Fasting Immunoreactive Insulin Levels Research Articles

Insulin resistance and type 2 diabetes mellitus risk factors in systemic lupus erythematosus

Objective. To clarify the frequency of insulin resistance (IR) in patients with systemic lupus erythematosus (SLE), traditional and associated with rheumatic disease risk factors for its development, to assess the possibility of using the Finnish Type 2 Diabetes Risk Assessment Score (FINDRISC) questionnaire to detect IR.Material and methods. The cross-sectional study included 49 patients with SLE (46 women, 3 men) without diabetes mellitus and hyperglycemia, observed at the V.A. Nasonova Research Institute of Rheumatology in 2019–2020. The median age of the patients was 40 [33; 48] years, the duration of the disease was 3.0 [0.7; 8.0] years. Glucocorticoids (GC) were received by 41 (84%) patients, hydroxychloroquine – by 38 (78%), immunosuppressive drugs – by 10 (20%), biological agents – by 5 (10%). The glucose and fasting immunoreactive insulin levels were examined, and the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) index was calculated in all patients. HOMA-IR value ≥2.77 corresponded to IR. Traditional risk factors for type 2 diabetes and the risk of its development in the next 10 years in patients with SLE were assessed using the Russian version of the FINDRISC questionnaire.Results. The median HOMA-IR level in SLE patients was 1.7 [1.2; 2.5]. IR was detected in 10 (20%) of 49 patients with SLE. Patients with and without IR were comparable in terms of sex, age, duration and activity of SLE, therapy, and type 2 diabetes traditional risk factors. BMI, WC and insulin levels were higher in patients with IR. HOMA-IR correlated with body mass index (BMI) (r=0.6; p<0.001), waist circumference (WC) (r=0.5; p<0.001), risk categories for developing type 2 diabetes according to FINDRISС (r=0.3; p=0.03), SLEDAI-2K index (r=–0.4; p<0.01), C3 complement levels in serum (r=0.3; p=0.04) and the duration of GC therapy (r=0.3; p=0.03).Conclusion. IR was diagnosed in 20% of SLE patients without a history of diabetes and with normal fasting glucose in venous blood. The lower SLE activity, the longer GC intake in patient, the higher the HOMA-IR index was detected in him. However, the IR appearance was reliably associated only with an increasing BMI and WC. The use of the FINDRISC questionnaire, which allows to stratify respondents in the general population by the risk of developing type 2 diabetes mellitus, did not help to identify SLE patients with IR.

Insulin deficiency promotes formation of toxic amyloid-β42 conformer co-aggregating with hyper-phosphorylated tau oligomer in an Alzheimer's disease model

