The relationship between first-phase insulin secretion and glucose metabolism

1992 ◽  
Vol 127 (4) ◽  
pp. 289-293 ◽  
Author(s):  
Elisabeth IM Widén ◽  
Johan G Eriksson ◽  
Agneta V Ekstrand ◽  
Leif C Groop
Keyword(s):  
Insulin Secretion ◽  
Glucose Metabolism ◽  
Glucose Uptake ◽  
Hepatic Glucose Production ◽  
Glucose Disposal ◽  
Second Phase ◽  
Cross Sectional ◽  
Oxidation Rates ◽  
First Phase Insulin Secretion ◽  
Total Glucose

A possible pathogenetic link between absence of first-phase insulin secretion and development of impaired glucose metabolism has been suggested by the results of several cross-sectional studies. First-phase insulin secretion measured during a + 7 mmol/l hyperglycemic glucose clamp correlated with total glucose disposal during the clamp (r = 0.65, p <0.001, N = 59). To examine whether restoration of first-phase insulin secretion improves peripheral glucose uptake in subjects with impaired glucose utilization, seven insulin-resistant subjects (age 54 (38–62) years; BMI 29.3 (21.7–35.8); fasting plasma glucose 5.5 (4.8–7.2) mmol/l; fasting insulin 57 (37–105) pmol/l with impaired first-phase (148 (29–587) vs controls 485 (326–1086) pmol/l× 10 min; p<0.05) and normal second-phase (1604 (777–4480) vs controls (1799 (763–2771) pmol/l × 110 min) insulin secretion were restudied. The impaired first-phase insulin secretion was restored by an iv insulin bolus at the start of the hyperglycemic clamp. Substrate oxidation rates and hepatic glucose production were determined by indirect calorimetry and [3-3H]glucose infusion. Total glucose uptake was impaired in the insulinresistant subjects with impaired first-phase insulin secretion compared to controls (18.8 (13.2–22.2) vs 34.8 (24.3–62.1) μmol·kg−1·min−1; p<0.01). Restoration of first-phase insulin secretion (1467 (746–2440) pmol/l× 10 min) did not affect glucose uptake (20.2 (9.9–23.8) μmol·kg−1·min−1), with no difference in oxidative and non-oxidative glucose metabolism between the experiments. Second-phase insulin secretion was similar during both experiments. We conclude that although first-phase insulin secretion correlates with total glucose uptake, replacement of impaired first-phase insulin secretion does not improve glucose uptake in subjects with impaired glucose disposal and normal second-phase insulin secretion. The data dispute a causal relationship between first-phase insulin secretion and impaired glucose uptake in these subjects.

scholarly journals Importance of the route of insulin delivery to its control of glucose metabolism

2021 ◽  
Author(s):  
Dale S. Edgerton ◽  
Mary Courtney Moore ◽  
Justin M. Gregory ◽  
Guillaume Kraft ◽  
Alan D. Cherrington
Keyword(s):  
Insulin Secretion ◽  
Glucose Metabolism ◽  
Glucose Uptake ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
The Body ◽  
Whole Body ◽  
Direct Effects ◽  
Pancreatic Insulin ◽  
Hepatic Glucose

Pancreatic insulin secretion produces an insulin gradient at the liver compared to the rest of the body (approximately 3:1). This physiologic distribution is lost when insulin is injected subcutaneously, causing impaired regulation of hepatic glucose production and whole body glucose uptake, as well as arterial hyperinsulinemia. Thus, the hepatoportal insulin gradient is essential to the normal control of glucose metabolism during both fasting and feeding. Insulin can regulate hepatic glucose production and uptake through multiple mechanisms, but its direct effects on the liver are dominant under physiologic conditions. Given the complications associated with iatrogenic hyperinsulinemia in patients treated with insulin, insulin designed to preferentially target the liver may have therapeutic advantages.

