Insulin sensitivity of the body in experimental hypothalamic obesity

Two-month hyperphagia after injury inflicted to the ventromedial hypothalamus in rats led to the development of marked obesity in an essential increase of the content of immunoreactive insulin, glucagon, and C-peptide in the blood. Increase of excessive body weight was attended by gradual diminution of the organisms sensitivity to exogenous insulin given in a dose of 0.03 U/100 g and maintenance of normal sensitivity to 0.1 U/100 g of exogenous insulin. It is most likely, therefore, that despite the increased function of the pancreatic islets and hyperinsulinemia, glucose tolerance decreased significantly due to diminished sensitivity of the peripheral tissues to insulin.     

Hyperinsulinemia of obesity is due to decreased clearance of insulin

The hyperinsulinemia of obesity could result from a decrease in the metabolic clearance rate of insulin (MCR-I), an increase in the secretory rate of insulin (SR-I), or a combination of both these processes. Because C-peptide and insulin are secreted in an equimolar ratio, the plasma concentrations of C-peptide (C) and insulin (I) are inversely proportional to their rates of metabolic clearance (C/I = MCR-I/MCR-C). We obtained 24-h integrated concentrations (IC) of insulin (IC-I) and C-peptide (IC-C) in 23 obese and 45 nonobese subjects over a period of normal activity and food intake. The IC-I was 69% higher in the obese subjects (P less than 0.0001). A 13% increase in the IC-C (P = 0.04), with a constant rate of C-peptide clearance, indicates a proportionate increase in SR-I. A 33% decrease in the IC-C/IC-I in the obese group (P less than 0.005) reflects a decrease in MCR-I; hence, 75% of the hyperinsulinemia is due to a decrease in the clearance of insulin. Because peripheral MCR-I (pMCR-I) is similar in obese and nonobese subjects, the decrease in MCR-I may be due to a decrease in the hepatic clearance of insulin. This conclusion was supported by our comparison of 24-h IC-C/IC-I ratios in the obese and nonobese subjects. Whereas the 24-h IC-C/IC-I of the nonobese resembled the fasting state, the 24-h IC-C/IC-I of the obese resembled the postprandial state, when insulin removal by the liver is known to be suppressed. These data are consistent with a decreased 24-h hepatic MCR-I (hMCR-I) as the cause of the hyperinsulinemia of obesity.     

Urine C-peptide excretion in hypocaloric states and factors affecting its excretion]

Recent evidence suggests that hyperinsulinemia may contribute to the development of various risk factors of atherosclerosis. To examine the effects of energy intake on insulin secretion, 24-h urine C-peptide was measured in twelve women with rheumatoid arthritis who were not taking any medicine and stayed in Koda hospital for a diet therapy which lasted 55 days. They were basically placed on a 1200 kcal/day vegan diet combined with three 3-5-day fasting periods (200 kcal/day). Urine C-peptide excretion markedly decreased from 31-40 to 8-14 micrograms/day during the fasting periods. Among the anthropometric variables examined, the average level of urine C-peptide excretions measured in the fasting periods showed a significant correlation with the percentage and the amount of body fat. However, such correlation was not observed while the calorie intake was 1200 kcal. No clinical laboratory parameter showed a significant correlation with urinary C-peptide excretion. These results suggest that the major determinant of urine C-peptide excretion is food intake and that hyperinsulinemia could be easily improved by restricting energy intake.     

测定血清INS、C-P对原发性高血压患者的临床意义

为探讨测定血清胰岛素（INS）,C－肽（C－P）对原发性高血压（EH）患者的应用价值,对32例EH患者的空腹和餐后2小时血糖（BG）、INS、C－P等指标进行测定,计算胰岛素敏感指数（ISI）,并与40名对照组进行比较,结果发现,EH组与对照组空腹血糖无明显差异,而空腹INS及餐后2小时BG、INS、C－P均明显高于对照组（P＜0．01）;胰岛素抵抗、高胰岛素血症比例均明显高于对照组（P＜0．01）。提示EH除血管和血液动力学异常外,尚存在多种物质代谢异常,同时血清INS、C－P的RIA测定在糖尿病以外疾病中的应用前景也很广扩。．     

