Mary Ann Banerji

Does Intra-Abdominal Adipose Tissue in Black Men Determine Whether NIDDM Is Insulin-Resistant or Insulin-Sensitive?

Insulin resistance in black Americans with non-insulin-dependent diabetes mellitus (NIDDM) is found in only 60% of those with a body mass index (BMI) of <30 kg/m2, suggesting that NIDDM can occur independent of peripheral insulin resistance. When insulin resistance is present, it is not necessarily correlated with obesity. Numerous studies have shown that increased amounts of intra-abdominal adipose tissue are associated with various metabolic abnormalities. We therefore investigated whether the occurrence of insulin resistance in black NIDDM men could be explained by the pattern of body adipose tissue distribution rather than total adiposity. Twenty-two near-normoglycemic black men (fasting plasma glucose [mean ± SD] = 104 ± 10 mg/dl, HbA1c = 4.6 ± 0.78%, age 48.9 ± 9.2 years, and BMI 26.5 ± 2.4 kg/m2) were studied. The euglycemic insulin clamp with 1 mU · kg−1 · min−1 insulin infusion and D-[3-3H]glucose was used to measure insulin action. Whole-body computed tomography with 22 scans was used to determine body composition. Total body adipose tissue was 19.6 ± 7.5 1, and the percentage of body fat was 27 ± 7. Glucose disposal ranged from 2.5 to 8.1 mg · kg−1 · min−1 (10 men were insulin-sensitive and 12 were insulin-resistant). There was a strong inverse correlation between glucose disposal and the proportion of total adipose tissue in the intra-abdominal region (r = −0.78, P < 0.001), while there was no correlation between glucose disposal and total muscle volume, BMI, total adipose tissue volume, or total subcutaneous adipose tissue volume. When insulin resistance is present, it is highly correlated with an increase in the proportion of intra-abdominal adipose tissue. The data raise the possibility that insulin resistance in black NIDDM men may be a consequence of increased intra-abdominal adipose tissue mass.

Effect of intensive compared with standard glycemia treatment strategies on mortality by baseline subgroup characteristics: The ACCORD trial

OBJECTIVE To determine if baseline subgroups in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial can be identified for whom intensive compared with standard glycemia treatment had different effects on all-cause mortality. RESEARCH DESIGN AND METHODS Exploratory post hoc intention-to-treat comparisons were made between intensive and standard glycemia groups on all-cause mortality by subgroups defined by baseline characteristics. RESULTS There were few significant interactions between baseline characteristics and effects of intensive versus standard glycemia treatment on mortality: self-reported history of neuropathy (hazard ratio [HR] 1.95, 95% CI 1.41–2.69) versus no history of neuropathy (0.99, 0.79–1.26; P value for interaction 0.0008), higher A1C (A1C >8.5%: HR 1.64, 95% CI 1.22–2.22; A1C 7.5–8.4%: 1.00, 0.75–1.34; A1C <7.5%: 1.00, 0.67–1.50; P value for interaction 0.04), and aspirin use (HR 1.45, 95% CI 1.13–1.85, compared with 0.96, 0.72–1.27, in nonusers; P value for interaction 0.03). CONCLUSIONS We found a remarkable similarity of effect from intensive compared with standard glycemia treatment on mortality across most baseline subgroups. No differential effect was found in subgroups defined by variables anticipated to have an interaction: age, duration of diabetes, and previous history of cardiovascular disease. The three baseline characteristics that defined subgroups for which there was a differential effect on mortality may help identify patients with type 2 diabetes at higher risk of mortality from intensive regimens for glycemic control. Further research is warranted.

Early-Life Stress and the Development of Obesity and Insulin Resistance in Juvenile Bonnet Macaques

Stress is a risk factor for chronic illnesses such as obesity, type 2 diabetes, and hypertension and has been postulated to cause the metabolic syndrome via perturbation of the hypothalamo-pituitary-adrenal (HPA) axis. In our model of early-life stress (variable foraging demand [VFD]), food insecurity is imposed on monkey mothers for 16 weeks beginning when their nursing offspring are 3–5 months of age. Under VFD, food availability is never restricted, and the infants growth is unaffected. VFD rearing does, however, cause a range of neurobiological abnormalities, including dysregulation of the HPA axis, manifested in abnormal cerebrospinal fluid cortisol and corticotropin-releasing factor levels. We previously reported spontaneous occurrence of metabolic syndrome in 14% of normally reared peripubertal bonnet macaques given ad libitum access to standard monkey chow. Here, we show that compared with normally reared monkeys, peripubertal VFD juveniles exhibit greater weight, BMI, abdominal circumference, and glucagon-like peptide-1 and decreased glucose disposal rates during hyperinsulinemic-euglycemic clamps. Our data suggest that early-life stress during a critical period of neuro development can result in the peripubertal emergence of obesity and insulin resistance.

