Effect of new oral antidiabetic agent CS-045 on glucose tolerance and insulin secretion in patients with NIDDM.

OBJECTIVE: To study the effects of CS-045, a newly developed thiazolidine analogue, on glucose tolerance and insulin response to oral glucose load in patients with non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS: Nineteen NIDDM patients (mean +/- SD age 48.9 +/- 9.4 yr) whose previous glycemic control on diet and/or sulfonylurea (SU) therapy was judged stable but unsatisfactory (greater than 7.8 mM) were selected for this study. CS-045 (400 mg/day p.o.) was given alone or together with the previous SU drugs for 12 wk. A 75-g oral glucose tolerance test (OGTT) was performed before and after CS-045 treatment. Results: The following results were found after CS-045 treatment. 1) Fasting plasma glucose (FPG) and HbA1c decreased (n = 19, FPG, 11.0 +/- 2.4 vs. 8.4 +/- 2.7 mM [before vs. after], P less than 0.001; HbA1c, 8.0 +/- 1.1 vs. 7.4 +/- 1.3%, P less than 0.005), and glucose tolerance markedly improved. 2) Fasting insulin (immunoreactive insulin [IRI]) and insulin response during OGTT decreased (n = 19, fasting IRI, 77.4 +/- 49.8 vs. 56.5 +/- 24.6 pM [before vs. after], P less than 0.05; area under the curve of IRI, 540.3 +/- 350.5 vs. 426.4 +/- 216.3 pM.h, P less than 0.05). CONCLUSIONS: CS-045 is effective in improving glucose tolerance without stimulation of insulin secretion in NIDDM, suggesting an effect in improving insulin sensitivity.     

Glucagon and Insulin Binding to Liver Membranes in a Partially Nephrectomized Uremic Rat Model

To investigate the role of glucagon and insulin receptor binding in the glucagon hypersensitivity and insulin resistance which characterize the glucose intolerance of uremia, liver plasma membranes were prepared from control rats (blood urea nitrogen [BUN] 15+/-1 mg/100 ml, creatinine 0.7+/-0.2 mg/100 ml), and from 70% nephrectomized rats (BUN 30+/-2 mg/100 ml, creatinine 2.2+/-0.2 mg/100 ml), and from 90% nephrectomized rats (BUN 46+/-3 mg/100 ml, creatinine 4.20+/-0.7 mg/100 ml), 4 wk after surgery. As compared to controls, the 90% nephrectomized rats had significantly higher levels of plasma glucose (95+/-4 vs. 125+/-11 mg/100 ml), plasma insulin (28+/-9 vs. 52+/-11 muU/ml), and plasma glucagon (28+/-5 vs. 215+/-18 pg/ml). Similar, but less marked, elevations were observed in the 70% nephrectomized animals.In liver plasma membranes from nephrectomized rats, specific binding of (125)I-glucagon was increased by 80-120%. Furthermore, glucagon (2 muM)-stimulated adenylate cyclase activity in nephrectomized rats was twofold higher than in controls. In contrast, fluoridestimulated adenylate cyclase activity was similar in both groups of rats. In marked contrast to glucagon binding, specific binding of (125)I-insulin to liver membranes from nephrectomized rats was reduced by 40-50% as compared to controls. Data analysis suggested that the changes in both glucagon and insulin binding are a consequence of alterations in binding capacity rather than changes in affinity. Liver plasma membranes from nephrectomized rats degraded (125)I-glucagon and (125)I-insulin to the same extent as control rats.THESE RESULTS DEMONSTRATE THAT: (a) the 70 and 90% nephrectomized rats simulate the hyperglycemia, hyperinsulinemia, and hyperglucagonemia observed in clinical uremia; (b) in these animals specific binding of glucagon to liver membranes is increased and is accompanied by higher glucagon-stimulated adenylate cyclase activity; and (c) specific binding of insulin is markedly decreased. These findings thus provide evidence of oppositely directed, simultaneous changes in glucagon and insulin receptor binding in partially nephrectomized rats. Such changes may account for the hypersensitivity to glucagon and may contribute to resistance to insulin observed in the glucose intolerance of uremia.     

