GHTD-amide: a naturally occurring beta cell-derived peptide with hypoglycemic activity.

In the early 1970s, a peptide fraction with insulin potentiating activity was purified from human urine but the identity and origins of the active constituent remained unknown. Here we identify the active component and characterize its origins. The active peptide was identified as an alpha amidated tetrapeptide with the sequence GHTD-amide. The peptide was synthesized and tested for stimulation of glycogen synthesis and insulin potentiation by insulin tolerance testing in insulin-deficient rats, which confirmed GHTD-amide as the active peptide. Tissue localization using a peptide-specific anti-serum and epifluorescent and confocal microscopy showed decoration of pancreatic islets but not other tissues. Confocal microscopy revealed co-localization with insulin and immunogold and electron microscopy showed localization to dense core secretory granules. Consistent with these observations GHTD-amide was found in media conditioned by MIN6 islet beta cells. Sequence database searching found no annotated protein in the human proteome encoding a potential precursor for GHTD-amide. We conclude that the insulin potentiating activity originally described in human urine is attributable to the tetrapeptide GHTD-amide. GHTD-amide is a novel peptide produced by pancreatic beta cells and no precursor protein is present in the annotated human proteome. Stimulation of glycogen synthesis and co-localization with insulin in beta cells suggest that GHTD-amide may play a role in glucose homeostasis by enhancing insulin action and glucose storage in tissues.

Serum lipids and modernization in coastal and highland Papua New Guinea.

Previous studies in Melanesians of Papua New Guinea have documented low serum cholesterol concentrations with no age-related rise and a virtual absence of coronary heart disease. However, because of recent reports of the emergence of coronary heart disease in this population, serum lipid concentrations in adults aged > or = 25 years in three coastal (n = 1,489 and three highland (n = 388) village communities at different stages of modernization were examined as part of a survey undertaken in 1991. Total cholesterol concentrations were clearly higher than were levels recorded in earlier studies. Moreover, age-related increases in total cholesterol, low density lipoprotein cholesterol (LDL cholesterol), high density lipoprotein cholesterol (HDL cholesterol), and triglycerides (in women) were apparent. Mean total cholesterol levels in an urban community with a high risk of diabetes were similar to those observed in Australians, while HDL cholesterol concentrations were lower. Total cholesterol and LDL cholesterol levels were higher in urban coastal and periurban highland subjects than in their rural counterparts. Prevalence of hypercholesterolemia (> or = 5.2 mmol/liter) varied from 16% in rural highlanders to 56% in urban coastal subjects. Sex, age, village, body mass index, fat distribution, glucose intolerance, physical activity, and an index of relative modernity all contributed to variations in cholesterol and triglyceride concentrations. These results show that Papua New Guineans are by no means protected from dyslipidemia and serve warning that, unless effective preventative strategies can be developed, this and similar rapidly developing populations can expect an increasing incidence of coronary heart disease.

Lack of antibodies to glutamic acid decarboxylase in young adults of the high diabetes prevalence Wanigela people of Papua New Guinea.

Antibodies to glutamic acid decarboxylase (anti-GAD) are common in typical insulin-dependent diabetes mellitus, and also identify a sub-group of older persons who are originally misdiagnosed as having non-insulin-dependent disease (NIDDM). The Wanigela people of Papua New Guinea are highly susceptible to diabetes mellitus, with a prevalence of 20.4% in urbanised young adults aged 25-34 years. On the basis of clinical features including the presence of obesity and relatively high insulin concentrations the Wanigelas have NIDDM. To determine whether anti-GAD is present in this high prevalence form of diabetes, and to investigate whether there might be an autoimmune component to the disease, we measured anti-GAD in 93 newly-diagnosed diabetic subjects aged 25-44 years, and in 40 controls with normal glucose tolerance. There was no difference in mean levels of anti-GAD in diabetic subjects and normal controls. Two subjects had borderline elevated anti-GAD levels: one was a normal control, and the other a diabetic. This study shows that anti-GAD is not present in this (and probably other) high prevalence variant of NIDDM. Moreover, the results suggest strongly that diabetes in the Wanigela people is unlikely to have an autoimmune component to its pathogenesis.

Extraordinary prevalence of non-insulin-dependent diabetes mellitus and bimodal plasma glucose distribution in the Wanigela people of Papua New Guinea.