Insulin-Sensitive and Insulin-Resistant Variants in NIDDM

To define the sequence of events that is involved in the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM), we studied 16 NIDDM individuals (15 of 16 Black patients) with a mean age of 44 yr who had been near normoglycemic for 2–91 mo while off of antidiabetic medicine. With the euglycemic insulin clamp at 100 (μU/ml insulin, we defined two populations, one with normal peripheral insulin sensitivity (glucose disposal 7.51 ± 0.97 mg · kg−1 · min−1) and the other with insulin resistance (glucose disposal 3.35 ± 0.58 mg · kg−1 · min−1; P <.001). The populations did not differ in age, degree of obesity, fasting plasma glucose, glycosylated hemoglobin, clinical presentation, or clinical course. Basal plasma insulin levels were normal in the sensitive group and significantly elevated in the resistant group. Islet cell cytoplasmic antibodies were absent in all patients. Insulin action on the liver was normal in both groups. Basal hepatic glucose production measured with D-[3−3H]glucose was lower in the insulin-resistant group (1.53 ± 0.11 mg · kg−1 · min−1) than in the insulin-sensitive group (1.88 ± 0.06 mg · kg1 · min−1) or normal control subjects (1.93 ± 0.05 mg · kg−1 · min1). The decreased basal hepatic glucose production appeared to be secondary to the twofold higher fasting plasma insulin level seen in the insulin-resistant group. The insulin concentration necessary to suppress basal hepatic glucose production by 50% was 29.6 μU/ml in the insulin-sensitive group and 30.5 μU/ml in the insulin-resistant group. The absolute insulin-secretory responses to oral glucose and intravenous glucagon were significantly lower (50%) in the insulin-sensitive group than in the insulin-resistant group, whose absolute responses were similar to normal control subjects. Compared with individuals with impaired glucose tolerance, the insulin response to oral glucose in the insulin-resistant group was somewhat reduced. We hypothesize that NIDDM in this particular population consists of two subpopulations, one with primary insulin deficiency and normal insulin action and the other with primary peripheral insulin resistance and a mild impairment in glucose-mediated insulin secretion. In both, insulin action in the liver was initially normal.

Insulin Action in Black Americans With NIDDM

OBJECTIVE To assess the influences that obesity and hyperglycemia have on insulin action in black NIDDM patients. RESEARCH DESIGN AND METHODS Thirty-nine subjects were studied who had normal GHb levels and/or FPG <6.4 mM and who had not taken pharmacological agents for 2–91 mo before the study. Insulin action was studied using the euglycemic insulin clamp with a d-[3-3H] glucose infusion. Degree of obesity was assessed with BMI. During carefully monitored follow-up, 9 patients relapsed into a hyperglycemic state, and insulin action was restudied after acute reregulation of their plasma glucose. RESULTS Insulin action was related to the degree of obesity at the extremes of BMI: 7 of 8 patients (87.5%) with a BMI <24.0 kg/m2 were insulin sensitive, and 8 of 9 patients (88.9%) with a BMI >28.5 kg/m2 were insulin resistant. In the midrange BMI (24.0–28.5 kg/m2), patients were equally likely to be insulin resistant or insulin sensitive. A plot of frequency versus glucose disposal in those patients was compatible with a bimodal distribution (P < 0.025): 12 of 22 patients were normally insulin sensitive (glucose disposal 6.1–9.4 mg.kg−1 · min−1), and 10 were insulin resistant (glucose disposal 2.4–4.8 mg.kg−1 · min−1). Analysis of this midrange BMI group showed that in the insulin-sensitive group, an inverse relationship existed between BMI and glucose disposal (r = −0.64, P < 0.05), whereas no such relationship was found in the insulin-resistant group. The clinical characteristics of the midrange BMI group indicated that fasting plasma insulin, total cholesterol, and triglycerides were higher; whereas BMI, age, and FPG were not different in the insulin-resistant compared with the insulin-sensitive group. With the development of hyperglycemia, insulin action in the insulin-sensitive group. With the development of hyperglycemia, insulin action in the insulin-sensitive group was decreased, independent of obesity, whereas it was unchanged in the insulin-resistant group. CONCLUSIONS Insulin resistance exists in only ∼ 50% of black NIDDM patients. The relationship between obesity and insulin resistance is not a simple one. The data can be explained by one of two hypotheses: 1) insulin resistance in black NIDDM patients is an acquired defect related to the development of obesity and is modulated by hyperglycemia, or 2) NIDDM exists as two variants, one with primary insulin resistance and one with normal insulin sensitivity, and that insulin resistance causes central and/or generalized obesity.

