ABSTRACTOBJECTIVEEfficacy and safety of ultra-rapid acting oral prandial insulin Tregopil (Tregop... more ABSTRACTOBJECTIVEEfficacy and safety of ultra-rapid acting oral prandial insulin Tregopil (Tregopil) was compared with insulin aspart (IAsp) in patients with type-2 diabetes on stable doses of insulin glargine and metformin.RESEARCH DESIGN AND METHODSIn this open-label, active-controlled trial, patients with type-2 diabetes, with HbA1c ≥7% and ≤9% and 2-h postprandial glucose (PPG) ≥180 mg/dL were randomized (1:1:1) to Tregopil (30 mg [n=30], 45 mg [n=31]) and IAsp (n=30; dose titrated based on self-monitored blood glucose [SMBG]). Postprandial plasma glucose excursion (PPGE) and PPG were assessed from the standardized test meal (STM) and 9- point SMBG. The primary outcome measure was change from baseline (CFB) in HbA1c at week 24.RESULTSThe Tregopil (30 mg) arm showed significantly lesser 1-h PPGE (CFB) excursion after the STM versus IAsp (Estimated Treatment Difference [ETD], 95% CI, -45.33 mg/dL [-71.91, -8.75], P=0.001) and 1-h PPG trended towards a better control. The combined ...
Our aim was to evaluate pharmacodynamics (PD) of insulin tregopil (IN-105) in relation to pre-mea... more Our aim was to evaluate pharmacodynamics (PD) of insulin tregopil (IN-105) in relation to pre-meal dosing time in type 2 diabetes mellitus (T2DM) patients in a randomized, placebo-controlled, crossover study. Fifteen patients were randomised to 5 sequences (3 patients each) and administered 4 treatments (Insulin tregopil 30 mg given 30, 20 and 10 minutes before American diabetes association (ADA) meal and placebo given 20 minutes before ADA meal) in a partial replicate crossover fashion with a washout period of 1-2 days between periods. PD sampling was done from dosing to 180 min post-meal. AUC0-180min (glucose exposure), Cmin (minimum glucose concentration observed in the sampling period) and tmin (indicating time of peak PD effect) are presented in Table 1. Maximal reduction in plasma glucose (difference between baseline [meal administration] and minimum post-meal plasma glucose concentration) was 15.7 mg/dL, 9.5 mg/dL and 9.7 mg/dL for 30, 20 and 10 minutes groups, respectively. ...
Our aim was to evaluate pharmacodynamics (PD) of insulin tregopil (IN-105) in relation to meal co... more Our aim was to evaluate pharmacodynamics (PD) of insulin tregopil (IN-105) in relation to meal composition in type 2 diabetes mellitus patients in placebo-controlled, crossover study. Eighteen patients were randomised to 6 sequences and administered insulin tregopil 30 mg or placebo, 20 minutes prior to 2 meals (separated by 5 hours). Morning meal was ADA/high-fat/high-fibre meal while afternoon was ADA meal. PD sampling was done from dosing up to 180 minutes post dose. AUC0-180min (glucose exposure), Cmin (minimum glucose concentration observed) and tmin (time of peak PD effect) are presented in Table 1. Insulin tregopil administration following high-fat and high-fibre meal in morning resulted in glucose exposure (GM ratio of AUC0-180 min, baseline-corrected) of 92% and 98% compared to ADA meal, respectively; and 99% and 94%, respectively, after afternoon meal, compared to ADA meal. Maximal reduction in plasma glucose for ADA-ADA, high fibre-ADA and high fat-ADA meal groups was 42....
