Rate Of Glucose Production Research Articles

Gluconeogenesis during endurance exercise in cyclists habituated to a long-term low carbohydrate high-fat diet.

Blood glucose is an important fuel for endurance exercise. It can be derived from ingested carbohydrate, stored liver glycogen and newly synthesized glucose (gluconeogenesis). We hypothesized that athletes habitually following a low carbohydrate high fat (LCHF) diet would have higher rates of gluconeogenesis during exercise compared to those who follow a mixed macronutrient diet. We used stable isotope tracers to study glucose production kinetics during a 2h ride in cyclists habituated to either a LCHF or mixed macronutrient diet. The LCHF cyclists had lower rates of total glucose production and hepatic glycogenolysis but similar rates of gluconeogenesis compared to those on the mixed diet. The LCHF cyclists did not compensate for reduced dietary carbohydrate availability by increasing glucose synthesis during exercise but rather adapted by altering whole body substrate utilization. Endogenous glucose production (EGP) occurs via hepatic glycogenolysis (GLY) and gluconeogenesis (GNG) and plays an important role in maintaining euglycaemia. Rates of GLY and GNG increase during exercise in athletes following a mixed macronutrient diet; however, these processes have not been investigated in athletes following a low carbohydrate high fat (LCHF) diet. Therefore, we studied seven well-trained male cyclists that were habituated to either a LCHF (7% carbohydrate, 72% fat, 21% protein) or a mixed diet (51% carbohydrate, 33% fat, 16% protein) for longer than 8months. After an overnight fast, participants performed a 2h laboratory ride at 72% of maximal oxygen consumption. Glucose kinetics were measured at rest and during the final 30min of exercise by infusion of [6,6-(2) H2 ]-glucose and the ingestion of (2) H2 O tracers. Rates of EGP and GLY both at rest and during exercise were significantly lower in the LCHF group than the mixed diet group (Exercise EGP: LCHF, 6.0±0.9mgkg(-1) min(-1) , Mixed, 7.8±1.1mgkg(-1) min(-1) , P<0.01; Exercise GLY: LCHF, 3.2±0.7mgkg(-1) min(-1) , Mixed, 5.3±0.9mgkg(-1) min(-1) , P<0.01). Conversely, no difference was detected in rates of GNG between groups at rest or during exercise (Exercise: LCHF, 2.8±0.4mgkg(-1) min(-1) , Mixed, 2.5±0.3mgkg(-1) min(-1) , P=0.15). We conclude that athletes on a LCHF diet do not compensate for reduced glucose availability via higher rates of glucose synthesis compared to athletes on a mixed diet. Instead, GNG remains relatively stable, whereas glucose oxidation and GLY are influenced by dietary factors.

Propionate Increases Hepatic Pyruvate Cycling and Anaplerosis and Alters Mitochondrial Metabolism

In mammals, pyruvate kinase (PK) plays a key role in regulating the balance between glycolysis and gluconeogenesis; however, in vivo regulation of PK flux by gluconeogenic hormones and substrates is poorly understood. To this end, we developed a novel NMR-liquid chromatography/tandem-mass spectrometry (LC-MS/MS) method to directly assess pyruvate cycling relative to mitochondrial pyruvate metabolism (VPyr-Cyc/VMito) in vivo using [3-13C]lactate as a tracer. Using this approach, VPyr-Cyc/VMito was only 6% in overnight fasted rats. In contrast, when propionate was infused simultaneously at doses previously used as a tracer, it increased VPyr-Cyc/VMito by 20–30-fold, increased hepatic TCA metabolite concentrations 2–3-fold, and increased endogenous glucose production rates by 20–100%. The physiologic stimuli, glucagon and epinephrine, both increased hepatic glucose production, but only glucagon suppressed VPyr-Cyc/VMito. These data show that under fasting conditions, when hepatic gluconeogenesis is stimulated, pyruvate recycling is relatively low in liver compared with VMito flux and that liver metabolism, in particular pyruvate cycling, is sensitive to propionate making it an unsuitable tracer to assess hepatic glycolytic, gluconeogenic, and mitochondrial metabolism in vivo.

