We determined whether overnight inhibition of lipolysis by a long-acting nicotinic acid derivative (acipimox) decreases gluconeogenesis from lactate in NIDDM patients. For this purpose, 250 mg of acipimox or placebo was administered in a double-blind crossover study at 2400, 0400, and 0800 to 8 NIDDM patients (54 +/- 4 yr of age, body mass index 29.5 +/- 1.3 kg/m2, fasting plasma glucose 11 +/- 1 mM). The next morning, total hepatic glucose production (glucose Ra) and gluconeogenesis from lactate were determined using primed, continuous infusions of [3-3H]glucose and [U-14C]acetate. Glucose and lipid oxidation rates were measured using indirect calorimetry. Mean overnight serum free fatty acid concentrations averaged 242 +/- 8 microM after acipimox and 721 +/- 30 microM after placebo (P < 0.001). Inhibition of lipolysis decreased lipid oxidation from 33 +/- 3 to 22 +/- 2 J.kg-1 x min-1 (P < 0.001) and increased carbohydrate oxidation from 15 +/- 3 to 23 +/- 2 mumol.kg-1.min-1 (P < 0.005). Gluconeogenesis from lactate decreased by approximately 40%, from 6.2 +/- 0.6 to 3.8 +/- 0.5 mumol.kg-1 x min-1 (P < 0.005); lactate oxidation increased from 5.6 +/- 0.8 to 7.9 +/- 1.1 mumol.kg-1 x min-1 (P < 0.005), with no change in plasma lactate concentrations or total lactate Rd. Fasting plasma glucose concentrations were comparable at 2400 (10.0 +/- 1.1 vs. 10.6 +/- 1.3 mM, acipimox vs. placebo) and between 0900 and 1000 (10.6 +/- 1.3 and 11.3 +/- 1.3 mM, respectively). Also, total glucose production rates remained unchanged (14.0 +/- 1.2 vs. 14.9 +/- 1.3 mol.kg-1 x min-1, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Postoperative diabetes is a reported feature of the immunosuppressive agents cyclosporin A and FK 506. To date, however, no randomized comparative studies of the metabolic effects of these two drugs have been performed. In this study, extended (300 min) oral glucose tolerance tests (75 g) were performed a median of 8 mo (range 5-9 mo) postoperatively in 20 clinically stable liver transplant recipients randomly allocated to maintenance immunosuppression with either cyclosporin A (with or without azathioprine) or FK 506. None of the patients had clinically overt diabetes antedating transplantation. To avoid the confounding effects of corticosteroids, prednisolone was withdrawn at least 6 wk beforehand in each case. Ten healthy volunteers matched for age and body mass index served as control subjects. Overall blood glucose concentrations after the glucose challenge were significantly elevated in both groups of transplant recipients (P < 0.005 and P < 0.001 for cyclosporin A and FK 506 treatment groups, respectively) compared with the healthy control subjects. Venous whole-blood glucose concentration (mean +/- SE) 120 min after the ingestion of oral glucose was significantly higher in both the cyclosporin A (P < 0.05) and FK 506 (P < 0.01) treatment groups compared with the control subjects (6.6 +/- 0.5 vs. 8.8 +/- 0.9 vs. 5.2 +/- 0.2 mM, respectively). According to 1985 WHO criteria, 4 of 10 cyclosporin A-treated patients had impaired glucose tolerance, whereas 3 of 10 FK 506-treated patients had diabetes with 4 others having impaired glucose tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)