American Journal of Physiology-Gastrointestinal and Liver Physiology, 2004
The rate of liver glucokinase (GK) translocation from the nucleus to the cytoplasm in response to... more The rate of liver glucokinase (GK) translocation from the nucleus to the cytoplasm in response to intraduodenal glucose infusion and the effect of physiological rises of plasma glucose and/or insulin on GK translocation were examined in 6-h-fasted conscious rats. Intraduodenal glucose infusion (28 mg·kg-1·min-1after a priming dose at 500 mg/kg) elevated blood glucose levels (mg/dl) in the artery and portal vein from 90 ± 3 and 87 ± 3 to 154 ± 4 and 185 ± 4, respectively, at 10 min. At 120 min, the levels had decreased to 133 ± 6 and 156 ± 5, respectively. Plasma insulin levels (ng/ml) in the artery and the portal vein rose from 0.7 ± 0.1 and 1.8 ± 0.3 to 11.8 ± 1.5 and 20.2 ± 2.0 at 10 min, respectively, and 12.4 ± 3.1 and 18.0 ± 4.8 at 30 min, respectively. GK was rapidly exported from the nucleus as determined by measuring the ratio of the nuclear to the cytoplasmic immunofluorescence (N/C) of GK (2.9 ± 0.3 at 0 min to 1.7 ± 0.2 at 10 min, 1.5 ± 0.1 at 20 min, 1.3 ± 0.1 at 30 min,...
Insulin resistance is an underappreciated facet of type 1 diabetes that occurs with remarkable co... more Insulin resistance is an underappreciated facet of type 1 diabetes that occurs with remarkable consistency and considerable magnitude. Although therapeutic innovations are continuing to normalize dysglycemia, a sizable body of data suggests a second metabolic abnormality—iatrogenic hyperinsulinemia—principally drives insulin resistance and its consequences in this population and has not been addressed. We review this evidence to show that injecting insulin into the peripheral circulation bypasses first-pass hepatic insulin clearance, which leads to the unintended metabolic consequence of whole-body insulin resistance. We propose restructuring insulin therapy to restore the physiological insulin balance between the hepatic portal and peripheral circulations and thereby avoid the complications of life-long insulin resistance. As technology rapidly advances and our ability to ensure euglycemia improves, iatrogenic insulin resistance will become the final barrier to overcome to restore ...
The second meal phenomenon, which occurs in normal and diabetic individuals, refers to the improv... more The second meal phenomenon, which occurs in normal and diabetic individuals, refers to the improvement in glucose tolerance seen following a second identical meal. We previously showed that 4h of morning (AM) hyperinsulinemia, but not hyperglycemia, enhanced hepatic glucose uptake (HGU) and glycogen storage during a PM hyperinsulinemic hyperglycemic clamp (HIHG) later that day. Our aim was to determine if the duration of morning hyperinsulinemia is important for the PM response to a HIHG clamp. To determine this, we administered the same amount of insulin over 2h in the first half of the morning (Ins2h-A), over 2h in the 2nd half of the morning (Ins2h-B), or over the entire 4h (Ins4h) of the morning. We then assessed the impact of the AM insulin duration on HGU during a PM HIHG clamp in conscious dogs. The dogs underwent an AM hyperinsulinemic euglycemic clamp from 0-120 min, 120-240 min, or 0-240 min (Ins2h-A, Ins2h-B, or Ins4h; n=6/group). The insulin infusion rates used in the Ins4h were selected to mimic the rise in endogenous insulin secretion previously observed during a 4h AM duodenal glucose infusion (2.1 mU/kg/min (0-30 min), 2.4 mU/kg/min (30-60 min), and 1.5 mU/kg/min (60-240 min)). These rates were doubled in both 2h groups to match the total amount of insulin being infused in the 4h AM clamp. In the PM, all groups had 4x basal insulin, 2x basal glycemia, and portal glucose infusion to simulate a 2nd meal. During the 4h PM clamp, there were no significant differences between the two 2h groups. However, there was a marked effect on the mean HGU in the Ins4h group compared to the Ins2h-A and Ins2h-B groups (HGU of 6.3±0.9 vs 3.8±0.3 and 4.4±0.4 mg/kg/min; AUC of 1393±199 vs 822±68 and 971±93 mg/kg/4hr, P<0.05), respectively, despite matched hepatic