Women With Gestational Diabetes Mellitus Randomized to a Higher–Complex Carbohydrate/Low-Fat Diet Manifest Lower Adipose Tissue Insulin Resistance,Inflammation, Glucose,and Free Fatty Acids: A Pilot Study

OBJECTIVE

Diet therapy in gestational diabetes mellitus (GDM) has focused on carbohydrate restriction but is poorly substantiated. In this pilot randomized clinical trial, we challenged the conventional low-carbohydrate/higher-fat (LC/CONV) diet, hypothesizing that a higher–complex carbohydrate/lower-fat (CHOICE) diet would improve maternal insulin resistance (IR), adipose tissue (AT) lipolysis, and infant adiposity.

RESEARCH DESIGN AND METHODS

At 31 weeks, 12 diet-controlled overweight/obese women with GDM were randomized to an isocaloric LC/CONV (40% carbohydrate/45% fat/15% protein; n = 6) or CHOICE (60%/25%/15%; n = 6) diet. All meals were provided. AT was biopsied at 37 weeks.

RESULTS

After ∼7 weeks, fasting glucose (P = 0.03) and free fatty acids (P = 0.06) decreased on CHOICE, whereas fasting glucose increased on LC/CONV (P = 0.03). Insulin suppression of AT lipolysis was improved on CHOICE versus LC/CONV (56 vs. 31%, P = 0.005), consistent with improved IR. AT expression of multiple proinflammatory genes was lower on CHOICE (P < 0.01). Infant adiposity trended lower with CHOICE (10.1 ± 1.4 vs. 12.6 ± 2%, respectively).

CONCLUSIONS

A CHOICE diet may improve maternal IR and infant adiposity, challenging recommendations for a LC/CONV diet.     

Quantification of the Glycemic Response to Microdoses of Subcutaneous Glucagon at Varying Insulin Levels

OBJECTIVE

Glucagon delivery in closed-loop control of type 1 diabetes is effective in minimizing hypoglycemia. However, high insulin concentration lowers the hyperglycemic effect of glucagon, and small doses of glucagon in this setting are ineffective. There are no studies clearly defining the relationship between insulin levels, subcutaneous glucagon, and blood glucose.

RESEARCH DESIGN AND METHODS

Using a euglycemic clamp technique in 11 subjects with type 1 diabetes, we examined endogenous glucose production (EGP) of glucagon (25, 75, 125, and 175 μg) at three insulin infusion rates (0.016, 0.032, and 0.05 units/kg/h) in a randomized, crossover study. Infused 6,6-dideuterated glucose was measured every 10 min, and EGP was determined using a validated glucoregulatory model. Area under the curve (AUC) for glucose production was the primary outcome, estimated over 60 min.

RESULTS

At low insulin levels, EGP rose proportionately with glucagon dose, from 5 ± 68 to 112 ± 152 mg/kg (P = 0.038 linear trend), whereas at high levels, there was no increase in glucose output (19 ± 53 to 26 ± 38 mg/kg, P = NS). Peak glucagon serum levels and AUC correlated well with dose (r² = 0.63, P < 0.001), as did insulin levels with insulin infusion rates (r² = 0.59, P < 0.001).

CONCLUSIONS

EGP increases steeply with glucagon doses between 25 and 175 μg at lower insulin infusion rates. However, high insulin infusion rates prevent these doses of glucagon from significantly increasing glucose output and may reduce glucagon effectiveness in preventing hypoglycemia when used in the artificial pancreas.     

Increased Skeletal Muscle Capillarization After Aerobic Exercise Training and Weight Loss Improves Insulin Sensitivity in Adults With IGT

OBJECTIVE

Transcapillary transport of insulin is one determinant of glucose uptake by skeletal muscle; thus, a reduction in capillary density (CD) may worsen insulin sensitivity. Skeletal muscle CD is lower in older adults with impaired glucose tolerance (IGT) compared with those with normal glucose tolerance and may be modifiable through aerobic exercise training and weight loss (AEX+WL). We tested the hypothesis that 6-month AEX+WL would increase CD to improve insulin sensitivity and glucose tolerance in older adults with IGT.

RESEARCH DESIGN AND METHODS

Sixteen sedentary, overweight-obese (BMI 27–35 kg/m²), older (63 ± 2 years) men and women with IGT underwent hyperinsulinemic-euglycemic clamps to measure insulin sensitivity, oral glucose tolerance tests, exercise and body composition testing, and vastus lateralis muscle biopsies to determine CD before and after 6-month AEX+WL.

RESULTS

Insulin sensitivity (M) and 120-min postprandial glucose (G₁₂₀) correlated with CD at baseline (r = 0.58 and r = −0.60, respectively, P < 0.05). AEX+WL increased maximal oxygen consumption (VO_2max) 18% (P = 0.02) and reduced weight and fat mass 8% (P < 0.02). CD increased 15% (264 ± 11 vs. 304 ± 14 capillaries/mm², P = 0.01), M increased 21% (42.4 ± 4.0 vs. 51.4 ± 4.3 µmol/kg FFM/min, P < 0.05), and G₁₂₀ decreased 16% (9.35 ± 0.5 vs. 7.85 ± 0.5 mmol/L, P = 0.008) after AEX+WL. Regression analyses showed that the AEX+WL-induced increase in CD independently predicted the increase in M (r = 0.74, P < 0.01) as well as the decrease in G₁₂₀ (r = −0.55, P < 0.05).

CONCLUSIONS

Six-month AEX+WL increases skeletal muscle CD in older adults with IGT. This represents one mechanism by which AEX+WL improves insulin sensitivity in older adults with IGT.     

Detection of Abnormal Glucose Tolerance in Africans Is Improved by Combining A1C With Fasting Glucose: The Africans in America Study

OBJECTIVE

Abnormal glucose tolerance is rising in sub-Saharan Africa. Hemoglobin A_1c by itself and in combination with fasting plasma glucose (FPG) is used to diagnose abnormal glucose tolerance. The diagnostic ability of A1C in Africans with heterozygous variant hemoglobin, such as sickle cell trait or hemoglobin C trait, has not been rigorously evaluated. In U.S.-based Africans, we determined by hemoglobin status the sensitivities of 1) FPG ≥5.6 mmol/L, 2) A1C ≥ 5.7% (39 mmol/mol), and 3) FPG combined with A1C (FPG ≥5.6 mmol/L and/or A1C ≥5.7% [39 mmol/mol]) for the detection of abnormal glucose tolerance.

