Feedback inhibition by biosynthetic human insulin of insulin release in healthy human subjects

To determine the impact of biosynthetic human insulin (BHI) on endogenous insulin release, splanchnic output and arterial concentrations of C-peptide were measured in eight healthy men after intravenous administration of 0, 0.5, 1.25, U BHI . m-2 . h-1 for 70 min each. Euglycemia was maintained by a variable glucose infusion. Arterial levels of serum insulin were 48 +/- 6 pmol/liter before and 135 +/- 12, 265 +/- 18, and 593 +/- 47 pmol/liter after BHI infusion. Splanchnic C-peptide output was reduced by BHI infusion from 88 +/- 10 pmol/min before to 50 +/- 9, 28 +/- 10, and 18 +/- 16 pmol/min (P less than 0.0025). Simultaneously, arterial concentrations of C-peptide fell from 539 +/- 54 pmol/liter by 29 and 43% when 1.25 and 2.5 U . m-2 . h-1 of BHI were administered. Hepatic insulin uptake was directly related with BHI infusion rate (r = 0.88) and rose during BHI administration from a basal value of 58 +/- 7 to an uptake of 265 +/- 31 pmol/min when 2.5 U . m-2 . h-1 were infused (P less than 0.0005). Basal hepatic insulin clearance was 4.75 +/- 0.60 ml . kg-1 . min-1 and remained unchanged after BHI infusion as did hepatic fractional extraction of insulin, which was 61 +/- 4% in the basal state. Metabolic clearance rate of immunoreactive insulin (MCRi) was dose-dependently reduced by BHI infusion, whereas the relative share of hepatic insulin clearance in total MCRi rose simultaneously (P less than 0.01). We conclude that feedback inhibition of endogenous insulin release may play an important role in vivo. Furthermore, it appears that nonhepatic insulin degradation is a saturable phenomenon as total MCRi fell in the presence of its unchanged hepatic clearance rate after the infusion of large amounts of BHI.

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Dose-dependent effects of oral and intravenous glucose on insulin secretion and clearance in normal humans

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1988.254.3.e349 ◽

1988 ◽

Vol 254 (3) ◽

pp. E349-E357 ◽

Cited By ~ 14

Author(s):

H. Tillil ◽

E. T. Shapiro ◽

M. A. Miller ◽

T. Karrison ◽

B. H. Frank ◽

...

Keyword(s):

Insulin Secretion ◽

Compartmental Analysis ◽

Normal Subjects ◽

Insulin Clearance ◽

Base Line ◽

Metabolic Clearance ◽

Intravenous Glucose ◽

C Peptide ◽

Endogenous Insulin ◽

Normal Humans

Insulin secretion and clearance were studied in 2 groups of 7 normal subjects who each received 25, 50, and 100 g of glucose either orally or intravenously (iv) on separate occasions. Insulin secretion rates were calculated during a 1-h base line and for 5 h after glucose administration from a two-compartmental analysis of peripheral C-peptide concentrations using individual kinetic parameters derived after iv bolus injections of biosynthetic human C-peptide. Incremental glucose areas after oral or iv glucose increased as a function of the glucose dose (P = 0.0001). Incremental insulin secretion increased with increasing doses of both oral and iv glucose (P = 0.0001). The metabolic clearance rate (MCR) of endogenous insulin was calculated as the ratio of the total area under the insulin secretion rate curve and the simultaneous peripheral insulin concentration curve. The basal MCR was 1,879.5 +/- 110.5 ml/min (mean +/- SE). The poststimulatory MCR decreased with increasing doses of both oral and iv glucose concomitant with the greater insulin secretory response (P = 0.0014). This decrease in insulin clearance was not significantly different between oral and iv administration of glucose (P = 0.495). In conclusion diminished insulin clearance may be seen after marked stimulation of insulin secretion with larger doses of oral and iv glucose.

