Leaveism and illness-related behaviour.

BACKGROUND: Recent studies have suggested that leaveism may be a link between sickness absence and sickness presence (attending work despite illness). This paper examines one of the three components of leaveism (utilization of annual leave entitlements or flexi hours instead of sick leave). AIMS: To study whether leaveism provides additional information about employees' well-being not already predicted by sickness absence and sickness presence and to test previously suggested reasons for this behaviour. METHODS: Data from a heterogeneous sample of employees from a study on presenteeism was used to analyse the association between leaveism and self-rated health and to further investigate previously hypo thesized links with sickness absence and sickness presence. RESULTS: Data from 930 employees (response rate 31%) were analysed. Although the use of leave entitlements when unwell is less prevalent (mean = 1.5 days per year) than sickness absence (6.2 days) and sickness presence (7.4 days), this component of leaveism is significantly related to subjective health adjusted for sickness absence, sickness presence and other control variables. The results suggest that this component of leaveism is associated with fear of job loss, promotion prospects, more restrictive attendance policies and work overload. Contrary to expectations it is associated with lower, rather than higher, job enjoyment. CONCLUSIONS: Leaveism provides additional information about employees' illness-related behaviour and well-being and should be further considered in future research. Among those employees who try to avoid sick leave, high workload seems to be a stronger predictor of sickness presence, whereas fear of job loss seems to promote leaveism.

Role of the kidney in normal glucose homeostasis and in the hyperglycaemia of diabetes mellitus: therapeutic implications.

Considerable data have accumulated over the past 20 years, indicating that the human kidney is involved in the regulation of glucose via gluconeogenesis, taking up glucose from the circulation, and by reabsorbing glucose from the glomerular filtrate. In light of the development of glucose-lowering drugs involving inhibition of renal glucose reabsorption, this review summarizes these data. Medline was searched from 1989 to present using the terms 'renal gluconeogenesis', 'renal glucose utilization', 'diabetes mellitus' and 'glucose transporters'. The human liver and kidneys release approximately equal amounts of glucose via gluconeogenesis in the post-absorptive state. In the postprandial state, although overall endogenous glucose release decreases substantially, renal gluconeogenesis increases by approximately twofold. Glucose utilization by the kidneys after an overnight fast accounts for approximately 10% of glucose utilized by the body. Following a meal, glucose utilization by the kidney increases. Normally each day, approximately 180 g of glucose is filtered by the kidneys; almost all of this is reabsorbed by means of sodium-glucose co-transporter 2 (SGLT2), expressed in the proximal tubules. However, the capacity of SGLT2 to reabsorb glucose from the renal tubules is finite and, when plasma glucose concentrations exceed a threshold, glucose appears in the urine. Handling of glucose by the kidney is altered in Type 2 diabetes mellitus (T2DM): renal gluconeogenesis and renal glucose uptake are increased in both the post-absorptive and postprandial states, and renal glucose reabsorption is increased. Specific SGLT2 inhibitors are being developed as a novel means of controlling hyperglycaemia in T2DM.

Lack of glucagon response to hypoglycemia in diabetes: evidence for an intrinsic pancreatic alpha cell defect.

Despite excessive glucagon responses to infusion of arginine, plasma glucagon did not rise in six juvenile-type diabetics during severe insulin-induced hypoglycemia, whereas glucagon in the controls rose significantly. Thus in diabetics pancreatic alpha cells are insensitive to glucose even in the presence of large amounts of circulating insulin. An intrinsic defect common to both alpha and beta pancreatic cells-failure to recognize (or respond to) plasma glucose fluctuations-may be operative in juvenile diabetes.

The genetic basis of type 2 diabetes mellitus: impaired insulin secretion versus impaired insulin sensitivity.

Despite the fact that it is the prevalent view that insulin resistance is the main genetic factor predisposing to development of type 2 diabetes, review of several lines of evidence in the literature indicates a lack of overwhelming support for this concept. In fact, the literature better supports the case of impaired insulin secretion being the initial and main genetic factor predisposing to type 2 diabetes, especially 1) the studies in people at high risk to subsequently develop type 2 diabetes (discordant monozygotic twins and women with previous gestational diabetes), 2) the studies demonstrating compete alleviation of insulin resistance with weight loss, and 3) the studies finding that people with type 2 diabetes or IGT can have impaired insulin secretion and no insulin resistance compared with well matched NGT subjects. The fact that insulin resistance may be largely an acquired problem in no way lessens its importance in the pathogenesis of type 2 diabetes. Life style changes (exercise, weight reduction) and pharmacological agents (e.g., biguanides and thiazolidendiones) that reduce insulin resistance or increase insulin sensitivity clearly have major beneficial effects (122, 144-146, 153-155).

