The role of beta-adrenergic sensitivity in the pathogenesis of hypoglycaemia unawareness.
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Autonomic Nervous System↗
Biomedical subjects
J Gerich
Publications and source records attributed to J Gerich.
Avoidance of hypoglycemia restores hypoglycemia awareness by increasing beta-adrenergic sensitivity in type 1 diabetes.
BACKGROUND: Lack of awareness of hypoglycemia is a major limiting factor in the management of type 1 diabetes. OBJECTIVE: To examine whether reduction in the number of episodes of hypoglycemia restores hypoglycemia awareness by influencing beta-adrenergic sensitivity in patients with type 1 diabetes. DESIGN: Controlled interventional study. SETTING: Research unit and outpatient diabetes clinic of a university hospital. PATIENTS: 10 men with type 1 diabetes and hypoglycemia unawareness (mean age [+/-SD], 46 +/- 16 years; mean duration of diabetes, 20 +/- 10 years). INTERVENTION: Strict avoidance of hypoglycemia. MEASUREMENTS: beta-Adrenergic sensitivity was measured by isoproterenol testing before and at 2 and 4 months after strict avoidance of hypoglycemia. Hypoglycemia awareness and catecholamine response were measured by performing hypoglycemic clamp (glucose level, 3 mmol/L [54 mg/dL]) before and after 4 months of avoidance of hypoglycemia. RESULTS: After 4 months, the mean (+/-SE) number of episodes of hypoglycemia (glucose level < 3.9 mmol/L [70 mg/dL]) decreased from 8.4 +/- 0.9 to 1.4 +/- 0.3 per week (P < 0.001). Hemoglobin A(1c) values increased from 0.068 +/- 0.003 (6.8% +/- 0.3%) to 0.077 +/- 0.003 (7.7% +/- 0.3%) (P < 0.001). Autonomic symptom scores during hypoglycemic clamp increased from 1.8 +/- 0.6 to 3.3 +/- 0.7 (P = 0.004) and did not significantly differ from those of normal participants (4.7 +/- 0.8) (P > 0.2). Although catecholamine responses to hypoglycemia were unchanged, the dose of isoproterenol necessary to increase heart rate by 25 beats/min (IC(25)) decreased from 1.96 +/- 0.43 microgram before treatment to 1.09 +/- 0.17 microgram after 4 months of treatment (P = 0.01), a value similar to that in normal participants (0.85 +/- 0.20 microgram) (P > 0.2). Improvements in beta-adrenergic sensitivity (change in IC(25)(-1)) were correlated with improvements in autonomic symptoms (r = 0.65; P = 0.04). CONCLUSIONS: Avoidance of hypoglycemia in patients with type 1 diabetes who have hypoglycemia unawareness seems to restore hypoglycemia awareness, primarily by increasing beta-adrenergic sensitivity.
Adult↗
Pathogenesis of type 2 diabetes mellitus.
Type 2 diabetes mellitus is a heterogeneous disorder with genetic and acquired components. It is primarily due to impaired insulin secretion in that individuals with genetically impaired beta cell function cannot increase their insulin release sufficiently to compensate for insulin resistance. The resultant hyperglycemia is largely the consequence of excessive release of endogenous glucose due to increased gluconeogenesis. Nevertheless, clinical experience has demonstrated that therapies directed at improving beta cell function (sulfonylureas) and at improving hepatic (metformin) and muscle (thiazolidinediones) insulin sensitivity are effective treatments for the condition.
Diabetes Mellitus, Type 2↗
Oral glucose tolerance test indexes for insulin sensitivity and secretion based on various availabilities of sampling times.
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Administration, Oral↗
Clinical features of insulin resistance and beta cell dysfunction and the relationship to type 2 diabetes.
