Insulin resistance is the main determinant of impaired glucose tolerance in patients with liver cirrhosis

To clarify the pathogenesis of impaired glucose tolerance in patients with cirrhosis, several factors possibly affecting carbohydrate metabolism were studied in 12 cirrhotic patients with different blood glucose responses to an oral glucose tolerance test. Glucose levels, 120 min after the load, were inversely and significantly related to insulin sensitivity, measured by means of the euglycemic glucose clamp technique (r=–0.746). Basal and glucose-induced insulin secretion (insulin and C-peptide levels) only slightly correlated with glucose tolerance, which was not related to functional liver cell mass (galactose elimination), portal-systemic shunting (degree of varices at endoscopy), or maximal glucose-independent insulin secretion (peak C-peptide levels after a glucagon test). Multiple regression analysis identified insulin sensitivity and liver cell mass as the independent variables able to explain most of the variance of 120-min blood glucose (about 84%), and both of them contributed considerably to the regression. While reduced insulin sensitivity is probably the main cause of impaired glucose tolerance, the reduced hepatocellular mass only appears to modulate the degree, and therefore the clinical relevance, of this defect.Supported by a Grant from Ministero della Pubblica Istruzione, Rome, 1983.This work was presented at the III Italian Week on Digestive Diseases (SIMAD III), Bari, Italy, June 27–July 1, 1983 and published in abstract form (Ital J Gastroenterol 16:143, 1984).     

An abnormal screening glucose challenge test in pregnancy predicts postpartum metabolic dysfunction, even when the antepartum oral glucose tolerance test is normal

Objective In pregnancy, a normal result on the oral glucose tolerance test (OGTT) that follows an abnormal screening glucose challenge test (GCT) is considered a reassuring finding, requiring no further intervention. The obstetrical and metabolic implications of this presentation, however, have not been well studied. Thus, we sought to characterize the obstetrical and postpartum metabolic significance of an abnormal GCT in women with normal glucose tolerance (NGT) on antepartum OGTT. Design/patients/measurements A total of 259 women with NGT on antepartum OGTT (166 with an abnormal GCT and 93 with a normal GCT) underwent (i) metabolic evaluation in pregnancy, (ii) assessment of obstetrical outcome at delivery and (iii) repeat metabolic characterization by OGTT at 3 months postpartum. Results Neither infant birthweight nor Caesarean section rate differed between the abnormal GCT and normal GCT groups. At 3 months postpartum, however, compared to the normal GCT group, the abnormal GCT group exhibited greater glycaemia (mean area under the glucose curve (AUC_gluc) 19·6 vs. 18·3, P = 0·0021), lower insulin sensitivity (median insulin sensitivity index (IS_OGTT) 9·5 vs. 11·3, P = 0·0243) and poorer beta‐cell function (median insulinogenic index/Homeostasis Model Assessment of Insulin Resistance (HOMA‐IR) 9·8 vs. 14·1, P = 0·0013). On multiple linear regression analyses, an abnormal GCT emerged as (i) the strongest independent predictor of postpartum AUC_gluc (t = 2·77, P = 0·006) and (ii) the strongest independent negative predictor of log insulinogenic index/HOMA‐IR (t = –2·36, P = 0·0191). Furthermore, the GCT was the antepartum parameter that best predicted postpartum pre‐diabetes (area under the receiver operating characteristic curve (AROC) = 0·754). Conclusions An abnormal antepartum GCT, even when followed by a normal OGTT, is associated with postpartum glycaemia and beta‐cell dysfunction, factors that may portend an increased future risk of diabetes in this patient population.     

Glucose storage is a major determinant of in vivo "insulin resistance" in subjects with normal glucose tolerance

