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OBJECTIVE: Islet autoimmunity, age at onset and time to insulin treatment are often used to define subgroups of diabetes. However, the latter criterion is not clinical useful. Here, we examined whether an unbiased stratification of diabetes according to age at onset, fasting C-peptide and GAD autoantibodies (GADab) defines groups with differences in glycaemic control and markers of cardiometabolic risk.DESIGN AND METHODS: A cohort of 4,374 adults with relatively newly diagnosed diabetes referred to a Danish hospital during 1997-2012 was stratified according to age at onset above or below 30 years, fasting C-peptide above or below 300 pmol/l (CPEPhigh or CPEPlow), and presence or absence of GADab (GADpos or GADneg). HbA1c, BMI, blood pressure (BP), lipid profile, alanine aminotransferase (ALT) and creatinine were evaluated.RESULTS: GADab were present in 13% of the cohort. Age at onset was not associated with major differences between groups. Patients with insulin deficient diabetes (CPEPlow; n=503) had higher HbA1c but otherwise lower cardiometabolic risk (lower BMI, BP, LDL, triacylglycerol, and ALT, and higher HDL) than both patients with latent autoimmune diabetes of adults (LADA defined as GADposCPEPhigh; n=327) and patients with type 2 diabetes (GADnegCPEPhigh; n=3,544). Patients with LADA defined an intermediate group with higher HbA1c but otherwise lower cardiometabolic risk than patients with type 2 diabetes.CONCLUSIONS: Our results demonstrate that fasting C-peptide and GADab status, but not age at onset, define groups of patients with diabetes with clinically relevant differences in glycaemic control and cardiometabolic risk.

BACKGROUND: Insulin analogues have been developed to reduce the risk of hypoglycaemia in patients with diabetes who require insulin-based treatment, but their effect on this endpoint in patients with type 1 diabetes complicated by recurrent severe hypoglycaemia is unknown. We compared the occurrence of severe hypoglycaemic episodes in such patients during treatment with insulin analogues or human insulin. METHODS: In this investigator-initiated, prospective, randomised, open-label, blinded-endpoint crossover trial at seven medical centres in Denmark, we recruited patients (aged ≥18 years) with type 1 diabetes (diagnosed for >5 years) who had reported two or more episodes of severe hypoglycaemia in the preceding year. Patients were randomly assigned (1:1) using computer-generated site-specific randomisation lists in blocks of four to treatment with basal-bolus therapy with either analogue insulin (detemir and aspart) or human insulin (human neutral protamine Hagedorn and human regular) in a balanced crossover design. A 1-year plus 1-year treatment period was specified, consisting of two 3-month run-in periods, each followed by a 9-month maintenance period. The primary endpoint was the number of validated episodes of severe hypoglycaemia (defined by need for treatment assistance from others) reported during the maintenance periods, analysed by intention to treat. The study is registered with ClinicalTrials.gov, number NCT00346996. FINDINGS: Between May 9, 2007, and Oct 30, 2009, 159 patients were randomly assigned. 18 patients discontinued during the first run-in period, leaving 141 patients in the intention-to-treat population. 136 severe hypoglycaemic episodes were reported during treatment with human insulin and 105 episodes were reported during treatment with insulin analogues, resulting in an absolute rate reduction of 0.51 episodes (95% CI 0.19-0.84) per patient-year with insulin analogues. This result corresponds to a relative rate reduction of 29% (95% CI 11-48; p=0.010). INTERPRETATION: Treatment with insulin detemir and aspart in patients with type 1 diabetes and recurrent severe hypoglycaemia resulted in a clinically significant reduced rate of severe hypoglycaemia compared with human insulin. Patients with the greatest chance of benefitting from improved insulin therapy should be offered treatment with insulin analogues and be included in future trials of new insulins. BACKGROUND: Insulin analogues have been developed to reduce the risk of hypoglycaemia in patients with diabetes who require insulin-based treatment, but their effect on this endpoint in patients with type 1 diabetes complicated by recurrent severe hypoglycaemia is unknown. We compared the occurrence of severe hypoglycaemic episodes in such patients during treatment with insulin analogues or human insulin.METHODS: In this investigator-initiated, prospective, randomised, open-label, blinded-endpoint crossover trial at seven medical centres in Denmark, we recruited patients (aged ≥18 years) with type 1 diabetes (diagnosed for >5 years) who had reported two or more episodes of severe hypoglycaemia in the preceding year. Patients were randomly assigned (1:1) using computer-generated site-specific randomisation lists in blocks of four to treatment with basal-bolus therapy with either analogue insulin (detemir and aspart) or human insulin (human neutral protamine Hagedorn and human regular) in a balanced crossover design. A 1-year plus 1-year treatment period was specified, consisting of two 3-month run-in periods, each followed by a 9-month maintenance period. The primary endpoint was the number of validated episodes of severe hypoglycaemia (defined by need for treatment assistance from others) reported during the maintenance periods, analysed by intention to treat. The study is registered with ClinicalTrials.gov, number NCT00346996.FINDINGS: Between May 9, 2007, and Oct 30, 2009, 159 patients were randomly assigned. 18 patients discontinued during the first run-in period, leaving 141 patients in the intention-to-treat population. 136 severe hypoglycaemic episodes were reported during treatment with human insulin and 105 episodes were reported during treatment with insulin analogues, resulting in an absolute rate reduction of 0.51 episodes (95% CI 0.19-0.84) per patient-year with insulin analogues. This result corresponds to a relative rate reduction of 29% (95% CI 11-48; p=0.010).INTERPRETATION: Treatment with insulin detemir and aspart in patients with type 1 diabetes and recurrent severe hypoglycaemia resulted in a clinically significant reduced rate of severe hypoglycaemia compared with human insulin. Patients with the greatest chance of benefitting from improved insulin therapy should be offered treatment with insulin analogues and be included in future trials of new insulins.FUNDING: Novo Nordisk A/S.

