The kinetics of glucagon action on the liver during insulin-induced hypoglycemia

Glucagon’s effect on hepatic glucose production (HGP), under hyperglycemic conditions, is time dependent such that after an initial burst of HGP, it slowly wanes. It is not known whether this is also the case under hypoglycemic conditions, where an increase in HGP is essential. This question was addressed using adrenalectomized dogs to avoid the confounding effects of other counterregulatory hormones. During the study, infusions of epinephrine and cortisol were given to maintain basal levels. Somatostatin and insulin (800 µU·kg−1·min−1) were infused to induce hypoglycemia. After 30 min, glucagon was infused at a basal rate (1 ng·kg−1·min−1, baGGN group, n = 5 dogs) or a rate eightfold basal (8 ng·kg−1·min−1, hiGGN group, n = 5 dogs) for 4 h. Glucose was infused to match the arterial glucose levels between groups (≈50 mg/dL). Our data showed that glucagon has a biphasic effect on the liver despite hypoglycemia. Hyperglucagonemia stimulated a rapid, transient peak in HGP (4-fold basal production) over ~60 min, which was followed by a slow reduction in HGP to a rate 1.5-fold basal. During the last 2 h of the experiment, hiGGN stimulated glucose production at a rate fivefold greater than baGGN (2.5 vs. 0.5 mg·kg−1·min−1, respectively), indicating a sustained effect of the hormone. Of note, the hypoglycemia-induced rises in norepinephrine and glycerol were smaller in hiGGN compared with the baGGN group despite identical hypoglycemia. This finding suggests that there is reciprocity between glucagon and the sympathetic nervous system such that when glucagon is increased, the sympathetic nervous response to hypoglycemia is downregulated.

Accuracy of Capillary and Arterial Whole Blood Glucose Measurements Using a Glucose Meter in Patients under General Anesthesia in the Operating Room

Background The aim of this study was to evaluate the use of a glucose meter with surgical patients under general anesthesia in the operating room. Methods Glucose measurements were performed intraoperatively on 368 paired capillary and arterial whole blood samples using a Nova StatStrip (Nova Biomedical, USA) glucose meter and compared with 368 reference arterial whole blood glucose measurements by blood gas analyzer in 196 patients. Primary outcomes were median bias (meter minus reference), percentage of glucose meter samples meeting accuracy criteria for subcutaneous insulin dosing as defined by Parkes error grid analysis for type 1 diabetes mellitus, and accuracy criteria for intravenous insulin infusion as defined by Clinical and Laboratory Standards Institute guidelines. Time under anesthesia, patient position, diabetes status, and other variables were studied to determine whether any affected glucose meter bias. Results Median bias (interquartile range) was −4 mg/dl (−9 to 0 mg/dl), which did not differ from median arterial meter bias of −5 mg/dl (−9 to −1 mg/dl; P = 0.32). All of the capillary and arterial glucose meter values met acceptability criteria for subcutaneous insulin dosing, whereas only 89% (327 of 368) of capillary and 93% (344 of 368) arterial glucose meter values met accuracy criteria for intravenous insulin infusion. Time, patient position, and diabetes status were not associated with meter bias. Conclusions Capillary and arterial blood glucose measured using the glucose meter are acceptable for intraoperative subcutaneous insulin dosing. Whole blood glucose on the meter did not meet accuracy guidelines established specifically for more intensive (e.g., intravenous insulin) glycemic control in the acute care environment.

Correction for the Effect of Rising Plasma Glucose Levels on Quantification of MRglc with FDG-PET

Positron emission tomography (PET) using the tracer [18F]-fluorodeoxyglucose (FDG) is commonly used for measuring metabolic rate of glucose ( MRglc) in the human brain. Conventional PET methods (e.g., the Patlak method) for quantifying MRglc assume the tissue transport and phosphorylation mechanisms to be in steady state during FDG uptake. As FDG and glucose use the same transporters and phosphorylation enzymes, changing blood glucose levels can change the rates of FDG transport and phosphorylation. Compartmental models were used to simulate the effect of rising arterial glucose, from normal to hyperglycemic levels on FDG uptake for a typical PET protocol. The subsequent errors on the values of MRglc calculated using the Patlak method were investigated, and a correction scheme based on measured arterial glucose concentration ( Gp) was evaluated. Typically, with a 40% rise in Gp over the duration of the PET study, the true MRglc varied by only 1%; however, the Patlak method overestimated MRglc by 15%. The application of the correction reduced this error to −2%. In general, the application of the correction resulted in values of MRglc consistently significantly closer to the true steady state calculation of MRglc independently of changes to the parameters defining the model.