To examine whether overnight suppression of free fatty acid levels reduces hepatic glucose production, 20 NIDDM patients were given a slow-release formulation of the antilipolytic agent acipimox, in a double-blind crossover manner at bedtime for 4 wk. During acipimox treatment, serum free fatty acid concentrations were suppressed between 2400 and 0600 by 64% (P < 0.001), but no reduction in hepatic glucose production was observed (2.16 +/- 0.16 vs. 2.23 +/- 0.16 mg.kg-1 x min-1, acipimox vs. placebo). In contrast, from 0800 to 2000 a sustained 50% rise occurred in serum free fatty acids (P < 0.001). As a consequence, the 24-h area under the free fatty acid curve was similar during both treatment periods. In the morning, the rise in free fatty acid concentration occurred despite identical serum acipimox concentrations as those measured at midnight, when free fatty acid levels were suppressed. Although energy expenditure was higher (P < 0.05) during periods of elevated free fatty acid levels, the sums of energy expenditure measured in the morning and in the evening were similar during the acipimox and placebo periods. To exclude that the free fatty acid rise was caused by administration of acipimox only once at bedtime, additional experiments were performed administering acipimox every 2 h for 4 days. Despite similar acipimox concentration on day 1 and day 4 of this frequent dosing regimen, the free fatty acid concentrations were significantly higher on day 4 compared with day 1 (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Diabetes mellitus has been associated with both elevated plasma concentrations of the natriuretic and vasorelaxant hormone atrial natriuretic factor and with a reduced natriuretic response to this hormone. We now hypothesize that the vasodilator response to atrial natriuretic factor is attenuated in IDDM. Forearm vasodilator responses to the infusion of six increasing dosages of atrial natriuretic factor into the brachial artery were registered by venous occlusion strain gauge plethysmography in 10 patients with uncomplicated IDDM and in 10 age-, sex-, and weight-matched control subjects. Baseline levels of blood pressure, forearm blood flow, and plasma concentrations of atrial natriuretic factor were not different between control subjects and patients with diabetes. In control subjects, atrial natriuretic factor induced a percentage fall in the forearm vascular resistance of -29 +/- 5% at the lowest to -72 +/- 4% at the highest infusion rate. In patients with diabetes this fall was significantly attenuated, measuring -2 +/- 7 and -45 +/- 4%, respectively, (P < 0.001 vs. control subjects). During infusion of atrial natriuretic factor into the brachial artery, the calculated regional production of cGMP (second messenger of atrial natriuretic factor) increased from 1.2 +/- 1.1 to 22.8 +/- 4.8 pmol.min-1 x 100 ml-1 in the control subjects, whereas hardly any change occurred in the patients with diabetes (from -2.1 +/- 1.2 to 2.9 +/- 4.7 pmol.min-1 x 100 ml-1). Furthermore, both control and diabetic subjects demonstrated an equal forearm vasodilator response to increasing infusion rates of the control vasodilator sodium nitroprusside. We conclude that uncomplicated IDDM is associated with a specific reduction in the vascular responsiveness to atrial natriuretic factor.(ABSTRACT TRUNCATED AT 250 WORDS)

Recent data suggest that proinsulin is strongly associated with cardiovascular risk factors in diabetic subjects. However, this relationship has not been examined in nondiabetic subjects. Therefore, we examined the relation of proinsulin to lipids, obesity (body mass index), and waist-to-hip ratio in 260 nondiabetic individuals from the San Antonio Heart Study, a population-based study of diabetes and cardiovascular disease. Proinsulin was measured by radioimmunoassay, and insulin was measured by a Linco radioimmunoassay that does not cross-react with proinsulin. Fasting insulin was significantly associated with body mass index (0.42), waist-to-hip ratio (r = 0.30), triglyceride (r = 0.29), high-density lipoprotein cholesterol (r = -0.20), and systolic blood pressure (r = 0.16) but not significantly related to diastolic blood pressure (r = 0.11). Fasting proinsulin was significantly associated with body mass index (r = 0.19), waist-to-hip ratio (r = 0.25), triglyceride (r = 0.41), systolic blood pressure (r = 0.19), and diastolic blood pressure (r = 0.15). Proinsulin was more strongly related to increased triglyceride than insulin despite its weaker relationship to obesity. In multivariate analyses, proinsulin continued to be significantly related to triglyceride concentrations (explaining 23.1% of the variance) and to systolic blood pressure (explaining 4.0% of the variance), even after adjusting for insulin. These observations suggest that proinsulin should be measured in addition to insulin in epidemiological studies. Proinsulin may be a marker for metabolic decompensation in prediabetic subjects.