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Inhibition by proinsulin of endogenous C-peptide release in healthy man

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1986.251.2.e139 ◽

1986 ◽

Vol 251 (2) ◽

pp. E139-E145 ◽

Cited By ~ 1

Author(s):

W. K. Waldhausl ◽

P. Bratusch-Marrain ◽

S. Gasic ◽

M. Komjati ◽

L. Heding

Keyword(s):

Clearance Rate ◽

Glucose Utilization ◽

Metabolic Clearance ◽

Metabolic Clearance Rate ◽

C Peptide ◽

Endogenous Insulin ◽

Peptide Release ◽

Glucose Output ◽

Stimulation Of

To determine the role of proinsulin on endogenous insulin release, splanchnic output and arterial concentrations of C-peptide were measured in healthy subjects before and during infusion of human (HPI) and porcine (PPI) proinsulin at increasing rates for 70 min each (HPI, 328 and 656 micrograms X m-2 X h-1; PPI, 54, 134, and 268 micrograms/m-2 X h-1), while euglycemia was maintained by variable glucose infusion. By using this approach splanchnic C-peptide output was reduced by human proinsulin infusion from 143 +/- 16 (mean +/- SE) pmol/min to 111 +/- 18 and 75 +/- 11 pmol/min (P = 0.01). Simultaneously, arterial concentrations of C-peptide decreased from 716 +/- 40 pmol/l by 23 and 32%. Similar inhibition was induced by porcine PPI of splanchnic C-peptide output at an infusion rate of 268 micrograms X m-2 X h-1. Mean metabolic clearance rate was 2.7 and 3.7 ml X kg-1 X min-1 for HPI and PPI, respectively. Splanchnic glucose output was almost completely suppressed by human and porcine proinsulin at maximal infusion rates. This effect preceded both inhibition by proinsulin of splanchnic C-peptide output and stimulation of peripheral glucose utilization. We conclude that human and porcine proinsulin suppress endogenous insulin secretion at pharmacological concentrations. The observed constancy of the metabolic clearance rate of HPI demonstrates that its clearance remains a nonsaturable process up to supraphysiological HPI concentrations, while clearance of PPI appears to be subject to saturation. Furthermore, it appears that splanchnic glucose output responds earlier to proinsulin exposure than suppression of C-peptide release or stimulation of peripheral glucose utilization.

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Twenty-four hour C-peptide and insulin secretion rates and diurnal profiles of glucose, lipids and intermediary metabolites in cirrhosis

Clinical Science ◽

10.1042/cs0830597 ◽

1992 ◽

Vol 83 (5) ◽

pp. 597-605 ◽

Cited By ~ 10

Author(s):

Yolanta T. Kruszynska ◽

Janet Munro ◽

Philip D. Home ◽

Neil McIntyre

Keyword(s):

Insulin Secretion ◽

Fatty Acid ◽

Serum Insulin ◽

Insulin Clearance ◽

Metabolic Clearance ◽

Intermediary Metabolites ◽

C Peptide ◽

Control Subjects ◽

Glucose Profiles ◽

Cirrhotic Patients

1. To examine the contributions of hypersecretion and decreased insulin clearance to the hyperinsulinaemia of cirrhosis, insulin secretion was calculated over the day from serum C-peptide concentrations and C-peptide metabolic clearance rate. The latter was measured during infusions of recombinant human C-peptide. In cirrhotic patients (n = 9) insulin secretion rate was twice that of normal control subjects (n = 10), both in the basal state [02.00–07.00 hours, 15.7 ± 2.1 (mean ± sem) nmol/h (2.6 ± 0.4 units/h) versus 7.0 ± 0.9 nmol/h (1.2 ± 0.2 units/h), P<0.002] and over 24 h [787 ± 93 nmol (132 ± 16 units) versus 346 ± 34 nmol (58 ± 6 units), P<0.001]. However, the area under the serum insulin concentration curve was approximately six times greater in the cirrhotic patients (24 h basal, 6.3 ± 1.0 versus 1.1 ± 0.31 nmol l−1 h, P<0.001; 24 h total, 21.7 ± 3.2 versus 3.7 ± 0.7 nmol l−1 h, P<0.001). Thus, despite impairment of insulin clearance there is continuing hyper-section of insulin in cirrhosis. 2. The relationship of carbohydrate and lipid metabolism with insulin secretion was assessed. In cirrhotic patients, 24 h blood glucose profiles showed a worsening of glucose tolerance over breakfast, despite greater insulin secretion compared with other meals, suggesting that the insulin insensitivity of cirrhosis is worse at this time. 3. Cirrhotic patients showed impaired suppression of blood glycerol levels after meals but normal suppression of serum non-esterified fatty acid concentrations. The greatest differences in the profiles of serum lipids and lipid-related metabolites in cirrhotic patients and control subjects occurred at night. Whereas in control subjects, serum non-esterified fatty acid, blood glycerol and blood 3-hydroxybutyrate concentrations peaked between 01.00 and 03.00 hours, falling gradually thereafter until 08.00 hours, in cirrhotic patients serum non-esterified fatty acid and blood glycerol levels showed a gradual increase during the night to reach maximal levels at 08.00 hours when they were twice those of control subjects (P<0.001). 4. The blood 3-hydroxybutyrate and serum triacyl-glycerol profiles suggested that in cirrhotic patients there was preferential utilization of non-esterified fatty acids for ketogenesis and reduced re-esterification to triacylglycerol.