Interleukin-6 is a negative regulator of hepatic glucose production in the isolated rat liver

The mechanism underlying the increased rate of endogenous glucose production from the liver during exercise remains unknown. The cytokine interleukin-6 (IL-6) is known to be released during exercise and is thought that either IL-6 directly or via a “contraction factor” stimulates the release of stored glucose from the liver. Here we show that IL-6 does not directly increase hepatic glucose output (HGO). Moreover, IL-6 infused at the same time as glucagon caused a significant reduction in HGO. IL-6 infused with epinephrine caused no synergenic increase in HGO. To test if an unknown “contraction factor” was needed along with IL-6 to increase HGO, we used human fasted and exercised plasma perfused with or without IL-6 in our isolated liver system. We found that exercised plasma increased HGO, as expected, but when infused with IL-6, reductions in HGO were found. Our results provide evidence that IL-6 works as a negative regulator of HGO.

Methane production enhancement by an independent cathode in integrated anaerobic reactor with microbial electrolysis

Anaerobic digestion (AD) represents a potential way to achieve energy recovery from waste organics. In this study, a novel bioelectrochemically-assisted anaerobic reactor is assembled by two AD systems separated by anion exchange membrane, with the cathode placing in the inside cylinder (cathodic AD) and the anode on the outside cylinder (anodic AD). In cathodic AD, average methane production rate goes up to 0.070mLCH4/mL reactor/day, which is 2.59times higher than AD control reactor (0.027m3CH4/m3/d). And COD removal is increased ∼15% over AD control. When changing to sludge fermentation liquid, methane production rate has been further increased to 0.247mLCH4/mL reactor/day (increased by 51.53% comparing with AD control). Energy recovery efficiency presents profitable gains, and economic revenue from increased methane totally self-cover the cost of input electricity. The study indicates that cathodic AD could cost-effectively enhance methane production rate and degradation of glucose and fermentative liquid.

Maternal Glucose and Fatty Acid Kinetics and Infant Birth Weight in Obese Women With Type 2 Diabetes.

The objectives of this study were 1) to describe maternal glucose and lipid kinetics and 2) to examine the relationships with infant birth weight in obese women with pregestational type 2 diabetes during late pregnancy. Using stable isotope tracer methodology and mass spectrometry, maternal glucose and lipid kinetic rates during the basal condition were compared in three groups: lean women without diabetes (Lean, n = 25), obese women without diabetes (OB, n = 26), and obese women with pregestational type 2 diabetes (OB+DM, n = 28; total n = 79). Glucose and lipid kinetics during hyperinsulinemia were also measured in a subset of participants (n = 56). Relationships between maternal glucose and lipid kinetics during both conditions and infant birth weight were examined. Maternal endogenous glucose production (EGP) rate was higher in OB+DM than OB and Lean during hyperinsulinemia. Maternal insulin value at 50% palmitate Ra suppression (IC50) for palmitate suppression with insulinemia was higher in OB+DM than OB and Lean. Maternal EGP per unit insulin and plasma free fatty acid concentration during hyperinsulinemia most strongly predicted infant birth weight. Our findings suggest maternal fatty acid and glucose kinetics are altered during late pregnancy and might suggest a mechanism for higher birth weight in obese women with pregestational diabetes.

ПРОАНГІОГЕННА ДІЯ НОВОСИНТЕЗОВАНИХ СПОЛУК-АНАЛОГІВ ІНГІБІТОРІВ HIF-1

The effect of new compounds analog of inhibitors of HIF-1 on the metabolic and proliferative status of endothelial cells have been studied. It was shown that syn-isomer possesses of proproliferative effect and antiapoptotic effect with anti-isomer. These effects are consistent with the rates of glucose uptake and production of nitric oxide.

