Potentiation of hypoglycemic response of glibenclamide by piroxicam in rats and humans.

Influence of piroxicam (PX) on glibenclamide (GL) induced hypoglycemia has been studied in rats, healthy human volunteers and diabetics. GL per se has significantly reduced blood sugar levels in rats and in humans. PX per se has significantly reduced BSLs, in diabetics, while having no significant influence on blood sugar level in rats and healthy human volunteers. Prior administration of PX has potentiated the hypoglycemic effect of GL in rats, healthy human volunteers and diabetics. GL, PX + GL administration have also significantly influenced the glucose tolerance test (GTT) in healthy human volunteers.     

Adaptation of red cell enzymes and intermediates in metabolic disorders.

The metabolic activity of the red cell glycolytic pathway hexose monophosphate shunt (HMP) with dependent glutathione system was studied in patients with hyperthyroidism (n = 10), hyperlipoproteinemia (n = 16), hypoglycemia (n = 25) and hyperglycemia (n = 23). In uncontrolled diabetics and patients with hyperthyroidism the mean value of glucose phosphate isomerase (GPI), glucose-6-phosphate dehydrogenase (G-6-PD), glutathione reductase (GR) was increased, whereas these enzyme activities were reduced in patients with hypoglycemia. Apart from a few values of hexokinase (HK) which were lower than normal the results in hyperlipoproteinemia patients remained essentially unchanged, including the intermediates such as 2,3-diphosphoglycerate (2,3-DPG), adenosine triphosphate (ATP) and reduced glutathione (GSH). While increased rates of 2,3-DPG and ATP in hypoglycemia patients were obtained, these substrates were markedly reduced in diabetics.     

Hypoglycémie spontanée et insuffisance rénale chronique.

Although glucose intolerance occurs as a consequence of chronic renal failure, improvement of a diabetic state by deterioration of renal function is a well known phenomenon. Recently occasional cases of spontaneous hypoglycemia in patients with chronic renal failure have been reported; two such cases and the results of metabolic studies are described in this paper. Pituitary, thyroid and adrenal function appeared to be normal. The results of an oral glucose tolerance test were normal; an appropriate insulin response was demonstrated in one patient, and a slightly elevated basal insulin value with a delayed insulin response to oral administration of glucose was demonstrated in the other. An insulin tolerance test did not support the hypothesis of increased insulin sensitivity as a factor, and the growth hormone response to hypoglycemia was normal. An intravenous glucagon test caused a subnormal increase in plasma glucose concentration, and the intravenous administration of tolbutamide produced hypoglycemia without an increase insulin sensitivity as a factor, and the growth hormone response to hypoglycemia was normal. An intravenous glucagon test caused a subnormal increase in plasma glucose concnetration, and the intravenous administration of tolbutamide produced hypoglycemia without an increase in insulin values. The plasma alanine concentration was low and the proinsulin/insulin ratio was increased. The origin of this hypoglycemia is not clear but is probably multifactorial. However, low hepatic glycogen stores and inadequate gluconeogenesis due to substrate deficiency seem to be involved.     

Decreased response of epinephrine and norepinephrine to insulin-induced hypoglycemia in diabetic autonomic neuropathy

The responses of epinephrine, norepinephrine and other counter-regulatory hormones to insulin-induced hypoglycemia were investigated in 5 diabetics who showed signs of autonomic neuropathy, in 7 age-matched diabetics without autonomic neuropathy and in 7 healthy subjects. The presence of autonomic neuropathy was evaluated by decreased beat-to-beat variation in heat rates during hyperventilation or orthostatic hypotension. Catecholamines were determined by a totally automated plasma catecholamine analyzing system using a two-column system of high performance liquid chromatography. Plasma epinephrine and norepinephrine responses to hypoglycemia in diabetics with autonomic neuropathy were significantly lower than those in diabetics without autonomic neuropathy. Plasma glucagon response in diabetics was apparently attenuated compared to normal controls and there was no significant difference in glucagon response between the two patient groups. Other counter-regulatory hormone responses did not differ among the three groups. The data demonstrate that the responses of plasma epinephrine and norepinephrine to insulin-induced hypoglycemia are impaired in diabetics with autonomic neuropathy.     