Hypoglycemia unawareness.

Hypoglycemia unawareness can occur in diabetic as well as nondiabetic individuals. A single causative mechanism for its occurrence is not yet apparent. It is likely to be multifactorial but current evidence favors a major role for some type of CNS adaptation. Certainly in some instances, classic autonomic neuropathy could be a contributory factor in patients with longstanding diabetes. Most, if not all, individuals with this condition have reduced plasma epinephrine and/or norepinephrine responses during mild hypoglycemia. Although it may be difficult to distinguish between mere reductions in the magnitude of a response and a true alteration in the threshold to initiate that response, four studies (44, 59, 65, 86) have provided evidence for an increase in the threshold (greater hypoglycemia required) for activation of counterregulatory hormone secretion associated with reduced awareness of hypoglycemia; in one study (44), diabetic patients had developed abnormalities with improved glycemic control after intensive insulin therapy; in another study (59), diabetic patients had recurrent hypoglycemia but did not differ in glycemic control (as assessed by glycosylated hemoglobin values) from subjects aware of hypoglycemia. In the two other studies, patients with impaired counterregulatory hormone responses and hypoglycemia unawareness had lower glycosylated hemoglobin levels than the other patients (65, 86). Altered tissue sensitivity to catecholamines seems unlikely to provide a primary explanation since not all symptoms are adrenergic and since, as mentioned earlier, most patients with this condition have reduced or delayed catecholamine responses to hypoglycemia, which in themselves could explain reduced awareness of hypoglycemia. Furthermore, patients with diabetic autonomic neuropathy have been reported to have increased sensitivity to catecholamines (143). One frequent observation, dating back to the early descriptions of hypoglycemia unawareness (17-19), is that patients with this condition have had frequent episodes of hypoglycemia. Although it is easy to envision how reduced warning symptoms could result in development of severe hypoglycemia, it is quite possible that frequent episodes of hypoglycemia themselves might initiate the process. For example, as depicted in Fig. 4, episodes of mild hypoglycemia occurring in insulinoma patients, diabetic patients undergoing intensive insulin therapy, or patients with longstanding diabetes complicated by autonomic neuropathy and impaired glucagon secretion could lead to CNS adaptation.(ABSTRACT TRUNCATED AT 400 WORDS)

Nateglinide, alone or in combination with metformin, is effective and well tolerated in treatment-naïve elderly patients with type 2 diabetes.

AIM: The aim of this work was to assess the efficacy and tolerability of nateglinide alone or in combination with metformin in elderly patients with type 2 diabetes (T2DM). METHODS: Study 1 was a 12-week, multicentre, randomized, double blind and placebo-controlled study of nateglinide monotherapy (120 mg, before meals) in 66 drug-naïve patients with T2DM aged >or=65 years. Study 2 was a 104-week, multicentre, randomized, double blind and active-controlled study of nateglinide (120 mg, before meals) or glyburide (up to 5 mg bid) in combination with metformin (up to 1000 mg bid) in 69 treatment-naïve patients with T2DM aged >or=65 years. HbA(1c), fasting and postprandial glucose levels, and safety assessments were made. RESULTS: In Study 1, nateglinide significantly reduced HbA(1c) from baseline (7.6 +/- 0.1% to 6.9 +/- 0.1%; Delta = -0.7 +/- 0.1%, p < 0.001) and compared with placebo (between-group difference = -0.5%, p = 0.004 vs. nateglinide). No hypoglycaemia was reported. In Study 2, combination therapy with nateglinide/metformin significantly reduced HbA(1c) from baseline (7.8 +/- 0.2% to 6.6 +/- 0.1%; Delta = -1.2 +/- 0.2%, p < 0.001), as did glyburide/metformin (7.7 +/- 0.1% to 6.5 +/- 0.1%; Delta = -1.2 +/- 0.1%, p < 0.001). There was no difference between treatments (p = 0.310). One nateglinide/metformin-treated patient experienced a mild hypoglycaemic episode compared with eight episodes in eight patients on glyburide/metformin; one severe episode led to discontinuation. Target HbA(1c) (<7.0%) was achieved by 60% of patients receiving nateglinide (Study 1) and 70% of nateglinide/metformin-treated patients (Study 2). CONCLUSION: Initial drug treatment with nateglinide, alone or in combination with metformin, is well tolerated and produces clinically meaningful improvements in glycaemic control in elderly patients with T2DM.

