ArticleLiterature Review

Review article: Diabetes, genetics and ethnicity

Authors:
To read the full-text of this research, you can request a copy directly from the authors.

Abstract

The prevalence of insulin resistance and diabetes has increased in the past decades at an alarming rate in all Western countries and in those countries which are adopting a 'western life style'. This trend suggests the impact of environmental factors such as diet, obesity and physical activity on the pathogenesis of diabetes. However it is known that the prevalence and variation of prevalence, as consequence of environmental changes, it is different in various ethnic groups. Studies conducted in multiethnic populations suggest that some ethnic groups, such as Hispanics or Asian Indians, might have a particular predisposition, possibly on genetic basis, to develop insulin resistance and diabetes, when exposed to adverse conditions. According to the 'thrifty gene' hypothesis, a clustering of different genetic defects or polymorphisms, developed as genetic advantage in some populations, could predispose some ethnic groups to insulin resistance and diabetes in presence of an increased food supply. Multiple mutations, associated with small changes in insulin sensitivity, when combined, may induce a significant reduction in insulin sensitivity. This review deals with the possible relevance of genetic factors in the expression of insulin resistance and diabetes in relation to ethnicity.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the authors.

... In 1962, Neel [26] had put forward the "thrifty gene" hypothesis that some populations may have genes that determine increased fat storage, which in times of famine represented a survival advantage, but in a modern environment results in obesity and type 2 diabetes. To this day, the initial idea of Neel was modified in that it is not a single "thrifty" gene, but many nuclear and mitochondrial genes are forming specific metabolic phenotypes inherited from our predecessors that come into conflict with the contemporary diets and lifestyle [27,28]. In the past decades, insulin resistance and type 2 diabetes have increased at an alarming rate in all Western countries, particularly in countries where indigenous northern populations are adopting a "Western lifestyle". ...
... In the past decades, insulin resistance and type 2 diabetes have increased at an alarming rate in all Western countries, particularly in countries where indigenous northern populations are adopting a "Western lifestyle". Carulli et al. (2005) suggested the impact of environmental factors, such as diet, obesity, and low physical activity, on the pathogenesis of diabetes [28]. However, numerous data show that the prevalence of the MetS symptoms and variation of metabolic features depend on environmental conditions and thus differ in various ethnic groups [25,[29][30][31][32][33]. ...
... In the past decades, insulin resistance and type 2 diabetes have increased at an alarming rate in all Western countries, particularly in countries where indigenous northern populations are adopting a "Western lifestyle". Carulli et al. (2005) suggested the impact of environmental factors, such as diet, obesity, and low physical activity, on the pathogenesis of diabetes [28]. However, numerous data show that the prevalence of the MetS symptoms and variation of metabolic features depend on environmental conditions and thus differ in various ethnic groups [25,[29][30][31][32][33]. ...
Article
Full-text available
We present evidence that metabolic syndrome (MetS) represents the postreproductive stage of the human postembryonic ontogenesis. Accordingly, the genes governing this stage experience relatively weak evolutionary selection pressure, thus representing the metabolic phenotype of distant ancestors with β-oxidation of long-chain fatty acids (FAs) as the primary energy source. Mitochondria oxidize at high-rate FAs only when succinate, glutamate, or pyruvate are present. The heart and brain mitochondria work at a wide range of functional loads and possess an intrinsic inhibition of complex II to prevent oxidative stress at periods of low functional activity. Kidney mitochondria constantly work at a high rate and lack inhibition of complex II. We suggest that in people with MetS, oxidative stress is the central mechanism of the heart and brain pathologies. Oxidative stress is a secondary pathogenetic mechanism in the kidney, while the primary mechanisms are kidney hypoxia caused by persistent hyperglycemia and hypertension. Current evidence suggests that most of the nongenetic pathologies associated with MetS originate from the inconsistencies between the metabolic phenotype acquired after the transition to the postreproductive stage and excessive consumption of food rich in carbohydrates and a sedentary lifestyle.
... La bibliografía señala que la prevalencia es menor en individuos de raza caucásica que en el resto de las etnias estudiadas (raza negra, asiáticos e hispanos) (64,65) , hecho que también confirma el estudio Nurses' Health Study, tras 20 años de seguimiento (66) . 40 -Antecedente de DM2 en un familiar de primer grado: ...
... La diabetes mellitus constituye una de las principales causas de amputación no traumática de los pies. 64 La prevalencia de amputaciones entre los diabéticos es del 2% y la incidencia de úlceras del 6%. El riesgo de desarrollo de úlceras aumenta en los pacientes con una evolución de la diabetes superior a 10 años, de sexo masculino, con un escaso control metabólico y que presentan complicaciones cardiovasculares, oculares o renales. ...
... In the Botnia study, a positive family history with at least one affected first degree relative was associated with a hazard ratio (HR) of 2.2 for development of the disease [19]. In recent years a large number of genetic variants have been identified, which increase the risk for T2DM [20]. Genome-wide association studies provided by far the biggest increment to our knowledge of the genetics of T2DM [21][22][23][24][25][26]. ...
... Ethnicity. Studies in multiethnic populations suggest that some ethnic groups have a particular predisposition, most likely on a genetic basis, to develop insulin resistance and T2DM, when exposed to adverse conditions [20]. There are wide differences in the prevalence of diabetes between ethnic groups (A) [28]. ...
... The metabolic syndrome, a clustering of cardiometabolic risk factors (abdominal obesity, hyperglycaemia, dyslipidaemia, hypertension), increases an individual's probability of developing type 2 diabetes mellitus (T2DM) or cardiovascular disease, and varies significantly among ethnic groups [1]. Insulin resistance (IR) and T2DM has increased in countries which have adopted a 'western lifestyle' (comprised of reduced physical activity and a diet higher in fat) with some ethnic groups having a higher prevalence of this disease compared to other groups living in the same multiethnic environment. ...
... a diet higher in fat) with some ethnic groups having a higher prevalence of this disease compared to other groups living in the same multiethnic environment. It is more common in peoples of non-Caucasian compared to Caucasian (C) origin and most wide spread in Asia/Australasia with 82.7 million diagnosed, which is half of the world-wide prevalence. [1, 2]. South-Asians (SA), especially Asian-Indians appear to be the most insulin resistant. Compared with a 5% incidence in C, the prevalence of T2DM in Asian-Indians living in 'westernised' countries is around 19% and develops about 10 years earlier. South-East Asians are also highly susceptible with an estimated 8% and 12% incidence in p ...
Article
Full-text available
To identify biochemical and genetic variation relating to increased risk of developing type 2 diabetes mellitus and cardiovascular disease in young, lean male and female adults of different ethnicities.Fasting blood and urine and non-fasting blood following oral glucose intake were analysed in 90 Caucasians, South Asians and South East/East Asians.There were no differences in age, birthweight, blood pressure, body mass index, percent body fat, total energy, percentage of macronutrient intake, microalbumin, leptin, cortisol, adrenocorticotropic hormone, nitric oxide metabolites, C-reactive protein, homocysteine, tumor necrosis factor-α, interleukin-6, von Willebrand factor, vascular cell adhesion molecule-1, plasminogen activator inhibitor-1, and tissue plasminogen activator. Fasting total cholesterol (P = .000), triglycerides (P = .050), low density lipoprotein (P = .009) and non-fasting blood glucose (15 min) (P = .024) were elevated in South Asians compared with Caucasians, but there was no significant difference in glucose area under curve (AUC). Non-fasting insulin in South Asians (15-120 min), in South East/East Asians (60-120 min), and insulin AUC in South Asians and South East/East Asians, were elevated compared with Caucasians (P≤0.006). The molar ratio of C-peptide AUC/Insulin AUC (P = .045) and adiponectin (P = .037) were lower in South Asians compared with Caucasians. A significant difference in allele frequency distributions in Caucasians and South Asians was found for rs2166706 (P = 0.022) and rs10830963 (P = 0.009), which are both near the melatonin receptor MTNR1B.Elevated non-fasting insulin exists in young South Asians of normal fasting glucose and insulin. Hepatic clearance of insulin may be reduced in South Asians. No current biochemical evidence exists of endothelial dysfunction at this stage of development. MTNR1B signalling may be a useful therapeutic target in Asian populations in the prevention of type 2 diabetes mellitus.