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Sensitivity of insulin secretion to feedback inhibition by hyperinsulinaemia

Acta Endocrinologica ◽

10.1530/acta.0.0980081 ◽

1981 ◽

Vol 98 (1) ◽

pp. 81-86 ◽

Cited By ~ 55

Author(s):

Ralph A. DeFronzo ◽

Christian Binder ◽

John Wahren ◽

Philip Felig ◽

Eleuterio Ferrannini ◽

...

Keyword(s):

Insulin Secretion ◽

Plasma Glucose ◽

Plasma Insulin ◽

Feedback Inhibition ◽

Normal Subjects ◽

Insulin Concentration ◽

Plasma Insulin Concentration ◽

C Peptide ◽

Endogenous Insulin ◽

Arterial Plasma

Abstract. The ability of insulin to inhibit its own secretion was examined in 15 normal subjects given an intravenous infusion of insulin in a dose of 0.25, 0.50, 1.0, 5.0 or 10.0 mU/kg/min for two hours. Arterial plasma insulin concentration achieved during the infusion segregated into three levels of hyperinsulinaemia: 35 ± 1 (mean ± sem), 87 ± 15 and 828 ± 210 μU/ml. Plasma glucose concentration was kept constant at the basal level by a variable glucose infusion. Fasting C-peptide (0.29 ± 0.02 pmol/ml) fell significantly in all subjects during hyperinsulinaemia and reached a concentration of 0.19 ± 0.03 pmol/ml at 60 min and 0.14 ± 0.03 at 120 min after the start of the insulin infusion. The C-peptide response was not related to the infusion dose nor to the steady state plasma insulin concentration. It is concluded that (a) basal insulin secretion as evaluated from C-peptide measurements is inhibited by small (24 ± 3 μU/ml) physiological elevations in plasma insulin concentration independent of changes in plasma glucose, and (b) supraphysiological or even pharmacological elevations in plasma insulin do not result in a further decrease in endogenous insulin secretion above that achieved with mild hyperinsulinaemia.

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Mode of action of chloroquine in patients with non-insulin-dependent diabetes mellitus

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1991.260.6.e897 ◽

1991 ◽

Vol 260 (6) ◽

pp. E897-E904 ◽

Cited By ~ 4

Author(s):

J. K. Powrie ◽

G. D. Smith ◽

F. Shojaee-Moradie ◽

P. H. Sonksen ◽

R. H. Jones

Keyword(s):

Diabetes Mellitus ◽

Feedback Inhibition ◽

Controlled Trial ◽

Insulin Dependent Diabetes Mellitus ◽

Insulin Dependent Diabetes ◽

Dependent Diabetes Mellitus ◽

High Dose ◽

Metabolic Clearance ◽

C Peptide ◽

Insulin Dependent

Clinical studies have demonstrated that chloroquine and hydroxychloroquine improve glucose metabolism in patients with insulin-resistant diabetes mellitus. The mechanism of action has not been determined. We undertook a randomized double-blind placebo-controlled trial of 3 days of oral chloroquine phosphate, 250 mg four times daily, in 20 patients with non-insulin-dependent diabetes mellitus controlled by diet. Rates of glucose appearance (Ra) and disappearance (Rd) were evaluated by infusion of stable isotopically labeled D-glucose ([6,6-2H2]glucose) during hyperinsulinemic euglycemic clamps before and after treatment with chloroquine or placebo. Chloroquine significantly improved fasting plasma glucose from 199.8 +/- 8.6 to 165.6 +/- 7.6 mg/dl (P less than 0.01). Total exogenous glucose infusion required to maintain euglycemia significantly increased (1,792.6-2,040.1 mg.kg-1.330 min-1, P less than 0.05) due to an increase in Rd (2,348.0-2,618.9 mg.kg-1.330 min-1, P less than 0.01) without change in Ra. Metabolic clearance rate of insulin decreased by 39% from 14.4 +/- 1.3 to 11.0 +/- 0.6 ml.kg-1.min-1 (P less than 0.01) at plasma insulin levels of 150-200 mU/l but not at levels of 2,000-3,000 mU/l. In addition, chloroquine increased fasting C-peptide secretion by 17% and reduced feedback inhibition of C-peptide by 9.1 and 10.6% during low- and high-dose insulin infusions, respectively.

