Increased β-Cell Responsivity Independent of Insulin Sensitivity in Healthy African American Adults

Abstract Background Primary insulin hypersecretion predicts type 2 diabetes (T2DM) independent of insulin resistance. Enhanced β-cell glucose responsivity contributes to insulin hypersecretion. African Americans (AAs) are at a higher risk for T2DM than non-Hispanic Whites (NHWs). Whether AAs manifest primary insulin hypersecretion is an important topic that has not been examined systematically. Objective To examine if nondiabetic AA adults have a higher β-cell glucose responsivity compared with NHWs. Methods Healthy nondiabetic AA (n = 18) and NHW (n=18) subjects were prospectively recruited. Indices of β-cell function, acute C-peptide secretion (X0); basal (Φ B), first-phase (Φ 1), second-phase (Φ 2), and total β-cell responsivity to glucose (Φ TOT), were derived from modeling of insulin, C-peptide, and glucose concentrations during an intravenous glucose tolerance test. Insulin sensitivity was assessed by the hyperinsulinemic–euglycemic glucose clamp technique. Results Glucose disposal rate (GDR) during clamp was similar in AAs and NHWs (GDR: [AA] 12.6 ± 3.2 vs [NHW] 12.6 ± 4.2 mg/kg fat free mass +17.7/min, P = .49). Basal insulin secretion rates were similar between the groups. AA had significantly higher X0 (4423 ± 593 vs 1807 ± 176 pmol/L, P = .007), Φ 1 [377.5 ± 59.0 vs 194.5 ± 26.6 (109) P = 0.03], and Φ TOT [76.7 ± 18.3 vs 29.6 ± 4.7 (109/min), P = 0.03], with no significant ethnic differences in Φ B and Φ 2. Conclusions Independent of insulin sensitivity, AAs showed significantly higher first-phase and total β-cell responsivity than NHWs. We propose that this difference reflects increased β-cell responsivity specifically to first-phase readily releasable insulin secretion. Future studies are warranted to identify mechanisms leading to primary β-cell hypersensitivity in AAs.

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Effects on insulin secretion and insulin action of a 48-h reduction of plasma free fatty acids with acipimox in nondiabetic subjects genetically predisposed to type 2 diabetes

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00624.2006 ◽

2007 ◽

Vol 292 (6) ◽

pp. E1775-E1781 ◽

Cited By ~ 59

Author(s):

Kenneth Cusi ◽

Sangeeta Kashyap ◽

Amalia Gastaldelli ◽

Mandeep Bajaj ◽

Eugenio Cersosimo

Keyword(s):

Type 2 Diabetes ◽

Insulin Secretion ◽

Family History ◽

Second Phase ◽

Β Cell ◽

C Peptide ◽

Hyperglycemic Clamp ◽

History Of ◽

Plasma Ffa

Elevated plasma FFA cause β-cell lipotoxicity and impair insulin secretion in nondiabetic subjects predisposed to type 2 diabetes mellitus [T2DM; i.e., with a strong family history of T2DM (FH+)] but not in nondiabetic subjects without a family history of T2DM. To determine whether lowering plasma FFA with acipimox, an antilipolytic nicotinic acid derivative, may enhance insulin secretion, nine FH+ volunteers were admitted twice and received in random order either acipimox or placebo (double-blind) for 48 h. Plasma glucose/insulin/C-peptide concentrations were measured from 0800 to 2400. On day 3, insulin secretion rates (ISRs) were assessed during a +125 mg/dl hyperglycemic clamp. Acipimox reduced 48-h plasma FFA by 36% ( P < 0.001) and increased the plasma C-peptide relative to the plasma glucose concentration or ΔC-peptide/Δglucose AUC (+177%, P = 0.02), an index of improved β-cell function. Acipimox improved insulin sensitivity (M/I) 26.1 ± 5% ( P < 0.04). First- (+19 ± 6%, P = 0.1) and second-phase (+31 ± 6%, P = 0.05) ISRs during the hyperglycemic clamp also improved. This was particularly evident when examined relative to the prevailing insulin resistance [1/(M/I)], as both first- and second-phase ISR markedly increased by 29 ± 7 ( P < 0.05) and 41 ± 8% ( P = 0.02). There was an inverse correlation between fasting FFA and first-phase ISR ( r2 = 0.31, P < 0.02) and acute (2–4 min) glucose-induced insulin release after acipimox ( r2 =0.52, P < 0.04). In this proof-of-concept study in FH+ individuals predisposed to T2DM, a 48-h reduction of plasma FFA improves day-long meal and glucose-stimulated insulin secretion. These results provide additional evidence for the important role that plasma FFA play regarding insulin secretion in FH+ subjects predisposed to T2DM.

