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OBJECTIVE—To evaluate the effects of sibutramine (15 and 20 mg/day) on weight, metabolic control, and blood pressure in metformin-treated obese subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS—A 12-month randomized prospective placebo-controlled double-blind study was performed. It included 21 primary and secondary care centers in England, Canada, France, and Belgium. A total of 195 subjects (44% male) with type 2 diabetes and a BMI >27 kg/m2 were studied. Changes were assessed in weight, blood pressure and resting heart rate, HbA1c, fasting glucose, and lipids. RESULTS—Sibutramine induced significant weight loss (P < 0.001) with both 15 mg/day (5.5 ± 0.6 kg at 12 months) and 20 mg/day (8.0 ± 0.9 kg), whereas placebo did not (0.2 ± 0.5 kg). Weight loss ≥10% was achieved by 14 and 27% of subjects receiving 15 and 20 mg, respectively, but by none given placebo. Glycemic control improved in parallel with weight loss, and subjects who lost ≥10% weight showed significant decreases in both HbA1c (1.2 ± 0.4%, P < 0.0001) and fasting plasma glucose (1.8 mmol/l, P < 0.001). HDL cholesterol increased slightly with the higher dose, whereas plasma triglycerides fell with both doses, especially in subjects with weight loss of ≥10% (a 29% decrease, P < 0.01). Treatment was generally well tolerated. Sibutramine treatment raised sitting diastolic blood pressure by ≥5 mmHg in a higher proportion of patients than did placebo (43% with 15 mg/day vs. 25% with placebo, P < 0.05), but this effect was less evident in subjects who had a weight loss of ≥10% weight. Pulse rate increased significantly more with sibutramine, being ≥10 bpm higher in 42% of treated patients versus 17% with placebo (P < 0.01). CONCLUSIONS—Sibutramine can be an effective adjunct to metformin treatment in selected obese type 2 diabetic subjects and improves metabolic control in individuals who lose weight.

Orexins are novel appetite-stimulating peptides expressed in the lateral hypothalamic area (LHA), and their expression is stimulated by hypoglycemia in fasted rats. We investigated activation of orexin and other neurons during insulin-induced hypoglycemia using the immediate early gene product Fos. Insulin (50 U/kg) lowered plasma glucose by >50% after 5 h and stimulated feeding sixfold compared with saline-injected controls. Hypoglycemic rats allowed to feed and normoglycemic controls both showed sparse Fos-positive (Fos + ) neurons in the LHA and the paraventricular nucleus (PVN) and arcuate nucleus (ARC) and showed none in the nucleus of the solitary tract (NTS), which relays visceral feeding signals to the LHA. In the LHA, total numbers of Fos + neurons were comparable in fed hypoglycemic and control groups (60 ± 6 vs. 52 ± 4 cells/mm 2 , P > 0.05), as were Fos + neurons immunoreactive for orexin (1.4 ± 0.4 vs. 0.6 ± 0.4 cells/mm 2 , P > 0.05). By contrast, hypoglycemic rats that were fasted showed significantly more Fos + nuclei in the LHA (96 ± 10 cells/mm 2 , P < 0.05, vs. both other groups) and Fos + orexin neurons (8.4 ± 3.3 cells/mm 2 , P < 0.001, vs. both other groups). They also showed two- to threefold more Fos + nuclei ( P < 0.001) in the PVN and ARC than both fed hypoglycemic rats and controls and showed strikingly abundant Fos + neurons in the NTS and dorsal motor nucleus of the vagus. In parallel studies, whole hypothalamic orexin-A levels were not changed in hypoglycemic rats, whether fasted or freely fed, whereas orexin-B levels were 10-fold higher in hypoglycemic fasted rats than in control and hypoglycemic fed groups. These data support our hypothesis that orexin neurons are stimulated by falling glucose levels but are readily inhibited by signals related to nutrient ingestion and suggest that they may functionally link with neuronal activity in the NTS. Orexin-A and -B may play specific roles in behavioral or neuroendocrine responses to hypoglycemia.

Orexins (hypocretins), novel peptides expressed in specific neurons of the lateral hypothalamic area (LHA), stimulate feeding when injected intracerebroventricularly. We investigated their role in feeding in the rat by measuring hypothalamic prepro-orexin mRNA levels under contrasting conditions of increased hunger. Prepro-orexin mRNA levels increased significantly after 48 h of fasting (by 90-170%; P < 0.05) and after acute (6 h) hypoglycemia when food was withheld (by 90%; P < 0.02). By contrast, levels were unchanged during chronic food restriction, streptozotocin-induced diabetes, hypoglycemia when food was available, voluntary overconsumption of palatable food, or glucoprivation induced by systemic 2-deoxy-D-glucose. Orexin expression was not obviously related to changes in body weight, insulin, or leptin, but was stimulated under conditions of low plasma glucose in the absence of food. Orexins may participate in the short-term regulation of energy homeostasis by initiating feeding in response to falls in glucose and terminating it after food ingestion. The LHA is known to contain neurons that are stimulated by falls in circulating glucose but inhibited by feeding-related signals from the viscera; orexin neurons may correspond to this neuronal population.

