Basal Glucose Production Rate Research Articles

The Role of Inositol Phosphate Multikinase (IPMK) in Time Restricted Feeding in Animal Model

Obesity is a major public health problem of the U.S. and is associated with diabetes, cardiovascular diseases and other diseases. Most research studies focus on excessive food consumption as the main cause of obesity. However, emerging data indicate that the timing of feeding can have significant effects on body weight and metabolism. Numerous studies in animals and small clinical studies in humans have shown that eating erratically over the 24 hour period or out of phase with the circadian rhythm predisposes toward weight gain, steatosis, dyslipidemia, insulin resistance and diabetes. Furthermore, studies indicate that restricting food intake to the active period synchronizes the circadian rhythm and metabolism, enhances weight loss and improves metabolic outcomes. Time restricted feeding (TRF) increases the amplitudes of clock gene expression and pathways mediating nutrient sensing and hepatic metabolism. However, the mechanisms mediating the effects of TRF are not fully understood. Here we characterized mice (10 week-old) fed a high-fat diet ad libitum (ALF) or from 7 pm to 7 am (TRF) for 2 weeks. The basal glucose production rate was similar between the two groups. Under hyperinsulinemic-euglycemic clamp, the glucose infusion rate (GIR) was significantly greater in TRF group compared to ALF group indicating an increase in insulin sensitivity. Using radioisotopic tracers, we demonstrated that the hepatic glucose production (HGP) was significantly reduced and the glucose disappearance rate was increased in TRF group compared to ALF group. Moreover, a biochemical analyses of liver tissues revealed that Inositol phosphate multikinase (IPMK) act as a key enzyme for inositol polyphosphate biosynthesis and play a role in insulin-, nutrient-, and energy-mediated metabolic signaling, was increased during TRF. Moreover, deletion of IPMK in hepatocytes decreased insulin stimulated AKT phosphorylation while increased lipid accumulation and gluconeogenesis. Importantly, hepatic deletion of IPMK attenuated the beneficial effects of TRF suggesting that IPMK in the liver may contributes to beneficial effects of TRF. Our findings provide the potential mechanism by which TRF confers the beneficial effects and may provide a novel therapeutic strategy for treating diabetes.

Comparing Liver And Skeletal Muscle Sensitivity In Response To Acute And Chronic Calorie Restriction

PURPOSE: We determined the effects of acute and chronic calorie restriction on hepatic and skeletal muscle insulin sensitivity. METHODS: Twenty-three obese subjects (body-mass index, 36.3±0.7kg/m2) followed an energy-deficit diet (1,200kcals/day). Magnetic resonance spectroscopy, muscle biopsies, and a euglycemic-hyperinsulinemic clamp were used to determine insulin action, cellular insulin signaling and intrahepatic triglyceride content before, after 48-h, and after ~12 wks (7% weight loss) of diet therapy. RESULTS: Intrahepatic triglyceride content significantly decreased at both 48-h (-16.6±2.3%, p<0.001) and 7% weight loss (-40.7 ± 6.2%; p<0.001) compared to baseline. Basal glucose production rate significantly decreased at 48-h (-21.8±3.2%, p<0.001) and after 7% weight loss (-20.8±3.4%, p<0.001). Insulin-mediated glucose uptake did not significantly change at 48-h (-5.2±12.8%, p>0.05) but did significantly increase at 7% weight loss (26.1 ± 4.3%, p<0.05). Insulin-stimulated phosphorylation of Jun N-terminal kinase did not change at 48-h (-0.2 ± 16.2%, p>0.05) but did significantly decrease at 7% weight loss (-29.9 ± 12.6, p<0.05) and phosphorylation of Akt increased by 15.2 ± 14.6% (p>0.05) and 36.2 ± 8.8%,(p<0.05), after 48-h and 7% weight loss, respectively. CONCLUSION: A low calorie diet acutely reduced intrahepatic triglyceride content and improved hepatic insulin sensitivity whereas moderate weight loss is necessary to improve insulin sensitivity in the skeletal muscle.