Type 2 diabetes mellitus is a heterogeneous disorder characterized by varying degrees of impaired insulin secretion and insulin resistance. The metabolic manifestations of insulin resistance include (1) reduced insulin-stimulated glucose uptake, (2) reduced insulin-suppression of endogenous glucose production, and (3) reduced antilipolysis. All of these mechanisms contribute to the hyperglycemis of T2DM, both post-absorptively and postprandially. In addition, insulin resistance is involved in decreaswed insulin-induced vasodilation, dyslipidemia, and platelet hyperaggregability. The pathogenesis of T2DM involves a combination of genetic and environmental factors. Monogenic causes account for only a minority of insulin resistance and beta cell dysfunction. Among environmental factors the most important are obesity, reduced physical activity, and age. Obesity-associated insulin resistance is thought to be mediated mainly by FFAs whose clearance is reduced in subjects with T2DM. A number of clinical tests have been developed to assess insulin sensitivity and beta cell function in vivo. The euglycemic hyperinsulinemic clamp and the hyperglycemic clamp, respectively, represent the gold standard procedures. Recently, indices calculated parameters of the OGTT have been proposed as surrogates for assessing both insulin sensitivity and beta cell function in clinical situations and epidemiologic studies.
Diabetes Mellitus, Type 2↗
Use of the oral glucose tolerance test to assess insulin release and insulin sensitivity.
OBJECTIVE: The oral glucose tolerance test (OGTT) has often been used to evaluate apparent insulin release and insulin resistance in various clinical settings. However, because insulin sensitivity and insulin release are interdependent, to what extent they can be predicted from an OGTT is unclear. RESEARCH DESIGN AND METHODS: We studied insulin sensitivity using the euglycemic-hyperinsulinemic clamp and insulin release using the hyperglycemic clamp in 104 nondiabetic volunteers who had also undergone an OGTT. Demographic parameters (BMI, waist-to-hip ratio, age) and plasma glucose and insulin values from the OGTT were subjected to multiple linear regression to predict the metabolic clearance rate (MCR) of glucose, the insulin sensitivity index (ISI), and first-phase (1st PH) and second-phase (2nd PH) insulin release as measured with the respective clamps. RESULTS: The equations predicting MCR and ISI contained BMI, insulin (120 min), and glucose (90 min) and were highly correlated with the measured MCR (r = 0.80, P < 0.00005) and ISI (r = 0.79, P < 0.00005). The equations predicting 1st PH and 2nd PH contained insulin (0 and 30 min) and glucose (30 min) and were also highly correlated with the measured 1st PH (r = 0.78, P < 0.00005) and 2nd PH (r = 0.79, P < 0.00005). The parameters predicted by our equations correlated better with the measured parameters than homeostasis model assessment for secretion and resistance, the delta30-min insulin/delta30-min glucose ratio for secretion and insulin (120 min) for insulin resistance taken from the OGTT. CONCLUSIONS: We thus conclude that predicting insulin sensitivity and insulin release with reasonable accuracy from simple demographic parameters and values obtained during an OGTT is possible. The derived equations should be used in various clinical settings in which the use of clamps or the minimal model would be impractical.
Blood Glucose↗
Assessment of insulin secretion from the oral glucose tolerance test in white patients with type 2 diabetes.
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Diabetes Mellitus, Type 2↗
Role of glutamine in human carbohydrate metabolism in kidney and other tissues.
Glutamine is the most abundant amino acid in the human body and is involved in more metabolic processes than any other amino acid. Until recently, the understanding of many aspects of glutamine metabolism was based on animal and in vitro data. However, recent studies using isotopic and balance techniques have greatly advanced the understanding of glutamine metabolism in humans and its role in glucose metabolism in the kidney and other tissues. There is now evidence that in postabsorptive humans, glutamine is an important glucose precursor and makes a significant contribution to the addition of new carbon to the glucose carbon pool. The importance of alanine for gluconeogenesis, viewed in terms of the addition of new carbons, is less than previously assumed. It appears that glutamine is predominantly a renal gluconeogenic substrate, whereas alanine gluconeogenesis is essentially confined to the liver. As shown recently, renal gluconeogenesis contributes 20 to 25% to whole-body glucose production. Moreover, glutamine has been shown not only to stimulate net muscle glycogen storage but also to stimulate gluconeogenesis in normal humans. Finally, in humans with type II diabetes, conversion of glutamine to glucose is increased (more so than that of alanine). The available evidence on the hormonal regulation of glutamine gluconeogenesis in kidney and liver and its alterations under pathological conditions are discussed.