glucose loads. The longer duration (Ins4h) of AM hyperinsulinemia allowed for a 41% and 66% greater uptake of glucose in the PM clamp (vs Ins2hA + B). Thus, the duration of AM hyperinsulinemia is an important determinant of hepatic metabolism later in the day. Disclosure H.L.Waterman: None. M.S.Smith: None. B.Farmer: None. G.Kraft: None. M.Scott: None. D.S.Edgerton: None. A.D.Cherrington: Advisory Panel; Metavention, vTv Therapeutics, Diakard, Sekkei Bio, Sensulin Labs, LLC, Other Relationship; Fractyl Health, Inc., Novo Nordisk, Abvance Therapeutics, Research Support; Cellular Longevity, Inc, dba Loyal, Senda Biosciences. M.C.Moore: None. Funding National Institutes of Health (5T32DK007563-34, 5R01DK131082-02)
American Journal of Physiology-endocrinology and Metabolism, Mar 1, 1995
The aim of this study was to determine the effects of differing insulin concentrations on the glu... more The aim of this study was to determine the effects of differing insulin concentrations on the gluconeogenic response to equivalent prolonged hypoglycemia. Insulin was infused intraportally, for 3 h, into normal 18-h fasted conscious dogs at 2 (lower, n = 6) or 8 mU.kg-1.min-1 (high, n = 7) on separate occasions. This resulted in steady-state arterial insulin levels of 80 +/- 8 and 610 +/- 55 microU/ml, respectively. Glucose was infused during high dose to maintain the hypoglycemic plateau (50 +/- 1 mg/dl) equivalent to lower. Epinephrine (806 +/- 180 vs. 2,589 +/- 260 pg/ml), norepinephrine (303 +/- 55 vs. 535 +/- 60 pg/ml), cortisol (5.8 +/- 1.2 vs. 12.1 +/- 1.5 micrograms/dl), and pancreatic polypeptide (598 +/- 250 vs. 1,198 +/- 150 pg/ml) were all increased (P < 0.05) in the presence of high-dose insulin. Net hepatic glucose production increased significantly from 2.2 +/- 0.3 to 3.8 +/- 0.5 mg.kg-1.min-1 (P < 0.05) during high-dose infusion but remained at basal levels (2.3 +/- 0.4 mg.kg-1.min-1) during lower-dose insulin. During the 3rd h of hypoglycemia, gluconeogenesis accounted for between 42 and 100% of glucose production during high-dose infusion but only 22-52% during lower-dose insulin. Intrahepatic gluconeogenic efficiency, however, increased similarly during both protocols. Lipolysis, as indicated by arterial blood glycerol levels, increased by a greater amount during high- compared with lower-dose insulin infusion. Six hyperinsulinemic euglycemic control experiments (2 or 8 mU.kg-1.min-1, n = 3 in each) provided baseline data. Gluconeogenesis remained similar to basal levels, but lipolysis was significantly suppressed during both series of hyperinsulinemic euglycemic studies. In summary, these data suggest that 1) the important counterregulatory processes of gluconeogenesis and lipolysis can be significantly increased during prolonged hypoglycemia despite an eightfold increase in circulating insulin levels and 2) the amplified gluconeogenic rate present during the hypoglycemic high-dose insulin infusions was caused by enhanced substrate delivery to the liver rather than an increase in intrahepatic gluconeogenic efficiency.
Hepatic glucose uptake (HGU) is critical for maintaining normal postprandial glucose metabolism. ... more Hepatic glucose uptake (HGU) is critical for maintaining normal postprandial glucose metabolism. Insulin is clearly a key regulator of HGU, but the physiologic mechanisms by which it acts have yet to be established. This study sought to determine the mechanisms by which insulin regulates liver glucose uptake under postprandial-like conditions (hyperinsulinemia, hyperglycemia, and a positive portal vein-to-arterial glucose gradient). Portal vein insulin infusion increased hepatic insulin levels fivefold in healthy dogs. In one group (n = 7), the physiologic response was allowed to fully occur, while in another (n = 7), insulin’s indirect hepatic effects, occurring secondary to its actions on adipose tissue, pancreas, and brain, were blocked. This was accomplished by infusing triglyceride (intravenous), glucagon (portal vein), and inhibitors of brain insulin action (intracerebroventricular) to prevent decreases in plasma free fatty acids or glucagon, while blocking increased hypothala...