Changes In Liver And Skeletal Muscle Sensitivity In Response To Acute And Chronic Calorie Restriction On A Low Carbohydrate Diet

PURPOSE: We determined the effects of acute and chronic calorie restriction with a low-carbohydrate diet on hepatic and skeletal muscle insulin sensitivity. METHODS: Twelve obese subjects (body-mass index, 36.1±1.0kg/m2) followed a low-carbohydrate (<60g/d) energy-deficit diet (1,200kcals/day). Magnetic resonance spectroscopy, muscle biopsies, and a euglycemic-hyperinsulinemic clamp were used to determine insulin action, cellular insulin signaling and intrahepatic triglyceride content before, after 48 h, and after ~12 wks (7% weight loss) of diet therapy. RESULTS: Intrahepatic triglyceride content significantly decreased at both 48-h (28.6±3.8%) and 7% weight loss (-38.0 ± 4.5%; p<0.05) compared to baseline. Basal glucose production rate significantly decreased at 48 h (21.8±3.2%, p<0.001) and after 7% weight loss (20.8±3.4%, p<0.001). Insulin- mediated glucose uptake did not significantly increase at 48 h (4.4±12.7%, p>0.05) but did significantly increase at 7% weight loss (35.2 ± 8.4%, p<0.05). Insulin-stimulated phosphorylation of Jun N-terminal kinase decreased by (-15.4 ± 18.1%, p>0.05) and -41.3 ± 19.5, p<0.05) and phosphorylation of Akt increased by 19.2 ± 26.9% (p>0.05) and 36.1 ± 12.4%,(p<0.05), after 48-h and 7% weight loss respectively. CONCLUSIONS: A low carbohydrate calorie diet acutely reduced intrahepatic triglyceride content and improved hepatic insulin sensitivity whereas moderate weight loss is necessary to improve insulin sensitivity in the skeletal muscle.

Increased Hepatic Glucose Production in Fetal Sheep With Intrauterine Growth Restriction Is Not Suppressed by Insulin

Intrauterine growth restriction (IUGR) increases the risk for metabolic disease and diabetes, although the developmental origins of this remain unclear. We measured glucose metabolism during basal and insulin clamp periods in a fetal sheep model of placental insufficiency and IUGR. Compared with control fetuses (CON), fetuses with IUGR had increased basal glucose production rates and hepatic PEPCK and glucose-6-phosphatase expression, which were not suppressed by insulin. In contrast, insulin significantly increased peripheral glucose utilization rates in CON and IUGR fetuses. Insulin robustly activated AKT, GSK3β, and forkhead box class O (FOXO)1 in CON and IUGR fetal livers. IUGR livers, however, had increased basal FOXO1 phosphorylation, nuclear FOXO1 expression, and Jun NH2-terminal kinase activation during hyperinsulinemia. Expression of peroxisome proliferator–activated receptor γ coactivator 1α and hepatocyte nuclear factor-4α were increased in IUGR livers during basal and insulin periods. Cortisol and norepinephrine concentrations were positively correlated with glucose production rates. Isolated IUGR hepatocytes maintained increased glucose production in culture. In summary, fetal sheep with IUGR have increased hepatic glucose production, which is not suppressed by insulin despite insulin sensitivity for peripheral glucose utilization. These data are consistent with a novel mechanism involving persistent transcriptional activation in the liver that seems to be unique in the fetus with IUGR.

Dietary Fat and Carbohydrates Differentially Alter Insulin Sensitivity During Caloric Restriction