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Abstract 1924: Carriers of Loss-of-Function Mutations in ABCA1 Display Pancreatic Beta Cell Dysfunction

Circulation ◽

10.1161/circ.118.suppl_18.s_406 ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Menno Vergeer ◽

Liam R Brunham ◽

Joris Koetsveld ◽

Janine K Kruit ◽

C B Verchere ◽

...

Keyword(s):

Insulin Secretion ◽

Insulin Sensitivity ◽

Plasma Glucose ◽

Sensitivity Index ◽

Loss Of Function ◽

Β Cell ◽

C Peptide ◽

Cell Dysfunction ◽

Time Interaction

Background The ATP Binding Cassette transporter A1 (ABCA1) transports free cholesterol to nascent high-density lipoproteins (HDL) and maintains plasma HDL levels. In mice, ABCA1 is essential in regulating intracellular cholesterol homeostasis and insulin secretion in the β cell. The role of ABCA1 in human glucose metabolism is unclear. Objective and methods To assess the effects of ABCA1 dysfunction on glucose homeostasis in humans , we matched heterozygous carriers of disruptive mutations in ABCA1 and non-carriers for age, gender and BMI and performed oral glucose tolerance tests (OGTT; 9 vs. 8 respectively) and hyperglycemic clamping experiments (6 vs. 6). Results Carriers had lower HDL-C levels than non-carriers (0.58 ± 0.3 vs. 1.46 ± 0.4 mmol/L, p=0.001) but LDL-C did not differ (3.4 ± 1.0 vs. 2.8 ± 0.8 mmol/L, p=0.21). Fasting plasma glucose was not different (5.2 ± 1.5 vs. 5.0 ± 0.4 mmol/L). Glucose curves after OGTT were significantly higher in carriers than in non-carriers (genotype * time interaction, p=0.005; plasma glucose at t=60 min 9.0 ± 3.0 mmol/L vs. 6.0 ± 1.4 mmol/L respectively, p=0.02). During hyperglycemic clamps, carriers showed a lower first phase insulin and C-peptide response than non-carriers (genotype * time interaction, p<0.05 and p<0.01 respectively; insulin at t=5 min 164±118 vs. 352 ±141 pmol/L, p<0.05; C-peptide at t=5 min 1033 ± 628 vs. 1942 ± 723 pmol/L, p<0.05) but no difference in insulin sensitivity index (0.0216 ± 0.012 mg kg −1 . min −1 . pM −1 for carriers and 0.0197 ± 0.005 mg kg −1 . min −1 . pM −1 for non-carriers; p=0.73). Disposition index - a measure of β cell function, adjusted for insulin sensitivity - was lower in carriers than in non-carriers (1037 ± 610 vs. 2718 ± 1524; p<0.05). Non-carriers responded to an arginine stimulus with an increase in C-peptide levels (from 3558 ± 1240 pM to 6817 ± 1665 pM; p<0.005), whereas in carriers this increase did not reach statistical significance (from 3727 ± 1843 pM to 5480 ± 1757 pM; p=0.12). Conclusion Carriers of loss-of-function mutations in ABCA1 show impaired insulin secretion without insulin resistance, resulting in glucose intolerance. Our data confirm previous studies in mice and provide evidence for a role of ABCA1 in β cell dysfunction and the pathophysiology of diabetes mellitus in man.

