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Thiazolidinediones have proven efficacy in preventing diabetes in high-risk individuals. However, the effect of thiazolidinediones on glucose tolerance after cessation of therapy is unclear.To examine the effect of pioglitazone (PIO) on incidence of diabetes after discontinuing therapy in ACT NOW. Design, Settings and Patients: Two-hundred ninety-three subjects (placebo [PLAC], n = 138; PIO, n = 152) completed a median followup of 11.7 mo after study medication was stopped.Diabetes developed in 138 (12.3%) of PLAC vs 17 of 152 PIO patients (11.2%; P = not significant, PIO vs PLAC). However, the cumulative incidence of diabetes from start of study medication to end of washout period remained significantly lower in PIO vs PLAC (10.7 vs 22.3%; P.005). After therapy was discontinued, 23.0% (35/152) of PIO-treated patients remained normal-glucose tolerant (NGT) vs 13.8% (19/138) of PLAC-treated patients (P = .04). Insulin secretion/insulin resistance index (I0-120/G0-120 × Matsuda index) was markedly lower in subjects with impaired glucose tolerance (IGT) who converted to diabetes during followup vs those who remained IGT or NGT. The decline in-cell function (insulin secretion/insulin resistance index) was similar in subjects with IGT who developed diabetes, irrespective of whether they were treated with PIO or PLAC.1) The protective effect of PIO on incidence of diabetes attenuates after discontinuation of therapy, 2) cumulative incidence of diabetes in individuals exposed to PIO remained significantly (56%) lower than PLAC and a greater number of PIO-treated individuals maintained NGT after median followup of 11.4 mo, and 3) low insulin secretion/insulin resistance index is a strong predictor of future diabetes following PIO discontinuation.

The objective was to test the clinical utility of Quantose M(Q) to monitor changes in insulin sensitivity after pioglitazone therapy in prediabetic subjects. Quantose M(Q) is derived from fasting measurements of insulin, α-hydroxybutyrate, linoleoyl-glycerophosphocholine, and oleate, three nonglucose metabolites shown to correlate with insulin-stimulated glucose disposal.Participants were 428 of the total of 602 ACT NOW impaired glucose tolerance (IGT) subjects randomized to pioglitazone (45 mg/d) or placebo and followed for 2.4 years. At baseline and study end, fasting plasma metabolites required for determination of Quantose, glycated hemoglobin, and oral glucose tolerance test with frequent plasma insulin and glucose measurements to calculate the Matsuda index of insulin sensitivity were obtained.Pioglitazone treatment lowered IGT conversion to diabetes (hazard ratio = 0.25; 95% confidence interval = 0.13-0.50; P.0001). Although glycated hemoglobin did not track with insulin sensitivity, Quantose M(Q) increased in pioglitazone-treated subjects (by 1.45 [3.45] mg·min(-1)·kgwbm(-1)) (median [interquartile range]) (P.001 vs placebo), as did the Matsuda index (by 3.05 [4.77] units; P.0001). Quantose M(Q) correlated with the Matsuda index at baseline and change in the Matsuda index from baseline (rho, 0.85 and 0.79, respectively; P.0001) and was progressively higher across closeout glucose tolerance status (diabetes, IGT, normal glucose tolerance). In logistic models including only anthropometric and fasting measurements, Quantose M(Q) outperformed both Matsuda and fasting insulin in predicting incident diabetes.In IGT subjects, Quantose M(Q) parallels changes in insulin sensitivity and glucose tolerance with pioglitazone therapy. Due to its strong correlation with improved insulin sensitivity and its ease of use, Quantose M(Q) may serve as a useful clinical test to identify and monitor therapy in insulin-resistant patients.