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Reduction of hepatic insulin clearance after oral glucose ingestion is not mediated by glucagon-like peptide 1 or gastric inhibitory polypeptide in humans

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00289.2007 ◽

2007 ◽

Vol 293 (3) ◽

pp. E849-E856 ◽

Cited By ~ 46

Author(s):

Juris J. Meier ◽

Jens J. Holst ◽

Wolfgang E. Schmidt ◽

Michael A. Nauck

Keyword(s):

Gastric Inhibitory Polypeptide ◽

Insulin Clearance ◽

Oral Glucose ◽

Intravenous Glucose ◽

C Peptide ◽

Glucose Administration ◽

Glucose Ingestion ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Hepatic Insulin Clearance

Changes in hepatic insulin clearance can occur after oral glucose or meal ingestion. This has been attributed to the secretion and action of gastric inhibitory polypeptide (GIP) and glucagon-like peptide (GLP)−1. Given the recent availability of drugs based on incretin hormones, such clearance effects may be important for the future treatment of type 2 diabetes. Therefore, we determined insulin clearance in response to endogenously secreted and exogenously administered GIP and GLP-1. Insulin clearance was estimated from the molar C-peptide-to-insulin ratio calculated at basal conditions and from the respective areas under the curve after glucose, GIP, or GLP-1 administration. Oral glucose administration led to an ∼60% reduction in the C-peptide-to-insulin ratio ( P < 0.0001), whereas intravenous glucose administration had no effect ( P = 0.09). The endogenous secretion of GIP or GLP-1 was unrelated to the changes in insulin clearance. The C-peptide-to-insulin ratio was unchanged after the intravenous administration of GIP or GLP-1 in the fasting state ( P = 0.27 and P = 0.35, respectively). Likewise, infusing GLP-1 during a meal course did not alter insulin clearance ( P = 0.87). An inverse nonlinear relationship was found between the C-peptide-to-insulin ratio and the integrated insulin levels after oral and during intravenous glucose administration. Insulin clearance is reduced by oral but not by intravenous glucose administration. Neither GIP nor GLP-1 has significant effects on insulin extraction. An inverse relationship between insulin concentrations and insulin clearance suggests that the secretion of insulin itself determines the rate of hepatic insulin clearance.

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STUDIES ON LOW INSULIN RESPONDERS

Acta Endocrinologica ◽

10.1530/acta.0.090s005 ◽

1979 ◽

Vol 92 (2_Suppl) ◽

pp. S5-S32 ◽

Cited By ~ 8

Author(s):

S. Efendić ◽

E. Cerasi ◽

I. Elander ◽

Christina Thornqvist ◽

G. Fick ◽

...

Keyword(s):

Insulin Release ◽

Time Course ◽

Feedback Inhibition ◽

Insulin Response ◽

Insulinogenic Index ◽

Intravenous Glucose ◽

Endogenous Insulin ◽

Glucose Tolerance Tests ◽

Intravenous Glucose Tolerance Tests ◽

Insulin Responses

ABSTRACT The insulin responses to intravenous glucose infusion (GIT) and oral administration of glucose (OGTT) were measured in 226 control subjects and 25 chemical or mild maturity-onset non-obese diabetics. In addition, intravenous glucose tolerance tests (IVGTT) were performed in all subjects. The insulin response to GIT was analyzed by parameter identification in a mathematical model. This model assumes that glucose initiates insulin release by an immediate action, the magnitude of which is given by parameter KI. In addition, glucose induces a time-dependent potentiation (KP) of its initiating action. Insulin release is also modulated by negative feedback inhibition (KB), which displays an intermediary time course between KI and KP. The computer analysis of GIT allows the identification of a further parameter, KG, which defines sensitivity to endogenous insulin. In addition, a hypothetical plasma insulin value at 10 min was calculated, called IP, and reflecting the response to a standard glucose stimulation. Finally, the insulinogenic index (ΔI/ΔG) for the 10 min value of GIT was calculated.