The toxic conformer of amyloid β-protein (Aβ) ending at 42 (Aβ42), which contains a unique turn conformation at amino acid residue positions 22 and 23 and tends to form oligomers that are neurotoxic, was reported to play a critical role in the pathomechanisms of Alzheimer's disease (AD), in which diabetes mellitus (DM)-like mechanisms are also suggested to be operative. It remains to be established whether the attenuation of insulin signaling is involved in an increase of toxic Aβ42 conformer levels. The present study investigated the association between impaired insulin metabolism and formation of toxic Aβ42 conformers in the brains of an AD mouse model. In particular, we studied whether insulin deficiency or resistance affected the formation of toxic Aβ42 conformers in vivo. We induced insulin deficiency and resistance in 3xTg-AD mice, a mouse AD model harboring two familial AD-mutant APP (KM670/671NL) and PS1 (M146 V) genes and a mutant TAU (P301L) gene, by streptozotocin (STZ) injection and a high fructose diet (HFuD), respectively. Cognitive impairment was significantly worsened by STZ injection but not by HFuD. Dot blot analysis revealed significant increases in total Aβ42 levels and the ratio of toxic Aβ42 conformer/total Aβ42 in STZ-treated mice compared with control and HFuD-fed mice. Immunostaining showed the accumulation of toxic Aβ42 conformers and hyper-phosphorylated tau protein (p-tau), which was more prominent in the cortical and hippocampal neurons of STZ-treated mice compared with HFuD-fed and control mice. HFuD-fed mice showed only a mild-to-moderate increase of these proteins compared with controls. Toxic Aβ42 conformers were co-localized with p-tau oligomers (Pearson's correlation coefficient = 0.62) in the hippocampus, indicating their co-aggregation. Toxic Aβ42 conformer levels were inversely correlated with pancreatic insulin secretion capacity as shown by fasting immunoreactive insulin levels in STZ-treated mice (correlation coefficient = −0.5879, p = .04441), but not HFuD-fed mice, suggesting a decrease in serum insulin levels correlates with toxic Aβ42 conformer formation. Levels of p-Akt and phosphorylated glycogen synthase kinase-3β measured by a homogeneous time-resolved fluorescence assay were significantly lower in STZ-treated mice than in HFuD-fed mice, suggesting a greater inhibition of brain insulin signaling by STZ than HFuD, although both levels were significantly decreased in these groups compared with controls. Iba1-positive and NOS2-positive areas in the cortex and hippocampus were significantly increased in STZ-treated mice and to a lesser extent in HFuD-fed mice compared with controls. These findings suggest that insulin deficiency rather than insulin resistance and the resultant impairment of brain insulin signaling facilitates the formation of toxic Aβ42 conformer and its co-aggregation with p-tau oligomers, and that insulin deficiency is an important pathogenic factor in the progression of AD.

The Efficacy of Testosterone Ointment on Insulin Resistance in Men with Metabolic Syndrome

Low levels of testosterone are related with metabolic syndrome and type 2 diabetes mellitus. Testosterone levels are considered to be negatively correlated with insulin resistance and HbA1c levels. There are also reports that testosterone replacement therapy reduces insulin resistance or improves glycemic control. Transdermal administration of testosterone ointment (Glowmin) is a method of drug administration that keeps blood concentrations stable and constant. In this study, testosterone ointment (Glowmin) was administrated as a testosterone supplement to male metabolic syndrome with low free testosterone levels. This study included 5 male metabolic syndrome with low free testosterone levels (mean age, 50.6 ± 8.8 years; mean BMI, 29.5 ± 3.1 kg/m2; mean waist circumference, 97 ± 7 cm; free testosterone levels, <8.5 pg/ml; values indicate means ± SD). Glowmin was administrated to the submandibular area at a dose of 0.3 g twice a day for 6 months. Three months after administration, a significant decrease was observed in fasting immunoreactive insulin levels, homeostasis model assessment for insulin resistance, total cholesterol and LDL-C. Six-months after administration, each of these parameter estimates remained steady. In conclusion, transdermal administration of testosterone ointment (Glowmin) gradually reduced insulin resistance in male metabolic syndrome with low free testosterone levels.

Interleukin-6 as an Independent Predictor of Future Cardiovascular Events in Patients with Type-2 Diabetes without Structural Heart Disease

Background: An increased serum interleukin-6 (IL-6) level is associated with a risk of cardiovascular disease. Elevated IL-6 levels are also involved in the pathogenesis of insulin resistance and can predict the development of type-2 diabetes. We tested the hypothesis that elevated IL-6 levels can predict the incidence of cardiovascular events in type-2 diabetes. Methods: Eighty-two patients with type-2 diabetes without structural heart disease (48 males; 60 ± 12 years). The initial onset of a major adverse cardiovascular event was investigated. Results: During a mean of 3.4 ± 2.0 years of follow-up, 11 patients developed cardiovascular events (3 cardiovascular deaths, 2 non-fatal myocardial infarctions, 2 coronary revascularizations, and 4 strokes). Univariate analyses revealed that elevated IL-6 level, fasting immunoreactive insulin level, and the HOMA-R were associated with cardiovascular events. Based on multivariate analyses, elevated IL-6 levels independently predicted the incidence of cardiovascular events (HR 1.17, 95% CI 1.04–1.31, P=0.015). Kaplan–Meier curves revealed that patients with a high IL-6 concentration (>2.6 pg/mL) had a higher incidence of cardiovascular events than those with non-high IL-6 concentration (≤2.6 pg/mL, P=0.031). Conclusions: These results suggest that measurement of serum IL-6 concentration is a useful tool to identify high-risk patients for cardiovascular events in type-2 diabetes.