Long-term normoglycemic remission in black newly diagnosed NIDDM subjects.

We have defined and characterized the natural history of spontaneous near-normoglycemic remission off of antidiabetic medication in 79 black NIDDM subjects. They had initially presented with plasma glucose levels of 37.8 ± 19.3 mmol/l. Baseline clinical metabolic and 8-year prospective data were obtained (51 men and 28 women, mean age 45 ± 10 years, islet-cell or GAD antibody negative). After hospitalization and intensive outpatient treatment, near-normoglycemic remission (fasting plasma glucose 6.1 ± 0.83 mmol/l and HbA1c 0.95 ± 0.10 of upper limit of normal) occurred within 8 ± 10 months of insulin or sulfonylurea therapy. This was unrelated to the resolution of stress or significant weight loss (1.9 ± 4.97 kg). Metabolic studies performed during remission showed 17% normal, 33% impaired, and 50% diabetic glucose tolerance. Glucose disposal (1 mU · kg−1 · min−1) euglycemic insulin clamp with D-[3-3)H]glucose) was higher in the normal glucose tolerance group compared with the impaired and diabetic groups (37.8 ± 10.2 vs. 26.1 ± 10.7 and 26.7 ± 12.0 μmol · kg−1 · min−1; P < 0.05) despite similar BMIs in all three groups (28.8 ± 3.7 kg/m2). Insulin secretion was below the normal range. Of 79 patients, 27 relapsed. A Kaplan-Meier survival analysis gives a median time of 40 months to relapse. Higher presenting plasma glucose and male sex predicted earlier relapse. Near-normoglycemic remission may occur in up to 30% of black new-onset NIDDM patients. It appears to be associated with intensive initial glycemic regulation and may be a method of decreasing the development of microvascular complications in NIDDM.

Hyperfiltration in African-American Patients With Type 2 Diabetes: Cross-sectional and longitudinal data

OBJECTIVE Hyperfiltration may play a role in the development of diabetic nephropathy. African-American patients with diabetes have more than a fourfold increase in end-stage renal disease. The purpose of this study is to evaluate the impact of hyperfiltration on renal function in African-American patients with type 2 diabetes. RESEARCH DESIGN AND METHODS Renal function of 194 African-American patients with diagnosed type 2 diabetes from 1 month to 36 years was assessed by studies of isotopic glomerular filtration rate (GFR), serum creatinine, creatinine clearance, and 24-h urinary albumin excretion rates. Thirty-four patients with a duration of diagnosed type 2 diabetes from 1 month to 10 years were found to have hyperfiltration (GFR ≥140 ml · min−1 · 1.73 min2). Fifteen of these patients received longitudinal follow-up of renal function for as long as 15 years after the initial study. RESULTS Hyperfiltration is present in 15 (36%) of 42 patients whose duration of diagnosed type 2 diabetes is <1 year, and it persists for up to 10 years in 14–20% of patients with diagnosed type 2 diabetes. Patients with hyperfiltration are younger than their counterparts without hyperfiltration when matched for duration of diagnosed diabetes. When followed over time, those patients with hyperfiltration were not more likely to develop impaired renal function as measured by GFR or creatinine clearance. CONCLUSIONS Hyperfiltration does not identify patients at risk for deterioration in renal function

Utility of untimed urinary albumin measurements in assessing albuminuria in black NIDDM subjects.