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Increased insulin clearance in mice with double deletion of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptors

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00181.2017 ◽

2018 ◽

Vol 314 (5) ◽

pp. R639-R646 ◽

Cited By ~ 7

Author(s):

Andrea Tura ◽

Roberto Bizzotto ◽

Yuchiro Yamada ◽

Yutaka Seino ◽

Giovanni Pacini ◽

...

Keyword(s):

Insulin Secretion ◽

Insulin Clearance ◽

Second Phase ◽

Incretin Hormones ◽

Intravenous Glucose ◽

C Peptide ◽

Double Deletion ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

First Phase Insulin Secretion

To establish whether incretin hormones affect insulin clearance, the aim of this study was to assess insulin clearance in mice with genetic deletion of receptors for both glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), so called double incretin receptor knockout mice (DIRKO). DIRKO ( n = 31) and wild-type (WT) C57BL6J mice ( n = 45) were intravenously injected with d-glucose (0.35 g/kg). Blood was sampled for 50 min and assayed for glucose, insulin, and C-peptide. Data were modeled to calculate insulin clearance; C-peptide kinetics was established after human C-peptide injection. Assessment of C-peptide kinetics revealed that C-peptide clearance was 1.66 ± 0.10 10−3 1/min. After intravenous glucose administration, insulin clearance during first phase insulin secretion was markedly higher in DIRKO than in WT mice (0.68 ± 0.06 10−3 l/min in DIRKO mice vs. 0.54 ± 0.03 10−3 1/min in WT mice, P = 0.02). In contrast, there was no difference between the two groups in insulin clearance during second phase insulin secretion ( P = 0.18). In conclusion, this study evaluated C-peptide kinetics in the mouse and exploited a mathematical model to estimate insulin clearance. Results showed that DIRKO mice have higher insulin clearance than WT mice, following intravenous injection of glucose. This suggests that incretin hormones reduce insulin clearance at physiological, nonstimulated levels.

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Influence of Tacrolimus on Glucose Metabolism before and after Renal Transplantation: A Prospective Study

Journal of the American Society of Nephrology ◽

10.1681/asn.v123583 ◽

2001 ◽

Vol 12 (3) ◽

pp. 583-588 ◽

Cited By ~ 1

Author(s):

ELLY M. VAN DUIJNHOVEN ◽

JOHANNES M. M. BOOTS ◽

MAARTEN H. L. CHRISTIAANS ◽

BRUCE H. R. WOLFFENBUTTEL ◽

JOHANNES P. VAN HOOFF

Keyword(s):

Insulin Resistance ◽

Insulin Secretion ◽

Insulin Sensitivity ◽

Glucose Metabolism ◽

Sensitivity Index ◽

Intravenous Glucose ◽

Prospective Longitudinal Study ◽

C Peptide ◽

Before And After ◽

Prospective Longitudinal

Abstract. Most studies concerning the influence of tacrolimus on glucose metabolism have been performed either in animals or after organ transplantation. These clinical studies have largely been transversal with patients who were using steroids. Therefore, this prospective, longitudinal study investigated the influence of tacrolimus on glucose metabolism before and after transplantation. Eighteen Caucasian dialysis patients underwent an intravenous glucose tolerance test before and 5 d after the start of tacrolimus. Insulin sensitivity index (kG), insulin resistance (insulin/glucose ratio and homeostasis model assessment), and C-peptide and insulin secretion were calculated. Trough levels of tacrolimus were measured. After transplantation, the occurrence of posttransplantation diabetes mellitus (PTDM) was prospectively monitored. Statistical analysis was performed using the Wilcoxon signed ranks test and Spearman's rho for correlation. Before tacrolimus, kG was indeterminate in three patients. During tacrolimus, kG decreased in 16 of 18 patients, from a median of 1.74 mmol/L per min to 1.08 mmol/L per min (P < 0.0001). The correlation between C-peptide and insulin data was excellent. Insulin secretion decreased from 851.0 mU × min/L to 558.0 mU × min/L (P = 0.014), whereas insulin resistance did not change. Insulin sensitivity correlated negatively with tacrolimus trough level. After transplantation, three patients developed PTDM; before tacrolimus, two had an indeterminate and one a low normal kG. During tacrolimus administration, kG decreased in almost all patients as a result of a diminished insulin secretion response to a glucose load, whereas insulin resistance did not change. Patients with an abnormal or indeterminate kG seem to be at risk of developing PTDM while on tacrolimus.

