Carbohydrate metabolism in pregnancy. Part I. Diurnal plasma glucose profile in normal and diabetic women.

Diurnal plasma glucose profiles and oral glucose tolerance during pregnancy were studied in normal women, chemical diabetics, and insulin-requiring diabetics. In normal women the mean diurnal plasma glucose rose by only 0.22 mmol/1 (4 mg/100 m1) during pregnancy. Mild chemical diabetes resulted in an increase in both the mean diurnal glucose concentration and the fluctuation of plasma glucose levels during the day. Fluctuation in glucose concentration in insulin-dependent diabetics was about three times that found in non-diabetic women of similar gestation, with relative hyperglycaemia during the day and hypoglycaemia at night. In non-diabetic women and those with chemical diabetes the mean dirunal glucose correlated closely with the total area under the three-hour oral glucose tolerance curve and significantly, but less closely, with the two-hour glucose tolerance test value.     

Plasma free fatty acids in pregnant insulin-independent Natal Indian diabetics

A study was undertaken in Natal Indians to determine the insulin secretory response and the comparative degree of free fatty acidaemia in normal and insulin-independent diabetic pregnant women. The fasting plasma FFA and glucose levels were found to be substantially greater in the diabetic subjects. The pattern of plasma FFA and glucose response to exogenous insulin was similar in both groups. Endogenous insulin produced a similar FFA response, but a markedly obtunded blood sugar response occurred among the diabetics despite adequate plasma insulin levels. The significance of the differential effect of endogenous insulin on FFA and glucose metabolism in pregnant insulin-independent Natal Indian diabetics is discussed.     

Placental growth hormone is not suppressed by oral glucose loading in normal human pregnancy.

Placental growth hormone (PGH) progressively replaces pituitary growth hormone in the maternal circulation from mid-gestation onwards in human pregnancy. Our previous investigations have shown that placental growth hormone concentrations correlate well with foetal growth. Despite the apparent correlation between PGH and birthweight, the physiology of its secretion during pregnancy has not been well defined. We investigated the response of maternal serum PGH to oral glucose loading in pregnant women (n = 24) who demonstrated normal glucose tolerance at a mean gestation of 29 weeks. Mean (SEM) fasting PGH concentrations were high (36.9 [6.4] ng/ml). No suppression of PGH was noted at one, two or three hours after a 75 g oral glucose load. Similarly, no changes were noted in growth hormone binding protein or in calculated free PGH over the course of the glucose tolerance test. As expected, insulin concentrations rose sixfold and insulin like growth factor binding protein 1 concentrations fell by 20 % with glucose loading. Correlation analysis showed maternal weight, BMI, fasting serum glucose serum insulin to be significantly correlated with the babies' birthweight. Our results support the proposition that PGH concentrations in maternal serum are not suppressed by oral glucose loading in non-diabetic mothers.     

Metabolic effects of chronic prazosin treatment

The effects of chronic (3 mg/day for 1 week) administration of the vasodilator drug prazosin on several metabolic and endocrine variables were evaluated in 12 hypertensive patients, 6 with normal and 6 with abnormal oral glucose tolerance test (OGTT). After 1 week prazosin treatment there were no significant modifications in fasting plasma glucose, serum free fatty acids (FFA), cholesterol, triglycerides, insulin (IRI), growth hormone (GH), prolactin (PRL) and gastrin levels; oral glucose tolerance and IRI response to glucose were unchanged in normal subjects, while in chemical diabetics there was a significant improvement in glucose tolerance and a slight increse in IRI secretion. Therefore, the untoward metabolic effects of acute prazosin administration, i.e. increased plasma glucose and serum FFA, are not sustained during chronic treatment, which may even improve glucose metabolism in diabetic patients.     

Chronobiological pattern of growth hormone secretion in normal subjects and in retinopathic diabetics. Lack of suppression by a plurichronocorticoid drug.