Increased lipolysis and its consequences on gluconeogenesis in non-insulin-dependent diabetes mellitus.

The present studies were undertaken to determine whether lipolysis was increased in non-insulin-dependent diabetes mellitus (NIDDM) and, if so, to assess the influence of increased glycerol availability on its conversion to glucose and its contribution to the increased gluconeogenesis found in this condition. For this purpose, we infused nine subjects with NIDDM and 16 age-, weight-matched nondiabetic volunteers with [2-3H] glucose and [U-14C] glycerol and measured their rates of glucose and glycerol appearance in plasma and their rates of glycerol incorporation into plasma glucose. The rate of glycerol appearance, an index of lipolysis, was increased 1.5-fold in NIDDM subjects (2.85 +/- 0.16 vs. 1.62 +/- 0.08 mumol/kg per min, P less than 0.001). Glycerol incorporation into plasma glucose was increased threefold in NIDDM subjects (1.13 +/- 1.10 vs. 0.36 +/- 0.02 mumol/kg per min, P less than 0.01) and accounted for twice as much of hepatic glucose output (6.0 +/- 0.5 vs. 3.0 +/- 0.2%, P less than 0.001). Moreover, the percent of glycerol turnover used for gluconeogenesis (77 +/- 6 vs. 44 +/- 2, P less than 0.001) was increased in NIDDM subjects and, for a given plasma glycerol concentration, glycerol gluconeogenesis was increased more than two-fold. The only experimental variable significantly correlated with the increased glycerol gluconeogenesis after taking glycerol availability into consideration was the plasma free fatty acid concentration (r = 0.80, P less than 0.01). We, therefore, conclude that lipolysis is increased in NIDDM and, although more glycerol is thus available, increased activity of the intrahepatic pathway for conversion of glycerol into glucose, due at least in part to increased plasma free fatty acids, is the predominant mechanism responsible for enhanced glycerol gluconeogenesis. Finally, although gluconeogenesis from glycerol in NIDDM is comparable to that of alanine and about one-fourth that of lactate is terms of overall flux into glucose, glycerol is probably the most important gluconeogenic precursor in NIDDM in terms of adding new carbons to the glucose pool.

Characterization of the effects of arginine and glucose on glucagon and insulin release from the perfused rat pancreas.

To characterize the mechanisms by which arginine and glucose affect pancreatic alpha and beta cell function, the effects of these agents over their full dose response, both alone and in various combinations, were studied using the perfused rat pancreas. Arginine (0-38 mM), in the absence of glucose, stimulated biphasic glucagon (IRG) secretion (Km approximately 3-4 mM) at concentrations less than 1 mM and caused nonphasic insulin (IRI) release (Km approximately 12-13 mM) but only at concentrations greater than 6 mM. Glucose (0-27.5 mM) alone stimulated biphasic IRI release (Km approximately 9-10 mM) at concentrations in excess of 5.5 mM and caused nonphasic inhibition of IRG secretion (Kt approximately 5-6 mM) at concentrations as low as 4.1 mM. These results demonstrate fundamental differences in pancreatic alpha and beta cell secretory patterns in response to glucose and arginine and suggest that glucagon secretion is more sensitive to the effect of both glucose and arginine. Various concentrations of arginine in the presence of 5.5 mM glucose stimulated biphasic IRG and IRI release: IRG responses were diminished and IRI responses were enhanced compared with those seen with arginine in the absence of glucose. Glucose (0-27.5 mM) in the presence of 3.2 or 19.2 mM arginine caused similar inhibition of IRG secretion (Km approximately 5-6 mM) and stimulation of IRI release (Km approximately 9-10 mM) as that seen with glucose alone, although greater IRG and IRI release occurred. This augmentation of IRI secretion was greater than that expected from mere additive effects of glucose and arginine. Classical Lineweaver-Burk analysis of these results indicates that glucose is a non-competitive inhibitor arginine-stimulated glucagon secretion and suggests that glucose and arginine affect pancreatic alpha and beta cell function via different mechanisms. In addition, comparison of simultaneous insulin and glucagon secretion patterns under various conditions suggests that endogenous insulin per se has little or no direct effect on IRG secretion and that endogenous glucagon does not appreciably affect pancreatic beta cell function.