OBJECTIVE To determine the usefulness of an untimed morning urine specimen in screening a black NIDDM population attending an urban diabetes clinic for microalbuminuria. RESEARCH DESIGN AND METHODS Untimed morning specimens were provided by 218 black NIDDM subjects. Of the 218 subjects, 123 also provided 24-h urine specimens. The 24-h specimens were assayed for albumin excretion rate (AER) in milligrams per 24 h, and the albumin-to-creatinine ratio (A-to-C) in micrograms per milligram was determined on the untimed morning urine specimen. RESULTS Correlation between the A-to-C ratio and the 24-h AER was 0.96 (P = 0.0001). In the range of clinical proteinuria, r was 0.92 (P = 0.003, n = 7). In the range of microalbuminuria, r was 0.55 (P = 0.005, n = 26), and in the normal range, r was 0.59 (P ≤ 0.0001, n = 90). Analysis of the untimed urine specimens from 218 black NIDDM subjects showed that 171 had A-to-C < 30 μg/mg, 38 had A-to-C 30–300 μg/mg, and 9 had A-to-C > 300 μg/mg. Data were grouped according to duration of NIDDM and the presence or absence of hypertension. None of the newly diagnosed NIDDM patients (< 1 year) (n = 40) had microalbuminuria. The frequency of microalbuminuria and clinical proteinuria increased with 1) duration of NIDDM 5–10 years (odds ratio [OR], 3.39; 95% CI 1.17–9.82),2) duration of NIDDM > 10 years (OR, 11.03; 95% CI 4.16–29.25), and 3) presence of hypertension (OR, 2.59; 95% CI I.20–5.61). CONCLUSIONS The A-to-C ratio obtained from an untimed morning urine specimen correlates with the AER from a 24-h collection. In black subjects with newly diagnosed NIDDM, microalbuminuria is not present to a significant degree. Duration of NIDDM > 5 years is associated with increased prevalence of microalbuminuria, and hypertension is associated with microalbuminuria and clinical proteinuria in this population.

The Mechanism of Hyperchloremic Acidosis During the Recovery Phase of Diabetic Ketoacidosis

To determine the mechanism of hyperchloremic acidosis during recovery from diabetic ketoacidosis (DKA), serial measurements were made in eight patients of serum and urinary electrolytes and organic acids, and of urinary net acid. On admission, the average decrease in serum total CO2 was 17.5 mmol/L, corresponding to the excess anion gap, 18.5 meq/L, and the serum organic acids, 17.1 meq/L. With the treatment, the anion gap and organic acids decreased by 16.1 and 14.7 meq/L, respectively, but the serum CO2 increased only by 8.4 mmol/L; serum electrolyte balance was maintained by increase in chloride concentration. Fluid retention was insufficient to explain the disparity between the increase in CO2 and the decrease in organic acids. Renal loss of bicarbonate precursors during treatment was modest and was exceeded by renal bicarbonate production. The disparity between the increase in serum CO2 and the decrease in organic acids during treatment of DKA may be explained to a large extent by a difference in volume of distribution between bicarbonate and organic anions The renal loss of ketone anions before admission, however, is ultimately responsible for the persistence of substantial metabolic acidosis.

Do blacks with NIDDM have an insulin-resistance syndrome?

NIDDM has been postulated to be a component of a more generalized metabolic syndrome, Syndrome X, caused by insulin resistance. Although the components of the syndrome include glucose intolerance, hypertension, increased TG, and decreased HDL cholesterol, their relationship to insulin resistance and/or hyperinsulinemia is controversial. Recent investigations have shown racial differences in the relationship between insulin resistance and BP in nondiabetic populations. We assessed the relationship between insulin resistance and the other components of the syndrome in 37 black men and 53 black women with NIDDM. Insulin sensitivity was determined by measuring glucose disposal with the euglycemic insulin clamp technique with a 1 mU · kg−1 · min−1 insulin infusion. We also determined fasting lipid profiles and BP. In this group of black men and women with NIDDM, 30% were insulin sensitive, and 70% were insulin resistant. No correlation existed between insulin sensitivity and sBP or dBP in either sex. Fasting serum TGs were inversely correlated with insulin sensitivity for both men (r = −0.401, P = 0.02) and women (r = −0.366, P = 0.008). Serum HDL cholesterol was highly correlated with insulin sensitivity for men (r = 0.421, P = 0.01) but not for women (r = 0.071, P = 0.62). Fasting serum TG levels and serum HDL-cholesterol levels were highly correlated in an inverse relationship in men (r = −0.368, P = 0.03), but not women (r = −0.199, P = 0.17). In summary, BP does not correlate with insulin resistance in blacks with NIDDM. Normal insulin sensitivity occurs in 33% of black men and 25% of black women with NIDDM. In black women with NIDDM, serum HDL cholesterol does not correlate with either insulin sensitivity or fasting serum TGs. The data fail to support a major association of insulin resistance with metabolic abnormalities in black women with NIDDM and show only a weak association in black men with NIDDM.