It is unknown whether intensive lifestyle modification (ILS) or metformin changes sex steroids among premenopausal women without a history of polycystic ovarian syndrome (PCOS).We examined 1-year intervention impact on sex steroids (estradiol, testosterone, dehydroepiandrosterone, and androstenedione [A4]) and SHBG and differences by race/ethnicity.A subgroup of Diabetes Prevention Program participants who were premenopausal, not using estrogen, without a history of PCOS or irregular menses, and who reported non-Hispanic white (NHW), Hispanic, or African-American race/ethnicity (n = 301).Randomization arms were 1) ILS with the goals of weight reduction of 7% of initial weight and 150 minutes per week of moderate intensity exercise, 2) metformin 850 mg twice a day, or 3) placebo.Neither intervention changed sex steroids compared to placebo. ILS, but not metformin, increased median SHBG by 3.1 nmol/L (~11%) compared to decreases of 1.1 nmol/L in the placebo arm (P.05). This comparison remained significant after adjustment for changes in covariates including waist circumference. However, associations with glucose were not significant. Median baseline A4 was lower in Hispanics compared to NHWs (5.7 nmol/L vs 6.5 nmol/L, P.05) and increases in A4 were greater in Hispanics compared to NHWs (3.0 nmol/ vs 1.2 nmol/L, P.05), and these differences did not differ significantly by intervention arm. No other racial/ethnic differences were significant.Among premenopausal glucose-intolerant women, no intervention changed sex steroids. ILS increased SHBG, although associations with glucose were not significant. SHBG and sex steroids were similar by race/ethnicity, with the possible exception of lower baseline A4 levels in Hispanics compared to NHWs.

Objective: Increased free fatty acids (FFAs) are leading candidates in the pathogenesis of insulin resistance and hypertension in obese subjects. We evaluated the effect of sustained elevations of FFA on blood pressure, endothelial function, insulin secretion, inflammatory markers, and renin-angiotensin system. Research Design and Methods: Twenty-four obese, African-American, normotensive diabetic subjects received a sequential 48-h infusion of Intralipid (20%, 40 ml/h) plus heparin (250 units/h) or normal saline (40 ml/h) plus heparin (250 units/h). Results: Blood pressure was significantly increased within 4 h of lipid infusion and reached a peak increment of 13 mm Hg in systolic and 5 mm Hg in diastolic blood pressure at 24 h (P < 0.01). Compared to baseline, lipid infusion reduced flow-mediated dilatation by 11% at 24 h and 18% at 48 h (P < 0.001). FFA and triglyceride levels increased from a baseline of 0.5 ± 0.2 mmol/liter and 135 ± 76 mg/dl to 1.8 ± 1.0 mmol/liter and 376 ± 314 mg/dl at 48 h, respectively (P < 0.01). C-Reactive protein increased by 35% at 24 h and by 110% at 48 h of lipid infusion. There were no significant changes in plasma renin and aldosterone levels during lipid or saline infusions. Conclusion: Increased FFA levels result in a rapid and sustained elevation in blood pressure, impaired endothelial function, and increased inflammatory markers in obese subjects with type 2 diabetes. The model of FFA-induced hypertension may be useful in examining disease mechanisms associated with the development of hypertension in obese subjects.

Context: Insulin resistance is an important feature of type 2 diabetes. Ectoenzyme nucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) inhibits insulin signaling, and a recent meta-analysis reported a nominal association between the Q allele in the K121Q (rs1044498) single nucleotide polymorphism in its gene ENPP1 and type 2 diabetes. Objective and Intervention: We examined the impact of this polymorphism on diabetes incidence as well as insulin secretion and sensitivity at baseline and after treatment with a lifestyle intervention or metformin vs. placebo in the Diabetes Prevention Program (DPP). Design, Setting, Participants, and Outcome: We genotyped ENPP1 K121Q in 3548 DPP participants and performed Cox regression analyses using genotype, intervention, and interactions as predictors of diabetes incidence. Results: Fasting glucose and glycated hemoglobin were higher in QQ homozygotes at baseline (P < 0.001 for both). There was a significant interaction between genotype at rs1044498 and intervention under the dominant model (P = 0.03). In analyses stratified by treatment arm, a positive association with diabetes incidence was found in Q allele carriers compared to KK homozygotes [hazard ratio (HR), 1.38; 95% confidence interval (CI), 1.08–1.76; P = 0.009] in the placebo arm (n = 996). Lifestyle modification eliminated this increased risk. These findings persisted after adjustment for body mass index and race/ethnicity. Association of ENPP1 K121Q genotype with diabetes incidence under the additive and recessive genetic models showed consistent trends [HR, 1.10 (95% CI, 0.99–1.23), P = 0.08; and HR, 1.16 (95% CI, 0.92–1.45), P = 0.20, respectively] but did not reach statistical significance. Conclusions: ENPP1 K121Q is associated with increased diabetes incidence; the DPP lifestyle intervention eliminates this increased risk.

