John N. Clore

Diabetes and hypertension in severe obesity and effects of gastric bypass-induced weight loss.

ObjectiveTo evaluate the preoperative relationships of hypertension and diabetes mellitus in severe obesity and the effects of gastric bypass (GBP)-induced weight loss. Summary Background DataSevere obesity is associated with multiple comorbidities, particularly hypertension and type 2 diabetes mellitus, that may affect life expectancy. MethodsThe database of patients who had undergone GBP by one general surgeon at a university hospital between September 1981 and January 2000 was queried as to weight, body mass index (BMI), pre- and postoperative diabetes, hypertension, and other comorbidities, including sleep apnea, hypoventilation, gastroesophageal reflux, degenerative joint disease, urinary incontinence, venous stasis, and pseudotumor cerebri. ResultsOf 1,025 patients treated, 15% had type 2 diabetes mellitus and 51% had hypertension. Of those with diabetes, 75% also had hypertension. There was a progressive increase in age between patients who had neither diabetes nor hypertension, either diabetes or hypertension, or both diabetes and hypertension. At 1 year after GBP (91% follow-up), patients lost 66 ± 18% excess weight (%EWL) or 35 ± 9% of their initial weight (%WL). Hypertension resolved in 69% and diabetes in 83%. Patients who resolved their hypertension or diabetes had greater %EWL and %WL than those who did not. African-American patients had a higher risk of hypertension than whites before GBP and were less likely to correct their hypertension after GBP. There was significant resolution of other obesity comorbidity problems. At 5 to 7 years after GBP (50% follow-up), %EWL was 59 ± 24 and %WL was 31 ± 13; resolution of hypertension was 66% and diabetes 86%. ConclusionsThese data suggest that type 2 diabetes mellitus and hypertension may be indirectly related to each other through the effects of obesity, but not directly as to cause and effect. The longer a person remains severely obese, the more likely he or she is to develop diabetes, hypertension, or both. GBP-induced weight loss is effective in correcting diabetes, hypertension, and other comorbidities but is related to the %EWL achieved. Severely obese African-Americans were more likely to have hypertension and respond less well to GBP surgery than whites. These data suggest that GBP surgery for severe obesity should be provided earlier to patients to prevent the development of diabetes and hypertension and their complications.

A pilot study of vitamin E versus vitamin E and pioglitazone for the treatment of nonalcoholic steatohepatitis

BACKGROUND & AIMSnInsulin resistance and oxidative stress contribute to the pathogenesis of nonalcoholic steatohepatitis (NASH). We conducted a pilot study for the following reasons: (1) to test the hypothesis that a combination of an antioxidant (vitamin E) and an insulin sensitizer (pioglitazone) would be superior to vitamin E alone for the treatment of NASH, and (2) to define the effects of these interventions on insulin-sensitive metabolic functions and correlate the effects with changes in liver histology.nnnMETHODSnA randomized prospective trial was performed to compare the efficacy and safety of vitamin E alone (400 IU/day) vs. vitamin E (400 IU/day) and pioglitazone (30 mg/day) in nondiabetic, noncirrhotic subjects with NASH. Metabolic functions were assessed by a 2-step, hyperinsulinemic (10 and 40 mU/m2/min) euglycemic clamp.nnnRESULTSnA total of 10 patients were randomized to each arm. Two patients on combination therapy discontinued treatment; one because of pregnancy and the other because of hepatotoxicity. Treatment with vitamin E only produced a significant decrease in steatosis (mean grade, 2.2 vs. 1.4; P < .02). Compared with baseline, combination therapy produced a significant decrease in steatosis (mean, 2.3 vs. 1; P < .002), cytologic ballooning (1.3 vs. 0.2; P < .01), Mallorys hyaline (0.7 vs. 0.2; P < .04), and pericellular fibrosis (1.2 vs. 0.6; P < .03). Although vitamin E had no significant effects, combination therapy produced a significant increase in metabolic clearance of glucose and a decrease in fasting free fatty acid (FFA) and insulin. The decrease in fasting FFA and insulin independently predicted improvement in hepatic steatosis and cytologic ballooning.nnnCONCLUSIONSnA combination of vitamin E and pioglitazone produces a greater improvement in NASH histology. The improvement in steatosis and cytologic ballooning are related to treatment-associated decreases in fasting FFA and insulin levels.