American Journal of Physiology-Endocrinology and Metabolism, 2020
Bromocriptine mesylate treatment was examined in dogs fed a high fat diet (HFD) for 8 wk. After 4... more Bromocriptine mesylate treatment was examined in dogs fed a high fat diet (HFD) for 8 wk. After 4 wk on HFD, daily bromocriptine (Bromo; n = 6) or vehicle (CTR; n = 5) injections were administered. Oral glucose tolerance tests were performed before beginning HFD (OGTT1), 4 wk after HFD began (Bromo only), and after 7.5 wk on HFD (OGTT3). After 8 wk on HFD, clamp studies were performed, with infusion of somatostatin and intraportal replacement of insulin (4× basal) and glucagon (basal). From 0 to 90 min (P1), glucose was infused via peripheral vein to double the hepatic glucose load; and from 90 to 180 min (P2), glucose was infused via the hepatic portal vein at 4 mg·kg−1·min−1, with the HGL maintained at 2× basal. Bromo decreased the OGTT glucose ΔAUC0–30and ΔAUC0–120by 62 and 27%, respectively, P < 0.05 for both) without significantly altering the insulin response. Bromo dogs exhibited enhanced net hepatic glucose uptake (NHGU) compared with CTR (~33 and 21% greater, P1 and P2, ...
Oral insulin avoids the need for injections, and insulin enters via the hepatic portal vein (Po),... more Oral insulin avoids the need for injections, and insulin enters via the hepatic portal vein (Po), the normal route of secretion. We examined the effect of I338, an acylated analog designed for oral use, dosed either Po to match the oral absorption profile or IV to match the steady state basal subcutaneous (SC) plasma profile, on a Po glucose challenge. To achieve steady-state concentrations in normal dogs, I338 was infused IV 45 min daily for 4 days. On day 5 a primed, continuous infusion of 3-3H glucose was given. After 90 min of equilibration and 30 min of basal sampling, a clamp was conducted (0-300 min), with somatostatin to inhibit pancreatic secretion and basal glucagon replacement. In the LOW dogs (n=5) I338 (pmol/kg/min) was infused either Po at 40 (0-45 min to mimic oral absorption) or IV at 1 (0-300 min to mimic subcutaneous [SC] delivery), approximately an equivalent daily dose (1800 vs. 1440 pmol/kg, Po vs. IV). High dose dogs (HI; n=4) received I338 at 50 (Po) or 5 (IV)...
ABSTRACTOBJECTIVEEfficacy and safety of ultra-rapid acting oral prandial insulin Tregopil (Tregop... more ABSTRACTOBJECTIVEEfficacy and safety of ultra-rapid acting oral prandial insulin Tregopil (Tregopil) was compared with insulin aspart (IAsp) in patients with type-2 diabetes on stable doses of insulin glargine and metformin.RESEARCH DESIGN AND METHODSIn this open-label, active-controlled trial, patients with type-2 diabetes, with HbA1c ≥7% and ≤9% and 2-h postprandial glucose (PPG) ≥180 mg/dL were randomized (1:1:1) to Tregopil (30 mg [n=30], 45 mg [n=31]) and IAsp (n=30; dose titrated based on self-monitored blood glucose [SMBG]). Postprandial plasma glucose excursion (PPGE) and PPG were assessed from the standardized test meal (STM) and 9- point SMBG. The primary outcome measure was change from baseline (CFB) in HbA1c at week 24.RESULTSThe Tregopil (30 mg) arm showed significantly lesser 1-h PPGE (CFB) excursion after the STM versus IAsp (Estimated Treatment Difference [ETD], 95% CI, -45.33 mg/dL [-71.91, -8.75], P=0.001) and 1-h PPG trended towards a better control. The combined ...
Our aim was to evaluate pharmacodynamics (PD) of insulin tregopil (IN-105) in relation to pre-mea... more Our aim was to evaluate pharmacodynamics (PD) of insulin tregopil (IN-105) in relation to pre-meal dosing time in type 2 diabetes mellitus (T2DM) patients in a randomized, placebo-controlled, crossover study. Fifteen patients were randomised to 5 sequences (3 patients each) and administered 4 treatments (Insulin tregopil 30 mg given 30, 20 and 10 minutes before American diabetes association (ADA) meal and placebo given 20 minutes before ADA meal) in a partial replicate crossover fashion with a washout period of 1-2 days between periods. PD sampling was done from dosing to 180 min post-meal. AUC0-180min (glucose exposure), Cmin (minimum glucose concentration observed in the sampling period) and tmin (indicating time of peak PD effect) are presented in Table 1. Maximal reduction in plasma glucose (difference between baseline [meal administration] and minimum post-meal plasma glucose concentration) was 15.7 mg/dL, 9.5 mg/dL and 9.7 mg/dL for 30, 20 and 10 minutes groups, respectively. ...