Role of glucagon, catecholamines, and growth hormone in human glucose counterregulation. Effects of somatostatin and combined alpha- and beta-adrenergic blockade on plasma glucose recovery and glucose flux rates after insulin-induced hypoglycemia.

To further characterize mechanisms of glucose counterregulation in man, the effects of pharmacologically inducd deficiencies of glucagon, growth hormone, and catecholamines (alone and in combination) on recovery of plasma glucose from insulin-induced hypoglycemia and attendant changes in isotopically ([3-(3)H]glucose) determined glucose fluxes were studied in 13 normal subjects. In control studies, recovery of plasma glucose from hypoglycemia was primarily due to a compensatory increase in glucose production; the temporal relationship of glucagon, epinephrine, cortisol, and growth hormone responses with the compensatory increase in glucose appearance was compatible with potential participation of all these hormones in acute glucose counterregulation. Infusion of somatostatin (combined deficiency of glucagon and growth hormone) accentuated insulin-induced hypoglycemia (plasma glucose nadir: 36+/-2 ng/dl during infusion of somatostatin vs. 47+/-2 mg/dl in control studies, P < 0.01) and impaired restoration of normoglycemia (plasma glucose at min 90: 73+/-3 mg/dl at end of somatostatin infusion vs. 92+/-3 mg/dl in control studies, P<0.01). This impaired recovery of plasma glucose was due to blunting of the compensatory increase in glucose appearance since glucose disappearance was not augmented, and was attributable to suppression of glucagon secretion rather than growth hormone secretion since these effects of somatostatin were not observed during simultaneous infusion of somatostatin and glucagon whereas infusion of growth hormone along with somatostatin did not prevent the effect of somatostatin. The attenuated recovery of plasma glucose from hypoglycemia observed during somatostatin-induced glucagon deficiency was associated with plasma epinephrine levels twice those observed in control studies. Infusion of phentolamine plus propranolol (combined alpha-and beta-adrenergic blockade) had no effect on plasma glucose or glucose fluxes after insulin administration. However, infusion of somatostatin along with both phentolamine and propranolol further impaired recovery of plasma glucose from hypoglycemia compared to that observed with somatostatin alone (plasma glucose at end of infusions: 52+/-6 mg/dl for somatostatin-phentolamine-propranolol vs. 72+/-5 mg/dl for somatostatin alone, P < 0.01); this was due to further suppression of the compensatory increase in glucose appearance (maximal values: 1.93+/-0.41 mg/kg per min for somatostatin-phentolamine-propranolol vs. 2.86+/-0.32 mg/kg per min for somatostatin alone, P < 0.05). These results indicate that in man (a) restoration of normoglycemia after insulin-induced hypoglycemia is primarily due to a compensatory increase in glucose production; (b) intact glucagon secretion, but not growth hormone secretion, is necessary for normal glucose counterregulation, and (c) adrenergic mechanisms do not normally play an essential role in this process but become critical to recovery from hypoglycemia when glucagon secretion is impaired.

Failure of substrate-induced gluconeogenesis to increase overall glucose appearance in normal humans. Demonstration of hepatic autoregulation without a change in plasma glucose concentration.

It has been proposed that increased supply of gluconeogenic precursors may be largely responsible for the increased gluconeogenesis which contributes to fasting hyperglycemia in non-insulin-dependent diabetes mellitus (NIDDM). Therefore, to test the hypothesis that an increase in gluconeogenic substrate supply per se could increase hepatic glucose output sufficiently to cause fasting hyperglycemia, we infused normal volunteers with sodium lactate at a rate approximately double the rate of appearance observed in NIDDM while clamping plasma insulin, glucagon, and growth hormone at basal levels. In control experiments, sodium bicarbonate was infused instead of sodium lactate at equimolar rates. In both experiments, [6-3H]-glucose was infused to measure glucose appearance and either [U-14C]lactate or [U-14C]alanine was infused to measure the rates of appearance and conversion of these substrates into plasma glucose. Plasma insulin, glucagon, growth hormone, C-peptide, and glycerol concentrations, and blood bicarbonate and pH in control and lactate infusion experiments were not significantly different. Infusion of lactate increased plasma lactate and alanine to 4.48 +/- 3 mM and 610 +/- 33 microM, respectively, from baseline values of 1.6 +/- 0.2 mM and 431 +/- 28 microM, both P less than 0.01; lactate and alanine rates of appearance increased to 38 +/- 1.0 and 8.0 +/- 0.3 mumol/kg per min (P less than 0.01 versus basal rates of 14.4 +/- 0.4 and 5.0 +/- 0.5 mumol/kg per min, respectively). With correction for Krebs cycle carbon exchange, lactate incorporation into plasma glucose increased nearly threefold to 10.4 mumol/kg per min and accounted for about 50% of overall glucose appearance. Alanine incorporation into plasma glucose increased more than twofold. Despite this marked increase in gluconeogenesis, neither overall hepatic glucose output nor plasma glucose increased and each was not significantly different from values observed in control experiments (10.8 +/- 0.5 vs. 10.8 +/- 0.5 mumol/kg per min and 5.4 +/- 0.4 vs. 5.3 +/- 0.3 mM, respectively). We, therefore, conclude that in normal humans there is an autoregulatory process independent of changes in plasma glucose and glucoregulatory hormone concentrations which prevents a substrate-induced increase in gluconeogenesis from increasing overall hepatic glucose output; since this process cannot be explained on the basis of inhibition of gluconeogenesis from other substrates, it probably involves diminution of glycogenolysis. A defect in this process could explain at least in part the increased hepatic glucose output found in NIDDM.

