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)

Abnormal regulation of HGP by hyperglycemia in mice with a disrupted glucokinase allele

1997 ◽  
Vol 273 (4) ◽  
pp. E743-E750 ◽  
Author(s):  
Luciano Rossetti ◽  
Wei Chen ◽  
Meizhu Hu ◽  
Meredith Hawkins ◽  
Nir Barzilai ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Glucose Disposal ◽  
Relative Role ◽  
Β Cells ◽  
Plasma Insulin Concentration ◽  
Hyperglycemic Clamp ◽  
Human Diabetes ◽  
Hepatic Glucose

Glucokinase (GK) catalyzes the phosphorylation of glucose in β-cells and hepatocytes, and mutations in the GK gene have been implicated in a form of human diabetes. To investigate the relative role of partial deficiencies in the hepatic vs. pancreatic GK activity, we examined insulin secretion, glucose disposal, and hepatic glucose production (HGP) in response to hyperglycemia in transgenic mice 1) with one disrupted GK allele, which manifest decreased GK activity in both liver and β-cells (GK+/−), and 2) with decreased GK activity selectively in β-cells (RIP-GKRZ). Liver GK activity was decreased by 35–50% in the GK+/− but not in the RIP-GKRZ compared with wild type (WT) mice. Hyperglycemic clamp studies were performed in conscious mice with or without concomitant pancreatic clamp. In all studies [3-3H]glucose was infused to measure the rate of appearance of glucose and HGP during 80 min of euglycemia (Glc ∼5 mM) followed by 90 min of hyperglycemia (Glc ∼17 mM). During hyperglycemic clamp studies, steady-state plasma insulin concentration, rate of glucose infusion, and rate of glucose disappearance (Rd) were decreased in both GK+/− and RIP-GKRZ compared with WT mice. However, whereas the basal HGP (at euglycemia) averaged ∼22 mg ⋅ kg−1 ⋅ min−1in all groups, during hyperglycemia HGP was suppressed by only 48% in GK+/− compared with ∼70 and 65% in the WT and RIP-GKRZ mice, respectively. During the pancreatic clamp studies, the ability of hyperglycemia per se to increase Rd was similar in all groups. However, hyperglycemia inhibited HGP by only 12% in GK+/−, vs. 42 and 45%, respectively, in the WT and RIP-GKRZ mice. We conclude that, although impaired glucose-induced insulin secretion is common to both models of decreased pancreatic GK activity, the marked impairment in the ability of hyperglycemia to inhibit HGP is due to the specific decrease in hepatic GK activity.

Escape of hepatic glucose production during hyperglycemic clamp

1989 ◽  
Vol 257 (5) ◽  
pp. E704-E711 ◽  
Author(s):  
D. Elahi ◽  
G. S. Meneilly ◽  
K. L. Minaker ◽  
D. K. Andersen ◽  
J. W. Rowe
Keyword(s):  
Insulin Secretion ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Insulin Level ◽  
Immunoreactive Insulin ◽  
Basal Rate ◽  
Square Wave ◽  
Hyperglycemic Clamp ◽  
Hepatic Glucose ◽  
Glucagon And Insulin

The role of the pattern of insulin secretion on hepatic glucose production (HGP) was evaluated with hyperglycemic and euglycemic clamp studies in six normal young nonobese subjects. In the hyperglycemic studies, glucose levels were raised and maintained at 98 mg/dl above basal for 150 min. Each subject responded with a biphasic pattern of immunoreactive insulin (IRI) release. HGP was completely suppressed by 20 min, coincident with the first-phase insulin release. HGP then rose steadily, surpassing the basal rate by 100 min when IRI had reached the peak levels of the first phase. By 130 min, when IRI had surpassed the peak first-phase levels, HGP began to fall. In the euglycemic studies with a square wave of hyperinsulinemia (approximately 25 microU/ml), HGP was suppressed to approximately 60% of basal and remained at that rate. We next repeated the hyperglycemic studies with somatostatin, glucagon, and insulin infusions. In these studies with a square wave of hyperinsulinemia (approximately 40 microU/ml, the level observed during the first phase IRI of the previous hyperglycemic clamps), HGP was suppressed to approximately 43% of basal rate and remained at that rate. These studies indicate insulin regulation of HGP is not only dependent on insulin level but may be strongly influenced by the pattern, over time, of insulin secretion.

