Showing papers on "Insulin resistance published in 1978"

Insulin resistance, insulin insensitivity, and insulin unresponsiveness ; a necessary distinction

Abstract: Insulin resistance may be said to exist whenever normal concentrations of insulin produce a less than normal biologic response. Hormone resistant states may be divided into those due to decreased sensitivity to a hormone (i.e., a shift in the dose-response curve to the right), those due to a decrease in the maximal response to the hormone, and those that are combinations of decreased sensitivity and decreased responsiveness. This distinction is important, since the molecular mechanisms that produce these various forms of insulin resistance may be different. Disorders associated with alterations prior to the interaction of insulin with its receptor are more likely to produce states of decreased sensitivity, where disorders associated with alterations at the intracellular steps in insulin action are more likely to produce decreased responsiveness. Alterations in the insulin receptor itself may produce either, although most frequently changes in receptor affinity as well as in receptor number will be manifest as changes in sensitivity. This is a result of the large number of "spare" receptors for most insulin effects. In many studies, the differential diagnosis between states of altered sensitivity and altered responsiveness is difficult due to the complicated and interrelated nature of the metabolic pathways of insulin action. This is frequently further complicated by incomplete data (usually the result of studying response to only one hormone concentration rather than a full dose-response) and change in rates of basal metabolism in different diseases. The latter is a particularly difficult problem, but it is clear that use of "fold-" or "percent-" stimulation may further obscure the nature of the change when complete data are not provided. With more precise use of these terms and a more complete understanding of insulin action, it will be possible to begin to segregate the roles of the various prereceptor, receptor and postreceptor factors that are involved in producing the differing patterns of metabolism observed in disease.

Alterations in insulin binding induced by changes in vivo in the levels of glucocorticoids and growth hormone.

Abstract: Previous studies have shown that the sensitivity of tissues to insulin is diminished in states of glucocorticoid and GH excess and is increased when these hormones are deficient. To evaluate the role of the insulin receptor in these states, we have studied [125I]insulin binding to purified liver plasma membranes obtained from rats with a variety of perturbations of both glucocorticoids and GH. Glucocorticoid excess was produced in rats by administration of ACTH (40 U /day for 4 days dexamethasone (1mg/day for 4 days). This resulted in an insulinresistant state. Associated with this insulin resistance, there was a 50–60% decrease in insulin binding to its specific receptors in liver. Conversely, adrenalectomy, which produces an increase in insulin sensitivity, was associated with an increase in insulin binding to liver. Computer-assisted Scatchard analysis using a negative cooperative model for the insulin-receptor interaction indicated that, in contrast to our findings with obesity, the changes in insulin...

Sensitivity of corticosteroid-dependent insulin-resistant lipogenesis in marrow preadipocytes of obese-diabetic (db/db) mice

Abstract: IT is well known that adipocytes with specific cell-membrane insulin receptors respond to insulin by increasing glucose uptake, oxidation and lipogenesis in the presence of glucose1–4. Maintenance of adipocyte insulin sensitivity during a state of relative muscle cell insulin resistance has been considered a possible mechanism for obesity in diabetes mellitus5. I now report that a distinct cell phenotype resists insulin but accumulates lipid in response to corticosteroid. Furthermore, corti-costeroid-induced lipogenesis is significantly greater in marrow preadipocytes of mutant diabetic-obese mice.

Extreme insulin resistance in ataxia telangiectasia: defect in affinity of insulin receptors.

Abstract: The syndrome of ataxia telangiectasia is associated with glucose intolerance and insulin resistance. We examined the status of insulin receptors on circulating monocytes and on cultured fibroblasts from two siblings with ataxia telangiectasia and severe insulin resistance. 125I-insulin binding to monocytes of the two patients consistently demonstrated an 80 to 85 per cent decrease in receptor affinity. In contrast, the defect in receptor affinity was not expressed on the patients' cultured fibroblasts or on monocytes or fibroblasts obtained from unaffected family members. Whole plasma and immunoglobulin-enriched fractions of plasma from the patients inhibited the normal binding of insulin to its receptors on cultured human lymphocytes (IM -9 line) and on human placental membranes. We conclude that the insulin resistance in the two siblings with ataxia telangiectasia was associated with defects in the affinity of the receptors for insulin, probably caused by circulating inhibitors of insulin binding.

Insulin binding and effects in isolated soleus muscle of lean and obese mice.

Abstract: To get some insight into the mechanisms of insulin resistance in obesity, insulin binding and biological effects were investigated in soleus muscles isolated from normal and obese mice. Basal and insulin-stimulated 2-deoxyglucose uptake were measured at the steady state of insulin binding. The results were consistent with the concept of spare receptors, i.e., maximal insulin effect was achieved when only about 20% of total receptors was occupied. When similar studies were applied to muscles of gold thioglucose obese or genetically obese (ob/ob) mice, and compared to lean controls: a) insulin binding was decreased; b) the insulin dose-response curve of 2-deoxyglucose uptake was shifted to the right; c) maximally insulin-stimulated 2-deoxyglucose uptake, glycolysis, and glycogen synthesis were markedly decreased. Insulin binding and effects returned toward normal after a 40-h fast in obese mice. These results point to two loci for the insulin resistance of skeletal muscle in obesity: 1) a decrease in the number of insulin receptors, which results in a diminished insulin sensitivity; and 2) one or more alterations beyond receptor that are responsible for the decreased responsiveness of the tissue to insulin and appear to play a major role in the insulin resistance of muscle in obesity.