In diabetic subjects, polyol pathway activity might inhibit neutrophil function and cause nerve damage. The effects of ponalrestat, an aldose reductase inhibitor, were assessed on neutrophil intracellular killing of Escherichia coli and on autonomic function in diabetic subjects in a randomized double-blind, placebo-controlled, crossover trial. We studied 31 diabetic subjects with autonomic dysfunction and 21 age- and sex-matched control subjects. During two 12-wk treatment periods, the diabetic subjects took either 600 mg of ponalrestat or matching placebo once daily. Neutrophil killing of E. coli was measured by a microbiological assay technique. Kmax by neutrophils from the diabetic subjects was lower than in the control group (Kmax of diabetic subjects 54.5 +/- 26.4 vs. control subjects 67.3 +/- 16.3, P = 0.045). Ponalrestat significantly increased bacterial killing in the diabetic subjects (Kmax of ponalrestat 75.1 +/- 16.5 vs. placebo 58.2 +/- 20.8, P = 0.003) so that there was no longer any significant difference in Kmax between the control subjects and the diabetic subjects on active treatment. Ponalrestat had no significant effect on a range of standard cardiovascular autonomic nerve function tests. We conclude that neutrophil killing of E. coli is impaired in diabetic subjects with autonomic dysfunction. This is restored to normal by ponalrestat.

The aim of this study was to determine if differing concentrations of insulin can modify the counterregulatory response to equivalent hypoglycemia in normal humans. Experiments were conducted in 9 normal, lean men, who had fasted overnight. Insulin was infused in two separate, randomized protocols so that steady-state levels of 486 +/- 33 (low) and 3056 +/- 236 pM (high) were obtained. Glucose was infused during both protocols to ensure that the rate of fall of plasma glucose (0.07 mM/min) and hypoglycemic plateau (2.8 +/- 0.1 mM) were similar. Despite similar plasma glucose levels, EPI (8.7 +/- 0.7 vs. 5.5 +/- 0.7 nM), NE (3.3 +/- 0.3 vs. 2.3 +/- 0.2 nM), and cortisol (811 +/- 36 vs. 611 +/- 72 nM) significantly increased during high compared with low insulin infusion, respectively (P < 0.05). Glucagon, growth hormone, and pancreatic polypeptide levels increased briskly and significantly but were not different during the two insulin infusions. HGP rose significantly from 12.1 +/- 0.3 to 18.1 +/- 1.1 mumol.kg-1 x min-1 in response to the high insulin level (P < 0.05) but remained unchanged (12.1 +/- 0.4 and 11.7 +/- 1.4 mumol.kg-1 x min-1) in the presence of th low insulin level. GRa increased significantly during high insulin levels (3.4 +/- 0.3 to 4.8 +/- 0.7 mumol.kg-1 x min-1, P < 0.05) but remained at a basal rate (3.0 +/- 0.3 to 2.7 +/- 0.6 mumol.kg-1 x min-1) in the presence of low insulin levels. sBP and heart rate increased more during high insulin infusion (18 +/- 5 vs. 6 +/- 5 mmHg and 18 +/- 4 vs. 7 +/- 2 beats/min, respectively, P < 0.05). In summary, the 6-fold higher insulin level resulted in significantly greater increases in catecholamine and cortisol secretion, HGP, lipolysis, heart rate, and sBP despite equivalent hypoglycemia. We conclude that at moderate hypoglycemia, high doses of insulin can augment certain aspects of the counterregulatory response in normal humans.

Diabetic hypoglycemia produces cognitive-motor slowing, which is assumed to increase risk of automobile crashes. This study investigated driving decrements during and after hypoglycemia, and the patients' awareness of driving decrements. We used a randomized, single-blind, crossover design and conducted the study at the University of Virginia's General Clinical Research Center. We studied a volunteer sample of 27 consecutive adult type I diabetic patients who responded to newspaper ads. Two dropped out (final n = 25). Mean age (+/- SD) was 35.9 +/- 14 yr. Diabetes history was 14.6 +/- 10.5 yr, with HbA1 of 10.8 +/- 2.9%. Driving experience was 19 +/- 13.2 yr. Participants drove a state-of-the-art driving simulator on two consecutive days: Control day involved four euglycemia (mean blood glucose, 6.3 +/- 0.89 mM) driving tests; experimental day involved testing at euglycemia, mild hypoglycemia (mean blood glucose, 3.6 +/- 0.33 mM), moderate hypoglycemia (mean blood glucose, 2.6 +/- 0.28 mM), and again at euglycemia. Patients were blind to blood glucose manipulations and levels. Driving performance was not disrupted at mild hypoglycemia nor after recovery from moderate hypoglycemia. Moderate hypoglycemia disrupted steering, causing more swerving (P < 0.03), spinning (P < 0.03), time over midline (P < 0.05), and time off road (P < 0.01). It also resulted in an apparent compensatory slowing, with more very slow driving (P < 0.04). Global driving performance decrements were observed in 35% of the patients, only 50% of whom stated they would not drive under similar conditions. Driving decrements were unrelated to demographic, disease, or driving history variables.(ABSTRACT TRUNCATED AT 250 WORDS)

