Secretion and hepatic removal of insulin in female obese subjects with reactive hypoglycemia

In the present study insulin and C-peptide responses to oral glucose as well as C-peptide to insulin ratios and relations were evaluated in 10 nondiabetic obese female subjects with reactive hypoglycemia and in 10 age- and weight-matched controls. Insulin levels and incremental areas did not differ significantly in the two groups, whereas C-peptide concentrations and incremental areas were significantly higher in the obese group with reactive hypoglycemia. C-peptide to insulin molar ratio increments after glucose load as well as relations between incremental areas of the two peptides were significantly higher in obese subjects with reactive hypoglycemia than in controls. Our results suggest that B-cell response to oral glucose as well as insulin uptake by the liver in obese subjects with reactive hypoglycemia are greater than in controls.     

Salicylates increase insulin secretion in healthy obese subjects

CONTEXT: Conflicting results on the effects of salicylates on glucose tolerance in subjects with normal glucose tolerance or type 2 diabetes have been reported. OBJECTIVE: The objective of the study was to investigate the effects of a salicylate derivative (triflusal) on insulin sensitivity and insulin secretion. DESIGN, SETTING, AND PARTICIPANTS: This was a double-blind, randomized, crossover study with three treatment periods corresponding to two dose levels of triflusal and placebo in healthy obese subjects. MAIN OUTCOME MEASURES: Insulin sensitivity and insulin secretion, evaluated through frequently sampled iv glucose tolerance test that was performed after each treatment period, were measured. Insulin secretion was also evaluated in vitro in mice and human islets of Langerhans. RESULTS: The administration of triflusal led to decreased fasting serum glucose concentration in the study subjects. Insulin sensitivity did not significantly change after each treatment period. Insulin secretion, however, significantly increased in a dose-dependent fashion after each triflusal treatment period. The administration of 800 mum of the main triflusal metabolite to whole mice islets of Langerhans led to a sustained increase in intracellular calcium concentration level. This was followed by a significantly increase in insulin secretion. In human islets, 200 mum of 2-hydroxy-4-trifluoromethylbenzoic acid was sufficient to increase insulin release. CONCLUSIONS: The administration of a salicylate compound led to lowering of serum glucose concentration. We suggest that this effect was mediated through increased insulin secretion induced by salicylate directly on the beta-cell.     

Relationship between blood pressure and plasma insulin in non-obese and obese non-diabetic subjects

Summary In this study, we have measured plasma insulin at fasting and following an oral glucose load and blood pressure after glucose load in 367 (247 non-obese, 120 obese) normotensive and untreated mildly hypertensive subjects. Overall, there was no independent association between fasting plasma insulin levels and blood pressure values. After controlling for age and body weight, a significant relationship between postglucose plasma insulin levels and diastolic blood pressure was found. When non-obese and obese subjects were examined separately, significant relationships were identified between postglucose plasma insulin levels and both systolic and diastolic blood pressure values in the former but not in the latter. A comparison of sex-, age-, and weight-matched hyperinsulinaemic vs normoinsulinaemic subjects showed that the former had significantly higher values of blood pressure only if not obese. These results demonstrate that the plasma insulin response to glucose is independently correlated with blood pressure.     

肥胖和非肥胖糖耐量受损患者胰岛素敏感性和1相胰岛素分泌研究

目的研究肥胖和非肥胖糖耐量受损(IGT)患者的胰岛素敏感性和β细胞1相胰岛素分泌功能,以探讨在IGT患者中肥胖对胰岛素抵抗和1相胰岛素分泌的影响。方法共有99位受试者(包括正常对照者32名,肥胖IGT44例,非肥胖IGT23例)接受了口服75 g葡萄糖耐量试验(OGTT)和胰岛素改良的减少样本数(采血样12次)的Bergman微小模型技术结合静脉葡萄糖耐量试验(FSIGTT)。胰岛素抵抗由FSIGTT中胰岛素敏感性指数(SI)加以评估,而OGTT中糖负荷后30 min胰岛素增值与血糖增值之比值[ΔI30/ΔG30=(I30 min-I0 min) /(G30 min-G0 min)]和FSIGTT中急性胰岛素分泌反应(AIRg)则用以评价胰岛β细胞分泌功能。处理指数(DI =AIRg×SI)用于评价AIRg是否代偿机体的胰岛素抵抗。结果与正常对照组[(7.52±10.89)×10-4]相比,二组IGT患者之SI明显降低,而肥胖IGT组的SI[(1.72±1.11)×10-4]较非肥胖组[(3.15±1.49)×10-4]更低(均P<0.01); AIRg和ΔI30/ΔG30在正常组(412±191,14.45±8.47)和肥胖IGT组(378±235,17.02±11.30)之间差异无统计学意义,但均大于非肥胖组(196±160,8.93±6.69,均P<0.01);与正常组(2 851±1 180)相比,DI指数在二组IGT显著降低(595±485,584±517),但后二组间此值差异无统计学意义。SI与2 h胰岛素、体重指数、尿酸和胆固醇呈显著的负相关性(校正r2=0.603,P<0.01);而AIRg与ΔI30/ΔG30显著正相关,与空腹血糖负相关(校正r2=0.479,P<0.01)。结论IGT患者存在胰岛素抵抗和β细胞功能异常。与非肥胖IGT患者相比,肥胖IGT患者胰岛素抵抗程度更为严重,但胰岛β细胞胰岛素1相分泌相对充分。     