The effects of ethanol on hydrolysis of cellulose and pretreated barley straw by some commercial cellulolytic enzyme products

The effect of ethanol at levels ranging from 2.5% v/v to 15% v/v on the activities of two recently developed commercial cellulosic biomass hydrolytic enzyme products, Accellerase&reg; 1500 and Accellerase&reg; XY, was investigated. The substrates used for study of the effect of ethanol on Accellerase&reg; 1500 included α-cellulose, cellobiose and barley straw pretreated by the soaking in aqueous ammonia method. The initial rates of glucose production and final glucose concentrations obtained at 48 h of hydrolysis were used as the response factors. To study the effect of ethanol on Accellerase&reg; XY, beechwood xylan and the pretreated barley straw were used as substrates. The response factors included the initial rates of xylose production and final xylose concentrations obtained at 48 h of hydrolysis. It was found that ethanol acted as either activator or inhibitor depending on its concentration and the type of substrate used. At 10% v/v, which is expected to be the final concentration of ethanol in a commercial cellulosic biomass-based process, ethanol acted as an inhibitor in all cases. However, even at this ethanol level, both commercial enzymes still retained at least about 50% of their activities.

Coping with an exogenous glucose overload: glucose kinetics of rainbow trout during graded swimming.

This study examines how chronically hyperglycemic rainbow trout modulate glucose kinetics in response to graded exercise up to critical swimming speed (Ucrit), with or without exogenous glucose supply. Our goals were 1) to quantify the rates of hepatic glucose production (Ra glucose) and disposal (Rd glucose) during graded swimming, 2) to determine how exogenous glucose affects the changes in glucose fluxes caused by exercise, and 3) to establish whether exogenous glucose modifies Ucrit or the cost of transport. Results show that graded swimming causes no change in Ra and Rd glucose at speeds below 2.5 body lengths per second (BL/s), but that glucose fluxes may be stimulated at the highest speeds. Excellent glucoregulation is also achieved at all exercise intensities. When exogenous glucose is supplied during exercise, trout suppress hepatic production from 16.4 ± 1.6 to 4.1 ± 1.7 μmol·kg(-1)·min(-1) and boost glucose disposal to 40.1 ± 13 μmol·kg(-1)·min(-1). These responses limit the effects of exogenous glucose to a 2.5-fold increase in glycemia, whereas fish showing no modulation of fluxes would reach dangerous levels of 114 mM of blood glucose. Exogenous glucose reduces metabolic rate by 16% and, therefore, causes total cost of transport to decrease accordingly. High glucose availability does not improve Ucrit because the fish are unable to take advantage of this extra fuel during maximal exercise and rely on tissue glycogen instead. In conclusion, trout have a remarkable ability to adjust glucose fluxes that allows them to cope with the cumulative stresses of a glucose overload and graded exercise.

Prevention of diet-induced hepatic steatosis and hepatic insulin resistance by second generation antisense oligonucleotides targeted to the longevity gene mIndy (Slc13a5).

Reducing the expression of the Indy (I'm Not Dead Yet) gene in lower organisms extends life span by mechanisms resembling caloric restriction. Similarly, deletion of the mammalian homolog, mIndy (Slc13a5), encoding for a plasma membrane tricarboxylate transporter, protects from aging- and diet-induced adiposity and insulin resistance in mice. The organ specific contribution to this phenotype is unknown. We examined the impact of selective inducible hepatic knockdown of mIndy on whole body lipid and glucose metabolism using 2'-O-methoxyethyl chimeric anti-sense oligonucleotides (ASOs) in high-fat fed rats. 4-week treatment with 2'-O-methoxyethyl chimeric ASO reduced mIndy mRNA expression by 91% (P=0.001) compared to control ASO. Besides similar body weights between both groups, mIndy-ASO treatment lead to a 74% reduction in fasting plasma insulin concentrations as well as a 35% reduction in plasma triglycerides. Moreover, hepatic triglyceride content was significantly reduced by the knockdown of mIndy, likely mediating a trend to decreased basal rates of endogenous glucose production as well as an increased suppression of hepatic glucose production by 25% during a hyperinsulinemic-euglycemic clamp. Together, these data suggest that inducible liver-selective reduction of mIndy in rats is able to ameliorate hepatic steatosis and insulin resistance, conditions occurring with high calorie diets and during aging.

