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Background: Postburn insulin dysfunction is a significant contributor to morbidity and mortality. A satisfactory mechanism for explaining this phenomenon remains elusive; however, resistin has been postulated to be involved. Initially discovered as an insulin antagonist secreted from adipose tissue in murine models, resistin’s function in humans has been more obscure. Resistin is not expressed significantly in human adipocytes although it has been detected in monocytes. We postulate that mononuclear activation at the site of burn injury affects the release of resistin and contributes to insulin dysfunction. Methods: Plasma from burned and healthy control individuals was characterized for glucose, insulin, and resistin protein levels. Adipose tissue from both groups was analyzed for resistin transcript; levels were found to be somewhat higher in the burned group though not significantly so. Circulating monocyte expression of resistin transcript was assayed in similar fashion. Results: In addition to finding that insulin and glucose were elevated postburn, a finding in agreement with past studies, we demonstrate that circulating resistin levels are significantly elevated as well. Insulin resistance was found to increase at a similar rate to resistin expression in the burn population, suggesting a correlation in these events. Adipose tissue from both groups was analyzed for resistin transcript; levels were found to be somewhat higher in the burned group though not significantly so. Circulating monocyte expression of resistin transcript was assayed and found to be profoundly elevated in the burn population. Conclusions: This data suggests that resistin is produced by activated monocytes in the adipose tissue around the periphery of burn wound. We suggest that postburn insulin function is adversely affected by resistin produced as a result of this monocyte activation.

This study aimed to examine brain energy metabolism during moderate insulin-induced hypoglycaemia in Type 1 diabetic patients and healthy volunteers.Type 1 diabetic patients (mean diabetes duration 13 +/- 2.5 years; HbA1c 6.8 +/- 0.3%) and matched controls were studied before, during (0-120 min) and after (120-240 min) hypoglycaemic (approximately 3.0 mmol/l) hyperinsulinaemic (1.5 mU x kg(-1) min(-1)) clamp tests. Brain energy metabolism was assessed by in vivo 31P nuclear magnetic resonance spectroscopy of the occipital lobe (3 Tesla, 10-cm surface coil).During hypoglycaemia, the diabetic patients showed blunted endocrine counter-regulation. Throughout the study, the phosphocreatine:gamma-ATP ratios were lower in the diabetic patients (baseline: controls 3.08 +/- 0.29 vs diabetic patients 2.65 +/- 0.43, p0.01; hypoglycaemia: 2.97 +/- 0.38 vs 2.60 +/- 0.35, p0.05; recovery: 3.01 +/- 0.28 vs 2.60 +/- 0.35, p0.01). Intracellular pH increased in both groups, being higher in diabetic patients (7.096 +/- 0.010 vs. 7.107 +/- 0.015, p0.04), whereas intracellular magnesium concentrations decreased in both groups (controls: 377 +/- 33 vs 321 +/- 39; diabetic patients: 388 +/- 47 vs 336 +/- 68 micromol/l; p0.05).Despite a lower cerebral phosphocreatine:gamma-ATP ratio in Type 1 diabetic patients at baseline, this ratio does not change in control or diabetic patients during modest hypoglycaemia. However, both groups exhibit subtle changes in intracellular pH and intracellular magnesium concentrations.

Objectives Severe hypoglycemia is associated with cognitive decline and dementia in older persons with type 2 diabetes. The role of antidiabetic treatments on severe hypoglycemia is unknown in dementia. The aims were to determine the prevalence of severe hypoglycemic events and investigate associations among severe hypoglycemic and specific antidiabetic treatments (classes of oral agents and types of insulin analogs) in a large sample of nursing home patients with diabetes according to dementia status. Design Cross-sectional observational study. Setting A total of 150 nursing homes across Italy. Participants A total of 2258 patients with type 2 diabetes (dementia = 1138, no dementia = 1120). Measurements Diagnosis of dementia before nursing home admission. Data were collected regarding functional status, glycemic control, antidiabetic treatments, comorbidities, and biochemical and clinical measurements. Logistic regression models with severe hypoglycemia as the dependent variable were used to test associations with antidiabetic agents. Results Patients had a mean age (SD) of 82 (8) years, body mass index (BMI) of 25.4 (4.8), fasting plasma glucose (FPG) of 7.5 (3.0) mmol/L, postprandial glucose (PPG) of 10.3 (3.6) mmol/L, HbA1c of 7.1% (54 mmol/L), and impairments in activities of daily living (ADLs) of 3.7 (2.1). Severe hypoglycemia was more prevalent in patients with dementia (18%) compared with patients without dementia (8%). Patients with dementia were older, showed greater ADL impairments, greater number of comorbidities, lower FPG, and higher PPG compared with those without dementia. Adjusted logistic regression models in patients with dementia showed that rapid- and long-acting insulin analogs were associated with reduced odds ratio (OR) (OR 0.333; 95% confidence interval [CI] 0.184–0.602; OR 0.248, 95% CI 0.070–0.882, respectively), whereas sulphonylureas and combined metformin + sulphonylurea were associated with increased ORs (OR 8.805, 95% CI 4.260–18.201; OR 6.639; 95% CI 3.273–14.710, respectively) of experiencing severe hypoglycemia. No correlations were found in patients without dementia. Conclusion In older nursing home patients with type 2 diabetes, severe hypoglycemia was significantly higher in dementia. Our findings suggest that sulphonylureas should be used with caution, whereas rapid- and long-acting insulin analogs seem safer.

