Pulsatile Insulin Secretion Dictates Systemic Insulin Delivery by Regulating Hepatic Insulin Extraction In Humans

Published on Jun 1, 2005in Diabetes7.199
· DOI :10.2337/diabetes.54.6.1649
Juris J. Meier60
Estimated H-index: 60
(UCLA: University of California, Los Angeles),
Johannes D. Veldhuis90
Estimated H-index: 90
Peter C. Butler65
Estimated H-index: 65
(UCLA: University of California, Los Angeles)
In health, insulin is secreted in discrete pulses into the portal vein, and the regulation of the rate of insulin secretion is accomplished by modulation of insulin pulse mass. Several lines of evidence suggest that the pattern of insulin delivery by the pancreas determines hepatic insulin clearance. In previous large animal studies, the amplitude of insulin pulses was related to the extent of insulin clearance. In humans (and in large animals), the amplitude of insulin oscillations is ∼100-fold higher in the portal vein than in the systemic circulation, despite only a fivefold dilution, implying preferential hepatic extraction of insulin pulses. In the present study, by direct hepatic vein sampling in healthy humans, we sought to establish the extent of first-pass hepatic insulin extraction and to determine whether the pattern of insulin secretion (insulin pulse mass and amplitude) dictates the hepatic insulin clearance and thereby delivery of insulin to extrahepatic insulin-responsive tissues. Five nondiabetic subjects (two men and three women, mean age 32 years [range 25–39], BMI 24.9 kg/m2 [21.2–27.1]) participated. Insulin and C-peptide delivery from the splanchnic bed was measured in basal overnight-fasted state and during a glucose infusion of 2 mg · kg−1 · min−1 by simultaneous sampling from the hepatic vein and an arterialized vein along with direct estimation of splanchnic blood flow. Fractional insulin extraction was calculated from the difference between the C-peptide and insulin delivery rates from the liver. The time patterns of insulin concentrations and hepatic insulin clearance were analyzed by deconvolution and Cluster analysis, respectively. Cross-correlation analysis was used to relate C-peptide secretion and insulin clearance. Glucose infusion increased peripheral glucose concentrations from 5.4 ± 0.1 to 6.4 ± 0.4 mmol/l ( P < 0.05). Likewise, insulin and C-peptide concentrations increased during glucose infusion ( P < 0.05). Hepatic insulin clearance increased with glucose infusion (1.06 ± 0.18 vs. 2.55 ± 0.38 pmol · kg−1 · min−1; P < 0.01), but fractional hepatic insulin clearance was stable (78.2 ± 4.4 vs. 84 0. ± 3.9%, respectively; P = 0.18). Insulin secretory–burst mass rose during glucose infusion ( P < 0.05), whereas the interburst interval remained unchanged (4.4 ± 0.2 vs. 4.5 ± 0.3 min; P = 0.36). Cluster analysis identified an oscillatory pattern in insulin clearance, with peaks occurring approximately every 5 min. Cross-correlation analysis between prehepatic C-peptide secretion and hepatic insulin clearance demonstrated a significant positive association without detectable (<1 min) time lag. Insulin secretory–burst mass strongly predicted insulin clearance ( r = 0.81, P = 0.0043). In conclusion, in humans, ∼80% of insulin is extracted during the first liver passage. The liver rapidly responds to fluctuations in insulin secretion, preferentially extracting insulin delivered in pulses. The mass (and therefore amplitude) of insulin pulses traversing the liver is the predominant determinant of hepatic insulin clearance. Therefore, through this means, the pulse mass of insulin release dictates both hepatic (directly) as well as extra-hepatic (indirectly) insulin delivery. These findings emphasize the dual role of the liver and pancreas and their relationship mediated through magnitude of insulin pulse mass in regulating the quantity and pattern of systemic insulin delivery.
  • References (44)
  • Citations (161)
📖 Papers frequently viewed together
632 Citations
128 Citations
309 Citations
78% of Scinapse members use related papers. After signing in, all features are FREE.
#1Claus B. JuhlH-Index: 25
#2Sturis JH-Index: 1
Last. O. SchmitzH-Index: 52
view all 4 authors...