We investigated the short-term effect of the TXB inhibitor picotamide on albuminuria induced by exercise in 15 microalbuminuric (i.e., with UAE at rest between 20 and 200 micrograms/min) type II diabetic patients (12 men and 3 women, age 56 +/- 2, BMI 28 +/- 1 kg/m2) and in six normal age-matched control subjects. The diabetic subjects performed five submaximal exercise tests (90% of theoretical heart rate) on a cycle ergometer: the first two under basal conditions; the third and fifth after subjects had received picotamide (900 mg/day) or placebo (3 tablets/day) for 10 days; the fourth exercise always was performed after 10 days of wash-out. Control subjects performed two exercises: the first in baseline conditions and the second after 10 days of picotamide administration (900 mg/day). When diabetic patients were untreated, a significant (P < 0.05) increase in UAE with respect to baseline levels was observed immediately after and 1 h after the exercise test. After picotamide administration, UAE significantly decreased (P < 0.05) immediately after and 1 h after exercise, as compared with diabetic patients given a placebo. In normal subjects, exercise was followed by a slight increase in UAE, which was not significantly affected by picotamide administration. Our results show that short-term administration of picotamide is associated with a reduction in UAE after exercise in type II diabetes patients with microalbuminuria while at rest. Picotamide, a TXB synthetase and receptor inhibitor, may decrease exercise-induced albuminuria in diabetic patients through a reduction in circulating TXB levels and inhibition of TXB action, which in turn may act by lowering glomerular capillary hydraulic pressure.

NEFAs characteristically are elevated in obese NIDDM patients in both the basal state and after insulin. This elevation might aggravate glycemic control both by decreasing peripheral glucose disposal (glucose-fatty acid cycle), and by increasing HGO. Thus, lowering plasma NEFA levels might improve carbohydrate metabolism. We therefore measured HGO and fuel use (by indirect calorimetry) both in the basal state and during the last 30 min of a hyperinsulinemic clamp (0.025U.kg-1.h-1) in 8 obese NIDDM patients (BMI 34.8 +/- 1.0 kg/m2) after complete overnight suppression of plasma NEFA levels with acipimox, a new nicotinic acid analogue. After acipimox, mean basal plasma NEFA and glycerol levels were lower than control values (0.11 +/- 0.02 vs. 0.65 +/- 0.04 mM, P < 0.001; and 16 +/- 3 vs. 68 +/- 7 microM, P = 0.004, respectively) and were accompanied by a fall in lipid oxidation (acipimox vs. placebo: 16.1 +/- 1.2 vs. 38.8 +/- 2.4 mg.m-2 x min-1; P < 0.001) and a rise in glucose oxidation (91.1 +/- 6.2 vs. 54.1 +/- 9.0 mg.m-2 x min-1; P = 0.002). Basal HGO and fasting plasma glucose levels were lower (94.1 +/- 9.2 vs. 118.5 +/- 9.5 mg.m-2 x min-1, P = 0.01; and 8.3 +/- 1.2 vs. 9.8 +/- 1.2 mM; P < 0.001), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Twelve subjects with insulin-dependent diabetes mellitus were treated using continuous subcutaneous insulin infusion (CSII) and intraportal insulin infusion (IPII) via the umbilical vein for 4 mo. Glucose control improved in both CSII and IPII groups, but a decrease in glucose and HbAIc was more rapid and more significant in the IPII group than in CSII, even though insulin requirement was lower during IPII than CSII (40 +/- 2 vs. 50 +/- 2 U/day, P less than 0.05). The insulin plasma fasting levels were different (88 +/- 10.7 in the IPII group vs. 263 +/- 23 pM in CSII, P less than 0.001). High plasma levels of lactate, pyruvate, alanine, cortisol, and growth hormone were decreased in both groups, with their full normalization only in the IPII group. Glucagon concentrations were low in both groups at the beginning of the study (30.0 +/- 4.1 in the CSII group and 32.3 +/- 1.8 ng/L in IPII); they were equalized to control values in the IPII group and were low in the CSII group at the study's end (46.0 +/- 3.7 in IPII vs. 31.7 +/- 3.1 ng/L in CSII, P less than 0.05. We conclude that intraportal administration of insulin via the umbilical vein at rates of 0.01-0.05 U.kg-1.hr-1 reduces plasma levels of glucose, three carbon precursors, cortisol, and growth hormone by a direct action on the liver, and the hepatic action of peripherally administered insulin is manifested only when the infusion rate is increased to 0.1-0.3 U.kg-1.hr-1.(ABSTRACT TRUNCATED AT 250 WORDS)