Alanine↗
Abnormal renal and hepatic glucose metabolism in type 2 diabetes mellitus.
Release of glucose by liver and kidney are both increased in diabetic animals. Although the overall release of glucose into the circulation is increased in humans with diabetes, excessive release of glucose by either their liver or kidney has not as yet been demonstrated. The present experiments were therefore undertaken to assess the relative contributions of hepatic and renal glucose release to the excessive glucose release found in type 2 diabetes. Using a combination of isotopic and balance techniques to determine total systemic glucose release and renal glucose release in postabsorptive type 2 diabetic subjects and age-weight-matched nondiabetic volunteers, their hepatic glucose release was then calculated as the difference between total systemic glucose release and renal glucose release. Renal glucose release was increased nearly 300% in diabetic subjects (321+/-36 vs. 125+/-15 micromol/min, P < 0.001). Hepatic glucose release was increased approximately 30% (P = 0.03), but increments in hepatic and renal glucose release were comparable (2.60+/-0.70 vs. 2.21+/-0.32, micromol.kg-1.min-1, respectively, P = 0.26). Renal glucose uptake was markedly increased in diabetic subjects (353+/-48 vs. 103+/-10 micromol/min, P < 0.001), resulting in net renal glucose uptake in the diabetic subjects (92+/-50 micromol/ min) versus a net output in the nondiabetic subjects (21+/-14 micromol/min, P = 0.043). Renal glucose uptake was inversely correlated with renal FFA uptake (r = -0.51, P < 0.01), which was reduced by approximately 60% in diabetic subjects (10. 9+/-2.7 vs. 27.0+/-3.3 micromol/min, P < 0.002). We conclude that in type 2 diabetes, both liver and kidney contribute to glucose overproduction and that renal glucose uptake is markedly increased. The latter may suppress renal FFA uptake via a glucose-fatty acid cycle and explain the accumulation of glycogen commonly found in the diabetic kidney.
3-Hydroxybutyric Acid↗
Improved glucose counterregulation and autonomic symptoms after intraportal islet transplants alone in patients with long-standing type I diabetes mellitus.
BACKGROUND: Defective glucose counterregulation and hypoglycemia unawareness are both well-recognized risk factors for recurrent episodes of severe hypoglycemia in patients with type I diabetes. At present, no conventional therapy is available to routinely overcome these acquired impairments in long-standing diabetes. METHODS: To test the hypothesis that successful intraportal islet transplantation could improve this syndrome, hormonal counterregulatory responses and symptoms were studied during stepped hypoglycemic clamp tests before and after intraportal islet transplantation in three patients with type I diabetes who were prone to severe hypoglycemia. RESULTS: As compared with matched nondiabetic control subjects, before islet transplantation, glucagon responses were absent while epinephrine and cortisol responses were either markedly decreased or absent in all diabetic subjects. One patient also had decreased norepinephrine and growth hormone responses. Autonomic warning symptoms were absent in all patients during hypoglycemia. One month after successful islet transplantation, there was no improvement in the glucagon response. However, glycemic thresholds and/or peak incremental responses of epinephrine, norepinephrine, and cortisol improved in all patients. Moreover, all patients had developed autonomic warning symptoms so that glycemic thresholds were detectable within the examined range. CONCLUSION: We conclude that intraportal islet transplantation does not restore hypoglycemia-induced glucagon secretion, but it improves the responses of most counterregulatory hormones and hypoglycemic warning symptoms even in long-standing type I diabetes.
