on insulin and growth hormone secretion in hyperprolactinemia and obesity. Eur J Endocrinol 1996;135:205–10. ISSN 0804–4643 In hyperprolactinemic patients an exaggerated glucose-induced insulin secretion has been reported, but these results have not been confirmed by other researchers. On the other hand, there are few data concerning somatotrope secretion in this condition. In order to clarify these points, in seven normal weight hyperprolactinemic female patients (HP: age 18–46 years, body mass index = 21.8 ± 0.6 kg/m2, basal prolactin = 91.7 ± 16.5 μg/l) we studied the effects of glucose load (100 g orally) and/or arginine (0.5 g/kg infused over 30 min on insulin glucose and growth hormone (GH) levels. These results were compared with those obtained in seven patients with simple obesity (OB: age 23–48 years, body mass index = 38.3 ± 2.6 kg/m2) in whom exaggerated insulin and low GH secretion are well known. Seven normal women (NS: age 26–32 years, body mass index = 20.6 ± 1.9 kg/m2) were studied as controls. The insulin response to glucose in HP (area under curve = 11460.8 ± 1407.5 mU·min·1−1) was not significantly different from NS (7743.7 ±882.9 mU·min·1−1) and OB (14 504.8 ± 1659.9 mU·min·1−1). The arginine-induced insulin release in HP and OB was similar (4219.4 ± 631.7 and 4107.3 ± 643.2 mU·min·1−1. respectively), both being higher (p < 0.02) than in NS (2178.1 ± 290.9 mU·min·1−1). Glucose and arginine had an additive effect on insulin release in HP and NS (19 769.1 ± 3249.6 and 10996.6 ± 1201.0 mU·min·1−1, respectively) and a synergistic effect in OB (28117.3± 5224.7 mU·min·1−1). In HP the insulin response to the combined administration of glucose and arginine was not significantly different from the one in OB, and both were higher (p < 0.05) than in NS. The increase in glucose levels after glucose administered on its own or combined with arginine was higher (p < 0.02) and longer lasting in OB than in NS and HP. After arginine in OB, the glucose levels did not show the late decrease under baseline values observed in HP and NS. Glucose inhibited GH secretion both in HP and NS (p < 0.05), while arginine stimulated it in all groups, although the GH response in HP and NS was higher (p < 0.03) than in OB. The arginine-induced GH secretion was inhibited by glucose in HP and NS but not in OB. These results demonstrate that both in hyperprolactinemic patients and in obesity there is a clear increase in insulin secretion. The insulin hyperresponsiveness in hyperprolactinemia is more clearly demonstrated by combined stimulation with glucose and arginine. In spite of similar insulin hypersecretion in hyperprolactinemic and obese patients, GH secretion is reduced only in the latter; with these data the hypothesis that somatotrope insufficiency in obesity is due to hyperinsulinism is unlikely. Ezio Ghigo, Divisione di Endocrinologia, Ospedale Molinette, C.so Dogliotti 14, 10126 Torino, Italy

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Increased Slc12a1 expression in β-cells and improved glucose disposal in Slc12a2 heterozygous mice

Journal of Endocrinology ◽

10.1530/joe-15-0327 ◽

2015 ◽

Vol 227 (3) ◽

pp. 153-165 ◽

Cited By ~ 7

Author(s):

Saeed Alshahrani ◽

Mohammed Mashari Almutairi ◽

Shams Kursan ◽

Eduardo Dias-Junior ◽

Mohamed Mahmoud Almiahuob ◽

...

Keyword(s):