We assessed the metabolism of the two KBs, AcAc and 3-BOH; the relationships between ketogenesis and FFA inflow rate; and the effect of chronic sulfonylurea treatment in mild NIDDM patients (plasma glucose less than 10 mM). We studied 10 nonobese NIDDM patients in a crossover, randomized, double-blind, placebo-controlled fashion. Each patient was studied 4 times: after a run-in period with placebo, after 3 mo of placebo treatment, after 3 mo of glibenclamide treatments, respectively, and after 3 mo of sulfonylurea treatment during an acute exogenous Intralipid infusion. Ten normal, nondiabetic subjects served as the control group. Glibenclamide treatment decreased plasma FFAs. When these substrates were exogenously increased, plasma FFAs were comparable with placebo and baseline concentrations. In NIDDM patients, baseline and placebo blood total KB concentration was significantly higher than in control subjects (216 +/- 22 and 244 +/- 25, respectively vs. 127 +/- 18 microM; P less than 0.01). Glibenclamide treatment significantly decreased total KBs to 177 +/- 19 microM (P less than 0.05). When FFAs were exogenously increased, total KBs were similar to the placebo and baseline period. In the baseline study, the AcAc/3-BOH ratio was 0.72 +/- 0.06 in control subjects, whereas in NIDDM patients, the ratio was 1.61 +/- 0.13 at baseline (P less than 0.001 vs. control subjects), 1.66 +/- 0.15 during placebo, 1.57 +/- 0.09 during glibenclamide (NS vs. baseline), and 1.51 +/- 0.23 during glibenclamide plus placebo FFAs. Both the AcAc interconversion rate to 3-BOH and the 3-BOH interconversion rate to AcAc were significantly lower in NIDDM patients than in control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Many first-degree relatives of patients with non-insulin-dependent diabetes mellitus (NIDDM) are characterized by insulin resistance. Because metformin improves peripheral insulin sensitivity, we examined the acute effect of metformin and placebo on glucose and lipid metabolism in nine insulin-resistant first-degree relatives of NIDDM patients with the euglycemic insulin-clamp technique combined with indirect calorimetry and infusion of [3-3H]glucose. Either placebo or 500 mg metformin was taken in random order twice the day before and once 1 h before the clamp. Nine healthy individuals without family history of diabetes served as control subjects. Basal plasma glucose was normal and did not differ between the metformin and the placebo study (4.8 +/- 0.2 vs. 5.0 +/- 0.2 mM) and neither did basal hepatic glucose production (10.59 +/- 0.54 vs. 10.21 +/- 0.80 mumol.kg-1.min-1). Insulin-stimulated glucose disposal was significantly increased by 25% after metformin compared with placebo (26.67 +/- 2.87 vs. 21.31 +/- 1.73 mumol.kg-1.min-1, P less than 0.05). The enhancement in glucose utilization was primarily due to normalization of nonoxidative glucose disposal (from 8.02 +/- 1.35 to 15.07 +/- 2.69 mumol.kg-1.min-1, P less than 0.01, vs. 15.65 +/- 2.72 mumol.kg-1.min-1 in control subjects). In contrast, glucose oxidation during the clamp was slightly lower after metformin compared with both placebo (11.59 +/- 0.83 vs. 13.30 +/- 1.00 mumol.kg-1.min-1, P = 0.06) and healthy control subjects (15.68 +/- 1.38 mumol.kg-1.min-1, P less than 0.05). We conclude that acutely administered metformin improves peripheral insulin sensitivity in insulin-resistant normoglycemic individuals primarily by stimulating the nonoxidative pathway of glucose metabolism.

