Prehepatic Insulin Production in Man: Kinetic Analysis Using Peripheral Connecting Peptide Behavior*

Eaton, R. Philip; Allen, Richard C.; Schade, David S.; Erickson, Kathryn; Standefer, J C

doi:10.1210/jcem-51-3-520

Cited by 364 publications

(256 citation statements)

References 34 publications

Supporting

Mentioning

249

Contrasting

Unclassified

Order By: Relevance

“…Similarly free T 4 (22.0±7.8 vs 20.6±8.1 pmol/l, portal vs peripheral, p=0.3), which was measured as a negative control, showed no significant difference between portal and peripheral levels. Portal insulin levels were significantly elevated when compared to peripheral levels as previously demonstrated [11], serving as a positive control (466.6±302.9 vs 78.5±50.9 pmol/l, portal vs peripheral, p=0.03). This was despite a smaller gradient for the one Type 1 diabetic subject receiving exogenous insulin.…”

Section: Resultssupporting

confidence: 76%

Portal and peripheral cortisol levels in obese humans

2004

View full text Add to dashboard Cite

Aims/hypothesis. Excess total body and visceral fat has been associated with insulin resistance, diabetes and the metabolic syndrome. Excess glucocorticoids produce both central obesity and diabetes. However, systemic glucocorticoid levels are normal in typical Type 2 diabetes and persons with idiopathic obesity. Glucocorticoids can be produced locally through the enzyme 11β hydroxysteroid dehydrogenase type 1 (11β HSD-1). Transgenic mice with selective overexpression in adipose tissue of 11β HSD-1 to levels seen in humans develop visceral obesity, hyperlipidaemia and insulin-resistant diabetes associated with a 2.7-fold increase in corticosterone levels in portal compared to peripheral circulation. To examine whether the liver is exposed to higher levels of glucocorticoids, which may undergo metabolic degradation prior to measurement in the systemic circulation, we assessed concentrations of cortisol in the portal and peripheral circulation in morbidly obese humans.Methods. Portal and peripheral blood samples were obtained simultaneously from six morbidly obese humans with and without diabetes during bariatric abdominal surgery. The samples were assessed for serum cortisol to determine whether an increase in the portal to peripheral circulation is found in obese humans. Insulin, which undergoes metabolic clearance in the liver, and thyroxin (free T 4 ), which does not, were also assessed. Results. Levels of serum cortisol (698.8±200.4 vs 696.3±232.4 nmol/l, portal vs peripheral, p=0.9) and free T 4 (22.0±7.8 vs 20.6±8.1 pmol/l, portal vs peripheral, p=0.3) were not significantly different in portal compared to peripheral circulation. Portal insulins were significantly higher than peripheral levels (466.7±302.9 vs 78.5±50.9 pmol/l, portal vs peripheral, p=0.03). Conclusions/interpretation. These observations suggest that in morbidly obese humans the liver is not exposed to excess glucocorticoids.

show abstract

Section: Resultssupporting

confidence: 76%

Portal and peripheral cortisol levels in obese humans

2004

View full text Add to dashboard Cite

show abstract

“…The reference method for clinical measurement of pre-hepatic pancreatic insulin secretion is deconvolution of plasma C-peptide concentrations using rate constants and volumes of distribution derived by two-compartment modelling of the decay of plasma C-peptide concentrations after a bolus injection of synthetic C-peptide [42,43]. In a recent methodological comparison, both the combined model and population parameter deconvolution approaches to estimating pancreatic secretion rates provided secretion measures which were consistent with those from the reference method [44].…”

Section: Discussionmentioning

confidence: 93%

Loss of beta cell function as fasting glucose increases in the non-diabetic range