We determined the effects of acute and chronic calorie restriction with either a low-fat, high-carbohydrate (HC) diet or a low-carbohydrate (LC) diet on hepatic and skeletal muscle insulin sensitivity. Twenty-two obese subjects (body mass index, 36.5 +/- 0.8 kg/m2) were randomized to an HC (>180 g/day) or LC (<50 g/day) energy-deficit diet. A euglycemic-hyperinsulinemic clamp, muscle biopsy specimens, and magnetic resonance spectroscopy were used to determine insulin action, cellular insulin signaling, and intrahepatic triglyceride (IHTG) content before, after 48 hours, and after approximately 11 weeks (7% weight loss) of diet therapy. At 48 hours, IHTG content decreased more in the LC than the HC diet group (29.6% +/- 4.8% vs 8.9% +/- 1.4%; P < .05) but was similar in both groups after 7% weight loss (LC diet, 38.0% +/- 4.5%; HC diet, 44.5% +/- 13.5%). Basal glucose production rate decreased more in the LC than the HC diet group at 48 hours (23.4% +/- 2.2% vs 7.2% +/- 1.4%; P < .05) and after 7% weight loss (20.0% +/- 2.4% vs 7.9% +/- 1.2%; P < .05). Insulin-mediated glucose uptake did not change at 48 hours but increased similarly in both groups after 7% weight loss (48.4% +/- 14.3%; P < .05). In both groups, insulin-stimulated phosphorylation of c-Jun-N-terminal kinase decreased by 29% +/- 13% and phosphorylation of Akt and insulin receptor substrate 1 increased by 35% +/- 9% and 36% +/- 9%, respectively, after 7% weight loss (all P < .05). Moderate calorie restriction causes temporal changes in liver and skeletal muscle metabolism; 48 hours of calorie restriction affects the liver (IHTG content, hepatic insulin sensitivity, and glucose production), whereas moderate weight loss affects muscle (insulin-mediated glucose uptake and insulin signaling).

Alterations in liver, muscle, and adipose tissue insulin sensitivity in men with HIV infection and dyslipidemia

Dyslipidemia is common in patients with HIV infection. In this study, a two-stage euglycemic hyperinsulinemic clamp, with infusion of stable isotopically labeled tracers, was used to evaluate insulin action in skeletal muscle, liver, and adipose tissue in HIV-infected men with dyslipidemia (HIV-DL; plasma triglyceride >250 mg/dl and HDL <45 mg/dl; n=12), HIV-infected men without dyslipidemia (HIV w/o DL; n=12), and healthy men (n=6). Basal rates of glucose production (glucose R(a)), glucose disposal (glucose R(d)), and lipolysis (palmitate R(a)) were similar between groups. The relative suppression of glucose R(a) (63+/- 4, 77+/- 2, and 78+/- 3%, P=0.008) and palmitate R(a) (49+/-4, 63+/-3, and 68+/-3%, P=0.005) during ow-dose insulin infusion (plasma insulin approximately 30 microU/ml), and the relative stimulation of glucose R(d) (214+/-21, 390+/-25, and 393+/-46%, P=0.001) during high-dose insulin infusion (plasma insulin approximately 75 microU/ml) were lower in HIV-DL than in HIV w/o DL and healthy volunteers, respectively. Suppression of basal glucose R(a) correlated with plasma adiponectin (r=0.44, P=0.02) and inversely with plasma IL-6 (r=-0.49, P<0.001). Stimulation of glucose R(d) correlated directly with adiponectin (r=0.48, P<0.01) and inversely with IL-6 (r=-0.49, P=0.02). We conclude that dyslipidemia in HIV-infected men is indicative of multiorgan insulin resistance, and circulating adipokines may be important in the pathogenesis of impaired insulin action.

Does overnight normalization of plasma glucose by insulin infusion affect assessment of glucose metabolism in Type 2 diabetes?

In order to perform euglycaemic clamp studies in Type 2 diabetic patients, plasma glucose must be reduced to normal levels. This can be done either (i) acutely during the clamp study using high-dose insulin infusion, or (ii) slowly overnight preceding the clamp study using a low-dose insulin infusion. We assessed whether the choice of either of these methods to obtain euglycaemia biases subsequent assessment of glucose metabolism and insulin action. We studied seven obese Type 2 diabetic patients twice: once with (+ ON) and once without (- ON) prior overnight insulin infusion. Glucose turnover rates were quantified by adjusted primed-constant 3-3H-glucose infusions, and insulin action was assessed in 4-h euglycaemic, hyperinsulinaemic (40 mU m-2 min-1) clamp studies using labelled glucose infusates (Hot-GINF). Basal plasma glucose levels (mean +/- sd) were 5.5 +/- 0.5 and 10.7 +/- 2.9 mmol/l in the + ON and - ON studies, respectively, and were clamped at -5.5 mmol/l. Basal rates of glucose production (GP) were similar in the + ON and - ON studies, 83 +/- 13 vs. 85 +/- 14 mg m-2 min-1 (NS), whereas basal rates of glucose disappearance (Rd) were lower in the + ON than in the - ON study, 84 +/- 8 vs. 91 +/- 11 mg m-2 min-1 (P = 0.02). During insulin infusion in the clamp period, rates of GP, 23 +/- 11 vs. 25 +/- 10 mg m-2 min-1, as well as rates of Rd, 133 +/- 32 vs. 139 +/- 37 mg m-2 min-1, were similar in the + ON and - ON studies, respectively (NS). Apart from basal rates of Rd, assessment of glucose turnover rates in euglycaemic clamp studies of Type 2 diabetic patients is not dependent on the method by which plasma glucose levels are lowered.