Insulin Resistance in Patients with Cancer

Abstract: Disturbed glucose metabolism is a well-recognized feature in cancer. This study was designed to elucidate the role of peripheral tissues for glucose metabolism in this disease. Ten cancer patients and 11 appropriate controls were subjected to insulin challenge (0.10 unit/kg body weight) and i.v. glucose tolerance test. The fractional uptake or release of insulin, glucose, free fatty acids, glycerol, acetoacetate, and lactate in the forearm was determined. In isolated skeletal muscle fibers obtained from biopsies from the rectus abdominal muscle, the incorporation rate of glucose carbon into glycogen and CO2 and the incorporation of palmitic acid carbon and leucine carbon into CO2 as well as insulin stimulation of the incorporation of glucose carbon into glycogen and leucine carbon into proteins were determined. In cancer patients the response of blood glucose to insulin challenge was smaller than in controls. Neither the elimination rate of insulin from plasma nor the fractional uptake of glucose in the forearm was significantly changed in these patients. The incorporation rate of glucose carbon into glycogen and CO2 was significantly decreased, and the insulin stimulation of this incorporation was smaller in cancer patients than in controls. The incorporation rate of palmitic acid and leucine into CO2 did not differ between the groups. Peripheral tissues are of importance for the disturbed glucose metabolism in cancer disease since skeletal muscles showed specifically lowered capacity for glucose utilization with and without insulin stimulation in vitro. All of these results were compatible with an insulin resistance in the liver and in the skeletal muscles in cancer.

Insulin resistance due to a defect distal to the insulin receptor: demonstration in a patient with leprechaunism.

Abstract: We have studied a 2-year-old girl with acanthosis nigricans, glucose intolerance, marked hyperinsulinemia, and somatic features characteristic of the leprechaunism syndrome. Circulating plasma insulin levels were increased up to 50-fold and the patient showed a blunted hypoglycemic response to an injection of exogenous insulin (0.2 units/kg), indicating the presence of severe insulin resistance. Insulin purified from the patient's plasma was normal on the basis of chromatographic, electrophoretic, and immunologic criteria. Furthermore, the purified insulin competed effectively with 125I-labeled insulin for binding to insulin receptors on cultured IM-9 lymphocytes and rat fat cells and also exhibited normal biological potency when tested on rat fat cells. Anti-insulin receptor and anti-insulin antibodies were not detected in the patient's plasma, and plasma levels of glucagon, growth hormone, and cortisol were normal. Insulin binding to the patient's circulating monuclear leukocytes was only slightly depressed into the low normal range and could not account for the severe insulin resistance. Studies on the patient's fibroblasts revealed normal levels of insulin receptors but a total absence of insulin's ability to accelerate glucose transport. Because rates of glucose transport and metabolism were normal in the basal state in the absence of insulin, we conclude that this patient's insulin resistance is due to an inherited cellular defect in the coupling mechanism between occupied insulin receptors and the plasma membrane glucose transport system.

The Evolving Clinical Course of Patients with Insulin Receptor Autoantibodies: Spontaneous Remission or Receptor Proliferation with Hypoglycemia

Abstract: Three patients with insulin resistance caused by autoantibodies to the insulin receptor were investigated serially over a 3-yr period. Major changes in carbohydrate metabolism, insulin receptor status, and titer of antireceptor antibodies were observed in each case. In one patient, normalization of glucose tolerance, insulin sensitivity, and receptor binding were associated with a spontaneous fall in the titer of antireceptor antibody. A second, more severely affected patient had two entirely distinct phase to her illness. The first, or hyperglycemic phase, was characterized by insulin resistance, negligible insulin binding to receptors on circulating monocytes, and high titers of circulating antireceptor antibodies. The second phase was characterized by refractory hypoglycemia, in association with proliferation of membrance insulin receptors; these occurred despite persistence of high titers of antireceptor antibody. An unusual heptic lesion, diffuse adenomatosis, was observed during this phase. A third patient showed features of both of the other patients, with spontaneous fall in antibody titer as well as a later phase of receptor proliferation. These studies demonstrate that patients with antibodies to insulin receptors may have a fluctuating clinical course. There may be spontaneous changes in antibody titers as well as independent changes in receptor concentration. Hypoglycemia and hepatic proliferation are newly recognized clinical sequelae in patients with this syndrome.

A prospective study of glucose tolerance, insulin, C-peptide, and glucagon responses in patients with pancreatic carcinoma.