Objectives The study sought to determine the prognostic importance of left atrial (LA) dilation in patients with type 2 diabetes mellitus (T2DM) and no history of cardiovascular disease (CVD). Background T2DM is associated with the development of CVD, and morphological changes in the heart may appear before symptoms arise. Methods A total of 305 T2DM patients without known CVD referred to a diabetes clinic were included consecutively (age 58.6 ± 11.3 years, diabetes duration 2.0 [interquartile range: 0 to 6.0] years). Each patient underwent a comprehensive echocardiogram and a myocardial perfusion scintigraphy (MPS) at inclusion. Patients were divided according to left atrial volume index (LAVi) ≥32 ml/m2. Patients were followed for median of 5.6 (interquartile range: 5.1 to 6.1) years for the occurrence of major cardiac events and death. Results LAVi ≥32 ml/m2 was found in 105 patients (34%). During follow-up, 60 patients (20%) experienced the composite endpoint, of whom 28 (9%) died. Patients with LAVi ≥32 ml/m2 had a significantly higher cardiac event rate and death rate (p Conclusions Increased LAVi was an independent and incremental predictor of cardiovascular morbidity and mortality in T2DM patients with no history of CVD. (Presence of Macrovascular Disease in Type 2 Diabetes Mellitus; NCT00298844).

Objective Nocturnal hypoglycemia is a feared complication to insulin treated diabetes. Impaired awareness of hypoglycemia (IAH) increases the risk of severe hypoglycemia. EEG changes are demonstrated during daytime hypoglycemia. In this explorative study, we test the hypothesis that specific hypoglycemia-associated EEG-changes occur during sleep and are detectable in time for the patient to take action. Research design and methods Ten patients with type 1 diabetes (duration 23.7 years) with IAH were exposed to insulin-induced hypoglycemia during the daytime and during sleep. EEG was recorded and analyzed real-time by an automated multi-parameter algorithm. Participants received an auditory alarm when EEG changes met a predefined threshold, and were instructed to consume a meal. Results Seven out of eight participants developed hypoglycemia-associated EEG changes during daytime. During sleep, nine out of ten developed EEG changes (mean BG 2.0 mmol/l). Eight were awakened by the alarm. Four corrected hypoglycemia (mean BG 2.2 mmol/l), while four (mean BG 1.9 mmol/l) received glucose infusion. Two had false alarms. EEG-changes occurred irrespective of sleep stage. Post hoc improvement indicates the possibility of earlier detection of hypoglycemia. Conclusions Continuous EEG monitoring and automated real-time analysis may constitute a novel technique for a hypoglycemia alarm in patients with IAH.