... In the Botnia study, a positive family history with at least one affected first degree relative was associated with a hazard ratio (HR) of 2.2 for development of the disease [19]. In recent years a large number of genetic variants have been identified, which increase the risk for T2DM [20]. Genome-wide association studies provided by far the biggest increment to our knowledge of the genetics of T2DM [21][22][23][24][25][26]. ...
... Ethnicity. Studies in multiethnic populations suggest that some ethnic groups have a particular predisposition, most likely on a genetic basis, to develop insulin resistance and T2DM, when exposed to adverse conditions [20]. There are wide differences in the prevalence of diabetes between ethnic groups (A) [28]. ...
... A further limitation of the present study is the significance of ethnicity in the association between micronutrients and trace elements and diabetes. There are many studies which have investigated how ethnicity and genetics may affect the pathogenesis and development of diabetes and insulin resistance [36]. However, in the current study, this limitation is not a particularly significant one as the Qatari population is relatively homogenous and so there was little to no ethnic variation between the Qataris in our study, which make up more than 85% of the QBB. ...
Article
Full-text available
Objective: The objectives of this study were to investigate associations between micronutrient levels and diabetes and to explore the association in individuals with controlled and uncontrolled diabetes. Methods: A case–control study, matched on age and gender, was performed on participants with (cases) and without diabetes (controls), who were Qatari or long-term residents (≥15 years of residence). Participants with diabetes were divided into those with controlled and uncontrolled diabetes using an HbA1c cutoff of 7%. Levels of micronutrients were measured from serum and categorized into normal and abnormal levels. Results: A total of 1118 participants (374 cases and 744 controls) were included with a mean age of 41.7 years (SD 9.9), of whom 53.9% were female. Of those with diabetes, 229 had controlled diabetes and 145 had uncontrolled diabetes. Compared to those without diabetes, participants with diabetes had significantly lower mean magnesium (0.80 mmol/L (SD 0.07) vs. 0.84 mmol/L (SD 0.06), respectively, p < 0.001). Lower magnesium and iron were observed in participants with uncontrolled compared to participants with controlled diabetes. After multivariable logistic regression, diabetes was associated with hypomagnesemia (OR 3.2, 95% CI 3.4–213.9) and low iron (OR 1.49, 95% CI 1.03–2.15). Uncontrolled diabetes showed stronger odds of association with hypomagnesemia (OR 5.57, 95% CI 3.65–8.52). Conclusion: In an affluent setting in the MENA region, diabetes was associated with low magnesium and low iron, and this association was stronger in individuals with uncontrolled diabetes.
... Studies in multiethnic populations with varying T2D rates suggest that some ethnic groups may have a genetic predisposition to developing insulin resistance and diabetes when exposed to adverse conditions [122]. It is thought that between 35% and 70% of type 2 diabetes cases are genetically predisposed [123]. ...
Article
Full-text available
Numerous studies have shown that oxidative stress resulting from an imbalance between the production of free radicals and their neutralization by antioxidant enzymes is one of the major pathological disorders underlying the development and progression of type 2 diabetes (T2D). The present review summarizes the current state of the art advances in understanding the role of abnormal redox homeostasis in the molecular mechanisms of T2D and provides comprehensive information on the characteristics and biological functions of antioxidant and oxidative enzymes, as well as discusses genetic studies conducted so far in order to investigate the contribution of polymorphisms in genes encoding redox state-regulating enzymes to the disease pathogenesis.
... On the other hand, compared to Asian individuals, European individuals with diabetes are at higher risk of complications such as myocardial infarction, coronary artery disease, lower-extremity gangrene, and large vessel disease but have a lower risk of small vessel disease and diabetic eye and kidney diseases [5,9,10]. This predisposition of different ethnic groups to T2DM and its complications are commonly attributed to the complex interaction of genetic and environmental factors [15,16]. ...
Article
Full-text available
Background: Obesity and ethnicity play important roles in cardiovascular complications in patients with type 2 diabetes mellitus (T2DM). This study aimed to compare cardiometabolic risk profiles between Chinese and Finnish older adults of central obesity with prediabetes or T2DM. Methods: Study subjects were 60-74 years old and originated from two population samples. The Finnish subjects came from the Kuopio Ischemic Heart Disease (KIHD) study (n = 1089), and the Chinese subjects came from the Shanghai High-risk Diabetic Screen (SHiDS) study (n = 818). The KIHD and SHiDS studies used similar questionnaires to determine participants' baseline characteristics regarding the history of medication use and diseases and lifestyle factors. All study subjects participated in glucose tolerance tests and anthropometry assessments, including waist circumference measurements. Results: Among study subjects of central obesity with prediabetes (n = 298), fasting and 2-h glucose, and fasting insulin and insulin resistance were significantly higher in Chinese than in Finnish (p < 0.0001-0.016). In addition, triglyceride (TG) level was higher and the low-density lipoprotein cholesterol (LDL) and LDL to high-density lipoprotein cholesterol (HDL) ratio were lower in Chinese than in Finnish (p < 0.0001-0.003). Among subjects of central obesity with T2DM (n = 251), Chinese subjects had significantly less proportions of antihypertensive, glycaemic control medication, and statin users as well as lower level of physical activity (p < 0.0001 for all), while higher blood pressure (p = 0.002 for systolic blood pressure and p < 0.0001 for diastolic blood pressure), TG levels (p < 0.05) and HDL (p = 0.002) than the Finnish counterparts. There were no differences in β-cell function (HOMA-β) between Chinese and Finnish both in prediabetes and T2DM. Conclusions: Our results indicated that Chinese and Finnish older adults of central obesity with prediabetes and T2DM had similar β-cell function. However, Chinese individuals with prediabetes are prone to insulin resistance. Meanwhile, lipid metabolism dysfunction is also different between Chinese and Finnish. Chinese older adults of central obesity with prediabetes showed higher TG, but Finnish showed higher LDL and LDL/HDL. Strategic for T2DM prevention and treatment should be ethnically specific.
... The proportion of male and females was approximately equal, with the expected predominance of White British adults. The slightly higher representation of Asian/Asian British participants in the elevated glucose group might reflect the elevated risk of diabetes in this ethnic group [20]. *Usable audit data provided for 82 and 72 participants for BP and Glu audits, respectively ...
Research
Full-text available
The basis for the present evaluation is to improve understanding in Stoke-on-Trent around how to improve uptake of NHS HC, and how those who attend and are identified as ‘at risk’ of chronic disease, are followed-up.
... On the other hand, compared to Asian individuals, European individuals with diabetes are at higher risk of complications such as myocardial infarction, coronary artery disease, lower-extremity gangrene, and large vessel disease but have a lower risk of small vessel disease and diabetic eye and kidney diseases [4,8,9]. This predisposition of different ethnic groups to T2DM and its complications are commonly attributed to the complex interaction of genetic and environmental factors [13,14]. ...