原发性高血压与高胰岛素血症

本文对３２例不伴糖尿病的原发性高血压（ＥＨ）患者及２０名对照组进行口服葡萄糖耐量试验（ＯＧＴＴ），同时测定血糖、胰岛素、Ｃ肽、胆固醇及甘油三酯水平，结果提示ＥＨ患者存在糖而时减低（４６．７％），高脂血症（５０％）、肥胖（４３．８％）、高胰岛素血症（ＨＩＳ）及胰岛素抵抗（ＩＳＲ），ＩＳＲ可有在这些代谢中起主导作用，故认为高血压病不单纯是血压升高，而量一种代谢性疾病，治疗上也不应是单纯地控制高血压，而     

Effect of sulfonylurea on glucose, insulin and C-peptide responses to a meal stimulus in a patient with type 2 diabetes and liver disease

The influence of two sulfonylureas on blood glucose and plasma immunoreactive insulin (IRI) and C-peptide responses to a standardized meal was investigated in a patient with type 2 diabetes and a liver disease with enhanced peripheral levels of liver enzymes. The very high fasting values of plasma IRI and C-peptide were further elevated by the meal. This response to the meal was markedly enhanced by both sulfonylureas, glipizide and glibenclamide. The blood glucose increment after the meal was diminished by sulfonylureas. Sulfonylureas thus seem to have beneficial effects in this diabetic patient, who had a liver disease and markedly elevated basal levels of plasma IRI and C-peptide concentrations.     

原发性肝癌并发糖代谢紊乱

目的 探讨原发性肝癌并发糖代谢紊乱的可能发生机制。方法 测定７０例原发性肝癌患者空腹血糖、空腹及餐后２小时胰岛素、Ｃ肽浓度。对检测结果进行统计分析，组间分采用ｔ检验。结果 原发性肝癌并发糖代谢紊乱４４．２９％（３１／７０），其中低血糖占２５．７１％（１８／７０），其空腹胰岛素及Ｃ肽浓度均正常，与对照组比较差异无显著性，并发高血糖占１８．６％（１３／７０），其空腹胰岛素、餐后２小时胰岛素、Ｃ肽浓度均显著升高，与对照组比较有显著性差异（ｐ〈０．０１）。结论 原发性肝癌并发低血糖可能与肝葡萄糖产生率降低及葡萄糖利用率增加有关。原发性肝癌伴高血糖可能与调节血糖激素灭活障碍及胰岛素抵抗有关。     

Insulin-inducible changes in the relative ratio of PTP1B splice variants

The skeletal muscle activity of protein tyrosine phosphates 1B (PTP1B), a modulator of insulin and IGF-1 signaling, is reduced in obese nondiabetic subjects and in subjects with type 2 diabetes in comparison with leaner, nondiabetic controls. PTP1B mRNA, like many other signaling molecules, including the insulin receptor, is alternatively spliced. Since we have shown that the ratio of the insulin receptor splice variants is modulated by insulin in vitro and is related to insulin levels in vivo, we hypothesized that the relative ratios of the alternatively spliced PTP1B mRNA might also vary in humans in proportion to the degree of hyperinsulinemia. This was tested in 21 nondiabetic Pima Indians, a population at increased risk for obesity and type 2 diabetes. The relative ratio of the PTP1B splice variants was quantified using RT-PCR of total RNA extracted from fractionated monocytes. The ratio of the splice variants was positively correlated with fasting plasma insulin concentration (r = 0.757; P = 0.0001), 2-h plasma insulin concentration following an oral glucose tolerance test (r = 0.614; P = 0.01, n = 16), and percentage of body fat (r = 0.746; P = 0.0001). These data indicate that variability in the ratio of the two splice variants is due, in part, to in vivo levels of chronic hyperinsulinemia. This simple, noninvasive assay is therefore a potential biomarker for chronic hyperinsulinemia, similar to the HbAlc assay in use to monitor glucose management in diabetic patients.     