Udgivelsesdato: 2009-Oct AIM: Evaluation of the evidence base for recommending different insulin treatment regimens in type 1 diabetes. METHODS: A computerised literature survey was conducted using The Cochrane Controlled Trials Register and the Pub Med database for the period of 1982-2007. RESULTS: A meta-analysis on only 49 out of 1295 references showed that CSII compared with conventional or multiple insulin injections therapy demonstrated a significant reduction in mean HbA1c (primary outcome) of 1.2% CI [0.73; 1.59] (P

Udgivelsesdato: 2006-Aug OBJECTIVE: To thoroughly examine the mechanisms for insulin resistance in polycystic ovary syndrome (PCOS) and to evaluate the effects of pioglitazone treatment on insulin resistance, beta-cell function, LH secretion, and glucose metabolism. DESIGN: Randomized, blinded, placebo-controlled study. SETTING: Outpatient clinic, at a university hospital in Denmark. PATIENT(S): Thirty obese women with PCOS and 14 weight-matched healthy females. INTERVENTION(S): Sixteen weeks of blinded treatment with pioglitazone (30 mg/d) or placebo. MAIN OUTCOME MEASURE(S): Fasting blood samples, 24-hour 20-minute integrated blood sampling (LH, insulin, and C-peptide), euglycemic hyperinsulinemic clamps including 3-(3)H glucose, and indirect calorimetry were performed before and after the intervention period. RESULT(S): Patients with PCOS had significantly lower insulin sensitivity compared with controls, including significantly decreased insulin-stimulated oxidative and nonoxidative glucose metabolism. Pioglitazone treatment resulted in significantly lower levels of fasting insulin and significantly higher insulin sensitivity, increased insulin-stimulated glucose oxidation, and increased insulin-stimulated inhibition of lipid oxidation. During 24-hour blood sampling, significantly lower area under-the-curve insulin and lower median insulin levels were observed. Secretion profiles of LH and E(2) and T levels did not change significantly. CONCLUSION(S): Insulin resistance in PCOS was characterized by hyperinsulinemia, impaired insulin-stimulated oxidative and nonoxidative glucose metabolism, which was partly reversed by pioglitazone treatment.

Udgivelsesdato: 2006-Jul Accumulation of intramuscular long-chain acyl-CoA esters (LCACoA) has previously in animal and human models been suggested to play an important role in lipid induced insulin resistance. The aim of this study was to examine whether myotubes established from type 2 diabetic (T2D) subjects and lean controls express differences in long-chain acyl-CoA esters (LCACoA) precultured under physiological conditions and during chronic exposure to palmitate (PA) and oleic acids (OA) with/without acute insulin stimulation. No significant differences were found between diabetic and control myotubes, neither in the total amount nor among individual LCA-CoA species during basal and acute insulin stimulation. LCA-CoA accumulated during exposure to palmitic acid but not during exposure to oleic acid. During PA and OA exposure, only palmitoyl-CoA, oleoyl-CoA and total LCA-CoA change. PA exposure increased the palmitoyl-CoA, whereas oleoyl-CoA was reduced and vice versa during OA exposure. No differences were found in the LCA-CoA level between T2D and control subjects, neither in the total amount nor in the individual specific LCA-CoA species during fatty acid exposure. Chronic (24 h), high PA, but not OA exposure induced insulin resistance at the level of glycogen synthesis in control subjects. These results indicate that (1) no primary defects are responsible for LCA-CoA accumulation in diabetic subjects; (2) LCA-CoA changes in vivo are partly adaptive to changes in the PA level and possibly other saturated fatty acids; and (3) PA induced insulin resistance may be mediated through an increased level of palmitoyl-CoA.