Preprint
Full-text available
Background Obesity and ethnicity play important roles in cardiovascular complications in patients with T2DM. This study aimed to compare cardiometabolic risk profiles between Chinese and Finnish older adults with prediabetes or type 2 diabetes mellitus (T2DM) and central obesity. Methods Study subjects were 60-74 years old and originated from two population samples. The Finnish subjects came from the Kuopio Ischemic Heart Disease (KIHD) study (n = 1089), and the Chinese subjects came from the Shanghai High-risk Diabetic Screen (SHiDS) study (n = 818). The KIHD and SHiDS studies used similar questionnaires to determine participants’ baseline characteristics regarding the history of medication use and diseases and lifestyle factors. All study subjects participated in glucose tolerance tests and anthropometry assessments, including waist circumference measurements. Results Among study subjects with prediabetes and central obesity (n = 298), fasting glucose, 2-h glucose, fasting insulin, insulin resistance, and triglyceride (TG) levels were significantly higher while the low-density lipoprotein cholesterol (LDL) and LDL to high-density lipoprotein cholesterol (HDL) ratio were lower in Chinese individuals than Finnish individuals (p <0.0001-0.003). Among subjects with T2DM and central obesity (n = 251), Chinese subjects had significantly less proportions of antihypertensive, glycaemic control medication, and statin users as well as lower level of physical activity (p < 0.0001 for all), while higher blood pressure (p = 0.002 for systolic blood pressure and p < 0.0001 for diastolic blood pressure), TG levels (p < 0.05) and HDL (p = 0.002) than the Finnish counterparts. There were no differences in β-cell function (HOMA-β) between Chinese and Finnish both in prediabetes and T2DM. Conclusions Our results indicated that Chinese and Finnish older adults with prediabetes and T2DM had similar β-cell function. However, Chinese individuals with prediabetes are prone to lipid metabolism dysfunction and insulin resistance. Strategies for preventing prediabetes from developing into diabetes in Chinese individuals should be focused on interventions such as exercise to increase insulin sensitivity and prevent insulin resistance. For Finnish individuals with prediabetes, more attention should be given to weight control.
... The prevalence of acanthosis is higher among African American, Hispanic, and Native American people and Pacific Islanders than among non-Hispanic White people (17,18). Strong evidence shows a disproportionate prevalence of type 2 diabetes and obesity among racial/ethnic minority populations (19)(20)(21). ...
Article
Full-text available
Introduction: Waist circumference is a common anthropometric measure for predicting abdominal obesity and insulin resistance. We developed optimal waist circumference cut points for children aged 2 to 8 years in the US-Affiliated Pacific (USAP) region based on the relationship of waist circumference and acanthosis nigricans in this population. Methods: We conducted a cross-sectional analysis from the Children's Healthy Living Program's 2012-2013 data on 4,023 children. We used receiver-operating characteristic analysis to determine the sensitivity and specificity for acanthosis nigricans across waist circumference, by sex and age. We determined optimal waist circumference cutoff points corresponding to Youden index (J), (equal to [sensitivity + specificity] - 1), with acanthosis nigricans. We compared these cut points with the 90th percentile. Results: The 90th-percentile cut points for boys aged 2 to 5 years (58.15 cm) and 6 to 8 years (71.63 cm) were slightly higher than for girls in both age groups (aged 2-5 y, 57.97 cm; 6-8 y: 70.37 cm). The optimal cut points (corresponding to the highest sensitivity and specificity) were as follows: for boys aged 2 to 5 years, 90th percentile (58.25 cm; sensitivity, 48.0%; specificity, 91.5%); for boys aged 6 to 8 years, 78th percentile (63.59 cm; sensitivity, 86.8%; specificity, 82.8%); for girls aged 2 to 5 years, 62nd percentile (53.27 cm; sensitivity, 71.4%; specificity, 63.1%), and for girls aged 6 to 8 years, 80th percentile (63.63 cm; sensitivity, 55.4%; specificity, 82.9%). Conclusion: Among USAP children, waist circumference was a reasonable predictor for acanthosis nigricans. Further analysis is warranted to examine causes of acanthosis nigricans at lower-than-expected waist circumference percentiles. The cut points can be used for early detection of metabolic risk.
... While there are no nationwide statistics for diabetes, in a study of residents over 60 years of age in Sonacotra-Adoma hostels in the Rhône region, the incidence of diabetes was at 15.5%, against 8% in the rest of the population over 60 (Hadjiat and Fevotte 2008). The role of ethnicity in the prevalence of type-2 diabetes is important and has been widely reported in the epidemiological literature (Agyemang et al. 2011;Carulli et al. 2005). Dr. Ismail confirmed that diabetes is a feature, especially for the older North Africans whom he sees. ...
Book
This open access book offers new insights into the ageing-migration nexus and the nature of home. Documenting the hidden world of France’s migrant worker hostels, it explores why older North and West African men continue to live past retirement age in this sub-standard housing. Conventional wisdom holds that at retirement labour migrants ought to instead return to their families in home countries, where their French pensions would have far greater purchasing power. This paradox is the point of departure for a book which transports readers from the banlieues of Paris to the banks of the Senegal River and the villages of the Anti-Atlas. In intimate ethnographic detail, the author brings to life the experiences of these older labour migrants by sharing in the life of the hostels as a resident, by observing at close quarters the men's family life on the other side of the Mediterranean as a guest in their homes, and even by accompanying them in their travels by bus, sea, and air. The monograph evaluates several theories of migration against rich qualitative data gathered from multiple methods: biographical narrative and semi-structured interviews, participant observation, and archival research. In the process, it offers a thoughtful contribution to broader debates on what it means for migrants to belong and achieve inclusion in society. “This book makes an important contribution to our understanding of transnationalism and integration. It also offers an unusually nuanced view of the strains that migration places on families” Christina Boswell, University of Edinburgh “A fascinating read which poignantly shows that the ageing-migration nexus is a theoretically profuse source of information about return migration, retirement and the meaning of home “Based on a prize-winning PhD thesis, and enriched by unique field research in migrant-worker hostels in France, this book engages in truly innovative fashion with the linked themes of migration, ageing and ‘home’. ” Russell King, University of Sussex
... In contrast, Posadas-Sánchez et al. reported a significant association between the -514C>T variant with an increased risk of T2D in Mexicans [39]. Notably, the main difference with respect to the later study is that we included ethnicity as a confounder, as it has been shown to be a requirement for mixed populations such Mexicans [4,20,40]. ...
Article
PurposeBoth type 2 diabetes (T2D) and low levels of high-density lipoprotein cholesterol (HDL-C) are very prevalent conditions among Mexicans. Genetic variants in the LIPC gene have been associated with both conditions. This study aimed to evaluate the association of the -514C < T (rs1800588) LIPC gene polymorphism with different metabolic traits, particularly the effects of this polymorphism on HDL-C plasma levels and T2D risk.Methods Mediation analysis was used to assess the direct and indirect effects of the -514C>T LIPC gene variant on HDL-C levels, T2D risk, and body mass index (BMI), in 2105 Mexican mestizo participants. We also assessed the functional effect of the -514C>T LIPC variant on the promoter activity of a reporter gene in the HepG2 cell line.ResultsDirect effects show that the -514C>T LIPC polymorphism is significantly associated with increased HDL-C plasma levels (β = 0.03; p < 0.001). The -514C>T variant resulted in an indirect protective effect on T2D risk through increasing HDL-C levels (β = − 0.03; p < 0.001). Marginal direct association between -514C>T and T2D was found (β = 0.08; p = 0.06). Variables directly influencing T2D status were European ethnicity (β = − 7.20; p < 0.001), age (β = 0.04; p < 0.001), gender (β = − 0.15; p = 0.017) and HDL-C (β = − 1.07; p < 0.001). In addition, we found that the -514C>T variant decreases the activity of LIPC promoter by 90% (p < 0.001).Conclusions The -514C>T polymorphism was not directly associated with T2D risk. HDL-C acts as a mediator between -514C>T LIPC gene variant and T2D risk in the Mexican population.
