Safety and tolerability of vildagliptin vs. thiazolidinedione as add-on to metformin in type 2 diabetic patients with and without mild renal impairment: a retrospective analysis of the GALIANT study.

OBJECTIVE: This retrospective analysis assessed safety and tolerability of vildagliptin (Vilda) as an add-on to metformin in type 2 diabetes mellitus (T2DM) patients with normal renal function (GFR >80mL/min/1.73m(2)) and mild renal impairment (GFR: >50 to ≤80mL/min/1.73m(2)). METHODS: Adverse events (AE) from this 12-week, randomized, open-label study comparing Vilda 100mg and thiazolidinediones (TZD) as an add-on therapy in patients with T2DM inadequately controlled (HbA(1c): 7-10%) on a stable dose of metformin (≥1000mg/day) were analyzed. RESULTS: Of 2627 randomized patients, 1278 in the Vilda and 635 in the TZD groups had normal renal function; 463 in the Vilda and 230 in the TZD groups had mild renal impairment. Higher incidence of headache and rash was noted in both Vilda groups, whereas those with mild renal impairment receiving TZD experienced a higher incidence of peripheral edema and URI. Fewer patients in the Vilda group discontinued the study due to AEs compared to TZD group. Serious AEs were greater in TZD groups (normal: 2.4%; mild renal impairment: 3.0%) compared to Vilda groups (normal: 1.6%; mild renal impairment: 2.4%). CONCLUSION: The safety profile of Vilda or TZD as an add-on to metformin was similar in patients with mild renal impairment and normal renal function.

Distribution of somatostatin-14 and somatostatin-28 gastrointestinal-pancreatic cells of rats and humans.

Somatostatin-14 and somatostatin-28 are biologically active peptides derived from the posttranslational cleavage of prosomatostatin. Because both peptides are found in variable concentrations in the gastrointestinal (GI) tract and pancreas, it has been contended that somatostatin-28 is either an intermediate in the processing to somatostatin-14 or a terminal product derived from prosomatostatin. To address this question, two antisera were used to recognize epitopes in two regions of somatostatin-14; one with high specificity for somatostatin-14 and the other interacting with prosomatostatin, somatostatin-28, and somatostatin-14. Distribution of these peptides was measured in extracts of pancreas and mucosa and submucosa/muscularis from the rat and human GI mucosal biopsies; the antisera were used to immunostain cells in these tissues. Extracts of human and rat intestinal mucosa contained both somatostatin-28 and somatostatin-14. By immunocytochemistry, D cells in stomach and pancreas and neural processes in the intestine, extending into the mucosal villi adjacent to endocrine cells, stained with both antisera indicating the presence of somatostatin-14, prosomatostatin, and possibly somatostatin-28. In contrast, endocrine cells in the gut reacting with antisera against somatostatin-28 did not immunostain with somatostatin-14-specific antisera. Thus, these data suggest that somatostatin-28 is the terminal peptide processed from prosomatostatin in intestinal mucosal cells, whereas somatostatin-14 is the major final product in gastric and pancreatic D cells and neurons. The localization of somatostatin-28 and somatostatin-14 in different cells in the pancreas and GI tract implies that they serve different functions.

Effect of ingested carbohydrate, fat, and protein on the release of somatostatin-28 in humans.

The level of somatostatin-28, a bioactive peptide derived from pro-somatostatin in gastrointestinal epithelial cells, increases in human plasma after food intake. To determine if an equivalent response occurs with individual components of a mixed meal, somatostatin-28 and prosomatostatin, somatostatin-14, and somatostatin-13, in combination, were measured in healthy men before and after intake of (a) a mixed meal (715 kcal), (b) carbohydrate (100 g equivalent glucose), (c) protein (22 and 45 g), and (d) fat (25 and 50 g). After the mixed meal, somatostatin-28 levels doubled within 120 min and gradually declined by 4 h. With carbohydrate, somatostatin-28 levels were unaltered. After 22 and 45 g of protein, somatostatin-28 increased equivalently within 60 min, representing 30% of the amount with the mixed meal. With 25 g fat, a somatostatin-28 increase similar to that with the meal was seen; this response was doubled with 50 g fat. No changes in prosomatostatin, somatostatin-14, or somatostatin-13 were observed with the mixed meal or with the separate macronutrients. The authors conclude that fat is the major stimulus for somatostatin-28 secretion in humans and hypothesize that somatostatin-28 is an inhibitor of the endocrine and exocrine pancreas during nutrient absorption.

Circulating prosomatostatin-derived peptides. Differential responses to food ingestion.

