Metabolic and endocrine effects of physiological increments in plasma ghrelin concentrations.

BACKGROUND: Growing evidence indicates that the administration of large amounts of ghrelin to humans increases circulating concentrations of several pituitary and adrenal hormones, induces hyperglycemia and reduces serum insulin concentrations. At present, it is not known whether physiological increments in plasma ghrelin concentrations affect glucose kinetics or hormone concentrations in humans. METHODS AND RESULTS: We compared the effects of two- and three-fold increments in plasma ghrelin concentrations in eight healthy subjects during a 2 h intravenous infusion of 7.5 (GHRE7.5), 15 (GHRE15) pmol kg(-1) min(-1) acylated human ghrelin or placebo (PL), in a randomized double-blind study. Compared with PL (146 +/- 24 pM) plasma ghrelin concentrations increased at 120 min (p<0.001) about two-fold after GHRE7.5 (300 +/- 35 pM) and three-fold after GHRE15 (494 +/- 30 pM). GHRE15 significantly increased circulating concentrations of NEFA, GH, ACTH, epinephrine, and prolactin (p<0.01). GHRELIN7.5 significantly (p<0.01) increased only serum GH concentrations. Neither ghrelin infusions changed glucose flux or circulating concentrations of glucose, insulin, C-peptide, glucagon, IGF-1, cortisol and norepinephrine. CONCLUSIONS: GH secretion is the only response that is stimulated by physiological increments in plasma ghrelin concentrations; about three-fold increases in plasma ghrelin concentrations are required to elicit the responses of epinephrine, prolactin, ACTH and NEFA.

Make your diabetic patients walk: long-term impact of different amounts of physical activity on type 2 diabetes.

OBJECTIVE: To establish the impact of different amounts of increased energy expenditure on type 2 diabetes care. RESEARCH DESIGN AND METHODS: Post hoc analysis of long-term effects of different amounts of increased energy expenditure (metabolic equivalents [METS] per hour per week) through voluntary aerobic physical activity was performed in 179 type 2 diabetic subjects (age 62 +/- 1 years [mean +/- SE]) randomized to a physical activity counseling intervention. Subjects were followed for 2 years and divided into six groups based on their increments in METs per hour per week: group 0 (no activity, n = 28), group 1-10 (6.8 +/- 0.3, n = 27), group 11-20 (17.1 +/- 0.4, n = 31), group 21-30 (27.0 +/- 0.5, n = 27), group 31-40 (37.5 +/- 0.5, n = 32), and group >40 (58.3 +/- 1.8, n = 34). RESULTS: At baseline, the six groups did not differ for energy expenditure, age, sex, diabetes duration, and all parameters measured. After 2 years, in group 0 and in group 1-10, no parameter changed; in groups 11-20, 21-30, 31-40, and >40, HbA(1c), blood pressure, total serum cholesterol, triglycerides, and estimated percent of 10-year coronary heart disease risk improved (P < 0.05). In group 21-30, 31-40, and >40, body weight, waist circumference, heart rate, fasting plasma glucose, serum LDL and HDL cholesterol also improved (P < 0.05). METs per hour per week correlated positively with changes of HDL cholesterol and negatively with those of other parameters (P < 0.001). After 2 years, per capita yearly costs of medications increased (P = 0.008) by USD393 in group 0, did not significantly change in group 1-10 (USD 206, P = 0.09), and decreased in group 11-20 (USD -196, P = 0.01), group 21-30 (USD -593, P = 0.009), group 31-40 (USD -660, P = 0.003), and group >40 (USD -579, P = 0.001). CONCLUSIONS: Energy expenditure >10 METs . h(-1) . week(-1) obtained through aerobic leisure time physical activity is sufficient to achieve health and financial advantages, but full benefits are achieved with energy expenditure >20 METs . h(-1) . week(-1).

Insulin is required for prandial ghrelin suppression in humans.