Nyctohemeral variations in plasma concentrations of HGH, glucose, and FFA were studied in 22 normal subjects and 48 diabetic patients affected with retinopathy. In the normal subjects, (fourteen males and eight females, mean age 40+/-3 years; body weight less than 110% of I.B.W.) the determinations were made on blood samples drawn every hour. Seven of these normal subjects were examined before and after 10 days of administration of a new plurichronocorticoid drug (administered at 08(00) and 15(00), with a total amount of 14 mg of prednisolone and 15 mg of cortisone). In patients with diabetic retinopathy (32 male and sixteen female patients, mean age 46+/-2 years, body weight less than 110% of I.B.W.) the determinations were made on blood samples drawn every 3 hrs. All the diabetic patients were insulin treated and were under good or discrete metabolic control, and presented advanced retinopathy. Both in the normal subjects and in retinopathic diabetics, the mean HGH curve showed a characteristic elevation during the early nighttime hours (between 21(00) and 02(00). Despite higher values in plasma glucose and FFA, in diabetics the nocturnal elevation of HGH was only slightly lower than in the normals. The comparison between daytime and nighttime determinations, both in the normal subjects and in the diabetics, reveals statistically significant differences. These results suggest that in subjects with diabetic retinopathy, in the phase of good or discrete metabolic control, spontaneous HGH secretion is not increased, and that nocturnal elevation of HGH is not substantially influenced by higher plasma levels of glucose and FFA. Ten days of plurichronocorticoid treatment with a new drug which exhausts its activity before the evening, did not modify the circadian rhythm of HGH.     

Nocturnal free fatty acids are uniquely elevated in the longitudinal development of diet-induced insulin resistance and hyperinsulinemia

Obesity is strongly associated with hyperinsulinemia and insulin resistance, both primary risk factors for type 2 diabetes. It has been thought that increased fasting free fatty acids (FFA) may be responsible for the development of insulin resistance during obesity, causing an increase in plasma glucose levels, which would then signal for compensatory hyperinsulinemia. But when obesity is induced by fat feeding in the dog model, there is development of insulin resistance and a marked increase in fasting insulin despite constant fasting FFA and glucose. We examined the 24-h plasma profiles of FFA, glucose, and other hormones to observe any potential longitudinal postprandial or nocturnal alterations that could lead to both insulin resistance and compensatory hyperinsulinemia induced by a high-fat diet in eight normal dogs. We found that after 6 wk of a high-fat, hypercaloric diet, there was development of significant insulin resistance and hyperinsulinemia as well as accumulation of both subcutaneous and visceral fat without a change in either fasting glucose or postprandial glucose. Moreover, although there was no change in fasting FFA, there was a highly significant increase in the nocturnal levels of FFA that occurred as a result of fat feeding. Thus enhanced nocturnal FFA, but not glucose, may be responsible for development of insulin resistance and fasting hyperinsulinemia in the fat-fed dog model.     

Thiazolidinediones improve beta-cell function in type 2 diabetic patients

Thiazolidinediones (TZDs) improve glycemic control and insulin sensitivity in patients with type 2 diabetes mellitus (T2DM). There is growing evidence from in vivo and in vitro studies that TZDs improve pancreatic beta-cell function. The aim of this study was to determine whether TZD-induced improvement in glycemic control is associated with improved beta-cell function. We studied 11 normal glucose-tolerant and 53 T2DM subjects [age 53+/-2 yr; BMI 29.4+/-0.8 kg/m2; fasting plasma glucose (FPG) 10.3+/-0.4 mM; Hb A1c 8.2+/-0.3%]. Diabetic patients were randomized to receive placebo or TZD for 4 mo. Subjects received 1) 2-h OGTT with determination of plasma glucose, insulin, and C-peptide concentrations and 2) two-step euglycemic insulin (40 and 160 mU.m-2.min-1) clamp with [3-(3)H]glucose. T2DM patients were then randomized to receive 4 mo of treatment with pioglitazone (45 mg/day), rosiglitazone (8 mg/day), or placebo. Pioglitazone and rosiglitazone similarly improved FPG, mean plasma glucose during OGTT, Hb A1c, and insulin-mediated total body glucose disposal (Rd) and decreased mean plasma FFA during OGTT (all P<0.01, ANOVA). The insulin secretion/insulin resistance (disposition) index [DeltaISR(AUC)/Deltaglucose(AUC)/IR] was significantly improved in all TZD-treated groups: +1.8+/-0.7 (PIO+drug-na?ve diabetics), +0.7+/-0.3 (PIO+sulfonylurea-treated diabetics), and 0.7+/-0.2 (ROSI+sulfonylurea-withdrawn diabetics) vs. -0.2+/-0.3 in the two placebo groups (P<0.01, all TZDs vs. placebo, ANOVA). Improved insulin secretion correlated positively with increased body weight, fat mass, and Rd and inversely with decreased plasma glucose and FFA during the OGTT. In T2DM patients, TZD treatment leads to improved beta-cell function, which correlates strongly with improved glycemic control.     