Antepartum predictors of the development of type 2 diabetes in Latino women 11-26 months after pregnancies complicated by gestational diabetes.

In this study, we sought to identify antepartum characteristics that predict the de novo development of diabetes 11-26 months after the index pregnancy in a carefully characterized cohort of women with gestational diabetes mellitus (GDM). Oral and frequently sampled intravenous glucose tolerance tests (OGTTs and FSIGTs), hyperinsulinemic-euglycemic clamps with labeled glucose, and body composition studies were performed on 91 islet cell antibody-negative Latino women with GDM during the third trimester of pregnancy. The women were documented to be diabetes-free within 6 months postpartum. Their diabetes status was ascertained again between 11 and 26 months postpartum. Logistic regression analysis was used to identify independent predictors of the development of diabetes within that interval. Fourteen of the women developed diabetes by World Health Organization criteria 11-26 months after delivery of the index pregnancy. Three antepartum variables were independent predictors of diabetes: the 1-h postchallenge plasma glucose concentration from the 100-g OGTT at which GDM was diagnosed (higher = increased risk; P = 0.003); an index of pancreatic beta-cell compensation for insulin resistance, defined as the product of the 30-min incremental plasma insulin:glucose ratio on a 75-g OGTT and the insulin sensitivity index from a hyperinsulinemic-euglycemic clamp (lower = increased risk, P = 0.009); and the basal glucose production rate after an overnight fast (higher = increased risk; P = 0.04). We conclude that postchallenge hyperglycemia, poor pancreatic beta-cell compensation for insulin resistance, and elevated endogenous glucose production during pregnancy precede the development of type 2 diabetes in young Latino women by at least 1-2 years.

Assessment of Insulin Action in NIDDM in the Presence of Dynamic Changes in Insulin and Glucose Concentration

Both glucose and insulin are important regulators of glucose uptake and hepatic glucose release. Because insulin concentrations rarely if ever increase under daily living conditions, unless glucose concentrations also increase, we sought to determine whether hepatic and extrahepatic responses to changes in insulin and glucose concentration are impaired in patients with non-insulin-dependent diabetes mellitus (NIDDM). To address this question, glucose metabolism was measured in diabetic and nondiabetic subjects. A computer-driven infusion system was used to produce a nondiabetic postprandial insulin profile in both groups while sufficient exogenous glucose was infused to mimic nondiabetic postprandial glucose concentrations. Although NIDDM was associated with greater (P < 0.05) hepatic glucose release both before and during the prandial insulin infusion, suppression did not differ in the diabetic and nondiabetic subjects (-1.06 +/- 0.20 vs. -0.86 +/- 0.15 mmol/kg every 4 h). In contrast, stimulation of both glucose disappearance (0.77 +/- 0.27 vs. 1.68 +/- 0.27 mmol/kg every 4 h) and forearm glucose uptake (187 +/- 81 vs. 550 +/- 149 mumol/dl every 4 h) was lower (P < 0.05) in diabetic than in nondiabetic subjects. Thus, despite increased basal rates of glucose production, obese individuals with NIDDM had decreased stimulation of glucose disappearance but normal suppression of hepatic glucose release in response to nondiabetic prandial glucose and insulin concentrations. These data indicate that the increase in glucose that occurs with carbohydrate ingestion is likely to compensate for hepatic but not extrahepatic insulin resistance.