Angiotensin II type 1 receptor blockers improve insulin sensitivity in patients with schizophrenia being treated with olanzapine

Olanzapine (OLZ) is known to cause weight gain and metabolic disturbances, which may have serious implications with respect to medical comorbidities such as metabolic syndrome and insulin resistance. The aim of this study was to evaluate the effects of two angiotensin II type 1 receptor blockers (ARBs) which are widely used as antihypertensive agents, valsartan (VAL) and telmisartan (TEL), on insulin resistance in patients with schizophrenia treated with OLZ. Thirty inpatients with schizophrenia with OLZ monotherapy over 8 weeks participated in this study. To assess insulin resistance, the homeostasis model assessment of insulin resistance (HOMA-IR), fasting plasma glucose (PG) levels and immunoreactive insulin (IRI) levels were measured [HOMA-IR = fasting PG level (mmol/L) x fasting IRI level (μU/ml)/22.5]. VAL add-on treatment was performed in insulin-resistant patients (HOMA-IR > 1.6) for 12 weeks. After a 12-week VAL washout period, TEL add-on treatment was carried out for 12 weeks. The effects of ARBs on insulin resistance and other metabolic variables were assessed. In all 30 patients, both body mass index and abdominal circumference were strongly correlated with HOMA-IR. Twelve patients showed high HOMA-IR and were deemed to be insulin resistant. Add-on therapy of VAL and TEL resulted in a significant decrease in fasting IRI levels and HOMA-IR. No differences in any effects were observed between VAL and TEL. No adverse effects of either ARBs were observed in this study. ARBs for patients treated with OLZ improved insulin sensitivity and attenuated insulin resistance.

THE ROLE OF TUMOR NECROSIS FACTOR‐ALPHA IN COGNITIVE IMPROVEMENT AFTER PEROXISOME PROLIFERATOR‐ACTIVATOR RECEPTOR GAMMA AGONIST PIOGLITAZONE TREATMENT IN ALZHEIMER'S DISEASE