Effect of loss of first-phase insulin secretion on hepatic glucose production and tissue glucose disposal in humans

1989 ◽  
Vol 257 (2) ◽  
pp. E241-E246 ◽  
Author(s):  
L. Luzi ◽  
R. A. DeFronzo
Keyword(s):  
Insulin Secretion ◽  
Insulin Infusion ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Second Phase ◽  
C Peptide ◽  
Hyperglycemic Clamp ◽  
Study Protocols ◽  
Hepatic Glucose ◽  
First Phase Insulin Secretion

To examine the importance of first-phase insulin secretion on total body glucose homeostasis, six normal subjects (age, 24 +/- 1 yr; ideal body wt, 100 +/- 1%) received three hyperglycemic (+75 mg/100 ml) clamp studies in combination with [3-3H]glucose: study I, 150 min hyperglycemic clamp; study II, hyperglycemic clamp plus somatostatin (6 micrograms/min) plus basal glucagon replacement (0.4 ng.kg-1.min-1) plus an insulin infusion designed to mimic only the second phase of insulin secretion; and study III, hyperglycemic clamp plus somatostatin plus basal glucagon plus an insulin infusion designed to mimic both the first and second phase of insulin secretion. Basal plasma C-peptide concentrations averaged 0.21 +/- 0.01 pmol/ml in the three study protocols. In study I the plasma C-peptide response demonstrated an early burst within the first 10 min followed by a gradually increasing phase of C-peptide secretion that lasted until the end of the study. In studies II and III plasma C-peptide declined within the first 10 min after somatostatin was started and averaged 0.06 +/- 0.01 and 0.05 +/- 0.01 pmol/min, respectively. Basal hepatic glucose production (2.3 +/- 0.2 mg.kg-1.min-1) was suppressed by 90% at 20 min and remained suppressed thereafter in studies I and III. In contrast, in study II hepatic glucose production was inhibited by only 50% (1.1 +/- 0.2 mg.kg-1.min-1) at 60 min (P less than 0.01 vs. studies I and III) and remained incompletely suppressed even after 150 min.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Acute and Short-term Chronic Testosterone Fluctuation Effects on Glucose Homeostasis, Insulin Sensitivity, and Adiponectin: A Randomized, Double-Blind, Placebo-Controlled, Crossover Study

2014 ◽  
Vol 99 (6) ◽  
pp. E1088-E1096 ◽  
Author(s):  
Christian Høst ◽  
Lars C. Gormsen ◽  
David M. Hougaard ◽  
Jens S. Christiansen ◽  
Steen B. Pedersen ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Glucose Metabolism ◽  
Crossover Study ◽  
High Molecular Weight ◽  
Glucose Disposal ◽  
Short Term ◽  
High Molecular Weight Adiponectin ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Total Glucose

Context: Low levels of adiponectin and T in men have been shown to predict development of the metabolic syndrome, but the effects of T on glucose metabolism are incompletely understood and may be influenced either directly or indirectly through changes in body composition or in levels of adiponectin. Objective: The aim of the study was to test whether T exerts its effects on glucose metabolism directly or indirectly. Design, Setting, and Participants: In a randomized, double-blind, placebo-controlled, crossover study, 12 healthy young males were studied on four separate occasions. They received GnRH agonist treatment 1 month before 3 of 4 trial days to induce castrate levels of T. On trial days, T gel containing either high or low physiological T dose or placebo was applied to the body. On a fourth trial day, participants constituted their own eugonadal controls. Intervention: Each study comprised a 5-hour basal period and a 3-hour hyperinsulinemic euglycemic clamp. Main Outcome Measures: We measured the effect of acute T on peripheral glucose disposal, total adiponectin and subforms, and other indices of glucose metabolism. Results: Short-term hypogonadism was associated with increased high molecular weight adiponectin levels (P &lt; .03) and increased oxidative glucose disposal (P = .03) but not total glucose disposal (P = .07). Acute T treatment was an independent suppressor of high molecular weight adiponectin levels (P = .04) but did not affect total glucose disposal (P = .17). Conclusions: These data show that T can act through putative fast nongenomic pathways to affect adiponectin levels in humans. The early hypogonadal state is characterized by a marked shift in fuel oxidation from lipids toward glucose, which may rely partly on buffering capabilities of adiponectin.