Analysis of factors associated with durable remission of diabetes after Roux-en-Y gastric bypass

BACKGROUNDnData on the durability of remission of type 2 diabetes mellitus (T2DM) after gastric bypass are limited. Our purpose was to identify the rate of long-term remission of T2DM and the factors associated with durable remission.nnnMETHODSnA total of 177 patients with T2DM who had undergone Roux-en-Y gastric bypass from 1993 to 2003 had 5-year follow-up data available. T2DM status was determined by interview and evaluation of the diabetic medications. Patients with complete remission or recurrence of T2DM were identified.nnnRESULTSnFollow-up ranged from 5 to 16 years. Of the 177 patients, 157 (89%) had complete remission of T2DM with a decrease in their mean body mass index from baseline (50.2 +/- 8.2 kg/m(2)) to 31.3 +/- 7.2 kg/m(2) postoperatively (mean percentage of excess weight loss 70.0% +/- 18.6%). However, 20 patients (11.3%) did not have T2DM remission despite a mean percentage of excess weight loss of 58.2% +/- 12.3% (P <.0009). Of the 157 patients with initial remission of their T2DM, 68 (43%) subsequently developed T2DM recurrence. Remission of T2DM was durable in 56.9%. Durable (>5-year) resolution of T2DM was greatest in the patients who originally had either controlled their T2DM with diet (76%) or oral hypoglycemic agents (66%). The rate of T2DM remission was more likely to be durable in men (P = .00381). Weight regain was a statistically significant, but weak predictor, of T2DM recurrence.nnnCONCLUSIONnEarly remission of T2DM occurred in 89% of patients after Roux-en-Y gastric bypass. T2DM recurred in 43.1%. Durable remission correlated most closely with an early disease stage at gastric bypass.

Dietary n‐3 polyunsaturated fatty acids decrease hepatic triglycerides in Fischer 344 rats

Dietary fatty acid composition modifies hepatic lipid metabolism. To determine the effects of fatty acids on hepatic triglyceride storage, rats were fed diets enriched in carbohydrates (control), fish oil, or lard. After 4 weeks, the animals were fasted overnight. In the morning, the animals were either sacrificed or fed 8 g of their respective diets before sacrifice. Animals ingested more food calories with diets containing fish oil than with other diets. However, fish oil–fed animals weighed less and had less body fat. In fish oil–fed animals, liver triglyceride was lower by 27% (P < .05) and 73% (P < .01) than in control‐ and lard‐fed animals, respectively. Fish oil altered the postprandial gene expression of hepatic regulators of fatty acid degradation and synthesis. Fish oil feeding blunted the normal postprandial decline in fatty acid degradation genes (PPARα, CPT1, and ACO) and blunted the normal postprandial rise in triglyceride synthesis genes (SREBP1‐c, FAS, SCD‐1). Therefore, the direct postprandial effect of fish oil ingestion decreases the propensity for hepatic triglyceride storage. In conclusion, n‐3 polyunsaturated fatty acids decrease total body weight, total body fat, and hepatic steatosis. (HEPATOLOGY 2004;39:608–616.)

Dehydroepiandrosterone: the "missing link" between hyperinsulinemia and atherosclerosis?

A well‐established epidemiologic association exists between hyperinsulinemia and macrovascular disease. However, the mechanism or mechanisms by which hyperinsulinemia promotes atherogenesis is unknown. Recent evidence indicates that the adrenal steroid dehydroepiandrosterone (DHEA) exerts multiple antiatherogenic effects and also suggests that hyperinsulinemia may reduce serum DHEA and DHEA‐sulfate levels by decreasing production and enhancing metabolic clearance. We advance the hypothesis that hyperinsulinemia promotes macrovascular disease in part by reducing serum DHEA and DHEA‐sulfate levels and illustrate how this may be the case in two clinical conditions characterized by hyperinsulinemic insulin resistance: aging and obesity.— Nestler, J. E., Clore, J. N., Blackard, W. G. Dehydroepiandrosterone: the “missing link” between hyperinsulinemia and atherosclerosis? FASEB J. 6: 3073‐3075; 1992.

The central role of obesity (hyperinsulinemia) in the pathogenesis of the polycystic ovary syndrome

Insulin resistance and hyperinsulinemia appear to be almost universal features of the polycystic ovary syndrome. We propose that obesity permits full phenotypic expression of the polycystic ovary syndrome in women predisposed to develop this condition by generating an insulin-resistant, and consequently hyperinsulinemic, state. The resultant hyperinsulinemia may produce hyperandrogenism by affecting multiple facets of androgen metabolism.

Relation of Diabetic Patients' Health-Related Control Appraisals and Physician–Patient Interpersonal Impacts to Patients' Metabolic Control and Satisfaction with Treatment

Desire for healthcare control, health locus of control, perceived control over diabetes, satisfaction with diabetes treatment, and general personality traits were assessed in 54 Type 1 and Type 2 diabetic patients of the same male endocrinologist during a regularly scheduled office visit. At the end of the consultation, both patients and the physician completed a measure describing the interpersonal impacts produced in each by the others control and affiliation behaviors. Patient success at diabetes control was assessed via glycosylated hemoglobin A1C (HA1C) level on the day of the visit and variability in HA1C levels across several visits. Patients satisfaction with treatment was unrelated to diabetes control measures. Patients desire for behavioral involvement in their own healthcare and NEO Agreeableness scores were positively associated with diabetes control. Better diabetes control also resulted when the physician perceived patients to be more controlling and less submissive, and when there was more reciprocity in patient and physicians perceptions of the others controlling interpersonal behavior. Findings support the conclusion that both a patients self-reported desire for involvement in his or her healthcare and the transactional fit of patient–physician interpersonal behaviors are potentially important contributors to better diabetes outcomes.