To the Editor: Some clinical trials have shown that agonists of the nuclear receptor peroxisome proliferator-activator receptor gamma (PPRAγ) improve cognition and memory in patients with Alzheimer's disease (AD).1,2 A pilot study demonstrated that 6 months of treatment with a PPARγ agonist, pioglitazone, improved cognition and hyperinsulinemia in patients with mild AD with type II diabetes mellitus,3 although the reason for these benefits is not fully understood. In animal models of AD, pioglitazone treatment resulted in the reduction of numbers of activated microglia associated with a lower plaque burden, partly by suppressing proinflammatory gene expression.4 The aim of the present study was to investigate the role of inflammatory-associated proteins in the improvement of cognition after pioglitazone treatment in patients with mild AD. A 6-month, randomized, open-controlled trial was conducted in patients with mild AD associated with type II diabetes mellitus. Thirty-four patients with probable AD5 were randomly assigned to treatment with pioglitazone 15 mg daily (n=17, pioglitazone group) or not (n=17, control group). Twenty-six of these patients were included in a 2009 study3 of patients with mild AD. The study protocol has been described elsewhere in detail.3 In this study, plasma cytokines, including tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), and high-sensitivity C-reactive protein (hs-CRP), were quantified at baseline and Month 6 using commercially available enzyme-linked immunoassays and nephrometry, respectively. The minimum detectable concentrations were 0.5 pg/mL, 0.2 pg/mL, and 0.02 mg/dL, respectively. Values were expressed as means ± standard deviations. Statistical analysis was performed using the Student t-test, chi-square test, Mann-Whitney U test, Wilcoxon signed-rank test, and Spearman rank correlation test. Table 1 shows comparisons of subject characteristics and Alzheimer's Disease Assessment Scale Cognitive Subscale, Japanese version (ADAS-Jcog) scores, plasma cytokines, and hs-CRP changes. There were no significant differences between the pioglitazone group and the control group in terms of age, sex, education, duration of symptoms, Mini-Mental State Examination (MMSE) score, apolipoprotein E ɛ4 status, or prevalence of use of donepezil. At baseline, no significant differences were found in ADAS-Jcog scores, plasma cytokines, or hs-CRP levels between the groups. At Month 6, ADAS-Jcog scores had decreased significantly in the pioglitazone group and increased significantly in the control group. There was a significant difference between the groups in ADAS-Jcog score changes (Month 6–baseline). When compared with baseline values, TNF-α, IL-6, and hs-CRP levels at Month 6 decreased in the pioglitazone group, whereas they increased in the control group, but no statistically significant change in either value was found in the two groups. There was a significant difference in TNF-α level changes (Month 6–baseline) between the groups. Changes in ADAS-Jcog scores significantly correlated with changes in TNF-α (correlation coefficient (r)=0.38, P=.04) but not in IL-6 (r=0.19) and hs-CRP levels (r=0.14). During the study, both groups showed stable fasting plasma glucose and hemoglobin A1c levels. When compared with baseline, fasting immunoreactive insulin levels at Month 6 decreased significantly in the pioglitazone group (from 7.8 ± 3.9 to 5.7 ± 2.4 μU/mL, P<.05) but not in the control group (from 6.7 ± 4.8 to 6.5 ± 2.9 μU/mL). It was found that reduction of TNF-α levels after pioglitazone treatment was associated with cognitive improvement. A previous study found that PPARγ agonists inhibit Aβ production stimulated by inflammatory cytokines.6 Proinflammatory cytokine TNF-α, which plays a role in immune system to brain communication, contributes to an exacerbation of neurodegeneration by microglial activation. A recent study showed that high serum TNF-α is associated with long-term cognitive decline in community-dwelling subjects with AD.7 An increase in TNF-α regulates synaptic scaling and results in disease progression in AD.8 Therefore, treatment to reduce TNF-α levels might provide some therapeutic benefits for AD. Although a number of studies have examined potential mechanisms through which PPARγ might act to ameliorate AD pathogenesis and progression, the anti-inflammatory action of PPARγ agonists is at least one plausible explanation for the beneficial effect on AD. Conflict of Interest: The editor in chief has reviewed the conflict of interest checklist provided by the authors and has determined that the authors have no financial or any other kind of personal conflicts with this paper. Author Contributions: Haruo Hanyu: study concept and design, acquisition of subjects and data, analysis and interpretation of data, and preparation of letter. Tomohiko Sato, Hirofumi Sakurai, and Toshihiko Iwamoto: acquisition of subjects and data analysis. Sponsor's Role: None.

Reduced pancreatic B cell compensation to the insulin resistance of aging: impact on proinsulin and insulin levels.

