Wiedemann-Beckwith syndrome: presentation of clinical and cytogenetic data on 22 new cases and review of the literature

Summary The main features of Wiedemann-Beckwith syndrome (WBS) include macroglossia, abdominal wall defects, visceromegaly, gigantism, hypoglycemia, ear creases, nevus flammeus, and mid-face hypoplasia. Twenty-two cases of WBS were examined clinically and cytogenetically, and compared to 226 previously reported cases. Aspects of the clinical evaluations are discussed. All individuals examined were chromosomally normal with no evidence of 11p abnormality as has been reported recently. The relevance of a possible relationship between clinical findings, chromosome abnormalities, and genes present on 11p is discussed. Transmission of this condition is most consistent with autosomal dominant inheritance with incomplete penetrance.     

Portal vein hypoglycemia is essential for full induction of hypoglycemia-associated autonomic failure with slow-onset hypoglycemia

Antecedent hypoglycemia leads to impaired counterregulation and hypoglycemic unawareness. To ascertain whether antecedent portal vein hypoglycemia impairs portal vein glucose sensing, thereby inducing counterregulatory failure, we compared the effects of antecedent hypoglycemia, with and without normalization of portal vein glycemia, upon the counterregulatory response to subsequent hypoglycemia. Male Wistar rats were chronically cannulated in the carotid artery (sampling), jugular vein (glucose and insulin infusion), and mesenteric vein (glucose infusion). On day 1, the following three distinct antecedent protocols were employed: 1) HYPO-HYPO: systemic hypoglycemia (2.52 +/- 0.11 mM); 2) HYPO-EUG: systemic hypoglycemia (2.70 +/- 0.03 mM) with normalization of portal vein glycemia (portal vein glucose = 5.86 +/- 0.10 mM); and 3) EUG-EUG: systemic euglycemia (6.33 +/- 0.31 mM). On day 2, all groups underwent a hyperinsulinemic-hypoglycemic clamp in which the fall in glycemia was controlled so as to reach the nadir (2.34 +/- 0.04 mM) by minute 75. Counterregulatory hormone responses were measured at basal (-30 and 0) and during hypoglycemia (60-105 min). Compared with EUG-EUG, antecedent hypoglycemia (HYPO-HYPO) significantly blunted the peak epinephrine (10.44 +/- 1.35 vs. 15.75 +/- 1.33 nM: P = 0.01) and glucagon (341 +/- 16 vs. 597 +/- 82 pg/ml: P = 0.03) responses to next-day hypoglycemia. Normalization of portal glycemia during systemic hypoglycemia on day 1 (HYPO-EUG) prevented blunting of the peak epinephrine (15.59 +/- 1.43 vs. 15.75 +/- 1.33 nM: P = 0.94) and glucagon (523 +/- 169 vs. 597 +/- 82 pg/ml: P = 0.66) responses to day 2 hypoglycemia. Consistent with hormonal responses, the glucose infusion rate during day 2 hypoglycemia was substantially elevated in HYPO-HYPO (74 +/- 12 vs. 49 +/- 4 micromol x kg(-1) x min(-1); P = 0.03) but not HYPO-EUG (39 +/- 7 vs. 49 +/- 4 micromol x kg(-1) x min(-1): P = 0.36). Antecedent hypoglycemia local to the portal vein is required for the full induction of hypoglycemia-associated counterregulatory failure with slow-onset hypoglycemia.     

Oxidative stress in the brain tissue of laboratory mice with acute post insulin hypoglycemia