Our aim was to evaluate pharmacodynamics (PD) of insulin tregopil (IN-105) in relation to meal co... more Our aim was to evaluate pharmacodynamics (PD) of insulin tregopil (IN-105) in relation to meal composition in type 2 diabetes mellitus patients in placebo-controlled, crossover study. Eighteen patients were randomised to 6 sequences and administered insulin tregopil 30 mg or placebo, 20 minutes prior to 2 meals (separated by 5 hours). Morning meal was ADA/high-fat/high-fibre meal while afternoon was ADA meal. PD sampling was done from dosing up to 180 minutes post dose. AUC0-180min (glucose exposure), Cmin (minimum glucose concentration observed) and tmin (time of peak PD effect) are presented in Table 1. Insulin tregopil administration following high-fat and high-fibre meal in morning resulted in glucose exposure (GM ratio of AUC0-180 min, baseline-corrected) of 92% and 98% compared to ADA meal, respectively; and 99% and 94%, respectively, after afternoon meal, compared to ADA meal. Maximal reduction in plasma glucose for ADA-ADA, high fibre-ADA and high fat-ADA meal groups was 42....
American Journal of Physiology-Gastrointestinal and Liver Physiology, 2004
The rate of liver glucokinase (GK) translocation from the nucleus to the cytoplasm in response to... more The rate of liver glucokinase (GK) translocation from the nucleus to the cytoplasm in response to intraduodenal glucose infusion and the effect of physiological rises of plasma glucose and/or insulin on GK translocation were examined in 6-h-fasted conscious rats. Intraduodenal glucose infusion (28 mg·kg-1·min-1after a priming dose at 500 mg/kg) elevated blood glucose levels (mg/dl) in the artery and portal vein from 90 ± 3 and 87 ± 3 to 154 ± 4 and 185 ± 4, respectively, at 10 min. At 120 min, the levels had decreased to 133 ± 6 and 156 ± 5, respectively. Plasma insulin levels (ng/ml) in the artery and the portal vein rose from 0.7 ± 0.1 and 1.8 ± 0.3 to 11.8 ± 1.5 and 20.2 ± 2.0 at 10 min, respectively, and 12.4 ± 3.1 and 18.0 ± 4.8 at 30 min, respectively. GK was rapidly exported from the nucleus as determined by measuring the ratio of the nuclear to the cytoplasmic immunofluorescence (N/C) of GK (2.9 ± 0.3 at 0 min to 1.7 ± 0.2 at 10 min, 1.5 ± 0.1 at 20 min, 1.3 ± 0.1 at 30 min,...
Insulin resistance is an underappreciated facet of type 1 diabetes that occurs with remarkable co... more Insulin resistance is an underappreciated facet of type 1 diabetes that occurs with remarkable consistency and considerable magnitude. Although therapeutic innovations are continuing to normalize dysglycemia, a sizable body of data suggests a second metabolic abnormality—iatrogenic hyperinsulinemia—principally drives insulin resistance and its consequences in this population and has not been addressed. We review this evidence to show that injecting insulin into the peripheral circulation bypasses first-pass hepatic insulin clearance, which leads to the unintended metabolic consequence of whole-body insulin resistance. We propose restructuring insulin therapy to restore the physiological insulin balance between the hepatic portal and peripheral circulations and thereby avoid the complications of life-long insulin resistance. As technology rapidly advances and our ability to ensure euglycemia improves, iatrogenic insulin resistance will become the final barrier to overcome to restore ...