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PACAP stimulates insulin secretion but inhibits insulin sensitivity in mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1998.274.5.e834 ◽

1998 ◽

Vol 274 (5) ◽

pp. E834-E842 ◽

Cited By ~ 16

Author(s):

Karin Filipsson ◽

Giovanni Pacini ◽

Anton J. W. Scheurink ◽

Bo Ahrén

Keyword(s):

Insulin Secretion ◽

Insulin Sensitivity ◽

Elimination Rate ◽

Insulin Response ◽

Area Under The Curve ◽

Glucose Disposal ◽

Sensitivity Index ◽

Maximal Effect ◽

Intravenous Glucose

Although pituitary adenylate cyclase-activating polypeptide (PACAP) stimulates insulin secretion, its net influence on glucose homeostasis in vivo has not been established. We therefore examined the action of PACAP-27 and PACAP-38 on insulin secretion, insulin sensitivity, and glucose disposal as derived from the minimal model of glucose disappearance during an intravenous glucose tolerance test in anesthetized mice. PACAP-27 and PACAP-38 markedly and equipotently potentiated glucose-stimulated insulin secretion, with a half-maximal effect at 33 pmol/kg. After PACAP-27 or PACAP-38 (1.3 nmol/kg), the acute (1–5 min) insulin response was 3.8 ± 0.4 nmol/l (PACAP-27) and 3.3 ± 0.3 nmol/l (PACAP-38), respectively, vs. 1.4 ± 0.1 nmol/l after glucose alone ( P < 0.001), and the total area under the curve for insulin (AUCinsulin) was potentiated by 60% ( P < 0.001). In contrast, PACAP-27 and PACAP-38 reduced the insulin sensitivity index (SI) [0.23 ± 0.04 10−4min−1/(pmol/l) for PACAP-27 and 0.29 ± 0.06 10−4min−1/(pmol/l) for PACAP-38 vs. 0.46 ± 0.02 10−4min−1/(pmol/l) for controls ( P < 0.01)]. Furthermore, PACAP-27 or PACAP-38 did not affect glucose elimination determined as glucose half-time or the glucose elimination rate after glucose injection or the area under the curve for glucose. Moreover, glucose effectiveness and the global disposition index (AUCinsulin times SI) were not affected by PACAP-27 or PACAP-38. Finally, when given together with glucose, PACAP-27 did not alter plasma glucagon or norepinephrine levels but significantly increased plasma epinephrine levels. We conclude that PACAP, besides its marked stimulation of insulin secretion, also inhibits insulin sensitivity in mice, the latter possibly explained by increased epinephrine. This complex action explains why the peptide does not enhance glucose disposal.

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Maternal exposure to dexamethasone or cortisol in early pregnancy differentially alters insulin secretion and glucose homeostasis in adult male sheep offspring

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00689.2006 ◽

2007 ◽

Vol 293 (1) ◽

pp. E75-E82 ◽

Cited By ~ 55

Author(s):

M. J. De Blasio ◽

M. Dodic ◽

A. J. Jefferies ◽

K. M. Moritz ◽

E. M. Wintour ◽

...