Adult↗
Effects of glucagon on renal and hepatic glutamine gluconeogenesis in normal postabsorptive humans.
Glutamine is an important gluconeogenic amino acid in postabsorptive humans. To assess the effect of glucagon on renal and hepatic glutamine gluconeogenesis, we infused six normal healthy postabsorptive subjects with glucagon at a rate chosen to produce circulating glucagon concentrations found during hypoglycemia and, using a combination of isotopic and net balance techniques, determined the systemic, renal, and hepatic glucose release and renal and hepatic production of glucose from glutamine. Infusion of glucagon increased systemic and hepatic glucose release (both P < .02), but had no effect on renal glucose release (P = .26). Systemic and hepatic glutamine gluconeogenesis increased from 0.45 +/- 0.3 and 0.11 +/- 0.02 micromol x kg(-1) x min(-1), respectively, to 0.61 +/- 0.04 (P = .002) and 0.31 +/- 0.03 micromol x kg(-1) x min(-1) (P = .001), respectively, whereas renal glutamine gluconeogenesis was unchanged (from 0.33 +/- 0.03 to 0.30 +/- 0.04 micromol x kg(-1) x min(-1), P = .20). The hepatic contribution to systemic glutamine gluconeogenesis increased from 25.2% +/- 6.2% to 51.6% +/- 5.5% (P = .002), while that of the kidney decreased from 74.8% +/- 6.2% to 48.4% +/- 5.5% (P = .003). Glucagon had no effect on the renal net balance, fractional extraction, or uptake and release of either glucose or glutamine. We thus conclude that glucagon stimulates glutamine gluconeogenesis in normal postabsorptive humans, predominantly due to an increase in hepatic glutamine conversion to glucose. Thus, under certain conditions such as counterregulation of hypoglycemia, the liver may be an important site of glutamine gluconeogenesis.
Adult↗
Human kidney and liver gluconeogenesis: evidence for organ substrate selectivity.
To assess the contribution of the human kidney to gluconeogenesis (GN) and its role in conversion of glutamine and alanine to glucose, we used a combination of isotopic and organ balance techniques in nine normal postabsorptive volunteers and measured both overall and renal incorporation of these precursors into glucose before and after infusion of epinephrine. In the postabsorptive basal state, renal incorporation of glutamine (27 +/- 2 mumol/min) and alanine (2.1 +/- 0.5 mumol/min) into glucose accounted for 72.8 +/- 3.3 and 3.9 +/- 0.5% of their overall incorporation into glucose (37 +/- 2 and 51 +/- 6 mumol/min, respectively) and 19.0 +/- 3.5 and 1.4 +/- 0.2%, respectively, of overall renal glucose release. Infusion of epinephrine, which increased systemic and renal glucose release more than twofold (P < 0.001), increased overall glutamine and alanine incorporation into glucose (both P < 0.001) and increased renal GN from glutamine (P < 0.001) but not from alanine (P = 0.15). Renal glutamine GN now accounted for 90.3 +/- 4.0% of overall glutamine GN (P = 0.01 vs. basal), whereas renal alanine GN still accounted for only 4.8 +/- 1.7% of overall alanine GN (P = 0.36 vs. basal). With the assumption that kidney and liver are the only gluconeogenic organs in humans, these results indicate that glutamine GN occurs primarily in kidney, whereas alanine GN occurs almost exclusively in liver. Isotopic studies of glutamine and alanine incorporation into plasma glucose may provide a selective, noninvasive method to assess hepatic and renal GN.
Adult↗
Effects of physiological hyperinsulinemia on systemic, renal, and hepatic substrate metabolism.