肝硬化患者糖代谢异常及胰岛素抵抗的临床研究

目的　探讨肝硬化糖代谢异常及胰岛素抵抗的病因和机制。方法　对 2 8例肝硬化患者 ,30例正常人进行了空腹血糖 (FPG)、餐后 2小时血糖 (PPG)、血清空腹胰岛素 (FINS)的检测 ,计算胰岛素释放指数 (IRI)及胰岛素敏感指数 (ISI) ,对各项结果进行比较分析。结果　肝硬化组存在着糖耐量异常 ,餐后 2小时血糖、血清空腹胰岛素、胰岛素释放指数显著高于正常对照组 (P <0 .0 1)。胰岛素敏感指数 ,显著低于正常对照组 (P <0 .0 1)。肝硬化Child分级比较 ,随着病情加重 ,糖代谢紊乱逐渐突出。结论　肝硬化失代偿患者存在糖代谢异常 ,这种代谢异常和肝功能损害、胰岛素抵抗有关     

Normalization of blood glucose in diabetic rats with phlorizin treatment reverses insulin-resistant glucose transport in adipose cells without restoring glucose transporter gene expression.

Insulin secretion and insulin sensitivity were evaluated in eight clinically stable cirrhotic patients and in 12 controls. OGTT was normal in cirrhotics but plasma insulin response was increased approximately twofold compared with controls. Subjects received a three-step (0.1, 0.5, 1.0 mU/kg.min) euglycemic insulin clamp with indirect calorimetry, [6-3H]-glucose, and [1-14C]-palmitate. During the two highest insulin infusion steps glucose uptake was impaired (3.33 +/- 0.31 vs. 5.06 +/- 0.40 mg/kg.min, P less than 0.01, and 6.09 +/- 0.50 vs. 7.95 +/- 0.52 mg/kg.min, P less than 0.01). Stimulation of glucose oxidation by insulin was normal; in contrast, nonoxidative glucose disposal (i.e., glycogen synthesis) was markedly reduced. Fasting (r = -0.553, P less than 0.01) and glucose-stimulated (r = -0.592, P less than 0.01) plasma insulin concentration correlated inversely with the severity of insulin resistance. Basal hepatic glucose production was normal in cirrhotics and suppressed normally with insulin. In postabsorptive state, plasma FFA conc (933 +/- 42 vs. 711 +/- 44 mumol/liter, P less than 0.01) and FFA turnover (9.08 +/- 1.20 vs. 6.03 +/- 0.53 mumol/kg.min, P less than 0.01) were elevated in cirrhotics despite basal hyperinsulinemia; basal FFA oxidation was similar in cirrhotic and control subjects. With low-dose insulin infusion, plasma FFA oxidation and turnover failed to suppress normally in cirrhotics. During the two higher insulin infusion steps, all parameters of FFA metabolism suppressed normally. In summary, stable cirrhotic patients with normal glucose tolerance exhibit marked insulin resistance secondary to the impaired nonoxidative glucose disposal. Our results suggest that chronic hyperinsulinism may be responsible for the insulin resistance observed in cirrhosis.     

Iron Excess, Early Glucose Intolerance and Impaired Insulin Secretion in Idiopathic Haemochromatosis

Abstract. The relationship between iron storage and glucose metabolism was studied in 21 relatives of 4 patients with idiopathic haemochromatosis and in 10 healthy control subjects. In all individuals, plasma iron and iron binding capacity were measured and liver function was assessed. In addition, intravenous and oral glucose tolerance tests (IVGTT, OGTT), as well as tolbutamide (TTT) and insulin tolerance tests (ITT), were performed. Serum insulin (IRI) was measured. Liver biopsies were performed on the 21 relatives only.
In the relatives of patients with haemochromatosis, glucose tolerance was impaired and insulin secretion in response to hyperglycaemia diminished and/or delayed. Glucose intolerance increased with age but did not depend on abnormal liver function or excessive iron storage. Insulin release in response to tolbutamide was normal and insulin tolerance test failed to reveal insulin resistance.
The results suggest that:
1. There is an early glucose intolerance in healthy relatives of patients suffering from idiopathic haemochromatosis.
2. The glucose intolerance seems unrelated to measurable anomalies in iron metabolism.
3. The delayed insulin secretion in response to glucose resembles that observed in common maturity-onset diabetes mellitus.
4. The results obtained are compatible with the hypothesis that haemochromatosis and diabetes mellitus might be two distinct but genetically linked entities.     

Hyperglucagonemia and insulin-mediated glucose metabolism.