Admission hyperglycemia has been associated with increased hospital mortality in critically ill patients; however, it is not known whether hyperglycemia in patients admitted to general hospital wards is associated with poor outcome. The aim of this study was to determine the prevalence of in-hospital hyperglycemia and determine the survival and functional outcome of patients with hyperglycemia with and without a history of diabetes. We reviewed the medical records of 2030 consecutive adult patients admitted to Georgia Baptist Medical Center, a community teaching hospital in downtown Atlanta, GA, from July 1, 1998, to October 20, 1998. New hyperglycemia was defined as an admission or in-hospital fasting glucose level of 126 mg/dl (7 mmol/liter) or more or a random blood glucose level of 200 mg/dl (11.1 mmol/liter) or more on 2 or more determinations. Hyperglycemia was present in 38% of patients admitted to the hospital, of whom 26% had a known history of diabetes, and 12% had no history of diabetes before the admission. Newly discovered hyperglycemia was associated with higher in-hospital mortality rate (16%) compared with those patients with a prior history of diabetes (3%) and subjects with normoglycemia (1.7%; both P < 0.01). In addition, new hyperglycemic patients had a longer length of hospital stay, a higher admission rate to an intensive care unit, and were less likely to be discharged to home, frequently requiring transfer to a transitional care unit or nursing home facility. Our results indicate that in-hospital hyperglycemia is a common finding and represents an important marker of poor clinical outcome and mortality in patients with and without a history of diabetes. Patients with newly diagnosed hyperglycemia had a significantly higher mortality rate and a lower functional outcome than patients with a known history of diabetes or normoglycemia.

The objective of this study was to define the relationship among the circulating insulin level (IRI), the MCR of dehydroepiandrosterone (MCR-D), and the production rate of DHEA (PR-D) in 10 women with the polycystic ovary syndrome and acanthosis nigricans (PCOS-AN). Seven normal weight and 10 obese women served as controls. Measurement of the MCR-D and PR-D was accomplished by iv saline infusion (0.9% NaCl solution) on day 1 as a control and a 4-h iv dehydroepiandrosterone (unlabeled) infusion (1 mg/h) was performed on day 2. Mean MCR-D was more than 2-fold higher in the obese controls compared to the normal weight controls. However, the plasma concentration of DHEA(PC-D) was not significantly different in the normal and obese control women, since the PR-D was increased proportionately to the MCR-D. The MCR-D and the PR-D were coupled through insulin in the control women, and their correlation coefficients with IRI were positive and identical (0.77 and 0.73, respectively). In contrast, IRI was negatively correlated with PR-D in the PCOS-AN women. Also, unlike the control women, there was minimal or no change in the MCR-D across a broad range of IRI in the PCOS-AN women. Thus, the MCR-D and PR-D were not coupled in these women.

We have studied the effects of 3 days of hydrocortisone (30 mg every 8 h), dexamethasone (1 mg every 8 h), and prednisone (7.5 mg every 8 h) ingestion on glucose intolerance and insulin resistance in three groups of lean normal volunteers and compared these parameters to specific insulin binding in erythrocytes. All three glucocorticoids caused significant reduction of glucose tolerance as assessed by glucose and insulin areas under oral glucose tolerance text curves and insulin sensitivity in response to 0.1 U insulin/kg BW, iv. Although both hydrocortisone and dexamethasone caused significant reduction in insulin binding compared to that during the pretreatment period (11.0 +/- 0.7 vs. 9.0 +/- 0.5% (P less than 0.01) and 11.8 +/- 0.7 vs. 9.0 +/- 0.5% (P less than 0.05), respectively), prednisone ingestion did not significantly alter insulin binding (10.6 +/- 0.6 before vs. 9.4 +/- 0.5% after). Decreased insulin binding with hydrocortisone and dexamethasone was caused by decreased binding affinity rather than by a decreased number of receptors. In two subjects in whom receptor binding was measured daily for 3 days during prednisone (one subject) or hydrocortisone (one subject) ingestion, the inhibition of binding was highest on the first day, with subsequent reduction of this inhibited binding toward normal by the third day. We conclude that although hydrocortisone, dexamethasone, and prednisone all cause deterioration of glucose tolerance and decreased insulin sensitivity, only hydrocortisone and dexamethasone exhibit significant decreases in insulin binding to erythrocytes. This decreased binding is not due to changes in receptor numbers but to decreased affinity brought about by hyperinsulinemia. Prednisone ingestion caused significant insulin resistance with an insignificant decrease in insulin binding. We believe that other mechanisms, such as alteration of postreceptor events, may play a major role in the induction of insulin resistance in hypercortisolism in man.