In vivo "resistance" to the action of insulin on glucose uptake is commonly found in obesity and is characteristic of noninsulin-dependent diabetes mellitus in obese subjects. To investigate the relationship among glucose uptake, glucose oxidation, and nonoxidative glucose disposal (storage) in subjects with normal glucose tolerance, we studied 25 caucasians and 79 southwestern American Indians, including lean and obese subjects in both groups. The euglycemic clamp technique with simultaneous indirect calorimetry was used to determine rates of glucose uptake and glucose oxidation. These studies were performed at two rates of insulin infusion (40 and 400 mU/m2 X min), with resulting mean plasma insulin concentrations of 113 and 1839 microU/ml, respectively. At the lower insulin infusion rate, there was no glucose storage in subjects with a glucose uptake rate of about 2.2 mg/kg fat free mass X min. In contrast, glucose storage accounted for over 45% of the glucose disposal in subjects with glucose uptake rates over 7.0 mg/kg fat free mass X min studied at similar insulin concentrations. At the high insulin infusion rate, over 70% of the difference in glucose uptake between subjects with a low or high capacity for glucose disposal was due to glucose storage. These studies demonstrated that in normal subjects at both physiological and maximally stimulating plasma insulin concentrations, glucose storage is a major factor in distinguishing between those with low or high rates of insulin-mediated glucose disposal. Since glucose storage may be a specifically activated process, we hypothesize that failure to activate glucose storage is a major defect causing in vivo insulin resistance in subjects with normal glucose tolerance.     

Abnormal glucose tolerance, not small vessel diameter, is a determinant of long-term prognosis in patients treated with balloon coronary angioplasty.

AIMS: We sought to find out what factors are important for long-term prognosis, the small vessel itself or abnormal glucose tolerance, in patients treated with coronary angioplasty. BACKGROUND: Patients with coronary artery disease with diabetes mellitus often show diffuse and small coronary artery narrowing. Impaired glucose tolerance has also been reported to be a risk factor for cardiovascular disease. METHODS: Among 584 patients who underwent first elective balloon coronary angioplasty, diabetes mellitus and impaired glucose tolerance were present in 197 patients. Large and small vessels were defined by reference vessel diameter before coronary angioplasty as either larger or smaller than 2.5 mm. Patients were categorized into the following four groups: 175 patients with normal glucose tolerance and reference diameter <2.5 mm (group SN), 212 patients with normal glucose tolerance and reference diameter greater than or = 2.5 mm (group LN), 101 patients with abnormal glucose tolerance and reference diameter <2.5 mm (group SD), and 96 patients with abnormal glucose tolerance and reference diameter greater than or = 2.5 mm (Group LD). The cardiac events were compared for a period of 8 years after coronary angioplasty among the four groups. RESULTS: There was no difference in the percentage diameter stenosis immediately after coronary angioplasty among the four groups. However, group SD showed unfavourable prognosis despite similar minimal lumen diameter after coronary angioplasty compared with group SN. Event-free survival curve of group LD showed a sudden drop approximately 5 years after the coronary angioplasty. In multivariate analysis, the cardiac events were associated with the presence or absence of abnormal glucose tolerance. Furthermore, patients with bad glycaemic control (HbA1c>6.0%) at index coronary angioplasty showed worse event free survival than those with good glycaemic control. CONCLUSIONS: An important determinant for long-term prognosis after coronary angioplasty is a presence of abnormal glucose tolerance per se and not small vessel diameter.     

Y chromosome polymorphism is a strong determinant of male fitness in Drosophila melanogaster

In many species, the Y (or W) chromosome carries relatively few functional genes. This observation motivates the null hypothesis that the Y will be a minor contributor to genetic variation for fitness. Previous data and theory supported the null hypothesis, but evidence presented here shows that the Y of Drosophila melanogaster is a major determinant of a male's total fitness, with standing genetic variation estimated to be 68% of that of an entire X/autosome genomic haplotype. Most Y-linked genes are expressed during spermatogenesis, and correspondingly, we found that the Y influences fitness primarily through its effect on a male's reproductive success (sperm competition and/or mating success) rather than his egg-to-adult viability. But the fitness of a Y highly depended on the genetic makeup of its bearer, reverting from high to low in different genetic backgrounds. This pattern leads to large epistatic (inconsistent among backgrounds) but no additive (consistent among backgrounds) Y-linked genetic variance for fitness. On a microevolutionary scale, the observed large epistatic variation on the Y substantially reduces heritable variation for fitness among males, and on a macroevolutionary scale, the Y produces strong selection for genomic rearrangements that move interacting genes onto the nonrecombining region of the Y.     