Glucose-insulin interaction in obese individuals with asymptomatic reactive hypoglycemia

Summary The interrelationship of glucose and insulin was investigated in obese nondiabetic subjects with asymptomatic reactive hypoglycemia. Results were compared to those obtained from obese control subjects and normal individuals. The diagnostic criteria for asymptomatic reactive hypoglycemia were the appearance of blood glucose values of 40 mg/dl and below during the postabsorptive phase of a 6-h OGTT and the absence of related symptoms. The blood glucose nadir occurred earlier in obese hypoglycemics than in obese controls. Maximum insulin response was similar in both obese groups, but occurred significantly later in obese hypoglycemics than in obese subjects without hypoglycemia and normal subjects. In obese hypoglycemics the blood glucose nadir was inversely proportional to the time of the insulin peak (i.e. the later the insulin peak the lower the blood glucose nadir) but correlated poorly to maximum insulin values. Delayed insulin response was found to be the major abnormality in asymptomatic reactive hypoglycemia and a probable cause of the decreased ability to maintain post-hyperglycemic glucose homeostasis. Decreased glucose tolerance in some obese hypoglycemics pre-treated with prednisolone suggests that asymptomatic reactive hypoglycemia could be the manifestation of an early diabetic stage.     

Effects of naloxone on prolactin, growth hormone and cortisol response to insulin hypoglycemia in obese subjects

Recent studies suggest that opioid peptides may influence the secretion of pituitary gland hormones. Since obese patients often show impaired growth hormone (GH), prolactin (PRL) and cortisol responses to stimuli and raised beta endorphin levels, the opioid regulation of such hormone secretion could be different from that in normal weight subjects. In order to verify this hypothesis we studied the effect of iv naloxone, an opiate receptor antagonist, on GH, PRL and cortisol response to insulin-induced hypoglycemia in 9 obese female subjects. Seven normal weight females were used as control group. A control test using saline showed that the PRL and GH responses to insulin stress were impaired in obese subjects, whereas no difference was seen in the cortisol response. Naloxone did not modify the PRL and GH response but provoked a rise in the cortisol response in both obese and normal weight subjects. These findings suggest that while the opioid peptides do not play an important role in regulating the GH and PRL response to insulin hypoglycemia, they influence the cortisol response. In obese patients the impairment in GH and PRL response to stimuli cannot be related to alterations in opioid peptide regulation.     

Increased insulin sensitivity in patients with idiopathic reactive hypoglycemia

We performed a euglycemic hyperinsulinemic glucose clamp in 20 patients selected from a large number of subjects referred to our clinic with symptoms suggesting reactive hypoglycemia. Diagnosis was made on the basis of blood glucose measurements during symptoms in their daily life and confirmed by a 5-h oral glucose tolerance test. The patients were divided into the following groups: 8 patients with idiopathic reactive hypoglycemia (IRH), i.e. biochemical hypoglycemia associated with symptoms and plasma insulin concentrations in the normal range; 6 patients with nonhypoglycemia (NH), i.e. patients experiencing the symptoms evoking hypoglycemia at essentially normal plasma glucose levels; and 6 patients with alimentary hypoglycemia secondary to previous gastric surgery (GS). Eight normal volunteers formed the control group (N). Hypoglycemia in this study was considered to be present when plasma glucose concentrations were below 2.5 mmol/L. The peak cortisol levels after glycemic nadir were higher (2P less than 0.05) in IRH compared to GS and N. In the same group, a partially deficient glucagon response to hypoglycemia was noted. During the euglycemic clamp, the glucose uptake appeared to be significantly greater in the IRH group than in NH, GS, and N groups (8.13 +/- 0.49 vs. 7.02 +/- 0.35, 6.48 +/- 0.22, and 6.66 +/- 0.42 mg/kg.min, respectively; 2P less than 0.05). Therefore, our data suggest that increased insulin sensitivity represents a feature of idiopathic reactive hypoglycemia.     

