Jason J. Winnick

Carbohydrate feedings during team sport exercise preserve physical and CNS function.

PURPOSE This study was designed to examine the effect of carbohydrate (CHO) feedings on physical and central nervous system (CNS) function during intermittent high-intensity exercise with physical demands similar to those of team sports such as basketball. METHODS Twenty active men (N = 10) and women (N = 10), with experience competing in team sports, performed three practice sessions before two experimental trials during which they were fed either a 6% CHO solution or a flavored placebo (PBO). Experimental trials consisted of four 15-min quarters of shuttle running with variable intensities ranging from walking (30% VO(2max)), to running (120% VO(2max)), to maximal sprinting, and 40 jumps at a target hanging at 80% of their maximum vertical jump height. Subjects received 5 mL.kg(-1) of fluid before exercise and 3 mL.kg(-1) after exercise, in addition to 3 mL.kg(-1) over a 5-min span after the first and third quarters, and 8 mL.kg(-1) during a 20-min halftime. During each break, the subjects performed a battery of tests measuring peripheral and CNS function, including 20-m sprints, a 60-s maximal jumping test, internal and external mood evaluation, cognitive function, force sensation, tests of motor skills, and target-jumping accuracy. RESULTS Compared with PBO, CHO feedings during exercise resulted in faster 20-m sprint times and higher average jump height in the fourth quarter (P < 0.05). CHO feedings also reduced force sensation, enhanced motor skills, and improved mood late in exercise versus PBO (P < 0.05). CONCLUSION These results suggest that CHO feedings during intermittent high-intensity exercise similar to that of team sports benefited both peripheral and CNS function late in exercise compared with a flavored placebo.

Insulin Delivery Into the Peripheral Circulation: A Key Contributor to Hypoglycemia in Type 1 Diabetes.

Hypoglycemia limits optimal glycemic control in type 1 diabetes mellitus (T1DM), making novel strategies to mitigate it desirable. We hypothesized that portal (Po) vein insulin delivery would lessen hypoglycemia. In the conscious dog, insulin was infused into the hepatic Po vein or a peripheral (Pe) vein at a rate four times of basal. In protocol 1, a full counterregulatory response was allowed, whereas in protocol 2, glucagon was fixed at basal, mimicking the diminished α-cell response to hypoglycemia seen in T1DM. In protocol 1, glucose fell faster with Pe insulin than with Po insulin, reaching 56 ± 3 vs. 70 ± 6 mg/dL (P = 0.04) at 60 min. The change in area under the curve (ΔAUC) for glucagon was similar between Pe and Po, but the peak occurred earlier in Pe. The ΔAUC for epinephrine was greater with Pe than with Po (67 ± 17 vs. 36 ± 14 ng/mL/180 min). In protocol 2, glucose also fell more rapidly than in protocol 1 and fell faster in Pe than in Po, reaching 41 ± 3 vs. 67 ± 2 mg/dL (P < 0.01) by 60 min. Without a rise in glucagon, the epinephrine responses were much larger (ΔAUC of 204 ± 22 for Pe vs. 96 ± 29 ng/mL/180 min for Po). In summary, Pe insulin delivery exacerbates hypoglycemia, particularly in the presence of a diminished glucagon response. Po vein insulin delivery, or strategies that mimic it (i.e., liver-preferential insulin analogs), should therefore lessen hypoglycemia.

Changes in Glucose and Fat Metabolism in Response to the Administration of a Hepato-Preferential Insulin Analog