Abstract: Ninety-nine patients suspected of having pancreatic carcinoma were studied prospectively for carbohydrate tolerance. Thirty-two patients were proven subsequently to have pancreatic carcinoma; the remainder served as a control group. There was an increased incidence of carbohydrate intolerance in patients with pancreatic carcinoma compared to the control group. Insulin and C-peptide measurements during glucose tolerance tests suggest abnormal beta cell function and possibly insulin resistance as causes for this abnormality. Although factors related to malignancy in general could partly account for the results, a specific factor occurring in patients with pancreatic carcinoma must also be considered as it could serve as a marker for the early detection of this disease.

Insulin resistance, acanthosis nigricans, and normal insulin receptors in a young woman: evidence for a postreceptor defect.

Abstract: We have previously described a group of young females with virilization, acanthosis nigricans, insulin resistance, and markedly decreased binding of insulin to its receptor (syndrome of insulin resistance and acanthosis nigricans type A). The present report concerns a 15-yr-old female with clinical features indistinguishable from the type A patients, including virilization, acanthosis nigricans, and extreme resistance to endogenous and exogenous insulin. Insulin levels were 400-650 microU/ml while fasting and were over 2200 microU/ml when stimulated. Proinsulin was less than 10% of the total immunoassayable insulin. In distinct contrast to the type A patients, insulin receptors on cells from this patient were entirely normal on the basis of specificity, negative cooperativity, affinity, concentration, and interaction with antiinsulin receptor antibodies. These findings suggest the presence of an intracellular defect as the cause of the observed insulin resistance.

Longitudinal study on the establishment of insulin resistance in hypothalamic obese mice.

Abstract: A longitudinal in vivo and in vitro analysis of the genesis of insulin resistance has been carried out in mice made obese by chemical lesion (goldthioglucose, GTG) of the hypothalamus. Six weeks after GTG administration, glycemia and glucose disposal were normal but associated with increased insulin concentration, suggesting incipient insulin resistance. The in vitro counterpart of the latter in obese mice was observed in soleus muscle that was somewhat less responsive to insulin than controls, in liver that had increased basal lipogenesis but was uninfluenced by insulin, and in hepatic plasma membranes in which a slight decrease of insulin binding was measured. At this stage of obesity, basal adipose tissue lipogenesis was increased but the tissue responded in a normal fashion to insulin. These relatively discrete early metabolic changes were corroborated in vivo by a normal hypoglycemic effect of exogenous insulin. Sixteen weeks after GTG administration, hyperglycemia and gross hyperinsulinemia were rec...

Pathogenesis of glucose intolerance in uremia

Abstract: The pathogenesis of glucose intolerance in uremia was examined with the glucose clamp technique. Hyperglycemic clamp ( n = 8): The plasma glucose concentration is acutely raised and maintained at 125 mg/dl above basal levels. Under these steady state conditions the glucose infusion rate, M , equals the amount of glucose metabolized: Predialysis M averaged 4.23 ± 0.36 mg/kg/min and increased to 7.71 ± 0.43 postdialysis ( p M/l ratio, a measure of tissue sensitivity to insulin, increased by 80% ± 25% ( p p n = 10): The plasma insulin concentration is acutely raised by 100 μU/ml and the plasma glucose concentration is held constant at the basal level. Predialysis both M (3.37 ± 0.36 mg/kg/min) and M/1 (3.56 ± 0.33 mg/kg/min per μU/ml X 100) were significantly less than controls ( p M and M/1 increased significantly ( p n = 6), 2.15 ± 0.09 mg/kg/min, was similar to controls and fell (87% ± 4%) normally during the insulin clamp. In five uremic subjects in whom insulin binding to monocytes was measured, there was no correlation with tissue sensitivity to insulin ( M/1 ). Significant abnormalities in both growth hormone and glucagon physiology were present in uremic individuals, but no correlation with either the presence or degree of glucose intolerance was demonstrable. In conclusion, glucose intolerance is universally present in uremic subjects and results primarily from peripheral tissue insensitivity to insulin. Insulin secretion is usually enhanced in an attempt to compensate for this insulin resistance but in occasional subjects uremia also inhibits beta cell sensitivity to glucose. Hepatic glucose production is unaffected by uremia. The lack of correlation between insulin binding and tissue sensitivity to insulin suggests that the cellular mechanism accounting for the insulin resistance is probably the result of a defect in intracellular metabolism or in the glucose transport system.

The Effects of Dietary Carbohydrate Content on Insulin Binding and Glucose Metabolism by Isolated Rat Adipocytes

Abstract: The effects of changes in the amount of dietary carbohydrate (CHO) on cellular insulin and glucose metabolism have been assessed in rat adipocytes. Feeding animals a 67% CHO (fat-free) diet resulted in decreased insulin binding but enhanced activity of both the glucose transport system and intracellular pathways of glucose metabolism. Feeding rats a 67% fat (CHO-free) diet resulted in decreased insulin receptors as well as decreased activity of the glucose transport system and intracellular glucose metabolism. Therefore, the in vivo insulin resistance caused by a high fat, low CHO diet seems to be adequately explained, since all aspects of insulin's cellular action were depressed. On the other hand, at first approximation, the increased in vivo insulin response caused by a high CHO diet appears contradictory to the observed decrease in insulin binding. However, a probable explanation for this apparent paradox is provided by the enhanced activity of the cellular insulin effector systems distal to the insulin receptor. Therefore, the increased in vivo insulin responsiveness after high CHO feedings is most likely due to post receptor increases in various aspects of glucose metabolism.