Type 2 diabetes mellitus is associated with insulin resistance, reduced B cell function, and an increase in the proinsulin (PI) to immunoreactive insulin (IRI) ratio (PI/IRI); the latter is thought to be an indication of B cell dysfunction. Normal aging is associated with insulin resistance and reduced B cell function, but it is not known whether changes in PI and the PI/IRI ratio are also a feature of the aging-associated B cell dysfunction. Therefore, we tested whether the aging-associated changes in insulin sensitivity and B cell function result in changes in PI and IRI levels that are proportionate or whether they are disproportionate as in type 2 diabetes. Twenty-six healthy older (mean +/- SEM age, 67 +/- 1 yr) and 22 younger (28 +/- 1 yr) subjects with similar body mass indexes (27.9 +/- 0.6 vs. 26.3 +/- 1.0 kg/m2) were studied. PI was measured by a RIA recognizing both intact PI and its conversion intermediates. The insulin sensitivity index (SI) was quantified using the minimal model, and B cell function was measured as fasting insulin levels, the acute insulin response to glucose (AIRglucose), and as the acute insulin response to arginine at maximal glycemic potentiation (AIRmax). B cell function was also adjusted for SI based on the known hyperbolic relationship between these two variables. Older and younger subjects had similar fasting glucose (5.3 +/- 0.1 vs. 5.2 +/- 0.1 mmol/L), IRI (83 +/- 8 vs. 76 +/- 9 pmol/L), PI (8.9 +/- 0.8 vs. 10.6 +/- 2.0 pmol/L), and PI/IRI ratio (12.3 +/- 1.3% vs. 13.9 +/- 1.6%; all P = NS) despite a 50% reduction of insulin sensitivity (SI, 1.94 +/- 0.21 vs. 3.88 +/- 0.38 x 10(-5) min(-1)/pmol x L; P < 0.001) and in B cell function [SI x fasting IRI, 139 +/- 18 vs. 244 +/- 24 x 10(-5)(P < 0.001); SI x AIRglucose, 0.75 +/- 0.13 vs. 1.70 +/- 0.15 x 10(-2) min(-1) (P < 0.001); SI x AIRmax, 3.63 +/- 0.53 vs. 6.81 +/- 0.70 x 10(-2) min(-1) (P < 0.001)] in the older subjects. These findings suggest that the B cell dysfunction in older subjects is not associated with disproportionate proinsulinemia. However, in older subjects the B cell response to the insulin resistance of aging is reduced whether measured as fasting levels of PI or IRI or as the acute response to secretagogues. Thus, when examined in terms of the degree of insulin sensitivity, the lower fasting IRI levels in older subjects suggest that the utility of fasting insulin levels as a surrogate measure of insulin resistance in older individuals may be limited.

Hyperinsulinemia increases the risk of gestational hypertension

Objective: To determine whether hyperinsulinemia is related to gestational hypertension. Methods: We measured the arterial blood pressure and the level of immunoreactive insulin (IRI) during a 75 g oral glucose tolerance test in a total of 84 pregnant women. Hyperinsulinemia was defined as a fasting IRI level ≥ 9 IU/1, while gestational hypertension was defined as arterial blood pressure ≥ 140 90 mmHg. Results: The incidence of gestational hypertension was higher in the hyperinsulinemic group ( n = 29) than in the control group ( n = 55) (24.1% vs. 7.3%, respectively P < 0.05). After controlling for maternal age, parity, pre-pregnancy body mass index and the gestational age at the time of oral glucose tolerance test (OGTT), using a multiple regression model, the relative risk of developing gestational hypertension for a fasting insulin level was 1.19 (95% C.I., 1.03 – 1.38). Conclusion: Pregnant women with hyperinsulinemia are at increased risk of developing gestational hypertension.

EFFECTS OF HYPERINSULINAEMIA ON RENAL FUNCTION AND THE PRESSOR SYSTEM IN INSULIN‐RESISTANT OBESE ADOLESCENTS

1. In the present study, using the euglycaemic hyperinsulinaemic glucose clamp technique, we investigated the effects of hyperinsulinaemia on sodium-water metabolism and the pressor system in obesity, both of which have been reported to be closely associated with insulin resistance and/or hyperinsulinaemia. 2. Sixteen obese young subjects and 24 non-obese young subjects who were all normotensives, participated in this study. The 2 h euglycaemic hyperinsulinaemic glucose clamp was performed in a fasting state. The mean glucose infusion rate needed to maintain a fasting blood sugar level (FBS) during the last 30 min of the clamp was used as an indicator of insulin sensitivity (M-value). Before and after the clamp, the following parameters were measured: creatinine clearance (Ccr); urinary excretion of sodium (UNaV); fractional excretion of sodium (FENa); plasma renin activity (PRA); plasma aldosterone concentration (PAC) and plasma noradrenaline concentration (PNA). 3. The M-value was significantly lower in obese subjects compared with non-obese subjects, although FBS and fasting immunoreactive insulin levels were similar in both groups. UNaV and FENa fell only in obese subjects during the clamp, while Ccr showed no significant change in either group. PNA and PRA increased significantly and PAC tended to increase in both groups. 4. These results suggest that obese subjects have insulin resistance with respect to glucose metabolism, but that urinary sodium excretion and the pressor system remain insulin-sensitive; the sensitivity of the sodium retaining action to hyperinsulinaemia was actually higher in obese subjects than in non-obese subjects. Therefore, if compensatory endogenous hyperinsulinaemia was raised by insulin resistance, these two factors may lead to chronic sodium retention and pressor system stimulation and, in turn, to hypertension in obesity.