Impaired glucose tolerance is a more advanced stage of alteration in the glucose metabolism than impaired fasting glucose

BACKGROUND: Recent reports have shown a lack of agreement between the impaired glucose tolerance (IGT) and the impaired fasting glucose (IFG) categories, suggesting that correspond to different impaired glucose metabolism stages. OBJECTIVE: To determine the differences of serum insulin levels between subjects with IFG and IGT diagnoses. METHODS: Cross-sectional study of 52 subjects with IFG and 48 with IGT diagnosis, and a euglycemic group of 140 subjects. Serum glucose and insulin were measured in both fasting and 2-h 75-g oral post-load glucose (2-h PG). RESULTS: Subjects with IFG showed the highest fasting and 2-h PG serum insulin levels, whereas subject with IGT the lowest. Serum insulin values showed no significative changes between the fasting and 2-h PG conditions in the subjects with IGT, whereas the subjects with IFG showed significative hyperinsulinemia. The serum glucose 2-h PG showed an increase of 0.2 mmol/l (CI(95%) 0.07-0.33), 0.5 mmol/l (CI(95%) 0.41-0.58) and 3.6 mmol/l (CI(95%) 3.39-3.81) with respect to basal values, whereas the increase of serum insulin 2-h PG was of 54 pmol/l (CI(95%) 53.71-55.29), 918 pmol/l (CI(95%) 917.49-918.51) and 0.5 pmol/l (CI(95%) 0.15-0.84) for the euglycemic, IFG and IGT subjects, respectively. CONCLUSIONS: This study demonstrates that subjects with IFG show hyperinsulinemia whereas those with IGT have low insulin secretion in response to oral load glucose, suggesting that IFG and IGT correspond to different stages of impaired glucose metabolism.     

Exercise test and glucose homeostasis in rats treated with alloxan during the neonatal period or fed a high calorie diet

Background: Animal models appear well‐suited for studies into the role of exercise in the prevention of non‐insulin‐dependent diabetes mellitus (NIDDM). The aim of the present study was to analyze glucose homeostasis and blood lactate during an exercise swimming test in rats treated with alloxan during the neonatal period and/or fed a high calorie diet from weaning onwards. Methods: Rats were injected with alloxan (200 mg/kg, i.p.) or vehicle (citrate buffer) at 6 days of age. After weaning, rats were divided into four groups and fed either a balanced diet or a high‐caloric diet as follows: C, control group (vehicle + normal diet); A, alloxan‐treated rats fed the normal diet; H, vehicle‐treated rats fed the high‐caloric diet; and HA, alloxan‐treated rats fed the high‐caloric diet. Results: Fasting serum glucose levels were higher in groups A and AH compared with the control group. The Homeostatic Model Assessment index varied in the groups as follows: H>A>HA = C. There were no differences in free fatty acids or blood lactate concentrations during the swim test. Conclusions: Alloxan‐treated rats fed a normal or high‐caloric diet have the potential to be used in studies analyzing the role physical exercise plays in the prevention of NIDDM.     

Hyperproinsulinaemia in impaired glucose tolerance is associated with a delayed insulin response to glucose

Summary In subjects with impaired glucose tolerance hyperproinsulinaemia has been shown to be predictive for progression to Type II (non-insulin-dependent) diabetes mellitus. These findings are often interpreted as early indicators of an impaired beta-cell function. The aim of our study was to assess the potential determinants of hyperproinsulinaemia in subjects with impaired glucose tolerance. The study group consisted of 110 subjects, 45–74 years of age with mean 2 h plasma glucose concentrations between 8.6 and 11.1 mmol/l following two oral glucose tolerance tests. Subsequently, the hyperglycaemic clamp technique (10 mmol/l, with a priming infusion of 20 % glucose solution, 150 mg/kg) was used to assess the beta-cell function (time needed to reach the insulin peak) and insulin sensitivity (M/I value: glucose metabolised divided by insulin response, 150–180 min). Results showed that the intact-proinsulin:insulin ratio increased with increasing time needed to reach the insulin peak (0.065, 0.079 and 0.101; time needed to reach the insulin peak ≤ 5 min, 5 to 15 min, > 15 min; p < 0.05). The split-proinsulin:insulin ratio showed a similar association with the time needed to reach the insulin peak. These associations were independent of age, sex, body mass index and waist:hip ratio. In conclusion, this study shows that relative hyperproinsulinaemia is associated with an impaired beta-cell function in a study group of subjects with impaired glucose tolerance selected after two oral glucose tolerance tests. [Diabetologia (1999) 42: 177–180] Received: 5 June 1998 and in final revised form: 5 October 1998     

Increased insulinogenic index is an independent determinant of nonalcoholic fatty liver disease activity score in patients with normal glucose tolerance

Background

Although insulin resistance is involved in nonalcoholic fatty liver disease, role of abnormalities in early phase of insulin secretion has not been examined.