... The global number of patients diagnosed with DT2 has increased from 30 million in 1985 to 392 million in 2015 [1]. Obesity and lack of exercise significantly enhance the risk of developing DT2, which shows a higher incidence in industrial compared to underdeveloped countries [2]. DT2 is associated with increased incidences of secondary diseases, such as arteriosclerosis leading to strokes, ischemic heart disease and lower limb amputations, reduction of glomerular filtration and kidney failure, and retinopathy leading to blindness [1,3]. ...
Article
Full-text available
Background The effect of the daily consumption of Morinda citrifolia (Noni) fruit juice on the physiological status of patients with diabetes type 2 (DT2) was tested over a period of two months. Methods Morinda citrifolia (Noni) fruit juice (NFJ), 2 ml per kg bw per day, was consumed by twenty patients with DT2 after they underwent a standard treatment regimen including carbohydrate reduced diet and treatment with an antidiabetic drug and/or insulin. NFJ consumption started only after no further improvement was achieved. The intake of NFJ was terminated after eight weeks. The fasting blood sugar level was monitored every morning during the entire treatment period. Blood samples were taken before, at, and four and eight weeks after the start of NFJ intake. The analysis of the blood samples included the concentration of blood glucose, HbA1c, C-peptide, hs-CRP, triglycerides, total cholesterol, LDL, and HDL. Results The consumption of NFJ by 20 patients with DT2 resulted in a significant mean decrease of the morning blood sugar level monitored over a period of eight weeks. While NFJ reduced the blood glucose level in several but not all hyperglycemic patients, it did not cause hypoglycemia in normoglycemic patients. NFJ consumption also reduced the mean HbA1c value significantly (p= 0.033). Significant decreases (p= 0.01) were also achieved for high sensitive CRP values in patients starting with high levels (>2 mg/L), whereas no change was observed in patients with normal values (< 2 mg/L). The level of C-peptide showed a significant mean increase after four weeks of NFJ consumption in those patients who started with low levels (<3 μg/l, p=0.004, N=11) but not in patients with higher levels (> 3 μg/L). Conclusion The daily consumption of NFJ has the potential to regulate elevated blood sugar levels and some other pathological parameters in patients with DT2. NFJ therefore serves as a suitable additive to the diet of diabetic patients.
... Not only does diabetes occur early in some ethnic groups [2,3], but there is also a greater predisposition to develop diabetes-related complications [4]. This disproportionate predisposition of certain ethnic groups to T2DM and its complications is commonly attributed to the complex interaction of genetic and environmental factors [5,6]. Several studies have compared the prevalence and severity of diabetes complications between South Asians and White Europeans [7][8][9][10][11][12]. ...
Article
Full-text available
Aims: To estimate the risk of developing long-term major cardiovascular and renal complications in relation to levels of body mass index (BMI) in a population of White European (WE), African-Caribbean (AC), and South Asian (SA) patients with type 2 diabetes mellitus (T2DM). Materials and methods: Patients with new diagnosis of T2DM, aged ≥ 18 years from January 2000 (n = 69,436) and their age-sex-ethnicity matched non-diabetic controls (n = 272,190) were identified from UK primary care database. Incidence rates ratios (IRRs) for non-fatal major cardiovascular events (MACE) and chronic kidney disease (CKD) in patients with T2DM compared to controls were estimated using multivariate Mantel-Cox model. Results: Among normal weight patients with T2DM, WEs had significantly higher prevalence of cardiovascular multi-morbidity (95% CI 9.5, 11.3), compared to SAs (95% CI 4.8, 9.5). AC and SA overweight and obese patients had similar prevalence, while obese WEs had significantly higher prevalence. During a median 7 years of follow-up, risk of MACE was significantly higher for overweight (95% CI of IRR 1.50, 2.46) and obese (95% CI of IRR 1.49, 2.43) SAs compared to their WE counterparts. However, similar risk levels were observed for normal weight WEs and SAs, respectively. Risk of CKD was higher and uniform for BMI ≥ 25 kg/m2 amongst WEs and ACs, whereas only overweight patients had significantly higher risk of CKD amongst SA [IRR 2.08 (95% CI 1.49, 2.93)]. Conclusion: Risk of MACE/CKD varies over levels of BMI within each ethnic group, with overweight SAs having a disproportionate risk of CKD.
... While there are no nationwide statistics for diabetes, in a study of residents over 60 years of age in Sonacotra-Adoma hostels in the Rhône region, the incidence of diabetes was at 15.5%, against 8% in the rest of the population over 60 (Hadjiat and Fevotte 2008). The role of ethnicity in the prevalence of type-2 diabetes is important and has been widely reported in the epidemiological literature (Agyemang et al. 2011;Carulli et al. 2005). Dr. Ismail confirmed that diabetes is a feature, especially for the older North Africans whom he sees. ...
Chapter
Full-text available
This chapter focuses on health-related factors as a rationale for preferring back-and-forth migration over return at retirement. For some respondents being in good health was a prerequisite for coming to France in the first place, given the rigorous recruitment practices which prioritised physical strength and conditioning. Later in life, health again orders migration, but this time it is the fact of poor health which dictates some people’s trips to France, in order to receive healthcare. Hostel residents do not differ markedly from the rest of the elderly population in France as regards health conditions. What does distinguish them however is their earlier onset of health problems. As a consequence many hostel residents have, over the years, developed strong relationships of trust in French medical services. Maintaining inclusion in the French healthcare system is therefore an important priority for older hostel residents, and one which timetables their trips to France. Just as was found in Chap. 3, the men’s ‘non-standard’ biographies have a bearing on their interactions with healthcare providers. As discussed in Sect. 4.3, non-standard biographical features include premature ageing due to difficult working conditions and work accidents; language barriers in the patient-carer relationship; and lack of family entourage to provide informal care, meaning that an extra duty of care falls upon formal providers.
... 10,11 Some literature says that etiology about relationship between depression and diabetes is unknown but it appears too complex and many factors seem to play together like biologic, genetic, life style and psychological factors are the major contributors for the existing relationship. [12][13][14] The purpose of this study was to explore the burden of depression in outpatients with diabetes mellitus and various factors related to it. As management of depression can assist in alleviating patient suffering and contribute to improve clinical outcome while reducing the cost of patient management and associated resource utilization especially in developing countries. ...
Article
Full-text available
It was a descriptive cross-sectional study conducted to determine the frequency of depression and association with factors in type 2 diabetics in diabetic clinic of Fauji Foundation Hospital Rawalpindi from 1st January - 30th June 2014. In all 110 diabetic patients were selected using convenient Sampling. Data was collected by using a pretested structured proforma. Beck's Depression Inventory (BDI) scale was used to screen depression. There were 20 males (18.2%) and 90 females (81.8%) in this study. Females had more mood disturbances and depression as compared to males, however difference was not statistically significant (p<0.769). 28.2% individuals had mild mood disturbances, while borderline clinical depression was present in 23.6% of study group, 20.9% were having moderate depression and 9.1% were having severe depression, rest 1.2% had extreme depression. Overall 55.5% respondents had depression in this study. Obesity was present in 60% of diabetics, 62.7% were hypertensives and 26.4% had ischaemic heart disease. Depression was statistically significantly associated with hypertension (p< 0.002).
... Rates of diabetes in 1985 were estimated at 30 million, increasing to 135 million in 1995 and 217 million in 2005 [39,40]. This increase is believed to be primarily due to the global population aging, a decrease in exercise, and increasing rates of obesity. ...
