Citations

Type 2 diabetes is characterized by an ∼60% loss of β-cell mass, a marked defect in postprandial insulin secretion, and a failure to suppress postprandial glucagon concentrations. It is possible that postprandial hyperglucagonemia in type 2 diabetes is due to impaired postprandial insulin secretion. To address this, we studied eight adult Goettingen minipigs before and after an ∼60% reduction in β-cell mass induced by alloxan. Pigs were studied fasting and after ingestion of a mixed meal. Insulin and glucagon secretion were determined by deconvolution of blood hormone concentrations measured at 1-min intervals. The relationship between insulin and glucagon release was analyzed using cross-correlation and forward versus reverse cross–approximate entropy. We report that glucagon and insulin were secreted in ∼4-min pulses. Prealloxan, postprandial insulin secretion drove an ∼20% suppression of glucagon concentrations (P < 0.01), through inhibition of glucagon pulse mass. The alloxan-induced ∼60% deficit in β-cell mass lead to an ∼70% deficit in postprandial insulin secretion and loss of the postprandial insulin-driven suppression of glucagon secretion. We conclude that postprandial hyperglucagonemia in type 2 diabetes is likely due to loss of intraislet postprandial suppression of glucagon secretion by insulin.

The splanchnic bed produces cortisol at rates approximating extraadrenal tissues by converting cortisone to cortisol via the 11β-hydroxysteroid dehydrogenase (11β-HSD) type 1 pathway. It is not known whether splanchnic cortisol production is regulated by nutrient ingestion and/or by the accompanying changes in hormone secretion. To address this question, 18 healthy humans were randomized to ingest either a mixed meal or to receive an intravenous saline infusion while total-body, splanchnic, and d3 cortisol production (an index of 11β-HSD type 1 activity) were measured using the combined hepatic catheterization and d4 cortisol infusion methods. Fasting glucose and insulin concentrations did not differ on the meal and saline study days. Glucose and insulin concentrations increased after meal ingestion, peaking at 11.0 ± 1.0 mmol/l and 451 ± 64 pmol/l, respectively, at 45 min, then fell to baseline thereafter. In contrast, glucose and insulin concentrations slowly fell to 5.1 ± 0.1 mmol/l and 27 ± 6 pmol/l during the 6 h of observation on the saline study day. Fasting cortisol concentration did not differ on the meal and saline study days. Cortisol increased (P < 0.05) to a peak of 353 ± 55 nmol/l after meal ingestion but did not change after saline infusion. The increase in cortisol after meal ingestion was associated with an increase in both total body cortisol (from 748 ± 63 to 1,620 ± 235 nmol/min; P < 0.01) and total body d3 cortisol (from 99 ± 11 to 143 ± 11 nmol/min; P < 0.01) production, whereas there was no change in either on the saline study day. The increase in total-body cortisol and d3 cortisol production after meal ingestion originated in extrasplanchnic tissues since splanchnic cortisol production (mean 0–360 min: 254 ± 83 vs. 262 ± 36 nmol/min) and splanchnic d3 cortisol production (mean 0–360 min: 72 ± 22 vs. 77 ± 14 nmol/min) did not differ on the meal and saline study days. We conclude that ingestion of a mixed meal does not alter either splanchnic cortisol production or the conversion of d4 cortisol to d3 cortisol or, therefore by implication, flux via the splanchnic 11β-HSD type 1 pathway.

Background— Although age-adjusted cardiovascular disease (CVD) mortality has declined over the past decades, controversies remain about whether this trend was similar across locations of death and disease categories and about the existence of age and sex disparities. Methods and Results— We examined CVD mortality trends in Olmsted County, Minnesota, between 1979 and 2003 using the categories defined by the American Heart Association, including coronary heart disease (CHD), non-CHD diseases of the heart, and noncardiac circulatory diseases. Data on demographics, cause, and location of death of all 6378 residents who died of CVD were analyzed. Although decreases in the age-adjusted rates occurred in all groups, the magnitude of the decline varied widely. Lesser annual declines were noted in out-of-hospital than in-hospital deaths (1.8% versus 4.8%; P <0.001), in older than in younger persons (1.5% at age ≥85 years versus 3.9% for those ≤74 years of age; P <0.001), and in women relative to men (2.5% versus 3.3%; P =0.007). Furthermore, although CHD showed a marked annual decrease (3.3%), more modest decrements were found for non-CHD diseases of the heart (2.1%) and noncardiac circulatory diseases (2.4%) ( P =0.02 and P =0.04 for the comparison with CHD decline, respectively). Conclusions— Over the past 25 years, CVD mortality declined markedly in the community, but there were large disparities in the magnitude of the decline, resulting in a shift in the distribution toward out-of-hospital and non-CHD deaths. Further reduction in CVD mortality will require strategies directed at elderly persons and women, in whom out-of-hospital rates have improved only minimally.

Abstract Non-alcoholic fatty liver disease (NAFLD) is common and may progress to cirrhosis and its complications. The pathogenesis of steatosis and cellular injury is thought to be related mostly to insulin resistance and oxidative stress. Therefore, management entails identification and treatment of metabolic risk factors, improving insulin sensitivity, and increasing antioxidant defences in the liver. Weight loss and exercise improve insulin sensitivity. Bariatric surgery may improve liver histology in patients with morbid obesity. Insulin sensitising drugs showed promise in pilot trials as have a number of hepatoprotective agents. Further randomised, well controlled trials are required to determine the efficacy of these drugs.

Abstract Purpose: Colon cancer cells with high-frequency microsatellite instability (MSI-H) display resistance to 5-fluorouracil (5-FU) that can be reversed by restoring DNA mismatch repair (MMR) proficiency. Given that thymidylate synthase (TS) is inhibited by 5-FU, we studied the relationship between MSI and TS expression, and the prognostic effect of these and other markers (i.e., p53 and 17p allelic imbalance). Experimental Design: Dukes' stage B2 and C colon carcinomas (n = 320) from participants in 5-FU-based adjuvant therapy trials were analyzed for MSI and 17p allelic imbalance. Expression of MMR (hMLH1, hMSH2), TS, and p53 proteins were analyzed by immunohistochemistry. Correlations between markers and associations with overall survival were determined. Results: Of 320 cancers studied, 60 (19%) were MSI-H. TS expression variables were similar in MSI-H and microsatellite stable/low-frequency MSI (MSS/MSI-L) cancers, and unrelated to MMR proteins. MSI-H tumors had lower stage (P = 0.0007), fewer metastatic lymph nodes (P = 0.004), and improved overall survival (P = 0.01). Loss of MMR proteins was also associated with better overall survival (P = 0.006). None of the TS variables were prognostic. Histologic grade (P = 0.0008) and nodal status (P = 0.0002) were associated with overall survival, in contrast to 17p allelic imbalance or p53. Only MSI status or loss of MMR proteins, histologic grade, and tumor stage were independent markers for overall survival. Conclusions: MSI-H tumors show earlier stage at presentation and better stage-adjusted survival rates. MSI status and TS expression were unrelated and TS was not prognostic, suggesting that TS levels cannot explain therapeutic resistance to 5-FU reported in MSI-H colon cancers.