Chemical ablation of gastric inhibitory polypeptide receptor action by daily (Pro3) GIP administration improves glucose tolerance and ameliorates insulin resistance and abnormalities of islet structure in obesity-diabetes.

Glucose-dependent insulinotropic polypeptide (gastric inhibitory polypeptide [GIP]) is an important incretin hormone secreted by endocrine K-cells in response to nutrient ingestion. In this study, we investigated the effects of chemical ablation of GIP receptor (GIP-R) action on aspects of obesity-related diabetes using a stable and specific GIP-R antagonist, (Pro3)GIP. Young adult ob/ob mice received once-daily intraperitoneal injections of saline vehicle or (Pro3)GIP over an 11-day period. Nonfasting plasma glucose levels and the overall glycemic excursion (area under the curve) to a glucose load were significantly reduced (1.6-fold; P <0.05) in (Pro3)GIP-treated mice compared with controls. GIP-R ablation also significantly lowered overall plasma glucose (1.4-fold; P <0.05) and insulin (1.5-fold; P <0.05) responses to feeding. These changes were associated with significantly enhanced (1.6-fold; P <0.05) insulin sensitivity in the (Pro3)GIP-treated group. Daily injection of (Pro3)GIP reduced pancreatic insulin content (1.3-fold; P <0.05) and partially corrected the obesity-related islet hypertrophy and ß-cell hyperplasia of ob/ob mice. These comprehensive beneficial effects of (Pro3)GIP were reversed 9 days after cessation of treatment and were independent of food intake and body weight, which were unchanged. These studies highlight a role for GIP in obesity-related glucose intolerance and emphasize the potential of specific GIP-R antagonists as a new class of drugs for the alleviation of insulin resistance and treatment of type 2 diabetes.

A longitudinal study of infant feeding and obesity throughout the life course

Background: The Centers for Disease Control and Prevention and the US Department of Health and Human Services promote breastfeeding as a strategy for reducing childhood overweight. We evaluated the relation between infant feeding and the development of overweight and obesity throughout life course. Methods: We investigated the association between infant feeding and obesity among 35 526 participants in the Nurses' Health Study II who were followed prospectively from 1989 to 2001. Mothers of participants provided information by mailed questionnaires on the duration of breast- and bottle-feeding, as well as the type of milk or milk substitute in the bottle. Information on body shape at ages 5 and 10, weight at age 18, current weight between 1989 and 2001, and height was reported by the participants. Results: The duration of breastfeeding, including exclusive breastfeeding, was not related to being overweight (25 body mass index (BMI)

Obesity in People with Learning Disabilities: the impact of nurse led health screenings and health promotion activities

Background. Obesity appears to be more common among people with intellectual disabilities, with few studies focusing on achieving weight reduction. Aim. Firstly, to follow up people identified as overweight and obese following special health screening clinics and to determine the actions taken. Secondly, to evaluate the impact of health promotion classes on participants' weight loss. Methods. A clinic led by two learning disbaility nurses was held for all people aged 10 years and over (n=464) who attended special services within the area of one Health and Social Services Trust in Northern Ireland. In a second study, the nurses organised health promotion classes for 20 people over a 6 - 8 week period. Findings. The health screen identified 64% of adults and 26% of 10 - 19 year olds as being overweight or obese. Moreover, those aged 40 - 49 years who were obese had significantly higher levels of blood pressure. However, information obtained from a follow up questionnaire sent after 3 months suggested that of the 122 people identified for wiehgt reduciton, action had been taken for only 34% of them and only three were reported to have lost weight. The health promotion classes, however, led to a significant reduction in weight and body mass index scores. Conclusion. Health screening per se has limited impact on reducing obesity levels in this client group. Rather, health personnel such as general practitioners, nurses and health promotion staff need to work in partnership with service staff, carers and people with intellectual disabiltieis to create more active lifestyles.

Early administration of the glucose-dependent insulinotropic polypeptide receptor antagonist (Pro(3))GIP prevents the development of diabetes and related metabolic abnormalities associated with genetically inherited obesity in ob/ob mice

Aims/hypothesis Ablation of gastric inhibitory polypeptide ( GIP) receptor action is reported to protect against obesity and associated metabolic abnormalities. The aim of this study was to use prediabetic ob/ob mice to examine whether 60 days of chemical GIP receptor ablation with (Pro(3)) GIP is able to counter the development of genetic obesity-related diabetes.

Enhanced cAMP generation and insulin-releasing potency of two novel Tyr(1)-modified enzyme-resistant forms of glucose-dependent insulinotropic polypeptide is associated with significant antihyperglycaemic activity in spontaneous obesity-diabetes

Glucose-dependent insulinotropic polypeptide (GIP) is an important incretin hormone, which potentiates glucose-induced insulin secretion. Antihyperglycaemic actions of GIP provide significant potential in Type 11 diabetes therapy. However, inactivation of GIP by the enzyme dipeptidyl peptidase IV (DPP IV) and its consequent short circulating half-life limit its therapeutic use. Therefore two novel Tyr(1)-Modified analogues of GIP, N-Fmoc-GIP (where Fmoc is 9-fluorenylmethoxycarbonyl) and N-palmitate-GIP, were synthesized and tested for metabolic stability and biological activity. Both GIP analogues were resistant to degradation by DPP IV and human plasma. In Chinese hamster lung (CHL) cells expressing the cloned human GIP receptor, both analogues exhibited a 2-fold increase in cAMP-generating potency compared with native GIP (EC50 values of 9.4, 10.0 and 18.2 nM respectively). Using clonal BRIN-BD11 cells, both analogues demonstrated strong insulinotropic activity compared with native GIP (P <0.01 to P <0.001). In obese diabetic (ob/ob) mice, administration of N-Fmoc-GIP or N-palmitate-GIP (25 nmol/kg) together with glucose (18 mmol/kg) significantly reduced the peak 15 min glucose excursion (1.4- and 1.5-fold respectively; P <0.05 to P <0.01) compared with glucose alone. The area under the curve (AUC) for glucose was significantly lower after administration of either analogue compared with glucose administered alone or in combination with native GIP (1.5-fold; P <0.05). This was associated with a significantly greater AUC for insulin (2.1-fold; P <0.001) for both analogues compared with native GIP. A similar pattern of in vivo responsiveness was evident in lean control mice. These data indicate that novel N-terminal Tyr(1) modification of GIP with an Fmoc or palmitate group confers resistance to degradation by DPP IV in plasma, which is reflected by increased in vitro potency and greater insulinotropic and antihyperglycaemic activities in an animal model of Type 11 diabetes mellitus.