Aims

We examined which anthropometric and metabolic parameters, including insulinogenic index during oral glucose tolerant test, were independently associated with the disease activity of nonalcoholic fatty liver disease.

Methods

A total of 114 consecutive biopsy-proven nonalcoholic fatty liver disease patients without type 2 diabetes were enrolled.

Results

Age, aspartate aminotransferase, free fatty acid, ferritin type IV collagen, hyaluronic acid, procollagen N-terminal peptide, fasting plasma glucose and 2-h insulin after glucose loading were significantly higher in patients with impaired glucose tolerance than those with normal glucose tolerance. Multiple stepwise regression analysis revealed that glycated haemoglobin, decreased density ratio of liver to spleen in computed tomography and increased insulinogenic index were independently associated with nonalcoholic fatty liver disease activity score in normal glucose tolerance patients, whereas aspartate aminotransferase and 2-h insulin in impaired glucose tolerance subjects. However, there were no significant independent correlations between insulinogenic index and steatosis grade/fibrosis stage in normal glucose tolerance patients.

Conclusion

The present study suggests that increased early phase of insulin secretion may contribute to nonalcoholic fatty liver disease activity score in patients with normal glucose tolerance.     

胰岛素抵抗是糖耐量正常人群糖耐量恶化的最重要危险因素

目的　探讨胰岛素抵抗和胰岛素分泌对糖耐量正常人群糖耐量恶化的影响。方法　以口服葡萄糖耐量试验 (OGTT)做人群普查 ,确定糖耐量正常者 (NGT)〔空腹血糖 (FPG) <5 .8mmol/L及 2小时血糖 (PG2h) <6 .7mmol/L〕12 5例 ,测定血浆胰岛素。 6年后随访再以OGTT确定该人群糖耐量状态 ,以稳态模型 (HomaModel)公式评估胰岛素抵抗 (IR)、胰岛素分泌功能 (IS) ,并分析其对糖耐量恶化的影响。结果　 12 5例糖耐量正常人中 ,6年后 2 3例糖耐量恶化〔IGT 2 0例 ,糖尿病(DM) 3例〕。糖耐量恶化者初访时FPG、PG2h与糖耐量仍正常者无明显差别 ,但前者 1小时血糖(PG1h)、1小时胰岛素 (INS1h)均较后者高 (P <0 .0 5 ) ,且前者较肥胖 (P <0 .0 5 )及胰岛素敏感性更差 (P <0 .0 5 )。按胰岛素敏感性三分变量分组 ,胰岛素敏感性最差组的糖耐量恶化率为胰岛素敏感组的 3倍 (34.2 %比 11.9%和 9.5 % ,P <0 .0 5 )。Logistic回归结果显示初访时的胰岛素敏感性与糖耐量恶化显著负相关 ,而年龄、性别、PG2h、体重指数 (BMI)及IS均与糖耐量恶化相关不显著。结论胰岛素抵抗是糖耐量正常人群糖耐量恶化最重要的危险因素     

Effect of dietary environment on the development of impaired glucose tolerance and pancreatic hormone secretion in neonatal streptozocin-treated (NSZ) rats

Summary The effects of four different diets, a balanced (BD), a high protein (HP), a high fat (HF), and a high carbohydrate (HC) diet on glucose tolerance and pancreatic hormone secretion were compared during the ten-week period immediately after weaning in rats having glucose intolerance induced by streptozocin in the neonatal period (NSZ). Feeding HF or HC produced a decrease in calorie intake and a delay in body weight increase. All NSZ rats showed glucose intolerance as adults; the HF rats showed a further deterioration of glucose tolerance and a decreased insulinogenic index after oral glucose loading. Plasma insulin levels of HC rats were lowest. The glucose-induced insulin and somatostatin secretion from the isolated perfused pancreas was almost identical in all four groups. The arginine-induced insulin and glucagon secretion was decreased in HF and HC rats, compared to both HP and BD rats, but somatostatin secretion was not. These results indicate that a high fat or high carbohydrate dietary environment is an important factor in the development of glucose intolerance and in the impairment of pancreatic hormone responsiveness to stimulation. This study was supported by grant-in-aid n ^o 0163005 for Scientific Research from the Ministry of Science, Education and Culture of Japan.     