Magnesium requirement for somatostatin inhibition of insulin secretion

1984 ◽  
Vol 105 (1) ◽  
pp. 83-86 ◽  
Author(s):  
Donald L. Curry ◽  
Leslie L. Bennett
Keyword(s):  
Insulin Secretion ◽  
Calcium Concentration ◽  
Inhibitory Effect ◽  
Secretory Process ◽  
Magnesium Ion ◽  
Second Phase ◽  
Intracellular Membrane ◽  
Calcium Magnesium ◽  
First Phase Insulin Secretion ◽  
Insulin Secretory Response

Abstract. Rat pancreas perfusions were performed using a perfusate with a fixed calcium concentration of 5 mEq/l and magnesium varying from 0 to 0.6 mEq/dl. Insulin secretion was stimulated by a constant glucose infusion of 300 mg/dl. This glucose concentration produces the typical biphasic insulin secretory response. We observed that in the absence of magnesium, somatostatin concentrations of 0.5 and 2.0 ng/ml were without effect on first phase insulin secretion. However, these same somatostatin levels produced 50% or more inhibition of insulin secretion in the presence of magnesium at 0.3 or 0.6 mEq/l. Similarly, in the absence of magnesium, somatostatin at 50 ng/ml failed to inhibit second phase insulin secretion, whereas this same somatostatin level produced about 50% inhibition of insulin secretion in the presence of magnesium at 0.3 mEq/l. Thus, altering perfusate magnesium concentrations without changing calcium is an important determinant of the degree of inhibition of secretion produced by somatostatin. In particular, in the absence of magnesium ion, somatostatin concentrations which would 'normally' produce 50% inhibition of secretion (ID50) are without effect. Therefore, magnesium ion is necessary for the full inhibitory effect of somatostatin to occur. These results suggest that inhibitors, as well as potentiators, of the insulin secretory process may act by altering intracellular/membrane calcium-magnesium ratios, but in opposite directions.

scholarly journals Leptin administration improves skeletal muscle insulin responsiveness in diet-induced insulin-resistant rats

2001 ◽  
Vol 280 (1) ◽  
pp. E130-E142 ◽  
Author(s):  
Ben B. Yaspelkis ◽  
James R. Davis ◽  
Maziyar Saberi ◽  
Toby L. Smith ◽  
Reza Jazayeri ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Glucose Uptake ◽  
Whole Body ◽  
Glucose Disposal ◽  
High Fat ◽  
Insulin Resistant ◽  
Skeletal Muscle Glucose Uptake ◽  
Uptake And Transport

In addition to suppressing appetite, leptin may also modulate insulin secretion and action. Leptin was administered here to insulin-resistant rats to determine its effects on secretagogue-stimulated insulin release, whole body glucose disposal, and insulin-stimulated skeletal muscle glucose uptake and transport. Male Wistar rats were fed either a normal (Con) or a high-fat (HF) diet for 3 or 6 mo. HF rats were then treated with either vehicle (HF), leptin (HF-Lep, 10 mg · kg−1 · day−1 sc), or food restriction (HF-FR) for 12–15 days. Glucose tolerance and skeletal muscle glucose uptake and transport were significantly impaired in HF compared with Con. Whole body glucose tolerance and rates of insulin-stimulated skeletal muscle glucose uptake and transport in HF-Lep were similar to those of Con and greater than those of HF and HF-FR. The insulin secretory response to either glucose or tolbutamide (a pancreatic β-cell secretagogue) was not significantly diminished in HF-Lep. Total and plasma membrane skeletal muscle GLUT-4 protein concentrations were similar in Con and HF-Lep and greater than those in HF and HF-FR. The findings suggest that chronic leptin administration reversed a high-fat diet-induced insulin-resistant state, without compromising insulin secretion.

Intraportal administration of neuropeptide Y and hepatic glucose metabolism

2008 ◽  
Vol 294 (4) ◽  
pp. R1197-R1204 ◽  
Author(s):  
Makoto Nishizawa ◽  
Masakazu Shiota ◽  
Mary Courtney Moore ◽  
Stephanie M. Gustavson ◽  
Doss W. Neal ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Neuropeptide Y ◽  
Glucose Uptake ◽  
Infusion Rate ◽  
Whole Body ◽  
Glucose Disposal ◽  
Control Group ◽  
Intravenous Glucose ◽  
Hepatic Glucose ◽  
Hepatic Glucose Uptake