Plasma fibrinogen levels in type II diabetics

Plasma fibrinogen levels measured by an immunoassay method on 170 type II diabetic patients exhibited a bimodal distribution with one small population demonstrating levels greater than those of the normal reference range. The mean plasma level of fibrinogen in the type II diabetics was higher than that of the normal population. Spearman's correlations demonstrated statistically significant positive relationships in type II diabetic patients between fibrinogen levels and fasting glucose levels, serum cholesterol, glycosylated hemoglobin and urinary albumin excretion rate. These relationships suggest that increased plasma fibrinogen may be another marker for coronary heart disease complications encountered by diabetics.     

Effect of feeding regimen on diurnal variation of breathing movements in late-gestation fetal sheep

There is a diurnal variation in the mean incidence and amplitude of fetal breathing movements (FBMs) in sheep after approximately 120 days gestation. To determine whether this variation is caused by diurnal fluctuations in plasma glucose or prostaglandin (PG) concentrations, we studied two groups of pregnant sheep fed either once daily at 1100 h or every 2 h for 24 h. Maternal and fetal blood samples were taken every 2 h from 0900 to 0900 h the next day for assay of plasma glucose and PGE2 and PGF2 alpha concentrations. FBMs were recorded throughout the 24 h. The mean fetal plasma glucose concentrations of the once-daily and multifed groups were not different, but there was a significant difference between the two groups in the 24-h pattern of fetal glucose concentrations. In the once-daily fed group, plasma glucose concentrations reached a peak 8 h after maternal feeding and then declined, whereas in the multifed group, fetal plasma glucose concentrations reached a plateau and were constant from 1300 to 0900 h the next day. Fetal plasma PGE2 and PGF2 alpha concentrations did not show a significant change with time of day in either group. There was a significant diurnal variation in the incidence and amplitude of FBMs in each of the two feeding groups, and the 24-h pattern of FBMs did not differ significantly between groups. Therefore it would appear that the diurnal variation of FBMs is not a consequence of the maternal feeding regimen or diurnal changes in plasma glucose or PG concentrations.     

Correlation between maternal inflammatory markers and fetomaternal adiposity

Outside pregnancy, both obesity and diabetes mellitus are associated with changes in inflammatory cytokines. Obesity in pregnancy may be complicated by gestational diabetes mellitus (GDM) and/or fetal macrosomia. The objective of this study was to determine the correlation between maternal cytokines and fetomaternal adiposity in the third trimester in women where the important confounding variable GDM had been excluded. Healthy women with a singleton pregnancy and a normal glucose tolerance test at 28weeks gestation were enrolled at their convenience. Maternal cytokines were measured at 28 and 37weeks gestation. Maternal adiposity was assessed indirectly by calculating the Body Mass Index (BMI), and directly by bioelectrical impedance analysis. Fetal adiposity was assessed by ultrasound measurement of fetal soft tissue markers and by birthweight at delivery. Of the 71 women studied, the mean maternal age and BMI were 29.1years and 29.2kg/m(2) respectively. Of the women studied 32 (45%) were obese. Of the cytokines, only maternal IL-6 and IL-8 correlated with maternal adiposity. Maternal TNF-α, IL-β, IL-6 and IL-8 levels did not correlate with either fetal body adiposity or birthweight. In this well characterised cohort of pregnant non-diabetic women in the third trimester of pregnancy we found that circulating maternal cytokines are associated with maternal adiposity but not with fetal adiposity.     