Increased Transcapillary Escape Rate of Albumin in Nondiabetic Men in Response to Hyperinsulinemia

Diabetic patients manifest increased vascular permeability. To determine whether insulin per se might increase vascular permeability, five nondiabetic men were studied by the hyperinsulinemic-euglycemic clamp technique. Each subject received a 0.72-nmol/kg body wt i.v. insulin bolus, followed by a 72-pmol · kg−1 ·min−1 insulin infusion for 4 h. Euglycemia was maintained by the Biostator glucose controller. At 7 h of study, 10 μCi i.v. 125I-labeled albumin was injected as bolus dose. Frequent blood samples were drawn during the next 70 min for determination of the transcapillary escape rate (TER) of albumin. Subjects returned 1–2 wk later for a control study, during which 0.45% saline was infused at a rate identical to the dextrose and insulin infusion rates during the hyperinsulinemic clamp. The mean ± SE serum insulin levels during the hyperinsulinemic clamp and saline infusion were 9786 ± 126 and 46 ± 4 pM, respectively, whereas serum glucose during the two sessions was similar (5.0 ± 0.2 vs. 4.8 ± 0.1 mM, NS). Identical fluid volumes were infused during the two sessions (1767 ± 197 ml/7 h), and urine outputs did not differ significantly (1615 ± 309 vs. 1035 ± 248 ml/7 h). The TER of albumin was greater in all five men after hyperinsulinemia than after saline infusion (18.3 ± 2.7 vs. –2.8 ± 2.3%/h, P = 0.01). The serum albumin level at the end of the hyperinsulinemic-euglycemic clamp study was 14% lower than the value at the start of the study (37 ± 1 vs. 42 ± 1 g/L, P < 0.05), whereas no significant change in serum albumin levels occurred during the saline infusion. These observations suggest that acute hyperinsulinemia can increase the TER of radiolabeled albumin, probably by increasing vascular permeability.

Impact of HbA1c Measurement on Hospital Readmission Rates: Analysis of 70,000 Clinical Database Patient Records

Management of hyperglycemia in hospitalized patients has a significant bearing on outcome, in terms of both morbidity and mortality. However, there are few national assessments of diabetes care during hospitalization which could serve as a baseline for change. This analysis of a large clinical database (74 million unique encounters corresponding to 17 million unique patients) was undertaken to provide such an assessment and to find future directions which might lead to improvements in patient safety. Almost 70,000 inpatient diabetes encounters were identified with sufficient detail for analysis. Multivariable logistic regression was used to fit the relationship between the measurement of HbA1c and early readmission while controlling for covariates such as demographics, severity and type of the disease, and type of admission. Results show that the measurement of HbA1c was performed infrequently (18.4%) in the inpatient setting. The statistical model suggests that the relationship between the probability of readmission and the HbA1c measurement depends on the primary diagnosis. The data suggest further that the greater attention to diabetes reflected in HbA1c determination may improve patient outcomes and lower cost of inpatient care.

Suppression of serum insulin level by diazoxide does not alter serum testosterone or sex hormone-binding globulin levels in healthy, nonobese women.

Suppression of serum insulin levels with diazoxide is associated with a decrease in serum testosterone and an increase in serum sex hormone-binding globulin in obese women with the polycystic ovary syndrome. To determine whether physiologic insulin levels play a regulatory role in the androgen status of nonobese women with normal menses, the androgen status of five nonobese normal women was assessed on two occasions: during a control study and after 10 days of oral diazoxide (100 mg, three times daily) administration. Insulin release in response to 100 gm oral glucose administration decreased from 108.0 +/- 28.2 to 49.3 +/- 5.2 nmol.min/L (p = 0.05) after diazoxide administration. However, despite suppression of insulin release, diazoxide administration did not affect serum total testosterone (diazoxide, 0.73 +/- 0.10; control, 0.69 +/- 0.11 nmol/L; p = NS) or sex hormone-binding globulin (diazoxide, 79.7 +/- 16.6; control, 70.2 +/- 12.6 nmol/L; p = NS) concentrations. These observations suggest that physiologic insulin levels in nonobese healthy women do not regulate testosterone metabolism and that diazoxide does not exert a direct or independent effect on serum testosterone or sex hormone-binding globulin levels.