Biochemical Conversion of Torrefied Norway Spruce After Pretreatment with Acid or Ionic Liquid

The chemical effects of torrefaction and the possibility to combine torrefaction with biochemical conversion were explored in experiments with five preparations of wood of Norway spruce that had been torrefied using different degrees of severity. Compositional analysis and analyses using solid-state CP/MAS 13C NMR, Fourier-transform infrared (FTIR) spectroscopy, and Py-GC/MS showed small gradual changes, such as decreased hemicellulosic content and increased Klason lignin value, for torrefaction conditions in the range from 260 °C and 8 min up to 310 °C and 8 min. The most severe torrefaction conditions (310 °C, 25 min) resulted in substantial loss of glucan and further increase of the Klason lignin value, which was attributed to conversion of carbohydrate to pseudo-lignin. Even mild torrefaction conditions led to decreased susceptibility to enzymatic hydrolysis of cellulose, a state which was not changed by pretreatment with sulfuric acid. Pretreatment with the ionic liquid (IL) 1-butyl-3-methylimidazolium acetate overcame the additional recalcitrance caused by torrefaction, and the glucose yields after 72 h of enzymatic hydrolysis of wood torrefied at 260 °C for 8 min and at 285 °C for 16.5 min were as high as that of IL-pretreated non-torrefied spruce wood. Compared to IL-pretreated non-torrefied reference wood, the glucose production rates after 2 h of enzymatic hydrolysis of IL-pretreated wood torrefied at 260 °C for 8 min and at 285 °C for 16.5 min were 63 and 40 % higher, respectively. The findings offer increased understanding of the effects of torrefaction and indicate that mild torrefaction is compatible with biochemical conversion after pretreatment with alternative solvents that disrupt pseudo-lignin-containing lignocellulose.

Effects of glucagon-like peptide-1 on glucagon secretion in patients with non-alcoholic fatty liver disease

We evaluated the glucagon-suppressive effect of glucagon-like peptide-1 (GLP-1) and its potential effects on endogenous glucose production and whole body lipolysis in non-diabetic patients with non-alcoholic fatty liver disease (NAFLD). On two separate days, 10 non-diabetic patients with liver biopsy-verified NAFLD (NAFLD activity score 2.5±1.0) and 10 matched controls underwent 2h intravenous infusions of GLP-1 (0.8 pmol×kg(-1)×min(-1)) and placebo. Since GLP-1-mediated glucagon suppression has been shown to be glucose-dependent, plasma glucose was clamped at fasting level during the first hour, and then raised and clamped at 'postprandial level' (fasting plasma glucose level plus 3 mmol/L) for the remaining hour. We evaluated relative plasma levels of glucagon, endogenous glucose production and whole body lipolysis rates with stable isotopes and respiratory quotient using indirect calorimetry. Compared to controls, patients with NAFLD were insulin resistant (homeostasis model assessment (HOMA(IR)): 3.8±2.2 vs. 1.6±1.5, p=0.003) and had fasting hyperglucagonaemia (7.5±5.3 vs. 5.8±1.5 mmol/L, p=0.045). Similar relative glucagon suppression was seen in both groups during GLP-1 infusion at fasting (-97±75 vs. -93±41 pmol/L×min(-1)p=0.566) and 'postprandial' plasma glucose levels (-108±101 vs. -97±53 pmol/L×min(-1), p=0.196). Increased insulinotropic effect of GLP-1 was observed in NAFLD patients. No effect of GLP-1 on endogenous glucose production was observed in any of the groups. Patients with NAFLD exhibited fasting hyperglucagonaemia, but intact GLP-1-mediated glucagon suppression independently of plasma glucose concentrations. Preserved glucagonostatic effect and increased insulinotropic effects of GLP-1 in NAFLD may be important to maintain normo-glycaemia in these patients.

3,5 Diiodo-L-Thyronine (T2) Does Not Prevent Hepatic Steatosis or Insulin Resistance in Fat-Fed Sprague Dawley Rats.