Optimal daytime feeding regimen to prevent postprandial hypoglycemia in type 1 glycogen storage disease

To determine the optimal daytime dietary regimen for type 1 glycogen storage disease (GSD), we used uncooked cornstarch (UCS) at a basal glucose production rate (GPR) in single and divided doses, with mixed meals at 0700 and 1700 h. This regimen was compared with a 1.5 times larger single dose of UCS at 0700 h, and with dextrose at GPR at 1200 h. Two-hour UCS loads (amount equal to GPR in 2 h) given with a mixed meal at 0700 h and 180 min later maintained mean blood glucose (BG) concentrations at greater than or equal to 4.2 mmol/L for 300 min. BG was significantly greater from 240 to 300 min compared with a single 4-h UCS load, and at 300 min compared with a single 6-h UCS load. Similar effects were noted when the divided UCS regimen was given with a mixed meal at 1700 h, but not when isoenergetic amounts of dextrose were given on the same schedules with a mixed meal at 1200 h. A daytime schedule of six UCS feedings (with the three main meals and 180 min later) at GPR maintains BG at concentrations that should minimize biochemical abnormalities and optimize clinical outcome in patients with GSD.

Insulin resistance, but normal basal rates of glucose production in patients with newly diagnosed mild diabetes mellitus

Fasting hyperglycemia in Type II (non-insulin-dependent) diabetes has been suggested to be due to hepatic overproduction of glucose and reduced glucose clearance. We studied 22 patients (10 lean and 12 obese) with newly diagnosed mild diabetes mellitus (fasting plasma glucose less than 15 mmol/l, urine ketone bodies less than 1 mmol/l), and two age- and weight-matched groups of non-diabetic control subjects. Glucose turnover rates and sensitivity to insulin were determined using adjusted primed-continuous [3-3H]glucose infusion and the hyperinsulinemic euglycemic clamp technique. Insulin-stimulated glucose utilization was reduced in both diabetic groups (lean patients: 313 +/- 35 vs 531 +/- 22 mg.m-2.min-1, p less than 0.01; obese patients: 311 +/- 28 vs 453 +/- 26 mg.m-2.min-1, p less than 0.01). Basal plasma glucose concentrations decreased 0.43 +/- 0.05 mmol/l per h (p less than 0.01). Glucose production rates were smaller than glucose utilization rates (lean patients: 87 +/- 3 vs 94 +/- 3 mg.m-2.min-1, p less than 0.01; obese patients: 79 +/- 5 vs 88 +/- 5 mg.m-2.min-1, p less than 0.01), were not correlated to basal glucose or insulin concentrations, and were not different from normal (lean controls: 87 +/- 4 mg.m-2.min-1; obese controls: 80 +/- 5 mg.m-2.min-1). These results suggest that the basal state in the diabetic patients is a compensated condition where glucose turnover rates are maintained near normal despite defects in insulin sensitivity.

Increased insulin action in rats with mild insulin deficiency induced by neonatal streptozotocin

The effect of chronic moderate insulin deficiency on in vivo insulin action was studied in young rats after neonatal (day of birth) streptozotocin (n0-STZ model) at a time (4 wk) when basal hyperglycemia is not yet established. The insulin action was quantified in vivo during insulin-glucose clamps performed on anesthetized rats while in the postabsorptive state; under basal or hyperinsulinemic conditions, total glucose production and utilization were assessed with a [3- 3H]-glucose perfusion, and local glucose utilization was estimated by measuring 2-deoxy-D-[1-3H]glucose 6-phosphate accumulation in various tissues. Compared with controls, the 4-wk-old n0-STZ rats were normoglycemic and hypoinsulinemic (P less than 0.05). The basal glucose production rate in the diabetics was significantly greater (P less than 0.05). During the clamp studies, suppression of endogenous glucose production by submaximal (1 nmol/l) or maximal (30 nmol/l) hyperinsulinemia was similar in both groups. Overall glucose utilization in the diabetics was significantly higher in the basal state and, after submaximal or maximal hyperinsulinemia, it remained significantly greater (P less than 0.001) than the corresponding utilization in the controls. This was correlated with an increased stimulation of glucose utilization in soleus muscle, diaphragm, white adipose tissue, and brown adipose tissue. In vitro studies using inguinal adipocytes showed that the glucose oxidative pathway retained normal sensitivity to insulin in the n0-STZ rats while the glucose conversion into lipids was significantly higher at sub-maximal insulin concentration compared with the control group.(ABSTRACT TRUNCATED AT 250 WORDS)

On the determination of basal glucose production rate in patients with Type 2 (non-insulin-dependent) diabetes mellitus using primed-continuous 3-3H-glucose infusion