Effects of chromium supplementation on fasting insulin levels and lipid parameters in healthy, non-obese young subjects

Trivalent chromium is an essential trace element for normal carbohydrate metabolism and insulin sensitivity. Because of this biological activity, chromium supplementation has been studied as a potential therapy of insulin resistant states and dyslipidemias, and has been promoted as a health aid to the general population. To determine if there is a risk of subclinical chromium deficiency in young, otherwise healthy adults, we evaluated the effect of chromium supplementation, versus placebo, on insulin levels and serum lipids in a double-blind, randomized trial in 26 young adults (mean age 36 years). Fasting levels of glucose, immunoreactive insulin (IRI), and lipids (total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides) were measured before and after 90 days of daily supplementation with a chromium (III)-nicotinate preparation, containing 220 μg elemental chromium, or placebo. There were no statistically significant differences in the percentage change of fasting glucose, IRI or lipids between the chromium ( n = 15) and placebo ( n = 11) groups after 90 days of supplementation. However, those individuals within the chromium group with initial fasting IRI levels greater than 35 pmol/l had a significant decrease in IRI level after supplementation ( P < 0.03) despite no significant changes in serum lipids. These subjects may benefit from chromium supplementation by improving insulin sensitivity and cardiovascular risk over time.

Noninvasive Quantitative Evaluation of Early Atherosclerosis and the Effect of Monatepil, a New Antihypertensive Agent An Interim Report

In two studies on the same group of patients we evaluated noninvasive methods of assessing atherosclerosis and determined the effect of the new calcium channel-blocking agent monatepil on the progression of early atherosclerosis in humans. Computed tomography (CT) of the lower abdominal aorta and ultrasonography of the carotid arteries were used as noninvasive methods to determine the extent of atherosclerosis. To evaluate the CT images, we developed a new medical image analysis program. This enabled aortic calcification volume (ACV) to be quantified using plain CT images, and aortic wall volume (AWV) and aortic wall and calcification volume (AWCV) to be quantified from contrast CT images. Interobserver coefficients of variation of ACV, AWV, and AWCV (n = 8) were 4.7, 2.4, and 5.0%, respectively. In the monatepil study, the effect of the drug on serum lipid profiles was evaluated. Preliminary results show that shortly after monatepil administration, total serum cholesterol levels decreased significantly from 253.8 +/- 35.6 to 244.8 +/- 38.6 mg/dL (P < .009) and triglyceride levels tended to decrease. A positive correlation between the change in total cholesterol and changes in mean platelet volume was found (P = .028). Fasting immunoreactive insulin levels decreased in the four patients in which they were determined. Although this is a preliminary study, results indicate that CT of the lower abdominal aorta in combination with our new analysis program may be a precise, reproducible means of assessing early atherosclerosis. We have also shown that monatepil significantly decreases total cholesterol levels. However, the long-term effects of monatepil on the progression of atherosclerosis remain to be determined.