Udgivelsesdato: 2003-Nov OBJECTIVE: This study was performed to prospectively evaluate a screening model for gestational diabetes mellitus on the basis of clinical risk indicators. STUDY DESIGN: In a prospective multicenter study with 5235 consecutive pregnant women, diagnostic testing with a 2-hour 75-g oral glucose tolerance test was routinely performed in women with risk indicators and offered to women without risk indicators as part of the study. RESULTS: Forty-four percent of the women underwent testing, 43% declined participation, 6% did not speak Danish, and 7% could not be contacted. By extrapolation of the results from tested women to the whole group in question, a 2.4% prevalence of gestational diabetes mellitus was calculated. Sensitivity and specificity of the model was 80.6 (73.7-87.6) and 64.8 (63.5-66.1), respectively (95% CIs). CONCLUSION: Under ideal conditions, sensitivity of the model was comparable with universal screening by fasting glucose or a 1-hour 50-g glucose challenge test. Both screening and diagnostic testing could be avoided in two thirds of all pregnant women.

Udgivelsesdato: 2003-Mar-21 Insulin resistance in skeletal muscle is a hallmark feature of type 2 diabetes. An increasing number of enzymes and metabolic pathways have been implicated in the development of insulin resistance. However, the primary cellular cause of insulin resistance remains uncertain. Proteome analysis can quantitate a large number of proteins and their post-translational modifications simultaneously and is a powerful tool to study polygenic diseases like type 2 diabetes. Using this approach on human skeletal muscle biopsies, we have identified eight potential protein markers for type 2 diabetes in the fasting state. The observed changes in protein expression indicate increased cellular stress, e.g. up-regulation of two heat shock proteins, and perturbations in ATP (re)synthesis and mitochondrial metabolism, e.g. down-regulation of ATP synthase beta-subunit and creatine kinase B, in skeletal muscle of patients with type 2 diabetes. Phosphorylation appears to play a key, potentially coordinating role for most of the proteins identified in this study. In particular, we demonstrated that the catalytic beta-subunit of ATP synthase is phosphorylated in vivo and that the levels of a down-regulated ATP synthase beta-subunit phosphoisoform in diabetic muscle correlated inversely with fasting plasma glucose levels. These data suggest a role for phosphorylation of ATP synthase beta-subunit in the regulation of ATP synthesis and that alterations in the regulation of ATP synthesis and cellular stress proteins may contribute to the pathogenesis of type 2 diabetes.

Calculating T-scores using an older reference population reduces inconsistency between measurement sites when osteoporosis is diagnosed in the elderly. The present analysis in a younger, early postmenopausal cohort examined 5-yr consistency of normalization by local and femoral neck-equivalent T-scores. NHANES (femur) and Hologic (spine and forearm) references were applied to baseline, 1-, 2-, 3-, and 5-yr scans in 925 untreated women in a national cohort study, and alternative local and neck-equivalent scores calculated. The baseline prevalence of osteopenia/osteoporosis was 35.5%/4.1% (spine), 31.0%/1.2% (neck), 31.3%/1.2% (total hip), and 37.2%/2.5% (forearm). It increased to 54.6%/7% by combining sites. The prevalences at 5-yr were 57.2%/12.4% (spine), 51.9%/5.0% (neck), 46.6%/3.7% (total hip), 52.5%/7.4% (forearm), and 77.3%/17.8% (any). A T-score cut-off at the lowest of four sites of –1.65 for osteopenia and –3.37 for osteoporosis was equivalent in patient numbers to T p

Udgivelsesdato: 2001-Nov-29 There is no consensus regarding the results from in vivo and in vitro studies on the impact of chronic high insulin and/or high glucose exposure on acute insulin stimulation of glycogen synthase (GS) kinetic parameters in human skeletal muscle. The aim of this study was to evaluate the kinetic parameters of glycogen synthase activity in human myotube cultures at conditions of chronic high insulin combined or not with high glucose exposure, before and after a subsequent acute insulin stimulation. Acute insulin stimulation significantly increased the fractional activity (FV(0.1)) of GS, increased the sensitivity of GS to the allosteric activator glucose 6-phosphate (A(0.5)) and increased the sensitivity of GS to its substrate UDPG (K(m(0.1))) when myotubes were precultured at low insulin with/without high glucose conditions. However, this effect of acute insulin stimulation was abolished in myotubes precultured at high insulin with or without high glucose. Furthermore, we found significant correlations between the fractional velocities FV(0.1) of GS and K(m(0.1)) (rho=-0.72, P