Keyword(s):

Insulin Secretion ◽

Insulin Sensitivity ◽

Glucose Tolerance ◽

Glucose Homeostasis ◽

Adult Male ◽

Early Pregnancy ◽

Male Offspring ◽

Second Phase ◽

Intravenous Glucose ◽

Pregnant Sheep

An adverse intrauterine environment increases the risk of developing various adult-onset diseases, whose nature varies with the timing of exposure. Maternal undernutrition in humans can increase adiposity, and the risk of coronary heart disease and impaired glucose tolerance in adult life, which may be partly mediated by maternal or fetal endocrine stress responses. In sheep, dexamethasone in early pregnancy impairs cardiovascular function, but not glucose homeostasis in adult female offspring. However, male offspring are often more susceptible to early life “programming”. Pregnant sheep were infused intravenously with saline (0.19 ml/h), dexamethasone (0.48 mg/h), or cortisol (5 mg/h), for 2 days from 26 to 28 days of gestation. In male offspring, size at birth and postnatal growth were measured, and glucose tolerance [intravenous glucose tolerance test (IVGTT)], insulin secretion, and insulin sensitivity of glucose, α-amino nitrogen, and free fatty acid metabolism were assessed at 4 yr of age. We show that cortisol, but not dexamethasone, treatment of mothers causes fasting hyperglycemia in adult male offspring. Maternal cortisol induced a second-phase hyperinsulinemia during IVGTT, whereas maternal dexamethasone induced a first-phase hyperinsulinemia. Dexamethasone improved glucose tolerance, while cortisol had no impact, and neither affected insulin sensitivity. This suggests that maternal glucocorticoid exposure in early pregnancy alters glucose homeostasis and induces hyperinsulinemia in adult male offspring, but in a glucocorticoid-specific manner. These consequences of glucocorticoid exposure in early pregnancy may lead to pancreatic exhaustion and diabetes longer term and are consistent with stress during early pregnancy contributing to such outcomes in humans.

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Switching to unboosted atazanavir improves glucose tolerance in highly pretreated HIV-1 infected subjects

Acta Endocrinologica ◽

10.1530/eje-06-0648 ◽

2007 ◽

Vol 156 (4) ◽

pp. 503-509 ◽

Cited By ~ 27

Author(s):

Monica Guffanti ◽

Andrea Caumo ◽

Laura Galli ◽

Alba Bigoloni ◽

Andrea Galli ◽

...

Keyword(s):

Insulin Sensitivity ◽

Glucose Tolerance ◽

Fasting Glucose ◽

Density Lipoprotein ◽

Lipoprotein Cholesterol ◽

Second Phase ◽

Β Cell ◽

C Peptide ◽

Metabolic Alterations ◽

Hiv 1

Objective: To evaluate the 24-week effects on glucose tolerance of switching from a protease inhibitor (PI)-based to an unboosted atazanavir-including regimen in highly pretreated HIV-1 infected subjects with metabolic alterations. Design: Prospective, open-label, single-center, 24-week pilot study. Methods: Twenty-one subjects underwent an oral glucose tolerance test (OGTT) at baseline (BL) and after 24 weeks of unboosted atazanavir. Insulin sensitivity and β-cell responsiveness were evaluated on the basis of static and dynamic data; fasting glucose, insulin, C-peptide, triglycerides (TG), total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-c), low-density lipoprotein-cholesterol (LDL-c), TC/HDL-c ratio, CD4+ cell count and HIV-1 RNA were measured. Results: After 24 weeks of unboosted atazanavir, the 120-min glucose level was significantly lower than the one measured at BL (P=0.021); there were no statistically significant differences in the insulin concentration profile. The SIoral, an OGTT-based index of insulin sensitivity, was significantly higher at week 24 (P=0.017); the indices of first- and second-phase β-cell responsiveness did not significantly change. There was no significant difference between BL and 24-week fasting glucose, insulin or C-peptide levels, and consequently no change in fasting homeostasis model assessment indices of insulin sensitivity and β-cell function. There were significant improvements in TG (P=0.009), TC (P=0.0001), LDL-c (P=0.019) and TC/HDL-c ratio (P=0.001), and a similar trend in HDL-c levels (P=0.069). No significant changes in the immunological and virological parameters were detected. Conclusions: Our results show that switching from a PI-based to an unboosted atazanavir-including regimen leads to a significant improvement in glucose tolerance in highly pretreated HIV-1 infected subjects with metabolic alterations.