Carbohydrate metabolism in pregnancy. Part II. Relation between maternal glucose tolerance and glucose metabolism in the newborn.

The objective of clinical management of the pregnant diabetic woman is to prevent the serious adverse effects of an abnormal glucose environment on the fetus. Neonatal glucose assimilation and insulin release over the first two hours of life were correlated with various indices of maternal carbohydrate metabolism in the third trimester. Of the 31 mothers studied 21 were defined as normal and 10 as having chemical diabetes. Neontal glucose assimilation during the first two hours of life correlated strongly with functions of both maternal glucose tolerance and mean diurnal glucose level, the strongest correlation being with the area under the three-hour oral glucose tolerance curve (P less than 0.001), Two-hour neonatal plasma glucose values of under 1.7 mmol/1 (30 mg/100 ml) were found only in the newborn of women whose glucose tolerance area measured over 41.6 area units (750 traditional units); thus, even in the borderline diabetic range glucose tolerance testing during the last trimester of pregnancy may be valuable in predicting likelihood of neonatal hypoglycaemia. The findings also shed light on the possible sensitizing role of mild maternal hyperglycaemia on fetal insulin production and secretion.     

Metabolic effects of weight reduction in obese diabetics and nondiabetics.

A weight loss of about 10 kg was acheived by means of individual periods of total fasting, hypocaloric diets and physical activity in three groups of patients: maturity-onset diabetics, patients with pathological OGTT and overweight persons with normal OGTT. Adipocyte volume decreased in all groups, glucose tolerance improved. IRI curves showed a significant overall lowering and FFA concentrations during OGTT were dimished.     

Inhibition of adipose tissue lipolysis increases intramuscular lipid and glycogen use in vivo in humans

This study investigates the consequences of inhibition of adipose tissue lipolysis on skeletal muscle substrate use. Ten subjects were studied at rest and during exercise and subsequent recovery under normal, fasting conditions (control trial, CON) and following administration of a nicotinic acid analog (low plasma free fatty acid trial, LFA). Continuous [U-13C]palmitate and [6,6-2H2]glucose infusions were applied to quantify plasma free fatty acid (FFA) and glucose oxidation rates and to estimate intramuscular triacylglycerol (IMTG) and glycogen use. Muscle biopsies were collected to measure 1) fiber type-specific IMTG content; 2) allosteric regulators of hormone-sensitive lipase (HSL), glycogen phosphorylase, and pyruvate dehydrogenase; and 3) the phosphorylation status of HSL at Ser563 and Ser565. Administration of a nicotinic acid analog (acipimox) substantially reduced plasma FFA rate of appearance and subsequent plasma FFA concentrations (P < 0.0001). At rest, this substantially reduced plasma FFA oxidation rates, which was compensated by an increase in the estimated IMTG use (P < 0.05). During exercise, the progressive increase in FFA rate of appearance, uptake, and oxidation was prevented in the LFA trial and matched by greater IMTG and glycogen use. Differential phosphorylation of HSL or relief of its allosteric inhibition by long-chain fatty acyl-CoA could not explain the increase in muscle TG use, but there was evidence to support the contention that regulation may reside at the level of the glucose-fatty acid cycle. This study confirms the hypothesis that plasma FFA availability regulates both intramuscular lipid and glycogen use in vivo in humans.     