To determine the effect of physiological hyperinsulinemia on renal and hepatic substrate metabolism, we assessed systemic and renal glucose release and uptake, systemic and renal gluconeogenesis from glutamine, and certain aspects of systemic and renal glutamine and free fatty acid (FFA) metabolism. These were assessed under basal postabsorptive conditions and during 4-h hyperinsulinemic euglycemic clamp experiments in nine normal volunteers using a combination of isotopic techniques and renal balance measurements. Hepatic glucose release (HGR) and glutamine gluconeogenesis were calculated as the difference between systemic and renal measurements. Infusion of insulin suppressed systemic glucose release and glutamine gluconeogenesis by approximately 50% during the last hour of the insulin infusion (P < 0.001). Renal glucose release and glutamine gluconeogenesis decreased from 2.3 +/- 0.4 to 0.9 +/- 0.2 (P < 0.002) and from 0.52 +/- 0.07 to 0.14 +/- 0.03 micromol. kg-1. min-1 (P < 0.001), respectively. HGR and glutamine gluconeogenesis decreased from 8.7 +/- 0.4 to 4.5 +/- 0.5 (P < 0.001) and from 0.35 +/- 0.02 to 0.27 +/- 0.03 micromol. kg-1. min-1 (P < 0.002), respectively. Renal glucose uptake (RGU) increased from 1.61 +/- 0.19 to 2.18 +/- 0.25 micromol. kg-1. min-1 (P = 0.029) but accounted for only approximately 5% of systemic glucose disposal (40.6 +/- 4.3 micromol. kg-1. min-1). Both systemic and renal FFA clearance increased approximately fourfold (P < 0.001 for both). Nevertheless, renal FFA uptake decreased (P = 0.024) and was inversely correlated with RGU (r = -0.582, P = 0.011). Finally, insulin increased systemic glutamine release (P = 0.007), uptake (P < 0.005), and clearance (P < 0.001) but left renal glutamine uptake and release unaffected (P > 0.4 for both).
Adult↗
Effects of autonomic neuropathy on counterregulation and awareness of hypoglycemia in type 1 diabetic patients.
OBJECTIVE: The recent EURODIAB Study has identified autonomic neuropathy as an independent risk factor for severe hypoglycemia in patients with type 1 diabetes. We tested the hypothesis that counterregulatory catecholamine responses and awareness of hypoglycemia are impaired to a greater extent in type 1 diabetic patients with autonomic neuropathy (AN+) than in those without autonomic neuropathy (AN-). RESEARCH DESIGN AND METHODS: We studied 22 type 1 diabetic patients (8 AN+, 14 AN-) matched for age, duration of diabetes, glycemic control, and history of hypoglycemic episodes. We also studied 33 nondiabetic control subjects using the stepped hypoglycemic clamp technique and determined glycemic thresholds and magnitudes of counterregulatory hormone responses and of hypoglycemia symptoms. RESULTS: Both groups of diabetic patients had reduced awareness of hypoglycemia as evidenced by an elevated glycemic threshold for autonomic symptoms > or =2 SD above normal but neither the magnitude nor thresholds for symptoms differed in AN+ patients and AN-patients. Both groups also had impaired glucagon, epinephrine, norepinephrine, growth hormone and cortisol responses to hypoglycemia. However, in AN+ patients compared with AN-patients, magnitudes of epinephrine and norepinephrine responses (194+/-49 vs. 784+/-206 pmol/l, P < 0.007, and 316+/-56 vs. 610+/-87 pmol/l, P < 0.02, respectively) and epinephrine and norepinephrine glycemic thresholds (2.33+/- 0.10 vs. 2.82+/-0.10 mmol/l, P < 0.009 and 2.34+/-0.06 vs. 2.79+/-0.10 mmol/l, P < 0.008, respectively) were impaired to a greater extent. This was associated with a 50% greater requirement of exogenous glucose to prevent more severe hypoglycemia during the 2.3 mmol/l glycemic plateau (P < 0.002). No differences were observed between other counterregulatory hormone responses in AN+ and AN- patients. CONCLUSIONS: We conclude that in patients with type 1 diabetes, autonomic neuropathy further reduces counterregulatory catecholamine responses. Since this should increase the risk for severe hypoglycemia, one might consider safer therapeutic goals in these patients.