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A reduced incretin effect mediated by the rs7903146 variant in the TCF7L2 Gene is an early marker of beta-cell dysfunction in obese youth

10.2337/figshare.12665477 ◽

2020 ◽

Author(s):

Alfonso Galderisi ◽

Domenico Trico ◽

Bridget Pierpont ◽

Veronika Shabanova ◽

Stephanie Samuels ◽

...

Keyword(s):

Insulin Secretion ◽

Insulin Sensitivity ◽

Beta Cell ◽

Plasma Glucose ◽

Metabolic Phenotype ◽

Glucose Disposal ◽

Incretin Effect ◽

Tcf7l2 Gene ◽

Intravenous Glucose ◽

Hyperglycemic Clamp

Background. The risk genotype for the common variant rs7903146 of the transcription factor-7-like-2 gene (TCF7L2) has been found to affect the incretin response in healthy and obese adults, however, whether a similar functional defect is also present in obese adolescents remains unexplored. Herein, we examined the functional effect of the rs7903146 variant in the TCF7L2 gene on the incretin effect and determined its translational metabolic manifestation by performing deep phenotyping of the incretin system, beta-cell function relative to insulin sensitivity, the Gastrointestinal Induced Glucose Disposal (GIGD) in obese youths with normal and impaired glucose tolerance. Methods Thirty nine non-diabetic obese adolescents (15[14,18] years; BMI 37[33, 43]kg/m2) were genotyped for the rs7903146 of TCF7L2 and underwent a 3-hour OGTT followed by an iso-glycemic intravenous glucose infusion (iso-IVGTT) to match the plasma glucose concentrations during the OGTT and a hyperglycemic clamp with arginine stimulation. The incretin effect was measured as 100*(AUC-SROGTT – AUC-SRiso-IVGTT)/AUC-SROGTT [AUC-SR=AUC of C-peptide secretion rate]. Participants were grouped into tertiles according to the percentage incretin effect (High-, Moderate- and Low-incretin effect) to describe their metabolic phenotype. Results The presence of T risk allele for TCF7L2 was associated with a markedly reduced incretin effect compared to the wild type genotype(0.3[-7.2,14] vs 37.8[12.5-52.4], p<0.002) When the cohort was stratified by incretin effect, the High-, Moderate- and Low-incretin groups did not differ with respect to anthropometric features, while the Low-incretin group exhibited higher 1-h glucose (p=0.015), a reduced disposition index, insulin sensitivity and insulin clearance, compared with the High-incretin group. Gastrointestinal induced glucose disposal (GIGD) was reduced in the Low-incretin group (p=0.001). The three groups did not differ with respect to intravenous glucose-induced insulin secretion and arginine response during the hyperglycemic clamp. Conclusion A reduced incretin effect and its association with the TCF7L2 variant rs7903146 identify an early metabolic phenotype in obese non-diabetic youths, featured by a higher plasma glucose peak at 1hr, lower insulin secretion, sensitivity and clearance, and gastrointestinal glucose disposal.