Insulin Secretion ◽

Insulin Response ◽

Chloride Concentration ◽

Glucose Disposal ◽

Β Cells ◽

Pancreatic Β Cells ◽

Glucose Levels ◽

Fasting Glycemia ◽

Blood Glucose Levels ◽

Glucose Stimulated Insulin Secretion

The products of theSlc12a1andSlc12a2genes, commonly known as Na+-dependent K+2Cl−co-transporters NKCC2 and NKCC1, respectively, are the targets for the diuretic bumetanide. NKCCs are implicated in the regulation of intracellular chloride concentration ([Cl−]i) in pancreatic β-cells, and as such, they may play a role in glucose-stimulated plasma membrane depolarization and insulin secretion. Unexpectedly, permanent elimination of NKCC1 does not preclude insulin secretion, an event potentially linked to the homeostatic regulation of additional Cl−transporters expressed in β-cells. In this report we provide evidence for such a mechanism. Mice lacking a single allele ofSlc12a2exhibit lower fasting glycemia, increased acute insulin response (AIR) and lower blood glucose levels 15–30 min after a glucose load when compared to mice harboring both alleles of the gene. Furthermore, heterozygous expression or complete absence ofSlc12a2associates with increased NKCC2 protein expression in rodent pancreatic β-cells. This has been confirmed by using chronic pharmacological down-regulation of NKCC1 with bumetanide in the mouse MIN6 β-cell line or permanent molecular silencing of NKCC1 in COS7 cells, which results in increased NKCC2 expression. Furthermore, MIN6 cells chronically pretreated with bumetanide exhibit increased initial rates of Cl−uptake while preserving glucose-stimulated insulin secretion. Together, our results suggest that NKCCs are involved in insulin secretion and that a singleSlc12a2allele may protect β-cells from failure due to increased homeostatic expression ofSlc12a1.

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Contribution of parasympathetic muscarinic augmentation of insulin secretion to olanzapine-induced hyperinsulinemia

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00315.2017 ◽

2018 ◽

Vol 315 (2) ◽

pp. E250-E257 ◽

Cited By ~ 5

Author(s):

Michael R. Rickels ◽

Elys M. Perez ◽

Amy J. Peleckis ◽

Erica Alshehabi ◽

Huong-Lan Nguyen ◽

...

Keyword(s):

Insulin Secretion ◽

Glucose Tolerance ◽

Insulin Response ◽

Study Drug ◽

Psychiatric Disease ◽

Double Blind ◽

Study Drug Administration ◽

Intravenous Glucose ◽

Obesity And Diabetes ◽

Hepatic Insulin Extraction

Atypical antipsychotic drugs have been associated with the development of obesity and diabetes. In particular, olanzapine can induce peripheral insulin resistance and compensatory hyperinsulinemia independent of weight gain or psychiatric disease. To determine if this compensatory increase in insulin is mediated by parasympathetic muscarinic stimulation, we randomized 15 healthy subjects 2:1 to receive double-blind olanzapine or placebo for 9 days under diet- and activity-controlled inpatient conditions. Before and after 7 days of study drug administration, subjects underwent frequently sampled intravenous glucose tolerance tests with either saline or atropine infused on subsequent days to assess insulin secretion and hepatic insulin extraction in the absence or presence of muscarinic blockade. We found that olanzapine led to an increase in the acute insulin response to glucose, which was not seen with placebo, and was attenuated in the olanzapine group by atropine. Deconvolution of C-peptide data confirmed an increase in insulin secretion with olanzapine, which was blocked by atropine, with a modest reduction in hepatic insulin extraction with olanzapine. These results support the contribution of muscarinic augmentation of insulin secretion to olanzapine-induced hyperinsulinemia, and provide a mechanism for the compensatory hyperinsulinemia that normally serves to prevent deterioration of glucose tolerance under conditions of metabolic challenge.

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Effects of chronic bromocriptine (CB-154) treatment on the plasma glucose and insulin secretion response to neurocytoglucopenia in rats

Journal of Endocrinology ◽

10.1677/joe.0.1620237 ◽

1999 ◽

Vol 162 (2) ◽

pp. 237-242 ◽

Cited By ~ 9

Author(s):

A Ribeiro-de-Oliveira ◽

RM Guerra ◽

RB Foscolo ◽

U Marubayashi ◽

AM Reis ◽

...

Keyword(s):