Using primed-continuous 3-3H-glucose infusion, basal glucose production rate has been reported to be 140% higher than normal or almost normal in hyperglycaemic patients with Type 2 (non-insulin-dependent) diabetes mellitus. To determine whether these markedly different results could be due to the mode of priming: fixed or adjusted, or the mode of calculation: steady state or non-steady state equations, we studied 11 patients with Type 2 diabetes (fasting plasma glucose 8-20 mmol/l). For 6 h 3-3H-glucose (0.40 microCi/min) was infused preceded by a priming dose of 40 microCi (fixed priming), or 40 microCi.plasma glucose (mmol/l).5(-1) (adjusted priming). In diabetic patients the plasma glucose concentration was not constant but declined 0.52 +/- 0.07 mmol.l-1.h-1. Furthermore, the rate of fall was correlated to the fasting plasma glucose concentration (r = 0.90, p less than 0.01). Thus, the fasting state was not a steady state condition. Using adjusted priming a constant tracer steady state level was obtained within 60 min. In contrast, using fixed priming tracer steady state was not reached within 6 h. The initial tracer level was far below, and increased in time towards the steady state level observed after adjusted priming. Consequently, using Steele's equations after fixed priming, glucose production rates calculated after 90-120 min were overestimated in proportion to fasting hyperglycaemia. The fasting state in patients with Type 2 diabetes is not a steady state condition. Adjusted priming seems most appropriate in Type 2 diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)

Glucose turnover rate and peripheral insulin sensitivity in alcoholic patients without liver damage.

Glucose intolerance is frequently found in alcoholic patients and an impaired insulin response has been documented in them. To look for alternative mechanisms that could explain this intolerance, a glucose turnover using tritiated glucose and an euglycemic glucose clamp were performed to measure the glucose production rate and peripheral insulin sensitivity, respectively. Two groups of recently abstinent chronic male alcoholic patients without evidence of liver damage were studied. The glucose turnover technique showed a higher basal glucose production rate in alcoholics, compared with normal volunteers (2.83 +/- 0.29 vs. 1.84 +/- 0.22 mg/kg/min); an intravenous ethanol load significantly increased this rate. The euglycemic glucose clamp did not show peripheral insulin resistance in alcoholics, compared with controls.

Clinical benefits and mechanisms of a sustained response to intermittent insulin therapy in type 2 diabetic patients with secondary drug failure

To test the hypothesis that short-term insulin therapy may induce long-lasting metabolic improvements in patients with type 2 diabetes resistant to oral therapy, 19 patients were studied before and four weeks after insulin therapy, and again four weeks after resumption of oral medication. The mechanisms associated with changes of glycemic control after discontinuation of insulin therapy were also evaluated. During insulin therapy, blood glucose levels (228 ± 13 versus 123 ±18 mg/dl, p <0.001) and the basal glucose production rate (p <0.001) decreased, and the insulin secretory response to glucagon at a standardized glucose level, insulin action in vivo, and insulin binding and action in vitro in fat cells improved significantly. During the postinsulin oral therapy, blood glucose levels increased (194 ± 11 mg/dl, p <0.001) but remained below pre-insulin treatment values (p <0.01). The mean daily glucose concentration after post-insulin oral therapy correlated with the initial pre-insulin therapy glucose concentration ( r = 0.83, p <0.001). The improved rate of in vivo glucose disposal and the enhanced insulin secretory response persisted during oral therapy whereas the basal glucose production rate returned to its pre-insulin therapy value. It is concluded that patients with type 2 diabetes in whom oral therapy fails show favorable responses to insulin therapy. After discontinuation of insulin therapy, blood glucose concentrations tend to return to their individual initial values. Therefore, most of these patients require long-term insulin therapy. The mechanism behind the change of glycemic control after cessation of insulin therapy seems to be an increase in the basal glucose production rate rather than deterioration of extrahepatic insulin action or the insulin secretory response.

Glucose, fatty acid, and urea kinetics in patients with severe pancreatitis. The response to substrate infusion and total parenteral nutrition.