Article
Full-text available
Changes in gene activity and content PGC-1a, probably due to its polymorphisms far-reaching effects on metabolic processes in patients with type 2 diabetes. This study aimed to determine the PGC-1a gene polymorphisms and T2D Thr394Thr meta-analysis was performed.
... Al respecto se debe indicar que no se han reconocido los genes principales para este padecimiento, pero se cuenta con evidencia científica que apoya fuertemente esta propensión genética (Carulli, et al, 2005;González-Sarmiento, 2010). La relevancia de los factores genéticos, se contemplo seriamente a partir de las evidencias surgidas de los estudios en gemelos, al revelar que hay una mayor incidencia de aparición de la diabetes mellitus en gemelos homocigóticos, así como de las indagaciones realizadas en los indios Pima y de los factores heredados en la resistencia a la insulina en poblaciones caucásicas (Newman, et al, 1987;Warram, et al, 1990); estos factores genéticos se ven exacerbados por los estilos de vida de las personas. ...
Chapter
Full-text available
En los últimos años la diabetes mellitus y la obesidad se han constituido en una problemática bastante relevante en salud pública, especialmente cuando éstas han alcanzado dimensiones epidémicas mundialmente como lo afirma la Organización Mundial de Salud (2012a; 2012b). En este sentido, la diabetes mellitus, en el mundo existen más de 347 millones de personas con este padecimiento. En el año 2004, se calculó que fallecieron 3.4 millones de personas por esta causa, asimismo más del 80% de las defunciones por diabetes se registró en naciones de ingresos bajos y medios, donde la edad de esas muertes correspondió a personas de menos de 70 años, y un 55% de las mismas correspondía al género femenino. Mientras que desde el año 1980, la obesidad se ha acrecentado en todo el mundo
... Rates of diabetes in 1985 were estimated at 30 million, increasing to 135 million in 1995 and 217 million in 2005 [39,40]. This increase is believed to be primarily due to the global population aging, a decrease in exercise, and increasing rates of obesity. ...
Article
Full-text available
Changes in gene activity and content PGC-1a, probably due to its polymorphisms far-reaching effects on metabolic processes in patients with type 2 diabetes. This study aimed to determine the PGC-1a gene polymorphisms and T2D Thr394Thr meta-analysis was performed.
... The urbanization process and ''western lifestyle'' benefit the development of metabolic disturbances such as diabetes and obesity, whose prevalence stably rises in developed societies in past decades. As insulin signaling is critical in controlling energy balance, genes regulating insulin production and function could be subjected to the selection driven by dietary and other ''western lifestyle''-specific environmental factors [47]. ...
Article
Diabetes mellitus arises from defects in insulin secretion, or action, or both. In pancreatic islets, insulin production is tightly regulated with Zn2+, whose transport into β-cells is mediated by Zn2+-transporter-8 (ZnT-8), a product of the SLC30A8 gene. Therefore, altered activity of ZnT-8 is expected to be associated with impaired glucoseinduced insulin response and promote progression from glucose intolerance to diabetes. Recent findings do emerged a role of SLC30A8 in diabetes. Genome-wide association scans for type 2 diabetes (T2D) susceptibility loci revealed and then replicated a highly significant association between the R325W variant of SLC30A8 (marker rs13266634) and T2D in Caucasians. A role of ZnT-8 as a new major self-antigenic determinant in type 1 diabetes (T1D) was found. Marker rs13266634 was also shown to modulate anti-ZnT-8 self-antibody specificity in islet autoimmunity. Hence, these findings suggest for a dual role of SLC30A8 in diabetes, which is consisted in conferring genetic susceptibility to T2D and being a major islet self-antigen in T1D as well. Here we characterize an emerging role of ZnT-8 in diabetes and discuss potential mechanisms of its involvement in the etiology of both forms of diabetes.
... Subjects originating from South Asia, China, and Africa develop T2DM at a higher rate, at an earlier age, and at lower ranges of BMI than their European counterparts [24]. A clustering of different genetic defects or polymorphisms, the ''thrifty gene'' hypothesis, a genetic susceptibility to insulin resistance and higher central adiposity at similar BMI levels, or epigenetic changes occurring during gestation, might play a role in influencing metabolic phenotypes of Asian populations [25][26][27]. For these reasons, the WHO consultation group recommends a lower cutoff of BMI for Asians with respect to native European populations [28]. ...
Article
Full-text available
The aim of this study was to review current evidence on interventional studies aimed at the prevention of type 2 diabetes in Asian population with lifestyle interventions. Prevalence of type 2 diabetes sharply increased in most Asian countries during the last decades. This issue has now also relevant implication for Europe where different surveys are also consistently revealing an higher prevalence of type 2 diabetes and other and major CVD risk factors among subjects originating from Asian Countries than in the native population. Nutrition and lifestyle transition seem to play a role in disclosing the predisposition for the development of type 2 diabetes and great interest is now shown toward the possibility to intervene with lifestyle intervention on at risk populations. A meta-analysis of Randomized Controlled Trials showed that lifestyle interventions are highly effective also in the Asian population. All studies were, however, conducted with an individual approach based on the identification of high-risk individuals. When ethnic minority groups have to be addressed, an approach directed to the community rather than to the individual might, however, be more effective. This review reinforces the importance for policy-makers to consider the involvement of the whole community of minority immigrant groups with lifestyle intervention programs.
... Some T2D-associated polymorphisms are more common in SA than in Europeans [36]. Despite identification of some promising genetic variants, however, the genetic basis of T2D remains unclear [37]. ...
Article
Full-text available
Many ethnic minorities in Europe have a higher type 2 diabetes (T2D) prevalence than their host European populations. The risk size differs between ethnic groups, but the extent of the differences in the various ethnic minority groups has not yet been systematically quantified. We conducted a meta-analysis of published data on T2D in various ethnic minority populations resident in Europe compared to their host European populations. We systematically searched MEDLINE (using PUBMED) and EMBASE for papers on T2D prevalence in ethnic minorities in Europe published between 1994 and 2014. The ethnic minority groups were classified into five population groups by geographical origin: South Asian (SA), Sub-Saharan African (SSA), Middle Eastern and North African (MENA), South and Central American (SCA), and Western Pacific (WP). Pooled odds ratios with corresponding 95 % confidence interval (CI) were calculated using Review Manager 5.3. Twenty articles were included in the analysis. Compared with the host populations, SA origin populations had the highest odds for T2D (3.7, 95 % CI 2.7-5.1), followed by MENA (2.7, 95 % CI 1.8-3.9), SSA (2.6, 95 % CI 2.0-3.5), WP (2.3, 95 % CI 1.2-4.1), and lastly SCA (1.3, 95 % CI 1.1-1.6). Odds ratios were in all ethnic minority populations higher for women than for men except for SCA. Among SA subgroups, compared with Europeans, Bangladeshi had the highest odds ratio of 6.2 (95 % CI 3.9-9.8), followed by Pakistani (5.4, 95 % CI 3.2-9.3) and Indians (4.1, 95 % CI 3.0-5.7). The risk of T2D among ethnic minority groups living in Europe compared to Europeans varies by geographical origin of the group: three to five times higher among SA, two to four times higher among MENA, and two to three times higher among SSA origin. Future research and policy initiatives on T2D among ethnic minority groups should take the interethnic differences into account.
... However, there are reasons to believe that this so-called defect may not simply represent a random genetic mutation but may be the result of evolutionary pressures for adaptation to variable food intake and survival, which selected genetic types more susceptible to developing InsR. [8][9][10][11][12][13][14] Thus, the downregulation of epimerase may be viewed instead as a genetically programmed metabolic switch meant to downregulate glucose utilization, thus favoring metabolism of fat for fuel. Specifically, epimerase inhibition results in the reduction of DCI produced from MI in various tissues, while intracellular glucose disposal is influenced by DCI derived cellular mediator DCI-IPG. Figure 2 depicts the intracellular roles of DCI-IPG. ...