The effect of chronic physiologic hyperglucagonemia on basal and insulin-mediated glucose metabolism was evaluated in normal subjects, using the euglycemic insulin clamp technique (+50, +100, and +500 microU/ml). After glucagon infusion fasting glucose increased from 76 +/- 4 to 93 +/- 2 mg/dl and hepatic glucose production (HGP) rose from 1.96 +/- 0.08 to 2.25 +/- 0.08 mg/kg X min (P less than 0.001). Basal glucose oxidation after glucagon increased (P less than 0.05) and correlated inversely with decreased free fatty acid concentrations (r = -0.94; P less than 0.01) and decreased lipid oxidation (r = -0.75; P less than 0.01). Suppression of HGP and stimulation of total glucose disposal were impaired at each insulin step after glucagon (P less than 0.05-0.01). The reduction in insulin-mediated glucose uptake was entirely due to diminished non-oxidative glucose utilization. Glucagon infusion also caused a decrease in basal lipid oxidation and an enhanced ability of insulin to inhibit lipid oxidation and augment lipid synthesis. These results suggest that hyperglucagonemia may contribute to the disturbances in glucose and lipid metabolism in some diabetic patients.     

Gastric inhibitory polypeptide (GIP) responses after oral glucose ingestion in hyperthyroidism

Gastric inhibitory polypeptide (GIP) is a gastrointestinal hormone stimulated after oral nutrient ingestion, but not after intravenous nutrient administration. GIP stimulates insulin release in the presence of hyperglycemia and as such is considered a major enteroinsular hormone. Since elevated glucose and insulin levels are found in hyperthyroidism, we compared the GIP responses to oral glucose ingestion in 12 hyperthyroid patients and 10 age-matched controls. Seventy-five grams of oral glucose was ingested after overnight fasting and samples were obtained at 0, 30, 60, 90, 120, and 180 min for serum glucose and immunoreactive insulin (IRI) and GIP (IRGIP). The mean serum glucose levels in hyperthyroid subjects were significantly higher (P less than or equal to 0.05) at every time studied except at 180 min. At 60 min, peak mean glucose was 171 +/- 14 mg/dl versus 128 +/- 7 mg/dl in controls (P less than 0.02). Except for fasting, mean IRI levels were significantly higher (P less than 0.001) in hyperthyroid subjects than in controls at all times studied. At 60 min, IRI rose to a peak of 125 +/- 11 microU/ml in hyperthyroid subjects versus 50 +/- 9 microU/ml in controls (P less than 0.001). Mean fasting, stimulated, and incremental IRGIP levels were slightly higher but not statistically different in the hyperthyroid subjects versus controls. Glucose and IRI responses are exaggerated in hyperthyroidism after oral glucose ingestion. Even though GIP has insulinotropic action, its role in the hyperinsulinism found in hyperthyroid subjects appears to be minimal.     

Decreased Glucagon Receptors in Diabetic Rat Hepatocytes: EVIDENCE FOR REGULATION OF GLUCAGON RECEPTORS BY HYPERGLUCAGONEMIA

The effects of endogenous and exogenous hyperglucagonemia on the specific binding of glucagon to hepatocyte receptors was studied, as was the response of cAMP to glucagon. In streptozotocin diabetic rats, blood glucose and plasma glucagon increased and plasma insulin decreased as compared with controls. Insulin treatment in diabetic rats restored blood glucose and plasma glucagon toward normal and elevated plasma insulin. Specific binding of (125)I-glucagon to isolated hepatocytes (10(6) cells) decreased in diabetic rats (8.17+/-0.38%) compared to controls (14.05+/-0.87%) and was restored by insulin treatment (12.25+/-0.93%). Specific binding of (125)I-insulin in controls was 7.30+/-10.16%; it increased in diabetic rats to 12.50+/-0.86%, and decreased in diabetic rats after insulin treatment (9.08+/-0.87%). Scatchard analysis and the competition plots of the data indicate that decreased glucagon binding and increased insulin binding in diabetes were due to change in the number of receptors rather than a change in their affinity. Hepatocyte cAMP response to glucagon (0.25-5.0 ng/ml) was almost abolished in diabetic rats and was restored with insulin treatment.Specific glucagon binding by hepatocytes from chronically hyperglucagonemic (glucagon injected) rats was decreased (P < 0.005) to 8.76+/-0.61% compared with controls (13.20+/-0.74%) and acutely hyperglucagonemic animals (13.53+/-1.33%). The decreased binding was associated with a 70% decrease in hepatocyte cAMP response to glucagon compared with a normal response in acutely hyperglucagonemic rats.These data appear to support the concept of receptor regulation by ambient hormone level. In both endogenous and exogenous hyperglucagonemia, however, there was a disproportionately large decrease in cAMP response to glucagon compared to the decrease in glucagon binding.     