Malondialdehyde (MDA), Cu,Zn-superoxide dismutase (Cu,Zn-SOD) and selenium-dependent glutathione peroxidase (GSPHx) are currently considered to be basic markers of oxidative stress. MDA is one of the end-products of the peroxidation of membrane lipids, whereas enzymes Cu,Zn-SOD and GSHPx belong to the natural antioxidants. The role of oxygen free radicals in the pathogenesis of many diseases is well documented. The aim of this study was to ascertain the influence of insulin-induced acute hypoglycemia on oxidative stress in the brain tissue. Hypoglycemia was induced in ICR mice by intraperitoneal administration of insulin at a dose 24 IU/kg. There was a correlation between the severity of hypoglycemia and the levels of MDA, Cu,Zn-SOD and GSHPx. The results showed that in severe hypoglycemia (serum glucose concentration below 1.0 mmol/l) the lipoperoxidation in brain tissue expressed as the level of MDA was higher in comparison with normoglycemic controls (glycemia around 3.7 mmol/l) as well as in comparison with the levels of MDA during moderate hypoglycemia (glycemia ranging between 1-2 mmol/l). This indicates the enhancement of lipoperoxidation in the brain tissue during severe hypoglycemia. However, both enzymes - Cu,Zn-SOD or GSHPx - did not show a similar tendency.     

Insulinothérapie : insuline ou analogues ? Injection ou perfusion ? Boucle ouverte ou boucle fermée ?

Insulin has been purified, humanized and then synthesized by microorganisms. It is mandatory to be able to use insulin, whose kinetics and reproducibility allow glycemia near to normal without increasing hypoglycemia. Use of insulin analogs allows a slight improvement in glycemic control and decrease hypoglycemia frequency. Flexibility of treatment is also improved. “Continuous subcutaneous insulin infusion” (CSII) using rapid analogs mimics physiologic insulin secretion. Major indications are: high HbA1c despite well-managed basal-bolus regimen, severe hypoglycemia, brittle diabetes or “dawn phenomenon”. Children, adolescents as well as pregnancy are also good indications. “Continuous intraperitoneal insulin infusion” major interest is the predominant absorption via the portal system. Kinetic is comparable to rapid analogs delivered subcutaneously. The dramatic reduction of severe hypoglycemic events has been related to good reproducibility of insulin absorption and restoration of glucagon response. Hypoglycemia prone type 1 diabetic patients, uncontrolled with well-managed CSII as well as subcutaneous insulin resistance are the major indications. The association of optimized insulin therapy to “real time continuous glucose monitoring” allows better doses adaptation. Alarms can be set to avoid glycemic excursions and thus severe hypoglycemia. Using these devices, HbA1c is significantly improved without any increase in hypoglycemic events. These devices are one of the steps towards the “closed-loop insulin delivery” concept. Restoration of missing beta-cell function by an automated, glucose-modulated, insulin-delivery system would allow near normal glycemia without the risk of hypoglycemia. First studies show a good regulation of interprandial glycemia; prandial doses seem more difficult to assess. Nevertheless the “holy grail” might be closer than we think.     

Relative hyperglycemia is associated with complications following an acute myocardial infarction: a post-hoc analysis of HI-5 data

Background

Hyperglycemia is associated with increased morbidity and mortality in patients with an acute myocardial infarction (AMI). We evaluated whether complications after AMI are associated with absolute or relative glycemia.

Methods

A total of 192 patients with AMI were randomized to intensive or conventional insulin therapy. Absolute glycemia was defined as mean blood glucose level (BGL) during the first 24 h following randomization. Relative glycemia was defined by the stress hyperglycaemia ratio (SHR), calculated as mean BGL divided by average glucose concentration over the prior 3 months estimated from glycosylated haemoglobin. The primary endpoint was a “complicated AMI”, defined as an AMI complicated by death, congestive cardiac failure, arrhythmia, cardiac arrest, reinfarction, cardiogenic shock, inotrope use or emergency revascularization.

Results

There was not a significant association between mean BGL and complicated AMI (odds ratio (OR) 1.05 per mmol/L glucose increment, 95% confidence intervals (CI) 0.93–1.19). In contrast, SHR was positively associated with a complicated myocardial infarction (OR 1.22 per 0.1 SHR increment, 95% CI 1.06–1.42), and individual complications of death (OR 1.55, 95% CI 1.14–2.11), congestive cardiac failure (OR 1.27, 95% CI 1.05–1.54), arrhythmia (OR 1.31, 95% CI 1.12–1.54) and cardiogenic shock (OR 1.42, 95% CI 1.03–1.97). The relationship between SHR and a complicated AMI was independent of diabetic status, intensive insulin therapy, sex and hypoglycemia.