(Cell 153, 747–758; May 9, 2013)In this article, we claimed that Angptl-8, which we termed betatrophin and is also referred to in the literature as TD26, RIFL, C19orf80, and Lipasin, was the agent by which the insulin antagonist S961 induces robust β cell replication in mice. Gusarova et al., in a Matters Arising article, subsequently showed that targeted Angptl-8/betatrophin overexpression in mice increases blood triglycerides but does not induce β cell growth (Cell, 2014, 159, 691–696). When we repeated our original experiments with a larger number of mice, we also failed to observe β-cell expansion upon Angptl-8/betatrophin overexpression and reported these results in a Correspondence (Cell, 2014, 159, 467–468). We have subsequently repeated a series of blinded experiments with the Kushner lab and have now determined conclusively that our conclusion that Angptl-8/betatrophin causes specific β cell replication is wrong and cannot be supported (PLoS One, 2016, 11, e0159276). Therefore, the most appropriate course of action is to retract the paper. We regret and apologize for this mistake.

In this issue of Cell, Gusarova et al. (2014) show that deletion of ANGPTL8 in mice does not affect the compensatory proliferation of pancreatic beta cells in response to insulin resistance induced by a high-fat diet or treatment with the insulin antagonist S961. They also show that overexpression of human ANGPTL8 in mouse liver leads to elevated serum triglyceride levels but not significant pancreatic beta cell proliferation. They conclude that ANGPTL8 (also called betatrophin [Yi et al., 2013]/RIFL [Ren et al., 2012]/lipasin [Zhang, 2012]) does not control pancreatic beta cell expansion.

L-diabetes represents a subtype of non-autoimmunopathic and non-adipose diabetes mellitus. It is hypothesized that ATP-sensory brain centres measure the cerebral ATP concentration and announce a hypoglycaemia if the setpoint is undercut. The disease involves a decreased ATP formation in the CNS that is independent of blood glucose levels, and that leads to a "hypoglycaemia" false alarm. UGT1-polymorphisms, a sensitive sympathetic system, an IgM deficit and an increased porousity of the mucous membrane of the small intestine have been postulated in its etiology. These causative factors bring about increasing amounts of toxins and radicals which impair the ATP generation in the CNS so that through the announcement of a non-existing hypoglycaemia the release of the insulin antagonists hGH, cortisol and adrenaline is induced.

Normally, during pregnancy, progesterone acts as a potent insulin antagonist and results in hyperglycaemia; therefore, it is very rare for a bitch to become hypoglycaemic. A 4-year-old Great Dane pregnant bitch was presented because of severe weakness and dystocia. Despite various treatments such as the administration of calcium gluconate and oxytocin by the referring veterinarian, the dog remained lethargic and recumbent. On initial laboratory tests, the only abnormality was marked hypoglycaemia. Within few minutes following administration of intravenous Dextrose, the dog became alert, bright and was able to stand. Parturition occurred 40 min after administration of Dextrose, and the dog delivered live, healthy pups. There are only four cases of preparturient hypoglycaemia in dogs in the veterinary literature. All prior cases were small breed dogs. The present report is unique because it describes hypoglycaemia in a pregnant Great Dane.

The work in the author's laboratory is funded by a grant from the Medical Research Council of Canada. The author thanks Susanne Bordeleau-Chenier for excellent secretarial assistance.

Sixty minutes of restraint stress, preceded by chlorpromazine administration which stimulates somatotrophic hormone secretion (STH), produced an acute post-stress diabetic response (PDR) in normal-intact rats as well as in adrenalectomized rats. This PDR lasted 3 to 4 hours and was evaluated by glucemia and glucosuria determination and by the appearance of an insulin antagonist, alpha2-glycoprotein STH-dependent, called alpha2-inhibitor, which inhibits glucose uptake by isolated tissues. When tested in the suprahepatic blood of animals after stress it showed increased activity, both in normal and in adrenalectomized rats. This result permits us to state that alpha2-inhibitor may be produced in the liver by and action of STH and without primary glucocorticoid participation. The post-stress hyperglucemic response of adrenalectomized rats had a similar tendency to that of the control, although with initial and final values of glucemia significantly below the control. This response supports the diea that postadrenalectomy gluconeogenesis was evoked during and after the systemic stress.