Insulin modulates circulating endothelin-1 levels in humans

Recent data indicate that insulin stimulates synthesis of the vasoconstrictor peptide endothelin-1 (ET-1) by cultured vascular endothelial cells in vitro. To determine whether insulin modulates ET levels in vivo and whether this effect is important in the pathogenesis of obesity-associated hypertension, we measured circulating immunoreactive ET-1 levels during euglycemic hyperinsulinemic clamps (20 mU/m 2 · min −1 for 120 minutes) in eight obese women (body mass index, 36 ± 1 kg/m 2) before and after 10 weeks on an 800-kcal/d protein-sparing liquid diet. During the clamp that preceded weight loss, insulin levels were increased from 17 ± 2 to 51 ± 3 mU/L and this was associated with an increment in ET-1 level from 28 ± 3 to 33 ± 3 pg/mL ( P < .05). After weight loss, insulin levels were increased from 10 ± 2 to 47 ± 3 mU/L during the clamp, and there was a corresponding increase in ET-1 levels from 24 ± 3 to 30 ± 3 pg/mL ( P < .025). The reduction in basal ET-1 level (from 28 ± 3 to 24 ± 3 pg/mL) with weight loss correlated strongly with the reduction in fasting immunoreactive insulin level (from 17 ± 2 to 10 ± 2 mU/L; r = .92, P < .01). The decrease in blood pressure with weight loss from 130 ± 6 73 ± 3 to 118 ± 4 72 ± 3 mm Hg) did not correlate with the corresponding reduction in circulating ET-1 levels. These results indicate that insulin modulates ET-1 levels in vivo. The importance of hyperinsulinemia-induced secretion of ET in the pathogenesis of hypertension remains to be established.

Insulin resistance in polycystic ovary syndrome

Patients with polycystic ovary syndrome (PCO) who are obese and exhibit acanthosis nigricans have been reported to have insulin resistance. We studied 21 euglycemic, euprolactinemic patients with PCO without acanthosis nigricans. Eleven of these patients were hirsute and the remaining 10 were not. Eight women with chronic anovulation, who were weight matched with the PCO patients, were studied along with the 11 ovulatory control subjects. Compared to control subjects, women with chronic anovulation had similar levels of immunoreactive luteinizing hormone (LH), bioactive LH, 17β-estradiol, testosterone (T), and dehydroepiandrosterone sulfate but significantly higher fasting immunoreactive insulin levels (p < 0.05). The nonhirsute patients with PCO had higher immunoreactive insulin levels compared to patients with chronic anovulation and control subjects (p < 0.05) while hirsute patients with PCO had higher immunoreactive insulin levels than nonhirsute ones (p < 0.05). There was a significant positive correlation between fasting immunoreactive insulin levels and serum. T. Fasting immunoreactive insulin also showed a significant correlation with serum LH and bioactive LH. After receiving 100 gm of oral glucose, hirsute patients with PCO had significantly higher insulin responses compared to those of control subjects despite similar glucose responses. Red blood cell insulin-binding sites and receptor affinities were similar in hirsute patients and control subjects. These data suggest that the hyperinsulinemia of patients with PCO may be related, in part, to the elevated LH and androgen levels and may be a postreceptor defect.

Serum insulin, insulin antibodies and insulin requirement in the first period of insulin treatment in non-insulin resistant diabetics.

Twelve insulin-sensitive diabetics were studied for 200 days after the initiation of mixed beef-pork NPH insulin. Normalization of the fasting blood glucose was not accompanied by any elevation in the pre-treatment fasting immunoreactive insulin level. Insulin antibodies appeared in 2 patients on the second week of insulin treatment, in 6 others within 87 days. In 4 patients no antibodies were found 200 days after the start of insulin. The appearance of antibodies was accompanied in two patients by a decrease in insulin requirement, in others there was no change. When antibodies were present, the total maximum insulin binding capacity was 4 to 12 U/l, but the total insulin constituted only 3 to 36% of the binding capacity. Insulin wastage caused by the destruction of the immune complexes was calculated to be 0.35 to 5.6 U/die only, and this explains the negligible effect of insulin antibodies on insulin requirement in non-resistant patients.

High- and low-carbohydrate diets in diabetes mellitus. Study of effects on diabetic control, insulin secretion, and blood lipids.