Influence of uremia and hemodialysis on the turnover and metabolic effects of glucagon.

To evaluate the mechanism and role of hyperglucagonemia in the carbohydrate intolerance of uremia, 19 patients with chronic renal failure (12 of whom had undergone chronic hemodialysis for at least 11 mo) and 35 healthy control subjects were studied. Plasma glucagon, glucose, and insulin were measured in the basal state, after glucose ingestion (100 g), after intravenous alanine (0.15 g/kg), and during a 3-h continuous infusion of glucagon (3 ng/kg per min) which in normal subjects, raised plasma glucagon levels into the upper physiological range. Basal concentrations of plasma glucagon, the increment in glucagon after infusion of alanine, and post-glucose glucagon levels were three- to fourfold greater in uremic patients than in controls. The plasma glucagon increments after the infusion of exogenous glucagon were also two- to threefold greater in the uremics. The metabolic clearance rate (MCR) of glucagon in uremics was reduced by 58% as compared to controls. In contrast, the basal systemic delivery rate (BSDR) of glucagon in uremics was not significantly different from controls. Comparison of dialyzed and undialyzed uremics showed no differences with respect to plasma concentrations, MCR, or BSDR of glucagon. However, during the infusion of glucagon, the increments in plasma glucose in undialyzed uremics were three- to fourfold greater than in dialyzed uremics or controls. When the glucagon infusion rate was increased in controls to 6 ng/kg per min to produce increments in plasma glucagon comparable to uremics, the glycemic response remained approximately twofold greater in the undialyzed uremics. The plasma glucose response to glucagon in the uremics showed a direct linear correlation with oral glucose tolerance which was also improved with dialysis. The glucagon infusion resulted in 24% reduction in plasma alanine in uremics but had no effect on alanine levels in controls. It is concluded that (a) hyperglucagonemia in uremia is primarily a result of decreased catabolism rather than hypersecretion of this hormone; (b) sensitivity to the hyperglycemic effect of physiological increments in glucagon is increased in undialyzed uremic patients; and (c) dialysis normalizes the glycemic response to glucagon, possibly accounting thereby for improved glucose tolerance despite persistent hyperglucagonemia. These findings thus provide evidence of decreased hormonal catabolism contributing to a hyperglucagonemic state, and of altered tissue sensitivity contributing to the pathophysiological action of this hormone.     

Hyperglucagonemia of Renal Failure

Elevation of plasma glucagon concentration has been observed in starvation and illnesses associated with increased catabolism such as diabetes mellitus and severe infections. Thus, we examined plasma glucose, immunoreactive insulin (IRI, microunits per milliliter) and glucagon (IRG, picograms per milliliter) responses to a beef meal (1 g/kg body wt) and intravenous glucose (1.5 g/min for 45 min) in patients with chronic renal failure (CRF).After the beef meal (n = 6), plasma glucose did not change, IRI rose from 10.1+/-1.2 to 16.3+/-1.1 (P < 0.01), and IRG rose from a fasting value of 225+/-26 to 321+/-40 (P < 0.01) by 90 min (mean+/-SEM).Intravenous infusion of glucose in CRF patients resulted in significant elevations and prolonged disappearance of plasma glucose and insulin when compared to control subjects (P < 0.01). Glucose infusion failed to suppress elevated plasma glucagon concentrations to normal levels.6 wk of chronic hemodialysis in five patients resulted in normal plasma glucose and insulin responses to the same intravenous glucose load. In contrast, plasma glucagon concentration remained unchanged after hemodialysis and there was no correlation of plasma glucagon levels with carbohydrate intolerance.     

Insulin resistance in liver cirrhosis. Positron-emission tomography scan analysis of skeletal muscle glucose metabolism.