SUMMARY Using the effect of insulin on isolated rat hemidiaphragm as an assay system, it has been possible to demonstrate a circulating insulin antagonist in some new cases of diabetes of the growth-onset type as well as during the exacerbation of diabetes secondary to infections. Three out of four acromegalics with diabetes also showed evidence of insulin antagonist, while one diabetic patient with thyrotoxicosis requiring 155 u. insulin/day had no antagonist. The antagonist present in the new diabetics and during infection exhibited some characteristics similar to the antagonist previously described during diabetic acidosis [Field & Stetten, 1956a], but different from the insulin inhibitor present during chronic insulin resistance.

Diabetic levels of the synalbumin insulin antagonist were found in 30% of a group of 50 women who had had unexplained intrauterine foetal deaths. Four per cent of the control group had similar levels of antagonism. Previous reports of an increased foetal mortality in potentially diabetic women were confirmed.

Aucun effet diabetogene ni hyperglycemiant aigu de l'hydrochlorothiazide (HCT) n'a ete decele par des determinations de la glycemie a jeun (avant et 2–8 h apres l'administration d'HCT) et de la tolerance au glucose effectuees chez des rats normaux et des rats sensibilises a un effet diabetogene par une pancreatectomie subtotale ou par l'injection d'une dose subdiabetogene d'alloxane, au cours d'un traitement de 6 semaines par des doses de 50–200 mg/kg · jour d'HCT p. o. — De fortes doses (plus de 3 ml/kg) de N-monomethylamide de l'acide acetique (NMMAA), solvant qui fut utilise dans la preparation d'une solution injectable commerciale d'hydrochlorothiazide, ont par contre exerce des effets diabetogenes tres marques chez le rat. Toute dose lethale de NMMAA a induit chez cet animal un syndrome diabetique, c'est-a-dire une hyperglycemie progressive avec aeido-cetose metabolique, ressemblant au syndrome diabetique aigu induit par l'injection d'une forte dose de serum anti-insulinique. — Des fractions de doses lethales administrees quotidiennement pendant plusieurs jours ont exerce des effets diabetogenes et lethaux cumulatifs: la substance ou l'un de ses metabolites toxiques apparait persister longtemps dans l'organisme du rat.-Des doses sublethales de NMMAA ont induit une hyperglycemie reversible d'une duree de quelques jours. Nous avons donc constate que le diabete produit par le NMMAA etait soit transitoire soit lethal. Aucun signe de toxicite ne s'est manifeste au cours d'un traitement de 6–8 mois par des doses inferieures a 0,5 ml/kg · jour. — Chez les rats intoxiques par une dose lethale de NMMAA, une correlation positive tres significative a ete notee entre les valeurs seriques d'insuline immuno-reactive (IRI) et les valeurs de glycemie. Bien qu'ils aient ete, a glycemie comparable, superieurs a ceux constates dans le serum de rats normaux apres surcharge de glucose, les taux d'IRI se trouvant dans le serum des rats intoxiques n'ont pas ete en mesure de s'opposer a l'elevation reguliere de la glycemie jusqu'a la mort. — L'effet hypoglycemiant d'insuline cristalline porcine est apparu inhibe chez les rats intoxiques par le NMMAA, compare a l'effet observe chez des rats normaux ou en diabete alloxanique.-Utilisant l'augmentation de l'oxydation du premier atome de carbone du glucose-l-C14 par le tissu adipeux epididymaire du rat, in vitro, comme index metabolique de l'activite insulino ide du serum (ILA), nous n'avons pas constate, dans le serum des rats intoxiques et en etat de forte hyperglycemie, des taux d'ILA significativement superieurs a ceux presents dans le serum de rats temoins a jeun. Alors que, chez des rats normaux, la fraction de l'ILA serique supprimable par serum anti-insulinique (SILA) s'elevait fortement, comme l'IRI, au cours de l'hyperglycemie induite par une surcharge de glucose, cette fraction SILA n'est pas apparue en quantites decelables dans le serum des animaux intoxiques. L'IRI serique de ces animaux n'a donc semble-t-il pas exerce d'effet «insulin-like» sur le tissu adipeux isole de rat normal.-Les faits observes amenent a la conclusion que les rats intoxiques par le NMMAA inactivent et l'insuline endogene et l'insuline exogene. Bien qu'ayant perdu son activite metabolique, l'insuline endogene inactivee reste immunologiquement competente.