Thyroid hormone mimetics are alluring potential therapies for diseases like dyslipidemia, nonalcoholic fatty liver disease (NAFLD), and insulin resistance. Though diiodothyronines are thought inactive, pharmacologic treatment with 3,5- Diiodo-L-Thyronine (T2) reportedly reduces hepatic lipid content and improves glucose tolerance in fat-fed male rats. To test this, male Sprague Dawley rats fed a safflower-oil based high-fat diet were treated with T2 (0.25 mg/kg-d) or vehicle. Neither 10 nor 30 days of T2 treatment had an effect on weight, adiposity, plasma fatty acids, or hepatic steatosis. Insulin action was quantified in vivo by a hyperinsulinemic-euglycemic clamp. T2 did not alter fasting plasma glucose or insulin concentration. Basal endogenous glucose production (EGP) rate was unchanged. During the clamp, there was no difference in insulin stimulated whole body glucose disposal. Insulin suppressed EGP by 60% ± 10 in T2-treated rats as compared with 47% ± 4 suppression in the vehicle group (p = 0.32). This was associated with an improvement in hepatic insulin signaling; insulin stimulated Akt phosphorylation was ~2.5 fold greater in the T2-treated group as compared with the vehicle-treated group (p = 0.003). There was no change in expression of genes thought to mediate the effect of T2 on hepatic metabolism, including genes that regulate hepatic lipid oxidation (ppara, carnitine palmitoyltransferase 1a), genes that regulate hepatic fatty acid synthesis (srebp1c, acetyl coa carboxylase, fatty acid synthase), and genes involved in glycolysis and gluconeogenesis (L-pyruvate kinase, glucose 6 phosphatase). Therefore, in contrast with previous reports, in Sprague Dawley rats fed an unsaturated fat diet, T2 administration failed to improve NAFLD or whole body insulin sensitivity. Though there was a modest improvement in hepatic insulin signaling, this was not associated with significant differences in hepatic insulin action. Further study will be necessary before diiodothyronines can be considered an effective treatment for NAFLD and dyslipidemia.

Catalytic conversion of sugarcane bagasse to cellulosic ethanol: TiO2 coupled nanocellulose as an effective hydrolysis enhancer

The present study deals with the production of cellulosic ethanol from bagasse using the synthesized TiO2 coupled nanocellulose (NC-TiO2) as catalyst. Aspergillus nidulans AJSU04 cellulase was used for the hydrolysis of bagasse. NC-TiO2 at various concentrations was added to bagasse in order to enhance the yield of reducing sugars. Complex interaction between cellulase, bagasse, NC-TiO2 and the reaction environment is thoroughly studied. A mathematical model was developed to describe the hydrolysis reaction. Ethanol production from enzymatically hydrolyzed sugarcane bagasse catalyzed with NC-TiO2 was carried out using Saccharomyces cerevisiae ATCC 20602. The glucose release rates and ethanol concentrations were determined. Ethanol produced was found to be strongly dependent on pretreatment given, hydrolysis and fermentation conditions. The study confirmed the promising accessibility of NC-TiO2, for enhanced glucose production rates and improved ethanol yield.

Effect of subcutaneous insulin detemir on glucose flux, lipolysis and electroencephalography in type 1 diabetes.

The aim of the present study was to investigate the effects of subcutaneous detemir on glucose flux, lipid metabolism and brain function. Twelve people with type 1 diabetes received, in random order, 0.5 units/kg body weight detemir or NPH insulin. Glucose concentration was clamped at 5 mmol/l then increased to 10 mmol/l. Glucose production rate (glucose Ra), glucose uptake (glucose Rd) and glycerol production (glycerol Ra) were measured with a constant intravenous infusion of [6,6(2) H(2)]glucose and [(2)H(5)]glycerol. Electroencephalography direct current (DC) and alternating current (AC) potentials were measured. While detemir induced similar effects on glucose Ra, glucose Rd and glycerol Ra during euglycaemia compared with NPH, it triggered a distinct negative shift in DC potentials, with a significant treatment effect in frontal cerebrocortical channels (p < 0.001). AC spectral power showed significant differences in theta and alpha frequencies during euglycaemia (p = 0.03). Subcutaneous detemir exerts different effects on brain function when compared with NPH in people with type 1 diabetes. This may be an important mechanism behind the limitation of weight gain with detemir.