Epicardial adipose tissue and insulin resistance in obese subjects

CONTEXT: Epicardial adipose tissue has been recently recognized as a source of bioactive molecules as well as free fatty acids, adiponectin, and inflammatory cytokines. Epicardial fat reflects intraabdominal visceral fat, and the echocardiographic assessment of this tissue is an easy and reliable marker of visceral adiposity. OBJECTIVE: In this study we evaluated whether epicardial adipose tissue is related to insulin sensitivity and glucose metabolism in obese subjects. PATIENTS: Thirty obese subjects (20 women and 10 men; mean age, 40.8 +/- 11.5 yr; body mass index, 43 +/- 9.1 kg/m2) were included in this study. No subject was taking drugs or had a history or evidence of metabolic, cardiovascular, respiratory, or hepatic disease. MAIN OUTCOME MEASURES: Each subject underwent a transthoracic echocardiogram to evaluate epicardial adipose tissue thickness, a euglycemic hyperinsulinemic clamp to estimate insulin sensitivity, and an oral glucose tolerance test to evaluate glucose tolerance. RESULTS: The thickness of the epicardial adipose tissue on the right ventricle varied between 4 and 17.4 mm. Echocardiographic epicardial adipose tissue was significantly correlated with whole-body glucose uptake index from the clamp and with all indices of insulin resistance and glucose intolerance measured, except the 120-min plasma glucose level after an oral glucose tolerance test. CONCLUSIONS: Our study showed that the epicardial fat is significantly related to obesity-related insulin resistance. This finding could be of potential interest in clinical practice and research of obesity-related risk stratification.     

Evaluation of insulin resistance in non-obese subjects with impaired glucose tolerance

Insulin resistance was estimated in nine subjects with impaired glucose tolerance (IGT) and eleven healthy, age and body-weight matched controls. Glucose tolerance and insulin response were evaluated by means of a 2h-glucose infusion test. Insulin resistance was determined by measuring the steady state plasma glucose response (SSPG) to a continuous infusion of glucose (6 mg . kg-1 . min-1 or 12 mg . kg-1 . min-1), insulin, epinephrine and propranolol for 150 minutes as described previously by other authors. The endogenous insulin secretion (C-peptide) was inhibited by epinephrine and propranolol in controls and subjects with IGT irrespective of a low (6 mg . kg-1 . min-1) or high (12 mg . kg-1 . min-1) glucose infusion. Steady-state plasma levels of exogenous insulin were virtually identical in all groups studied. There were no significant differences in the pancreatic glucagon, growth hormone, FFA and glycerol response during the SSPG period between controls and subjects with IGT. In comparison to controls the mean SSPG was significantly higher in subjects with IGT (during low and high glucose infusion) suggesting the existence of insulin resistance in these subjects. A higher glucose dose as described earlier by other investigators does not provide a better discrimination of controls and subjects with IGT concerning their degree of insulin resistance. Finally, there was a direct correlation between the SSPG and glucose tolerance in the total group. In conclusion, our results have confirmed the validity of an infusion technique of glucose, insulin, epinephrine and propranolol for evaluation of insulin sensitivity in vivo. In addition, our findings have added further support for insulin resistance in subjects with IGT which is directly proportional to the degree of glucose intolerance.     

Further support for heterogeneity of insulin response and insulin sensitivity in non-obese subjects with glucose intolerance

The relationship of insulin secretion and insulin sensitivity was studied in 67 age- and body weight-matched non-obese subjects, classified as having a normal glucose tolerance or glucose intolerance (50 g oral glucose load). Insulin response was studied by means of a 2 h glucose infusion. For the determination of insulin sensitivity a 1 h priming dose-constant insulin infusion technique was used. The per cent decrease of plasma glucose level at comparable steady-state insulin levels served as a measure of body sensitivity to exogenous insulin. In patients with glucose intolerance the early (delta IRI area 0-5 min) and late (delta IRI area 30-120 min) insulin responses to iv glucose were significantly reduced in comparison to controls. Controls and subjects with glucose intolerance showed considerable heterogeneity of insulin responses. Patients with glucose intolerance and relative insulin deficiency were not less responsive to insulin than subjects with normal glucose tolerance. There was, however, a wide variation of insulin sensitivity within the two groups. There was a weak significant inverse correlation between insulin response to glucose and insulin sensitivity for the two groups combined and for controls and subjects with glucose intolerance separately. The results demonstrate that the majority of non-obese patients with glucose intolerance and relative insulin deficiency does not exhibit a reduced responsiveness to insulin and therefore hypoinsulinaemia but not insulin resistance is the primary defect for an abnormal glucose tolerance in these group of subjects.     