Prosomatostatin (pro-S) and its bioactive posttranslational products, somatostatin-14 (S-14), somatostatin-13 (S-13), and somatostatin-28 (S-28), were measured in human plasma by the use of immunoglobulins to the NH2-terminus of S-28 conjugated with agarose to separate them and, thereafter, by RIA with an antiserum recognizing the COOH-terminus of pro-S, and by specific RIA for the NH2-terminus of S-14 and pro-S. In healthy men, mean basal levels of pro-S were 4 pg equivalent S-14/ml; S-14/S-13 combined were 9 pg equivalent S-14/ml; and S-28 levels were 16 pg/ml. After a 700-kcal meal, pro-S, S-14, and S-14/S-13 did not change, whereas S-28 levels doubled by 120 min and remained elevated for 240 min. To evaluate the origins of these peptides, their levels were compared in peripheral, portal, gastric, and mesenteric veins of anesthetized patients and in patients with total resection of stomach and pancreas before and after nutrient intake. The stomach and small intestine were sources of both peptides; however, most S-28 originated in the small intestine. These findings suggest that, in contrast to S-14, S-28 is a hormone and may modulate postprandial nutrient absorption and use.

Differential alterations of the circulating prosomatostatin-derived peptides during insulin-induced hypoglycemia in man.

Insulin-induced hypoglycemia stimulates a rise of somatostatin-like immunoreactivity (SLI) in the venous circulation of man. Plasma SLI is comprised of a heterogenous group of peptides including somatostatin-28 (SS-28) somatostatin-28-(15-28), somatostatin-28-(16-28), and prosomatostatin (Pro-SS). To determine which of these Pro-SS related peptides is released after hypoglycemia, we developed an immunoadsorption method that rapidly and accurately separates SS-28 from the other somatostatins. This method involves the selective retention of SS-28 on a conjugate of agarose with immunoglobulins that recognize an epitope in the NH2-terminal region of SS-28. Pro-SS, SS-28-(15-28), SS-28-(16-28), henceforth referred to collectively as SS-28-(15-28), and SS-28, once separated, were then analyzed by RIA with a COOH-terminal antibody. Ten normal men were studied after an overnight fast. Pork insulin (0.05 U/kg) was injected iv, and blood was collected before and after the onset of hypoglycemia. The mean basal SS-28-(15-28) level was 13 +/- 1 (+/- SEM) pg/mL, and the mean basal SS-28 levels were 19 +/- 3 (+/- SEM) pg/mL. Plasma SS-28-(15-28) did not increase after insulin administration, but the mean SS-28 level increased by 76% (P less than 0.01). We propose that the release of SS-28, presumably from the gastrointestinal tract, during hypoglycemia occurs as a result of activation of the autonomic nervous system and speculate that SS-28, because of its ability to inhibit insulin secretion, may be important in counterregulation during glucopenia.

Rubella screening and vaccination programme at a Melbourne maternity hospital. A five-year review.

Antibody to rubella virus titres were measured in 7133 serum samples collected from pregnant women and nurses between 1976 and 1980. A significant decline in susceptibility to rubella was found in women under 25 years of age, but not in those over 25 years of age. Most of the former would have been vaccinated at school. One hundred and sixty of 325 women vaccinated with Cendehill vaccine (Cendevax) were subsequently retested. Two failed to develop antibodies and 19 initially "seronegative" women responded poorly. Ten of 38 women with low prevaccination titres had a significant boost in titre, and the remaining 28 showed little or no change. All 13 women who were revaccinated with RA 27/3 vaccine (Almevax) after responding poorly to Cendevax vaccination had a boost in titre; in 10, the rise was four-fold or greater. it is disappointing that Almevax is no longer available in Australia.

Metabolic effect of high environment temperature on non-diabetic and diabetic rats.

Blood lipids and glucose were studied in streptozotocin diabetic rats during hyperthermia. Blood glucose, free fatty acids (F.F.A.) and glycerol of diabetic rats with a rectal temperature of 42 degrees C (hyperthermic) were elevated significantly above those values found in normothermic (TR = 38 degrees C) diabetic or normothermic non-diabetic rats as well as hyperthermic non-diabetic rats. Streptozotocin diabetes caused an elevation in blood triglycerides of normothermic rats, but this hypertriglyceridemia was depressed in diabetic rats during hyperthermia. As in the case of diabetic animals, hyperthermia also caused a depression in the blood triglycerides of non-diabetic rats. However, unlike in the diabetic animals, the blood F.F.A. of non-diabetic rats were depressed during hyperthermia. Although hyperthermia caused a significant increase in the blood glucose of the diabetic animals, no significant change in blood glucose was shown in the hyperthermic non-diabetic rats. Blood cholesterol did not change significantly in the non-diabetic or diabetic animals during hyperthermia. The blood changes of these "energy substrates" are discussed with respect to their possible role in the extreme sensitivity of diabetics to high environmental temperature and "heat stress".