Objective: The objective was to study the clinical impact of mild carbohydrate intolerance in pregnant women with risk factors for gestational diabetes mellitus. Study Design: This was a historical cohort study of 2904 pregnant women examined for gestational diabetes on the basis of risk factors. Information on oral glucose tolerance test results and clinical outcomes was collected from laboratory charts and medical records. Results: The following outcomes increased significantly with increasing glucose values during the oral glucose tolerance test: shoulder dystocia, macrosomia, emergency cesarean section, assisted delivery, hypertension, and induction of labor. However, when corrections were made for other risk factors, hypertension and induction of labor were only marginally associated with glucose levels. Conclusion: In a group of nondiabetic pregnant women with risk factors for gestational diabetes, there was a graded increase in the frequency of shoulder dystocia and other maternal-fetal complications with increasing glucose levels during an oral glucose tolerance test. (Am J Obstet Gynecol 2001;185:413-19.)

The effect of hyperglycemia, per se, on glucose utilization and hepatic glucose production was reevaluated in eight C-peptide-negative insulin-dependent diabetic patients using primed-continuous noncontaminated 3-3H-glucose infusion and labeled glucose infusates. The night before study, euglycemia was maintained by a variable insulin infusion. During the studies, insulin was infused at basal replacement rates determined as the rate required to maintain euglycemia in the morning. After a 2-hour equilibration period, either plasma glucose level was increased to 12 mmol/L for 4 hours using a variable glucose infusion, or no glucose was infused (control day). On the hyperglycemic day, glucose utilization increased 16% (86 +/- 2 to 99 +/- 4 mg.m-2.min-1, P < .02) and glucose production decreased 45% (85 +/- 3 to 47 +/- 4 mg.m-2.min-1, P < .01). On the control day, both glucose utilization and glucose production decreased (84 +/- 3 to 68 +/- 3 and 84 +/- 3 to 65 +/- 3 mg.m-2.min-1, respectively; both P < .01). Therefore, comparing rates at the end of the hyperglycemic and control studies, glucose utilization was increased by 45% and glucose production was decreased by 28% in response to hyperglycemia (both P < .01). Thus hyperglycemia, at basal insulin levels enhanced glucose utilization and suppressed glucose production in insulin-dependent diabetic patients. Quantitatively, the enhancement of glucose utilization was more important than the suppressive effect on glucose production.

The effect of glibenclamide treatment on insulin action in isolated fat cells was studied in eight moderately obese patients with non-insulin-dependent diabetes mellitus (NIDDM). Insulin receptor binding and the effect of insulin on glucose transport and lipogenesis were determined before and after 3 months of glibenclamide therapy. At the end of the treatment period, mean daytime plasma glucose concentrations were reduced (10.8 +/- 0.4 versus 7.0 +/- 0.3 mmol/L, p less than 0.001) whereas mean daytime plasma insulin level was increased (40 +/- 12 versus 71 +/- 9 mU/L, p less than 0.001). Adipocyte insulin receptor binding as well as basal glucose transport and metabolism were unaffected by drug treatment. In contrast, insulin-stimulated glucose transport and lipogenesis were both significantly enhanced (p less than 0.05). These findings are comparable to those of another study involving seven moderately obese subjects with NIDDM who had biopsies of the lateral vastus muscle taken for measurement of insulin receptor function and glycogen synthase activity before and during 2 months of gliclazide treatment. In that study insulin receptors purified with wheatgerm agglutinin showed unchanged insulin binding and receptor kinase activity. Moreover, gliclazide had no impact on maximal glycogen synthase activity. However, under physiologic hyperinsulinemic conditions gliclazide therapy was associated with an increased sensitivity of glycogen synthase for its allosteric activation by glucose-6-phosphatase (p less than 0.04). In conclusion, sulfonylurea treatment of NIDDM enhances insulin-stimulated peripheral glucose utilization in part through a potentiation of insulin action on adipose tissue glucose transport and lipogenesis and skeletal muscle glycogen synthase.