2004

View full text Add to dashboard Cite

Aims/hypothesis. Our aim was to define the level of glycaemia at which pancreatic insulin secretion, particularly first-phase insulin release, begins to decline. Methods. Plasma glucose and insulin concentrations were measured during an IVGTT in 553 men with non-diabetic fasting plasma glucose concentrations. In 466 of the men C-peptide was also estimated. IVGTT insulin secretion in first and late phases was assessed by: (i) the circulating insulin response; (ii) population parameter deconvolution analysis of plasma C-peptide concentrations; and (iii) a combined model utilising both insulin and C-peptide concentrations. Measurements of insulin sensitivity and elimination were also derived by modelling analysis.Results. As fasting plasma glucose (FPG) increased, IVGTT first-phase insulin secretion declined by 73%, 71% and 68% for the three methods respectively. The FPG values at which this decline began, determined by change point regression, were 4.97, 5.16 and 5.42 mmol/l respectively. The sensitivity of late-phase insulin secretion to glucose declined at FPG concentrations above 6.0 mmol/l. Insulin elimination, but not insulin sensitivity, varied with FPG. IntroductionThe respective roles of insulin deficiency and insulin resistance in the development of Type 2 diabetes mellitus remain controversial [1,2]. In response to a glucose stimulus, two phases of insulin secretion may be distinguished [3]. The first occurs as an immediate response to a rise in blood glucose concentrations. Low first-phase insulin release is an early abnormality in deteriorating glucose homeostasis and predicts the subsequent development of Type 2 diabetes [4,5,6,7]. Late-phase insulin release is more prolonged, but of lesser amplitude. It includes the progressively increasing second phase of insulin secretion seen in response to sustained hyperglycaemia [3], and also the compensatory insulin secretion that is the feedback response to a continued increase in circulating glucose. This late-phase insulin secretion may seem to be preserved even when glucose metabolism is defective,In the course of this work, our colleague and co-author James Jeffs died unexpectedly after a short illness. His contribution will be greatly missed.

show abstract

“…Beta-cell insulin secretion rate (ISR) was calculated by deconvolution of plasma C-peptide concentrations using a two-compartment mathematical model [25]. Standard parameters for C-peptide clearance were used [26] assuming the experimental protocol had no effect on C-peptide kinetics.…”

Section: Methodsmentioning

confidence: 99%

Interaction between specific fatty acids, GLP-1 and insulin secretion in humans

et al. 2002

View full text Add to dashboard Cite

Aims/hypothesis. Fatty acids affect insulin secretion in vivo, but little is known about the effects of specific fatty acids. Our aim was to investigate differential effects of acutely increased plasma monounsaturated, polyunsaturated and saturated fatty acids on glucosestimulated insulin secretion in healthy humans. Methods. A new experimental protocol was used to increase plasma monounsaturated (MUFA test), polyunsaturated (PUFA test) or saturated (SFA test) nonesterified fatty acids for 2 h by repeated oral fat feeding and continuous intravenous heparin infusion. This was followed by a hyperglycaemic clamp (10 mmol/l) to test insulin secretion in response to a prior plasma NEFA increase. Results. Total plasma NEFA concentrations were increased during the fat tests compared to the control visit (1.7-fold increase for MUFA and SFA tests and 1.4-fold increase for PUFA test; p<0.001). Exaggerated responses in plasma insulin, C-peptide and proinsulin concentrations were seen during the hyperglycaemic clamp after increasing plasma NEFA concentrations compared with the control (p<0.01). The effects were greatest for the MUFA test followed by the PUFA test and SFA test (p<0.01). Plasma GLP-1 concentrations increased during fat feeding, with a higher response during the MUFA test compared to PUFA and SFA tests (p<0.01). Conclusion/interpretation. Increasing plasma NEFA concentrations by oral fat feeding with heparin infusion augments glucose-stimulated insulin secretion with the greatest effect for monounsaturated fatty acids and the lowest effect for saturated fatty acids. Monounsaturated fatty acids also increase GLP-1 more than saturated fatty acids. Therefore, the exaggerated insulin concentrations could be due to both NEFA and GLP-1. [Diabetologia (2002[Diabetologia ( ) 45:1533[Diabetologia ( -1541 Keywords Monounsaturated fatty acids, polyunsaturated fatty acids, saturated fatty acids, insulin secretion, GLP-1. High fat diets lead to obesity, which in turn is one of the main causes of the development of Type II (noninsulin-dependent) diabetes mellitus. Both obesity and Type II diabetes are characterized by increased plasma non-esterified fatty acid concentrations [1] and raised fasting plasma NEFA concentrations are a risk marker for the development of Type II diabetes in Caucasian subjects [2] and in Pima Indians [3]. Increased plasma NEFA concentrations can have adverse effects on various tissues. Excess plasma NEFA concentrations can lead to a reduced skeletal muscle glucose uptake and oxidation [4,5,6], increased hepatic glucose output [7] and a decrease in hepatic insulin clearance [8,9]. These mechanisms could lead to glucose intolerance and insulin resistance leading to Type II diabetes.Inappropriately high concentrations of plasma NEFA have also been shown to alter glucose-stimulat-

show abstract

Prehepatic Insulin Production in Man: Kinetic Analysis Using Peripheral Connecting Peptide Behavior*

Cited by 364 publications

References 34 publications

Portal and peripheral cortisol levels in obese humans

Portal and peripheral cortisol levels in obese humans

Loss of beta cell function as fasting glucose increases in the non-diabetic range

Interaction between specific fatty acids, GLP-1 and insulin secretion in humans

Contact Info

Product

Resources

About