The second meal phenomenon, which occurs in normal and diabetic individuals, refers to the improv... more The second meal phenomenon, which occurs in normal and diabetic individuals, refers to the improvement in glucose tolerance seen following a second identical meal. We previously showed that 4h of morning (AM) hyperinsulinemia, but not hyperglycemia, enhanced hepatic glucose uptake (HGU) and glycogen storage during a PM hyperinsulinemic hyperglycemic clamp (HIHG) later that day. Our aim was to determine if the duration of morning hyperinsulinemia is important for the PM response to a HIHG clamp. To determine this, we administered the same amount of insulin over 2h in the first half of the morning (Ins2h-A), over 2h in the 2nd half of the morning (Ins2h-B), or over the entire 4h (Ins4h) of the morning. We then assessed the impact of the AM insulin duration on HGU during a PM HIHG clamp in conscious dogs. The dogs underwent an AM hyperinsulinemic euglycemic clamp from 0-120 min, 120-240 min, or 0-240 min (Ins2h-A, Ins2h-B, or Ins4h; n=6/group). The insulin infusion rates used in the Ins4h were selected to mimic the rise in endogenous insulin secretion previously observed during a 4h AM duodenal glucose infusion (2.1 mU/kg/min (0-30 min), 2.4 mU/kg/min (30-60 min), and 1.5 mU/kg/min (60-240 min)). These rates were doubled in both 2h groups to match the total amount of insulin being infused in the 4h AM clamp. In the PM, all groups had 4x basal insulin, 2x basal glycemia, and portal glucose infusion to simulate a 2nd meal. During the 4h PM clamp, there were no significant differences between the two 2h groups. However, there was a marked effect on the mean HGU in the Ins4h group compared to the Ins2h-A and Ins2h-B groups (HGU of 6.3±0.9 vs 3.8±0.3 and 4.4±0.4 mg/kg/min; AUC of 1393±199 vs 822±68 and 971±93 mg/kg/4hr, P&lt;0.05), respectively, despite matched hepatic glucose loads. The longer duration (Ins4h) of AM hyperinsulinemia allowed for a 41% and 66% greater uptake of glucose in the PM clamp (vs Ins2hA + B). Thus, the duration of AM hyperinsulinemia is an important determinant of hepatic metabolism later in the day. Disclosure H.L.Waterman: None. M.S.Smith: None. B.Farmer: None. G.Kraft: None. M.Scott: None. D.S.Edgerton: None. A.D.Cherrington: Advisory Panel; Metavention, vTv Therapeutics, Diakard, Sekkei Bio, Sensulin Labs, LLC, Other Relationship; Fractyl Health, Inc., Novo Nordisk, Abvance Therapeutics, Research Support; Cellular Longevity, Inc, dba Loyal, Senda Biosciences. M.C.Moore: None. Funding National Institutes of Health (5T32DK007563-34, 5R01DK131082-02)
American Journal of Physiology-endocrinology and Metabolism, Mar 1, 1995
The aim of this study was to determine the effects of differing insulin concentrations on the glu... more The aim of this study was to determine the effects of differing insulin concentrations on the gluconeogenic response to equivalent prolonged hypoglycemia. Insulin was infused intraportally, for 3 h, into normal 18-h fasted conscious dogs at 2 (lower, n = 6) or 8 mU.kg-1.min-1 (high, n = 7) on separate occasions. This resulted in steady-state arterial insulin levels of 80 +/- 8 and 610 +/- 55 microU/ml, respectively. Glucose was infused during high dose to maintain the hypoglycemic plateau (50 +/- 1 mg/dl) equivalent to lower. Epinephrine (806 +/- 180 vs. 2,589 +/- 260 pg/ml), norepinephrine (303 +/- 55 vs. 535 +/- 60 pg/ml), cortisol (5.8 +/- 1.2 vs. 12.1 +/- 1.5 micrograms/dl), and pancreatic polypeptide (598 +/- 250 vs. 1,198 +/- 150 pg/ml) were all increased (P &lt; 0.05) in the presence of high-dose insulin. Net hepatic glucose production increased significantly from 2.2 +/- 0.3 to 3.8 +/- 0.5 mg.kg-1.min-1 (P &lt; 0.05) during high-dose infusion but remained at basal levels (2.3 +/- 0.4 mg.kg-1.min-1) during lower-dose insulin. During the 3rd h of hypoglycemia, gluconeogenesis accounted for between 42 and 100% of glucose production during high-dose infusion but only 22-52% during lower-dose insulin. Intrahepatic gluconeogenic efficiency, however, increased similarly during both protocols. Lipolysis, as indicated by arterial blood glycerol levels, increased by a greater amount during high- compared with lower-dose insulin infusion. Six hyperinsulinemic euglycemic control experiments (2 or 8 mU.kg-1.min-1, n = 3 in each) provided baseline data. Gluconeogenesis remained similar to basal levels, but lipolysis was significantly suppressed during both series of hyperinsulinemic euglycemic studies. In summary, these data suggest that 1) the important counterregulatory processes of gluconeogenesis and lipolysis can be significantly increased during prolonged hypoglycemia despite an eightfold increase in circulating insulin levels and 2) the amplified gluconeogenic rate present during the hypoglycemic high-dose insulin infusions was caused by enhanced substrate delivery to the liver rather than an increase in intrahepatic gluconeogenic efficiency.