Variability of NPH Insulin Preparations

In 1968-69 certain juvenile diabetics receiving NPH insulin began having pre-breakfast glucosuria and mid-morning hypoglycemic reactions. A mail survey of our clinic population and a study done at the Quebec camp for diabetic children in 1969 revealed that certain lot numbers were associated with poor control and that a change to new lot numbers or alternate insulin preparations resulted in better control. “Suspect” insulin preparations and non-suspect insulins were given to newly diagnosed diabetics, and plasma insulin and glucose levels were measured over a 24-hour period. The data confirmed that the “suspect” insulins were causing early hypoglycemia and failing to control hyperglycemia during the latter hours of the 24-hour period. The lower glucose levels were associated with higher plasma insulin levels. The “suspect” insulins were further found to have elevated levels of free insulin in the supernatant fluid.The requirements for quality control of modified insulin preparations are reviewed and suggestions are offered for their improvement.     

Studies on rats with islet beta cell tumors induced by nicotinamide and streptozotocin.

Islet beta cell adenomata were induced in rats by combined treatment with nicotinamide and streptozotocin. Three weeks after treatment marked alterations in glucose tolerance were noted in animals which later exhibited large beta cell tumors. Eight months after treatment, the rats known to have beta cell tumors on the basis of marked hypoglycemia and later confirmed by autopsy showed variable response to a glucose load. Some tumor-bearing rats showed fast response to glucose load, their blood sugar levels were elevated moderately and returned to normal or below normal levels rapidly; these animals are described as having "fast-acting tumors". Rats with "slow-acting tumors" responded sluggishly to a glucose load; their blood glucose pattern was similar to that of subdiabetic animals. Animals with beta cell tumors exhibited elevated serum insulin levels 30 min after glucose administration. Insulin biosynthesis by beta cell adenomata was demonstrated by in vitro incorporation of [14C]leucine into proinsulin and insulin. In the small number of tumor samples studied, a stimulatory effect of glucose on insulin biosynthesis was observed.     

Clinical Presentation and Diagnostic Approach to Hypoglycemia in Adults Without Diabetes Mellitus

ObjectiveTo review the clinical presentation, causes, and diagnostic approach to spontaneous hypoglycemia in adults without diabetes mellitus.MethodsA literature review was performed using the PubMed and Google Scholar databases.ResultsHypoglycemia is uncommon in people who are not on glucose-lowering medications. Under normal physiologic conditions, multiple neural and hormonal counterregulatory mechanisms prevent the development of abnormally low levels of plasma glucose. If spontaneous hypoglycemia is suspected, the Whipple triad should be used to confirm hypoglycemia before pursuing further diagnostic workup. The Whipple criteria include the following: (1) low levels of plasma glucose, (2) signs or symptoms that would be expected with low levels of plasma glucose, and (3) improvement in those signs or symptoms when the level of plasma glucose increases. Spontaneous hypoglycemia can be caused by conditions that cause endogenous hyperinsulinism, including insulinoma, postbariatric hypoglycemia, and noninsulinoma pancreatogenous hypoglycemia. Spontaneous hypoglycemia can also be seen with critical illness, hepatic or renal dysfunction, hormonal deficiency, non–diabetes-related medications, and non–islet cell tumors. The initial diagnostic approach should begin by obtaining a detailed history of the nature and timing of the patient’s symptoms, medications, underlying comorbid conditions, and any acute illness. A laboratory evaluation should be conducted at the time of the spontaneous symptomatic episode. Supervised tests such as a 72-hour fast or mixed-meal test may be needed to recreate the situation under which the patient is likely to experience symptoms.ConclusionWe provide an overview of the physiology of counterregulatory response to hypoglycemia, its causes, and diagnostic approaches to spontaneous hypoglycemia in adults.     

Simplification of the intravenous glucose tolerance test (ivGTT) in rats

A simplified technique was established for the intravenous glucose tolerance test (ivGTT) in unanesthetized rats. In order to evaluate the relation between insulin secretion, glucose load and glucose disappearance rate, precatheterized rats were given glucose ranging in dose from 0.25 to 2.0 g/kg bw by intravenous injection. A highly linear correlation was observed in glucose disappearance rate during a period of 4-32 min. A glucose load greater than 0.5 g/kg ow induced a maximum response in insulin secretion. Small blood samples were collected using the orbital bleeding technique at 4, 16 and 28 minutes after a glucose load of 1.0 g/kg bw had been given and then T1/2, the time taken for the glucose level to fall by one half, was calculated. The mean T1/2 was significantly longer in alloxan- or cyproheptadin-diabetic rats than that in the intacts. These data indicate that a glucose load of 1.0 g/kg administered by intravenous injection with the T1/2 calculated between 4 and 32 minutes would provide an accurate means of assessing pancreatic endocrine function.     