Insulin-dependent regulation of the insulin-sensitivity of adipocytes

Abstract: THE responsiveness of a target organ to insulin is evidently subject to regulation. This phenomenon is best demonstrated by the presence in man and animals of insulin-resistant states1–4. Since these states are usually accompanied by elevations in plasma insulin levels, a role for insulin in the modulation of insulin-sensitivity of target organs has been proposed4–6. Here we present direct evidence for ‘self-modulation’ by insulin of the insulin-sensitivity of adipocytes. The change in insulin-sensitivity occurs in conjunction with an alteration in the capability of the cells to bind insulin. However, it is not clear if this alteration contributes to the insulin resistance since the change in binding was detected only at relatively high concentrations of 125I-labelled insulin.

The Pathogenic Role of an Insulin-receptor Defect in Diabetes Mellitus of the Obese

Abstract: I-125-insulin binding to circulating monocytes was measured in 12 obese, maturity-onset diabetic patients, in 10 obese subjects, and in 12 normal persons The diabetic obese patients were extremely insulin resistant and had an impaired glucose tolerance, while the normoglycemic obese subjects were slightly insulin resistant and had borderline values of glucose tolerance The insulin secretion pattern of diabetic obese patients after a glucose load differed from that of the normal and normoglycemic obese subjects, showing a low initial response Insulin binding to monocytes from diabetic obese patients showed a 40 per cent decrease when compared with normal persons (p 01) In the total group of persons studied, the insulin binding correlated positively to both glucose tolerance (R = 069, p 01) After 10 days of treatment with a 1200-kcal diet the diabetic patients exhibited significant increases in glucose tolerance (p We conclude that a close correlation exists between insulin binding and insulin sensitivity in the three groups studied Among obese subjects the correlation was less pronounced (statistically insignificant) in diabetic obese persons, emphasizing that, especially in this group, there are other factors of importance for the insulin resistance in addition to the receptor defect

Kinetic Analysis of Plasma Insulin Disappearance in Nonketotic Diabetic Patients and in Normal Subjects: A TRACER STUDY WITH 125I-INSULIN

Abstract: The studies so far reported on the metabolic clearance rate of insulin in human diabetes mellitus have given conflicting results, probably because they have been conducted on few patients and have used a variety of experimental techniques and data treatments. We investigated the kinetics of insulin distribution and degradation in 35 normal subjects and in 42 nonketotic, nonobese, overtly diabetic patients, of whom 26 were above 40 yr old and 16 were 40 yr old or less at diagnosis. The design of the study combined (a) the use of a tracer to perturb minimally the steady state and to avoid glucose infusion; (b) the preparation of purified [(125)I]-monoiodoinsulin, which has a metabolic behavior similar to that of native insulin; and (c) noncompartmental analysis of the plasma immunoprecipitable (125)I-insulin disappearance curves, which were recorded for 2 h after pulse i.v. injection of the tracer.Metabolic clearance rate was found to be similar in diabetics (404+/-18 ml/min.m(2), mean+/-SEM) and in normals (420+/-14), although the latter-onset patients had slightly, if not significantly, lower metabolic clearance rate values than the earlier-onset diabetics (385+/-19 and 443+/-36, respectively). The initial distribution volume of the hormone also did not significantly differ in diabetics and normals and was similar to plasma volume. The reentry rate into the initial distribution volume of the hormone and the total, plasma-equivalent distribution volume of insulin were both significantly raised in diabetics (251+/-12 ml/min.m(2) and 10.3+/-0.5 liters/m(2)) in comparison with normals (195+/-8 and 7.5+/-0.3). The posthepatic delivery rate of insulin was found to be slightly raised in later-onset diabetics (194+/-20 mU/h.m(2)), but somewhat reduced in earlier-onset diabetics (133+/-15) in comparison with normals (172+/-14); these differences reflected the different basal plasma insulin concentrations in these three groups. Chronic treatment with oral hypoglycemic drugs, age, duration of the disease, and degree of metabolic control appeared to have only little effect on the kinetics of insulin.On the basis of these results, we conclude that insulin-independent adult diabetics show, already in the fasting state, a combination of insulin resistance and insulin deficiency and a derangement in insulin distribution, the precise significance of which is uncertain.