We studied insulin binding to erythrocytes in eight male type I diabetic patients in diabetic ketoacidosis (DKA) before and 24 h and 5 days after low dose insulin treatment. Mean specific [125I]insulin binding in DKA (mean +/- SEM, 13.3 +/- 0.6%) was significantly higher than values 24 h and 5 days after treatment (10.7 +/- 0.7% and 9.6 +/- 0.4%, respectively; P less than 0.001). These values after treatment were similar to those of 15 age-matched normal males (10.5 +/- 0.4%) and 6 controlled type I diabetic patients (10.1 +/- 0.7%). The affinity constant (Ka = 2.26 +/- 0.12 10(9) M-1) was significantly higher in DKA patients than in normal subjects (1.75 +/- 0.15 10(9) M-1) or type I controlled diabetics (1.55 +/- 0.15 10(9) M-1; P less than 0.01). Insulin binding correlated inversely with arterial pH (r = -0.80; P less than 0.001; n = 8). These results indicate an increase in specific [125I]insulin binding to erythrocytes in DKA, which is due to elevated receptor affinity (but not receptor numbers) and is reversible with treatment.

A 25-year-old obese woman with adult onset diabetes, with known insulin allergy, was evaluated for her insulin response to glucagon. Intravenous injection of glucagon produced severe generlaized allergic reaction. Skin tests with various insulin and glucagon preparations showed allergic reaction to be most pronounced with beef regular single peak and single component insulin, pork regular single peak, beef lente single peak, and neutral regular (beef-pork) single peak insulin. Allergic reactions to numerous glucagon preparations were found to be directly proportional to the amount of insulin contamination in those preparations. Purification of one glucagon lot by column chromatography verified the presence of proinsulin and insulin contaminants in the preparation.

Because of the impression obtained from our population with sickle cell anemia that there were no cases of diabetics, a study was conducted to investigate the prevalence of diabetes mellitus in: 1) 186 cases of pregnant black patients with sickle cell disease (HbS-S, S-C, or S-Thal) or HgA-S with random and 2-h postprandial blood glucose (compared to 2263 matched control patients); 2) a study of the hemoglobin pattern in 280 consecutive cases of nonpregnant black patients with confirmed diabetes mellitus in our outpatient clinic; and 3) a review of the records of 711 patients with sickle cell disease in our Sickle Cell Center with performance of a 100-g oral glucose tolerance test on 5 patients with random plasma glucose greater than 120 mg/dl. These studies showed: 1) there were no diabetics in pregnant black patients as compared to a 4% incidence of abnormal glucose tolerance in a control, matched population; 2) there were no cases of sickle cell disease in the diabetic population; and 3) there...