Insulin Secretion ◽

Chronic Treatment ◽

Insulin Response ◽

Major Effect ◽

Strong Increase ◽

Plasma Prolactin ◽

Dopaminergic Agonist ◽

Glucose Levels ◽

Plasma Insulin Levels ◽

Atropine Methyl Nitrate

Neurocytoglucopenia has been reported to increase both parasympathetic and sympathetic tone with a predominant effect on the latter, which accounts for the major effect of plasma hyperglycemia and the inhibition of insulin secretion. The aim of this study was to determine the effects of chronic treatment with bromocriptine (0.4 mg/100 g body wt per day), a potent sympatholytic D(2)-dopaminergic agonist, on hyperglycemia and insulin secretion in response to neurocytoglucopenia induced by 2-deoxy-d-glucose (2DG). After 2 weeks of bromocriptine treatment the animals, freely moving in their cages, were submitted to 2DG administration (50 mg/100 g body wt) via atrial catheter infusion. After 2DG infusion, the plasma prolactin of vehicle-treated (VEH) rats increased rapidly, reaching a peak at 10 min (34.3+/-7.6 ng/ml; P<0.01). In contrast, 2DG infusion failed to induce any significant change in the plasma prolactin levels of bromocriptine-treated (BR) rats. BR rats showed higher resting glucose levels than control rats (8.2+/-0.28 mM (BR) vs 6.0+/-0.18 mM (VEH); P<0.01). However, the hyperglycemic response of BR rats to 2DG injection was 30% lower than that of VEH rats (P<0.05). BR rats also showed a rapid rise in plasma insulin levels reaching a peak at 30 min after 2DG injection (243% higher than basal values; P<0.01). This increased rise in the insulin response to neurocytoglucopenia of BR rats was blocked by previous intravenous injection of atropine methyl nitrate (0.2 mg/100 g body wt). The present results suggest that chronic treatment with bromocriptine determines a strong increase in the parasympathetic tone response to neurocytoglucopenia, which is responsible for the higher stimulation of insulin secretion observed in BR rats. The data also provide further evidence that D(2)-dopaminergic agonist can block neurocytoglucopenia-induced prolactin release.

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The augmenting effect on insulin secretion by oral versus intravenous glucose is exaggerated by high-fat diet in mice

Journal of Endocrinology ◽

10.1677/joe-07-0460 ◽

2008 ◽

Vol 197 (1) ◽

pp. 181-187 ◽

Cited By ~ 22

Author(s):

Bo Ahrén ◽

Maria Sörhede Winzell ◽

Giovanni Pacini

Keyword(s):

Insulin Secretion ◽

High Fat Diet ◽

Insulin Response ◽

Area Under The Curve ◽

Oral Glucose ◽

Incretin Effect ◽

High Fat ◽

Intravenous Glucose ◽

Insulin Resistant ◽

Glucose Levels

To study whether the incretin effect is involved in adaptively increased insulin secretion in insulin resistance, glucose was infused at a variable rate to match glucose levels after oral glucose (25 mg) in normal anesthetized C57BL/6J female mice or in mice rendered insulin resistant by 8 weeks of high-fat feeding. Insulin response was markedly higher after oral than i.v. glucose in both groups, and this augmentation was even higher in high-fat fed than normal mice. In normal mice, the area under the curve (AUCinsulin) was augmented from 4.0±0.8 to 8.0±1.8 nmol/l×60 min by the oral glucose, i.e. by a factor of 2 (P=0.023), whereas in the high-fat fed mice, AUCinsulin was augmented from 0.70±0.4 to 12.4±2.5 nmol/l×60 min, i.e. by a factor of 17 (P<0.001). To examine whether the incretin hormone glucagon-like peptide-1 (GLP-1) is responsible for this difference, the effect of i.v. GLP-1 was compared in normal and high-fat fed mice. The sensitivity to i.v. GLP-1 in stimulating insulin secretion was increased in the high-fat diet fed mice: the lowest effective dose of GLP-1 was 650 pmol/kg in normal mice and 13 pmol/kg in the high-fat diet fed mice. We conclude that 1) the incretin effect contributes by ∼50% to insulin secretion by the oral glucose in normal mice, 2) this effect is markedly exaggerated in insulin-resistant mice fed a high-fat diet, and 3) this augmented incretin contribution in the high-fat fed mice may partially be explained by GLP-1.

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Insulin Secretion and Risk for Future Diabetes in Subjects with a Nonpositive Insulinogenic Index

Journal of Diabetes Research ◽

10.1155/2018/5107589 ◽

2018 ◽

Vol 2018 ◽

pp. 1-9 ◽

Cited By ~ 1

Author(s):

Daisuke Aono ◽

Rie Oka ◽

Mitsuhiro Kometani ◽

Yoshimichi Takeda ◽

Shigehiro Karashima ◽

...