Insulin secretion in alcoholics in a withdrawal state

Insulin secretion was studied after stimulation with oral glucose and intravenous glucagon in 23 chronic alcoholics in a withdrawal state. Each subject was studied twice at one week's interval between the examinations. The insulin and C-peptide responses to glucagon were lower in the early withdrawal state. Moreover, the insulin and C-peptide increments were, when related to the magnitude of the glycemic stimulus, lower in the early than in the late withdrawal state. The fasting values of blood glucose, insulin and C-peptide and the blood glucose and C-peptide levels after oral glucose were higher in the early withdrawal state. These findings indicate that glucose metabolism in alcoholics in a withdrawal state can be disturbed by impaired insulin secretion and insulin resistance.     

Hyperinsulinemia in polycystic ovary syndrome: relationship to clinical and hormonal factors

We analyzed the association between hyperandrogenism and hyperinsulinemia, and their relationship to body mass index, in a large series of patients with polycystic ovary syndrome (PCOS). A characteristic hormonal profile was sought in women with marked hyperinsulinemia. The patient group consisted of 73 women with PCOS, ranging in age from 16 to 29 years. The control group consisted of 34 healthy women with no evidence of hyperandrogenism, aged 19–30 years. None of the patients or control women had a body mass index above 27 kg/m². Follicle-stimulating hormone, luteinizing hormone, prolactin, testosterone, estradiol, androstenedione, dehydroepiandrosterone sulfate, sex hormone binding globulin, 17-hydroxyprogesterone, and free cortisol were determined by radioimmunoassay. The free testosterone index was calculated. The oral glucose tolerance test was used to analyze basal insulinemia, maximum insulin peak, and the insulinemia/glycemia index. In the group with PCOS body mass index was greater, free testosterone index was higher, and levels of dehydroepiandrosterone sulfate, testosterone, 17-hydroxyprogesterone (P < 0.001) and androstenedione (P < 0.05) were higher than in the control group. Of the insulin parameters, basal insulinemia, maximum insulin peak, and insulinemia/glycemia index were higher in the patient group (P < 0.001). In patients with marked insulinemia, free testosterone index was more markedly elevated, and gonadotrophin levels were normal. Our data confirm that a characteristic pattern of hyperinsulinemia is associated with PCOS. We found no causal relationship between hyperinsulinemia and androgen levels. A characteristic hormonal pattern was found in patients with marked hyperinsulinemia.Abbreviations BMI body mass index - 17OHP 17-hydroxyprogesterone - DHEAS dehydroepiandrosterone sulfate - FTI free testosterone index - I/G insulin/glucose ratio - OGTT oral glucose tolerance test - PCOS polycystic ovary syndrome - P_max maximun peak of insulin - SHBG sex hormone binding globulin - LH luteinizing hormone - FSH follicle-stimulating hormone     

The syndromes of insulin resistance and acanthosis nigricans. Insulin-receptor disorders in man.

In six patients with acanthosis nigricans variable degrees of glucose intolerance, hyperinsulinemia and marked resistance to exogenous insulin were found. Studies of insulin receptors on circulating monocytes suggest that the insulin resistance in these patients was due to a marked decrease in insulin binding to its membrane receptors. When these patients were fasted, there was a fall in plasma insulin but no increase in insulin binding, suggesting that the receptor defect was not secondary to the hyperinsulinemia. The clinical features shared by these cases and several similar ones previously reported may be divided into two unique clinical syndromes: Type A, a syndrome in younger females with signs of virilization or accelerated growth, in whom the receptor defect may be primary, and Type B, a syndrome in older females with signs of an immunologic disease, in whom circulating antibodies to the insulin receptor are found.     

A case of autoimmune hypoglycemia complicated with diabetic ketoacidosis

Autoimmune hypoglycemia is characterized by hyperinsulinemia, fasting hypoglycemia, and the presence of insulin auto- antibodies without previous exposure to exogenous insulin. We experienced a case of autoimmune hypoglycemia without diabetes mellitus or any evidence of insulinoma. The insulin auto-antibody and insulin receptor auto-antibody were present. We diagnosed the patient as having autoimmune hypoglycemia and treated with glucocorticoid. After treatment, the hypoglycemic symptoms were resolved. However, four months later, the patient was readmitted with transient diabetic ketoacidosis. After recovery, he showed no signs of diabetes mellitus. We believe that insulin auto-antibodies may play a role in autoimmune hypoglycemia and diabetic ketoacidosis, but its role and mechanism are not precisely known. Further studies are needed to define the action mechanisms and the functions of insulin auto-antibodies: here we present case with a relevant literature.     