Adult↗
Steady-state and non-steady-state measurements of plasma glutamine turnover in humans.
To compare steady-state glutamine turnover using nitrogen, carbon, and hydrogen tracers and to test the validity of monocompartmental equations to determine plasma glutamine turnover under non-steady-state conditions, we infused 10 normal postabsorptive volunteers simultaneously with [3,4-3H]glutamine, [2-15N]glutamine, and [U-14C]glutamine for 4 h to isotopic steady state. Eight of the ten subjects were subsequently infused in a stepwise fashion with exogenous glutamine. Plasma glutamine enrichment and specific activities fit a monoexponential model well (r = 0.89, 0.92, and 0.92 for [2-15N]-, [U-14C]-, and [3,4-3H]glutamine, respectively). Volumes of distribution for each tracer (362 +/- 58, 433 +/- 51, and 446 +/- 63 ml/kg) and the transfer rate constants (0.0224 +/- 0.0020, 0.0222 +/- 0.0020, and 0.0240 +/- 0.0023 min(-1)) for [2-15N]-, [U-14C]-, and [3,4-3H]glutamine, respectively, were not significantly different from one another. However, turnover of glutamine determined with [3,4-3H]glutamine (6.14 +/- 0.54 micromol x kg(-1) x min(-1)) exceeded that determined with [U-14C]glutamine (5.72 +/- 0.541 micromol x kg(-1) x min(-1); P < 0.03), which in turn exceeded that determined with [2-15N]glutamine (4.67 +/- 0.39 micromol x kg(-1) x min(-1), P < 0.01). The monocompartmental non-steady-state equations of both DeBodo et al. (DeBodo, R., R. Steele, A. Dunn, and J. Bishop. Rec. Prog. Horm. Res. 19: 445-448, 1963) and Finegood et al. (Finegood, D., R. Bergman, and M. Vranic. Diabetes 36: 914-924, 1987) yielded acceptable approximations of predicted rates of glutamine plasma appearance with deviations from predicted rates from 0.2 to 1.6% (Finegood et al.) and from 0.1 to 8.2% (DeBodo et al.). Use of a 0.75 pool fraction most closely approximated predicted rates.
Adult↗
Human kidney free fatty acid and glucose uptake: evidence for a renal glucose-fatty acid cycle.
To determine the relationship between free fatty acids (FFA) and glucose uptake by the human kidney, 12 postabsorptive normal volunteers underwent renal vein catheterization and were infused to isotopic steady state with [6-3H]glucose and [9,10-3H]palmitate. Arterial and renal vein palmitate specific activities were not significantly different (3,533 +/- 219 vs. 3,549 +/- 220 dpm/mumol, P = 0.64). Palmitate renal fractional extraction and uptake determined isotopically (7.2 +/- 1.1% and 9.1 +/- 1.4 mumol/min) were not significantly different from those calculated by net balance measurements (8.3 +/- 1.2% and 9.7 +/- 1.2 mumol/min, P > 0.07 and P > 0.7, respectively). Renal palmitate uptake accounted for 8.7 +/- 1.3% of its systemic turnover. Renal linoleate and oleate fractional extraction calculated by net balance measurements (8.0 +/- 0.9 and 7.7 +/- 1.2%, respectively) were not significantly different from each other and that of palmitate (all P > 0.7). Renal uptake of palmitate, linoleate (7.9 +/- 1.0 mumol/min), and oleate (10.9 +/- 2.0 mumol/min) were all directly proportional to their arterial concentrations (r = 0.70, 0.68, and 0.63, respectively, all P < 0.025). Renal glucose uptake (93 +/- 10 mumol/min) accounted for 12.6 +/- 1.5% of its systemic turnover and was inversely related to the sum of palmitate, linoleate, and oleate uptake (r = -0.74, P < 0.01). These data indicate that in postabsorptive humans: 1) the kidney is an important site of FFA and glucose disposal, 2) a renal glucose-fatty acid cycle may exist, and 3) there appears to be little or no release into the circulation of stored renal FFA.