BACKGROUND. Insulin resistance and glucose intolerance are a major feature of patients with liver cirrhosis. However, site and mechanism of insulin resistance in cirrhosis are unknown. We investigated insulin-induced glucose metabolism of skeletal muscle by positron-emission tomography to identify possible defects of muscle glucose metabolism in these patients. METHODS. Whole body glucose disposal and oxidation were determined by the combined use of the euglycemic-hyperinsulinemic clamp technique (insulin infusion rate: 1 mU/kg body wt per min) and indirect calorimetry in seven patients with biopsy-proven liver cirrhosis (Child: 1A, 5B, and 1C) and five healthy volunteers. Muscle glucose uptake of the thighs was measured simultaneously by dynamic [18F]fluorodeoxyglucose positron-emission tomography scan. RESULTS. Both whole body and nonoxidative glucose disposal were significantly reduced in patients with liver cirrhosis (by 48%, P < 0.001, and 79%, P < 0.0001, respectively), whereas glucose oxidation and the increase in plasma lactate were normal. Concomitantly, skeletal muscle glucose uptake was reduced by 69% in liver cirrhosis (P < 0.003) and explained 55 or 92% of whole body glucose disposal in cirrhotics and controls, respectively. Analysis of kinetic constants using a three-compartment model further indicated reduced glucose transport (P < 0.05) but unchanged phosphorylation of glucose in patients with liver cirrhosis. CONCLUSIONS. Patients with liver cirrhosis show significant insulin resistance that is characterized by both decreased glucose transport and decreased nonoxidative glucose metabolism in skeletal muscle.     

Mechanism of insulin resistance in human liver cirrhosis. Evidence of a combined receptor and postreceptor defect.

Insulin resistance in liver cirrhosis may depend on either reduced sensitivity (receptor defect) and/or reduced response to insulin (postreceptor defect). To clarify the mechanism of such resistance, a [3H]glucose infusion (0.2 microCi/min) was performed for 120 min before and during a euglycemic clamp at approximately 100, 1,000, and 10,000 microU/ml steady state plasma insulin concentration in 18 compensated cirrhotics with portal hypertension and impaired glucose tolerance, and 18 healthy volunteers with no family history of diabetes, matched for sex, age, and weight. Mean fasting plasma insulin (29.2 +/- 3.4 SEM vs. 14.8 +/- 1.1 microU/ml) was significantly higher (P less than 0.001) in cirrhotics, while fasting plasma glucose was much the same in the two groups. Glucose use (milligrams per kilogram per minute) was significantly lower in cirrhotics at all three steady state plasma insulin levels: 3.04 +/- 0.34 vs. 7.72 +/- 0.61 (P less than 0.001) at approximately 100; 6.05 +/- 1.07 vs. 11.45 +/- 1.24 (P less than 0.001) at approximately 1,000; and 11.69 +/- 0.69 vs. 14.13 +/- 0.74 (P less than 0.05) at approximately 10,000 microU/ml. Mean plasma C-peptide was significantly higher in cirrhotics both basally and during the steady states (P less than 0.001); it was completely suppressed at approximately 10,000 microU/ml in controls and only 57.5% of the baseline in cirrhotics. Endogenous glucose production (milligrams per kilogram per minute) was much the same in the two groups in the fasting state and almost entirely suppressed in the controls (0.10 +/- 0.05 vs. 0.48 +/- 0.11, P less than 0.001) at approximately 100 microU/ml; at approximately 1,000 microU/ml a residual glucose production, 0.07 +/- 0.05, was observed in the cirrhotics only. In addition, insulin binding and 3-ortho-methyl-glucose transport were studied in vitro in six cirrhotics and six controls. Insulin binding to circulating monocytes and isolated adipocytes was significantly lower (P less than 0.025) in cirrhotics in all insulin concentration studies. Glucose transport values on isolated adipocytes were significantly lower in cirrhotics both basally (P less than 0.001) and at maximal insulin concentration (P less than 0.05). These results suggest that insulin resistance in human cirrhosis is more dependent on depressed peripheral glucose use than on increased endogenous glucose production, and that a combined receptor and postreceptor defect in insulin action on target cells seems to be present.     