RESEARCH DESIGN AND METHODS

An oral glucose tolerance test (OGTT) was performed in 216 African immigrants (68% male, age 37 ± 10 years [mean ± SD], range 20–64 years). Abnormal glucose tolerance was defined as 2-h glucose ≥7.8 mmol/L.

RESULTS

Variant hemoglobin was identified in 21% (46 of 216). Abnormal glucose tolerance occurred in 33% (72 of 216). When determining abnormal glucose tolerance from the OGTT (2-h glucose ≥7.8 mmol/L), sensitivities of FPG for the total, normal, and variant hemoglobin groups were 32%, 32%, and 33%, respectively. Sensitivities for A1C were 53%, 54%, and 47%. For FPG and A1C combined, sensitivities were 64%, 63%, and 67%. Sensitivities for FPG and A1C and the combination did not vary by hemoglobin status (all P > 0.6). For the entire cohort, sensitivity was higher for A1C than FPG and for both tests combined than for either test alone (all P values ≤ 0.01).

CONCLUSIONS

No significant difference in sensitivity of A1C by variant hemoglobin status was detected. For the diagnosis of abnormal glucose tolerance in Africans, the sensitivity of A1C combined with FPG is significantly superior to either test alone.     

Testing for Rewards: A Pilot Study to Improve Type 1 Diabetes Management in Adolescents

OBJECTIVE

To evaluate the effectiveness of monetary reinforcement to increase the frequency of self-monitoring blood glucose (SMBG).

RESEARCH DESIGN AND METHODS

Ten adolescents with poorly controlled diabetes enrolled in a 12-week program in which they earned monetary reinforcers based on SMBG frequency ($0.10 per test, with bonuses for ≥4 tests per day, and $251.40 maximum).

RESULTS

SMBG increased from 1.8 ± 1.0 to 4.9 ± 1.0 tests per day (P < 0.001) with 90% completing four or more tests per day. Mean A1C fell from 9.3 ± 0.9% to 8.4 ± 1.5% (P = 0.05). Adolescents and parents reported high satisfaction with procedures.

CONCLUSIONS

Reinforcing adolescents for SMBG may increase testing and improve A1C.     

A 25-Year Longitudinal Evaluation of Gastric Emptying in Diabetes

OBJECTIVE

To evaluate the natural history of gastric emptying in diabetes.

RESEARCH DESIGN AND METHODS

Thirteen patients with diabetes (12, type 1; 1, type 2) had measurements of gastric emptying, blood glucose levels, glycated hemoglobin, upper gastrointestinal symptoms, and autonomic nerve function at baseline and after 24.7 ± 1.5 years.

RESULTS

There was no change in gastric emptying of either solids (% retention at 100 min) (baseline 58.5 ± 5% vs. follow-up 51.9 ± 8%; P = 0.35) or liquids (50% emptying time) (baseline 29.8 ± 3 min vs. follow-up 34.3 ± 6 min; P = 0.37). Gastric emptying of solid at follow-up was related to emptying at baseline (r = 0.56, P < 0.05). At follow-up, blood glucose concentrations were lower (P = 0.006), autonomic function deteriorated (P = 0.03), and gastrointestinal symptoms remained unchanged (P = 0.17).

CONCLUSIONS

In unselected patients with diabetes, gastric emptying appears remarkably stable over 25 years.There is limited information about the natural history of gastric emptying in diabetes (1–3). We have reported that gastric emptying and symptoms changed little after 12 years of follow-up, possibly because a deterioration in autonomic function was counteracted by better glycemic control (4). We reexamined patients from the same cohort after 25 years.     

Glycemia and Its Relationship to Outcomes in the Metformin in Gestational Diabetes Trial

OBJECTIVE

To determine how glucose control in women with GDM treated with metformin and/or insulin influenced pregnancy outcomes.

RESEARCH DESIGN AND METHODS

Women randomly assigned to metformin or insulin treatment in the Metformin in Gestational Diabetes (MiG) trial had baseline glucose tolerance test (OGTT) results and A1C documented, together with all capillary glucose measurements during treatment. In the 724 women who had glucose data for analysis, tertiles of baseline glucose values and A1C and of mean capillary glucose values during treatment were calculated. The relationships between maternal factors, glucose values, and outcomes (including a composite of neonatal complications, preeclampsia, and large-for-gestational-age [LGA] and small-for-gestational-age infants) were examined with bivariable and multivariate models.

RESULTS

Baseline OGTT did not predict outcomes, but A1C predicted LGA infants (P = 0.003). During treatment, fasting capillary glucose predicted neonatal complications (P < 0.001) and postprandial glucose predicted preeclampsia (P = 0.016) and LGA infants (P = 0.001). Obesity did not influence outcomes, and there was no interaction between glycemic control, randomized treatment, or maternal BMI in predicting outcomes. The lowest risk of complications was seen when fasting capillary glucose was <4.9 mmol/l (mean ± SD 4.6 ± 0.3 mmol/l) compared with 4.9–5.3 mmol/l or higher and when 2-h postprandial glucose was 5.9–6.4 mmol/l (6.2 ± 0.2 mmol/l) or lower.