Conclusions

Relative, but not absolute, glycemia during insulin treatment is independently associated with complications after an AMI. Future studies should investigate whether basing therapeutic glycaemic targets on relative glycemia improves patient outcomes.

     

Antecedent short-term central nervous system administration of estrogen and progesterone alters counterregulatory responses to hypoglycemia in conscious male rats

The aim of this study was to test the hypothesis that antecedent short-term administration of estradiol or progesterone into the central nervous system (CNS) reduces levels of neuroendocrine counterregulatory hormones during subsequent hypoglycemia. Conscious unrestrained male Sprague-Dawley rats were studied during randomized 2-day experiments. Day 1 consisted of an 8-h lateral ventricle infusion of estradiol (1 mug/mul; n = 9), progesterone (1 mug/mul; n = 9), or saline (0.2 mul/min; n = 10). On day 2, a 2-h hyperinsulinemic (30 pmol.kg(-1).min(-1)) hypoglycemic (2.9 +/- 0.2 mM) clamp was performed on all rats. Central administration of estradiol on day 1 resulted in significantly lower plasma epinephrine levels during hypoglycemia compared with saline, whereas central administration of progesterone resulted in increased levels of plasma norepinephrine and decreased levels of corticosterone both at baseline and during hypoglycemia. Glucagon responses during hypoglycemia were unaffected by prior administration of estradiol or progesterone. Endogenous glucose production following day 1 estradiol was significantly lower during day 2 hypoglycemia, and consequently, the glucose infusion rate to maintain the glycemia was significantly greater after estradiol administration compared with saline. These data suggest that 1) CNS administration of both female reproductive hormones can have rapid effects in modulating levels of counterregulatory hormones during subsequent hypoglycemia in conscious male rats, 2) forebrain administration of reproductive hormones can significantly reduce pituitary adrenal and sympathetic nervous system drive during hypoglycemia, 3) reproductive steroid hormones produce differential effects on sympathetic nervous system activity during hypoglycemia, and 4) reduction of epinephrine resulted in significantly blunted metabolic counterregulatory responses during hypoglycemia.     

Oral ingestion of insulin liposomes: Effects of the administration route

We prepared an insulin liposome suspension by hot dispersion (50 °C) of a lipid mixture comprising dipalmitoyl phosphatidylcholine (DPPC) and cholesterol (7:2 molar ratio) in an 80 UI/ml acid bovine insulin solution, followed by two minutes of cold sonification (4 °C). Free insulin was removed by ultracentrifugation and the washed insulin liposomes were resuspended in a 1% aqueous saline solution (pH 3). Administration of these liposomes in the buccal cavity of normal rats caused clear hypoglycemia (?37% of the initial glycemia after one hour and ?44% after $\text{2}\text{1}\text{2}$ hours), but the solution was inactive when introduced by a strictly intragastric route. Hypoglycemic effects were also obtained when a mixture containing a liposome suspension devoid of insulin and 10 UI/100 g b.w. of free insulin was given by the buccal route (?56% of initial glycemia one hour later and ?55% after $\text{2}\text{1}\text{2}$ hours). These results show that the route of liposomal insulin administration strongly influences its biological effects.     

A MaxEnt modelling approach to understand the climate change effects on the distributional range of White-bellied Sholakili Sholicola albiventris (Blanford, 1868) in the Western Ghats,India

Each species is uniquely influenced by anthropogenic climate change. Change in temperature and precipitation due to climate change may lead to species adaptation or extinction, or in some cases, a range shift. To know the influence of climate change on a restricted and endemic bird species of the Western Ghats (WG), White-bellied Sholakili (WBS) Sholicola albiventris (Blanford, 1868), we conducted a study by using species distribution modelling. We considered 73 spatial bias-corrected occurrence points of WBS along with environmental variables like the mean temperature of coldest quarter (Bio 11), precipitation of driest month (Bio 14) and mean precipitation of warmest quarter (Bio 18). We used the MaxEnt application with ENM evaluate tool in R statistical package for developing a climate model for WBS. Bio 11 was observed to be the most crucial climate variable shaping the habitat of WBS. The current study predicts that only 2823km² in WG is suitable for WBS. One-third of this area falls under the protected area network, of which 52% is becoming unsuitable to this narrow endemic due to climate warming. The model also predicts 26% to 45% habitat loss under different climate change scenarios by the 2050s.     