Investigation of a submerged membrane reactor for continuous biomass hydrolysis

Enzymatic hydrolysis of cellulose is one of the most costly steps in the bioconversion of lignocellulosic biomass. Use of a submerged membrane reactor has been investigated for continuous enzymatic hydrolysis of cellulose thus allowing for greater use of the enzyme compared to a batch process. The submerged 0.65μm polyethersulfone microfiltration membrane avoids the need to pump a cellulose slurry through an external loop. Permeate containing glucose is withdrawn at pressures slightly below atmospheric pressure. The membrane rejects cellulose particles and cellulase enzyme bound to cellulose. Here proof-of-concept experiments have been conducted using a modified, commercially available membrane filtration cell under low fluxes around 75L/(m2h). The operating flux is determined by the rate of glucose production. Maximizing the rate of glucose production involves optimizing mixing, reactor holding time, and the time the feed is held in the reactor prior to commencement of membrane filtration and continuous operation. Maximizing glucose production rates will require operating at low glucose concentration in order to minimize the adverse effects of product inhibition. Consequently practical submerged membrane systems will require a combined sugar concentration step in order to concentrate the product sugar stream prior to fermentation.

A Kinetic Model of Whole-Body Glucose Metabolism with Reference to the Domestic Dog (Canis lupus familiaris).

A new two-pool model to describe glucose kinetics in the steady state is presented. The pools are plasma glucose, Q 1, and tissue glucose, Q 2 (both µmol). The flows (all µmol/min) into the plasma pool (Pool 1) are absorbed glucose entry from dietary sources, labelled glucose infusion, and hepatic glucose production. There is one flow out of Pool 1, glucose uptake by the tissues. Inflows to the tissues pool (Pool 2) are from plasma and glycogenolysis. Outflows from Pool 2 are to plasma, glucose oxidation, and glycogenesis and other metabolism. Application of the model was illustrated using experimental data derived from healthy adult Labrador Retrievers in the fasted and fed (repeated meal feeding) states. In general, model derived estimates of glucose kinetics were representative of normal glucose metabolism, where rates of glucose production and uptake are similar and act to maintain blood glucose concentrations. Furthermore, estimates of within tissue glucose cycling indicated glycogenolysis in fasting and glycogenesis when fed. In the fasted state, model outputs were consistent with those reported in the canine literature derived using a single pool model.

SGLT-2 inhibition and glucagon: Cause for alarm?

Recent studies raised the alarm that the inhibition of sodium-coupled glucose transporter type-2 in humans increases endogenous glucose production rates by an unclear mechanism. Surprisingly, a potential explanation may be linked directly to the alpha-cell. Is this a mechanistic spoiler or an added benefit?

Weight Loss and the Prevention and Treatment of Type 2 Diabetes Using Lifestyle Therapy, Pharmacotherapy, and Bariatric Surgery: Mechanisms of Action.

Weight loss, whether achieved by lifestyle intervention, pharmacotherapy, or bariatric surgery, is highly effective as a primary interventional strategy in both the prevention and treatment of type 2 diabetes. In high-risk patients with prediabetes and/or metabolic syndrome, weight loss effectively prevents progression to type 2 diabetes mellitus (T2DM) and improves cardiovascular risk factors. These benefits are the result of improvements in insulin resistance, which is central to the pathophysiology of cardiometabolic disease. In patients with T2DM, weight loss improves glycemia, while reducing the need for conventional glucose-lowering medicines, by affecting all three processes that produce and sustain the hyperglycemic state, namely via increments in peripheral insulin sensitivity with improvements in insulin signal transduction at the cellular level, more robust insulin secretory responses, and reduced rates of hepatic glucose production. In both nondiabetic and diabetic subjects, hypocaloric feeding (e.g., treatment with very low-calorie diet or bariatric surgery) produces a rapid improvement in insulin sensitivity due to mobilization of fat from the intramyocellular, intrahepatocellular, and intra-abdominal compartments, and via a more long-term mechanism that correlates with the loss of total body fat. In diabetes, by improving glycemia, weight loss also enhances glucose homeostasis by reversing the defects in insulin action and secretion attributable to glucose toxicity. Regardless of the therapeutic approach, weight loss of ∼ 10 % maximally prevents future diabetes in patients with prediabetes or metabolic syndrome. In T2DM, greater degrees of weight loss lead to progressive improvements in glucose homeostasis. Therefore, when accompanied by greater weight loss, the metabolic benefits following bariatric surgery are generally more pronounced than those achieved following lifestyle and medical treatment. In addition, the mechanisms by which bariatric operations improve diabetes may include both weight-dependent and weight-independent mechanisms, and the latter may involve changes in gut hormones, bile acids, or gut microflora.