Accumulating evidence indicates that ghrelin plays a role in regulating food intake and energy homeostasis. In normal subjects, circulating ghrelin concentrations decrease after meal ingestion and increase progressively before meals. At present, it is not clear whether nutrients suppress the plasma ghrelin concentration directly or indirectly by stimulating insulin secretion. To test the hypothesis that insulin regulates postprandial plasma ghrelin concentrations in humans, we compared the effects of meal ingestion on plasma ghrelin levels in six C-peptide-negative subjects with type 1 diabetes and in six healthy subjects matched for age, sex, and BMI. Diabetic subjects were studied during absence of insulin (insulin withdrawal study), with intravenous infusion of basal insulin (basal insulin study) and subcutaneous administration of a prandial insulin dose (prandial insulin study). Meal intake suppressed plasma ghrelin concentrations (nadir at 105 min) by 32 +/- 4% in normal control subjects, 57 +/- 3% in diabetic patients during the prandial insulin study (P < 0.002 vs. control subjects), and 38 +/- 8% during basal insulin study (P = 0.0016 vs. hyperinsulinemia; P = NS vs. control subjects) but did not have any effect in the insulin withdrawal study (P < 0.001 vs. other studies). In conclusion, 1). insulin is essential for meal-induced plasma ghrelin suppression, 2). basal insulin availability is sufficient for postprandial ghrelin suppression in type 1 diabetic subjects, and 3). lack of meal-induced ghrelin suppression caused by severe insulin deficiency may explain hyperphagia of uncontrolled type 1 diabetic subjects.

Validation of a counseling strategy to promote the adoption and the maintenance of physical activity by type 2 diabetic subjects.

OBJECTIVE: There is enough evidence that physical activity is an effective therapeutic tool in the management of type 2 diabetes. The present study was designed to validate a counseling strategy that could be used by physicians in their daily outpatient practice to promote the adoption and maintenance of physical activity by type 2 diabetic subjects. RESEARCH DESIGN AND METHODS: The long-term (2-year) efficacy of the behavioral approach (n = 182) was compared with usual care treatment (n = 158) in two matched, randomized groups of patients with type 2 diabetes who had been referred to our Outpatient Diabetes Center. The outcome of the intervention was consistent patient achievement of an energy expenditure of >10 metabolic equivalents (METs)-h/week through voluntary physical activity. RESULTS: After 2 years, 69% of the patients in the intervention group (27.1 +/- 2.0 METs x h/week) and 18% of the control group (4.1 +/- 0.8 METs x h/week) achieved the target (P < 0.001) with significant (P < 0.001) improvements in BMI (intervention group 28.9 +/- 0.2 versus control group 30.4 +/- 0.3 kg/m(2)) and HbA(1c) (intervention group 7.0 +/- 0.1 versus control group 7.6 +/- 0.1%). CONCLUSIONS: This randomized, controlled study shows that physicians can motivate most patients with type 2 diabetes to exercise long-term and emphasizes the value of individual behavioral approaches in daily practice.

Ghrelin is not necessary for adequate hormonal counterregulation of insulin-induced hypoglycemia.

Ghrelin is a novel enteric hormone that stimulates growth hormone (GH), ACTH, and epinephrine; augments plasma glucose; and increases food intake by inducing the feeling of hunger. These characteristics make ghrelin a potential counterregulatory hormone. At present, it is not known whether ghrelin increases in response to insulin-induced hypoglycemia. To answer this question, we compared plasma ghrelin concentrations after a short-term insulin infusion that was allowed or not (euglycemic clamp) to cause hypoglycemia (2.7 +/- 0.2 mmol/l at 30 min) in five healthy volunteers. In both studies, plasma ghrelin concentrations decreased (P < 0.01) after insulin infusion (hypoglycemia by 14%, euglycemia by 22%), reached a nadir at 30 min, and returned to baseline at 60 min, without differences between the hypoglycemia and the euglycemia studies. Glucagon, cortisol, and GH increased in response to hypoglycemia despite the decreased ghrelin. There was a strong correlation (R(2) = 0.91, P < 0.002) between the insulin sensitivity of the subjects and the percentage suppression of ghrelin from baseline. These data demonstrate that ghrelin is not required for the hormonal defenses against insulin-induced hypoglycemia and that insulin can suppress ghrelin levels in healthy humans. These results raise the possibility that postprandial hyperinsulinemia is responsible for the reduction of plasma ghrelin that occurs during meal intake.