Muscle and liver insulin resistance indexes derived from the oral glucose tolerance test

OBJECTIVE: To derive indexes for muscle and hepatic insulin sensitivity from the measurement of plasma glucose and insulin concentrations during an oral glucose tolerance test (OGTT). RESEARCH DESIGN AND METHODS: A total of 155 subjects of Mexican-American origin (58 male and 97 female, aged 18-70 years, BMI 20-65 kg/m(2)) with normal glucose tolerance (n = 100) or impaired glucose tolerance (n = 55) were studied. Each subject received a 75-g OGTT and a euglycemic insulin clamp in combination with tritiated glucose. The OGTT-derived indexes of muscle and hepatic insulin sensitivity were compared with hepatic and muscle insulin sensitivity, which was directly measured with the insulin clamp, by correlation analysis. RESULTS: The product of total area under curve (AUC) for glucose and insulin during the first 30 min of the OGTT (glucose(0-30)[AUC] x insulin(0-30)[AUC]) strongly correlated with the hepatic insulin resistance index (fasting plasma insulin x basal endogenous glucose production) (r = 0.64, P < 0.0001). The rate of decay of plasma glucose concentration from its peak value to its nadir during the OGTT divided by the mean plasma insulin concentration (dG/dt / I) strongly correlated with muscle insulin sensitivity measured with the insulin clamp (P = 0.78, P < 0.0001). CONCLUSIONS: Novel estimates for hepatic and muscle insulin resistance from OGTT data are presented for quantitation of insulin sensitivity in nondiabetic subjects.     

Metabolic handling of orally administered glucose in cirrhosis.

We used a dual-isotope method (oral [1-14C]glucose and intravenous [6-3H]glucose) to examine whether the oral glucose intolerance of cirrhosis is due to (a) a greater input of glucose into the systemic circulation (owing to a lower first-pass hepatic uptake of ingested glucose, or to impaired inhibition of hepatic glucose output), (b) a lower rate of glucose removal, or (c) a combination of these mechanisms. Indirect calorimetry was used to measure oxidative and nonoxidative metabolism. Basal plasma glucose levels (cirrhotics, 5.6 +/- 0.4[SE], controls, 5.1 +/- 0.2 mmol/liter), and rates of glucose appearance (Ra) and disappearance (Rd) were similar in the two groups. After 75 g of oral glucose, plasma glucose levels were higher in cirrhotics than controls, the curves diverging for 80 min despite markedly higher insulin levels in cirrhotics. During the first 20 min, there was very little change in glucose Rd and the greater initial increase in plasma glucose in cirrhotics resulted from a higher Ra of ingested [1-14C]glucose into the systemic circulation, suggesting a reduced first-pass hepatic uptake of portal venous glucose. The continuing divergence of the plasma glucose curves was due to a lower glucose Rd between 30 and 80 min (cirrhotics 236 +/- 17 mg/kg in 50 min, controls 280 +/- 17 mg/kg in 50 min, P < 0.05, one-tailed test). Glucose metabolic clearance rate rose more slowly in cirrhotics and was significantly lower than in controls during the first 2 h after glucose ingestion (2.24 +/- 0.17 vs 3.30 +/- 0.23 ml/kg per min, P < 0.005), in keeping with their known insulin insensitivity. Despite the higher initial glucose Ra in cirrhotics, during the entire 4-h period the quantity of total glucose and of ingested glucose (cirrhotics 54 +/- 2 g [72% of oral load], controls 54 +/- 3 g) appearing in the systemic circulation were similar. Overall glucose Rd (cirrhotics 72.5 +/- 3.8 g/4 h, controls 77.2 +/- 2.2 g/4h) and percent suppression of hepatic glucose output over 4 h (cirrhotics, 53 +/- 10%, controls 49 +/- 8%) were also similar. After glucose ingestion much of the extra glucose utilized was oxidized to provide energy that in the basal state was derived from lipid fuels. Glucose oxidation after glucose ingestion was similar in both groups and accounted for approximately two-thirds of glucose Rd. The reduction in overall nonoxidative glucose disposal did not reach significance (21 +/- 5 vs. 29 +/- 3 g/4 h, 0.05 < P < 0.1). Although our data would be compatible with an impairment of tissue glycogen deposition after oral glucose, glucose storage as glycogen probably plays a small part part in overall glucose disposal. Our results suggest that the higher glucose levels seen in cirrhotics after oral glucose are due initially to an increase in the amount of ingested glucose appearing in the systemic circulation, and subsequently to an impairment in glucose uptake by tissues due to insulin insensitivity. Impaired suppression of hepatic glucose output does not contribute to oral glucose intolerance.     