Endogenous insulin secretion exposes the liver to three times higher insulin concentrations than the rest of the body. Because subcutaneous insulin delivery eliminates this gradient and is associated with metabolic abnormalities, functionally restoring the physiologic gradient may provide therapeutic benefits. The effects of recombinant human insulin (HI) delivered intraportally or peripherally were compared with an acylated insulin model compound (insulin-327) in dogs. During somatostatin and basal portal vein glucagon infusion, insulin was infused portally (PoHI; 1.8 pmol/kg/min; n = 7) or peripherally (PeHI; 1.8 pmol/kg/min; n = 8) and insulin-327 (Pe327; 7.2 pmol/kg/min; n = 5) was infused peripherally. Euglycemia was maintained by glucose infusion. While the effects on liver glucose metabolism were greatest in the PoHI and Pe327 groups, nonhepatic glucose uptake increased most in the PeHI group. Suppression of lipolysis was greater during PeHI than PoHI and was delayed in Pe327 infusion. Thus small increments in portal vein insulin have major consequences on the liver, with little effect on nonhepatic glucose metabolism, whereas insulin delivered peripherally cannot act on the liver without also affecting nonhepatic tissues. Pe327 functionally restored the physiologic portal–arterial gradient and thereby produced hepato-preferential effects.

A physiological increase in the hepatic glycogen level does not affect the response of net hepatic glucose uptake to insulin

To determine the effect of an acute increase in hepatic glycogen on net hepatic glucose uptake (NHGU) and disposition in response to insulin in vivo, studies were performed on two groups of dogs fasted 18 h. During the first 4 h of the study, somatostatin was infused peripherally, while insulin and glucagon were replaced intraportally in basal amounts. Hyperglycemia was brought about by glucose infusion, and either saline (n = 7) or fructose (n = 7; to stimulate NHGU and glycogen deposition) was infused intraportally. A 2-h control period then followed, during which the portal fructose and saline infusions were stopped, allowing NHGU and glycogen deposition in the fructose-infused animals to return to rates similar to those of the animals that received the saline infusion. This was followed by a 2-h experimental period, during which hyperglycemia was continued but insulin infusion was increased fourfold in both groups. During the initial 4-h glycogen loading period, NHGU averaged 1.18 +/- 0.27 and 5.55 +/- 0.53 mg x kg(-1) x min(-1) and glycogen synthesis averaged 0.72 +/- 0.24 and 3.98 +/- 0.57 mg x kg(-1) x min(-1) in the saline and fructose groups, respectively (P < 0.05). During the 2-h hyperinsulinemic period, NHGU rose from 1.5 +/- 0.4 and 0.9 +/- 0.2 to 3.1 +/- 0.6 and 2.5 +/- 0.5 mg x kg(-1) x min(-1) in the saline and fructose groups, respectively, a change of 1.6 mg x kg(-1) x min(-1) in both groups despite a significantly greater liver glycogen level in the fructose-infused group. Likewise, the metabolic fate of the extracted glucose (glycogen, lactate, or carbon dioxide) was not different between groups. These data indicate that an acute physiological increase in the hepatic glycogen content does not alter liver glucose uptake and storage under hyperglycemic/hyperinsulinemic conditions in the dog.

Hepatic Glycogen Supercompensation Activates AMP-Activated Protein Kinase, Impairs Insulin Signaling, and Reduces Glycogen Deposition in the Liver

OBJECTIVE The objective of this study was to determine how increasing the hepatic glycogen content would affect the liver’s ability to take up and metabolize glucose. RESEARCH DESIGN AND METHODS During the first 4 h of the study, liver glycogen deposition was stimulated by intraportal fructose infusion in the presence of hyperglycemic-normoinsulinemia. This was followed by a 2-h hyperglycemic-normoinsulinemic control period, during which the fructose infusion was stopped, and a 2-h experimental period in which net hepatic glucose uptake (NHGU) and disposition (glycogen, lactate, and CO2) were measured in the absence of fructose but in the presence of a hyperglycemic-hyperinsulinemic challenge including portal vein glucose infusion. RESULTS Fructose infusion increased net hepatic glycogen synthesis (0.7 ± 0.5 vs. 6.4 ± 0.4 mg/kg/min; P < 0.001), causing a large difference in hepatic glycogen content (62 ± 9 vs. 100 ± 3 mg/g; P < 0.001). Hepatic glycogen supercompensation (fructose infusion group) did not alter NHGU, but it reduced the percent of NHGU directed to glycogen (79 ± 4 vs. 55 ± 6; P < 0.01) and increased the percent directed to lactate (12 ± 3 vs. 29 ± 5; P = 0.01) and oxidation (9 ± 3 vs. 16 ± 3; P = NS). This change was associated with increased AMP-activated protein kinase phosphorylation, diminished insulin signaling, and a shift in glycogenic enzyme activity toward a state discouraging glycogen accumulation. CONCLUSIONS These data indicate that increases in hepatic glycogen can generate a state of hepatic insulin resistance, which is characterized by impaired glycogen synthesis despite preserved NHGU.