Oxytocin response to insulin-induced hypoglycemia in obese subjects before and after weight loss

The response of plasma oxytocin to an iv bolus injection of crystalline insulin (0.15 U/kg) was evaluated in 14 normal weight [mean body mass index (BMI) = 23] and in 9 obese (mean BMI = 42) men. Similar blood glucose decrements after insulin injection were observed in the two groups. Obese and normal weight subjects presented similar basal oxytocin levels. In both groups, oxytocin rose significantly during the insulin tolerance test (ITT); however, the peak oxytocin response in the obese men was significantly lower than in the normal weight subjects. Obese men were restudied after substantial weight loss. Basal oxytocin levels and glucose response to insulin did not change after weight reduction. The oxytocin response to the ITT was significantly higher than before slimming and did not differ from that observed in the normal weight subjects. A significant negative correlation between BMI values and oxytocin peak levels during ITT was observed in the lean controls and obese subjects (r = 0.516, p less than 0.02). These results demonstrate that in obese subjects the oxytocin secretory response during an insulin tolerance test is reduced, suggesting the existence of a hypothalamic-pituitary disorder in obesity.     

The effects of a low-dose intravenous insulin infusion upon plasma glucose and non-esterified fatty acid levels in very obese and non-obese human subjects

Summary After an overnight fast, the effects of a 30-min low-dose intravenous insulin infusion (2.6 units/h) upon plasma glucose and non-esterified fatty acids were compared in 29 very obese patients and 17 nonobese controls. The dose of insulin was chosen so as to have its sole or predominant hypoglycaemic effect upon hepatic glucose release. The proportional fall from basal values at 30 min of both plasma glucose and non-esterified fatty acids was significantly greater in the controls and there was no difference between males and females. In the controls the fall in plasma glucose and non-esterified fatty acids was significantly and inversely correlated with the basal plasma insulin level. Neither index of insulin sensitivity was significantly related with the basal plasma insulin in the obese subjects. Weight loss in the obese subjects led to increased insulin sensitivity; in particular, the degree of change in insulin-induced nonesterified fatty acids was significantly related to the percentage change in weight. Despite their extreme degree of obesity, the distributions of basal plasma insulin levels and the indices of insulin sensitivity in the obese subjects overlapped with those of the nonobese controls.     

Different aetiologies of Type 2 (non-insulin-dependent) diabetes mellitus in obese and non-obese subjects

Summary Insulin responses to intravenous glucose infusion and glucose utilization during hyperinsulinaemic euglycaemic clamp were determined in a large homogeneous group of 65-year-old male subjects. Twenty-eight had untreated Type 2 (non-insulin-dependent) diabetes mellitus and the remaining 44 control subjects had a normal glucose tolerance. Diabetic patients with abdominal obesity displayed peripheral insulin resistance in combination with defective insulin secretion, whereas non-obese diabetic patients showed only a secretory defect. Thus, Type 2 diabetes in obese and non-obese elderly male subjects may take two forms where the cause of hyperglycaemia differs.     

L-tryptophan does not increase weight loss in carbohydrate-craving obese subjects

Eight subjects, aged 26 to 50 years, who had long histories of carbohydrate (CHO) craving and were more than 45 kg above desirable body weight participated in a randomized, double-blind, crossover pilot study on the effects of L-tryptophan on weight loss and mood state. One g of tryptophan with 10 g of CHO was administered three times a day, 30 min before meals, as an adjunct to a weight-loss protocol that included nutritional consultation teaching low fat, high fiber diets ranging from 1200-1600 kcals/day, behavior modification, and supportive therapy. During the pretreatment period, body weight and plasma tryptophan levels were measured and the Beck Depression Inventory, SCL 90 rating, and Profile-of-Mood State (POMS) were used to assess mood. During the treatment periods, subjects kept daily records of food intake and the timing of medication. All patients were seen at least biweekly. After six weeks on medication, baseline measurements were repeated and the crossover between tryptophan and placebo was implemented. After an additional six weeks on placebo or tryptophan, the same measurements were repeated. For the eight patients who completed the three-month protocol, the mean weight loss for six weeks on placebo was 1.14 kg and for six weeks on tryptophan was 2.3 kg. Mean Beck scores were 8.8 during the control period, 8.3 on placebo, and 10.9 on tryptophan. Mean SCL 90 ratings were 69.2 during the control, 54.6 on placebo, and 64.2 on tryptophan. Mean scores for total mood disturbance on the POMS were 48 during the control period, 43 on placebo, and 52 on tryptophan.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differences in insulin clearance between metabolically healthy and unhealthy obese subjects