CONCLUSIONS

Glucose control in women with gestational diabetes mellitus treated with metformin and/or insulin is strongly related to outcomes. Obesity is not related to outcomes in this group. Targets for fasting and postprandial capillary glucose may need to be lower than currently recommended.Although treatment of gestational diabetes mellitus (GDM) has been shown to improve perinatal outcomes (1,2), there is lack of consensus about ideal glucose targets and how other factors, such as fetal abdominal circumference, should influence these targets (3,4). The Fifth International Workshop-Conference on Gestational Diabetes endorsed targets of capillary fasting glucose <5.3 mmol/l, 1-h postprandial <7.8 mmol/l, and/or 2-h postprandial <6.7 mmol/l until further data addressing optimal goals become available (5). Improved pregnancy outcomes have been reported in women achieving these targets compared with those in women who did not (6); the latter group had higher baseline mean BMI and A1C, which may have influenced outcomes. Obesity has been reported as an independent factor influencing outcome in women with GDM treated with diet but not in those treated with insulin (7,8).Published studies have compared women who aim for or achieve predetermined glucose targets with those who do not: it is not clear whether such aims are optimal and whether glycemia influences different outcomes equally. Several studies suggested that treatment intensity can be usefully stratified according to fetal abdominal circumference measured by ultrasound (3): intensive treatment of women carrying fetuses with an abdominal circumference above the 70–75th percentile lowered the frequency of large-for-gestational-age (LGA) infants without increasing rates of small-for-gestational-age (SGA) infants. However, lowering of mean maternal glucose to <4.8 mmol/l is associated with increased frequency of SGA infants (9).Data showing relationships between different fasting and postprandial glucose values and a range of outcomes would assist clinicians in setting target ranges for “optimal glucose control” more objectively. In the Metformin in Gestational Diabetes (MiG) trial, women with GDM, who had one or more home capillary blood glucose measures ≥5.5 mmol/l fasting or ≥6.7 mmol/l 2-h postprandial after lifestyle intervention, were randomly assigned to either insulin or metformin treatment (10). The primary objective of the trial was to compare metformin with insulin treatment, but prespecified secondary objectives were to determine the impact of glycemia on outcomes and to determine whether treatment with metformin or insulin was more effective at different levels of glycemia. Baseline glycemia measures and capillary glucose measures throughout treatment were recorded in the trial database. The specific aims of the present analysis were 1) to determine how glucose control influenced trial outcomes, including the primary outcome (a composite of neonatal complications), maternal preeclampsia, and rates of LGA and SGA infants; 2) to identify additional baseline factors influencing outcomes, including baseline glycemia and obesity; and 3) to examine any differences between treatment arms at different levels of glycemia.     

Adjusting Glucose-Stimulated Insulin Secretion for Adipose Insulin Resistance: An Index of β-Cell Function in Obese Adults

OBJECTIVE

The hyperbolic relationship between insulin secretion and sensitivity has been used to assess in vivo β-cell function (i.e., the disposition index). The disposition index emphasizes the importance of taking into account both skeletal muscle and hepatic insulin resistance to depict insulin secretion. However, we propose that adipose tissue insulin resistance also needs to be accounted for when characterizing glucose-stimulated insulin secretion (GSIS) because elevated plasma free fatty acids (FFAs) impair β-cell function.

RESEARCH DESIGN AND METHODS

To characterize the adipose disposition index, we used [1-¹⁴C] palmitate infusion to determine basal FFA turnover rate/adipose insulin resistance and an oral glucose tolerance test to characterize the first (i.e., 0–30 min) and second phase (i.e., 60–120 min) of GSIS. We validated a simplified version of the tracer infusion calculation as the product of (1/plasma FFA concentration × plasma insulin concentration) × GSIS in 44 obese insulin-resistant subjects.

RESULTS

The plasma FFA and palmitate tracer infusion calculations of the first- and second-phase disposition index were strongly correlated (r = 0.86, P < 0.000001 and r = 0.89, P < 0.000001, respectively). The first- and second-phase adipose disposition index derived from plasma FFA also was tightly associated with fasting hyperglycemia (r = −0.87, P < 0.00001 and r = −0.89, P < 0.00001, respectively) and 2-h glucose concentrations (r = −0.86, P < 0.00001 and r = −0.90, P < 0.00001).

CONCLUSIONS

Adjusting GSIS for adipose insulin resistance provides an index of β-cell function in obese subjects across the glucose spectrum. Plasma FFA–derived calculations of β-cell function may provide additional insight into the role of adipose tissue in glucose regulation.     

Mechanisms of Glucose Lowering of Dipeptidyl Peptidase-4 Inhibitor Sitagliptin When Used Alone or With Metformin in Type 2 Diabetes: A double-tracer study

OBJECTIVE

To assess glucose-lowering mechanisms of sitagliptin (S), metformin (M), and the two combined (M+S).

RESEARCH DESIGN AND METHODS

We randomized 16 patients with type 2 diabetes mellitus (T2DM) to four 6-week treatments with placebo (P), M, S, and M+S. After each period, subjects received a 6-h meal tolerance test (MTT) with [¹⁴C]glucose to calculate glucose kinetics. Fasting plasma glucose (FPG), fasting plasma insulin, C-peptide (insulin secretory rate [ISR]), fasting plasma glucagon, and bioactive glucagon-like peptide (GLP-1) and gastrointestinal insulinotropic peptide (GIP) were measured.

RESULTS

FPG decreased from P, 160 ± 4 to M, 150 ± 4; S, 154 ± 4; and M+S, 125 ± 3 mg/dL. Mean post-MTT plasma glucose decreased from P, 207 ± 5 to M, 191 ± 4; S, 195 ± 4; and M+S, 161 ± 3 mg/dL (P < 0.01). The increase in mean post-MTT plasma insulin and in ISR was similar in P, M, and S and slightly greater in M+S. Fasting plasma glucagon was equal (∼65–75 pg/mL) with all treatments, but there was a significant drop during the initial 120 min with S 24% and M+S 34% (both P < 0.05) vs. P 17% and M 16%. Fasting and mean post-MTT plasma bioactive GLP-1 were higher (P < 0.01) after S and M+S vs. M and P. Basal endogenous glucose production (EGP) fell from P 2.0 ± 0.1 to S 1.8 ± 0.1 mg/kg ⋅ min, M 1.8 ± 0.2 mg/kg ⋅ min (both P < 0.05 vs. P), and M+S 1.5 ± 0.1 mg/kg ⋅ min (P < 0.01 vs. P). Although the EGP slope of decline was faster in M and M+S vs. S, all had comparable greater post-MTT EGP inhibition vs. P (P < 0.05).

