Higher Serum Insulin Research Articles

Fasting Serum Insulin Concentration and Early Insulin Response as Risk Determinants for Developing Diabetes

Among a cohort of 348 women aged 50 on entering a 12-year prospective study, the incidence of diabetes was increased (17.1%) during follow-up in those who initially had fasting glucose concentration above the upper quintile, a fasting serum insulin concentration above the upper quintile (14.9%), a disappearance rate of glucose below the lowest quintile in an IV glucose tolerance test (12.7%), or early insulin response below the lowest quintile (17.1%). The incidence in all women was 4.9%. By multivariate analysis, the highest risk was for high fasting serum insulin concentration. Obesity and treatment with antihypertensive drugs further increased the risk. An initial low early insulin response was not however a prerequisite for the development of manifest diabetes. Determination of fasting insulin concentration, especially in overweight hypertensive subjects, is of value in order to find out which subjects are at high risk of developing diabetes.

The glucose clamp technique for the study of patients with hypoglycemia: insulin resistance as a feature of insulinoma

Occurrence of hypoglycemia during a prolonged fasting, accompanied by inappropriately high serum insulin levels, is considered a reliable index of the presence of insulinoma. Previous in vitro studies on insulin receptors, and in vivo hyperinsulinemic clamps have shown that patients with insulinoma are insulin resistant. In the present study 10 patients with insulinoma, 6 patients with nontumoral (also called functional or reactive hypoglycemia) hypoglycemia and 6 normal subjects were fasted for 24 h and their blood glucose levels were maintained constant by means of a programmed glucose infusion (isoglycemic glucose clamp) delivered by an artificial pancreas (Biostator). Blood glucose levels were monitored in continum, glucose infused (M) and glucose clearance (MCR) were evaluated at hourly intervals, and serum insulin (IRI) levels were evaluated every 6 h. Blood glucose levels were higher in controls than in patients with insulinoma and in patients with non tumoral hypoglycemia; M, MCR and IRI were progressively higher in controls, in patients with nontumoral hypoglycemia and in patients with insulinoma. The M/I index (M divided by IRI levels, an index of insulin sensitivity) was lower in patients with insulinoma than in other subjects and patients, indicating the existence of insulin resistance. These data indicate that: i) patients with insulinoma require large amounts of glucose to remain isoglycemic during a prolonged fast; ii) insulin resistance is a common feature of insulinoma and can be shown even under near physiologic conditions such as a 24-h fasting. The present study does not clarify whether insulin resistance occurs at the hepatic level or at other, peripheral levels.

Parental history of diabetes is associated with increased cardiovascular risk factors.

Serum insulin concentrations are higher in persons with a positive parental history of diabetes than in persons without such a history. Since hyperinsulinemia is associated with both an increased prevalence of hypertension and an atherogenic pattern of serum lipids and lipoproteins, we hypothesized that among nondiabetic persons, a parental history of diabetes would be associated with an atherogenic pattern of cardiovascular risk factors. In the San Antonio Heart Study, a population-based study of cardiovascular disease and diabetes, we examined 549 nondiabetic persons with a parental history of diabetes and 1167 nondiabetic persons without such a history. Compared to persons without a parental history of diabetes, those with such a history had a more atherogenic pattern of cardiovascular risk factors, including higher body mass index, higher systolic and diastolic blood pressures, higher serum insulin and triglyceride concentrations, and lower levels of high density lipoprotein cholesterol. After adjustment for serum insulin concentration, body mass index, and waist-to-hip ratio, the differences in lipids, lipoproteins, and blood pressure between the two parental history groups were no longer statistically significant. Since persons with a parental history of diabetes are more likely to be prediabetics, the present results suggest that prediabetics have an increased risk of coronary heart disease even before they become diabetic. This phenomenon may help explain why the duration of clinical diabetes is only weakly associated with the risk of coronary heart disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypothalamic monoamines associated with the cephalic phase insulin response.