Hepatic portal venous delivery of a nitric oxide synthase inhibitor enhances net hepatic glucose uptake

Hepatic portal venous infusion of nitric oxide synthase (NOS) inhibitors causes muscle insulin resistance, but the effects on hepatic glucose disposition are unknown. Conscious dogs underwent a hyperinsulinemic (4-fold basal) hyperglycemic (hepatic glucose load 2-fold basal) clamp, with assessment of liver metabolism by arteriovenous difference methods. After 90 min (P1), dogs were divided into two groups: control (receiving intraportal saline infusion; n = 8) and LN [receiving NG-nitro-l-arginine methyl ester (l-NAME), a nonspecific NOS inhibitor; n = 11] intraportally at 0.3 mg·kg−1·min−1 for 90 min (P2). During the final 60 min of study (P3), l-NAME was discontinued, and five LN dogs received the NO donor SIN-1 intraportally at 6 μg·kg−1·min−1 while six received saline (LN/SIN-1 and LN/SAL, respectively). Net hepatic fractional glucose extraction (NHFE) in control dogs was 0.034 ± 0.016, 0.039 ± 0.015, and 0.056 ± 0.019 during P1, P2, and P3, respectively. NHFE in LN was 0.045 ± 0.009 and 0.111 ± 0.007 during P1 and P2, respectively ( P < 0.05 vs. control during P2), and 0.087 ± 0.009 and 0.122 ± 0.016 ( P < 0.05) during P3 in LN/SIN-1 and LN/SAL, respectively. During P2, arterial glucose was 204 ± 5 vs. 138 ± 11 mg/dl ( P < 0.05) in LN vs. control to compensate for l-NAME's effect on blood flow. Therefore, another group (LNlow; n = 4) was studied in the same manner as LN/SAL, except that arterial glucose was clamped at the same concentrations as in control. NHFE in LNlow was 0.052 ± 0.008, 0.093 ± 0.023, and 0.122 ± 0.021 during P1, P2, and P3, respectively ( P < 0.05 vs. control during P2 and P3), with no significant difference in glucose infusion rates. Thus, NOS inhibition enhanced NHFE, an effect partially reversed by SIN-1.

Pregnancy impairs the counterregulatory response to insulin-induced hypoglycemia in the dog

The impact of pregnancy on the counterregulatory response to insulin-induced hypoglycemia was examined in six nonpregnant (NP) and six pregnant (P; 3rd trimester) conscious dogs by tracer and arteriovenous difference techniques. After basal sampling, insulin was infused intraportally at 30 pmol·kg−1·min−1 for 180 min. Insulin rose from 70 ± 15 to 1,586 ± 221 pmol/l and 27 ± 4 to 1,247 ± 61 pmol/l in the 3rd h in NP and P, respectively. Arterial glucose fell from 5.9 ± 0.2 to 2.3 ± 0.2 mmol/l in P. Glucose was infused in NP to equate the rate of fall of glucose and the steady-state concentrations in the groups (5.9 ± 0.2 to 2.3 ± 0.1 mmol/l in NP). Glucagon was 32 ± 6, 69 ± 11, and 48 ± 10 ng/l (basal and 1st and 3rd h) in NP, but the response was attenuated in P (34 ± 5, 46 ± 6, 41 ± 9 ng/l). Cortisol and epinephrine rose similarly in both groups, but norepinephrine rose more in NP (Δ3.01 ± 0.46 and Δ1.31 ± 0.13 nmol/l, P < 0.05). Net hepatic glucose output (NHGO; μmol·kg−1·min−1) increased from 10.6 ± 1.8 to 21.2 ± 3.3 in NP (3rd h) but did not increase in P (15.1 ± 1.5 to 15.3 ± 2.8 μmol·kg−1·min−1, P < 0.05 between groups). The glycogenolytic contribution to NHGO in NP increased from 5.8 ± 0.7 to 10.4 ± 2.5 μmol·kg−1·min−1 by 90 min but steadily declined in P. The increase in glycerol levels and the gluconeogenic contribution to NHGO were 50% less in P than in NP, but ketogenesis did not differ. The glucagon and norepinephrine responses to insulin-induced hypoglycemia are blunted in late pregnancy in the dog, impacting on the magnitude of the metabolic responses to the fall in glucose.

Hepatic glucose autoregulation: responses to small, non-insulin-induced changes in arterial glucose

The purpose of this study was to determine whether the sedentary dog is able to autoregulate glucose production (Ra) in response to non-insulin-induced changes (<20 mg/dl) in arterial glucose. Dogs had catheters implanted >16 days before study. Protocols consisted of basal (−30 to 0 min) and bilateral renal arterial phloridzin infusion (0–180 min) periods. Somatostatin was infused, and glucagon and insulin were replaced to basal levels. In one protocol (Phl ± Glc), glucose was allowed to fall from t = 0–90 min. This was followed by a period when glucose was infused to restore euglycemia (90–150 min) and a period when glucose was allowed to fall again (150–180 min). In a second protocol (EC), glucose was infused to compensate for the renal glucose loss due to phloridzin and maintain euglycemia from t = 0–180 min. Arterial insulin, glucagon, cortisol, and catecholamines remained at basal in both protocols. In Phl ± Glc, glucose fell by ∼20 mg/dl by t = 90 min with phloridzin infusion. Radid not change from basal in Phl ± Glc despite the fall in glucose for the first 90 min. Rawas significantly suppressed with restoration of euglycemia from t = 90–150 min ( P < 0.05) and returned to basal when glucose was allowed to fall from t = 150–180 min. Radid not change from basal in EC. In conclusion, the liver autoregulates Rain response to small changes in glucose independently of changes in pancreatic hormones at rest. However, the liver of the resting dog is more sensitive to a small increment, rather than decrement, in arterial glucose.