Metformin and troglitazone have equal and additive beneficial effects on glycemic control in patients with type 2 diabetes. Metformin acts primarily by decreasing endogenous glucose production, and troglitazone by increasing the rate of peripheral glucose disposal.

Ghrelin is a novel peptide that acts on the growth hormone (GH) secretagogue receptor in the pituitary and hypothalamus. It may function as a third physiological regulator of GH secretion, along with GH-releasing hormone and somatostatin. In addition to the action of ghrelin on the GH axis, it appears to have a role in the determination of energy homeostasis. Although feeding suppresses ghrelin production and fasting stimulates ghrelin release, the underlying mechanisms controlling this process remain unclear. The purpose of this study was to test the hypotheses, by use of a stepped hyperinsulinemic eu-hypo-hyperglycemic glucose clamp, that either hyperinsulinemia or hypoglycemia may influence ghrelin production. Having been stable in the period before the clamp, ghrelin levels rapidly fell in response to insulin infusion during euglycemia (baseline ghrelin 207 Ϯ 12 vs. 169 Ϯ 10 fmol/ml at t ϭ 30 min, P Ͻ 0.001). Ghrelin remained suppressed during subsequent periods of hypoglycemia (mean glucose 53 Ϯ 2 mg/dl) and hyperglycemia (mean glucose 163 Ϯ 6 mg/dl). Despite suppression of ghrelin, GH showed a significant rise during hypoglycemia (baseline 4.1 Ϯ 1.3 vs. 28.2 Ϯ 3.9 g/l at t ϭ 120 min, P Ͻ 0.001). Our data suggest that insulin may suppress circulating ghrelin independently of glucose, although glucose may have an additional effect. We conclude that the GH response seen during hypoglycemia is not regulated by circulating ghrelin. growth hormone; somatostatin; hypothalamus; hypoglycemia; glucose clamp GHRELIN IS A NOVEL PEPTIDE that acts on the growth hormone (GH) secretagogue receptor in the pituitary and hypothalamus, possibly functioning as a third physiological regulator of GH secretion along with GHreleasing hormone (GHRH) and somatostatin. In addition to the action of ghrelin on the GH axis, it appears to have a role in the determination of energy homeostasis (3, 12, 13). Ghrelin acts as an orexigenic hormone, stimulating both neuropeptide Y (NPY) and agoutirelated peptide, and thus feeding (14, 21). Although feeding suppresses ghrelin production and fasting stimulates ghrelin release, the underlying mechanisms controlling these processes remain unclear (4,19). This relationship is the opposite of that seen with leptin (14), which has been shown to be increased by insulin (18). Specifically, the roles that alterations in plasma glucose and insulin have in regulating ghrelin secretion have not been established. To address this issue, we employed a stepped hyperinsulinemic eu-hypo-hyperglycemic glucose clamp. This procedure allowed us to examine the ghrelin response to marked variations in circulating concentrations of insulin and glucose in human subjects. METHODSEleven young adult volunteers (9 women, 2 men) participated in the study. The age of the subjects was 24 Ϯ 4 yr (range 18-31 yr), and the body mass index was 22.1 Ϯ 2.8 kg/m 2 (18.4-26.6 kg/m 2 ). All subjects were healthy and taking no medication. They were instructed to maintain their normal physical activity and to consume a normal diet contai...

To determine the relationship between circulating metabolic fuels and their local concentrations in peripheral tissues we measured glycerol, glucose, and amino acids by microdialysis in muscle and adipose interstitium of 10 fasted, nonobese human subjects during (a) baseline, (b) euglycemic hyperinsulinemia (3 mU/kg per min for 3 h) and, (c) local norepinephrine reuptake blockade (NOR). At baseline, interstitial glycerol was strikingly higher (P < 0.0001) in muscle (3710 jLM) and adipose tissue (2760 ,uM) compared with plasma (87 ,LM), whereas interstitial glucose (muscle 3.3, fat 3.6 mM) was lower (P < 0.01) than plasma levels (4.8 mM). Taurine, glutamine, and alanine levels were higher in muscle than in adipose or plasma (P < 0.05). Euglycemic hyperinsulinemia did not affect interstitial glucose, but induced a fall in plasma glycerol and amino acids paralleled by similar changes in the interstitium of both tissues. Local NOR provoked a fivefold increase in glycerol (P < 0.001) and twofold increase in norepinephrine (P < 0.01) in both muscle and adipose tissues. To conclude, interstitial substrate levels in human skeletal muscle and adipose tissue differ substantially from those in the circulation and this disparity is most pronounced for glycerol which is raised in muscle as well as adipose tissue. In muscle, insulin suppressed and NOR increased interstitial glycerol concentrations. Our data suggest unexpectedly high rates of intramuscular lipolysis in humans that may play an important role in fuel metabolism. (J. Clin. Invest. 1995. 96:370-377.)