The objective of this study was to test the hypothesis that high-frequency oscillations in insulin release is a part of the mechanistic basis of a prompt and adequate insulin response to iv-glucose and GLP-1 exposure. In ten healthy subjects, five different insulin release patterns were induced for 360 min using computer-based glucose infusion (glucose delivered in a constant, a regular pulsatile, an irregular pulse frequency, an irregular pulse amplitude or a regular but very fast-pulsatile man...
3 CitationsSource
#1Pankaj Shah (Mayo Clinic)H-Index: 23
#2Adrian VellaH-Index: 43
Last. Robert A. RizzaH-Index: 78
view all 10 authors...
The present study sought to determine whether elevated plasma free fatty acids (FFAs) alter the ability of insulin and glucose to regulate splanchnic as well as muscle glucose metabolism. To do so, FFAs were increased in 10 subjects to ∼1 mmol/l by an 8-h Intralipid/heparin (IL/Hep) infusion, whereas they fell to levels near the detection limit of the assay (<0.05 mmol/l) in 13 other subjects who were infused with glycerol alone at rates sufficient to either match ( n = 5, low glycerol) or doubl...
64 CitationsSource
#1Lise L. Kjems (Edin.: University of Edinburgh)H-Index: 1
#2B. M. Kirby (Edin.: University of Edinburgh)H-Index: 11
Last. Peter C. Butler (SC: University of Southern California)H-Index: 65
view all 9 authors...
Most insulin is secreted in discrete pulses at an interval of ∼6 min. Increased insulin secretion after meal ingestion is achieved through the mechanism of amplification of the burst mass. Conversely, in type 2 diabetes, insulin secretion is impaired as a consequence of decreased insulin pulse mass. β-cell mass is reported to be deficient in type 2 diabetes. We tested the hypothesis that decreased β-cell mass leads to decreased insulin pulse mass. Insulin secretion was examined before and after ...
105 CitationsSource
#1Stephen J. VoreH-Index: 6
#2E. Dale AycockH-Index: 2
Last. Peter C. Butler (SC: University of Southern California)H-Index: 65
view all 4 authors...
Induction of anesthesia is accompanied by modest hyperglycemia and a decreased plasma insulin concentration. Most insulin is secreted in discrete pulses occurring at ∼6- to 8-min intervals. We sought to test the hypothesis that anesthesia inhibits insulin release by disrupting pulsatile insulin secretion in a canine model by use of direct portal vein sampling. We report that induction of anesthesia causes an abrupt decrease in the insulin secretion rate (1.1 ± 0.2 vs. 0.7 ± 0.1 pmol · kg−1 · min...
12 CitationsSource
#1Soon H. Song (SC: University of Southern California)H-Index: 3
#2Susan McIntyre (Edin.: University of Edinburgh)H-Index: 4
Last. Peter C. Butler (SC: University of Southern California)H-Index: 65
view all 6 authors...
Insulin is secreted in a high frequency pulsatile manner. These pulses are delivered directly into the portal vein and then undergo extraction and dilution before delivery into the systemic circulation. The reported frequency of these insulin pulses estimated in peripheral blood varies from an interpulse interval of 4-20 min. We postulated that this discrepancy is due to the attenuation of the pulse signal in the systemic circulation vs. the portal circulation. In the present study we measured p...
128 CitationsSource
#1Thomas Laedtke (SC: University of Southern California)H-Index: 1
#2Lise Kjems (Mayo Clinic)H-Index: 1
Last. Peter C. Butler (SC: University of Southern California)H-Index: 65
view all 7 authors...
Impaired insulin secretion in type 2 diabetes is characterized by decreased first-phase insulin secretion, an increased proinsulin-to-insulin molar ratio in plasma, abnormal pulsatile insulin release, and heightened disorderliness of insulin concentration profiles. In the present study, we tested the hypothesis that these abnormalities are at least partly reversed by a period of overnight suspension of β-cell secretory activity achieved by somatostatin infusion. Eleven patients with type 2 diabe...
100 CitationsSource
#1Niels Pørksen (Aarhus University Hospital)H-Index: 22
#2Claus B. Juhl (Aarhus University Hospital)H-Index: 25
Last. O. Schmitz (Aarhus University Hospital)H-Index: 52
view all 7 authors...
Insulin is largely secreted as serial secretory bursts superimposed on basal release, insulin secretion is regulated through changes of pulse mass and frequency, and the insulin release pattern aff...