A capacity of freshly-drawn, normal serum to antagonize the action of insulin in the epididymal fat pad system has been found to be increased in the serum of untreated diabetic patients. A comparable increase has also been found in the serum of very obese subjects who are not apparently diabetic. The current status of insulin antagonism in diabetes has been briefly reviewed. Although a search for the diabetogenic insulin antagonist has been under way for several decades now, failure thus far to convincingly demonstrate its presence appears to have carried little conviction of its absence. To the several candidates currently in nomination, another has been added.

A study is reported of the changes in fasting plasma lipids in a group of patients with chronic renal failure. When compared with the findings in a control group of normal subjects the group of patients showed increases in the mean plasma concentrations of triglyceride, cholesterol, total low density lipoproteins, glycerol, glucose and immunoreactive growth hormone, together with an increase in pre-β-lipoproteins on electrophoresis. These findings in patients with chronic renal failure were considered to represent the end results of the combination of a number of factors. It would seem probable that of importance amongst these factors is the accumulation of insulin antagonists.

Insulin resistance is currently believed to be associated with insulin-neutralizing substances in the blood. Lowell (1), employing the mouse convulsion assay for insulin, has shown that the injection of mixtures of insulin and serum from insulin-resistant diabetic patients into mice caused a significantly smaller incidence of convulsive symptoms than the injection of the same amounts of insulin alone. He points out, however, that the quantitative interpretation of these experiments is difficult because of the variations of the response of the animals to insulin and the nonspecific effects of the injection of serum. It would be desirable, therefore, to employ a method for the determination of insulin-inactivating properties of serum which does not involve the administration of insulin-serum mixtures to the intact animal. In the course of our recent work on the chemical combination of insulin with the rat diaphragm (2, 3) it became apparent that this technique would provide a method for the detection of insulin-inactivating substances in any solution. Accordingly, we have tested serum from normal, diabetic, and insulin-resistant subjects and found, in confirmation of the results of Lowell, that serum from insulin-resistant patients has the property of opposing the action of insulin.

Among the disputed questions considered in this presentation are (1) Relationships between a) the known metabolic abnormalities in diabetes and the development of microangiopathy, and b) insulin antibodies and nodular glomerulosclerosis; (2) Sensitivity to insulin and availability of insulin in idiopathic diabetes mellitus and in other conditions associated with impaired glucose tolerance; (3) The role of pituitary growth hormone in the etiology of idiopathic diabetes; (4) The status of “bound insulin,” ILA, etc.; and (5) The identification of the “synalbumin” insulin antagonist as the B chain of insulin. Also included are the presentation of data on insulin and growth hormone-secretory responses to glucose loading in obese and nonobese diabetic and nondiabetic subjects and a discussion of the interrelationships among the peptide hormones, glucose and free fatty acids in blood.

Albumin prepared from serum of diabetic patients inhibits the effect of insulin on rat diaphragm muscle but not on their epididymal fat pads when injected intravenously to make a foreign protein concentration of 3.8 g/100 ml in the plasma of the rat. At this concentration, albumin from normal subjects had no insulin inhibitory effect on either tissue. — These observations confirm, underin vivo conditions, that diabetic albumin is more antagonistic to insulin than albumin prepared from normal subjects.

SummaryThe administration of testosterone propionate in doses of 10, 25, or 50 mg daily for a period of 10 days to 13 patients with diabetes mellitus failed to alter significantly the responsiveness to insulin in all but one. It is suggested that the presence of the side-chain attached to carbon atom 17 in the steroid molecule may be essential for this activity.

The incidence of excessive synalbumin antagonism has been studied in a small randomly selected population survey. One hundred and forty-two volunteers were tested, 70 men and 72 women, between the ages of 18 and 45 years, none of whom had overt diabetes. — Fifteen men (21%) and 26 women (36%) were synalbumin positive with an overall incidence of 28%, which is not dissimilar to the previously reported incidence of 25%.

The enzyme glutathione-insulin transhydrogenase, that catalyzes sulfhydryldisulfide interchange, inactivates both insulin and proinsulin; the inactivation of insulin takes place at a greater rate than that of proinsulin. Under the experimental conditions used, the enzyme reactivates scrambled proinsulin but does not reactivate scrambled insulin. However, in the presence of connecting peptide of proinsulin reactivation of scrambled insulin is observed, indicating that for the generation of immunoreactive insulin covalent binding of C-peptide is not necessary and residues 31, 32, 59, and 60 of proinsulin may be omitted.