Prevention of exercise-associated dysglycemia: a case study-based approach.

Regular physical activity is associated with many health benefits for people with type 1 diabetes, including improved quality of life, increased vigor, enhanced insulin sensitivity, and protection against cardiovascular disease and other diabetes-related complications (1). Despite its benefits, exercise can aggravate dysglycemia because it causes major changes to glucose production and utilization rates (2). For example, mild to intense aerobic exercise (e.g., walking, cycling, jogging, and most individual and team sports) increases the risk of hypoglycemia during the activity and in recovery because of impaired rates of glucose production, whereas very intense aerobic exercise (>80% of maximal aerobic capacity) and anaerobic exercise (e.g., sprinting and heavy weightlifting) can cause glucose levels to rise because of reduced rates of glucose disposal (3,4). Numerous strategies have been developed to help limit hypoglycemia during exercise in individuals with type 1 diabetes. One of the main reasons hypoglycemia occurs is the inability to naturally reduce insulin levels at the onset of exercise (1). Strategies to help limit hypoglycemia include exercising in the fasted state (5), reducing the insulin for the meal before exercise (6,7), interrupting basal insulin infusion for patients on insulin pump therapy (8–10), and increasing carbohydrate intake (11–14). Continuous glucose monitoring (CGM) can also help to prevent hypoglycemia in people with type 1 diabetes (15). In contrast, very little has been done to develop strategies for exercise-associated hyperglycemia, even though the mechanisms for this effect are largely established (16). The inability to naturally raise insulin levels after intense exercise to combat a rise in catecholamines is the main reason why post-exercise hyperglycemia occurs (17), although excursions associated with aggressive insulin reductions or excessive carbohydrate intake also likely bear some blame (18). In instances of exercise-associated hyperglycemia caused by intense exercise, insulin concentrations …

Evidence That in Uncontrolled Diabetes, Hyperglucagonemia Is Required for Ketosis but Not for Increased Hepatic Glucose Production or Hyperglycemia.

Several lines of evidence implicate excess glucagon secretion in the elevated rates of hepatic glucose production (HGP), hyperglycemia, and ketosis characteristic of uncontrolled insulin-deficient diabetes (uDM), but whether hyperglucagonemia is required for hyperglycemia in this setting is unknown. To address this question, adult male Wistar rats received either streptozotocin (STZ) to induce uDM (STZ-DM) or vehicle and remained nondiabetic. Four days later, animals received daily subcutaneous injections of either the synthetic GLP-1 receptor agonist liraglutide in a dose-escalating regimen to reverse hyperglucagonemia or its vehicle for 10 days. As expected, plasma glucagon levels were elevated in STZ-DM rats, and although liraglutide treatment lowered glucagon levels to those of nondiabetic controls, it failed to attenuate diabetic hyperglycemia, elevated rates of glucose appearance (Ra), or increased hepatic gluconeogenic gene expression. In contrast, it markedly reduced levels of both plasma ketone bodies and hepatic expression of the rate-limiting enzyme involved in ketone body production. To independently confirm this finding, in a separate study, treatment of STZ-DM rats with a glucagon-neutralizing antibody was sufficient to potently lower plasma ketone bodies but failed to normalize elevated levels of either blood glucose or Ra. These data suggest that in rats with uDM, hyperglucagonemia is required for ketosis but not for increased HGP or hyperglycemia.