Serum thyrotropin response to combined arginine and thyrotropin-releasing hormone administration provides evidence for an altered somatostatinergic tone in acromegaly.

The aim of this study was to evaluate plasma thyrotropin (TSH), prolactin (PRL) and growth hormone (GH) responses to the TSH-releasing hormone (TRH) test and to a combined arginine-TRH test (ATT-TRH) in 10 normal subjects and in 15 acromegalic patients. In controls, TSH responsiveness to TRH was enhanced by ATT (p less than 0.001). When considering the 15 acromegalic patients as a whole, no significant difference in TSH responses was detected during the two tests. However, patients without suppression of plasma GH levels after oral glucose load showed an increased TSH responsiveness to the ATT-TRH test if compared to TRH alone (p less than 0.025), while patients with partial suppression of plasma GH levels after glucose ingestion showed a decreased TSH responsiveness to ATT-TRH (p less than 0.05). No difference was recorded in PRL and GH responses, evaluated as area under the curve, during TRH or ATT-TRH tests in controls and in acromegalics. In conclusion, (1) normal subjects have an enhanced TSH response to the ATT-TRH test and (2) acromegalic patients without suppression of GH levels after oral glucose load show a TSH responsiveness to the ATT-TRH test similar to that of controls, while acromegalics with partial GH suppression after oral glucose load have a decreased TSH responsiveness to the ATT-TRH test. These data suggest that acromegaly is a heterogeneous disease as far as the somatostatinergic tone is concerned.     

Pre-exposure to glucagon impairs glucose recovery after insulin-induced hypoglycemia in man

The effect of a two hour period of hypo- and hyperglucagonemia on a subsequent insulin-induced hypoglycemia was studied in nine healthy volunteers. Hypoglucagonemia was provoked by somatostatin (50 micrograms/h) and hyperglucagonemia by glucagon infusion (3.25 ng/kg/min) together with somatostatin, while saline alone was given as control. Hypoglycemia was induced by insulin infusion (2.4 U/h) for two hours. The hyperglycemic effect of glucagon was transient and similar nadir glucose levels were obtained in the three experiments. Preinfusion with glucagon impaired glucose recovery in spite of preserved secretion of epinephrine during restitution of blood glucose in this experiment. It is concluded, that a period of elevated glucagon levels deteriorates the restitution of blood glucose following hypoglycemia. Hyperglucagonemia, commonly apparent in poorly controlled diabetics, may therefore be of importance in explaining the impaired recovery of blood glucose seen in such patients after hypoglycemia.     

The leucocyte migration inhibition test and subpopulations of peripheral lymphocytes in insulin-dependent diabetics.

The leucocyte migration inhibition test (LMT) was performed by the agarose plate method with thyroid and pancreatic antigens in patients with insulin-dependent or independent diabetes mellitus. The mean migration indices with thyroglobulin, thyroid mitochondria and beef insulin were not significantly different in insulin-dependent diabetics from those in insulin-independent diabetics or normal controls. However, significant inhibition of leucocyte migration was observed in insulin-dependent diabetics when thyroid microsome or pancreatic extract was used as antigen. Although no significant difference was found in the percentages of T and B lymphocytes between insulin-dependent diabetics and insulin-independent diabetics or normal controls, the results of LMT strongly suggest the presence of cellular immunity against the thyroid and pancreas in insulin-dependent juvenile-onset diabetes.     

Diabetic dimorphism according to acetylator status.

Two groups of diabetics and 19 normal controls had their rate of acetylation of sulphadimidine measured. Among 47 patients with maturity onset diabetes the 29 fast acetylators were older at diagnosis and, at a given glucose concentration, had a higher pretreatment fasting insulin concentration than slow acetylators. They also had a larger first-phase insulin secretion in response to intravenous glucose both before and after one month''s dietary treatment. The greatest difference between fast and slow acetylators was in the first-phase secretion of insulin after a month''s treatment. The proportion of fast acetylators among the second group of diabetics, who had been admitted to improve their glucose concentrations or for treatment of tissue damage, was similar to that among the normal controls (50% and 47% respectively). The data seem to indicate that diabetics are fast acetylators unexpectedly often, but it is not clear whether the dimorphism according to acetylator status produces a differential risk of neuropathy or of any other type of diabetic tissue damage.     

A case of autoimmune insulin antibody syndrome associated with polymyositis, empty sella and apparent high urinary output of immunoreactive insulin.