Keyword(s):

Insulin Secretion ◽

Glucose Tolerance ◽

Insulin Response ◽

Tolerance Test ◽

Rank Test ◽

Oral Glucose ◽

Insulinogenic Index ◽

Glucose Response ◽

Historical Cohort ◽

Future Diabetes

Aim. To characterize subjects with a nonpositive insulinogenic index and longitudinally observe changes in their glucose tolerance. Subjects and Methods. A historical cohort study was conducted using data from the medical checkups of public school workers. Indices of insulin secretion and insulin sensitivity derived from oral glucose tolerance test (OGTT) and the incidences of diabetes and impaired glucose tolerance (IGT) were compared among subgroups of subjects with different insulinogenic index (change in insulin/change in glucose over the first 30 min on the OGTT). Results. Of the 1464 nondiabetic subjects at baseline, 72 (4.9%) subjects had a nonpositive insulinogenic index: 42 of those subjects had a nonpositive glucose response (ΔGlu0–30 ≤ 0) and 30 had a nonpositive insulin response (ΔIns0–30 ≤ 0). Compared with subjects who had normal glucose tolerance (NGT) with insulinogenic index ≥ 0.4, subjects with a nonpositive glucose response had a higher first-phase Stumvoll and lower incidences of diabetes and IGT based on a log-rank test (p<0.05), whereas subjects with a nonpositive insulin response had lower indices of insulin secretion and a higher incidence of diabetes (p<0.05). Conclusions. These results demonstrate that in the first 30 min on the OGTT, subjects with a nonpositive insulinogenic index due to a nonpositive glucose response (ΔGlu0–30 ≤ 0) had a lower risk for future diabetes and that subjects with nonpositive insulin response (ΔIns0–30 ≤ 0) had a higher risk for future one.

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β-cell function in black South African women: exploratory associations with insulin clearance, visceral and ectopic fat

Endocrine Connections ◽

10.1530/ec-21-0153 ◽

2021 ◽

Author(s):

Melony C Fortuin-de Smidt ◽

Amy E Mendham ◽

Jon Hauksson ◽

Ali Alhamud ◽

Darko Stefanovski ◽

...

Keyword(s):

Insulin Secretion ◽

Cell Function ◽

Insulin Clearance ◽

African Women ◽

Ectopic Fat ◽

Β Cell ◽

Black African ◽

Β Cell Function ◽

Hepatic Insulin Extraction ◽

South African Women

The role of ectopic fat, insulin secretion and clearance in the preservation of β-cell function in black African women with obesity who typically present with hyperinsulinemia is not clear. We aim to examine the associations between disposition index (DI, an estimate of β-cell function), insulin secretion and clearance and ectopic fat deposition. This is a cross-sectional study of 43 black South African women (age 20-35 years) with obesity (BMI 30-40 kg/m2) and without type 2 diabetes that measured the following: DI, insulin sensitivity (SI), acute insulin response (AIRg), insulin secretion rate (ISR), hepatic insulin extraction and peripheral insulin clearance (frequently-sampled intravenous glucose tolerance test); pancreatic and hepatic fat, visceral adipose tissue (VAT) and abdominal subcutaneous adipose tissue (aSAT) volume (magnetic resonance imaging), intramyocellular (IMCL) and extramyocellular fat content (EMCL) (magnetic resonance spectroscopy). DI correlated positively with peripheral insulin clearance (β 55.80, p=0.002). Higher DI was associated with lower VAT, pancreatic fat and soleus fat, but VAT explained most of the variance in DI (32%). Additionally, higher first phase ISR (p=0.033) and lower hepatic insulin extraction (p=0.022) associated with lower VAT, independent from SI, rather than with ectopic fat. In conclusion, peripheral insulin clearance emerged as an important correlate of DI. However, VAT was the main determinant of a lower DI above ectopic fat depots. Importantly, VAT, but not ectopic fat, associated with both lower insulin secretion and higher hepatic insulin extraction. Prevention of VAT accumulation in young black African women should therefore be an important target for beta cell preservation.

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β-cell function in black South African women: Associations with insulin clearance and ectopic fat

10.21203/rs.3.rs-35455/v2 ◽

2020 ◽

Author(s):

Melony Cathlin Fortuin-de Smidt ◽

Amy E Mendham ◽

Jon Hauksson ◽

Ali Alhamud ◽

Darko Stefanovski ◽

...