CONCLUSIONS

M+S combined produce additive effects to 1) reduce FPG and postmeal plasma glucose, 2) augment GLP-1 secretion and β-cell function, 3) decrease plasma glucagon, and 4) inhibit fasting and postmeal EGP compared with M or S monotherapy.In diet-treated patients with type 2 diabetes mellitus (T2DM) and HbA_1c of ∼8.0%, sitagliptin (S) reduces HbA_1c by 0.6–0.7% over a 6-month period (1). A slightly greater HbA_1c decline (∼0.8–0.9%) is observed when metformin (M) therapy is added to S (2). Dipeptidyl peptidase (DPP)-4 inhibitors predominantly affect the postprandial plasma glucose excursion, but a significant, albeit modest, reduction in fasting plasma glucose (FPG) also is observed (1–3). The mechanism of action of the DPP-4 inhibitors has been well studied and includes increased plasma glucagon-like peptide (GLP)-1 and gastrointestinal insulinotropic peptide (GIP) levels, resulting in increased insulin and reduced glucagon secretion (4–6). The increase in plasma insulin and the decline in glucagon inhibit basal endogenous glucose production (EGP) and enhance the suppression of EGP without affecting splanchnic (hepatic) glucose uptake or gastric emptying (6,7). Therapy with S and M combined (M+S) exerts an additive effect to reduce HgA_1c; the mechanism of action of this combination has yet to be examined. Several studies have demonstrated that M inhibits DPP-4 activity, thus increasing plasma active GLP-1 levels (8–10). There are also reports indicating that the decline in plasma glucose with M therapy can restore the β-cells’ sensitivity to the stimulatory effect of incretins on insulin secretion (11,12). Despite these reports, we still do not fully understand the reasons why the use of M in diabetic patients is not accompanied by changes in insulin release. In the current study, we used the double-tracer technique (7) to examine the mechanism(s) via which M+S and each agent alone reduce the fasting and postmeal plasma glucose concentration in T2DM.     

Effective Translation of an Intensive Lifestyle Intervention for Hispanic Women With Prediabetes in a Community Health Center Setting

OBJECTIVE

The Diabetes Prevention Program (DPP) demonstrated that weight loss from intensive lifestyle intervention (ILI) in adults with prediabetes could decrease progression to type 2 diabetes. Inner-city, low-income Hispanic women are at high risk for developing type 2 diabetes; however, this type of intervention is not well established in this group. We hypothesized that a DPP intervention modified for a community health center (CHC) setting would decrease weight and improve metabolic measures in Hispanic women with prediabetes.

RESEARCH DESIGN AND METHODS

Women diagnosed with prediabetes on a screening oral glucose tolerance test were recruited from a CHC. Participants (90% of whom were Hispanic) were randomized to either usual care (age 43 ± 9.7 years, BMI 35.2 ± 7.3 kg/m²) or ILI (age 43.8 ± 10.8 years, BMI 35.4 ± 8.5 kg/m²), structured as 14 weeks of group sessions focused on food choices, behavior change, physical activity, and weight loss. One year after enrollment, 122 women repeated baseline measures.

RESULTS

Groups had similar baseline weight, BMI, and fasting and 2-h glucose. One year later, the ILI group had lost 3.8 kg (4.4%), while the usual care group had gained 1.4 kg (1.6%, P < 0.0001). Two-hour glucose excursion decreased 15 mg/dL (0.85 mmol/L) in the ILI and 1 mg/dL (0.07 mmol/L) in the usual care group (P = 0.03). Significant decreases favoring the ILI group were noted in BMI, percent body fat, waist circumference, and fasting insulin.

CONCLUSIONS

A 14-week ILI program based on the DPP can effectively be translated into a predominantly Hispanic CHC setting, resulting in decreased weight, improved fasting insulin, and smaller glucose excursions 1 year after enrolling in the program.     

A randomized controlled trial investigating the effects of a low-glycemic index diet on pregnancy outcomes in gestational diabetes mellitus

OBJECTIVE

The prevalence of gestational diabetes mellitus (GDM) is rising. There is little evidence to demonstrate the effectiveness of one dietary therapy over another. We aimed to investigate the effect of a low–glycemic index (LGI) versus a conventional high-fiber diet on pregnancy outcomes, neonatal anthropometry, and maternal metabolic profile in GDM.

RESEARCH DESIGN AND METHODS

Ninety-nine women (age 26–42 years; mean ± SD prepregnancy BMI 24 ± 5 kg/m²) diagnosed with GDM at 20–32 weeks’ gestation were randomized to follow either an LGI (n = 50; target glycemic index [GI] ~50) or a high-fiber moderate-GI diet (HF) (n = 49; target GI ~60). Dietary intake was assessed by 3-day food records. Pregnancy outcomes were collected from medical records.

RESULTS

The LGI group achieved a modestly lower GI than the HF group (mean ± SEM 47 ± 1 vs. 53 ± 1; P < 0.001). At birth, there was no significant difference in birth weight (LGI 3.3 ± 0.1 kg vs. HF 3.3 ± 0.1 kg; P = 0.619), birth weight centile (LGI 52.5 ± 4.3 vs. HF 52.2 ± 4.0; P = 0.969), prevalence of macrosomia (LGI 2.1% vs. HF 6.7%; P = 0.157), insulin treatment (LGI 53% vs. HF 65%; P = 0.251), or adverse pregnancy outcomes.

CONCLUSIONS

In intensively monitored women with GDM, an LGI diet and a conventional HF diet produce similar pregnancy outcomes.Gestational diabetes mellitus (GDM) is commonly defined as any degree of glucose intolerance with onset or first recognition during pregnancy (1). In developed nations, between 4 and 8% of pregnant women are presently affected (2–4), and the prevalence will rise dramatically if the guidelines of the new International Association of Diabetes in Pregnancy Study Groups (IADPSG) are adopted (3). The main adverse outcome of GDM is excessive fetal growth resulting in higher risk of large-for-gestational-age (LGA) infants (birth weight >90th centile). Higher birth weight has been linked with childhood obesity (5), cardiovascular disease (6), and diabetes (5) later in life.In the medical management of GDM, the primary goal is to maintain maternal blood glucose concentrations, especially postprandial levels, within an acceptable range (7). Interventions that reduce postprandial glucose levels, including dietary strategies such as carbohydrate restriction, have been shown to be effective in reducing LGA and later obesity in type 1 diabetic offspring (8).Postprandial glycemia can be reduced without carbohydrate restriction by slowing down the rate of carbohydrate digestion and absorption. Compared with moderate–or high–glycemic index (GI) foods containing similar amount of carbohydrates, low-GI (LGI) foods have been demonstrated to reduce postprandial glucose in healthy individuals (9). The GI of various foods has been shown to be the same in pregnancy as in the nonpregnant state (10). An LGI meal pattern may therefore represent an alternative strategy for reducing postprandial glycemia in GDM without restricting carbohydrate (11).The effect of an LGI eating pattern on obstetric outcomes in GDM has been little studied. Moses et al. (12) found that a significantly higher proportion of women in the higher-GI group met the criteria to commence insulin compared with women in the LGI group. In addition, 47% of the women in the high-GI group who met the criteria for insulin commencement avoided insulin by switching to an LGI diet. However, they found no significant differences in key fetal and obstetric outcomes.To our knowledge, this study is the first randomized controlled trial to determine the efficacy of an LGI diet versus a conventional healthy diet on pregnancy outcomes in GDM. Our hypothesis was that an LGI diet would reduce birth weight (primary end point), birth weight centile, ponderal index, and the prevalence of LGA infants.     