Patients with autoimmune insulin antibody are characterized by hypoglycemic attacks and antibodies to insulin in serum without prior insulin administration. In the present report, a patient with hypoglycemia due to autoimmune insulin antibody associated with primary empty sella syndrome and polymyositis appeared to have high urinary immunoreactive insulin (IRI) in the face of normal urinary C peptide. Consequently, the urinary IRI/C peptide ratio was apparently high. The amelioration of hypoglycemic attacks and polymyositis by prednisolone treatment was accompanied by the disappearance of the antibodies and complete normalization of the urinary IRI and IRI/C peptide ratio. No comparable rise in the urinary IRI and IRI/C peptide ratio was observed in the patients with other disorders studied. Glucose clamp and glucose tolerance study showed decreased sensitivity to exogenous or newly secreted insulin, prolonged half disappearance time of serum insulin, and normal disappearance of blood glucose. These results were consistent with the idea that autoantibodies buffered the effect of exogenous or newly secreted insulin and maintained a relatively constant level of serum free insulin which was not high enough when a large amount of glucose was loaded, but was too high after prolonged fasting, which eventually caused hypoglycemic attacks.     

Erythrocyte membrane ATPases in diabetes: effect of dikanut (Irvingia gabonensis)

The levels of the three ATPases found in the erythrocyte membrane of diabetic patients were significantly lower than normal subjects. The distribution of the enzymes was also different. Na+,K+-ATPase and Mg2+-ATPase reflected the status of blood glucose more than Ca2+-ATPase. The ratio between two of the ATPases was sensitive to glycemic response. When dikanut, a viscous preparation, was fed to diabetics for 4 weeks, blood glucose became normal and the activities of the three ATPases increased significantly. The ratio among the enzymes also approached that of normal subjects. A relationship was found between the blood glucose level and erythrocyte membrane ATPases which, if linked to insulin binding or level, may provide a rapid inexpensive assay in diabetes research.     

Glucoreceptors located in the brain mediate NPY release induced by hypoglycemia in normal men

The NPY secretory pattern after an insulin tolerance test (ITT) (0.15 IU/kg body weight) was evaluated in 8 normal men. They were infused with normal saline (control test), glucose or fructose. Insulin-induced hypoglycemia produced a significant increment in serum NPY in the control test. The infusion of fructose was unable to change the NPY secretory pattern during insulin-induced hypoglycemia. In contrast, the NPY increase during ITT was completely abolished when the concomitant infusion of glucose prevented insulin-induced hypoglycemia. These results exclude a direct role of hyperinsulinemia in the mechanism underlying the stimulation of NPY secretion during ITT. Furthermore, since glucose but not fructose crosses the blood-brain-barrier (BBB), the NPY increase during ITT appears to be generated by low glucose concentrations at the level of glucosensitive areas located inside the brain.     

A Comparison of the Oral and Intravenous Glucose Tolerance Tests in Non-Diabetic,Possible Diabetic and Diabetic Subjects

Results of standard three-hour oral glucose tolerance tests (OGTT) and intravenous glucose tolerance tests (IVGTT), performed on the same subjects, were compared in an attempt to determine their value in the diagnosis of borderline diabetes. A total of 83 such tests were carried out on 81 subjects. Applying the U.S. Public Health Service point count method to the results of the OGTT test, there were 38 normals, 23 possible diabetics and 22 diabetics. A constant (K) was calculated from the glucose disappearance rate in the IVGTT curves.K disagreed with the OGTT classification to a significant extent, especially in the possible diabetic and non-diabetic groups. Also, the correlation coefficients between K and the OGTT values were not impressive. This does not mean that one test is superior to the other, only that the accuracy of either test in diagnosing early diabetes is doubtful.Technically, the IVGTT was more difficult and time-consuming, and six of the 81 subjects suffered from thrombophlebitis at the site of glucose injection.     

The Interaction of Transport and Metabolism on Brain Glucose Utilization: A Reevaluation of the Lumped Constant

Abstract: The relative cerebral cortical metabolism of glucose (GLU) and 2-deoxy-D-glucose (DG) was measured in vivo in control and insulin-treated hypoglycemic rats. The ratio of the utilization rate constants for the two hexoses, i.e., K _DG/ K _CLU is defined as the Hexose Utilization Index (HUI). The HUI was found to be invariant in rats whose cerebral glucose content exceeded 1 μmo1.g⁻¹ wet weight (HUI = 0.48 ± 0.07). Severe hypoglycemia (plasma glucose <2 mM) effected a shift in the HUI to 1.04 ± 0.21. The results are consistent with a model in which the interpretation of the HUI is determined by the rate of transport into brain, or subsequent phosphorylation, as the rate-limiting step for hexose utilization.     