Different effects of glyburide and glipizide on insulin secretion and hepatic glucose production in normal and NIDDM subjects

Diabetes ◽  
1987 ◽  
Vol 36 (11) ◽  
pp. 1320-1328 ◽  
Author(s):  
L. Groop ◽  
L. Luzi ◽  
A. Melander ◽  
P. H. Groop ◽  
K. Ratheiser ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Hepatic Glucose

scholarly journals The Irs1 Branch of the Insulin Signaling Cascade Plays a Dominant Role in Hepatic Nutrient Homeostasis

2009 ◽  
Vol 29 (18) ◽  
pp. 5070-5083 ◽  
Author(s):  
Shaodong Guo ◽  
Kyle D. Copps ◽  
Xiaocheng Dong ◽  
Sunmin Park ◽  
Zhiyong Cheng ◽  
...  
Keyword(s):  
Tyrosine Phosphorylation ◽  
High Fat Diet ◽  
Insulin Infusion ◽  
Dominant Role ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
High Fat ◽  
Lipogenic Genes ◽  
Hepatic Glucose ◽  
Nutrient Homeostasis

ABSTRACT We used a Cre-loxP approach to generate mice with varied expression of hepatic Irs1 and Irs2 to establish the contribution of each protein to hepatic nutrient homeostasis. While nutrient-sensitive transcripts were expressed nearly normally in liver lacking Irs2 (LKO2 mice), these transcripts were significantly dysregulated in liver lacking Irs1 (LKO1 mice) or Irs1 and Irs2 together (DKO mice). Similarly, a set of key gluconeogenic and lipogenic genes was regulated nearly normally by feeding in liver retaining a single Irs1 allele without Irs2 (DKO/1 mice) but was poorly regulated in liver retaining one Irs2 allele without Irs1 (DKO/2 mice). DKO/2 mice, but not DKO/1 mice, also showed impaired glucose tolerance and insulin sensitivity—though both Irs1 and Irs2 were required to suppress hepatic glucose production during hyperinsulinemic-euglycemic clamp. In contrast, either hepatic Irs1 or Irs2 mediated suppression of HGP by intracerebroventricular insulin infusion. After 12 weeks on a high-fat diet, postprandial tyrosine phosphorylation of Irs1 increased in livers of control and LKO2 mice, whereas tyrosine phosphorylation of Irs2 decreased in control and LKO1 mice. Moreover, LKO1 mice—but not LKO2 mice—that were fed a high-fat diet developed postprandial hyperglycemia. We conclude that Irs1 is the principal mediator of hepatic insulin action that maintains glucose homeostasis.

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

2007 ◽  
Vol 292 (6) ◽  
pp. E1775-E1781 ◽  
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.

Effect of a selective rise in hepatic artery insulin on hepatic glucose production in the conscious dog

1999 ◽  
Vol 276 (4) ◽  
pp. E806-E813
Author(s):  
Dana K. Sindelar ◽  
Kayano Igawa ◽  
Chang A. Chu ◽  
Jim H. Balcom ◽  
Doss W. Neal ◽  
...  
Keyword(s):  
Portal Vein ◽  
Hepatic Artery ◽  
Insulin Infusion ◽  
Hepatic Glucose Production ◽  
Control Period ◽  
Glucose Production ◽  
Insulin Level ◽  
Hepatic Glucose ◽  
Glucose Output ◽  
Selective Increase

In the present study we compared the hepatic effects of a selective increase in hepatic sinusoidal insulin brought about by insulin infusion into the hepatic artery with those resulting from insulin infusion into the portal vein. A pancreatic clamp was used to control the endocrine pancreas in conscious overnight-fasted dogs. In the control period, insulin was infused via peripheral vein and the portal vein. After the 40-min basal period, there was a 180-min test period during which the peripheral insulin infusion was stopped and an additional 1.2 pmol ⋅ kg−1⋅ min−1of insulin was infused into the hepatic artery (HART, n = 5) or the portal vein (PORT, n = 5, data published previously). In the HART group, the calculated hepatic sinusoidal insulin level increased from 99 ± 20 (basal) to 165 ± 21 pmol/l (last 30 min). The calculated hepatic artery insulin concentration rose from 50 ± 8 (basal) to 289 ± 19 pmol/l (last 30 min). However, the overall arterial (50 ± 8 pmol/l) and portal vein insulin levels (118 ± 24 pmol/l) did not change over the course of the experiment. In the PORT group, the calculated hepatic sinusoidal insulin level increased from 94 ± 30 (basal) to 156 ± 33 pmol/l (last 30 min). The portal insulin rose from 108 ± 42 (basal) to 192 ± 42 pmol/l (last 30 min), whereas the overall arterial insulin (54 ± 6 pmol/l) was unaltered during the study. In both groups hepatic sinusoidal glucagon levels remained unchanged, and euglycemia was maintained by peripheral glucose infusion. In the HART group, net hepatic glucose output (NHGO) was suppressed from 9.6 ± 2.1 μmol ⋅ kg−1⋅ min−1(basal) to 4.6 ± 1.0 μmol ⋅ kg−1⋅ min−1(15 min) and eventually fell to 3.5 ± 0.8 μmol ⋅ kg−1⋅ min−1(last 30 min, P < 0.05). In the PORT group, NHGO dropped quickly ( P < 0.05) from 10.0 ± 0.9 (basal) to 7.8 ± 1.6 (15 min) and eventually reached 3.1 ± 1.1 μmol ⋅ kg−1⋅ min−1(last 30 min). Thus NHGO decreases in response to a selective increase in hepatic sinusoidal insulin, regardless of whether it comes about because of hyperinsulinemia in the hepatic artery or portal vein.

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.