Does a reduced glucose intake prevent hyperglycemia in children early after cardiac surgery? a randomized controlled crossover study

Introduction

Hyperglycemia in children after cardiac surgery can be treated with intensive insulin therapy, but hypoglycemia is a potential serious side effect. The aim of this study was to investigate the effects of reducing glucose intake below standard intakes to prevent hyperglycemia, on blood glucose concentrations, glucose kinetics and protein catabolism in children after cardiac surgery with cardiopulmonary bypass (CPB).

Methods

Subjects received a 4-hour low glucose (LG; 2.5 mg/kg per minute) and a 4-hour standard glucose (SG; 5.0 mg/kg per minute) infusion in a randomized blinded crossover setting. Simultaneously, an 8-hour stable isotope tracer protocol was conducted to determine glucose and leucine kinetics. Data are presented as mean ± SD or median (IQR); comparison was made by paired samples t test.

Results

Eleven subjects (age 5.1 (20.2) months) were studied 9.5 ± 1.9 hours post-cardiac surgery. Blood glucose concentrations were lower during LG than SG (LG 7.3 ± 0.7 vs. SG 9.3 ± 1.8 mmol/L; P < 0.01), although the glycemic target (4.0-6.0 mmol/L) was not achieved. No hypoglycemic events occurred. Endogenous glucose production was higher during LG than SG (LG 2.9 ± 0.8 vs. SG 1.5 ± 1.1 mg/kg per minute; P = 0.02), due to increased glycogenolysis (LG 1.0 ± 0.6 vs. SG 0.0 ± 1.0 mg/kg per minute; P < 0.05). Leucine balance, indicating protein balance, was negative but not affected by glucose intake (LG -54.8 ± 14.6 vs. SG -58.8 ± 16.7 μmol/kg per hour; P = 0.57).

Conclusions

Currently recommended glucose intakes aggravated hyperglycemia in children early after cardiac surgery with CPB. Reduced glucose intake decreased blood glucose concentrations without causing hypoglycemia or affecting protein catabolism, but increased glycogenolysis.

Trial registration

Dutch trial register NTR2079.     

Three 15-min Bouts of Moderate Postmeal Walking Significantly Improves 24-h Glycemic Control in Older People at Risk for Impaired Glucose Tolerance

OBJECTIVE

The purpose of this study was to compare the effectiveness of three 15-min bouts of postmeal walking with 45 min of sustained walking on 24-h glycemic control in older persons at risk for glucose intolerance.

RESEARCH DESIGN AND METHODS

Inactive older (≥60 years of age) participants (N = 10) were recruited from the community and were nonsmoking, with a BMI <35 kg/m² and a fasting blood glucose concentration between 105 and 125 mg dL⁻¹. Participants completed three randomly ordered exercise protocols spaced 4 weeks apart. Each protocol comprised a 48-h stay in a whole-room calorimeter, with the first day serving as the control day. On the second day, participants engaged in either 1) postmeal walking for 15 min or 45 min of sustained walking performed at 2) 10:30 a.m. or 3) 4:30 p.m. All walking was on a treadmill at an absolute intensity of 3 METs. Interstitial glucose concentrations were determined over 48 h with a continuous glucose monitor. Substrate utilization was measured continuously by respiratory exchange (VCO₂/VO₂).

RESULTS

Both sustained morning walking (127 ± 23 vs. 118 ± 14 mg dL⁻¹) and postmeal walking (129 ± 24 vs. 116 ± 13 mg dL⁻¹) significantly improved 24-h glycemic control relative to the control day (P < 0.05). Moreover, postmeal walking was significantly (P < 0.01) more effective than 45 min of sustained morning or afternoon walking in lowering 3-h postdinner glucose between the control and experimental day.

CONCLUSIONS

Short, intermittent bouts of postmeal walking appear to be an effective way to control postprandial hyperglycemia in older people.Insulin secretion (relative to increased insulin resistance) declines with older age, and an impaired β-cell compensation for any existing aging- or disuse-related insulin resistance will accelerate the risk of postchallenge hyperglycemia and consequent type 2 diabetes (1). There also is evidence that glycemic exposure is a continuous risk factor for cardiovascular disease, with no apparent threshold (2–4). Therefore, higher levels of glycemia (even in the nondiabetic range) have significant clinical implications. Most of the glycemic exposure among people who develop micro- and macrovascular complications from diabetes comprises isolated postprandial hyperglycemia (i.e., a 2-h postchallenge glucose concentration ≥200 mg dL⁻¹, but a fasting level <126 mg dL⁻¹) (5,6). Isolated postprandial hyperglycemia is particularly common in older people (7,8). Data from epidemiologic studies suggest that postchallenge glucose concentrations increase with age by ∼6–9 mg dL⁻¹ per decade (9), whereas fasting glucose levels increase by 1–2 mg dL⁻¹ per decade (10). Thus, postprandial hyperglycemia may represent a key factor in the progression from impaired glucose tolerance (IGT) toward frank type 2 diabetes and cardiovascular disease in older people (1).Both insulin and exercise (muscle contractions) stimulate the translocation of GLUT4 transporter proteins to the plasma membrane in skeletal muscle, and the effects of these processes are at least to some degree additive (11,12). Muscle contractions per se will initiate glucose uptake independent of insulin secretion, however, and therefore exercise can supplement peripheral insulin action in the presence of an aging-related low or blunted insulin secretory response. Time of day may influence how effective exercise is on subsequent glycemic control, however, as there is evidence that insulin secretion is markedly lower in the afternoon compared with the early morning in older people (13), and the benefits of exercise may be best realized the closer that exposure is to the time it is needed (i.e., postprandially). Thus, timing of the exercise exposure (as well as volume [frequency × duration]) is an important element to consider with regard to treating those older people vulnerable to postprandial hyperglycemia, especially later in the day. We investigated whether smaller bouts of walking performed after each meal (during the period of absorption) would have a greater benefit for postprandial, as well as for 24-h, glucose control than would a single large bout of walking performed once per day. We are not aware of any study comparing the benefits of several intermittent bouts of postmeal exercise with a single sustained bout (of similar daily volume) on continuous measures of glucose homeostasis in older people.     