First-Phase Insulin and Amylin after Bariatric Surgery: A Prospective Randomized Trial on Patients with Insulin Resistance or Diabetes after Gastric Bypass or Sleeve Gastrectomy

BackgroundMost patients with severe obesity show glucose intolerance. Early after sleeve gastrectomy (LSG) or gastric bypass (LRYGB), a marked amelioration in glycemic control occurs. The underlying mechanism is not yet clear.ObjectiveTo determine whether the improvement in glycemic control on the level of endocrine pancreatic function is due to an increased first-phase insulin secretion comparing LRYGB to LSG.SettingUniversity of Basel Hospital and St. Clara Research Ltd., Basel, Switzerland.MethodsSixteen morbidly obese patients with severe obesity and different degrees of insulin resistance were randomized to LSG or LRYGB, and islet cell functions were tested by intravenous glucose and intravenous arginine administration before and 4 weeks after surgery.ResultsFasting insulin and glucose levels and homeostasis model assessment insulin resistance were significantly lower in both groups after surgery compared to baseline, while no change was seen in fasting C-peptide, amylin, and glucagon. After intravenous glucose stimulation, no statistically significant pre- to postoperative change in area under the curve (AUC 0–60 min) was seen for insulin, glucagon, amylin, and C-peptide. No statistically significant pre- to postoperative change in incremental AUC for first-phase insulin release (AUC 0–10 min), second-phase insulin secretion (AUC 10–60 min), and insulin/glucose ratio could be shown in either group. Arginine-stimulated insulin and glucagon release showed no pre- to postoperative change.ConclusionIntravenous glucose and arginine administrations show no pre- to postoperative changes of insulin release, amylin, glucagon, or C-peptide concentrations, and no differences between LRYGB and LSG were found. The postoperative improvement in glycemic control is not caused by changes in endocrine pancreatic hormone secretion.     

Effects of hemipancreatectomy on insulin secretion and glucose tolerance in healthy humans

Pancreatic tissue obtained by hemipancreatectomy from healthy living related donors has been transplanted into recipients with Type I diabetes mellitus. To determine the metabolic consequences of this procedure for the donors, we carried out oral glucose-tolerance testing and 24-hour monitoring of serum glucose levels and urinary C-peptide excretion as a measure of insulin secretion in 28 donors, both before and one year after hemipancreatectomy. The mean fasting serum glucose level was significantly higher one year after the procedure (mean +/- SD, 5.4 +/- 0.9 vs. 4.9 +/- 0.5 mmol per liter; P less than 0.003), as was the serum glucose value two hours after the administration of glucose (8.7 +/- 2.9 vs. 6.5 +/- 1.0 mmol per liter; P less than 0.001). The fasting serum insulin level was significantly lower one year after hemipancreatectomy (33.0 +/- 21.6 vs. 38.4 +/- 21.6 pmol per liter; P less than 0.05), as was the area under the insulin curves during the oral glucose-tolerance test (52,554 +/- 22,320 vs. 76,230 +/- 33,354 pmol per liter per minute; P less than 0.04). The mean 24-hour serum glucose-profile value was higher at one year, and the 24-hour urinary C-peptide excretion was lower in the 17 donors who underwent these studies. Seven of the 28 donors had abnormal glucose tolerance one year after hemipancreatectomy; however, insulin secretion in these 7 donors was indistinguishable from that in the 21 donors who had normal glucose tolerance. All 28 donors had fasting serum glucose concentrations lower than 7.8 mmol per liter, and their mean 24-hour plasma glucose levels remained within the normal range. We conclude that in healthy donors hemipancreatectomy results in a deterioration of insulin secretion and glucose tolerance, as measured one year later. Further study is required to ascertain whether the development of clinical diabetes mellitus is a risk inherent in hemipancreatectomy.     