Insulin response in skeletal muscle and fat cells of the genetically obese Zucker rat

Abstract: Isolated fat cells derived from 10-wk-old Zucker obese rats utilized substantially greater amounts of glucose per cell in the presence or absence of insulin than those from lean rats. Initial rates of deoxyglucose or 3-0-methylglucose uptake in fat cells from Zucker obese rats were also 5–10 times greater than those observed in cells from lean rats. However, while 240 μU/ml insulin elicited a maximal response in fat cells from lean rats, this dose of hormone was only about 50% as effective as 24 mU/ml insulin in stimulating glucose metabolism or hexose transport in obese rat cells. This apparent rightward shift in the dose response-relationship could not be adequately explained on the basis of decreased insulin receptors since ( 125 I-) insulin binding per fat cell was increased 2.5-3-fold in obesity, while receptor density on the cell surface in obesity was decreased only slightly. Soleus muscles from obese Zucker rats exhibited decreased basal rates of D(5- 3 H)glucose conversion to glycogen and H 2 O compared to those of lean controls. While the percent increase in glucose metabolism due to a supermaximal dose of insulin was similar in soleus muscles of lean and obese Zucker rats, a blunted response to a submaximal insulin dose was observed in muscles from the latter animals. This rightward shift in the dose-response relationship was also observed when deoxyglucose uptake was monitored in soleus muscles from obese rats. Binding of ( 125 I-) insulin to soleus muscles at a medium concentration of 57 μU/ml was significantly decreased in obese compared to lean rats. We conclude that (1) fat cells do not contribute to the insulin resistance of 10-wk obese Zucker rats since glucose utilization is higher in these cells at all concentrations of insulin tested, (2) obese Zucker rat soleus muscle metabolism is defective in two respects—impaired basal glucose utilization and a rightward shift in the insulin dose-response relationship with respect to hexose transport, and (3) this latter defect involving decreased sensitivity of muscle to insulin appears to result from a marked decrease in cell surface receptors for the hormone.

Hyperinsulinemia in obesity syndromes: Its metabolic consequences and possible etiology

Abstract: Animal models with genetic or experimentally produced (lesions of hypothalamus) obesities are numerous and unlikely to ever be reduced to a single pathophysiologic entity. However, obese animals have many similar traits in common. They are all hyperinsulinemic, an abnormality that occurs early in the development of these syndromes and appears to be of prime importance in producing most of the metabolic changes observed both in the early and late phases of the obesity syndromes. In all instances, obesity is an evolutional syndrome in which the early phase is different from the later one. The early phase is principally characterized by increased hepatic very low density lipoprotein (VLDL) output, increased adipose tissue lipogenesis and VLDL uptake, hence, increased fat accretion and fat cell size. These abnormalities are secondary to hyperinsulinemia and can be reversed toward normal by normalizing circulating insulin levels. The late phase is characterized by the continuation of the disorders of the early one plus a superimposed abnormality, the insulin resistance state, that is detectable particularly at the level of adipose and muscle tissues, and eventually brings about hyperglycemia. Insulin resistance is a multifactorial pathological condition that includes at least: (a) a decrease (more or less marked) in insulin binding to target tissues that is responsible for the decrease in tissue sensitivity to the hormone; (b) intracellular defects that are probably responsible for the decreased insulin responsiveness of target tissues. The origin of hyperinsulinemia in animal obesities is still ill-defined. Lesions of the ventromedial hypothalamus (VMH) produce rapid and lasting hyperinsulinemia. Such lesions produce, in addition, increased secretion of insulin and glucagon and changes in pancreatic insulin, glucagon, and somatostatin content in subsequently perfused pancreases. The locus responsible for these effects is not defined and may actually involve a series of interrelated loci. Whatever the latter may be, one of the routes of CNS influence upon endocrine pancreas is the vagus nerve, although a humoral factor has also been claimed. The etiology of hyperinsulinemia in genetically obese animals is unknown. Genetic inheritance could bear primarily upon some hypothalamic or other CNS sites, with secondary alterations in the endocrine pancreas function, or primarily on the islets of Langerhans with possible alteration in the respective function of the A, B, and D cells with resulting excessive insulin secretion.

Decreased insulin sensitivity of forearm muscle in myotonic dystrophy.

Abstract: Previous studies of patients with myotonic dystrophy have demonstrated hyperinsulinism after glucose loading. This hyperinsulinism has been attributed by some investigators to tissue insulin resistance. We have directly studied insulin sensitivity of forearm muscle in patients having such hyperinsulinism. The effect of an intrabrachial arterial insulin infusion (100 mu U/kg per min) on glucose uptake was determined in six cases of myotonic dystrophy, six normal subjects, and in seven disease control subjects with myotonia or wasting from other disorders. There was no significant difference in insulin tolerance comparing myotonic dystrophy patients to the normal and disease control groups. Glucose tolerance and basal insulin levels were normal in the myotonic dystrophy patients, but hyperinsulinism occurred after glucose ingestion. After 25 min of intra-arterial insulin, the mean peak muscle glucose uptake in myotonic dystrophy was 2.54 +/- 0.54 mu mol/min per 100 ml forearm compared to 5.24 +/- 0.86 mu mol/min per 100 ml for disease controls (P is less than 0.05). Myotonic dystrophy patients showed a peak glucose uptake increment of only 2.6 +/- 0.2-fold over basal contrasted with the disease control value of 6.5 +/- 1.0-fold (P is less than 0.02) and the normal control value of 8.8 +/- 1.1-fold (P is less than 0.01). Thus, there was an absolute as well as a relative decrease in muscle insulin sensitivity in myotonic dystrophy patients compared to both control groups. The peak increments in arterio-superficial venous glucose concentration differences after insulin infusion were not significantly different comparing myotonic dystrophy and control groups. These data suggest that in myotonic dystrophy, there is insulin insensitivity of skeletal muscle.