OBJECTIVE: To determine the current prevalence of impaired glucose tolerance (IGT) and non-insulin-dependent diabetes mellitus (NIDDM) in Melanesians of three coastal Papua New Guinean communities, to relate this to previous studies, and to investigate plasma glucose distributions in these populations. DESIGN: Cross-sectional survey, using 75 g oral glucose tolerance tests and World Health Organization criteria. SETTING: Rural Papuan villages of Wanigela and Kalo, and Wanigela people of the urban squatter settlement of Koki, Port Moresby. SUBJECTS: All adults aged 25 years or more living in the three communities were eligible, with response rates of 77.2% (Koki), 88.1% (Wanigela) and 72.5% (Kalo). MAIN OUTCOME MEASURES: Prevalence of abnormal glucose tolerance, risk factor levels, fasting and two-hour plasma glucose concentration. RESULTS: Age-standardised prevalence of NIDDM in Koki Wanigelas was 27.5% in men and 33.0% in women; an additional 20.5% of men and 22.0% of women had IGT. Even in the youngest age group (25-34 years), 36.5% of subjects had abnormal glucose tolerance. The overall prevalences of NIDDM and IGT in rural Wanigelas were 11.7% and 17.0% respectively. In Kalo both were uncommon. The prevalences of IGT and NIDDM in Koki had doubled over a 14-year period. The age-standardised prevalence of abnormal glucose tolerance in the Koki Wanigelas is the second highest in the world after the Arizona Pima Indians, and higher than in Micronesian Nauruans, even though the latter are more obese. Both fasting and two-hour glucose concentrations in all age groups in Koki were clearly bimodal, a mixture of two log-normal distributions. CONCLUSIONS: The Wanigela people of Papua New Guinea have an extra-ordinary susceptibility to glucose intolerance which is exposed after adoption of modern lifestyle habits. A "founder effect" may explain the high frequency of a diabetogenic genotype in this population.

Increasing prevalence of NIDDM in the Pacific island population of Western Samoa over a 13-year period.

OBJECTIVE: A survey of noncommunicable diseases (NCD) in the Pacific island population of Western Samoa in 1978 (n = 1,206) documented a relatively high prevalence of non-insulin-dependent diabetes mellitus (NIDDM) and obesity. A follow-up survey was performed in 1991 (n = 1,776) to assess changes in NCD prevalence and risk factor distribution over 13 years. RESEARCH DESIGN AND METHODS: In both surveys, the same representative villages from one urban and two rural areas were studied, and the survey procedure included an oral glucose tolerance test, anthropometric and blood pressure measurements, and physical activity assessment (1991 only). RESULTS: The age-standardized prevalence of NIDDM in 1991 was 9.5 and 13.4% in Apia (urban) for men and women, respectively. In Poutasi (rural), 5.3% of men and 5.6% of women had NIDDM, and in Tuasivi (rural) the prevalence was 7.0 and 7.5% for men and women, respectively. Age, body mass index (BMI), waist-to-hip circumference ratio, physical inactivity, and family history of diabetes all showed independent association with NIDDM and impaired glucose tolerance. Living in Apia (compared with Poutasi) was also associated with NIDDM. Between 1978 and 1991, the age-standardized prevalence of NIDDM in Apia increased from 8.1 to 9.5% in men and 8.2 to 13.4% in women. In Poutasi, a dramatic increase occurred in prevalence from 0.1 to 5.3% in men, but little change in women was noted (5.4 to 5.6%). In Tuasivi, the increases were 2.3 to 7.0% in men and 4.4 to 7.5% in women. In combined survey areas, increases were observed in the age-standardized prevalence of obesity and mean levels of total cholesterol, fasting triglycerides, and uric acid between surveys as well as a reduction in the prevalence of smoking. CONCLUSIONS: This is the first study using standardized methods to show a dramatic increase in the prevalence of NIDDM in a developing Pacific island population, and it indicates the importance of maintaining and expanding preventive programs for NIDDM and related lifestyle diseases in these populations.

Alpha thalassaemia in Papua New Guinea.

Haemoglobin Bart's was detected in cord blood samples from 81% of 217 infants born in Madang on the north coast of Papua New Guinea. Analysis of the alpha globin genes of 30 infants and adults from the same region showed that all but 3 were heterozygous or homozygous for the deletion form of alpha + thalassaemia. None of 18 cord blood samples from infants born in Goroka in the Eastern Highlands Province had haemoglobin Bart's, and in each case the alpha globin genes were normal. Preliminary geographical and linguistic analyses of both groups suggest that the prevalence of alpha thalassaemia may be related to altitude rather than to linguistic grouping and hence that resistance to malaria may be at least one reason why alpha thalassaemia is so common in some populations.