Hepatic glycogen can regulate hypoglycemic counterregulation via a liver-brain axis

Liver glycogen is important for the counterregulation of hypoglycemia and is reduced in individuals with type 1 diabetes (T1D). Here, we examined the effect of varying hepatic glycogen content on the counterregulatory response to low blood sugar in dogs. During the first 4 hours of each study, hepatic glycogen was increased by augmenting hepatic glucose uptake using hyperglycemia and a low-dose intraportal fructose infusion. After hepatic glycogen levels were increased, animals underwent a 2-hour control period with no fructose infusion followed by a 2-hour hyperinsulinemic/hypoglycemic clamp. Compared with control treatment, fructose infusion caused a large increase in liver glycogen that markedly elevated the response of epinephrine and glucagon to a given hypoglycemia and increased net hepatic glucose output (NHGO). Moreover, prior denervation of the liver abolished the improved counterregulatory responses that resulted from increased liver glycogen content. When hepatic glycogen content was lowered, glucagon and NHGO responses to insulin-induced hypoglycemia were reduced. We conclude that there is a liver-brain counterregulatory axis that is responsive to liver glycogen content. It remains to be determined whether the risk of iatrogenic hypoglycemia in T1D humans could be lessened by targeting metabolic pathway(s) associated with hepatic glycogen repletion.

Effects of 11β-hydroxysteroid dehydrogenase-1 inhibition on hepatic glycogenolysis and gluconeogenesis

The aim of this study was to determine the effect of prolonged 11β-hydroxysteroid dehydrogenase-1 (11β-HSD1) inhibition on basal and hormone-stimulated glucose metabolism in fasted conscious dogs. For 7 days prior to study, either an 11β-HSD1 inhibitor (HSD1-I; n = 6) or placebo (PBO; n = 6) was administered. After the basal period, a 4-h metabolic challenge followed, where glucagon (3×-basal), epinephrine (5×-basal), and insulin (2×-basal) concentrations were increased. Hepatic glucose fluxes did not differ between groups during the basal period. In response to the metabolic challenge, hepatic glucose production was stimulated in PBO, resulting in hyperglycemia such that exogenous glucose was required in HSD-I (P < 0.05) to match the glycemia between groups. Net hepatic glucose output and endogenous glucose production were decreased by 11β-HSD1 inhibition (P < 0.05) due to a reduction in net hepatic glycogenolysis (P < 0.05), with no effect on gluconeogenic flux compared with PBO. In addition, glucose utilization (P < 0.05) and the suppression of lipolysis were increased (P < 0.05) in HSD-I compared with PBO. These data suggest that inhibition of 11β-HSD1 may be of therapeutic value in the treatment of diseases characterized by insulin resistance and excessive hepatic glucose production.

Liver Glycogen Loading Dampens Glycogen Synthesis Seen in Response to Either Hyperinsulinemia or Intraportal Glucose Infusion

The purpose of this study was to determine the effect of liver glycogen loading on net hepatic glycogen synthesis during hyperinsulinemia or hepatic portal vein glucose infusion in vivo. Liver glycogen levels were supercompensated (SCGly) in two groups (using intraportal fructose infusion) but not in two others (Gly) during hyperglycemic-normoinsulinemia. Following a 2-h control period during which fructose infusion was stopped, there was a 2-h experimental period in which the response to hyperglycemia plus either 4× basal insulin (INS) or portal vein glucose infusion (PoG) was measured. Increased hepatic glycogen reduced the percent of glucose taken up by the liver that was deposited in glycogen (74 ± 3 vs. 53 ± 5% in Gly+INS and SCGly+INS, respectively, and 72 ± 3 vs. 50 ± 6% in Gly+PoG and SCGly+PoG, respectively). The reduction in liver glycogen synthesis in SCGly+INS was accompanied by a decrease in both insulin signaling and an increase in AMPK activation, whereas only the latter was observed in SCGly+PoG. These data indicate that liver glycogen loading impairs glycogen synthesis regardless of the signal used to stimulate it.

