Rochelle L Chaiken

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.

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.

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.

Patterns of Glucose and Lipid Abnormalities in Black NIDDM Subjects

Objective We had previously shown two variants among black non-insulin-dependent diabetic (NIDDM) subjects in a normoglycemic remission: one with insulin resistance and the other with normal insulin sensitivity. This study examined whether these two variants exist in the ordinary hyperglycemic black NIDDM population. Research Design and Methods Fifty-two black NIDDM subjects were assessed for insulin-stimulated glucose disposal (euglycemic clamp), glycemic control (fasting plasma glucose and HbA1c), and fasting lipid profiles. Results The distribution of glucose disposal in 30 black NIDDM subjects (body mass index; BMI < 30 kg/m2) was bimodal, which indicated two populations. Eighteen of 30 subjects (BMI 26.4 ± 0.5 kg/m2) had insulin resistance (glucose disposal 3.21 ± 0.24 mg·kg−1·min−1). Twelve of 30 subjects (BMI 24.83 ± 1.1 kg/m2) had normal insulin sensitivity (glucose disposal 7.19 ± 0.46 mg·kg−1·min−1). Twenty-one of the remaining 22 subjects (BMI 33.4 ± 0.7 kg/m2) were insulin resistant (glucose disposal 2.88 ± 0.21 mg·kg−1·min−1). Fasting serum triglyceride levels were lowest in the insulin-sensitive population (0.91 ± 0.07 mM) and different from the insulin-resistant population, BMI < 30 and > 30 kg/m2, (1.20 ± 0.10 mM, P < 0.05 and 1.42 ± 0.17 mM, P < 0.025, respectively). Fasting serum low-density lipoprotein cholesterol levels were not significantly different among the groups, although it did increase with insulin resistance and increasing obesity. Total serum cholesterol levels and glycemic control were similar for all three groups. Serum high-density lipoprotein cholesterol levels were higher in women compared with men. Conclusions In the hyperglycemic black NIDDM population, two variants exist: one with insulin resistance and one with normal insulin sensitivity. This insulin-sensitive variant represents 40% of subjects with a BMI < 30 kg/m2. Moreover, the insulin-sensitive group has a lower risk profile for cardiovascular disease.

HLA-DQ Associations Distinguish Insulin-Resistant and Insulin-Sensitive Variants of NIDDM in Black Americans

OBJECTIVE NIDDM in black Americans exists as two variants: one with a primary defect in insulin action (insulin-resistant variant) and the other with normal insulin action and a primary defect in insulin secretion (insulin-sensitive variant). The objective of this study was to determine whether these two variants were genetically distinct from each other and from normal control subjects as determined by HLA typing. RESEARCH DESIGN AND METHODS Insulin action was measured with the euglycemic insulin clamp with a 1 mU · kg−1 · min−1 insulin infusion with [3-3H]glucose. A glucose disposal of < 278 μmol · kg−1 · min−1 was considered insulin resistant, and a value greater than this was considered insulin sensitive. The study population consisted of 21 insulin-resistant and 25 insulin-sensitive black NIDDM patients and 89 normal, nondiabetic black control subjects from an urban hospital. HLA typing was performed with serological methods. RESULTS The frequency of HLA-DQW7 in the insulin-resistant population (76%) was significantly greater than that in the insulin-sensitive population (32%, corrected P < 0.018) and the normal control population (21%, corrected P < 0.001). The frequency of HLA-DQW6 was increased in the insulin-sensitive population (76%), corrected P < 0.023, as compared with the normal control subjects (33%). The relative risk of HLA-DQW7 in identifying insulin-resistant NIDDM patients compared with control subjects was 7. CONCLUSIONS At least one component that differentiates insulin-resistant and insulin-sensitive NIDDM in black Americans is under different genetic control. One or more loci responsible for insulin-resistant and insulin-sensitive NIDDM are likely to be in linkage disequilibrium with the DQ locus of the human MHC region of chromosome 6.

Metabolic Effects of Combination Glipizide and Human Proinsulin Treatment in NIDDM

The effects of 3 mo of treatment with a combination of glipizide and human proinsulin were studied in a small group of closely monitored patients. The patients had non-insulin-dependent diabetes mellitus (NIDDM) and poor glucose regulation, despite maximal sulfonylurea therapy. This was a randomized double-blind placebocontrolled trial in which there were three treatment groups who received either 20 mg glipizide given 30 min before breakfast and dinner and human proinsulin given subcutaneously at bedtime (n = 5), glipizide and human proinsulin placebo (n = 5), or glipizide placebo and human proinsulin (n = 5). Glycemic regulation was assessed by measurements of 24-h plasma glucose profiles and glycosylated hemoglobin. Our observations demonstrate that the combination of glipizide plus human proinsulin was more effective than either agent alone in controlling overall glycemia in patients with NIDDM. The data support the concept of use of an agent during the day that has its major effects postprandially and another agent at bedtime that is relatively hepatospecific.