Hepatic glucose uptake (HGU) is critical for maintaining normal postprandial glucose metabolism. ... more Hepatic glucose uptake (HGU) is critical for maintaining normal postprandial glucose metabolism. Insulin is clearly a key regulator of HGU, but the physiologic mechanisms by which it acts have yet to be established. This study sought to determine the mechanisms by which insulin regulates liver glucose uptake under postprandial-like conditions (hyperinsulinemia, hyperglycemia, and a positive portal vein-to-arterial glucose gradient). Portal vein insulin infusion increased hepatic insulin levels fivefold in healthy dogs. In one group (n = 7), the physiologic response was allowed to fully occur, while in another (n = 7), insulin’s indirect hepatic effects, occurring secondary to its actions on adipose tissue, pancreas, and brain, were blocked. This was accomplished by infusing triglyceride (intravenous), glucagon (portal vein), and inhibitors of brain insulin action (intracerebroventricular) to prevent decreases in plasma free fatty acids or glucagon, while blocking increased hypothala...
American Journal of Physiology-Endocrinology and Metabolism, 2020
Bromocriptine mesylate treatment was examined in dogs fed a high fat diet (HFD) for 8 wk. After 4... more Bromocriptine mesylate treatment was examined in dogs fed a high fat diet (HFD) for 8 wk. After 4 wk on HFD, daily bromocriptine (Bromo; n = 6) or vehicle (CTR; n = 5) injections were administered. Oral glucose tolerance tests were performed before beginning HFD (OGTT1), 4 wk after HFD began (Bromo only), and after 7.5 wk on HFD (OGTT3). After 8 wk on HFD, clamp studies were performed, with infusion of somatostatin and intraportal replacement of insulin (4× basal) and glucagon (basal). From 0 to 90 min (P1), glucose was infused via peripheral vein to double the hepatic glucose load; and from 90 to 180 min (P2), glucose was infused via the hepatic portal vein at 4 mg·kg−1·min−1, with the HGL maintained at 2× basal. Bromo decreased the OGTT glucose ΔAUC0–30and ΔAUC0–120by 62 and 27%, respectively, P < 0.05 for both) without significantly altering the insulin response. Bromo dogs exhibited enhanced net hepatic glucose uptake (NHGU) compared with CTR (~33 and 21% greater, P1 and P2, ...
Oral insulin avoids the need for injections, and insulin enters via the hepatic portal vein (Po),... more Oral insulin avoids the need for injections, and insulin enters via the hepatic portal vein (Po), the normal route of secretion. We examined the effect of I338, an acylated analog designed for oral use, dosed either Po to match the oral absorption profile or IV to match the steady state basal subcutaneous (SC) plasma profile, on a Po glucose challenge. To achieve steady-state concentrations in normal dogs, I338 was infused IV 45 min daily for 4 days. On day 5 a primed, continuous infusion of 3-3H glucose was given. After 90 min of equilibration and 30 min of basal sampling, a clamp was conducted (0-300 min), with somatostatin to inhibit pancreatic secretion and basal glucagon replacement. In the LOW dogs (n=5) I338 (pmol/kg/min) was infused either Po at 40 (0-45 min to mimic oral absorption) or IV at 1 (0-300 min to mimic subcutaneous [SC] delivery), approximately an equivalent daily dose (1800 vs. 1440 pmol/kg, Po vs. IV). High dose dogs (HI; n=4) received I338 at 50 (Po) or 5 (IV)...
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