Human platelet alpha granules contain a nonspecific inhibitor of megakaryocyte colony formation: its relationship to type beta transforming growth factor (TGF-beta)

Whole blood serum (WBS) and platelet-poor plasma-derived serum (PDS) from the same normal subject were compared for their abilities to support human megakaryocyte (MK) colony formation. In all cases, PDS promoted the growth of a higher number (20-50%) of MK colonies than did WBS. Increasing amounts of WBS decreased the number of colonies, whereas increasing concentration of PDS had no marked effects. Crude platelet extracts or platelet secretory products from thrombin-activated platelets also elicited an inhibition of MK colony formation in a dose-dependent manner. A complete inhibition was found for a dose equivalent to 1.10(9) platelets/ml and a 50% inhibition in a range of 1.10(7)-1.10(8) platelets/ml. These platelet products were also inhibitory for erythroid progenitor growth. Platelets from two patients with gray platelet syndrome elicited only a minor inhibition of MK growth, suggesting that the platelet alpha granule is the origin of this inhibition. When platelet extracts were acid-treated, the biological activity of the inhibitor on CFU-MK and CFU-E growth was 20-50-fold higher. In addition, a potent stimulatory activity on the growth of day 7 CFU-GM was observed. The enhancement of biological activities by acid treatment suggests that type beta transforming growth factor (TGF-beta) could be involved in this platelet inhibitory activity. The homogeneous native TGF-beta (from 1 pg to 1 ng/ml) produced the same effects previously induced by platelet products. It totally inhibited CFU-MK growth (at a 500 pg/ml), it inhibited CFU-E growth, and it stimulated growth of day 7 CFU-GM in the presence of a colony-stimulating factor. The inhibition of CFU-MK growth was also observed on purified progenitors. In conclusion, these results suggest that TGF-beta may be implicated in negative autocrine regulation of megakaryopoiesis. However, since this molecule has ubiquitous biological activities, its physiologic relevance as a normal regulator of megakaryopoiesis requires further investigation.     

Cerebral Blood Flow and Metabolism During Hypoglycemia in Newborn Dogs

: Cerebral blood flow (CBF) and cerebral metabolic rates (CMR) were studied in newborn dogs during insulin-induced hypoglycemia. Pups were anesthetized, paralyzed, and artificially ventilated with a mixture of 70% nitrous oxide and 30% oxygen to maintain normoxia and normocarbia. Experimental animals were given regular insulin (0.3 units/gm IV); controls received normal saline. CBF was determined using a modification of the Kety-Schmidt technique employing ¹³³Xe as indicator. Arteriovenous differences for oxygen, glucose, lactate, and β-hydroxybutyrate (β-OHB) were also measured, and CMRo₂ and CMR_substrates calculated. Two groups of hypoglycemic dogs were identified; those in which blood glucose levels were greater than 0.5 mm (group 1), and those in which they were less than 0.5 mm (group 2). CBF did not change significantly from control values of 23 ± 10 ml/min/100 g (mean ±s.d. ) at both levels of hypoglycemia. Similarly, hypoglycemia did not alter CMRo₂, significantly from its initial level of 1.05 ± 0.37 ml O₂/min/100 g. Glucose consumption in brain during normoglycemia accounted for 95% of cerebral energy supply with minimal contributions from lactate (4%) and β-OHB (0.5%). During hypoglycemia, CMR_glucose. declined by 29 and 52% in groups 1 and 2, respectively, while CMR,_lactate increased to the extent that this metabolite became the dominant fuel for oxidative metabolism in brain. The cerebral utilization of β-OHB was unaltered by hypoglycemia. The findings indicate that insulin-induced hypoglycemia in the newborn dog is associated with an increase in cerebral lactate utilization, supplementing glucose as the primary energy fuel and thereby preserving a normal CMRo₂. These metabolic responses may contribute to the tolerance of the immature nervous system to the known deleterious effects of hypoglycemia.     