We have studied insulin degrading activity (IDA) in cultured human fibroblasts and assessed the effect of various inhibitors of insulin processing on IDA. To evaluate the role of three enzymes of insulin degradation (neutral protease, microsomal glutathione insulin transhydrogenase, and lysosomal acid protease), we subfractionated homogenized fibroblasts into membrane (and nuclei) cytosol, mitochondria, microsomes, and lysosomes. Greater than 90% of IDA was found to be present in the cytosolar fraction containing neutral protease. IDA in intact fibroblasts was completely inhibited by 1 mM N-ethylmaleimide and partially by 0.5 mM dansylcadaverine (75%), 0.5 mM chloroquine (48%), 1 mg/ml bacitracin (32%) and Trasylol (30%). Lidocaine (5 mM) and glucagon (10(-6)M) exhibited about 15% inhibition with minimal inhibition (7%) by nonsuppressible insulin-like activity. Study of similar inhibitors on subfractionated components indicated inhibition of cytosolar enzyme by N-ethylmaleimide (100%), glucagon (30%), chloroquine (41%), nonsuppressible insulin-like activity (30%), Lidocaine (25%), dansylcadaverine (16%), and bacitracin (11%). Incubation of ammonium sulfate-fractionated cytosolar enzyme at 37 C with A14-125I-insulin resulted in generation of two intermediate peaks as early as 1 min. These peaks could be identified by HPLC but not by molecular sieve chromatography. These intermediates exhibited less immunoprecipitability with antiinsulin antibody and receptor binding with liver membrane preparations than intact insulin. Further incubation of A14-125I-insulin with the cytosolar enzyme(s) resulted in reduction of these peaks as well as insulin and formation of 125Iodotyrosine peak. We conclude that human fibroblast is capable of metabolizing cell-associated A14-125I-insulin in a time- and temperature-dependent manner. This process is inhibited by various inhibitors of insulin processing. The bulk of IDA consists of soluble neutral protease(s) with properties similar to other more purified neutral insulin protease preparations. This fraction, similar to the intact fibroblast degrades insulin to two intermediates with similar molecular weight to that of intact insulin but with more hydrophilicity and less binding affinity to antiinsulin antibody and liver membrane than intact insulin.

We evaluated basal plasma total immunoreactive insulin (insulin), androstenedione, and testosterone in 14 obese women: 8 with polycystic ovarian disease (PCOD) and 6 obese controls. All 3 hormones were significantly elevated (P less than 0.02 to P less than 0.001) in PCOD patients. A significant correlation among basal levels of plasma insulin, androstenedione, and testosterone was demonstrated. The PCOD group had significantly higher levels of glucose at 1, 2, and 3 h, with similar significant increases in plasma insulin levels at 0, 2, and 3 h. A significant correlation was found between plasma insulin response areas and plasma testosterone (P less than 0.001) in the control and PCOD patients. These studies demonstrate that hyperandrogenism correlates with hyperinsulinism.

INSULIN degradation is a complex and incompletely, understood process at present. In terms of overall clearance and metabolism, the liver is responsible for more than half of the total insulin degradation, with kidney responsible for most of the rest. The peripheral tissues, fat and muscle, probably degrade the remainder of the insulin in the body, but the absolute contribution of these tissues to insulin turnover is uncertain. It now appears that peripheral tissues can serve as a reservoir for insulin, presumably by the hormone binding reversibly to membrane receptors. The function of this remains to be established. At a cellular level in most tissues, insulin degradation is initiated by the hormone binding to specific receptors. The hormone-receptor complex is processed, including internalization and degradation of at least some of the hormone-receptor complexes. The enzyme or enzymes involved in the degradative process have not been established, but three systems have been implicated: insulin protease,...

We previously reported that circulating beta-endorphin levels are increased in obese hirsute women and that plasma immunoreactive insulin (IRI) levels are increased in proportion to the degree of hyperandrogenism in women with the polycystic ovary (PCO) syndrome. We, therefore, tested the hypothesis that endogenous opiates are at least partially responsible for the hyperinsulinemia and insulin resistance in this syndrome. In the first study, acute naloxone administration significantly reduced the plasma IRI response and IRI/glucose ratio in three euglycemic obese women with PCO and acanthosis nigricans (AN) and marked insulin resistance, but did not alter the glucose response. Naloxone had no effect on these parameters in the normal weight control subjects. In the second study, nalmefene, a new, orally active opiate antagonist, reduced IRI and the IRI/glucose ratio in four women with PCO-AN and marked hyperinsulinemia in a randomized, double blind, crossover protocol. We conclude that endogenous opiates are at least partially responsible for the hyperinsulinemia and insulin resistance in PCO-AN.