Effect of Moderate-Intensity Exercise Versus Activities of Daily Living on 24-Hour Blood Glucose Homeostasis in Male Patients With Type 2 Diabetes

OBJECTIVE

To investigate the impact of activities of daily living (ADL) versus moderate-intensity endurance-type exercise on 24-h glycemic control in patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS

Twenty males with type 2 diabetes participated in a randomized crossover study consisting of three experimental periods of 3 days each. Subjects were studied under sedentary control conditions, and under conditions in which prolonged sedentary time was reduced either by three 15-min bouts of ADL (postmeal strolling, ∼3 METs) or by a single 45-min bout of moderate-intensity endurance-type exercise (∼6 METs). Blood glucose concentrations were assessed by continuous glucose monitoring, and plasma insulin concentrations were determined in frequently sampled venous blood samples.

RESULTS

Hyperglycemia (glucose >10 mmol/L) was experienced for 6 h 51 min ±1 h 4 min per day during the sedentary control condition and was significantly reduced by exercise (4 h 47 min ± 1 h 2 min; P < 0.001), but not by ADL (6 h 2 min ± 1 h 16 min; P = 0.67). The cumulative glucose incremental areas under the curve (AUCs) of breakfast, lunch, and dinner were, respectively, 35 ± 5% (P < 0.001) and 17 ± 6% (P < 0.05) lower during the exercise and ADL conditions compared with the sedentary condition. The insulin incremental AUCs were, respectively, 33 ± 4% (P < 0.001) and 17 ± 5% (P < 0.05) lower during the exercise and ADL conditions compared with the sedentary condition.

CONCLUSIONS

When matched for total duration, moderate-intensity endurance-type exercise represents a more effective strategy to improve daily blood glucose homeostasis than repeated bouts of ADL. Nevertheless, the introduction of repeated bouts of ADL during prolonged sedentary behavior forms a valuable strategy to improve postprandial glucose handling in patients with type 2 diabetes.The level of glycemia (1–3), and particularly postprandial glycemia (4–6), has been associated with an increased risk for cardiovascular complications and mortality in patients with type 2 diabetes. Therefore, proper management of blood glucose concentrations is an important goal in type 2 diabetes treatment. Despite the application of oral blood glucose–lowering medication and the consumption of a healthy diet, postprandial hyperglycemia and excessive glycemic fluctuations remain predominant features in patients with type 2 diabetes (7,8). Therefore, additional treatment strategies are warranted to improve daily blood glucose homeostasis in patients with type 2 diabetes.Along with dietary modulation and proper medication, structured exercise is considered a cornerstone for type 2 diabetes treatment (9,10). The impact of structured exercise on long-term glycemic control (i.e., HbA_1c) can be largely ascribed to the cumulative glucoregulatory effects of each successive bout of exercise (11). In line with this view, we (12–15) and others (16–18) have demonstrated that a single bout of moderate-intensity to high-intensity exercise substantially improves glycemic control throughout the subsequent 24-h period in patients with type 2 diabetes. Besides regular exercise, an accumulating body of evidence also suggests an independent role for nonexercise physical activities in restoring or maintaining optimal glycemic control. In this regard, epidemiological studies have demonstrated that light physical activity is beneficially associated with postprandial blood glucose concentrations and markers of insulin sensitivity (19,20). These observations were recently reinforced by evidence from experimental studies, showing that short bouts of slow walking during the postprandial phase effectively reduce the glycemic response to a meal (21–23). So far, these experimental studies have been restricted to a single meal and nondiabetic populations. We hypothesized that simply performing activities of daily living (ADL) improves 24-h blood glucose homeostasis in patients with type 2 diabetes. Such a low-demanding physical activity strategy would provide an attractive alternative to the application of a more structured exercise regimen, because engaging in and adhering to structured exercise programs have been proven problematic for many patients with type 2 diabetes (9). For this reason, it would be relevant to investigate whether a modest increase in ADL could equal the benefits of more intense endurance-type exercise for glycemic control.In the current study we investigated the impact of repeated short bouts of ADL as opposed to a single session of moderate-intensity endurance-type exercise on daily blood glucose homeostasis in patients with type 2 diabetes. For this purpose, 24-h glycemic profiles of patients were assessed by continuous glucose monitoring under sedentary control conditions, and under conditions in which sedentary time was reduced either by three 15-min bouts of ADL (postmeal strolling; ∼3 METs) or by a single 45-min bout of cycling exercise (∼6 METs).     

Premeal Injection of Rapid-Acting Insulin Reduces Postprandial Glycemic Excursions in Type 1 Diabetes

OBJECTIVE

To assess the effect of three premeal timings of rapid-acting insulin on postprandial glucose excursions in type 1 diabetes.

RESEARCH DESIGN AND METHODS

Ten subjects participated in a three-way randomized crossover trial. Mean ± SD age was 45.5 ± 12.1 years, A1C was 8.55 ± 1.50%, duration of diabetes was 23.8 ± 7.8 years, and duration of continuous subcutaneous insulin infusion therapy was 8.5 ± 6.1 years. Insulin aspart was administered at 30, 15, or 0 min before mealtime.