Article
Full-text available
This article will review the evidence for the abilities of myo-inositol (MI) and D-chiro-inositol (DCI) to improve dysglycemia and related characteristics of metabolic syndrome (MetS), type 2 diabetes (T2D), gestational diabetes, and polycystic ovarian syndrome (PCOS) by acting in critical metabolic pathways of insulin resistance (InsR).
... Hall et al, [4], reported that the prevalence of T2D in some selected western African countries, including Nigeria and Ghana, to be up to 7%, while in South Africa and Uganda prevalence is reported to be more than 10%. Several predisposing factors have been attributed to the increase in the prevalence of T2D including rapid urbanization, poor eating habits, physical inactivity and obesity [5,6]. It has been proposed that high prevalence of T2D complications will impose a huge burden on the healthcare system in SSA if urgent interventions are not taken [7]. ...
Article
Full-text available
Functional Exercise Capacity (FEC) is a valid measure of physical fitness in health and disease. However, there is paucity of studies on FEC in African patients with Type-2 Diabetes (T2D). This study compared FEC between patients with T2D and healthy controls. Thirty five patients with T2D (18 men, 17 women) and 35 (16 men, 19 women) age-sex matched healthy controls participated in this case-control study. Anthropometric and demographic characteristics and cardiovascular parameters were measured following standard procedures. A glucometer was used to determine the Fasting Blood Glucose (FBG) level following at least 8 hours of overnight fasting. FEC was assessed using the Six-Minute Walk Test (6MWT) while Hand Grip Strength (HGS) test was measured with an electronic dynamometer. Data were analyzed using descriptive and inferential statistics. Alpha level was set at p< 0.05. Patients with T2D and controls were similar in age (p > 0.05). There were significant differences in the distance covered during 6MWT between patients and controls (t= 0.329; p =0.03), exercise capacity (t = 0.329; p = 0.03), FBG (t = 7.403; p = 0.001), systolic and diastolic blood pressure (t = 12.56; p = 0.001 and t = 27.23; p = 0.001) respectively. There were significant inverse relationships between 6MWD and Body mass index (r = -0.39; p = 0.02) and FBS(r = -0.51; p = 0.02) in patients with type-2 respectively. No significant association was found between exercise capacity and HGS (p > 0.05). Patients with type-2 diabetes demonstrated lower functional exercise capacity than healthy controls. High body mass index and fasting blood glucose were significantly associated with lower functional exercise capacity.
... Nevertheless, it remains unclear whether aging is generally associated with impaired insulin sensitivity; specific genetic or even acquired abnormalities could be responsible for reduced mitochondrial function not only during aging but also in other metabolic disorders (Stark & Roden 2007). Likewise, sex and ethnicity can variably affect metabolic characteristics including body fat and its distribution, lipid metabolism and insulin action, which further complicates interpretation of clinical metabolic studies (Woods et al. 2003;Carulli et al. 2005). ...
Article
Metabolic diseases, particularly obesity, dyslipidaemia and type 2 diabetes mellitus (T2DM), as well as conditions of increased risk for these diseases such as factors of the (dys)metabolic syndrome have become dramatically more prevalent over the last decade. Both in the indus-trialised world and, even more so, in developing regions and countries – which feature rapidly increasing economies and are adopting the so-called Western lifestyle – these diseases, particularly overweightness and obesity, are a growing health problem (Kopelman 2000). It is assumed that T2DM could be the largest epidemic in human history (Zimmet 2005) as more than 190 million people worldwide are diabetic and more than 300 million suffer from impaired glucose tolerance, the immediate pre-diabetic state. Recent calculations suggest that in the year 2025 more than 300 million people will have overt diabetes, mainly T2DM, with excessive growth in developing countries (King et al. 1998). Diabetes mellitus is already the leading cause of blindness among working-age adults, of end-stage renal disease and of non-traumatic loss of limb (Ullbrecht et al. 2004; Williamson et al. 2004). The global mortality attributable to diabetes in the year 2000 was estimated to be 2.9 million deaths, which was 5.2 % of all death. Thus diabetes is the fifth leading cause of death globally. About 2–3 % of the population in low-economy countries and up to 8 % in the United States and Canada die because of diabetes (Roglic et al. 2005). The costs caused by diabetes are enormous.Currently diabetes care accounts for 2–7 % of the total national health care budgets in Western countries, amounting to $132 billion in the United States in 2002 (ADA 2003). These data underline the importance of understanding the cellular mechanisms of the causes and complications of type 2 diabetes mellitus in order to offer better targeted and more effective treatment or even prevention of the disease. Over the last decades, we have learned a lot from in vitro experiments in isolated tissues and cell cultures, but especially from in vivo studies in mouse models of modified insulin secretion or action (Nandi et al. 2004). Nevertheless, the phenotypes resulting from the various tissue-specific knockout or overexpression mouse models of diabetes or metabolic diseases do not generally resemble the phenotypes of corresponding diseases in humans. In addition to species differences and technical limitations of metabolic studies in small animals, this observation can likely be explained by gene-environment interactions influencing the human phenotypes of metabolic disorders. This makes detailed studies in humans under in vivo conditions mandatory. Starting from simple endocrine and metabolic stimulation or suppression tests such as the insulin and glucagon administration or glucose tolerance tests, a series of more sophisticated tests has been developed over the last three decades. This development is mirrored by the near-exponential rise in original papers and reviews on the topics 'diabetes' and 'metabolic diseases' in peer-reviewed journals since 1970 (Figure 1.1). Among those publications, some key methodological papers speeded up the development of clinical metabolic research. These key papers include the description and validation of standardised insulin sensitivity and secretion tests such as the glucose clamp (Tobin et al. 1979) and minimal modeling of glucose and insulin concentrations during the intravenous glucose tolerance test (Bergman et al. 1981). Later on, tissue-specific metabolism became accessible by applying in vivo mult-inuclear magnetic resonance spectroscopy (MRS) (Shulman et al. 1990; Krssak et al. 1999) or positron emission tomography (PET) (Nuutila et al. 1993). Novel applications of stable isotopes as labels of molecules, e.g. 2 H 2 O, later allowed quantification of complex metabolic fluxes such as rates of gluconeogenesis from different sources and glycogenolysis from one single blood sample (Landau et al. 1995) (NOTE: I would like to express my grief for my long-term mentor and friend, Professor Landau, an outstanding researcher and scientist in the field of metabolism, who passed away during the printing of this book). Combining the different techniques, e.g. MRS and 2 H 2 O (Kunert et al. 2003), further stimulated research on human metabolism and detailed metabolic phenotyping of various populations is now widely used.
... T2D risk allele frequencies demonstrated clear gradient matching paths of early human migration, suggesting potential differences in evolutionary adaptation to food availability, dietary patterns, or agricultural practices. This is consistent with "thrifty genotype" hypothesis [139,140], which proposes that susceptibility to obesity and T2D in some populations reflects historical positive selection for genotypes promoting efficiency of metabolism, and energy and fat storage, thus providing an advantage in times of nutrient shortage [141]. This might explain the extraordinarily high prevalence of diabetes now seen among certain populations [34,142,143], potentially reflecting historical feast and famine cycles [62], increasing the frequency of thrifty genotypes and genetic predisposition to obesity and diabetes. ...