Increasing Blood Glucose Variability Is a Precursor of Sepsis and Mortality in Burned Patients

High glycemic variability, rather than a mean glucose level, is an important factor associated with sepsis and hospital mortality in critically ill patients. In this retrospective study we analyze the blood glucose data of 172 nondiabetic patients 18–60 yrs old with second and third-degree burns of total body surface area greater than 30% and 5%, respectively, admitted to ICU in 2004–2008. The analysis identified significant association of increasing daily glucose excursion (DELTA) accompanied by evident episodes of hyperglycemia (>11 mmol/l) and hypoglycemia (<2.8 mmol/l), with sepsis and forthcoming death, even when the mean daily glucose was within a range of acceptable glycemia. No association was found in sepsis complication and hospital mortality with doses of intravenous insulin and glucose infusion. A strong increase in DELTA before sepsis and death is treated as fluctuation amplification near the onset of dynamical instability.     

Influence of physiological changes of glycaemia on VEPs and visual ERPs

Since hypoglycemia is known to influence cognitive functions, we checked whether the physiological changes in glycemia (after fasting or exertion) can explain the rather high intra-individual variability of event-related potentials (ERPs). Besides the ERPs to "change in coherence of a moving pattern" with reaction time (RT) recording, binocular pattern reversal VEPs and motion-onset VEPs (to linear and radial motion) were also examined in 14 healthy subjects prior to and after 24-h fasting that decreased glycemia from 5.3 to 3.9 mmol/l on the average. We only found one significant change in the latencies and amplitudes of VEPs and ERPs (with no change of RT). The N160 peak in the motion-onset VEPs to radial (expansive) motion (EM-VEPs) showed a larger amplitude at lower glycemia. For evaluation of the exertion influence, we tested glycemia prior to and after 90 min long exercise -- bicycle ergometry with the load set to 2 W/kg in women and 2.5 W/kg in men (average age-related values for W170/kg index). The changes of glycemia to exertion were, however, less distinct than those to fasting. We conclude that in healthy subjects the glycemia decrease due to 24-h fasting or intensive time-limited exercise never reaches the critical value to change the VEP, ERPs and RTs.     

Is hyperglycemia risky enough to justify the increased risk of hypoglycemia linked with tight diabetes control?

There is an ongoing debate about the possible disadvantages of human insulin use with respect to a possibly lower awareness of hypoglycemia than is associated with animal insulin usage. Participants in this debate have not, however, discussed a major contributory factor to this life-threatening acute complication of diabetes, the pressure on patients to achieve normal levels of blood glucose. This pressure stems from the view that hyperglycemia is the major causative factor in the long-term diabetic complications. However, the evidence that supranormal levels of tissue and plasma glucose contribute to the diabetic tissue damage is not as strong as the arguments on behalf of this position. Indeed, elevated glycemia may be no more than a crude index of other, unknown metabolic derangements which may be causative agents in diabetes-associated tissue damage. Intensive efforts to "normalize" glycemia lack experimental and clinical justification, distract attention from other possible mechanisms, and may impose an unnecessary risk on the insulin-dependent diabetic population since intensive "normalization" of glycemia lowers hypoglycemia awareness, and thus increases risk of hypoglycemia, irrespective of the type of insulin used.     