The multiphasic profile of free fatty acids during the intravenous glucose tolerance test is unresponsive to exogenous insulin

As small increments in insulin concentration profoundly affect lipolysis, our goal was to describe the free fatty acid (FFA) profile during the frequently sampled intravenous glucose tolerance test (FSIGT) and determine if both endogenous and exogenous insulin influenced the FFA profile. Thirteen subjects had both a glucose-only (GO-FSIGT) and insulin-modified FSIGT (IM-FSIGT). Both protocols were of 6 hours duration. At baseline an intravenous glucose bolus (0.3 g/kg) was given. In the IM-FSIGT, insulin was infused from 20 to 25 minutes (4 mU/kg. min). Six additional subjects had both an IM-FSIGT and a normal saline study (NS-Study). For the NS-Study, normal saline solution was infused instead of glucose and insulin. Fasting glucose, insulin, FFA and epinephrine concentrations were similar for all tests. Endogenous insulin peaked at 4 +/- 1 minute in both FSIGTs. The mean calculated peak time of exogenous insulin in the IM-FSIGT was 26 +/- 1 minute. Glucose concentrations were lower and epinephrine concentrations higher in the IM-FSIGT versus GO-FSIGT. During the FSIGTs, the FFA time course revealed four distinct phases, which did not differ between protocols. In phase I (0 to 11 minutes), FFA levels remained near basal (491 +/- 183 micromol/L); in phase II (11 to 79 minutes), FFA levels declined achieving a nadir of 139 +/- 63 micromol/L; in phase III (79 to 188 minutes), FFA levels rose linearly and reattained basal levels; and in phase IV (188 to 360 minutes), FFA levels rose above basal and plateaued at 732 +/- 214 micromol/L (P <.001). In the NS-Study, FFA levels remained near baseline (388 +/- 118 mEq/L) until 180 minutes and then trended upward to 618 +/- 258 micromol/L at 360 minutes. FFA concentrations from 180 to 360 minutes did not differ in the IM-FSIGT versus NS-Study. As the 4 FFA phases did not differ between protocols, the insulin effect on FFA levels in the FSIGT can be attributed to endogenous insulin. But the similarity in FFA levels from 180 to 360 minutes in the IM-FSIGT and NS-Study suggests diurnal variation and not a dynamic related to insulin or the FSIGT protocol is responsible for the final suprabasal FFA plateau.     

Subclinical abnormal glucose tolerance is a predictor of death in liver cirrhosis

AIM:To determine if subclinical abnormal glucose tolerance(SAGT)has influence on survival of non-diabetic patients with liver cirrhosis.METHODS:In total,100 patients with compensatedliver cirrhosis and normal fasting plasma glucose were included.Fasting plasma insulin(FPI)levels were measured,and oral glucose tolerance test(OGTT)was performed.According to OGTT results two groups of patients were formed:those with normal glucose tolerance(NGT)and those with SAGT.Patients were followed every three months.The mean follow-up was932 d(range of 180-1925).Survival was analyzed by the Kaplan-Meyer method,and predictive factors of death were analyzed using the Cox proportional hazard regression model.RESULTS:Of the included patients,30 showed NGT and70 SAGT.Groups were significantly different only in age,INR,FPI and HOMA2-IR.Patients with SAGT showed lower 5-year cumulated survival than NGT patients(31.7%vs 71.6%,P=0.02).Differences in survival were significant only after 3 years of follow-up.SAGT,Child-Pugh B,and high Child-Pugh and Model for EndStage Liver Disease(MELD)scores were independent predictors of death.The causes of death in 90.3%of cases were due to complications related to liver disease.CONCLUSION:SAGT was associated with lower survival.SAGT,Child-Pugh B,and high Child-Pugh and MELD scores were independent negative predictors of survival.     