Plasma free fatty acid transport during prolonged glucose consumption and its relationship to plasma triglyceride fatty acids in man

Plasma free fatty acid (FFA) transport in human subjects has been studied during the course of prolonged ingestion of different amounts of glucose. Compared with the fasting state, hypocaloric glucose intake resulted in marked suppression of net transport of FFA with no change in (fractional) turnover rate. There was no further suppression of net transport of FFA when the intake was increased to isocaloric or hypercaloric levels, but there was a significant increase in the (fractional) turnover rate, indicating an enhancement of clearance mechanisms. During the 20-24-hr period of fasting after isocaloric glucose consumption, the (fractional) turnover rate quickly fell to that found in the fasting individual, whereas net transport remained suppressed for much longer. This suggested that ingestion of glucose maintains an influence on lipolysis longer than on esterification. During this period of fasting after glucose administration, the contribution of plasma FFA to circulating triglyceride fatty acids increased with time and was positively and significantly correlated with the changes in the net transport of plasma FFA.     

Diurnal rhythms of plasma growth hormone,somatostatin, thyroid hormones,cortisol and glucose concentrations in rainbow trout,Oncorhynchus mykiss,during progressive food deprivation

Abstract

The diurnal patterns of changes in plasma cortisol, growth hormone (GH), somatostatin‐14 (SRIF), thyroid hormones (L‐thyroxine, T₄ and triiodo‐L‐thyronine, T₃) and glucose were investigated in rainbow trout, Oncorhynchus mykiss, both during single meal‐feeding and during a progressive fast of 13 weeks. All measured variables exhibited a diurnal pattern in fed rainbow trout, most of which appeared to be correlated with the time of feeding (30–60 min after the onset of light), while additional changes, associated with the scotophase were also found for cortisol. Although fasting had no affect on mean daily plasma cortisol or SRIF concentrations, there was a progressive increase in mean daily plasma GH concentrations and a progressive decrease in mean daily plasma thyroid hormone and glucose concentrations associated with fasting. However, for GH, significant changes were not evident until week 10 of the fast. In addition, fasting appeared to phase‐shift the diurnal patterns of plasma GH, cortisol and glucose concentrations; the consequence of such a shift is that conclusions as to the effects of fasting, if based on a single time of sampling, may be flawed.     

Plasma selenium decrease during pregnancy is associated with glucose intolerance

There is an increased requirement for selenium during pregnancy, presumably for fetal growth, which manifests as decreasing maternal blood and tissue selenium concentrations. These decreases are greater in pregnant women with gestational or preexisting diabetes. We measured selenium status and glucose tolerance between wk 12 and 34 of gestation in 22 pregnant women. We found that the increase in blood glucose in response to an oral glucose challenge at 12 wk gestation and the increase in fasting glucose during pregnancy were inversely correlated with plasma selenium concentration. Women with lower plasma glutathione peroxidase activities during pregnancy also tended to have higher fasting glucose levels. These inverse relationships between selenium status and glucose tolerance are consistent with earlier observations that suggest a link between selenium and glucose metabolism. The observation that changes in serum glucose were not accompanied by changes in insulin suggests that selenium may affect glucose metabolism downstream from insulin, or through independent energy regulatory pathways such as thyroid hormone.     

Fatty acid metabolism in fasting elephant seal pups

Summary The turnover of two plasma free fatty acids (FFA) were measured in 5 northern elephant seal pups (Mirounga angustirostris) after approximately 2 months of post-weaning fasting. Turnover was determined using simultaneous bolus injections of¹⁴C-palmitate,³H-oleate and Evans blue (EB) administered via an indwelling extradural intravertebral catheter. At this time in their natural fast, the seals exhibited plasma FFA levels and turnover values higher than reported for other marine mammals and most terrestrial carnivores. There was no consistent difference between plasma FFA turnover measured by palmitate or oleate tracers. The results imply that FFA metabolism is the primary source of energy during fasting. This is interesting in light of previous observations of minimal ketoacid accumulation and low levels of glucose and protein energy production during fasting in these juvenile seals.     