Indomethacin Stimulates Basal Glucose Production in Humans without Changes in Concentrations of Glucoregulatory Hormones

1993 ◽  
Vol 85 (6) ◽  
pp. 679-685 ◽  
Author(s):  
E. P. M. Corssmit ◽  
J. A. Romijn ◽  
E. Endert ◽  
H. P. Sauerwein
Keyword(s):  
Continuous Infusion ◽  
Control Experiment ◽  
Hepatic Glucose Production ◽  
Plasma Concentrations ◽  
Glucose Production ◽  
C Peptide ◽  
Hepatic Glucose ◽  
Glucoregulatory Hormones

1. To investigate whether indomethacin affects basal glucose production, we measured hepatic glucose production in six healthy postabsorptive subjects on two occasions: once after administration of indomethacin (150 mg orally) and once after administration of placebo. 2. Glucose production was measured by primed, continuous infusion of [3-3H]-glucose. 3. Indomethacin administration resulted in an increase in glucose production from 10.9 (SEM 0.3) μmol min−1 kg−1 to a maximum of 16.5 (SEM 1.6) μmol min−1 kg−1 (P <0.05) within ∼1 h, whereas in the control experiment glucose production declined gradually (P <0.01) (P <0.05 indomethacin versus control). There were no differences in plasma concentrations of insulin, C-peptide and counter-regulatory hormones between the two experiments. 4. Since indomethacin administration resulted in an increase in glucose production in the absence of any changes in concentrations of glucoregulatory hormones, we conclude that indomethacin stimulates hepatic glucose production through other mechanisms.

Effect of somatostatin on plasma glucagon and insulin, and glucose turnover in exercising sheep

1979 ◽  
Vol 47 (2) ◽  
pp. 273-278 ◽  
Author(s):  
R. P. Brockman
Keyword(s):  
Insulin Secretion ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Strenuous Exercise ◽  
Glucose Turnover ◽  
Moderate Exercise ◽  
Plasma Glucagon ◽  
Hepatic Glucose ◽  
Exercise Induced ◽  
Glucagon And Insulin

To examine the roles of glucagon and insulin in exercise, four sheep were run on a treadmill with and without simultaneous infusion of somatostatin (SRIF), a peptide that suppresses glucagon and insulin secretion. SRIF infusion suppressed the exercise-induced rise in plasma glucagon during both moderate (5--5.5 km/h) and strenuous exercise (7.0 km/h). In addition, SRIF prevented the rise insulin concentrations during moderate exercise. During strenuous exercise, insulin concentrations were depressed in both groups. The infusion of SRIF was associated with a reduction in exercise-induced glucose production, as determined by infusion of [6–3H]glucose, during the first 15 min of both moderate and strenuous exercise compared to controls. Beyond 15 min glucose production was not significantly altered by SRIF infusions. These data are consistent with glucagon having an immediate, but only transient, stimulatory effect on the exercise-induced hepatic glucose production.

scholarly journals Phenotypic and Molecular Evaluation of a Chromosome 1q Region with Linkage and Association to Type 2 Diabetes in Humans

2009 ◽  
Vol 94 (4) ◽  
pp. 1401-1408 ◽  
Author(s):  
Hua Wang ◽  
Nicholas P. Hays ◽  
Swapan K. Das ◽  
Rebekah L. Craig ◽  
Winston S. Chu ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Hepatic Glucose Production ◽  
Linkage Disequilibrium Block ◽  
Glucose Production ◽  
Risk Haplotype ◽  
Expression Of Genes ◽  
Hepatic Glucose

Abstract Objective: Linkage to type 2 diabetes (T2D) is well replicated on chromosome 1q21-q23. Within this region, T2D was associated with common single nucleotide polymorphisms that marked an extended linkage disequilibrium block, including the liver pyruvate kinase gene (PKLR), in several European-derived populations. In this study we sought to determine the molecular basis for the association and the phenotypic consequences of the risk haplotype. Research Design and Methods: Genes surrounding PKLR were resequenced in European-American and African-American cases and controls, and association with T2D was tested. Copy number variants (CNVs) were tested for four regions with real-time PCR. Expression of genes in the region was tested in adipose and muscle from nondiabetic subjects with each genotype. Insulin secretion, insulin sensitivity, and hepatic glucose production were tested in nondiabetic individuals with each haplotype combination. Results: No coding variant in the region was associated with T2D. CNVs were rare and not associated with T2D. PKLR was not expressed in available tissues, but expression of genes HCN3, CLK2, SCAMP3, and FDPS was not associated with haplotype combinations in adipose or muscle. Haplotype combinations were not associated with insulin secretion or peripheral insulin sensitivity, but homozygous carriers of the risk haplotype had increased hepatic glucose production during hyperinsulinemia. Conclusions: Noncoding variants in the PKLR region likely alter gene expression of one or more genes. Our extensive physiological and molecular studies suggest increased hepatic glucose production and reduced hepatic insulin sensitivity, thus pointing to PKLR itself as the most likely candidate gene in this population.

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