This study elucidated the hypothalamic monoamine systems associated with the cephalic phase insulin release. Male Wistar rats conditioned to drink a glucose solution were killed 2 min after the onset of their scheduled feeding; control rats were killed at the same time. The ventromedial (VMH) and lateral (LH) portions of the hypothalamus were analyzed for the monoamines and their principal metabolites. Serum was assayed for insulin and glucose. The results showed that the experimental animals had significantly higher serum insulin levels than did the control animals, although glucose levels were unchanged. In the LH, there were increased levels of norepinephrine, its metabolite dihydroxyphenylethylene glycol (DHPG), and serotonin [(5-hydroxytryptamine (5-HT)]. In the VMH, 5-HT, its metabolite 5-hydroxyindoleacetic acid, and the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) were all higher in the conditioned animals. 5-HT levels in the LH and DOPAC levels in the VMH were closely associated with serum insulin (r = 0.80 and 0.71, respectively). This study has defined, in the normal animal, changes in monoamines in specific areas of the hypothalamus associated with the cephalic phase insulin release.

動脈硬化の非薬物療法

To obtain accurate nutritional data from respective patients seem to be a challenging problem. However, from nutritional point of view, if following clinical evidence were obtained and corrected, a better dietary management of the disease would be possible.(1) the presence of impaired VLDL-catabolism in hyperlipidemic patients and of high serum insulin levels in hypertensive patients due to excess energy-intake.(2) the presence of intolerance against stress in hypertensive patients due to excess salt-intake.

Abnormalities of carbohydrate metabolism in spontaneously hypertensive rats.

The present study was performed to investigate as to whether peripheral insulin resistance exists in spontaneously hypertensive rats (SHR). After a 12 h fasting period, SHR had significantly higher serum glucose and higher plasma glucagon values in comparison to normotensive control rats (WKY). There was a tendency for higher serum insulin concentrations as well, but this difference did not reach significance. After oral glucose loading or glucose/insulin administration, serum glucose and insulin levels were also higher in SHR compared to WKY rats. Muscle glycogen and glucose concentrations were identical in fasted SHR and WKY rats. With an oral glucose load or glucose/insulin treatment there was a significant increase in muscle glycogen, whereas glucose values declined in skeletal muscle. Both total (a+b-form) phosphorylase activity as well as the active a-form of the enzyme were similar in skeletal muscle of SHR and WKY rats. Glucose/insulin administration or oral glucose loading induced a considerable reduction of both a+b-form and a-form activities. The decrease in muscle phosphorylase activities was almost identical in both groups of animals. There was also a comparable activity of muscle glycogen synthetase activity in all groups of rats. Despite subtile changes of glucose, glucagon and to a lesser degree insulin levels which would be suggestive of insulin resistance, the data obtained from skeletal muscle argue against peripheral insulin resistance in spontaneously hypertensive rats.

TRANSIENT HYPERINSULINISM IN ASPHYXIATED NEWBORN INFANTS

Hypoglycemia (H) in birth asphyxiated infants is commonly attributed to glycogen depletion. We have observed 3 term AGA infants with birth asphyxia, who developed hyperinsulinemic hypoglycemia (HH) in the early postnatal life. All had inappropriatelly high serum insulin concentrations for their blood glucose level, and needed glucose infusion rates of>8 mg/kg/min for several days to maintain normoglycemia. All infants recovered spontaneously.

Insulin resistance—a risk factor for coronary heart disease?

Fasting insulin secretion was assessed by measuring fasting serum C-peptide levels in 529 women and 399 men aged 18-90 years, to study the relationship between insulin secretion, insulin resistance and risk factors for coronary heart disease. Subjects with low serum high density lipoprotein (HDL) cholesterol levels showed higher mean serum insulin and C-peptide levels than subjects with normal HDL cholesterol levels. In male subjects these differences were significant for both serum insulin and serum C-peptide results (P less than 0.005). In female subjects serum insulin results differed significantly (P less than 0.0005) but for the difference in mean serum C-peptide levels P was equal to 0.012. Fasting serum C-peptide correlated negatively with serum HDL cholesterol. However, serum C-peptide also correlated with serum triglyceride and serum triglyceride correlated negatively with serum HDL cholesterol. Each correlation was statistically significant (P less than 0.001). Multiple regression analysis suggested that the apparent association of C-peptide with HDL cholesterol was a consequence of the interrelated association between C-peptide, triglyceride and HDL cholesterol. The analysis was consistent with the hypothesis that obesity and increased insulin resistance were associated with increased insulin secretion and in turn with high serum triglyceride levels and consequentially low levels of serum HDL cholesterol. The data were compatible with the suggestion that insulin resistance rather than fasting insulin concentration per se could be a risk factor for coronary heart disease.