Determination of Krebs cycle metabolic carbon exchange in vivo and its use to estimate the individual contributions of gluconeogenesis and glycogenolysis to overall glucose output in man.

Current isotopic approaches underestimate gluconeogenesis in vivo because of Krebs cycle carbon exchange and the inability to measure intramitochondrial precursor specific activity. We therefore applied a new isotopic approach that theoretically overcomes these limitations and permits quantification of Krebs cycle carbon exchange and the individual contributions of gluconeogenesis and glycogenolysis to overall glucose output. [6-3H]Glucose was infused to measure overall glucose output; [2-14C]acetate was infused to trace phosphoenolpyruvate gluconeogenesis and to calculate Krebs cycle carbon exchange as proposed by Katz. Plasma [14C]3-OH-butyrate specific activity was used to estimate intramitochondrial acetyl coenzyme A (CoA) specific activity, and finally the ratio between plasma glucose 14C-specific activity and the calculated intracellular phosphoenolpyruvate 14C-specific activity was used to determine the relative contributions of gluconeogenesis and glycogenolysis to overall glucose output. Using this approach, acetyl CoA was found to enter the Krebs cycle at twice (postabsorptive subjects) and three times (2 1/2-d fasted subjects) the rate of pyruvate, respectively. Gluconeogenesis in postabsorptive subjects (3.36 +/- 0.20 mumol/kg per min) accounted for 28 +/- 2% of overall glucose output and increased twofold in subjects fasted for 2 1/2-d (P less than 0.01), accounting for greater than 97% of overall glucose output. Glycogenolysis in postabsorptive subjects averaged 8.96 +/- 0.40 mumol/kg per min and decreased to 0.34 +/- 0.08 mumol/kg per min (P less than 0.01) after a 2 1/2-d fast. Since these results agree well with previously reported values for gluconeogenesis and glycogenolysis based on determinations of splanchnic substrate balance and glycogen content of serial liver biopsies, we conclude that the isotopic approach applied herein provides an accurate, noninvasive measurement of gluconeogenesis and glycogenolysis in vivo.

Increased proteolysis. An effect of increases in plasma cortisol within the physiologic range.

Prolonged exposure to glucocorticoids in pharmacologic amounts results in muscle wasting, but whether changes in plasma cortisol within the physiologic range affect amino acid and protein metabolism in man has not been determined. To determine whether a physiologic increase in plasma cortisol increases proteolysis and the de novo synthesis of alanine, seven normal subjects were studied on two occasions during an 8-h infusion of either hydrocortisone sodium succinate (2 micrograms/kg X min) or saline. The rate of appearance (Ra) of leucine and alanine were estimated using [2H3]leucine and [2H3]alanine. In addition, the Ra of leucine nitrogen and the rate of transfer of leucine nitrogen to alanine were estimated using [15N]leucine. Plasma cortisol increased (10 +/- 1 to 42 +/- 4 micrograms/dl) during cortisol infusion and decreased (14 +/- 2 to 10 +/- 2 micrograms/dl) during saline infusion. No change was observed in plasma insulin, C-peptide, or glucagon during either saline or cortisol infusion. Plasma leucine concentration increased more (P less than 0.05) during cortisol infusion (120 +/- 1 to 203 +/- 21 microM) than saline (118 +/- 8 to 154 +/- 4 microM) as a result of a greater (P less than 0.01) increase in its Ra during cortisol infusion (1.47 +/- 0.08 to 1.81 +/- 0.08 mumol/kg X min for cortisol vs. 1.50 +/- 0.08 to 1.57 +/- 0.09 mumol/kg X min). Leucine nitrogen Ra increased (P less than 0.01) from 2.35 +/- 0.12 to 3.46 +/- 0.24 mumol/kg X min, but less so (P less than 0.05) during saline infusion (2.43 +/- 0.17 to 2.84 +/- 0.15 mumol/kg X min, P less than 0.01). Alanine Ra increased (P less than 0.05) during cortisol infusion but remained constant during saline infusion. During cortisol, but not during saline infusion, the rate and percentage of leucine nitrogen going to alanine increased (P less than 0.05). Thus, an increase in plasma cortisol within the physiologic range increases proteolysis and the de novo synthesis of alanine, a potential gluconeogenic substrate. Therefore, physiologic changes in plasma cortisol play a role in the regulation of whole body protein and amino acid metabolism in man.