Two novel insulin receptor gene mutations in a patient with Rabson-Mendenhall syndrome: the first Korean case confirmed by biochemical, and molecular evidence

Rabson-Mendenhall syndrome (RMS) is a rare syndrome manifested by extreme insulin resistance with hyperinsulinemia, acanthosis nigricans, tooth dysplasia and growth retardation. Our patient was first noted at the age of 8 months due to pigmentations on skin-folded areas. Initial laboratory tests showed normal fasting glucose (69 mg/dL). Fasting insulin level was severely elevated, up to 554.6 μIU/mL, and c-peptide level was increased, up to 13.81 ng/mL. However, hemoglobin A1c was within normal range (4.8%). He is now 11 yr old. His growth development followed the 5-10th percentile and oral hypoglycemic agents are being administered. The last laboratory results showed insulin 364.1 μIU/mL, C-peptide 4.30 ng/mL, and hemoglobin A1c 7.6%. The boy was a compound heterozygote for the c.90C > A and c.712G > A mutations of the insulin receptor gene, INSR, which are nonsense and missense mutations. In summary, we report the first Korean case of RMS, which was confirmed by two novel mutations of the INSR.     

Is daytime insulin more physiologic and less atherogenic than bedtime insulin?

The question is whether bedtime insulin, one of the standard therapy regimens of type 2 diabetes, can be more atherogenic than daytime insulin. There is no study to answer this question. However, pharmacokinetics of drugs and physiopathology of type 2 diabetes are considered, we can assume that daytime OAD plus bedtime insulin therapy might be more atherogenic than daytime insulin plus bedtime OAD therapy. The rationale for combination therapy is based on the assumption that, if evening insulin lowers the fasting glucose concentration to normal, then daytime oral agents will be more effective in controlling postprandial hyperglycemia. However, exogenous insulin administration is not a convenient way to inhibit hepatic glucose production which determines fasting plasma glucose because in post absorptive period, hepatic glucose production is determined by high glucagon and low insulin levels. In postprandial period, beta cell-originated insulin inhibits glucagon synthesis by paracrine effect and also inhibits hepatic glucose production by using half of its concentration that administered to portal system. Since half of insulin that found in portal system is exposed to hepatic clearance to inhibit hepatic glucose production, portal insulin concentration is 2-4-folds higher than peripheral insulin concentration. But, exogenous insulin neither inhibits glucagon synthesis via paracrine effect, nor reaches desired portal concentrations because it has a short half-life and in opposition to physiologic states it is not administered to the portal system. On the contrary, its peripheral concentration is higher than portal one. Thus, exogenous insulin that is used to inhibit hepatic glucose production requires higher concentrations than physiologic values. Eventually, peripheral hyperinsulinemic state which is a risk factor of CVD is created iatrogenically. Bearing in mind that PI3K pathway, working synchronously with the diurnal rhythm of other metabolic hormones, is more active during daytime especially in postprandial period when aminoacids and glucose exist in the environment, and that decreased insulin response in PI3K pathway in diabetics, we may propose iatrogenically created hyperinsulinemia can cause more atherogenic effects via MAPK pathway. For that reason, using OAD instead of bedtime insulin may be a more convenient way to inhibit hepatic glucose production. Thus, glucagon synthesis inhibition can be achieved via paracrine effect of OAD-induced insulin secretion, as well as required portal insulin concentration can be reached by the direct secretion of insulin to the portal system. Moreover, lower peripheral hyperinsulinemia state can be provided.     

Transient effect of the combination of insulin and sulfonylurea (glibenclamide) on glycemic control in non-insulin dependent diabetics poorly controlled with insulin alone

In a double-blind cross-over study we compared the effects of insulin plus glibenclamide, 5 mg twice daily, with insulin plus placebo during 8-week periods on metabolic parameters in 13 non-insulin dependent diabetic (NIDDM) patients poorly controlled with insulin alone. The combination therapy improved diabetic control as assessed by fasting blood glucose (p less than 0.001), 24-hour urinary glucose (p less than 0.01) and glycohemoglobin (HbA1) concentrations (p less than 0.05 at week 12). The effect tended to cease with time. Significantly higher C-peptide values were found during combination treatment than during insulin-placebo (p less than 0.01) and the changes in fasting C-peptide concentrations correlated positively with the changes in HbA1 concentrations (r = 0.56, p less than 0.05). There was no difference in glucagon concentrations, insulin binding to erythrocytes or insulin sensitivity between the two study periods. Neither did the combination therapy influence blood lipids significantly. The present study shows that the combination of insulin and glibenclamide may be of limited value in the treatment of NIDDM patients poorly controlled with insulin alone. However, thus far the long-term results are uncertain. In the absence of significant effects on insulin binding and insulin sensitivity, the improved diabetic control seems to be explained, at least partly, by glibenclamide-induced stimulation of insulin secretion.     