Normotensive patients with insulin-dependent (type I) diabetes mellitus (n = 18) were given 25 mg captopril (b.i.d.) and placebo for 3 mo in a randomized double-blind crossover study. Patients had normal renal function, and none had retinopathy. Albuminuria was less than 20 micrograms/min in 12 patients and between 20 and 200 micrograms/min in the other 6. Patients were examined at the end of the placebo and captopril phases. Captopril caused little reduction in blood pressure obtained by 24-h ambulatory monitoring (systolic 126.0 +/- 2.7 to 123.9 +/- 2.4 mmHg, P less than 0.08; diastolic 74.2 +/- 1.9 to 72.1 +/- 1.9 mmHg, P less than 0.09). Captopril lowered glomerular filtration rate from 99.5 +/- 7.7 to 71.0 +/- 5.5 ml.min-1. 1.73 m-2 (P less than 0.01), whereas renal plasma flow (443.9 +/- 15.2 ml.min-1. 1.73 m-2) remained unchanged. Filtration fraction was reduced from 22.4 +/- 1.4 to 17.4 +/- 1.4% (P less than 0.01). Urinary albumin excretion was reduced from 59.1 +/- 0.15 to 27.7 +/- 13.9 micrograms/min (P less than 0.1). Reduction was related to the extent of initial albuminuria (r = 0.997, P less than 0.001), a relationship that remained significant after logarithmic transformation (r = 0.540, P less than 0.02). Dextran clearance was used to determine glomerular capillary function. Angiotensin inhibition caused reduction in effective glomerular pore size and also reduced flow via the nondiscriminatory shunt. Angiotensin inhibition in normotensive patients with type I diabetes was well tolerated. Reduction in albuminuria is mediated by a combination of hemodynamic changes and alterations in glomerular capillary function.

This study reports the responses to a 75-g oral glucose tolerance test (OGTT) in 1009 pregnant women from throughout Europe. We reached the following conclusions. 1) A pregnant woman tends to have blood glucose concentrations that are elevated for a longer period of time after an oral glucose load. Therefore, approximately 10% of women will reach or exceed 8 mM glucose at 2 h, but it is unlikely that 10% of European women have disordered carbohydrate metabolism. 2) The fasting and 1-h values should be included in any analysis of the response of the patient. By doing this, many fewer women will have responses regarded as abnormal; in this series, it reduced the 79 women with a 2-h value greater than 8 mM to 15 who were considered to have carbohydrate intolerance (2 with diabetes, 13 with impaired glucose tolerance [IGT]). 3) By increasing the 2-h cutoff value to greater than or equal to 9 mM, the number of women regarded as at risk would be reduced by greater than 50% (from 79 to 32 in this series), but 10 of the 13 women with two abnormal values would still have been detected, as would the 2 diabetic women. 4) From the obstetric viewpoint, mothers who screen positive do not have bigger babies, they deliver close to term, and they do not have particular stigmas such as a family history of diabetes or an increased tendency to smoke or to have an adverse obstetric outcome. However, they do tend to be older and heavier.(ABSTRACT TRUNCATED AT 250 WORDS)

A prospective study was undertaken to test the hypothesis that insulin treatment in patients with gestational diabetes mellitus (GDM) with fasting plasma glucose (FPG) greater than 5.3 mM significantly reduces adverse perinatal outcome. Assigned to insulin or diet treatment based on FPG were 471 GDM women. Four factors believed to be associated with infants large for gestational age (LGA) were evaluated: FPG, overall glycemic control, maternal weight, and treatment regimen. We found that when glycemic control was optimized, the key factors related to large infants were FPG and treatment modality. In the low-FPG group (less than 5.3 mM), diet therapy achieved an incidence of 5.3% LGA. When insulin therapy was used to optimize control, an incidence of 3.5% LGA was found. Patients in the mid-FPG group (5.3-5.8 mM) had a higher increased rate of LGA (28.6%) for diet-treated versus insulin-treated women (10.3%). In addition, a fourfold increased risk for LGA was found in the diet-treated obese subjects in the mid-FPG group compared with insulin-treated obese women. Finally, treatment with insulin resulted in similar incidence of LGA within all FPG groups. We concluded that FPG greater than 5.3 mM can be the basis for initiation of insulin treatment in GDM subjects with optimization of glycemic control as the goal. This approach may contribute significantly to reduced neonatal risk and may foster a standardized method for rapid and effective assignment to treatment.