Glucose, insulin, and somatostatin infusion for the determination of insulin sensitivity in vivo.

Abstract: Shen et al.1 and Reaven et al.2 have recently reported increased insulin resistance in adult-onset type diabetes based on the steady state plasma glucose (SSPG) method. In this method, epinephrine and propranolol were used to suppress endogenous insulin secretion. Epinephrine and propranolol themselves elevate SSPG levels.3 Also, plasma levels of growth hormone (HGH) and glucagon may not be suppressed under these conditions, since paradoxical rises or less suppressibility of HGH4 and glucagon5 following glucose loads have been reported in diabetic subjects. We have therefore used somatostatin, which has been shown to have no direct effect on glucose and lipid metabolism,6 to suppress endogenous secretion of insulin, glucagon, and HGH. Using the newly revised method, we have assessed insulin sensitivity in diabetics treated with diet alone, sulfonylureas, or insulin, and in obese nondiabetic subjects with hyperinsulinism.

Glucose Metabolism in Unipolar Depression

Abstract: Glucose utilization, serum insulin, human growth hormone, and free fatty acids were studied in 18 unipolar depressed patients and 14 normal controls, using the intravenous glucose tolerance test. Patients were kept drug-free for at least two weeks before testing, and physical activity and diet were carefully controlled. Previously described abnormalities in the balance between glucose and free fatty acids were not seen, but endogenous depression was associated with lowered glucose utilization rate with insulin resistance. Changes in kinetics of membrane transport in endogenous depression which could account for this finding are discussed.

Blood insulin responses to blood glucose levels in high output sepsis and septic shock

Abstract: To determine whether the secretion of insulin in severe sepsis is impaired as it is in hypovolemic shock, simultaneous determinations were made of cardiac output, blood glucose, insulin, alanine, and lactate in thirty-eight patients seriously infected with enteric and other organisms. Of these, seventeen were in the low output shock state with a mean cardiac index (CI) of 1.78 ± 0.48 L/M2/min. The remaining twenty-one were in the high output pattern characteristic of recovery with a mean cardiac index of 4.08 ± 0.82 L/M2/min. There were only modest differences within either group of any measured parameters dependent upon whether the patient was receiving an intravenous glucose infusion. However, in the whole group of patients with low CI the blood insulin was 9 ± 5 μU/ml, while in those with high CI the blood insulin was 38 ± 21 μU/ml. Cluster analysis gave a highly significant difference between the two groups with determinant weights: insulin, 77 per cent; glucose, 12 per cent; alanine, 9 per cent; and lactate, 2 per cent. For comparison with the normal insulin response, data derived from oral glucose tolerance tests in thirty-five healthy nondiabetic adults were employed. Analysis of the log10 insulin/log10 glucose ratios disclosed highly significant differences (p < 0.001) between the low CI and normal or high CI group. The difference between the high CI and normal was just significant (p < 0.05). It is concluded that both a slight reduction of insulin secretion and an insulin resistance are probably responsible for the pseudodiabetes observed in patients who are in the high CI pattern of recovery.

Anti-insulin receptor antibodies inhibit insulin binding and stimulate glucose metabolism in skeletal muscle

Abstract: Autoantibodies against the insulin receptor are found in the serum of some patients with severe insulin resistance. The effects of one of these sera on insulin binding and on glucose transport and metabolism were investigated in the isolated mouse soleus muscle. Preincubation of muscles with the patient's serum resulted in an inhibition of subsequent125I-insulin binding (half-maximal effect at 1∶500 dilution) and in a two to three-fold stimulation of glucose transport and metabolism (half-maximal effect at 1∶2000 dilution). The insulin-like effects were blocked by anti-human IgG, but not by antiinsulin antibodies. The magnitude of the serum effects on 2-deoxyglucose uptake and glycolysis was similar to that of insulin, but the effect on glycogen synthesis was smaller than that of insulin. It is suggested that the patient's serum and insulin promote glucose transport and glycolysis through a common pathway, but act differently on glycogen synthesis.