A Soluble Guanylate Cyclase–Dependent Mechanism Is Involved in the Regulation of Net Hepatic Glucose Uptake by Nitric Oxide in Vivo

OBJECTIVE We previously showed that elevating hepatic nitric oxide (NO) levels reduced net hepatic glucose uptake (NHGU) in the presence of portal glucose delivery, hyperglycemia, and hyperinsulinemia. The aim of the present study was to determine the role of a downstream signal, soluble guanylate cyclase (sGC), in the regulation of NHGU by NO. RESEARCH DESIGN AND METHODS Studies were performed on 42-h–fasted conscious dogs fitted with vascular catheters. At 0 min, somatostatin was given peripherally along with 4× basal insulin and basal glucagon intraportally. Glucose was delivered at a variable rate via a leg vein to double the blood glucose level and hepatic glucose load throughout the study. From 90 to 270 min, an intraportal infusion of the sGC inhibitor 1H-[1,2,4] oxadiazolo[4,3-a] quinoxalin-1-one (ODQ) was given in −sGC (n = 10) and −sGC/+NO (n = 6), whereas saline was given in saline infusion (SAL) (n = 10). The −sGC/+NO group also received intraportal SIN-1 (NO donor) to elevate hepatic NO from 180 to 270 min. RESULTS In the presence of 4× basal insulin, basal glucagon, and hyperglycemia (2× basal ), inhibition of sGC in the liver enhanced NHGU (mg/kg/min; 210–270 min) by ∼55% (2.9 ± 0.2 in SAL vs. 4.6 ± 0.5 in −sGC). Further elevating hepatic NO failed to reduce NHGU (4.5 ± 0.7 in −sGC/+NO). Net hepatic carbon retention (i.e., glycogen synthesis; mg glucose equivalents/kg/min) increased to 3.8 ± 0.2 in −sGC and 3.8 ± 0.4 in −sGC/+NO vs. 2.4 ± 0.2 in SAL (P < 0.05). CONCLUSIONS NO regulates liver glucose uptake through a sGC-dependent pathway. The latter could be a target for pharmacologic intervention to increase meal-associated hepatic glucose uptake in individuals with type 2 diabetes.

A Cyclic Guanosine Monophosphate–Dependent Pathway Can Regulate Net Hepatic Glucose Uptake in Vivo

We previously showed that hepatic nitric oxide regulates net hepatic glucose uptake (NHGU), an effect that can be eliminated by inhibiting hepatic soluble guanylate cyclase (sGC), suggesting that the sGC pathway is involved in the regulation of NHGU. The aim of the current study was to determine whether hepatic cyclic guanosine monophosphate (cGMP) reduces NHGU. Studies were performed on conscious dogs with transhepatic catheters. A hyperglycemic-hyperinsulinemic clamp was established in the presence of portal vein glucose infusion. 8-Br-cGMP (50 µg/kg/min) was delivered intraportally, and either the glucose load to the liver (CGMP/GLC; n = 5) or the glucose concentration entering the liver (CGMP/GCC; n = 5) was clamped at 2× basal. In the control group, saline was given intraportally (SAL; n = 10), and the hepatic glucose concentration and load were doubled. 8-Br-cGMP increased portal blood flow, necessitating the two approaches to glucose clamping in the cGMP groups. NHGU (mg/kg/min) was 5.8 ± 0.5, 2.7 ± 0.5, and 4.8 ± 0.3, whereas the fractional extraction of glucose was 11.0 ± 1, 5.5 ± 1, and 8.5 ± 1% during the last hour of the study in SAL, CGMP/GLC, and CGMP/GCC, respectively. The reduction of NHGU in response to 8-Br-cGMP was associated with increased AMP-activated protein kinase phosphorylation. These data indicate that changes in liver cGMP can regulate NHGU under postprandial conditions.