Article
Full-text available
The prevalence of Type 2 diabetes is rising rapidly in both developed and developing countries. Asia is developing as the epicentre of the escalating pandemic, reflecting rapid transitions in demography, migration, diet, and lifestyle patterns. The effective management of Type 2 diabetes in Asia may be complicated by differences in prevalence, risk factor profiles, genetic risk allele frequencies, and gene-environment interactions between different Asian countries, and between Asian and other continental populations. To reduce the worldwide burden of T2D, it will be important to understand the architecture of T2D susceptibility both within and between populations. This review will provide an overview of known genetic and nongenetic risk factors for T2D, placing the results from Asian studies in the context of broader global research. Given recent evidence from large-scale genetic studies of T2D, we place special emphasis on emerging knowledge about the genetic architecture of T2D and the potential contribution of genetic effects to population differences in risk.
... Although Hispanic ethnicity itself may not be an independent contributor to obesity or diabetes, 33,34 Hispanic populations are often immersed in a low-SES context, 35 which increases risk for obesity and related metabolic health outcomes. 24,[36][37][38] In addition, acculturation may also play a role in metabolic risk. ...
Article
Evidence of associations between the built environment and obesity risk has been steadily building, yet few studies have focused on the relationship between the built environment and aspects of metabolism related to obesity's most tightly linked comorbidity, type 2 diabetes. To examine the relationship between aspects of the neighborhood built environment and insulin resistance using accurate laboratory measures to account for fat distribution and adiposity. Data on 453 Hispanic youth (aged 8-18 years) from 2001 to 2011 were paired with neighborhood built environment and 2000 Census data. Analyses were conducted in 2011. Walking-distance buffers were built around participants' residential locations. Body composition and fat distribution were assessed using dual x-ray absorptiometry and waist circumference. Variables for park space, food access, walkability, and neighborhood sociocultural aspects were entered into a multivariate regression model predicting insulin resistance as determined by the homeostasis model assessment. Independent of obesity measures, greater fast-food restaurant density was associated with higher insulin resistance. Increased park space and neighborhood linguistic isolation were associated with lower insulin resistance among boys. Among girls, park space was associated with lower insulin resistance, but greater neighborhood linguistic isolation was associated with higher insulin resistance. A significant interaction between waist circumference and neighborhood linguistic isolation indicated that the negative association between neighborhood linguistic isolation and insulin resistance diminished with increased waist circumference. Reducing access to fast food and increasing public park space may be valuable to addressing insulin resistance and type 2 diabetes, but effects may vary by gender.
... [39] A large number of studies have revealed that some ethnic groups have an elevated risk of T2DM compared to other ethnicities. [19,40,41] In all these studies, which have not adjusted for some confounding variables (e.g., BMI), obesity might be a modifying factor for increased levels of the disease. However, some other studies have adjusted their results for BMI and still found variations by ethnicity. ...
Article
Full-text available
Obesity is a growing epidemic affecting all ages in both industrialized and developing countries. The most common suggested cause of this epidemic is the increasing levels of urbanization and lifestyle changes toward sedentary life and adopting western dietary patterns. The association between obesity and type 2 diabetes mellitus (T2DM) has been reproducibly observed in cross-sectional and prospective studies across various populations, even when using different fatness measures and diagnostic criteria for T2DM. However, there are some modifying factors that make such an association complex and multifactorial. These modifying factors include the duration of obesity, body fat distribution, physical activity, diet, and genetics/ethnicity. This review aims to summarize the evidence of this association and its potential modifying factors.
... Diabetes is a metabolic disorder of multiple etiologies characterized by chronic hyperglycemia with disturbance of carbohydrate, fat, and protein metabolism resulting from defects in insulin secretion, insulin action, or both. The disease is associated with microvascular, macrovascular, and metabolic complications.When the renal threshold for glucose reabsorption is exceeded, glucose spills over into the urine (glycosuria) and causes an osmotic diuresis (polyuria), which, in turn, results in dehydration, thirst and increased drinking (polydypsia) [1] . Insulin deficiency causes wasting through increased breakdown and reduced synthesis of proteins. ...
Data
Full-text available
Capra hircus(goat) is one of the domesticated animals used for milk, meat and fibre. Milk is one of the essential products in the human diet, rich in nutritive components. Goat's milk has vitamins, minerals, trace elements, electrolytes, enzymes, proteins, and fatty acids that are easily assimilated by the body. The fatty acids present in Caprus hircus milk was revealed to have more beneficial properties to health and used as a traditional medicine for.The present study is aimed to investigate the antidiabetic and anti-inflammatory effect of isopropanol extract of milk of Caprus hircus. The antidiabetic activity was evaluated by measuring blood glucose level in rats treated with isopropanol extract of caprine milk and comparing to normal and streptozotocin (STZ) induced rats. The isopropanol extract of Caprus hircus produced significant changes in the streptazotocin induced diabetic rats by reducing the glucose levels considerably. isopropanol extract treated group(200 mg/kg b.w) showed the mean value of 157.6±3.656 and 117.6±3.839 respectively as compared with a mean value 317.2±4.244 of diabetic control group. The anti-inflammatory activity was assessed by carrageenam induced paw edema model in rats.There was significant reduction (p< 0.01) in paw diameter in the group that received high dose (200 mg/kg b.w) of isopropanol extract of Caprus hircus milk from Mean±SEM of 0.184±0.004 to 0.052±0.003 (71.73%) as compared with the disease control group. The present study concludes that caprine milk extract confirmed promising anti diabetic activity in streptozotocin induced diabetic Wister rats and significant anti-inflammatory properties against carrageenan induced paw edema.
Article
Obesity is a major global concern and is generally attributed to a combination of genetic and environmental factors. Several hypotheses have been proposed to explain the evolutionary origins of obesity epidemic, including thrifty and drifty genotypes, and changes in thermogenesis. Here, we put forward the hypothesis of metaflammation, which proposes that due to intense selection pressures exerted by environmental pathogens, specific genes that help develop a robust defense mechanism against infectious diseases have had evolutionary advantages and that this may contribute to obesity in modern times due to connections between the immune and energy storage systems. Indeed, incorporating the genetic variations of gut microbiota into the complex genetic framework of obesity makes it more polygenic than previously believed. Thus, uncovering the evolutionary origins of obesity requires a multifaceted approach that considers the complexity of human history, the unique genetic makeup of different populations, and the influence of gut microbiome on host genetics.
Book
Full-text available
Resumen La Giardia lamblia es una de las principales causas de diarrea, pudiendo generar la muerte en población especial. Tradicionalmente ha sido tratada con metronidazol; no obstante, se han descrito cepas resistentes. El presente artículo es fruto de un estudio descriptivo realizado entre enero y noviembre de 2017 con muestras fecales obtenidas por expulsión en pacientes con diarrea en los cuales se encontró la presencia de quistes a través de tinción parasitológica con Lugol. El medio de cultivo empleado fue TYI-S 33 suplementado con suero fetal y expuesto al metronidazol a distintas concentraciones. Se plantea un nuevo método al evaluar las alteraciones morfológicas y ultraestructurales del parásito y se reporta la presencia de sepas de Blastocystis sp. resistentes al metronidazol. Palabras clave: Blastocystis Sp, Giardia lamblia, metronidazol. Introducción: El microorganismo Giardia lamblia es un protozoo de carácter intestinal causante de diarrea, teniendo la propiedad de interactuar durante su ciclo de vida con otros microorganismos. En Hispano América representa una fuente de pérdidas. Adicionalmente, en pacientes con características especiales puede generar muerte como consecuencia de desnutrición y deshidratación. El protozoo posee gran inestabilidad, fruto de la modificación de su estructura fenotípica y genotípica, estimulado por la exposición del parásito a medicamentos como el metronidazol [1]; el cual es consumido de forma irresponsable por la población quindiana. El presente proyecto tiene como objetivo evaluar la susceptibilidad de los quistes de G. lamblia ante el medicamento a partir de un cultivo en triplicado y sus interacciones con el mismo y el parásito Blastocystis Sp. Planteamiento del problema: El protozoo Giardia lamblia es una de las principales causas de diarrea con mayor incidencia en África, Asia y América Latina [1]. La giardiasis sintomática representa un problema de salud pública, causando diarrea aguda, deshidratación y desnutrición, con mayor morbimortalidad en lactantes, adultos mayores e inmunodeficientes [2-3]. Se estima que el 100% de los niños en países en vía de desarrollo han adquirido durante sus primeros años [4]. Las epidemias a menudo están asociadas a suministros de agua contaminadas por heces o hacinamiento [1], [5]. El protozoo genera daño por obstrucción mecánica y la interferencia en la absorción de las grasas y vitaminas liposolubles [6-8]; causa irritación directa de la mucosa intestinal y el sobrecrecimiento de bacterias [9-11].