原发性高血压和冠心病患者胰岛素和C-肽的临床观察

目的：观察原发性高血压（EH）和冠心病（CHD）患者的胰岛素抵抗及其差异。方法：检测原发性高血压（EH）52例,冠心病（CHD）47例和健康对照组35例的空腹和服糖2h后胰岛素和C-肽,并进行比较。结果：原发性高血压病人和冠心病人空腹及服糖后2h血糖、胰岛素和C-肽明显高于正常健康人（P〈0.01）。结论：原发性高血压和冠心病患者存在胰岛素抵抗、高胰岛素血症、高C-肽水平。     

The investigation of glucose metabolism and insulin secretion in subjects of chronic hepatitis B with cirrhosis

Aims: To investigate the situations of abnormal glucose metabolism and dysfunction of pancreatic islet beta cells in subjects of chronic hepatitis B (CHB) with cirrhosis. Methods: 106 hepatitis B virus (HBV) positive subjects with liver cirrhosis as well as with different grade of Child-Pugh and 37 healthy subjects were included in this study. The oral glucose tolerance test (OGTT), C-peptide and insulin release test were detected. Plasma glucose and insulin levels were analyzed periodically for 2 h after oral glucose loading. Results: There was no significant difference in the level of fasting plasma glucose and C-peptide between cirrhosis group and control group (P>0.05). The levels of OGTT 2 h glucose, insulin and C peptide were significantly higher in cirrhosis group than control group (P<0.01). Peak plasma glucose levels were obtained at 60 min in normal group and cirrhosis group. The peak insulin and C-peptide response occurred at 60 min in normal group, whereas it was delayed to 120 min in cirrhosis group. There was a significant difference between two groups in the pattern of plasma glucose levels at corresponding time points (P<0.05). The OGTT 2 h glucose and insulin levels were positively correlated with Child-Pugh Score (r1 = 0.389, r2 = 0.508, P<0.01). Conclusion: These findings implied that there was a certain degree of insulin resistance and abnormal glucose metabolism in the patients with liver cirrhosis.     

Interaction between the G1057D variant of IRS-2 and overweight in the pathogenesis of type 2 diabetes

The insulin receptor substrate-2 (IRS-2) is a major insulin signalling molecule. IRS-2 inactivation in mice induces a form of diabetes characterized by peripheral insulin resistance and reduced beta cell mass. We tested the hypothesis that a common non-conservative amino acid substitution of IRS-2 (G1057D) might interact with overweight in the pathogenesis of type 2 diabetes. The variant was genotyped in 193 Italian patients with type 2 diabetes and 206 control subjects. In the absence of overweight, the risk of type 2 diabetes decreased according to the dosage of the D1057 allele (odds ratio for GD genotype 0.46 [95% CI 0.25-0.86]; DD genotype 0.18 [0.04-0.68]; P for trend = 0.0012). Conversely, the interaction between overweight and genotype increased the risk of type 2 diabetes according to the dosage of the D1057 allele (odds ratio for GD genotype 2.50 [1.11-5.65]; DD genotype 5.74 [1.11-29. 78]; P for trend = 0.0047). Among controls, fasting C-peptide levels, after adjustment for plasma glucose, were inversely related to the dosage of the D1057 allele (P = 0.020). This finding suggested that carriers of the D1057 allele may have higher insulin sensitivity and supported the protective effect of this allele. Conversely, among overweight patients there was a parallel increase in fasting plasma glucose (P for trend = 0.037) and fasting C-peptide according to the dosage of the D1057 allele, suggesting that higher insulin resistance and relative beta cell failure contributed to the increased risk of type 2 diabetes in overweight carriers of this allele. These data provide evidence for a strong association between type 2 diabetes and the G1057D common genetic variant of IRS-2, which appears to be protective against type 2 diabetes in a codominant fashion. Overweight appears to modify the effect of this polymorphism toward a higher risk of type 2 diabetes. Carriers of this polymorphism may represent an elective target for prevention of type 2 diabetes through preventing or treating excessive weight.