Ten-year follow-up report on Birmingham Diabetes Survey of 1961. Report by the Birmingham Diabetes Survey Working Party.

In a diabetes survey in 1960-1, 808 patients from a whole-practice population who either had glycosuria or were used as age- and sex-matched controls were given a 50-g oral glucose tolerance test (GTT). Ten years later the test was repeated in 382 cases. Of the original group, 126 had died and a similar number refused the second test. The original GTT results were classed as normal or as showing GTT diabetes, lag storage, renal glycosuria, or miscellaneous abnormalities. Most of those who converted to florid diabetes came from the GTT diabetes group, all the remainder having shown another minor degree of abnormality in the test; 23% with GTT diabetes, however, remained unchanged, while 32% returned to normal or had only minor anomalies. Of the original lag-storage group 57% remained unchanged or became normal, though 24% had converted to a diabetic abnormality. Renal glycosuria was an innocent peculiarity. The various miscellaneous abnormalities tended to change and showed an excessive conversion to diabetes. There was no accelerating trend towards diabetes in the second five years of follow-up. Those who developed florid diabetes showed an excess mortality comparable to that of clinical diabetics in general. Those who remained normal had the lowest mortality, while those with minor abnormalities occupied an intermediate position.     

Glycosylated haemoglobin concentrations in newly diagnosed diabetics before and during treatment.

Concentrations of total glycosylated haemoglobins (Hb A1) were measured in 40 diabetics at diagnosis and at monthly intervals after treatment with chlorpropamide, insulin, or diet alone was begun. The mean Hb A1 concentration at presentation in 16 patients treated with chlorpropamide was significantly higher than that in 12 patients treated with insulin, and the duration of glycaemic symptoms was much longer in the chlorpropamide-treated group. In contrast, the mean plasma glucose concentration was similar in both groups. The mean concentrations of Hb A1 and plasma glucose at diagnosis in the 12 patients treated by diet alone were lower than those in the other two groups, and most of these patients were free of symptoms. Treatment quickly relieved symptoms and lowered plasma glucose in all patients. The Hb A1 concentration fell significantly with treatment such that after two months there was no significant difference between the three groups, although results remained above the normal range. These findings support the theory that the Hb A1 concentration reflects the blood glucose control over the previous one to two months and suggest that the duration of hyperglycaemia may be important in determining the Hb A1 concentration as well as the absolute blood glucose concentration.     

Insulin and Non-esterified Fatty Acid Metabolism in Asymptomatic Diabetics and Atherosclerotic Subjects

Glucose, insulin and non-esterified fatty acid (NEFA) metabolism was studied in 18 patients (mean age 49) with ischemic heart disease (IHD) who did not have any concurrent disorder known to affect glucose tolerance.Significant hyperglycemia and hyperinsulinemia were observed in the IHD patients after oral glucose. The serum NEFA declined to a lower level in IHD patients than in normal subjects who received glucose.In response to hypoglycemia following the oral administration of sodium tolbutamide the serum NEFA in IHD patients rose to a higher level in the rebound phase than in normal subjects. This rise was preceded by a sharp decline in the concentration of circulating insulin.In 72% of the patients (IHD sub-group) the blood glucose values after oral glucose satisfied the criteria for the diagnosis of diabetes mellitus. The metabolic changes following oral glucose in the IHD sub-group and in asymptomatic diabetics (AD), free of clinical atherosclerosis and with similar impairment in glucose tolerance, were compared. Despite insignificantly lower insulin concentrations, the AD showed a significantly lesser fall in circulating NEFA than did the patients in the IHD sub-group. After oral sodium tolbutamide the IHD sub-group patients showed a greater insulin response and a greater rebound increase in circulating NEFA than did the AD.These differences in response to oral glucose and to sodium tolbutamide suggest that the pathogenesis of the impaired glucose tolerance in IHD may be different from that responsible for abnormal carbohydrate tolerance in asymptomatic diabetics without evident atherosclerosis. The abnormalities demonstrated in glucose, insulin and NEFA metabolism may play a role in the genesis of the hyperlipoproteinemia and atherosclerosis of IHD. One possible mechanism leading to hyperlipoproteinemia in ischemic heart disease compatible with the data is discussed.