RESULTS

Area under the curve was lower in the −15 stratum (0.41 ± 0.51 mmol/l/min) than that in the −30 stratum (1.89 ± 0.72 mmol/l/min, P = 0.029) and 0 stratum (2.11 ± 0.66 mmol/l/min, P = 0.030). Maximum glucose excursion was lower in the −15 stratum (4.77 ± 0.52 mmol/l) than that in the −30 (6.48 ± 0.76 mmol/l, P = 0.025) and 0 stratum (6.93 ± 0.76 mmol/l, P = 0.022). Peak glucose level was lower in the −15 stratum (9.26 ± 0.72 mmol/l) than that in the −30 stratum (11.74 ± 0.80 mmol/l, P = 0.007) and the 0 stratum (12.29 ± 0.93, P = 0.009). Time spent in the 3.5–10 mmol/l range was higher in the −15 stratum (224.5 ± 25.0 min) than that in the 0 stratum (90.5 ± 23.2 min, P = 0.001). There was no significant difference in occurrence of glucose levels <3.5 mmol/l between strata (P = 0.901).

CONCLUSIONS

Administration of rapid-acting insulin analogs 15 min before mealtime results in lower postprandial glucose excursions and more time spent in the 3.5–10.0 mmol/l range, without increased risk of hypoglycemia.One of the most challenging aspects of attaining adequate glycemic control is limiting the postprandial raise of glucose. Current American Diabetes Association guidelines recommend aiming for postprandial blood glucose levels <10 mmol/l (1,2). With the advent of rapid-acting insulin analogs (insulin lispro, aspart, and glulisine), individuals with diabetes can attain lower postprandial glucose excursions (3–5). Therefore, because of the possibility of giving the dose of insulin at mealtime rather than 15–30 min before the meal, as was recommended for human insulin (6), rapid-acting insulin analogs have become the preferred mealtime insulin for people with type 1 diabetes (7,8).After a meal, the postprandial glucose peak mostly occurs between 1 and 2 h with a mean peak time of 75 min (9). Rapid-acting insulin analogs display a maximum effect at ∼100 min after subcutaneous injection (10). Thus, the question arises whether perhaps it would be better to inject the mealtime insulin 15 or even 30 min before the start of a meal. In this way the insulin peak action is better synchronized with the glycemic excursions after a meal, thereby potentially minimizing the height of the postprandial glucose excursions. Limited data address this topic. The aim of this study was to measure the effect of different premeal timing of rapid-acting insulin on postprandial excursions.     

Calorie Restriction and Matched Weight Loss From Exercise: Independent and Additive Effects on Glucoregulation and the Incretin System in Overweight Women and Men

OBJECTIVE

It is not known whether calorie restriction (CR) has additive benefits to those from exercise (EX)-induced weight loss. We hypothesized that weight loss from CR and EX (CREX) improves insulin sensitivity more than matched weight loss induced by EX or CR alone and that the incretin system may be involved in adaptations to CR.

RESEARCH DESIGN AND METHODS

Sedentary, overweight men and women (n = 52, 45–65 years of age) were randomized to undergo 6–8% weight loss by using CR, EX, or CREX. Glucose, insulin, C-peptide, insulin sensitivity, and incretin hormones (glucagon-like peptide 1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]) were measured during frequently sampled oral glucose tolerance tests (FSOGTTs). Incretin effects on insulin secretion were measured by comparing insulin secretion rates from the FSOGTTs to those from a glycemia-matched glucose infusion.

RESULTS

Despite similar weight losses in all groups, insulin sensitivity index values increased twofold more in the CREX group (2.09 ± 0.35 μM/kg/pM × 100) than in the CR (0.89 ± 0.39 μM/kg/pM × 100) and EX (1.04 ± 0.39 μM/kg/pM × 100) groups. Postprandial GLP-1 concentrations decreased only in the CR group (P = 0.04); GIP concentrations decreased in all groups. Incretin effects on insulin secretion were unchanged.

CONCLUSIONS

CR and EX have additive beneficial effects on glucoregulation. Furthermore, the adaptations to CR may involve reductions in postprandial GLP-1 concentrations. These findings underscore the importance of promoting both CR and EX for optimal health. However, because data from participants who withdrew from the study and from those who did not adhere to the intervention were excluded, the results may be limited to individuals who are capable of adhering to a healthy lifestyle intervention.     

Comparative Study of Glucose Homeostasis,Lipids and Lipoproteins,HDL Functionality,and Cardiometabolic Parameters in Modestly Severely Obese African Americans and White Americans With Prediabetes: Implications for the Metabolic Paradoxes

OBJECTIVE

To determine whether modestly severe obesity modifies glucose homeostasis, levels of cardiometabolic markers, and HDL function in African Americans (AAs) and white Americans (WAs) with prediabetes.

RESEARCH DESIGN AND METHODS

We studied 145 subjects with prediabetes (N = 61 WAs, N = 84 AAs, mean age 46.5 ± 11.2 years, mean BMI 37.8 ± 6.3 kg/m²). We measured fasting levels of lipids, lipoproteins, and an inflammatory marker (C-reactive protein [CRP]); HDL functionality (i.e., levels of paraoxonase 1 [PON1]); and levels of oxidized LDL, adiponectin, and interleukin-6 (IL-6). We measured serum levels of glucose, insulin, and C-peptide during an oral glucose tolerance test. Values for insulin sensitivity index (Si), glucose effectiveness index (Sg), glucose effectiveness at zero insulin (GEZI), and acute insulin response to glucose (AIR_g) were derived using a frequently sampled intravenous glucose tolerance test (using MINMOD software).

RESULTS

Mean levels of fasting and incremental serum glucose, insulin, and C-peptide tended to be higher in WAs versus AAs. The mean Si was not different in WAs versus AAs (2.6 ± 2.3 vs. 2.9 ± 3.0 × 10⁻⁴ × min⁻¹ [μU/mL]⁻¹). Mean values for AIR_g and disposition index as well as Sg and GEZI were lower in WAs than AAs. WAs had higher serum triglyceride levels than AAs (116.1 ± 55.5 vs. 82.7 ± 44.2 mg/dL, P = 0.0002). Mean levels of apolipoprotein (apo) A1, HDL cholesterol, PON1, oxidized LDL, CRP, adiponectin, and IL-6 were not significantly different in obese AAs versus WAs with prediabetes.

CONCLUSIONS

Modestly severe obesity attenuated the ethnic differences in Si, but not in Sg and triglyceride levels in WAs and AAs with prediabetes. Despite the lower Si and PON1 values, AAs preserved paradoxical relationships between the Si and HDL/apoA1/triglyceride ratios. We conclude that modestly severe obesity has differential effects on the pathogenic mechanisms underlying glucose homeostasis and atherogenesis in obese AAs and WAs with prediabetes.     