Immunologic Insulin Resistance

Abstract: The efficacy of sulfated beef insulin for plasma glucose control in 35 patients with immunologic insulin resistance was studied. Patients were on a mean dose of 550 U./day (range 200--2,000) of U-500 regular beef insulin. Mean maximum 125I-insulin-binding capacity was 191 mU./ml. serum (range 13--1,080). Mean in vivo half-life (T 1/2) of 125I-regular beef insulin was 614 minutes (range 114--1,300), as against a mean T 1/2 of 13.9 minutes (range 11.8--16.5) in normal controls. Treatment was successful in 34 patients and unsuccessful in one with lipoatrophic diabetes. The mean initial dose of sulfated insulin was 89 U./day (range 15--400) and at three months was 66 U./day (range 20--400). Twenty-eight patients who responded and survived have been on sulfated insulin for a mean of 39 months (range 2-66) and are on a mean dose of 25 U./day (range 0--100). The mean maximum binding capacity fell to 9 mU./ml. (range 0--34) during therapy (p less than 0.01). Mean 125I-insulin T 1/2 fell from 614 to 249 minutes after sulfated insulin therapy (p less than 0.001). A comparative study of 15 patients on consecutive days showed a 35 sulfated insulin T 1/2 of 60 minutes (range 15--94) and a mean 125I-regular insulin T 1/2 of 246 minutes (range 62--560, p less than 0.001). These results indicate that sulfated insulin is less antigenic than regular beef insulin and combines less avidly with human antibodies to regular beef insulin. The response to sulfated insulin therapy was significantly better than the response reported by other investigators to pork insulin or to steroid therapy in similar patients.

The Site of Insulin Resistance in Acute Uremia

Abstract: In order to define the mechanism of glucose intolerance in acutely uremic rats, various studies were carried out 24 hours after bilateral nephrectomy. Glucose removal following intravenous glucose was significantly ( p 600 μU./ml.) and threshold (75 μU./ml.) perfusate insulin levels. In contrast, there was a significant decrease in the ability of insulin (mean perfusate level = 225 μU./ml.) to enhance glucose uptake of perfused hindlimbs of uremic as compared with sham-operated rats. These results suggest that the insulin resistance of acute uremia may be due primarily to decreased insulin-mediated uptake of glucose by skeletal muscle without any decrease in sensitivity of the liver to insulin.

Insulin induced changes in insulin binding and insulin-sensitivity of adipocytes.

Abstract: The ability of insulin to regulate the insulin sensitivity of adipose tissue was directly studied by maintaining fat in Medium 199 for 17 hr in the presence or absence of the hormone (10.5 X 10−9M). Following this “chronic” treatment with insulin, the tissue was washed and the adipocytes isolated by collagenase treatment that removes essentially all of the insulin from the cells. The insulin responsiveness of the cells was then tested in “acute” 1–2 hr experiments and the results correlated with their ability to specifically bind 125I-labeled insulin. “Chronic” insulin treatment did not change the basal glucose transport rate as measured by 2-deoxyglucose uptake. Also, the maximum insulin-stimulated rate of 2-deoxyglucose uptake in the “acute” experiments was similar for both chronically insulin-treated and untreated cells. In these experiments, the only difference noted between the two groups of adipocytes was in their response to submaximally stimulating concentrations of insulin. Insulin-treated cells required approximately three times the amount of insulin to produce half-maximal stimulation of 2-deoxyglucose uptake than the amount needed by the untreated cells. “Chronic” insulin treatment also produced an alteration in the high affinity interaction between the fat cells and 151-labeled insulin. This alteration was characterized by a decrease in insulin binding at low concentrations of the labeled hormone, while at higher concentrations the binding was similar to that of untreated cells. These results show that a high concentration of insulin can produce insulin resistance in fat cells by causing a rightward shift in the insulin dose-response curve. Furthermore, this change in hormonal sensitivity may be a consequence of the insulin-induced decrease in the insulin binding ability of the fat cells.

Prolonged sulfonylurea administration decreases insulin resistance and increases insulin secretion in non-insulin-dependent diabetes mellitus: evidence for improved insulin action at a postreceptor site in hepatic as well as extrahepatic tissues