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Acute enhancement of insulin secretion by FFA in humans is lost with prolonged FFA elevation

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1999.276.6.e1055 ◽

1999 ◽

Vol 276 (6) ◽

pp. E1055-E1066 ◽

Cited By ~ 43

Author(s):

André Carpentier ◽

Steven D. Mittelman ◽

Benoǐt Lamarche ◽

Richard N. Bergman ◽

Adria Giacca ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Secretion ◽

Insulin Sensitivity ◽

Cell Function ◽

Peak Plasma ◽

Sensitivity Index ◽

Β Cell ◽

Intravenous Glucose ◽

Hyperglycemic Clamp

The in vivo effect of elevated free fatty acids (FFA) on β-cell function in humans remains extremely controversial. We examined, in healthy young men, the acute (90 min) and chronic (48 h) effects of an approximately twofold elevation of plasma FFA vs. control on glucose-stimulated insulin secretion (GSIS). GSIS was studied in response to a graded intravenous glucose infusion (peak plasma glucose, ∼10 mmol/l, n = 8) and a two-step hyperglycemic clamp (10 and 20 mmol/l, n = 8). In the acute studies, GSIS was significantly higher, insulin sensitivity index (SI) was lower, and disposition index (DI = insulin sensitivity × insulin secretion) was unchanged with elevated FFA vs. control [2-step clamp: DI = 8.9 ± 1.4 × 10−3l2 ⋅ kg−1 ⋅ min−2in control vs. 10.0 ± 1.9 × 10−3l2 ⋅ kg−1 ⋅ min−2with high FFA, P = nonsignificant (NS)]. In the chronic studies, there was no difference in absolute GSIS between control and high FFA studies, but there was a reduction in SI and a loss of the expected compensatory increase in insulin secretion as assessed by the DI (2-step clamp: DI = 10.0 ± 1.2 × 10−3l2 ⋅ kg−1 ⋅ min−2in control vs. 6.1 ± 0.7 × 10−3l2 ⋅ kg−1 ⋅ min−2with high FFA, P = 0.01). In summary, 1) acute and chronic FFA elevation induces insulin resistance; 2) with acute FFA elevation, this insulin resistance is precisely countered by an FFA-induced increase in insulin secretion, such that DI does not change; and 3) chronic FFA elevation disables this β-cell compensation.

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A minimal model of insulin secretion and kinetics to assess hepatic insulin extraction

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00473.2004 ◽

2006 ◽

Vol 290 (1) ◽

pp. E169-E176 ◽

Cited By ~ 79

Author(s):

Gianna Toffolo ◽

Marco Campioni ◽

Rita Basu ◽

Robert A. Rizza ◽

Claudio Cobelli

Keyword(s):

Insulin Secretion ◽

Minimal Model ◽

Insulin Delivery ◽

Intravenous Glucose Tolerance Test ◽

Insulin Degradation ◽

Second Phase ◽

Hepatic Extraction ◽

Minimal Models ◽

Intravenous Glucose ◽

C Peptide

The liver is the principal site of insulin degradation, and assessing its ability to extract insulin is important to understand several pathological states. Noninvasive quantification of hepatic extraction (HE) in an individual requires comparing the profiles of insulin secretion (ISR) and posthepatic insulin delivery rate (IDR). To do this, we propose here the combined use of the classical C-peptide minimal model with a new minimal model of insulin delivery and kinetics. The models were identified on insulin-modified intravenous glucose tolerance test (IM-IVGTT) data of 20 healthy subjects. C-peptide kinetics were fixed to standard population values, whereas insulin kinetics were assessed in each individual, along with IDR parameters, thanks to the presence of insulin decay data observed after exogenous insulin administration. From the two models, profiles of ISR and IDR were predicted, and ISR and IDR indexes of β-cell responsivity to glucose in the basal state, as well as during first- and second-phase secretion, were estimated. HE profile, obtained by comparing ISR and IDR profiles, showed a rapid suppression immediately after the glucose administration. HE indexes, obtained by comparing ISR and IDR indexes, indicated that the liver is able to extract 70 ± 9% of insulin passing through it in the basal state and 54 ± 14% during IM-IVGTT. In conclusion, insulin secretion, kinetics, and hepatic extraction can be reliably assessed during an IM-IVGTT by using insulin and C-peptide minimal models.

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