We examined whether intraportal delivery of neuropeptide Y (NPY) affects glucose metabolism in 42-h-fasted conscious dogs using arteriovenous difference methodology. The experimental period was divided into three subperiods (P1, P2, and P3). During all subperiods, the dogs received infusions of somatostatin, intraportal insulin (threefold basal), intraportal glucagon (basal), and peripheral intravenous glucose to increase the hepatic glucose load twofold basal. Following P1, in the NPY group ( n = 7), NPY was infused intraportally at 0.2 and 5.1 pmol·kg−1·min−1 during P2 and P3, respectively. The control group ( n = 7) received intraportal saline infusion without NPY. There were no significant changes in hepatic blood flow in NPY vs. control. The lower infusion rate of NPY (P2) did not enhance net hepatic glucose uptake. During P3, the increment in net hepatic glucose uptake (compared with P1) was 4 ± 1 and 10 ± 2 μmol·kg−1·min−1 in control and NPY, respectively ( P < 0.05). The increment in net hepatic fractional glucose extraction during P3 was 0.015 ± 0.005 and 0.039 ± 0.008 in control and NPY, respectively ( P < 0.05). Net hepatic carbon retention was enhanced in NPY vs. control (22 ± 2 vs. 14 ± 2 μmol·kg−1·min−1, P < 0.05). There were no significant differences between groups in the total glucose infusion rate. Thus, intraportal NPY stimulates net hepatic glucose uptake without significantly altering whole body glucose disposal in dogs.

Non-insulin-mediated glucose uptake in fed and fasted sheep

2000 ◽  
Vol 71 (3) ◽  
pp. 453-463 ◽  
Author(s):  
T. E. C. Weekes ◽  
Y. Obara ◽  
M. T. Rose
Keyword(s):  
Glucose Uptake ◽  
Glucose Utilization ◽  
Whole Body ◽  
Glucose Disposal ◽  
Metabolic Clearance ◽  
Normal Glucose ◽  
Total Glucose ◽  
A Minor ◽  
Turn Over ◽  
The Brain

AbstractIn ruminants and humans, the majority of whole body glucose utilization is not mediated by insulin. However, while in man most non-insulin-mediated glucose utilization (NIMGU) occurs in the brain, in ruminants the locations of NIMGU remain less well defined. As fasting would be expected to limit NIMGU to what would be regarded as an essential minimum, two studies were performed to establish the contribution of NIMGU to total glucose metabolism in fed and fasted sheep. Each study used four adult castrated male sheep. In study 1, a primed continuous infusion of U- [13C] glucose was begun at time 0 and continued for 7 h. After 3 h of isotope infusion (basal period) somatostatin (0•417 µg/kg per min; SS) was administered for 4 h, either alone (SS-only) or together with insulin (1•0 mU/kg per min; SS + insulin) with normal glucose to maintain euglycaemia for 2 h. Normal glucose was then infused for both the SS-only and SS + insulin treatments to induce and maintain hyperglycaemia over the final 2 h of the experiment. In study 2, fed or 72-h fasted sheep were infused with 6-[3H] glucose from time 0 for 8 h, with SS infusion starting at 3 h and continuing for 5 h. After 3 h of SS infusion, glucose was infused to induce and maintain hyperglycaemia. In both studies SS infusion inhibited insulin secretion, however in study 2, SS in fed sheep caused hyperglycaemia; this effect was not significant in the fasted animals. The rate of glucose utilization was reduced by SS-only as it eliminated insulin mediated glucose uptake (IMGU); under such conditions whole body glucose disposal should be NIMGU. In fed sheep, average NIMGU levels represented between proportionately 0•61 and 0•67 of the basal glucose metabolic clearance rate. During the infusion of SS + insulin in fed sheep, NIMGU fell to 0•34 during euglycaemia and 0•33 during hyperglycaemia, as the infused insulin caused IMGU to predominate. In fasted sheep the absolute rates of both IMGU and NIMGU were reduced, though NIMGU as a proportion of total turn-over (IMGU + NIMGU) increased to 0•88 of glucose metabolic clearance. Calculations suggest that, in contrast to man, only a minor proportion of NIMGU is utilized by the brain and central nervous system in fed or fasted sheep. It is suggested that skeletal muscle and the gastro-intestinal tract may make a major contribution to NIMGU, even in fasted sheep.

scholarly journals Age-Related Reduction in Glucose Elimination Is Accompanied by Reduced Glucose Effectiveness and Increased Hepatic Insulin Extraction in Man1

1998 ◽  
Vol 83 (9) ◽  
pp. 3350-3356 ◽  
Author(s):  
Bo Ahrén ◽  
Giovanni Pacini
Keyword(s):  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Glucose Tolerance Test ◽  
Tolerance Test ◽  
Oral Glucose ◽  
Tolerance Index ◽  
Second Phase ◽  
Oral Glucose Tolerance ◽  
Glucose Effectiveness ◽  
First Phase Insulin Secretion