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The Effect of Sodium-Glucose Cotransporter 2 Inhibitor Ipragliflozin on Insulin Resistance, Hepatic Insulin Clearance, Beta-Cell Function in the Japanese Patients with type 2 Diabetes

10.21203/rs.3.rs-882630/v1 ◽

2021 ◽

Author(s):

Tsuyoshi Okura ◽

Yohei Fujioka ◽

Risa Nakamura ◽

Sonoko Kitao ◽

Yuichi Ito ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Body Composition ◽

Beta Cell Function ◽

Cell Function ◽

Insulin Clearance ◽

C Peptide ◽

Sodium Glucose Cotransporter ◽

Hepatic Insulin Clearance

Abstract Introduction: Sodium-glucose cotransporter 2 inhibitor (SGLT2i) is a medication for type 2 diabetes mellitus (T2DM). Some reports showed SGLT2i improved insulin resistance, however, the effect on insulin resistance is not well established. Hepatic insulin clearance (HIC) is new pathophysiology of T2DM. The effect of SGLT2i on hepatic insulin clearance and insulin resistance is not well known. We investigated the effect of SGLT2i on insulin resistance, insulin secretion, incretins, body composition, and hepatic insulin clearance. Materials and Methods: We conducted a meal tolerance test (MTT), and the hyperinsulinemic-euglycemic clamp in 9 T2DM patients. 50 mg/day ipragliflozin was admitted, MTT and clamp were performed after 4 months. We calculated the postprandial C-peptide AUC to insulin AUC ratio as the HIC. We also measured GLP1, GIP, and glucagon levels during MTT. Results: Body weight, HbA1c, and body composition were not significantly changed after 4 months of treatment. Postprandial glucose, fasting, and postprandial insulin were significantly decreased. The insulin resistance of the glucose clamp was not changed, but HOMA-IR and insulin sensitivity index (ISI) were significantly improved. Incretins and glucagon were not changed. Hepatic insulin clearance was significantly increased, but whole-body insulin clearance was not changed. Fib 4 index and fatty liver index were significantly reduced. HOMA-beta and insulinogenic index was not changed but the C-peptide index was significantly increased. Conclusions: Although patients’ number was small, these results suggest that SGLT2i treatment decreased hepatic insulin resistance, increased hepatic insulin clearance, and decreased hyperinsulinemia, it might protect beta-cell function.

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Insulin delivery by somatic cell gene therapy

Journal of Molecular Endocrinology ◽

10.1677/jme.0.0110335 ◽

1993 ◽

Vol 11 (3) ◽

pp. 335-341 ◽

Cited By ~ 17

Author(s):

C Stewart ◽

N A Taylor ◽

K Docherty ◽

C J Bailey

Keyword(s):

Gene Therapy ◽

Somatic Cell ◽

Insulin Release ◽

Human Insulin ◽

Outer Region ◽

Insulin Delivery ◽

Control Group ◽

C Peptide ◽

Somatic Cell Gene Therapy ◽

Cell Gene

ABSTRACT The feasibility of somatic cell gene therapy as a method of insulin delivery has been studied in mice. Murine pituitary AtT20 cells were transfected with a human preproinsulin DNA in a plasmid containing a metallothionein promoter and a gene conferring resistance to the antibiotic G418. The AtT20MtIns-1·4 clone of cells was selected because of its higher insulin-releasing activity compared with other clones. After culturing for 24 h in Dulbecco's medium containing 10 mM glucose, the AtT20MtIns-1·4 cells released human insulin at about 5 ng/106 cells per 24 h. Insulin release was not significantly altered by raised concentrations of glucose, potassium or calcium, but insulin release was increased by 20 mm arginine, 5 mm isomethylbutylxanthine and 90 μm zinc. AtT20MtIns-1·4 cells (2 × 106) were implanted intraperitoneally into non-diabetic athymic nude (nu/nu) mice, and the mice were made diabetic by injection of streptozotocin after 7 days. Release of human insulin in vivo was assessed using a specific plasma human C-peptide assay. Human C-peptide concentrations were maintained at about 01 pmol/ml throughout the 29 days of the study. The development of streptozotocin-induced hyperglycaemia was delayed in recipients of the cells releasing human insulin, compared with a control group receiving an implant of non-transfected cells. At autopsy the implanted AtT20MtIns-1·4 cells in each recipient had formed a tumour-like aggregation, with an outer region of insulin-containing cells. The study suggests that somatic cell gene therapy offers a feasible approach to insulin delivery.

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