Adult↗
Role of the kidney in human leptin metabolism.
To assess the role of the human kidney in leptin metabolism, we measured renal leptin net balance and urinary leptin excretion in 16 normal postabsorptive volunteers with varying degrees of obesity. Arterial leptin concentrations (11.6 +/- 2.7 ng/ml) significantly exceeded renal vein concentrations (10.3 +/- 2.5 ng/ml, P < 0.001). Renal leptin fractional extraction averaged 13.1 +/- 1.1%, and renal leptin net balance (uptake) averaged 1,070 +/- 253 ng/min. Lineweaver-Burk analysis indicated that renal leptin uptake followed saturation kinetics with an apparent Michaelis-Menten constant of 10.9 ng/ml and maximal velocity of 1,730 ng/min. Leptin was generally undetectable in urine. Using literature values for systemic leptin clearance, we calculated that renal leptin uptake could account for approximately 80% of all leptin removal from plasma. These data indicate that the human kidney plays a substantial role in leptin removal from plasma by taking up and degrading the peptide.
Adult↗
Glutamine and alanine metabolism in NIDDM.
Gluconeogenesis is increased in NIDDM. We therefore examined the metabolism of glutamine and alanine, the most important gluconeogenic amino acids, in 14 postabsorptive NIDDM subjects and 18 nondiabetic volunteers using a combination of isotopic ([6-3H]glucose (20 microCi, 0.2 microCi/min), [U-14C]glutamine (20 microCi, 0.2 microCi/min), [3-13C]alanine (99% 13C, 2 mmol, 20 micromol/min), [ring-2H5]phenylalanine (99% 2H, 2 micromol/kg, 0.03 micromol x kg(-1) x min(-1)), and limb balance techniques. Alanine turnover (4.54 +/- 0.24 vs. 5.64 +/- 0.33 micromol x kg(-1) x min(-1)), de novo synthesis (3.00 +/- 0.25 vs. 4.01 +/- 0.33 micromol x kg(-1) x min(-1)), and conversion to glucose (1.02 +/- 0.09 vs. 1.56 +/- 0.17 micromol x kg(-1) x min(-1)) were increased in NIDDM subjects (all P < 0.01), while its forearm release (0.45 +/- 0.04 vs. 0.39 +/- 0.04 micromol x kg(-1) x min(-1)) was unaltered. Although glutamine turnover (4.81 +/- 0.23 vs. 4.40 +/- 0.31 micromol x kg(-1) x min(-1)) was unaltered in NIDDM, its conversion to glucose (0.57 +/- 0.04 vs. 1.08 +/- 0.10 micromol x kg(-1) x min(-1)) and to alanine (0.10 +/- 0.01 vs. 0.34 +/- 0.04 micromol x kg(-1) x min(-1)) (both P = 0.001) was increased while its oxidation (2.84 +/- 0.27 vs. 1.84 +/- 0.15 micromol x kg(-1) x min(-1), P = 0.03) and forearm release (0.77 +/- 0.05 vs. 0.62 +/- 0.09 micromol x kg(-1) x min(-1), P < 0.008) were both reduced. Our results thus demonstrate that there are substantial alterations of glutamine and alanine metabolism in NIDDM. Conversion of both amino acids to glucose and the proportion of their turnover used for gluconeogenesis are increased; release of both amino acids from tissues other than skeletal muscle seems to be increased. Finally, the reduction in glutamine oxidation, possibly the result of competition with glucose and free fatty acids as fuels, makes more glutamine available for gluconeogenesis without a change in its turnover.
Alanine↗