31 CitationsSource
#1William C. Duckworth (UNMC: University of Nebraska Medical Center)H-Index: 41
#2Robert G. Bennett (UNMC: University of Nebraska Medical Center)H-Index: 24
Last. Frederick G. Hamel (UNMC: University of Nebraska Medical Center)H-Index: 27
view all 3 authors...
I. Introduction II. Insulin Clearance A. Liver B. Kidney C. Other tissues D. Extracellular insulin degradation III. Cellular Insulin Uptake IV. Cellular Insulin Degradation A. Degradation products B. Assay for insulin degradation C. Insulin-degrading enzymes V. Biological Role of Insulin Degradation VI. Insulin-IDE-Proteasome Interactions and Control of Protein Degradation VII. Summary and Conclusions
571 CitationsSource
#1Niels Pørksen (Aarhus University Hospital)H-Index: 22
#2Thorbjørn Grøfte (Edin.: University of Edinburgh)H-Index: 1
Last. Peter C Butler (UVA: University of Virginia)H-Index: 3
view all 8 authors...
Glucagon-like peptide 1 (GLP-1) is a peptide hormone that is released from the gut after luminal stimulation. The hormone is a potent insulin secretagogue and is a potential novel pharmaceutical adjuvant in the treatment of NIDDM. Insulin is secreted as a series of punctuated secretory bursts superimposed on a basal insulin release. Recently, the contribution of these secretory bursts to overall insulin secretion has been evaluated, and studies using catheterization across the pancreas in a cani...
37 CitationsSource
#1Niels Pørksen (Aarhus University Hospital)H-Index: 22
#2Birgit Nyholm (Aarhus University Hospital)H-Index: 22
Last. O. Schmitz (Aarhus University Hospital)H-Index: 52
view all 5 authors...
Detection of insulin secretory bursts in peripheral blood is hampered by hepatic insulin extraction, dilution in the systemic insulin pool, and time-delayed damping of secretory burst amplitude. Pr...
82 CitationsSource
Cited By161
#1Jose G Miranda (Anschutz Medical Campus)
#2Wolfgang E. Schleicher (Anschutz Medical Campus)H-Index: 2
Last. Richard K.P. Benninger (Anschutz Medical Campus)H-Index: 24
view all 5 authors...
Diabetes results from insufficient insulin secretion as a result of dysfunction to β-cells within the islet of Langerhans. Elevated glucose causes β-cell membrane depolarization and action potential generation, voltage gated Ca2+ channel activation and oscillations in free-Ca2+ activity ([Ca2+]), triggering insulin release. Nuclear Factor of Activated T-cell (NFAT) is a transcription factor that is regulated by increases in [Ca2+] and calceineurin (CaN) activation. NFAT regulation links cell act...
#1Nicholas B. Whitticar (OU: Ohio University)H-Index: 2
#2Craig S. Nunemaker (Heritage College of Osteopathic Medicine)H-Index: 29
Pancreatic beta-cells are the only cells in the body that can synthesize and secrete insulin. Through the process of glucose-stimulated insulin secretion, beta-cells release insulin into circulation, stimulating GLUT4-dependent glucose uptake into peripheral tissue. Insulin is normally secreted in pulses which allows for robust signaling at the liver. Long before type 2 diabetes is diagnosed, beta-cells become oversensitive to glucose, causing impaired pulsatility and overstimulation in fasting ...
#1Lijuan Hu (NKU: Nankai University)H-Index: 2
#2Xijuan Chen (Tianjin Medical University)
Last. Feng Wang (NKU: Nankai University)H-Index: 3
view all 8 authors...
Harboring insulin-producing cells, the pancreas has more interstitial insulin than any other organ. In vitro, insulin activates both insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF1R) to stimulate pancreatic cancer cells. Whether intra-pancreatic insulin nourishes pancreatic cancer cells in vivo remains uncertain. In the present studies, we transplanted human pancreatic cancer cells orthotopically in euglycemic athymic mice whose intra-pancreatic insulin was intact or was de...
#1Julia H. Goedecke (South African Medical Research Council)H-Index: 5
#1Julia H. Goedecke (South African Medical Research Council)H-Index: 30
Last. Tommy Olsson (Umeå University)H-Index: 58
view all 2 authors...