Rates of glucose turnover and oxidation in normal volunteers (N = 16) and in severely ill patients with pancreatitis (N = 9) were isotopically determined. Glucose turnover was determined using primed constant infusions of either 6-3H-glucose or 6-d2-glucose, and glucose oxidation with either U-14C-glucose or U-13C-glucose after appropriate priming of the bicarbonate pool. Urea kinetics were determined using primed constant infusions of either (15N2)-urea or U-14C-urea, whereas free fatty acid (FFA) kinetics were determined by the constant infusion of 1,2-13C palmitate. Basal rates of glucose production and plasma glucose clearance were significantly higher in the patients than in the volunteers. During glucose infusion (4 mg/kg/min) endogenous glucose production was virtually totally suppressed in the volunteers (94 +/- 4%). There was significantly less suppression in the patients, however (44 +/- 1%). In addition, the percentage of available glucose oxidized (i.e., percentage of uptake oxidized) was significantly less in the patients than in the volunteers. The basal rate of urea production was significantly higher in the patients; however, in both patients and volunteers, glucose infusion resulted in a significant decrease. The rate of FFA turnover was similar in the patients and volunteers, and the patients and volunteers were equally sensitive to the suppressive effects of glucose infusion. When the patients were studied during total parenteral nutrition (TPN), there was no further suppression of endogenous glucose turnover than that seen during 2 hours of glucose infusion, and the mean rate of urea turnover measured during TPN (7.0 +/- 1.9 mumol/kg/min) was also not significantly different than the value determined during glucose infusion (8.9 +/- 1.8 mumol/kg/min). It was concluded from these studies that patients with pancreatitis are metabolically similar to septic patients, have an impairment in their ability to oxidize infused glucose when compared with normal volunteers, have an elevated rate of net protein catabolism, and have FFA kinetics similar to those seen in normal humans.

Quantification in vivo of the effects of insulin on glucose utilization in individual tissues of warm- and cold-acclimated rats.

Cold-acclimation of rats (3 weeks, 4 degrees C) had no effect on basal rates of glucose production or utilization. Under euglycaemic-clamp conditions, in which the circulating insulin concentration was increased by approx. 50 microunits/ml, cold-acclimated rats showed a greater increase in glucose utilization and a greater suppression of endogenous glucose production. Tissue sites of glucose utilization were investigated by using a tracer dose of 2-deoxy-D-[14C]glucose and a glucose metabolic index determined for each tissue. In 5 h-starved warm-acclimated rats, heart had the highest glucose metabolic index. This was increased further by both cold-acclimation and insulin treatment. The glucose metabolic index of skeletal muscle was 3.5-14-fold lower than that of heart, but, as a result of the large muscle mass, skeletal muscle made the largest contribution to whole-body glucose utilization. White and brown adipose tissue had low glucose metabolic indices in warm-acclimated rats under basal conditions, and the indices were not increased by the insulin treatment. However, cold-acclimation produced a significant increase in the glucose metabolic index of brown adipose tissue, but not of white adipose tissue. In contrast with the warm-acclimated rats, insulin treatment of cold-acclimated rats resulted in a marked increase in the glucose metabolic index of brown adipose tissue. The results provide evidence that cold-acclimation produces a selective alteration in the insulin-sensitivity of brown adipose tissue.

Glucose turnover during recovery from intensive exercise.

This study was undertaken to examine glucose turnover during a 30-min recovery period following an acute bout of intensive exercise (85% VO2 max) performed to exhaustion (11.7 ± 1.4 min). Plasma glucose (basal 85 ± 2 mg/dl) rose by 10 mg/dl at exhaustion and increased further during the initial phase of recovery, reaching a peak value of 35 mg/dl above basal at 5 min of recovery. Thereafter, there was a gradual decline, but the values remained 15–20 mg/dl above basal at 30 min. The early rise in plasma glucose during recovery was due to an imbalance between glucose production and utilization caused by a more rapid decline in utilization than production. At 5 min of recovery, glucose production was fivefold greater than in the basal state and comparable to peak values observed at exhaustion, while glucose utilization was 33% lower than observed at exhaustion and only 75% higher than in the basal state. Beyond 5 min of recovery glucose utilization and production again differed in the direction of response. Glucose production fell to basal values while glucose utilization remained 70–80% above baseline. The maintenance of basal rates of glucose production and increased rates of glucose utilization occurred in a setting in which plasma insulin levels were increased by 25–50%. Plasma catechol-amines, which rose 5–10-fold during exercise, fell rapidly during the initial 3 min of recovery. We conclude that recovery from exhaustive exercise is characterized by a biphasic imbalance between glucose production and utilization in which production exceeds utilization for the initial 5 min and utilization exceeds production at 10–30 min. The hormone-substrate milieu (modest increments in plasma insulin and glucose) accompanying the changes in glucose kinetics observed beyond 5 min suggests that the recovery period from acute exercise may be characterized by an increase in peripheral sensitivity to insulin, which could provide a mechanism for facilitating muscle glycogen repletion during recovery from intensive exercise.