Uptake and release of glucose by the human kidney. Postabsorptive rates and responses to epinephrine.

Despite ample evidence that the kidney can both produce and use appreciable amounts of glucose, the human kidney is generally regarded as playing a minor role in glucose homeostasis. This view is based on measurements of arteriorenal vein glucose concentrations indicating little or no net release of glucose. However, inferences from net balance measurements do not take into consideration the simultaneous release and uptake of glucose by the kidney. Therefore, to assess the contribution of release and uptake of glucose by the human kidney to overall entry and removal of plasma glucose, we used a combination of balance and isotope techniques to measure renal glucose net balance, fractional extraction, uptake and release as well as overall plasma glucose appearance and disposal in 10 normal volunteers under basal postabsorptive conditions and during a 3-h epinephrine infusion. In the basal postabsorptive state, there was small but significant net output of glucose by the kidney (66 +/- 22 mumol.min-1, P = 0.016). However, since renal glucose fractional extraction averaged 2.9 +/- 0.3%, there was considerable renal glucose uptake (2.3 +/- 0.2 mumol.kg-1.min-1) which accounted for 20.2 +/- 1.7% of systemic glucose disposal (11.4 +/- 0.5 mumol.kg-1.min-1). Renal glucose release (3.2 +/- 0.2 mumol.kg-1.min-1) accounted for 27.8 +/- 2.1% of systemic glucose appearance (11.4 +/- 0.5 mumol.kg-1.min-1). Epinephrine infusion, which increased plasma epinephrine to levels observed during hypoglycemia (3722 +/- 453 pmol/liter) increased renal glucose release nearly twofold (5.2 +/- 0.5 vs 2.8 +/- 0.1 mol.kg-1.min-1, P = 0.01) so that at the end of the infusion, renal glucose release accounted for 40.3 +/- 5.5% of systemic glucose appearance and essentially all of the increase in systemic glucose appearance. These observations suggest an important role for the human kidney in glucose homeostasis.

Mechanism of increased gluconeogenesis in noninsulin-dependent diabetes mellitus. Role of alterations in systemic, hepatic, and muscle lactate and alanine metabolism.

To assess the mechanisms responsible for increased gluconeogenesis in noninsulin-dependent diabetes mellitus (NIDDM), we infused [3-14C]lactate, [3-13C]alanine, and [6-3H]glucose in 10 postabsorptive NIDDM subjects and in 9 age- and weight-matched nondiabetic volunteers and measured systemic appearance of alanine and lactate, their release from forearm tissues, and their conversion into plasma glucose (corrected for Krebs cycle carbon exchange). Systemic appearance of lactate and alanine were both significantly greater in diabetic subjects (18.2 +/- 0.9 and 5.8 +/- 0.4 mumol/kg/min, respectively) than in the nondiabetic volunteers (12.6 +/- 0.7 and 4.2 +/- 0.3 mumol/kg/min, respectively, P less than 0.001 and P less than 0.01). Conversions of lactate and alanine to glucose were also both significantly greater in NIDDM subjects (8.6 +/- 0.5 and 2.4 +/- 0.1 mumole/kg/min, respectively) than in nondiabetic volunteers (4.2 +/- 0.4 and 1.8 +/- 0.1 mumol/kg/min, respectively, P less than 0.001 and P less than 0.025). The proportion of systemic alanine appearance converted to glucose was not increased in NIDDM subjects (42.7 +/- 1.9 vs. 44.2 +/- 2.9% in nondiabetic volunteers), whereas the proportion of systemic lactate appearance converted to glucose was increased in NIDDM subjects (48.3 +/- 3.8 vs. 34.2 +/- 3.8% in nondiabetic volunteers, P less than 0.025); the latter increased hepatic efficiency accounted for approximately 40% of the increased lactate conversion to glucose. Neither forearm nor total body muscle lactate and alanine release was significantly different in NIDDM and nondiabetic volunteers. Therefore, we conclude that increased substrate delivery to the liver and increased efficiency of intrahepatic substrate conversion to glucose are both important factors for the increased gluconeogenesis of NIDDM and that tissues other than muscle are responsible for the increased delivery of gluconeogenic precursors to the liver.