Macrovascular disease, especially coronary heart diseases, have been found to be linked to glucose intolerance. Insulin resistance in respect to glucose uptake in peripheral tissues seems to play an important role in the development of glucose intolerance, since subjects with coronary heart disease mainly are hyperinsulinemic. Insulin resistance may induce not only glucose intolerance but also hypertension, obesity, and dyslipoproteinemia (high very low-density lipoprotein and low high-density lipoprotein values), all variables that add to the risk of coronary heart disease. On the basis of these findings, a new syndrome has been postulated-syndrome X. This syndrome may be caused by inherited insulin resistance in skeletal muscles, and secondary to that arterial hypertension, obesity, and dyslipoproteinemia may develop. Insulin resistance in noninsulin-dependent diabetic persons and in hypertensive subjects is located in skeletal muscles, where insulin's ability to promote nonoxidative glucose metabolism is reduced. The key enzyme in this pathway, glycogen synthase, is proposed as the causal defect responsible for the insulin resistance state, at least in noninsulin-dependent diabetic patients. The pill (sex steroids) may induce a clinical situation that is similar to syndrome X. However, it is important to emphasize that many more studies are needed to substantiate these hypothetical mechanisms behind coronary heart disease.

Glucose tolerance, as estimated by the oral glucose tolerance test, depends upon several factors, the most important of which are insulin secretion and insulin action. A close correlation between the two variables, insulin secretion and insulin action, has been found in normal subjects, where they seem to compensate for each other. The result is that glucose tolerance is kept normal even if one of the variables is altered.3 Thus, most subjects with insulin resistance may compensate by hypersecretion of insulin. These subjects, therefore, will develop hyperinsulinemia both in the fasting state and after a meal. If beta cells are unable to produce enough insulin to overcome the insulin resistance, frank diabetes mellitus will be the result. Insulin resistance, therefore, may be present in a compensated form e.g., obesity, and an uncompensated form e.g., noninsulin-dependent diabetes mellitus (NIDDM). In between normal glucose tolerance and frank diabetes (fasting hyperglycemia), a clinical state characterized by partial compensation of insulin resistance has been defined, impaired glucose tolerance (IGT), a clinical state with normal fasting plasma glucose values, but postprandial hyperglycemia. Glucose intolerance, both as diabetes mellitus and IGT, has been shown to be linked to macrovascular diseases, especially CHD.4 Furthermore, glucose intolerance seems to be a common feature of subjects with arterial hypertension. In a recent paper, about 40% of the hypertensives were glucose intolerant,5 while dyslipoproteinemic subjects have been shown to be more glucose intolerant than controls.* Taken together, glucose intolerance seems to be a common characteristic of subjects with dyslipoproteinemia, arterial hypertension, and/or obesity. Since insulin resistance is the major underlying defect in glucose intolerance in the subjects described above, the following question may be raised: How can insulin resistance lead to hypertension, obesity, and dyslipoproinemia?

Summary The prevalence of diabetes has increased worldwide. We have undertaken an epidemiological analysis of drug-treated diabetes in a well defined community. We present estimates of prevalence, incidence, and mortality of patients with such diabetes during 1993–99, based on data for all 470 000 people living in the county of Fyn, Denmark. Although prevalence increased (odds ratio: female, 1·026 [95% CI 1·020–1·032]; male, 1·041 [1·036–1·047]), mortality in those treated declined (rate ratio: female, 0·976 [95% CI 0·952–1·001]; male, 0·966 [0·943–0·990]). We did not identify a clear trend for incidence. Future research into the causes of rising diabetes prevalence should take this fall in mortality into account to avoid incorrect conclusions about the relation between western lifestyle and the growing number of diabetics.