Acute ingestion of caffeine is associated with sympathoadrenal activation and awareness of hypoglycemia at a glucose level not usually considered hypoglycemic. Our data suggest that individuals who ingest moderate amounts of caffeine may develop hypoglycemic symptoms if plasma glucose levels fall into the "low-normal" range, as might occur in the late postprandial period after ingestion of a large carbohydrate load.

Studies performed in adults with long-standing obesity suggest a reduced lipolytic sensitivity to catecholamines in subcutaneous abdominal adipose tissue (AT). We used microdialysis to study the in situ lipolytic effects of dobutamine (selective ␤ 1 -agonist) and terbutaline (selective ␤ 2 -agonist) on glycerol release (lipolytic index) in abdominal subcutaneous AT in 10 obese girls aged 13-17 years, BMI 38 ± 2.1 kg/m 2 , and in 7 lean girls aged 11-17 years, BMI 21 ± 1.1 kg/m 2 , and compared them with 10 obese women aged 21-39 years, BMI 36 ± 1.6 kg/m 2 , and 10 lean women aged 18-42 years, BMI 21 ± 0.4 kg/m 2 . Terbutaline at 10 -6 mol/l stimulated glycerol release more efficiently in lean girls than in obese girls (peak response ~350 vs. 150% of control, P < 0.01). At the lower concentration of agonist, no significant difference was seen. In women, terbutaline was more effective in lean than in obese women in stimulating glycerol release at both 10 -8 mol/l (peak response lean ~175% vs. obese 125% of control) and 10 -6 mol/l (~300 vs. 150% of control, P < 0.05). No significant difference in glycerol release between obese and lean girls or women was detected with selective ␤ 1 -stimulation. Our data demonstrate a specific impairment in the capacity of ␤ 2 -adrenergic agonists to promote lipolysis in subcutaneous abdominal adipose tissue of obese adolescent girls and women. Thus, decreased mobilization of fat during activation of the adrenergic system might be present early in the development of adolescent obesity. Diabetes 49:2149-2153, 2000 T he prevalence of obesity in children as well as in adults is steadily increasing in the U.S. (1). The early-onset type of obesity deserves special attention because youth-onset obesity is often the precursor of the most intractable form of adult obesity (2). Furthermore, the comorbid conditions that accompany obesity in adults, such as type 2 diabetes, dyslipidemia, and hypertension, are seen with increasing frequency in overweight adolescents and even preadolescents (3,4).Although the pathogenesis of obesity is poorly understood, it is believed to result from a complex interaction between genetic and environmental factors (5), leading to a more efficient accumulation of fat and to an impaired ability to mobilize fat. Because catecholamines are the only hormones with pronounced lipolytic action in humans (6), the effect of obesity in adults on the responsiveness to catecholamines has been extensively studied. Both in vitro and in vivo studies have demonstrated that subcutaneous abdominal adipose tissue in obese adults is resistant to the lipolytic effects of catecholamines (7-9). Moreover, even though subcutaneous adipose tissue contains ␤ 1 -, ␤ 2 -, and ␤ 3 -adrenoceptors, obesityinduced catecholamine resistance appears primarily because of defects in ␤ 2 -stimulation (7), with impaired ␤ 1 -stimulation having a secondary role. Whereas obese children have been shown to have a reduced lipolytic response to systemic epinephrine infusion (9), the effect of juvenile obesi...