Connection between elastin haploinsufficiency and increased cell proliferation in patients with supravalvular aortic stenosis and Williams-Beuren syndrome

To elucidate the pathomechanism leading to obstructive vascular disease in patients with elastin deficiency, we compared both elastogenesis and proliferation rate of cultured aortic smooth-muscle cells (SMCs) and skin fibroblasts from five healthy control subjects, four patients with isolated supravalvular aortic stenosis (SVAS), and five patients with Williams-Beuren syndrome (WBS). Mutations were determined in each patient with SVAS and in each patient with WBS. Three mutations found in patients with SVAS were shown to result in null alleles. RNA blot hybridization, immunostaining, and metabolic labeling experiments demonstrated that SVAS cells and WBS cells have reduced elastin mRNA levels and that they consequently deposit low amounts of insoluble elastin. Although SVAS cells laid down approximately 50% of the elastin made by normal cells, WBS cells deposited only 15% of the elastin made by normal cells. The observed difference in elastin-gene expression was not caused by a difference in the stability of elastin mRNA in SVAS cells compared with WBS cells, but it did indicate that gene-interaction effects may contribute to the complex phenotype observed in patients with WBS. Abnormally low levels of elastin deposition in SVAS cells and in WBS cells were found to coincide with an increase in proliferation rate, which could be reversed by addition of exogenous insoluble elastin. We conclude that insoluble elastin is an important regulator of cellular proliferation. Thus, the reduced net deposition of insoluble elastin in arterial walls of patients with either SVAS or WBS leads to the increased proliferation of arterial SMCs. This results in the formation of multilayer thickening of the tunica media of large arteries and, consequently, in the development of hyperplastic intimal lesions leading to segmental arterial occlusion.     

Clinical Experience with the Oral Antidiabetic Compound,Tolazamide

In clinical experience totalling 82 patient-years with the sulfonylurea tolazamide, satisfactory control of glycemia was obtained in 70% of diabetics. The preponderance of elderly and newly diagnosed diabetics in the group probably increased the percentage of successes, because when tolazamide was compared with tolbutamide in the same patients the frequency of clinical effectiveness was similar. The ratio of effectiveness by weight for tolbutamide/tolazamide was 6.6/1.0. No toxic effects were detected, side effects were minimal and there appeared to be little tendency to induce unwarranted hypoglycemia.     

Relations among whole blood serotonin and sex,age, diet,and social status in Macaca nemestrina

Whole blood serotonin (WBS) determinations were made in 56 pigtailed macaques (Macaca nemestrina) with approximately equal numbers in three age groups: young-adult (4–5 years), middle-aged (13–14 years), and old (over 18 years). The animals were housed in ten living groups with one female and male of each age group in each living group. Half of the groups were fed a diet high in lipid, cholesterol, simple sugars, and sodium; the other half received a restricted diet. Three determinations per animal showed WBS levels to be stable at two times of day and at a 1-week interval, and individual differences were stable over several months' time. The mean WBS concentrations in M. nemestrina were found to be considerably higher than those reported for other species. The mean levels in females were almost 25% higher than in males. No significant effects of age, diet, or dominance status were detected.     

Differential gender responses to hypoglycemia are due to alterations in CNS drive and not glycemic thresholds