This study examined whether insulin secretion, insulin sensitivity, glucose effectiveness (SG), and hepatic extraction (HE) of insulin are altered by age when glucose tolerance is normal. A frequently sampled iv glucose tolerance test was performed in 20 elderly (E, 10/10 male/female, all 63 yr old) and in 20 young subjects (Y, 10/10 male/female, all 27 yr old), who were similar in body mass index and 2-h blood glucose during oral glucose tolerance test. E exhibited impaired glucose elimination (iv tolerance index, 1.31 ± 0.10 vs. 1.70 ± 0.12% min−1; P = 0.019). First-phase insulin secretion and SI did not differ between the groups, whereas E had lower glucose sensitivity of second-phase insulin secretion (0.40 ± 0.07 vs. 0.70 ± 0.08 (pmol/L)min−2/(mmol/L), P = 0.026), lower SG, 0.017 ± 0.002 vs. 0.025± 0.002 min−1, P = 0.004), and higher HE (81.3 ± 2.4 vs. 73.2 ± 2.1%, P = 0.013). Across both groups, SG correlated positively with glucose tolerance index (r = 0.58, P &lt; 0.001) and negatively with HE (r =− 0.54, P &lt; 0.001). Plasma leptin and glucagon did not change by age, whereas plasma pancreatic polypeptide (PP) was higher in E (122 ± 18 vs.66 ± 6 pg/mL, P = 0.004). PP did not, however, correlate to any other parameter. We conclude that E subjects with normal oral glucose tolerance have reduced SG, impaired second-phase insulin secretion, and increased HE, whereas SI and first-phase insulin secretion seem normal. SG seems most related to age-dependent impairment of glucose elimination, whereas leptin, glucagon, and PP do not seem to contribute.

Effect of growth hormone treatment on insulin secretion and glucose metabolism in prepubertal boys with short stature

1994 ◽  
Vol 131 (3) ◽  
pp. 246-250 ◽  
Author(s):  
Jan Åman ◽  
Sten Rosberg ◽  
Kerstin Albertsson-Wikland
Keyword(s):  
Growth Hormone ◽  
Insulin Secretion ◽  
Glucose Metabolism ◽  
Growth Hormone Treatment ◽  
Gh Deficiency ◽  
Hormone Treatment ◽  
Glucose Disposal ◽  
First Year ◽  
Gh Treatment ◽  
Prepubertal Boys

Aman J. Rosberg S, Albertsson-Wikland K. Effect of growth hormone treatment on insulin secretion and glucose metabolism in prepubertal boys with short stature. Eur Endocrinol 1994;131:246–50. ISSN 0804–4643 The purpose of this study was to evaluate the effect on insulin secretion and glucose metabolism of daily growth hormone (GH) treatment, 0.1 U/kg. for up to 3 years in 42 short prepubertal boys without GH deficiency. Their median height standard deviation (sd) score increased from −2.7 to −1.7, whereas their weight for height sd score was unchanged after 3 years of treatment. Fasting plasma glucose concentrations were unchanged, but median fasting insulin concentrations increased from 6.0 mU/l before treatment to 7.8 mU/l (p < 0.05) after the first year. No further increase was seen during the second or third years. The median insulin area under the curve 10–60 min after an intravenous glucose tolerance test increased from 480 mU·1−1·min−1 before treatment to 799 mU·1−1 · min−1 (p < 0.05) after 1 year. The median glucose disposal rate (K value) before GH treatment, 2.2%/min, was unchanged after 1 year of treatment. A significant positive correlation was found between the change in the height sd score and the change in fasting insulin concentration during the first (r = 0.45; p < 0.01) and second (r = 0.56; p < 0.05) years of GH treatment. It was concluded that GH treatment in prepubertal children without GH deficiency caused a moderate increase in fasting and stimulated insulin concentrations during the first year of treatment. There was no further change during the following years of treatment, and there were no negative effects on fasting plasma glucose concentrations or glucose disposal rates. The increase in insulin concentration was related positively to the growth response. Jan Åman, Department of Pediatrics, Örebro Medical Centre Hospital, S-701 85 Örebro, Sweden

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

2018 ◽  
Vol 314 (5) ◽  
pp. R639-R646 ◽  
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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