Short-term effects of a high-fiber, high-carbohydrate diet in very obese diabetic individuals.

The short-term effects of a weight-maintenance diet high in fiber and carbohydrate (HFHC) was studied in seven very obese individuals with type II diabetes mellitus. Such diets contained 68% of kcal as carbohydrate and total fiber content of 81 g (in contrast to 42% and 28 g during baseline). Fasting glucose concentrations, summed glucose concentrations, and 24-h glucosuria were unaffected in six of seven individuals. Fasting insulin levels decreased (-6.0 +/- 2.0 microU/ml, P less than 0.05), but meal-stimulated insulin concentrations were not altered. Triglyceride and HDL cholesterol concentrations were also unaffected. Total cholesterol concentrations fell in four individuals whose initial values exceeded 200 mg/dl. Basal glucose production rates were similar in the obese diabetic subjects, in five nonobese normal subjects, and in one obese normal individual (2.05 +/- 0.19 versus 2.63 +/- 0.30 and 1.85 mg/kg/min for the obese normal individual) while on baseline diets, and did not change with HFHC. During isoglycemic hyperinsulinemic glucose clamp procedures (maintenance of basal glucose concentrations), 40 mU/m2/min was infused intravenously for 2 h. Glucose disappearance rates increased significantly in the normal-weight control subjects, but did not increase during baseline diets in the obese type II diabetic subjects (4.65 +/- 0.80 versus 0.68 +/- 0.40 mg/kg/min). HFHC diet had no effect on glucose disappearance rates. Plasma insulin levels were 131.0 +/- 11.0, 120.0 +/- 11.0, and 120.0 +/- 5.0 microU/ml during these studies. These studies indicate that short-term HFHC diets without caloric restriction were ineffective in improving glycemic control or lessening insulin resistance in very obese patients with type II diabetes.

Effects of growth hormone on insulin action in man. Mechanisms of insulin resistance, impaired suppression of glucose production, and impaired stimulation of glucose utilization.

The present studies were undertaken to assess the mechanisms responsible for growth hormone-induced insulin resistance in man. The insulin dose-response characteristics for suppression of glucose production and stimulation of glucose utilization and their relationship to monocyte insulin binding were determined in six normal volunteers after 12-h infusion of growth hormone and 12-h infusion of saline. The infusion of growth hormone (2 micrograms . kg-1 . h-1) increased plasma growth hormone nearly threefold (to congruent to 9 ng/ml) within the range observed during sleep and exercise. This increased plasma insulin (14 +/- 1 versus 8 +/- 1 microunits/ml, P less than 0.005) concentrations without significantly altering plasma glucose concentrations or basal rates of glucose production and utilization. Insulin dose-response curves for both suppression of glucose production (half-maximal response at 37 +/- 3 versus 20 +/- 3 microunits/ml, P less than 0.01) and stimulation of glucose utilization (half-maximal response at 98 +/- 8 versus 52 +/- 8 microunits/ml, P less than 0.01) were shifted to the right with preservation of normal maximal responses to insulin. Monocyte insulin binding was unaffected. Thus, except at near maximal insulin receptor occupancy, the action of insulin on glucose production and utilization per number of monocyte insulin receptors occupied was decreased. These results indicate that increases in plasma growth hormone within the physiologic range can cause insulin resistance in man, which is due to decreases in both hepatic and extrahepatic effects of insulin. Assuming that insulin binding to monocytes reflects insulin binding in insulin sensitive tissues, this decrease in insulin action can be explained on the basis of a postreceptor defect.