Abstract: To determine whether long-term sulfonylurea therapy ameliorates glucose homeostasis in patients with NIDDM predominantly by improving insulin secretion or by improving insulin action, we evaluated changes in fasting plasma glucose concentrations, intravenous glucose tolerance, glucose-stimulated insulin secretion, facilitation of glucose disposal by exogenous insulin, and erythrocyte insulin receptor binding before and after prolonged (congruent to 4 mo) administration of tolazamide to 18 patients with NIDDM. Before tolazamide administration, 15 patients had decreased insulin secretion (50 +/- 31 vs 577 +/- 176 microU/ml X 10 min in nondiabetic subjects, P less than 0.05) and insulin resistance (Km 166 +/- 31 vs 58 +/- 3 microU/ml in nondiabetic subjects, P less than 0.05; Vmax 7.3 +/- 0.6 vs 9.8 +/- 0.2 mg/kg/min in nondiabetic subjects, P less than 0.05), whereas the other three patients had comparably impaired insulin secretion (56 +/- 52 microU/ml X min) but were not insulin resistant (Km 70 +/- 6 microU/ml; Vmax 10.8 +/- 0.6 mg/kg/min). The insulin-resistant patients had fasting hyperinsulinemia (19 +/- 4 vs 11 +/- 1 microU/ml in nondiabetic subjects, P less than 0.05), decreased erythrocyte insulin receptor binding (4.8 +/- 0.4 vs 5.8 +/- 0.3%/1.6 X 10(9) cells in nondiabetic subjects, P less than 0.05), and impairment in both insulin-induced suppression of glucose production (Km 97 +/- 31 vs 21 +/- 7 microU/ml in nondiabetic subjects, P less than 0.05), and insulin-induced stimulation of glucose utilization (Km and Vmax 176 +/- 29 microU/ml and 5.8 +/- 0.7 mg/kg/min vs 50 +/- 2 microU/ml and 9.1 +/- 0.6 mg/kg/min in nondiabetic subjects, both P less than 0.05). The nonresistant patients were not hyperinsulinemic (12 +/- micU/ml), had normal insulin receptor binding (5.9 +/- 0.5%/1.6 X 10(9) cells), and were less hyperglycemic than the insulin-resistant patients (128 +/- 11 vs 181 +/- 12 mg/dl, P less than 0.05). After tolazamide administration, both the early phase of glucose-induced insulin secretion (56 +/- 52 vs 141 +/- 68 microU/ml . 10 min) and insulin binding (5.9 +/- 0.5 vs 7.0 +/- 0.5%/1.6 X 10(9) cells) increased in all three nonresistant patients, but there was no consistent improvement in fasting hyperglycemia (128 +/- 11 vs 130 +/- 24 mg/dl), intravenous glucose tolerance (Kivgtt 0.77 +/- 0.18 vs 0.89 +/- 0.29%/min), or facilitation of glucose disposal by insulin (Km 70 +/- 5 vs 64 +/- 5 microU/ml; Vmax 10.8 +/- 0.6 vs 10.1 +/- 0.2 mg/kg/min).(ABSTRACT TRUNCATED AT 400 WORDS)

Acidemia and insulin resistance in the diabetic ketoacidotic rat.

Abstract: Insulin sensitivity with respect to changes in blood glucose, lactate, and ketone body concentrations has been studied in normal and streptozotocin-diabetic rats. Insulin was infused at doses ranging from 0.03 to 100 U/kg/hr and dose response curves established. Maximal responsiveness was achieved at 1 U/kg/hr for glucose and 0.3 U/kg/hr for ketone bodies in normal rats. In diabetic rats, responsiveness and sensitivity were directly proportional to pH. When pH was less than 6.9, there was little or no response. Ammonium chloride administration to normal rats or to mildly acidotic diabetic rats caused almost total loss of responsiveness to insulin. The insulin insensitivity found in severely acidemic diabetic rats could be reversed by sodium bicarbonate adminstration. Liver and muscle metabolite patterns suggested that loss of responsiveness and sensitivity was due both to effects at the insulin receptor and direct effects on glycolysis, presumptively at phosphofructokinase. Reversal of these changes with bicarbonate was associated with a fall in hepatic ATP content. It is suggested that the insulin resistance of severe diabetic ketoacidosis in the rat is secondary to inhibitory effects of hydrogen ion; the exact mechanism remains to be established.

The role of insulin resistance in the pathogenesis of diabetes mellitus.

Abstract: Publisher Summary This chapter discusses the role of insulin in the pathogenesis of diabetes in man. The situation is clearest in patients classified as having chemical diabetes. These individuals are not insulin deficient—their plasma insulin response to an oral glucose load is in absolute terms at least equal to that of normal individuals at all time intervals measured. Insulin is not as effective in promoting glucose uptake in these patients as in normal subjects. Insulin resistance exists in diabetics, and hyperglycemia in these patients cannot result solely because of a lack of insulin. The cause of the insulin resistance is theoretically because of secretion of abnormal forms of insulin, circulating insulin antagonists, or cellular unresponsiveness to the action of insulin. These issues are the focus of extensive investigation in many laboratories.

Effects of antiinsulin receptor autoantibody on the metabolism of rat adipocytes.

Abstract: We have studied the effects of the serum from a patient with an unusual form of diabetic syndrome with extreme insulin resistance on the metabolism of rat adipocytes in vitro. This serum and IgG fractions from it inhibited the [125I]insulin binding to isolated adipocytes and stimulated the 2-deoxyglucose uptake, glucose oxidation, and the incorporation of amino acids into protein. In addition, these fractions inhibited the lipolysis induced by β1-24 ACTH in isolated adipocytes. The insulin-like effects of this serum and the effects of insulin were not additive at their maximal concentrations. The inhibition of [125I]insulin binding was due to a decrease in receptor affinity rather than to a change in receptor number by Scatchard plot analysis. Both the inhibition of insulin binding and the insulin-like effects on rat adipocytes were neutralized by antihuman IgG. In addition, these insulin-like effects were abolished by trypsin treatment of adipocytes. These facts suggest that this serum has a circulating ...