We have studied whether the sucrose-induced reduction of insulin sensitivity and cellular insulin binding in normal man is related to the fructose or the glucose moiety. Seven young healthy subjects were fed their usual diets plus 1000 kcal extra glucose per day and eight young healthy subjects were fed their usual diets with addition of 1000 kcal extra fructose per day. The dietary regimens continued for 1 week. Before change of diet there were no statistically significant differences between body weight and fasting plasma concentrations of glucose. insulin, and ketone bodies in the two groups studied. High-glucose feeding caused no significant changes in insulin binding or insulin sensitivity whereas high-fructose feeding was accompanied by a significant reduction both of insulin binding (P < 0.05) and insulin sensitivity (P < 0.05).The changes in insulin binding and insulin sensitivity correlated linearly (r = 0.52, P < 0.01). We conclude that fructose seems to be responsible for the impaired insulin binding and insulin sensitivity induced by sucrose. Am. J. C/in. Nut,. 33:273-278, 1980.

125I-Insulin binding to monocytes from 14 gestational diabetics was measured before and after 6 weeks of treatment with a 5500 kJ, low-fat, low-sucrose diet. After the hypoenergetic feeding of gestational diabetics, fasting plasma concentrations of glucose (P less than 0.01) and insulin (P less than 0.05) decreased significantly, whereas insulin binding was unaltered. Provided the monocyte insulin receptor reflects insulin receptors of more determinant tissues for insulin action, our data indicate that an increased insulin receptor binding is not involved in the improved insulin effectiveness of gestational diabetics after hypoenergetic dieting.

A three-step hyperinsulinemic euglycemic clamp was performed in 14 nondialyzed uremic and ten age-matched healthy subjects. Nine of the uremics were restudied for a mean of 42 days (range, 21 to 88 days) after initiation of dialysis therapy. Insulin was infused at the following three rates: 0.5 mU X kg-1 X min-1, 2.0 mU X kg-1 X min-1, and 4.0 mU X kg-1 X min-1. Each dose was given for 120 minutes. Glucose uptake during the last 30 minutes of each clamp were consistently lower in uremic patients pre-dialysis than in controls (2.3 +/- 0.3 v 6.6 +/- 0.8 mg X kg-1 X min, 7.8 +/- 0.6 v 13.2 +/- 1.1 mg X kg-1 X min-1 and 9.6 +/- 0.7 v 15.5 +/- 1.0 mg X kg-1 X min-1, all P less than 0.001). Serum insulin levels were similar in the two groups, and blood glucose values during steady state were maintained at 79 +/- 2.77 +/- 2, and 77 +/- 2 mg/100 mL in uremic subjects and at 72 +/- 3, 73 +/- 2, and 75 +/- 2 mg/100 mL in healthy subjects. The insulin levels required to elicit half-maximal biological response in uremics (82 +/- 5 microU/mL) were markedly higher than in controls (54 +/- 8 microU/mL, P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of treatment of isolated rat adipocytes with prostaglandin E2 (PGE2) on subsequent [3H]PGE2 binding was studied. In addition, the antilipolytic effects of was studied. In addition, the antilipolytic effects of PGE2, adenosine, and insulin were studied in control and PGE2-treated adipocytes. Treatment of adipocytes with PGE2 (1 microM) decreased the binding of [3H]PGE2 by 61% (from 11.0 to 4.6 fmol/10(6) cells, P less than 0.005). Scatchard analysis of the binding data demonstrated that the decrease of PGE2 receptor binding was due to a decrease in the apparent number of PGE2 receptors while the apparent receptor affinity was unaltered. Reduction of the PGE2 receptor binding was specifically regulated inasmuch as structurally related compounds such as PGF2 alpha and arachidonic acid had only minor effects on subsequent [3H]PGE2 receptor binding. Reduction of the available receptor number was associated with a significant decrease in the antilipolytic effect of PGE2 on the isoproterenol-stimulated lipolysis (P less than 0.05). The maximal antilipolytic effect of PGE2 was decreased by 45%. Desensitization of the biological effect of PGE2 (antilipolysis) was only partially specifically regulated inasmuch as the antilipolytic compound phenylisopropyladenosine also had reduced antilipolytic effect in PGE2-treated cells. However, the antilipolytic effect of insulin was similar in control and PGE2-treated cells. It was found that the PGE2-induced decrease of [3H]PGE2 receptor binding may be due to a very tight coupling between the PGE2 molecule and its specific receptor. This tight coupling may then represent an occupancy of the receptor rather than a true loss of receptors.(ABSTRACT TRUNCATED AT 250 WORDS)