Metabolically healthy obese (MHO) are relatively insulin sensitive and have a favorable cardio-metabolic risk profile compared with metabolically abnormal obese (MAO). To evaluate whether MAO individuals have a decreased insulin clearance compared with MHO individuals, 49 MHO, 147 MAO, and 172 non-obese individuals were analyzed in this cross-sectional study. Insulin clearance and insulin sensitivity were assessed through euglycemic hyperinsulinemic clamp. MHO subjects exhibited significant lower triglycerides, total cholesterol, 2-h post-challenge glucose, fasting and 2-h post-challenge insulin, steady-state plasma insulin, alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyltransferase as compared with MAO individuals. Disposition index was higher in MHO subjects as compared with MAO individuals after adjusting for gender and age (P = 0.04). Insulin clearance was significantly lower in MAO individuals as compared with MHO and non-obese individuals. The difference between the two obese subgroups remained significant after adjusting for gender, age, waist circumference, fat mass, and insulin-stimulated glucose disposal (P = 0.03). The hepatic insulin extraction (C-peptide/insulin) in the fasting state was significantly higher in MHO subjects as compared with MAO individuals (P < 0.0001). In univariate analysis adjusted for gender and age, insulin clearance was correlated with hepatic insulin extraction (P = 0.01). In conclusion, insulin clearance differs among obese subjects with different metabolic phenotypes. Impaired insulin clearance may contribute to sustained fasting and post-meal hyperinsulinemia observed in MAO individuals.     

Relationship between insulin and blood pressure in Japanese obese subjects.

OBJECT: The association of obesity and hypertension is well recognized. However, the nature of the relationship between increased body weight and blood pressure (BP) elevation has remained obscure. PATIENTS AND METHODS: We evaluated BP, insulin sensitivity, insulin clearance and fasting plasma insulin concentration in 19 younger (over 40 years) and in 15 older (more than 40 years) obese subjects to determine the relationships between BP and other factors. Insulin sensitivity and clearance were determined with the euglycemic clamp technique. RESULTS: BP was not associated with insulin sensitivity although most of the subjects showed insulin resistance. In the younger obese group, a positive correlation between diastolic BP and body mass index (kg/m2) was found (r=0.740; p=0.043). In the older obese group, systolic and diastolic BP were correlated with fasting plasma insulin levels (r=0.705; p=0.003; r=0.574; p=0.025, respectively), and systolic BP was inversely correlated with insulin clearance (r=-0.715, p=0.003). CONCLUSION: These results suggest that insulin is an important factor in BP elevation in older obese subjects, but not in younger obese subjects.     

Adipocytokine profiles as influenced by insulin resistance in obese subjects

ObjectiveThis study aims to explore the baseline adipocytokine profiles of adult Saudis and evaluate their relationship in the development of insulin resistance.MethodsIn this cross-sectional study, 300 adult Saudis with varying glucose tolerance were recruited. They were grouped into NGT, IGT and DM. Anthropometrics, glucose and lipid profiles were analyzed by routine methods; leptin, adiponectin, resistin and CRP were measured by ELISA.ResultsInsulin resistance was significantly correlated with levels of CRP (R = 0.32, p = 0.02) in the NGT; with leptin levels (R = 0.46, p = 0.001) in the IGT; and with adiponectin levels (R = 0.25, p = 0.001) in all groups. In males, resistin and CRP exhibited significant correlations to insulin resistance (R = 0.33, p = 0.005); in females significant correlation was demonstrated between insulin resistance and adiponectin (R = 0.32, p = 0.003). Significant associations exist in the adipocytokine profiles of adults with different glucose tolerance.ConclusionCertain adipocytokines can be used not only as promising markers but also as potential adjunct therapy with regards to insulin sensitivity and obesity.