Eighteen diabetic patients not dependent on insulin, given diets high in carbohydrate (60%, 25% fat) or relatively low in carbohydrate (40%, 45% fat), were followed for 40 weeks as outpatients in a group-oriented educational program. Diabetic control was measured by the fasting and postprandial blood sugar levels and quantitative and qualitative urine-sugar tests. Glucose-insulin relationships were evaluated by measuring fasting immunoreactive insulin levels and by intravenous and oral glucose tolerance tests and a modified insulin infusion test after each 20-week diet period. Despite the increased carbohydrate load, control of diabetes and insulin secretory capacity were maintained. Serum cholesterol values were not altered by the change in dietary fat, and the high carbohydrate intake did not increase mean levels of serum triglycerides. The data suggest a seasonal trend for both serum cholesterol and triglycerides.

Studies in congenital generalized lipodystrophy (Seip-Berardinelli syndrome). I. Development of diabetes.

ABSTRACT Six cases of congenital generalized lipodystrophy have been studied at different ages from infancy to adolescence with regard to glucose tolerance, insulin secretion, and insulin sensitivity. During the first few years of life there is normal glucose tolerance. The fasting immuno-reactive insulin (IRI) levels are either slightly elevated or normal. The IRI response to glucose is exaggerated and prolonged, at least from the third year of life. Some degree of insulin resistance is already present in infancy. From the age of 8–10 years glucose tolerance decreases rapidly. The fasting IRI levels are usually grossly elevated, while fasting plasma glucose levels are only moderately elevated or normal. The IRI responses to oral and iv administered glucose, and to tolbutamide are exaggerated; the insulinogenic indices are high. Cortisone primed glucose tolerance tests become abnormal. Insulin resistance is marked, and increases with age. After cessation of growth at approximately 12 years of age, frank diabetes with fasting hyperglycaemia and diabetic glucose tolerance curves developed in the one patient followed beyond this age. Her fasting IRI was increased, but there was a poor IRI response to glucose stimulation, suggesting a partial exhaustion of the β-cells. Her initial IRI response to tolbutamide was still good, but not as brisk as in the younger patients. This type of diabetes is quite different from the juvenile form, and also from the diabetes of older age. It may be causally related to the lack of an adequate adipose organ necessary for the disposal of excesses of glucose, or possibly related to another anti-insulin mechanism.

Insulin levels in thyrotoxicosis and primary myxoedema: response to intravenous glucose and glucagon.

Glucose disappearance, insulin-like activity (ILA) and serum immunoreactive insulin (IRI) were studied after intravenous injection of glucose or glucagon in patients suffering from thyrotoxicosis or primary myxoedema. A group of normal subjects was also investigated. Glucose disappearance rate appeared to be normal in hyperthyroid, and markedly reduced in hypothyroid subjects. Fasting ILA levels were significantly higher than normal in myxoedema, and lower than normal in thyrotoxicosis. On the other hand, fasting IRI levels were higher than normal in myxoedema but normal in thyrotoxicosis. After glucose administration ILA in myxoedema remained at higher values than in thyrotoxicosis at any time of the study; in myxoedema, peak ILA levels were reached later than in thyrotoxicosis; peak IRI levels of similar magnitude were reached slightly earlier than normal in thyrotoxicosis, and later in myxoedema; in the latter condition, elevated IRI levels were observed for a longer period than in either euthyroidism or hyper-thyroidism. During this test the insulingogenic index showed only slight changes in normal and in thyrotoxic subjects, whereas it increased significantly up to 60 min in myxoedema. The data indicate that the reduced glucose utilization in hypothyroidism is not due to insulin deficiency, but rather to insulin resistance. It also seems possible that thyroid function influences the time of maximal insulin response to intravenous glucose administration. After glucagon injection, the increase in blood glucose was lower and shorter than normal in thyrotoxicosis; it was initially somewhat slower, but later higher and more sustained than normal, in myxoedema. The smaller increment in blood glucose in the former condition is probably connected with reduced glycogen stores. ILA response was very high and well sustained in myxoedema, whereas it was moderate and shortlasting in thyrotoxicosis. IRI response was higher than normal in hypothyroid subjects, and lower than normal in thyrotoxic subjects. No difference in the time required for maximal response was observed among the three groups.