Eight patients with rheumatoid arthritis were studied before and after 3 months of treatment with 20 mg of cortisol per day. A significant decrease in the urinary excretions of epinephrine and catecholamines in response to insulin hypoglycemia was seen after therapy. Adrenal cortical function was suppressed by the exogenous cortisol as measured by 8:00 AM plasma cortisol and by cortisol response to hypoglycemia. These data support the concept that in man, as in animals, full activity of phenylethanolamine N methyl transferase requires high levels of corticosteroids bathing the adrenal medulla. Suppression of endogenous corticosteroid production decreases the activity of this epinephrine forming enzyme and thereby results in a decrease in epinephrine production and excretion.

The administration of aminoglutethimide (AG) to rats and dogs significantly increased activity of phenylethanolamine-Nmethyl transferase in the adrenal. This stimulation occurred in spite of decreased adrenal and plasma corticosteroid levels. A significant stimulation was also noted in hypophysectomized rats treated with AG as well as in rats treated with large doses of dexamethasone. These findings suggest that the stimulatory effect of AG on PNMT is not mediated through the pituitary adrenal cortical axis. The increase in activity was noted as early as 24 hr after AG administration. No evidence of diurnal variation in this enzyme was demonstrated in rats. (Endocrinology 88: 384, 1971)

Electron microscopic studies of isolated rat adrenal cells, prepared by trypsin digestion, showed that this preparation consisted of more than 90% of fasciculata cells and less than 10% reticularis, glomerulosa and medullary cells. Morphological studies of isolated adrenal cells after incubation with and without ACTH or dibutyryl cAMP (dcAMP) showed that: a) the cell membrane remained intact with minimal amount of mitochondrial swelling; b) ACTH or dcAMP caused few morphological changes discernible by the electron microscope; and c) no significant depletion of the lipid globules occurred in response to ACTH or dcAMP in spite of active time dependent corticosterone synthesis. Chemical analysis of endogenous cholesterol and cholesterol ester, as well as analysis of pulse labeled endogenous total cholesterol, revealed no significant decrease of cholesterol in response to ACTH or dcAMP. Studies on cholesterol synthesis from labeled mevalonic acid suggested that an additional action of ACTH may be the regulati...

The role of endogenous adrenocorticotropin (ACTH) and adrenal glucocorticoids in the control of insulin secretion was studied in 12 normal human volunteers. They were given oral glucose (100 g) tolerance tests before and after administration of metyrapone for 24 hr. Their serum insulin response to oral glucose was significantly less after metyrapone administration than before. The insulin response to intravenous glucose and intravenous tolbutamide, however, was not affected by metyrapone administration. In 6 normal subjects, an ACTH infusion, with and without a glucose load, did not increase blood insulin levels but a significant degree of glucose intolerance was evident 2–3 hr after oral glucose loading. In 2 untreated cases of Addison's disease, the insulin response to oral glucose (but not intravenous glucose) was delayed but was increased after physiologic doses of cortisol. It is suggested that adrenocorticotropin does not affect insulin secretion in man and that physiologic levels of glucoc...

A soluble hepatic enzyme which preferentially cleaves insulin has been isolated from the 100,000 X g supernatant of rat liver. This enzyme was purified 97–fold by ultracentrifugation, Ca3(PO4)2 gel adsorption—elution, Sephadex G-200 filtration and DEAE-Sephadex A–50 chromatography. The enzyme was estimated to have a mol wt of 80,000 by its behavior on Sephadex G-200. The Km for insulin degradation was found to be 0.10μ.M. In fractionated liver homogenate, the 100,000 X g supernatant was found to be responsible for 96% of the total insulin degrading activity. The remaining 4% of activity was in the debris, mitochondrial and microsomal fractions. The enzyme exhibited a relatively narrow pH range with the optimum activity occurring at pH 7.6. The enzyme was shown to be proteolytic and independent of glutathione (GSH) for enzymatic activity. Marked specificity for insulin degradation was found as indicated by a 15–fold greater rate of insulin destruction over that for proinsulin. Human growth hormone was not ...

A 65-year-old deaf mute presented with clinical and laboratory evidence of ascorbic acid deficiency. He responded promptly to vitamin C administration, but adrenal cortical function tests revealed a complete lack of adrenal reserve. After being lost to follow-up for over a year, repeat adrenal evaluation again revealed normal baseline corticosteroid levels but no response to ACTH. Although no specific complaints could be elicited prior to therapy, hydrocortisone treatment resulted in an improvement in his clinical status.