Keyword(s):

Insulin Secretion ◽

South African ◽

Cell Function ◽

Insulin Clearance ◽

African Women ◽

Ectopic Fat ◽

Black South African ◽

Β Cell Function ◽

Hepatic Insulin Extraction ◽

South African Women

Abstract Background: The role of ectopic fat, insulin secretion and clearance in the preservation of β-cell function in black African women with obesity who typically present with hyperinsulinemia is not clear. We aim to examine the associations between disposition index (DI, an estimate of β-cell function), insulin secretion and clearance and ectopic fat deposition.Methods: This is a cross-sectional study of 43 black South African women (age 20-35 years) with obesity (BMI 30-40 kg/m2) and without type 2 diabetes that measured the following: DI, insulin sensitivity (SI), acute insulin response (AIRg), insulin secretion rate (ISR), hepatic insulin extraction and peripheral insulin clearance (frequently-sampled intravenous glucose tolerance test); pancreatic and hepatic fat, visceral adipose tissue (VAT) and abdominal subcutaneous adipose tissue (aSAT) volume (magnetic resonance imaging), intramyocellular (IMCL) and extramyocellular fat content (EMCL) (magnetic resonance spectroscopy). Results: DI correlated positively with peripheral insulin clearance before (β 55.80, p=0.002) and after adjusting for hepatic insulin extraction. Higher DI was associated with lower VAT, pancreatic fat and soleus fat, but VAT explained most of the variance in DI (32%). Additionally, higher first phase ISR (p=0.033) and lower hepatic insulin extraction (p=0.022) associated with lower VAT, independent from SI, rather than with ectopic fat. Conclusion: Peripheral insulin clearance emerged as an important correlate of DI, independent from hepatic insulin extraction. However, VAT was the main determinant of a lower DI above ectopic fat depots. Importantly, VAT, but not ectopic fat, was associated with both lower insulin secretion and higher hepatic insulin extraction, independent from SI, and may provide a novel explanation of these findings in black South African women with obesity.

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β -Cell Function in Black South African Women: Associations With Insulin Clearance And Ectopic Fat

10.21203/rs.3.rs-35455/v1 ◽

2020 ◽

Author(s):

Melony Cathlin Fortuin-de Smidt ◽

Amy E Mendham ◽

Jon Hauksson ◽

Ali Alhamud ◽

Darko Stefanovski ◽

...

Keyword(s):

Insulin Secretion ◽

South African ◽

Cell Function ◽

Insulin Clearance ◽

African Women ◽

Ectopic Fat ◽

Black South African ◽

Β Cell Function ◽

Hepatic Insulin Extraction ◽

South African Women

Abstract Background: The role of ectopic fat, insulin secretion and clearance in the preservation of β-cell function in obese, black African women who typically present with hyperinsulinemia is not clear. We aim to examine the associations between disposition index (DI, a measure of β-cell function), insulin secretion and clearance and ectopic fat deposition. Methods: This is a cross-sectional study of 43 obese (BMI 30-40 kg/m2) black South African ( women (age 20-35 years) without type 2 diabetes that measured the following: DI, insulin sensitivity (SI), acute insulin response (AIRg), insulin secretion rate (ISR), hepatic insulin extraction and peripheral insulin clearance (frequently-sampled intravenous glucose tolerance test); pancreatic and hepatic fat, visceral adipose tissue (VAT) and abdominal subcutaneous adipose tissue (SAT) volume (magnetic resonance imaging), intramyocellular (IMCL) and extramyocellular fat content (EMCL) (magnetic resonance spectroscopy). DI correlated positively with peripheral insulin clearance before (β 55.80, p=0.002) and after adjusting for hepatic insulin extraction. Higher DI was associated with lower VAT, pancreatic fat and soleus fat, but VAT explained most of the variance in DI (32%). Additionally, higher first phase ISR (p=0.033) and lower hepatic insulin extraction (p=0.022) associated with lower VAT, independent from SI, rather than with ectopic fat. Conclusion: Peripheral insulin clearance emerged as an important determinant of DI, independent from hepatic insulin extraction. However, VAT was the main determinant of a lower DI above ectopic fat depots. Importantly, VAT, but not ectopic fat, was associated with both lower insulin secretion and higher hepatic insulin extraction, independent from SI, and may provide a novel explanation of these findings in obese black South African women.

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