Serum fructosamine in assessment of diabetic control and relation to thyroid function

Measurement of serum fructosamine using a Roche kit is a simple and reliable method for the estimation of glycated serum proteins. The value of serum fructosamine can be affected by hyperglycemia in diabetics and an abnormal turnover rate of serum protein in patients with thyroid dysfunction. We measured the serum fructosamine level in 18 normal control subjects, 71 diabetics (8 IDDM, 63 NIDDM) and 46 non-diabetic untreated patients with thyroid dysfunction (28 hyperthyroidism, 18 hypothyroidism). The serum fructosamine level was significantly increased in the diabetics compared with the normal control subjects (3.84 +/- 0.15 mmol/l vs 2.58 +/- 0.08; mean +/- SE, P less than 0.01). The serum fructosamine level in the diabetics was positively correlated with the fasting plasma glucose and HbAlc level, showing the highest correlation with fasting plasma glucose at 2 weeks before and with the HbAlc level at 2 weeks after serum fructosamine measurement. In the patients with thyroid dysfunction, the serum fructosamine level in hyperthyroidism (2.08 +/- 0.03 mmol/l) and hypothyroidism (3.11 +/- 0.07 mmol/l) were significantly lower (P less than 0.001) and higher (P less than 0.001) than the normal control subjects (2.58 +/- 0.08 mmol/l), respectively. Furthermore, the serum fructosamine level in these patients was negatively correlated with the level of serum thyroid hormones such as T3 (P less than 0.001) and T4 (P less than 0.001). It is concluded that measurement of serum fructosamine is clinically useful for the evaluation of shorter-term glycemic control in diabetics, but its level for diabetic patients with thyroid dysfunction must be cautiously interpreted.     

Fasting plasma magnesium concentrations and glucose disposal in diabetes.

Fasting plasma concentrations of magnesium were measured by neutron activation analysis in 30 non-diabetics and 87 diabetics (55 non-insulin-treated, 32 insulin treated). Plasma concentrations of magnesium were lowest in the insulin treated group (mean 0.84 (SEM 0.01) mmol/1; 2.0 (0.02) mg/100 ml), intermediate in the non-diabetics (mean 0.89 (SEM 0.01) mmol/1; 2.2 (0.02) mg/100 ml), and highest in the non-insulin-treated diabetics (mean 0.95 (SEM 0.02) mmol/1; 2.3 (0.05) mg/100 ml). In all diabetics plasma magnesium concentrations were inversely related to plasma glucose values (rs = -0.33; p less than 0.01) and in non-insulin-treated patients to plasma insulin concentrations (rs = -0.28; p less than 0.05), the former confirming previous observations. In 67 of the diabetics the KG constant for disposal rate of glucose during a standard intravenous glucose tolerance test was directly related to fasting plasma magnesium concentrations, and this relation persisted after controlling for age, sex, body mass index, type of treatment, and glucose and insulin values. This direct relation of plasma magnesium concentration with glucose disposal was unexplained by its influence on insulin secretion but was related to insulin sensitivity; hence magnesium may be an important determinant of insulin sensitivity in maturity onset diabetes.     

Overwinter fasting and re-feeding in rainbow trout: plasma growth hormone and cortisol levels in relation to energy mobilisation

This study investigated the roles of cortisol and growth hormone (GH) during a period of fasting in overwintering salmonid fish. Indices of carbohydrate (plasma glucose, liver glycogen), lipid (plasma free fatty acids (FFAs)) and protein metabolism (plasma protein, total plasma amino acids) were determined, together with plasma GH, cortisol and somatolactin (SL) levels at intervals in three groups of rainbow trout (continuously fed; fasted for 9 weeks then fed; fasted for 17 weeks). In fasted fish, a decline in body weight and condition factor was accompanied by reduced plasma glucose and hepatic glycogen and increased plasma FFA. No consistent elevation of plasma GH occurred until after 8 weeks of fasting when plasma GH levels increased ninefold. No changes were observed in plasma total protein and AA until between weeks 13 and 17 when both were reduced significantly. When previously fasted fish resumed feeding, plasma glucose and FFA, and hepatic glycogen levels rapidly returned to control values and weight gain resumed. No significant changes in plasma cortisol levels, related to feeding regime, were evident at any point during the study and there was no evidence that SL played an active role in the response to fasting. The results suggest that overwinter fasting may not represent a significant nutritional stressor to rainbow trout and that energy mobilisation during fasting may be achieved without the involvement of GH, cortisol or SL.