Forearm glucose uptake in cirrhosis and its relationship to glucose tolerance.

1. Oral glucose-tolerance tests (100 g) were carried out in six patients with stable well-compensated cryptogenic cirrhosis and in 12 control subjects. 2. In confirmation of previous studies, patients with cirrhosis had high post-glucose serum insulin levels and were glucose intolerant (mean incremental glucose area 954 +/- 186 compared with 482 +/- 35 mmol 3 h-1 l-1 in controls; P < 0.05). 3. Forearm arteriovenous differences of glucose and forearm blood flow were measured to estimate the proportion of the glucose load metabolized in peripheral tissues. Values in cirrhotic patients and control subjects (5614 +/- 1630 compared with 5344 +/- 672 mumol of glucose min-1 l-1 of forearm in 3 h) were similar despite higher glucose levels and sustained high insulin levels in the cirrhotic patients. 4. Peak lactate concentrations after glucose were of similar magnitude in the two groups (0.66 +/- 0.12 compared with 0.62 +/- 0.75 mmol/l) but in the patients with cirrhosis the peak occurred later and was more sustained. 5. The glucose intolerance of cirrhosis is primarily due to impaired hepatic retention of the glucose load. Insulin resistance in peripheral tissues may also be important since the higher insulin concentrations found in cirrhotic patients failed to enhance peripheral glucose uptake.

Nesidioblastosis in Children

Three cases in which seizure disorder was first noticed were examined in the last seven years; low fasting glucose and high serum insulin levels then led to the diagnosis of severe hypoglycemia secondary to nesidioblastosis. Hypoglycemic episodes were uncontrolled by frequent oral feedings and intravenous administration of dextrose, glucagon, and diazoxide. Within three weeks after diagnosis, all three patients underwent subtotal pancreatectomy; all three survived and have been followed-up for two to seven years. Two remain euglycemic and have no evidence of CNS damage. The third has occasional fasting hypoglycemia that is treated with diazoxide; he continues to have a seizure disorder and is mentally retarded. Neonatal hypoglycemia secondary to hyperinsulinism requires prompt recognition and aggressive treatment to avoid irreversible CNS damage. Subtotal pancreatectomy safely and effectively restores the euglycemic state.

Iris neovascular tufts. Relationship to rubeosis, insulin, and hypotony.

Iris neovascular tufts are abnormal proliferations of twisted microcapillary loops that project from the iris pupillary border. They appear to be a morphologic variant of rubeosis iridis. This study searched for iris neovascular tufts by biomicroscopy and iris fluorescein angiography. They were found in two of 16 (12.5%) myotonic dystrophy patients, in two of 30 (6.7%) maturity-onset diabetics, and in zero of 14 (0%) juvenile-onset diabetics. Myotonic and adult-onset diabetics have in common pancreatic beta-cell dysfunction, abnormally high serum insulin levels, and possibly defective hormone-receptor interactions. Whether these factors contribute to the altered blood-iris barrier and iris neovascular tufts in these groups is uncertain, but a correlation is suggested because the myotonic with the highest insulin level also had the most prominent tufts. Hyperinsulinemia and ocular hypotony are associated with neovascular tufts.

Prolonged serum insulin decreasing effects of two synthetic somatostatin analogues studied in vivo by a new animal method. Preliminary communication.

A newly developed in vivo method, using the ob-ob strain of obese-hyperglycaemic mice with permanently very high serum insulin values, makes it possible to detect more prolonged serum insulin lowering properties than in normal animals. Two newly synthesized analogues of somatostatin, D-alanine-somatostatin and des-alanine-des glycine-des-amino-somatostatin produced a more prolonged and greater decrease in the serum insulin values of ob-ob mice than did somatostatin. Our new in vivo method makes it possible to investigate the duration of insulin suppression of new derivatives.