The aims of this study were 1) to determine whether differential glycemic thresholds are the mechanism responsible for the sexual dimorphism present in neuroendocrine responses during hypoglycemia and 2) to define the differences in counterregulatory physiological responses that occur over a range of mild to moderate hypoglycemia in healthy men and women. Fifteen (8 male, 7 female) lean healthy adults underwent four separate randomized 2-h hyperinsulinemic (1.5 mU. kg(-1).min(-1)) glucose clamp studies at euglycemia (90 mg/dl) or hypoglycemia of 70, 60, or 50 mg/dl. Plasma insulin levels were similar during euglycemic and hypoglycemic studies (91-96 +/- 8 microU/ml) in men and women. Hypoglycemia of 70, 60, and 50 mg/dl all resulted in significant increases (P < 0.05, P < 0.01) in epinephrine, glucagon, growth hormone, cortisol, and pancreatic polypeptide levels compared with euglycemic studies in men and women. Plasma norepinephrine levels were increased (P < 0.05) only relative to euglycemic studies at a hypoglycemia of 50 mg/dl. Muscle sympathetic nerve activity (MSNA) increased significantly during hyperinsulinemic-euglycemic control studies. Further elevations of MSNA did not occur until hypoglycemia of 60 mg/dl in both men and women. Plasma epinephrine, glucagon, growth hormone, and pancreatic polypeptide were significantly increased in men compared with women during hypoglycemia of 70, 60, and 50 mg/dl. MSNA, heart rate, and systolic blood pressure responses were also significantly increased in men at hypoglycemia of 60 and 50 mg/dl. In summary, these studies have demonstrated that, in healthy men and women, the glycemic thresholds for activation of epinephrine, glucagon, growth hormone, cortisol, and pancreatic polypeptide occur between 70 and 79 mg/dl. Thresholds for activation of MSNA occur between 60 and 69 mg/dl, whereas norepinephrine is not activated until glycemia is between 50 and 59 mg/dl. We conclude that 1) differential glycemic thresholds are not the cause of the sexual dimorphism present in counterregulatory responses to hypoglycemia; 2) reduced central nervous system efferent input appears to be the mechanism responsible for lowered neuroendocrine responses to hypoglycemia in women; and 3) physiological counterregulatory responses (neuroendocrine, cardiovascular, and autonomic nervous system) are reduced across a broad range of hypoglycemia in healthy women compared with healthy men.     

Different effects of the GABAergic agent sodium valproate on the oxytocin responses to angiotensin II and insulin-induced hypoglycemia in normal men.

The present study was performed in order to establish whether angiotensin II (ANG II) and/or insulin-induced hypoglycemia exert their oxytocin (OT)-releasing effects by interacting with a GABAergic pathway. For this purpose, in 14 normal men the OT responses to ANG II (infusion for 60 min of successively increasing doses of 4, 8 and 16 ng/kg.min, each dose for 20 min; n = 7) or to insulin (0.15 IU/kg)-induced hypoglycemia (n = 7) were evaluated with or without previous treatment with the GABAergic agonist sodium valproate (600 mg in 3 divided doses, p.o.). In all subjects insulin produced a similar hypoglycemic response regardless of sodium valproate administration. Both ANG II and insulin-induced hypoglycemia produced significant increases in plasma OT levels (mean peaks were about 60% higher than baseline). The pretreatment with sodium valproate was unable to change the OT response to hypoglycemia, whereas it abolished the ANG-II-induced OT rise. These data suggest that in man a GABAergic mechanism is involved in the regulation of the OT response to ANG II, but not in the mediation of poglycemia-induced OT release.     

Management of Type 2 Diabetes Mellitus in the Very Elderly: One Practice’s Experience

ObjectiveType 2 diabetes mellitus (T2DM) affects 25% of adults over age 65. Nevertheless, few clinical trials include patients over age 75.MethodsThis case series reports retrospective data on a cohort of 85 patients aged 80 and over (mean 88.1, range 80-104) with T2DM, managed by a single endocrinologist. The practice’s computerized data base was searched for all patients 80 years of age and older with a diagnosis of T2DM.ResultsThe major observations were the significant decrease in the use of agents associated with hypoglycemia (sulfonylureas and insulin), and the beneficial and well-tolerated use of glucagon like peptide-1 receptor analogues (GLP-1 RA). The mean A1c in the entire cohort dropped from 7.6% to 6.6% over a mean of 9 months. Nearly one-half of the cohort were treated with GLP1-RA, reflecting studies demonstrating the safety and efficacy of this class of drugs in less elderly patients. At presentation, 75% were on sulfonylurea and/or insulin; this number was reduced to 27%. Furthermore, none of the patients required short-acting (bolus) insulin to achieve the individualized A1c target.ConclusionPatients with T2DM aged 80 and over respond well to GLP1-RA drugs, drastically reducing the need for agents associated with hypoglycemia. The important question, which will require larger and prospective studies, is whether the lowering of A1c, as shown in this paper, and the use of GLP-1 RA specifically, are associated with improved morbidity and mortality in the very elderly.