The fat-derived hormone, leptin, is thought to regulate adipose tissue mass by acting on the brain to reduce food intake and increase thermogenesis. We have produced obesity in rats more than 8 weeks old by feeding a high-calorie diet and have then examined the inhibitory effect of intracerebroventricularly injected recombi-nant murine leptin on their food intake versus control rats. In control rats, randomized injections of leptin (0.5, 2.0, or 10.0 μg) or sterile saline vehicle into the lateral ventricle produced a dose-dependent reduction in normal laboratory diet consumed 1, 4, and 24 h after the lights were turned off. However, in diet-induced obesity, the dose-dependent inhibition of food intake was observed at 1 h only, and the effect was attenuated. Switching the diet-induced obese rats to a normal laboratory diet 1 week before injections of leptin were commenced resulted in a reduction in the daily food consumption. These data suggest that rats made obese by feeding a high-calorie diet override the normal satiety effects of leptin since when they are returned to a normal laboratory diet, they reduce their calorie intake, possibly as a result of a restoration of the satiety effects of endogenous leptin. However, the fact that the hypophagic response to exogenous leptin is impaired in these rats at this time suggests some residual impairment of the satiety signal, perhaps caused by reduced receptor sensitivity and/or near total occupation of receptors by endogenous leptin molecules, levels of which are raised in plasma.

Increased urinary albumin excretion rate (AER) in the microalbuminuric phase of diabetic nephropathy has been attributed to intraglomerular hypertension. This could be caused by constriction of efferent glomerular arterioles, which carry α-adrenoceptors. We tested the hypothesis that insulin-dependent diabetes mellitus (IDDM) patients with microalbuminuria are hypersensitive to vasoconstriction induced by norepinephrine (NE). We studied 15 IDDM patients with microalbuminuria (AER 32–295 mg/24 h), 13 IDDM patients with normal AER (5–24 mg/24 h), and 9 nondiabetic subjects (AER 8–22 mg/24 h). All were normotensive. NE-induced vasoconstriction was measured in dorsal hand veins, which carry α-receptors similar to those of glomerular efferent arterioles. Vein diameter was measured with a linear displacement probe during a stepped NE infusion (1–32 ng/min) into the vein, and venoconstriction was expressed as a percentage of the maximum passively distended venous diameter. Microalbuminuric IDDM patients exhibited significantly greater vasoconstriction (P < 0.005) at all NE infusion rates than both other groups. The NE infusion rate producing 50% of maximal venoconstriction (ED50) in the microalbuminuric IDDM group (median 1.1 ng/min, range 0.2–25.2 ng/min) was significantly less than in both the normoalbuminuric IDDM group (median 12.5 ng/min, range 4.9–40.5 ng/min, P = 0.00007) and the nondiabetic group (median 17.7 ng/min, range 5.9–42.2 ng/min, P = 0.0003). Dose-response curves and ED50 did not differ significantly between normalbuminuric IDDM and nondiabetic groups. IDDM patients with microalbuminuria are hypersensitive to NE-induced vasoconstriction. Such an abnormality in efferent glomerular arterioles could contribute to albuminuria and, if affecting the systemic resistance vessels, to the hypertension that coexists with later phases of nephropathy. This test may help identify at an early stage IDDM patients at risk of developing nephropathy.

Objective— To control insulin-induced edema in a patient with poorly controlled IDDM. Research Design and Methods— A 31-yr-old woman with a 14-yr history of poorly controlled IDDM first developed peripheral edema 3 yr after diagnosis of IDDM; the edema worsened whenever insulin dosage was increased. In August 1991, severe edema developed after treatment of ketoacidosis, with body weight increasing from 46 to 61 kg. No evidence of cardiac dysfunction or autonomic neuropathy existed, and serum albumin was consistently normal. Results— Treatment with 15 mg of ephedrine every 8 h produced a prompt diuresis, with body weight falling by 4 kg in 48 h and by 12 kg within 1 wk. Conclusions— Ephedrine may be an effective treatment for insulin-induced edema and may be preferable to the use of diuretics in such patients.

Photoelectric Plethysmography (PPG) Was Used to investigate blood flow changes closeto superficial subcutaneous injection sites. As a validation procedure, the PPG response to subcutaneous injection of a known hyperemic agent, prostaglandin E, (10−5 M), was shown to correlate strongly with subcutaneous blood flow changes estimated by the established technique of133Xe washout. Changes in blood flow over the subcutaneous injection sites of insulin (Actrapid) and insulin diluent were measured by photoelectric plethysmography in six nondiabetics and in six stable and seven brittle insulin-dependent diabetics. In all subject groups, an acute increase in local blood flow was seen within 2 min of both insulin and diluent injections, probably caused by injection trauma. At diluent injection sites, this acute hyperemia faded rapidly, blood flow returning to preinjection levels within 15–20 min, and there was no further increase in blood flow in any of the subjects. Insulin injected into the nondiabetics and stable diabetics caused a pronounced increase in local blood flow, sustained for at least 60 min after injection. In the brittle diabetics, however, there was no prolonged local hyperemia, the response being significantly less than that seen in both the nondiabetics and the stable diabetics. Insulin-related hyperemia close to injection (or infusion) sites may be important in subcutaneous insulin absorption. Its near-absence in brittle diabetics may contribute to the impaired response to subcutaneous insulin characteristic of these patients.