Decreased cardiac glycogen following phenformin injection in hyperglycemic, hyperinsulinemic anaesthetized rats.

The incidence of death due to heart disease in diabetics treated with phenformin was double that of other groups in the University Group Diabetes Program of the U.S.A.1 Despite some insights into the actions of oral hypoglycemic agents this observation has not been explained. The human diabetic myocardium contains large amounts of glycogen, consumes glucose at rates comparable to those of normal hearts, may experience high serum insulin levels, and is subject to ischemic disease. We have compared the effects of phenformin with insulin on tissue glycogen levels in a model of coexisting hyperinsulinemia and hyperglycemia in which glucose was infused at a rate 6 times greater than that needed to satisfy energy needs.

Connecting (C)-Peptide—A Spin-off of Insulin Secretion

Direct measurement of hormone concentrations, made possible by radioimmunoassay and other methods, has enhanced precision in estimating hormone secretion. No longer dependent on provocative or suppressive tests or on the evidence provided by serum electrolyte values, radioisotope studies, and other indirect indicators of hormone activity, assessment of glandular function can be made with greater confidence. Triidothyronine and tetraiodothyronine values are more reliable in diagnosing hyperthyroidism or hypothyroidism than is the basal metabolic rate; an elevated serum aldosterone level will dispel any doubts created by unexpectedly normal serum potassium levels in suspected aldosteronism; and high serum insulin levels are more diagnostic of insulinoma than is fasting hypoglycemia. Occasionally, however, serum hormone levels become fallible guides. Such is the case with immunoreactive insulin assays in patients receiving exogenous insulin. In vitro, circulating endogenous insulin antibodies compete with added antibodies for the labeled insulin, thus vitiating the insulin immunoassay. The latter then fails

Effects of long-term restricted insulin production in obese-hyperglycemic (genotype ob/ob) mice.

Primary hypersecretion of insulin has been suggested as one possibility for the genetic fault of ob/ob mice. To test this hypothesis, streptozotocin (SZO) was used to reduce permanently insulin secretion in young lean and obese mice. After establishment of hyperglycaemia and weight reduction in treated obese mice (obese-SZO), daily insulin replacment was begun in some (obese-SZO-Ins). Obese-SZO mice maintained insulin levels and body weights similar to lean controls, though they were shorter and fatter, while food intake and blood sugar levels exceeded lean values. Obese-SZO-Ins mice with reduced islet hyperplasia, but great insulin resistance, gained more weight than obese-SZO mice; had high serum insulin and controlled blood glucose; and exhibited hyperphagia. These results suggest that primary hypersecretion of insulin cannot be the genetic defect, as ob/ob mice are hyperphagic, hyperglycaemic, insulin resistant, and "obese" even when insulin levels are restricted.

The effect of severe trauma on urine loss of insulin.

Six trauma patients and five healthy volunteers were given an intravenous glucose infusion (5 Gm. per hour) for 6 hours. The serum insulin response and urine insulin excretion were measured and compared in the two groups. Glucose intolerance and serum insulin levels which were elevated but inappropriately low for the degree of glycemia characterized the trauma patients. Urine insulin concentrations and total urine insulin were increased significantly in the trauma patients. Renal function was similar in both groups, as determined by serum creatinine, blood urea nitrogen, and creatinine clearance. The increase in urine insulin concentration in the trauma patients reflected the higher serum insulin concentrations, but no correlation existed between serum insulin and urine insulin concentrations. A negative correlation was found between "insulin clearance" and serum insulin in both groups, indicating altered renal handling of insulin following injury which may be a contributory factor to the relative hypoinsulinemia of trauma.

PERSISTENT NEONATAL HYPOGLYCAEMIA.