Changes in plasma amino acids during the oral glucose tolerance test and the effect of these changes on hepatic encephalopathy

Changes in amino acid concentrations in plasma during a 100 g oral glucose tolerance test were investigated in patients with liver cirrhosis and in healthy controls. In the controls, almost all amino acid concentrations reached a nadir about 3 hours after glucose loading, then returned to initial levels after 6 hours. Immunoreactive insulin levels reached a peak about 30 minutes after loading, then decreased gradually, reaching initial levels after 6 hours. In the controls, the decrease ratios, defined as maximum decrease during the 3 hours after loading/initial concentration in plasma, were 0.607 and 0.554 for isoleucine (Ile) and leucine (Leu) respectively and 0.382 for valine (Val) which is significantly lower than for Ile or Leu. A similar tendency was recognized in patients with liver cirrhosis. The initial concentration of tyrosine (Tyr) and phenylalanine (Phe) in liver cirrhosis was significantly higher and their decrease ratios were significantly lower than in controls. Though no difference was observed between initial concentrations of tryptophan (Trp) in controls and liver cirrhosis patients, the decrease ratio of Trp in liver cirrhosis was lower (0.061) than that of controls (0.279) (p less than 0.001). The value, t-Trp/BCAA + AAA, i.e. total Trp concentration (mmol/l)/concentration (mmol/l) of branched chain amino acids (BCAA, Ile + Leu + Val) plus aromatic amino acids (AAA, Tyr + Phe), which is known to correlate with the brain Trp concentration of rats (Fernstrom, J. D. & Wurtman, R. J. (1972) Science 178, 414-416), changed significantly from 9.6 +/- 2.4 (mean +/- 1 SD) at the initiation to 12.9 +/- 3.3 at 3 hours after loading in controls (p less than 0.001), and in liver cirrhosis it changed from 10.3 +/- 1.9 to 15.8 +/- 3.1 (p less than 0.001).     

Diabetes Mellitus in Gonadal Dysgenesis: Studies of Insulin and Growth Hormone Secretion

On the basis of results obtained from an oral glucose tolerance test, (OGTT), twenty patients with gonadal dysgenesis were classified as normal (N = 8) and diabetic (N = 12). The two groups of patients were further tested by a rapid intravenous glucose injection, a tolbutamide test, an insulin sensitivity test and an oral amino acid load. Fasting levels of plasma growth hormone (GH) were normal in all subjects but one. Approximately 1/3 of the GH responses during testing periods were abnormal, being either absent during hypoglycaemia or following amino acid ingestion, or paradoxically increased during hyperglycaemia. No correlation was found between the degree of carbohydrate intolerance and the levels of plasma GH. There was no gross alteration of tissue sensitivity to exogenous insulin. The beta-cell response to tolbutamide, amino acid and intravenous glucose were comparable in patients with a normal or a diabetic OGTT. In both groups, the rates of decrease of blood glucose following tolbutamide or intravenous glucose were also similar and within the normal range. During OGTT, the diabetic group had a delayed insulin release and a low insulinogenic index. It is concluded that in gonadal dysgenesis the intolerance to an oral carbohydrate load is frequently associated with, but unrelated to, anomalies of the GH secretion. In diabetic subjects, the process of insulin secretion loses its normal sensitivity to the oral glucose stimulus while remaining unaltered and similiar to that of non-diabetic subjects in response to tolbutamide, amino acid and intravenous glucose.     

Insulin resistance in Graves'' disease: a quantitative in-vivo evaluation

Hyperthyroidism is considered to be an insulin-resistant state, but a quantitative evaluation of some action of insulin is still lacking. We performed euglycaemic clamp at about 350 and 7000 pmol l-1 plasma insulin concentration in combination with the 3H-glucose infusion in 12 patients with Graves' disease and in 12 matched controls. Fasting plasma insulin (126 +/- 6.5 vs. 77.5 +/- 5.7 pmol l-1; P less than 0.001), C-peptide (502 +/- 36 vs. 363 +/- 41 pmol l-1; P less than 0.001) and glucagon (47 +/- 3.3 vs. 33.3 +/- 3 pmol l-1; P less than 0.01) were significantly higher in hyperthyroids than in euthyroids. Basal hepatic glucose production was significantly higher in hyperthyroids than in euthyroids (18.3 +/- 1.4 vs. 9.2 +/- 0.5 mumol l-1; P less than 0.0001), and its suppression during physiological hyperinsulinaemia was only 50% in hyperthyroids. Glucose utilization and suppression of lipolysis were normally stimulated by insulin. All parameters altered during hyperthyroidism were normalized during methimazole-induced euthyroidism. We conclude that insulin resistance involves mainly glucose rather than lipid and is selective at the hepatic level.     