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.

Effects of alternations of plasma free fatty acid levels on pancreatic glucagon secretion in man.

The present investigation was undertaken to ascertain whether alterations in plasma free fatty acids (FFA) affect pancreatic glucagon secretion in man since FFA have been reported to influence pancreatic alpha cell function in other species. Elevation of plasma FFA from a mean (+/-SE) basal level of 0.478+/-0.036 mM to 0.712+/-0.055 mM after heparin administration caused plasma glucagon levels to fall approximately 50%, from a basal value of 122+/-15 pg/ml to 59+/-14 pg/ml (P < 0.001). Lowering of plasma FFA from a basal level of 0.520+/-0.046 mM to 0.252+/-0.041 mM after nicotinic acid administration raised plasma glucagon from a basal level of 113+/-18 pg/ml to 168+/-12 pg/ml (P < 0.005). Infusion of glucose elevated plasma glucose levels to the same degree that heparin raised plasma FFA levels. This resulted in suppression of plasma glucagon despite the fact that plasma FFA levels also were suppressed. Glucagon responses to arginine were diminished after elevation of plasma FFA (P < 0.01) and during infusion of glucose (P < 0.01). Diminution of plasma FFA by nicotinic acid did not augment glucagon responses to arginine. These results thus demonstrate that rather small alterations in plasma FFA within the physiologic range have a significant effect on glucagon secretion in man. Although the effects of glucose appear to predominate over those of FFA, alterations in plasma FFA may nevertheless exert an important physiologic influence over human pancreatic alpha cell function, especially in the postabsorptive state.

Adrenergic modulation of pancreatic glucagon secretion in man.

In order to characterize the influence of the adrenergic system on pancreatic glucagon secretion in man, changes in basal glucagon secretion during infusions of pure alpha and beta adrenergic agonists and their specific antagonists were studied. During infusion of isoproterenol (3 mug/min), a beta adrenergic agonist, plasma glucagon rose from a mean (+/-SE) basal level of 104+/-10 to 171+/-15 pg/ml, P < 0.0002. Concomitant infusion of propranolol (80 mug/min), a beta adrenergic antagonist, prevented the effects of isoproterenol, although propranolol itself had no effect on basal glucagon secretion. During infusion of methoxamine (0.5 mg/min), an alpha adrenergic agonist, plasma glucagon declined from a mean basal level of 122+/-15 to 75+/-17 pg/ml, P < 0.001. Infusion of phentolamine (0.5 mg/min), an alpha adrenergic antagonist, caused a rise in plasma glucagon from a mean basal level of 118+/-16 to 175+/-21 pg/ml, P < 0.0001. Concomitant infusion of methoxamine with phentolamine caused a reversal of the effects of phentolamine. The present studies thus confirm that catecholamines affect glucagon secretion in man and demonstrate that the pancreatic alpha cell possesses both alpha and beta adrenergic receptors. Beta adrenergic stimulation augments basal glucagon secretion, while alpha adrenergic stimulation diminishes basal glucagon secretion. Furthermore, since infusion of phentolamine, an alpha adrenergic antagonist, resulted in an elevation of basal plasma glucagon levels, there appears to be an inhibitory alpha adrenergic tone governing basal glucagon secretion. The above findings suggest that catecholamines may influence glucose homeostasis in man through their effects on both pancreatic alpha and beta cell function.

Insulin increases the maximum velocity for glucose uptake without altering the Michaelis constant in man. Evidence that insulin increases glucose uptake merely by providing additional transport sites.