The prevalence of type 2 diabetes (T2D) is higher in black Africans than their European counterparts. This review summarises the research exploring the pathogenesis of T2D in populations of African ancestry compared to white Europeans and shows that the pathogenesis differs by ethnicity. Black Africans present with a phenotype of low insulin sensitivity and hyperinsulinaemia as a result of increased insulin secretion and reduced hepatic insulin clearance. Whether hyperinsulinaemia precedes insul...
#1Marcello C. Laurenti (Mayo Clinic)H-Index: 3
#1Marcello C. Laurenti (Mayo Clinic)H-Index: 1
Last. Adrian Vella (Mayo Clinic)H-Index: 43
view all 9 authors...
BACKGROUND: Metabolic disorders such as type 2 diabetes have been associated with a decrease in insulin pulse frequency and amplitude. We hypothesized that the T-allele at rs7903146 in TCF7L2, previously associated with beta-cell dysfunction, would be associated with changes in these insulin pulse characteristics. METHODS: 29 nondiabetic subjects (age = 46 +/- 2, BMI = 28 +/- 1 Kg/M2) participated in this study. Of these, 16 were homozygous for the C allele at rs7903146 and 13 were homozygous fo...
#1Henning Hvid (Novo Nordisk)H-Index: 10
#2Jonas Kildegaard (Novo Nordisk)H-Index: 6
Last. Erica Nishimura (Novo Nordisk)H-Index: 16
view all 9 authors...
Background:Oral delivery of insulin was recently demonstrated to have therapeutic relevance in patients with diabetes. Insulin receptors are expressed in the gastrointestinal tract and can be activ...
#1Manish Raisingani (University of Arkansas for Medical Sciences)H-Index: 1
#1Manish RaisinganiH-Index: 2
Last. Preneet Cheema Brar (NYU: New York University)H-Index: 5
view all 2 authors...
: Background Prolonged neonatal hyperinsulinism (PHI) causes hypoglycemia in the neonatal period and is associated with perinatal stress. Even though diazoxide is an effective treatment option for PHI, it has serious adverse effects making an argument for safe yet expeditious wean off of diazoxide while ensuring normoglycemia. The objective of this study was to characterize clinical course, dose requirement and duration of treatment with diazoxide in our cohort of infants diagnosed with PHI. Met...
#1Bhoomika M. Patel (NU: Nirma University of Science and Technology)H-Index: 12
#2Ramesh K. GoyalH-Index: 27
Abstract Hepatic and systemic insulin resistance form the core of metabolic syndrome which is also associated with cardiovascular abnormalities, inflammation, and dyslipidemia. Skeletal muscles and adipose tissues are two main target organs for glucose disposal and hence have been studied for insulin resistance too. The liver is the first organ where insulin reaches after being secreted from pancreas and liver regulates glucose storage and disposal as per the body's demand in response to insulin...
2 CitationsSource
#1Leanne Hodson (NIHR: National Institute for Health Research)H-Index: 35
#1Leanne Hodson (NIHR: National Institute for Health Research)H-Index: 1
Last. Fredrik Karpe (NIHR: National Institute for Health Research)H-Index: 12
view all 2 authors...
In health, the liver is metabolically flexible over the course of the day, as it undertakes a multitude of physiological processes including the regulation of intrahepatic and systemic glucose and lipid levels. The liver is the first organ to receive insulin and through a cascade of complex metabolic processes, insulin not only plays a key role in the intrahepatic regulation of glucose and lipid metabolism, but also in the regulation of systemic glucose and lipid concentrations. Thus, when intra...
2 CitationsSource
#1Richard N. Bergman (Cedars-Sinai Medical Center)H-Index: 123
#2Francesca Piccinini (Cedars-Sinai Medical Center)H-Index: 3
Last. Marilyn Ader (Cedars-Sinai Medical Center)H-Index: 30
view all 5 authors...
There is wide variance among individuals in the fraction of insulin cleared by the liver (20% to 80%). Hepatic insulin clearance is 67% lower in African Americans than European Americans. Clearance is also lower in African American children 7–13 years of age. Lower hepatic insulin clearance will result in peripheral hyperinsulinemia: this exacerbates insulin resistance, which stresses the β-cells, possibly resulting in their ultimate failure and onset of type 2 diabetes. We hypothesize that lowe...
6 CitationsSource