Forty-one patients with gestational diabetes requiring insulin were enrolled in a randomized study to investigate the efficacy of an exercise program in normalizing glucose tolerance. Seventeen of 21 patients completed the exercise program while maintaining normoglycemia and obviating insulin therapy. Maternal and neonatal complications did not differ between the study and control groups. The type of program described appears to be safe and can serve as a model for exercise prescription for pregnant diabetic women to attain improved glucose tolerance.

The mainstay of management of the gestational diabetic woman is dietary manipulation to achieve and maintain normoglycemia. If normoglycemia cannot be sustained by diet alone, then insulin therapy is initiated. We instituted a series of studies to observe the value and safety of a cardiovascular fitness program to improve glucose tolerance in gestational diabetic women. We first evaluated the safety for pregnant women of five aerobic exercise machines by observing the effect of these different forms of exercise on uterine activity during the third trimester. We found that upper-extremity exercise produced no uterine contractions, but lower-extremity exercise tended to produce contractions. Upper-extremity exercise, in addition to dietary therapy, was then assigned to 10 gestational diabetic women who were matched for amount of glucose intolerance to 10 gestational diabetic women managed by diet alone. The mean fasting plasma glucose +/- SD after 6 wk was 4.87 +/- 0.34 mM in the diet group versus 3.89 +/- 0.37 mM in the diet-plus-exercise group. The mean postglucose challenge in the diet group was 10.40 +/- 0.16 mM versus 5.9 +/- 1.1 mM in the diet-plus-exercise group. Thus, upper-arm exercise may provide a useful treatment option for gestational diabetes and may obviate the need for insulin.

Although hypocaloric diets have been advocated for the management of the obese gravida and the obese mother with gestational diabetes, there is no general agreement on how severely calories should be restricted or on how this therapeutic approach compares with insulin therapy. The lack of consensus is in part because of the lack of studies comparing insulin management with the effects of different degrees of hypocaloric feeding and its effects on metabolism and glycemic status. We review the effects of 50 and 33% calorie restriction on glycemic status and intermediary fuel status in obese gestational diabetic subjects and compare the results with the administration of 20 U NPH and 10 U regular insulin every morning, a therapy of proven value in reducing macrosomia in gestational diabetes. When the two calorie-restriction regimens were compared after a 9-h overnight fast, glycemic status improved 10-20% on both. Ketonuria increased about twofold with 50% calorie restriction, but on average no increase in ketonuria was seen on the 33% calorie-restriction regimen. Both calorie-restriction programs led to a reduction in levels of plasma triglyceride, a correlate of infant birth weight. In contrast, the insulin regimen diminished ketonuria, but glycemic status improved little, and plasma triglyceride concentrations did not decline. Although more studies are needed to confirm these trends, the beneficial effect of 33% calorie restriction, which occurred without marked ketonuria, is consistent with previous studies in gestational diabetes. In addition, the simultaneous improvements observed in plasma glucose and triglyceride concentrations suggest that moderate calorie restriction may be valuable in preventing macrosomia in the offspring of the obese subject with gestational diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)

Birth weights of infants of 35 gestational diabetic mothers treated with calorie restriction alone (1200-1800 kcal) were compared with those of infants of 2337 nondiabetic women, including two control groups (A and B) matched for race, body mass index, age, and parity. All women were screened for gestational diabetes with the O'Sullivan screening method, and a 3-h oral glucose tolerance test was performed on all abnormal results. Control group A mothers had a normal screen, and control group B mothers had an abnormal screen with a normal glucose tolerance test. Pregnancy weight gain was significantly less for the gestational diabetic mothers (mean +/- SD 4.6 +/- 4.9 kg) than for the general prenatal population (9.3 +/- 5.3 kg), group A control subjects (9.7 +/- 5.3 kg), and group B control subjects (9.7 +/- 5.4 kg; P less than 0.0005). No infant of a gestational diabetic mother was below the 10th percentile for weight, and birth weights were similar to those of the control groups even though weight gain after the 28th wk of gestation was only 1.7 +/- 1.6 kg. The frequency of macrosomia (birth weight greater than or equal to 4000 g) was similar among the gestational diabetic mothers (9.3%), the general prenatal population (7.4%), and group A mothers (11.6%) but significantly higher for the group B control subjects (20.9%; chi 2 = 8.57, P less than 0.005). This study demonstrated that gestational diabetic mothers who are calorie restricted have infants with normal birth weights and a frequency of macrosomia less than that of screen-positive nondiabetic women with similar macrosomic risk factors.