Paradoxical release of growth hormone during oral glucose tolerance test in patients with abnormal glucose tolerance

Oral glucose tolerance tests were performed on 24 patients characterized as having abnormal glucose tolerance (AGT) and on 27 control subjects. Serums for glucose, growth hormone and insulin determinations were serially obtained for 4 hr after glucose administration. As serum glucose declined 2 hr or more after glucose ingestion a rise in growth hormone, as has been previously described, was observed in 40% of control subjects and 12% of AGT patients. However, of interest was a paradoxical early increase in growth hormone levels noted in 44% of lean AGT subjects occurring during the first 2 hr of the test with glucose levels rising. This response was seen in only one of 8 obese patients with AGT and in none of the control subjects. An abnormality in the hypothalamic glucose receptors in the ventromedial nucleus is a possible explanation for the changes observed. It is possible that this early inappropriate increase in growth hormone release may in some nonobese subjects with AGT contribute to the abnormal oral glucose tolerance tests observed.     

Impaired glucose tolerance as a determinant of early deterioration of left ventricular diastolic function in middle-aged healthy subjects

To clarify the determinants of an abnormal relaxation diastolic pattern assessed by Doppler echocardiography, 131 middle-aged healthy subjects were analyzed. By multivariate logistic regression analysis, fasting insulin levels (p = 0.0016) and peak glucose levels (p = 0.046) were independent predictors of an abnormal relaxation diastolic pattern 2 hours after 75 g OGTT.     

Pancreatic exocrine enzymes during the neonatal period in postmature rats

Summary Pancreatic content of exocrine enzymes in newborn rat pups shows a sharp decline soon after birth. To investigate if this decline is a preprogrammed and, therefore, inherently controlled phenomenon, or a result of external stimulus, prolonged gestation, or postmaturity (2 extra days in utero) in pregnant dams was induced by daily subcutaneous injection of progesterone from the 20th to 22nd days of gestation. Postmature pups showed the same high levels of lipase, trypsin(ogen), and amylase as control pups at birth. They also exhibited the same decline in these enzymes as control pups by the 2nd day after birth, suggesting that it is a response to external stimulus. Pups prevented from suckling retained the high levels of lipase, amylase, and trypsin(ogen) by the 2nd day. The stimulus, therefore, appeared to be the initiation of suckling. Pups prevented from suckling but given 5% glucose water orally every 4 h starting from birth for 24 h showed a sharp decline in amylase with only slight decreases in lipase and trypsin(ogen) by the 2nd day. The components in the feed, therefore, also seem to be an important determinant for selective enzyme release from the pancreas of the neonates. Electron microscopic studies revealed a sharp decrease in the number of zymogen granules in the continuously-suckled pups as compared to age-matched non-suckled counterparts. The reduction in enzyme content thus is the result of secretion in response to suckling. *** DIRECT SUPPORT *** A00DX035 00004     

Pancreatic exocrine enzymes during the neonatal period in postmature rats

Pancreatic content of exocrine enzymes in newborn rat pups shows a sharp decline soon after birth. To investigate if this decline is a preprogrammed and, therefore, inherently controlled phenomenon, or a result of external stimulus, prolonged gestation, or postmaturity (2 extra days in utero) in pregnant dams was induced by daily subcutaneous injection of progesterone from the 20th to 22nd days of gestation. Postmature pups showed the same high levels of lipase, trypsin(ogen), and amylase as control pups at birth. They also exhibited the same decline in these enzymes as control pups by the 2nd day after birth, suggesting that it is a response to external stimulus. Pups prevented from suckling retained the high levels of lipase, amylase, and trypsin(ogen) by the 2nd day. The stimulus, therefore, appeared to be the initiation of suckling. Pups prevented from suckling but given 5% glucose water orally every 4 h starting from birth for 24 h showed a sharp decline in amylase with only slight decreases in lipase and trypsin(ogen) by the 2nd day. The components in the feed, therefore, also seem to be an important determinant for selective enzyme release from the pancreas of the neonates. Electron microscopic studies revealed a sharp decrease in the number of zymogen granules in the continuously-suckled pups as compared to age-matched non-suckled counterparts. The reduction in enzyme content thus is the result of secretion in response to suckling.