The present studies were undertaken to assess the mechanism by which insulin increases glucose uptake in man. Because glucose uptake in most mammalian tissues occurs predominantly by a facilitated transport system that follows Michaelis-Menten kinetics, glucose uptake was measured isotopically in normal volunteers over the physiologic range of plasma glucose and insulin concentrations and was subjected to Lineweaver-Burk and Eadie-Hofstee analysis. With both methods, increases in plasma insulin from 18 microunits/ml to 80 and 150 microunits/ml were found to increase the maximum velocity (Vmax) for glucose uptake nearly three- and fivefold, respectively, (P less than 0.025 and P less than 0.001) without significantly altering the Michaelis constant (Km). Because an increase in the affinity or molecular activity of transport sites or provision of additional transport sites that differed from those present basally should have altered the Km, whereas a mere increase in the number of transport sites would have only increased the Vmax, our results indicate that in man, insulin may increase glucose uptake merely by providing additional transport sites.

Adrenergic mechanisms for the effects of epinephrine on glucose production and clearance in man.

THE PRESENT STUDIES WERE UNDERTAKEN TO ASSESS THE ADRENERGIC MECHANISMS BY WHICH EPINEPHRINE STIMULATES GLUCOSE PRODUCTION AND SUPPRESSES GLUCOSE CLEARANCE IN MAN: epinephrine (50 ng/kg per min) was infused for 180 min alone and during either alpha (phentolamine) or beta (propranolol)-adrenergic blockade in normal subjects under conditions in which plasma insulin, glucagon, and glucose were maintained at comparable levels by infusion of somatostatin (100 mug/h), insulin (0.2 mU/kg per min), and variable amounts of glucose. In additional experiments, to control for the effects of the hyperglycemia caused by epinephrine, variable amounts of glucose without epinephrine were infused along with somatostatin and insulin to produce hyperglycemia comparable with that observed during infusion of epinephrine. This glucose infusion suppressed glucose production from basal rates of 1.8+/-0.1 to 0.0+/-0.1 mg/kg per min (P < 0.01), but did not alter glucose clearance. During infusion of epinephrine, glucose production increased transiently from a basal rate of 1.8+/-0.1 to a maximum of 3.0+/-0.2 mg/kg per min (P < 0.01) at min 30, and returned to near basal rates at min 180 (1.9+/-0.1 mg/kg per min). Glucose clearance decreased from a basal rate of 2.0+/-0.1 to 1.5+/-0.2 ml/kg per min at the end of the epinephrine infusion (P < 0.01). Infusion of phentolamine did not alter these effects of epinephrine on glucose production and clearance. In contrast, infusion of propranolol completely prevented the suppression of glucose clearance by epinephrine, and inhibited the stimulation of glucose production by epinephrine by 80+/-6% (P < 0.001). These results indicate that, under conditions in which plasma glucose, insulin, and glucagon are maintained constant, epinephrine stimulates glucose production and inhibits glucose clearance in man predominantly by beta adrenergic mechanisms.

Effect of intermittent endogenous hyperglucagonemia on glucose homeostasis in normal and diabetic man.

UNLABELLED: Infusion of glucagon causes only a transient increase in glucose production in normal and diabetic man. To assess the effect of intermittent endogenous hyperglucagonemia that might more closely reflect physiologic conditions, arginine (10 g over 30 min) was infused four times to 8 normal subjects and 13 insulin-dependent diabetic subjects (4 of whom were infused concomitantly with somatostatin to examine effects of arginine during prevention of hyperglucagonemia). Each arginine infusion was separated by 60 min. Diabetic subjects were infused throughout the experiments with insulin at rates (0.07-0.48 mU/kg per min) that had normalized base-line plasma glucose and rates of glucose appearance (Ra) and disappearance (Rd). Basal plasma glucagon and arginine-induced hyperglucagonemia were similar in both groups; basal serum insulin in the diabetics (16+/-1 muU/ml, P < 0.05) exceeded those of the normal subjects (10+/-1 muU/ml, P < 0.05) but did not increase with arginine. Serum insulin in normal subjects increased 15-20 muU/ml with each arginine infusion. In both groups each arginine infusion increased plasma glucose and Ra. Increments of Ra in the diabetics exceeded those of normal subjects, (P < 0.02); Rd was similar in both groups. In normal subjects, plasma glucose returned to basal levels after each arginine infusion, whereas in the diabetics hyperglycemia persisted reaching 151+/-15 mg/dl after the last arginine infusion. When glucagon responses were prevented by somatostatin, arginine infusions did not alter plasma glucose or Ra. CONCLUSIONS: Infusion of arginine acutely increases plasma glucose and glucose production in man solely by stimulating glucagon secretion; physiologic increments in plasma glucagon (100-150 pg/ml) can result in sustained hyperglycemia when pancreatic beta cell function is limited.