Cross-sectional and Longitudinal Associations Between Objectively Measured Sedentary Time and Metabolic Disease: The Coronary Artery Risk Development in Young Adults (CARDIA) Study

OBJECTIVE

Prolonged sedentary time (ST) might be contributing to the diabetes epidemic, but most studies have been cross-sectional and few have objectively measured ST. The purpose of this study was to evaluate cross-sectional and 5-year longitudinal relationships between ST and metabolic parameters and outcomes.

RESEARCH DESIGN AND METHODS

This was an analysis of 2,027 Coronary Artery Risk Development in Young Adults (CARDIA) study participants (aged 38–50 years, 57% female, and mean BMI of 29.0 ± 7.0 kg/m²) with accelerometry data (≥4 days with ≥10 h/day) measured at the year 20 follow-up exam (2005–2006). Metabolic variables (fasting glucose, fasting insulin, 2-h postchallenge glucose, HOMA of insulin resistance [HOMA-IR], and HbA_1c) and outcomes (impaired fasting glucose [IFG], impaired glucose tolerance [IGT], prediabetes by HbA_1c, and diabetes) were assessed concurrently and 5 years later.

RESULTS

Average ST was 8.1 ± 1.7 h/day or 55 ± 10% of wear time. Each additional hour per day of ST was cross-sectionally associated with a 3% higher fasting insulin and HOMA-IR (both P < 0.01) but not 5-year changes in metabolic parameters. Having ≥10 h/day vs. <6 h/day of ST was associated with an odds ratio (OR) = 2.74 (95% CI 1.13, 6.62) for IGT and an OR = 3.80 (95% CI 1.39, 10.35) for diabetes. ST was not associated with prevalent IFG, prevalent prediabetes by HbA_1c, or 5-year incidence of any metabolic outcomes (all P > 0.05).

CONCLUSIONS

ST was independently related to insulin, HOMA-IR, and prevalent diabetes and IGT but did not predict 5-year changes in metabolic parameters or incidence of metabolic outcomes. These results suggest that higher ST may not be a risk factor for future metabolic outcomes, but more research with repeated ST measurement and longer follow-up is needed.     

Energy Balance After Sodium–Glucose Cotransporter 2 Inhibition

OBJECTIVE

Sodium–glucose cotransporter 2 (SGLT2) inhibitors cause substantially less weight loss than expected from the energy excreted via glycosuria. Our aim was to analyze this phenomenon quantitatively.

RESEARCH DESIGN AND METHODS

Eighty-six patients with type 2 diabetes (HbA_1c 7.8 ± 0.8% [62 ± 9 mmol/mol], estimated glomerular filtration rate [eGFR] 89 ± 19 mL ⋅ min⁻¹ ⋅ 1.73 m⁻²) received empagliflozin (25 mg/day) for 90 weeks with frequent (n = 11) assessments of body weight, eGFR, and fasting plasma glucose (FPG). Time-dependent glucose filtration was calculated as the product of eGFR and FPG; time-dependent glycosuria was estimated from previous direct measurements. The relation of calorie-to-weight changes was estimated using a mathematical model of human energy metabolism that simulates the time course of weight change for a given change in calorie balance and calculates the corresponding energy intake changes.

RESULTS

At week 90, weight loss averaged −3.2 ± 4.2 kg (corresponding to a median calorie deficit of 51 kcal/day [interquartile range (IQR) 112]). However, the observed calorie loss through glycosuria (206 kcal/day [IQR 90]) was predicted to result in a weight loss of –11.3 ± 3.1 kg, assuming no compensatory changes in energy intake. Thus, patients lost only 29 ± 41% of the weight loss predicted by their glycosuria; the model indicated that this difference was accounted for by a 13% (IQR 12) increase in calorie intake (269 kcal/day [IQR 258]) coupled with a 2% (IQR 5) increase in daily energy expenditure (due to diet-induced thermogenesis). This increased calorie intake was inversely related to baseline BMI (partial r = −0.34, P < 0.01) and positively to baseline eGFR (partial r = 0.29, P < 0.01).

CONCLUSIONS

Chronic glycosuria elicits an adaptive increase in energy intake. Combining SGLT2 inhibition with caloric restriction is expected to be associated with major weight loss.     

Frequency of Interruptions to Sitting Time: Benefits for Postprandial Metabolism in Type 2 Diabetes

OBJECTIVETo determine whether interrupting sitting with brief bouts of simple resistance activities (SRAs) at different frequencies improves postprandial glucose, insulin, and triglycerides in adults with medication-controlled type 2 diabetes (T2D).RESEARCH DESIGN AND METHODSParticipants (n = 23, 10 of whom were female, with mean ± SD age 62 ± 8 years and BMI 32.7 ± 3.5 kg · m⁻²) completed a three-armed randomized crossover trial (6- to 14-day washout): sitting uninterrupted for 7 h (SIT), sitting with 3-min SRAs (half squats, calf raises, gluteal contractions, and knee raises) every 30 min (SRA3), and sitting with 6-min SRAs every 60 min (SRA6). Net incremental areas under the curve (iAUC_net) for glucose, insulin, and triglycerides were compared between conditions.RESULTSGlucose and insulin 7-h iAUC_net were attenuated significantly during SRA6 (glucose 17.0 mmol · h · L⁻¹, 95% CI 12.5, 21.4; insulin 1,229 pmol · h · L⁻¹, 95% CI 982, 1,538) in comparison with SIT (glucose 21.4 mmol · h · L⁻¹, 95% CI 16.9, 25.8; insulin 1,411 pmol · h · L⁻¹, 95% CI 1,128, 1,767; P < 0.05) and in comparison with SRA3 (for glucose only) (22.1 mmol · h · L⁻¹, 95% CI 17.7, 26.6; P = 0.01) No significant differences in glucose or insulin iAUC_net were observed in comparison of SRA3 and SIT. There was no statistically significant effect of condition on triglyceride iAUC_net.CONCLUSIONSIn adults with medication-controlled T2D, interrupting prolonged sitting with 6-min SRAs every 60 min reduced postprandial glucose and insulin responses. Other frequencies of interruptions and potential longer-term benefits require examination to clarify clinical relevance.