Effects of jejuno-ileal bypass on serum lipoproteins and glucose tolerance in severely obese patients

Plasma insulin and blood glucose during oral glucose tolerance tests (OGTT) and serial determinations of serum lipoprotein fractions before and after jejuno-ileostomy in twenty severely obese (mean weight 137 kg) patients with a mean age of 29 years revealed statistically significant postoperative decreases in all parameters concomitant with a mean weight loss of 42 kg. Before the operation the patients were hyperinsulinaemic and had elevated blood glucose levels during OGTT though no patient had overt diabetes. Serum triglyceride and total cholesterol levels were normal but HDL cholesterol was significantly lower than in controls. During follow-up at least until body weight had levelled off a mean 19 months post-operative, there were statistically significant reductions in blood glucose and plasma insulin as well as serum total cholesterol and lipoprotein fractions. There was no change in serum triglycerides. The low preoperative HDL levels decreased. In a subgroup of these patients we have earlier shown postoperative increases in arterial tissue cholesterol coincident with the present significant decreases in HDL as well as in LDL cholesterol. Correlations between total cholesterol and lipoprotein cholesterol values in serum and blood glucose and plasma insulin at fast and during OGTT and changes in these parameters demonstrate interrelationships between lipid and carbohydrate metabolism. The bypass procedure most likely reduces the intestinal synthesis of HDL which in turn may increase hepatic cholesterol synthesis. Evidently there is a multifactorial aetiology for the low HDL levels in the severely obese both before and after jejuno-ileostomy.     

Role of insulin and glucagon in the response of glucose and alanine kinetics in burn-injured patients.

We investigated the roles of insulin and glucagon as mediators of changes in glucose and alanine kinetics during the hypermetabolic response to injury in 10 burn patients by infusing somatostatin with and without insulin replacement. Glucose and alanine kinetics were measured by primed-constant infusions of 6,6-d2-glucose and [3-13C]alanine. The basal rate of glucose production and alanine flux were significantly elevated in all patients. Lowering both hormones simultaneously caused an insignificant reduction in glucose production, but plasma glucose rose significantly (P less than 0.01), because of reduced clearance. Alanine flux and total plasma amino nitrogen increased significantly (P less than 0.05) above basal. Selectively lowering glucagon concentration decreased glucose production (P less than 0.05), and exogenous glucose was infused to maintain euglycemia. Alanine flux and total plasma amino nitrogen remained unchanged. In severely burned patients hyperglucagonemia stimulates increased glucose production, basal insulin suppression glucose production, stimulates basal glucose clearance, and is important for regulation of plasma amino acid concentrations, and the selective lowering of glucagon while maintaining basal insulin constant normalized glucose kinetics.     

Metabolic responses to plasma concentrations of theophylline.

We investigated the effect of intravenous infusions of aminophylline on plasma glucose, insulin (IRI), glucagon (IRG), growth hormone (HGH), cortisol, and free fatty acid (FFA) levels in healthy young subjects. Six received an intravenous loading dose of aminophylline (6.0 mg/kg over 20 min) followed by a maintenance dose (0.9 mg/kg/hr) for 100 min. Another 7 subjects initially received smaller loading (3.0 mg/kg) and maintenance (0.45 mg/kg/hr) doses, and after 60 min they received a second loading dose (3.0 mg/kg) followed by a larger maintenance dose (0.9 mg/kg/hr) over 120 min. In these fasting volunteers, infusion of aminophylline, which produced theophylline levels in the usual therapeutic range (10 to 20 microgram/ml) caused small increases in plasma glucose levels without changing IRI, IRG, HGH, or cortisol. There were rapid, pronounced, and prolonged rises in FFA associated with the aminophylline infusion. Increases in FFA paralleled the rise in theophylline levels. It is concluded that routine therapeutic doses of theophylline, i.e., doses that achieve serum levels normally encountered in treatment for bronchial asthma, cause a marked rise in FFA and a slight rise in glucose (8 +/- 3 mg/dl) without changing levels of IRI, IRG, HGH, or cortisol.