Two boys and one girl developed persisting hypoglycaemia 12, 24, and 48 hours after birth. Although there was no known history of hereditary diabetes mellitus, the birth weight was high in two cases, and some additional traits of foetopathia diabetica could not be excluded clinically. All had high serum insulin levels with frank hyperinsulinaemia in one case. Glucose tolerance tests also indicated hyperinsulinism. Diazoxide (8 to 27 mg/kg) elevated the blood glucose levels, but did not prevent severe hypoglycaemic episodes. The effects of subtotal pancreatectomy were only transient. The patients have now been kept on permanent diazoxide therapy for 2-4 years at dosages slightly lower than those used before operation. No islet-cell tumour was found at the subtotal pancreatectomy. In all 3 cases, the pancreatic islets were markedly hyperplastic and of irregular shape with the occurrence of large B-cells with giant hyperchromatic nuclei and chromophobe "agranular" or sparsely granulated cells. The predominating kind of islet cells showed tinctorial features of A2-cells but--in the absence of available material set aside for ultrastructural analysis--it could not be settled whether this was a result of a proliferation of A2-cells only or of "type IV cells" as well. Against the background of previously published reports, the present cases serve to illustrate that additional accuracy of diagnosis and classification of neonatal persistent hypoglycaemia requires quantitative information about the structural changes in the pancreatic islet cells, and that this can be obtained from conventional biopsy specimens.

Glucose Intolerance and Insulin Resistance in Patients With Liver Disease

A study of patients with compensated liver disease revealed (1) inappropriately high serum insulin levels in response to a glucose load administered either orally or intravenously, and (2) a diminished glucose response to injected insulin. These observations suggested "resistance" to the regulatory action of insulin on glucose metabolism. The actions of insulin on fat and protein metabolism, as reflected by lowering of free fatty acid (FFA) and free amino acid levels after glucose loads, were not altered. Since disappearance of injected insulin proceeded at a normal rate, insulin hypersecretion, as opposed to reduced insulin degradation, was suggested as the cause of the hyperinsulinemia. Potassium depletion, FFA elevation, and elevation of growth hormone levels could not be implicated as the cause of the abnormalities noted.

Differences in the development of the obese-hyperglycemic syndrome in obob and NZO mice.

Marked differences were shown in the development of the obese-hyperglycemic syndrome in NZO andobob mice. — In NZO mice glucose tolerance decreases continuously with increasing age and body weight. — Inobob mice three phases in the development of the obese-hyperglycemic syndrome are differentiated. In the first, dynamic phase glucose tolerance decreases and insulin secretion increases as does body weight. The intermediary or transitional phase, when the animals weigh about 55 g, is characterised by rapidly changing glucose patterns, i. e. an extremely poor glucose tolerance and extremely high serum insulin level is followed by improving glucose tolerance and decreasing insulin levels. In the third, static phase blood sugar values and serum insulin levels have nearly returned to those of the lean littermates. Body weight slowly decreases. The changes in glucose tolerance and serum insulin are parallelled by changes in islet cell morphology. The gluconeogenic capacity is increased during the dynamic and transitional phases, it declines during the static phase.

Pathogenetic aspects of the obese-hyperglycemic syndrome in mice (genotype obob). II. Extrapancreatic factors.

The cause of the pronounced insulin resistance of the hereditary obese-hyperglycemic syndrome in mice (obob) is so far unknown. To evaluate whether growth hormone (GH) is of pathogenetic significance in this context thein vivo incorporation of sulfate into costal cartilage was measured in obese-hyperglycemic mice and their lean littermates at various ages. It was found that a) GH administration raised the sulfation activity of the costal cartilage in both types of mice; b) the hormone further increased the insulin resistance of the obesehyperglycemic animals; c) the sulfate incorporation of the obese mice was considerably elevated after 1 month of age and remained high until the age of about 10 months. In 17 months old animals it had returned to a level similar to that of the lean littermates. In addition, the epiphyseal width of the tibia was increased in the obese mice. Since it was not clear whether the increased rate of sulfate in corporation was due to an elevated endogenous GH activity and/or the high serum insulin levels prevailing in the obese mice at this period of life a study of the pituitary morphology was carried out. The lack of obvious structural or quantitative differences between the pituitary alpha cells of the lean and obese mice did not exclude the possibility that the elevated sulfation activity was caused by the high serum insulin levels rather than an increased circulating GH activity. — Glucokinase activity, characterized by a highKm value, was found in the livers of both lean and obese mice. A significant elevation of this enzyme activity, but not of the hexokinase activity, in the obese mice strongly suggests that the insulin resistance does not extend to the liver cells in the obese-hyperglycemic syndrome.