Article
Background: The prevalence of obesity among U.S. adults has risen steadily over recent decades. Consequently, interest in identification of those at greatest metabolic risk necessitates the periodic assessment of underlying population characteristics. Thus, the aim of this study is to assess the efficacy of using insulin resistance (IR) as a predictor of metabolic syndrome (MetS). Methods: We performed a serial, cross-sectional analysis of nationally representative data from the National Health and Nutrition Examination Survey (NHANES). Data included nonpregnant adults who participated in NHANES between 2011 and 2018. IR was estimated using the homeostasis model assessment (HOMA). Optimal HOMA-IR cut points for MetS were identified using receiver operating characteristic curve analysis. Results: Data from 8897 participants representing 222 million individuals were analyzed. The estimated prevalence of MetS was 31.7% (n = 2958; 95% confidence interval 30.1-33.3). The optimal HOMA-IR to discriminate between individuals with and without MetS in the general population was 2.83 (sensitivity = 73.8%; specificity = 73.8%; area under the curve = 0.82). Conclusion: The HOMA-IR is a sensitive and specific method of screening for individuals with MetS. Prospective evaluation of this approach's efficacy in identifying those at risk for progression to MetS is warranted.
Article
Full-text available
Insulin is the main metabolic regulator of fuel molecules in the diet, such as carbohydrates, lipids, and proteins. It does so by facilitating glucose influx from the circulation into the liver, adipose tissue, and skeletal myocytes. The outcome of which is subjected to glycogenesis in skeletal muscle and lipogenesis in adipose tissue, as well as in the liver. Therefore, insulin has an anabolic action while, on the contrary, hypoinsulinemia promotes the reverse process. Protein breakdown in myocytes is also encountered during the late stages of diabetes mellitus. The balance of the blood glucose level in physiological conditions is maintained by virtue of the interactive functions of insulin and glucagon. In insulin resistance (IR), the balance is disturbed because glucose transporters (GLUTs) of cell membranes fail to respond to this peptide hormone, meaning that glucose molecules cannot be internalized into the cells, the consequence of which is hyperglycemia. To develop the full state of diabetes mellitus, IR should be associated with the impairment of insulin release from beta-cells of the pancreas. Periodic screening of individuals of high risk, such as those with obesity, hypercholesterolemia, and pregnant nulliparous women in antenatal control, is vital, as these are important checkpoints to detect cases of insulin resistance. This is pivotal as IR can be reversed, provided it is detected in its early stages, through healthy dietary habits, regular exercise, and the use of hypoglycemic agents. In this review, we discuss the pathophysiology, etiology, diagnosis, preventive methods, and management of IR in brief.
Article
Accurate measurement of the effects of disease status on healthcare costs is important in the pragmatic evaluation of interventions but is complicated by endogeneity bias. Mendelian Randomization, the use of random perturbations in germline genetic variation as instrumental variables, can avoid these limitations. We used a novel Mendelian Randomization analysis to model the causal impact on inpatient hospital costs of liability to six prevalent diseases and health conditions: asthma, eczema, migraine, coronary heart disease, Type 2 diabetes, and depression. We identified genetic variants from replicated genome-wide associations studies and estimated their association with inpatient hospital costs on over 300,000 individuals. There was concordance of findings across varieties of sensitivity analyses, including stratification by sex and methods robust to violations of the exclusion restriction. Results overall were imprecise and we could not rule out large effects of liability to disease on healthcare costs. In particular, genetic liability to coronary heart disease had substantial impacts on costs.
Article
Full-text available
La diabetes mellitus, es un grupo de trastornos metabólicos caracterizados por altos niveles de carbohidratos séricos. Datos del 2017, estiman que 425 millones de personas padecen diabetes en todo el mundo, representando alrededor del 90% de los casos la diabetes tipo 2, 8.8% de la población adulta, con tasas iguales tanto en mujeres como en hombres. La enfermedad duplica el riesgo de muerte prematura para una persona, registrándose en 2017 5 millones de muertes. Actualmente representa el mayor gasto en la atención médica personal que cualquier otra afección. Numerosos factores, además de las complicaciones médicas directamente relacionadas, contribuyen al impacto de la diabetes en la calidad de vida y la economía, asociándose una alta prevalencia de morbilidad que impacta negativamente en el empleo, el absentismo y la productividad laboral, existiendo gran pérdida de recursos relacionados con la productividad para los sistemas de salud y los gobiernos. Esta revisión buscará proporcionar una visión íntegra de la atención médica adecuada para pacientes con diabetes. Así como analizar los datos obtenidos en el estudio Steno-2 y su influencia como intervención multifactorial. El enfoque médico basado en evidencia es consistente con las pautas de la Asociación Americana de Diabetes (ADA), que se publican anualmente.
Article
Background & Aims Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related death worldwide. Effects of second-line oral antidiabetic medications on incident HCC risk in individuals with type 2 diabetes mellitus remain unclear. This study evaluated associations between sulfonylureas, thiazolidinediones, meglitinides and alpha-glucosidase inhibitors, and incident HCC risk. Methods We systematically reviewed all studies on PubMed, Embase and Web of Science databases. Studies were included if they documented: (1) exposure to oral antidiabetic medication classes; (2) HCC incidence; (3) relative risks/odds ratios (OR) for HCC incidence. Eight eligible observational studies were identified. We performed random-effects meta-analyses to calculate pooled adjusted ORs (aORs) and 95% confidence intervals (CI). Results Thiazolidinedione use (7 studies, 280,567 participants, 19,242 HCC cases) was associated with reduced HCC risk (aOR = 0.92, 95% CI = 0.86–0.97, I² = 43%), including among Asian subjects (aOR = 0.90, 95% CI = 0.83–0.97), but not Western subjects (aOR = 0.95, 95% CI = 0.87–1.04). Alpha-glucosidase inhibitor use (3 studies, 56,791 participants, 11,069 HCC cases) was associated with increased HCC incidence (aOR = 1.08; 95% CI = 1.02–1.14, I² = 21%). Sulfonylurea use (8 studies, 281,180 participants, 19,466 HCC cases) was associated with increased HCC risk in studies including patients with established liver disease (aOR = 1.06, 95% CI = 1.02–1.11, I² = 75%). Meglitinide use (4 studies, 58,237 participants, 11,310 HCC cases) was not associated with HCC incidence (aOR = 1.19; 95% CI = 0.89–1.60, I² = 72%). Conclusions Thiazolidinedione use was associated with reduced HCC incidence in Asian individuals with diabetes. Alpha-glucosidase inhibitor or sulfonylurea use was associated with modestly increased HCC risk; future research should determine whether those agents should be avoided in patients with chronic liver disease.
Chapter
Nutrition and lifestyle transition seem to play a role in disclosing the predisposition for the development of type 2 diabetes in different populations with special regard to Asian and African countries. Great interest is now shown toward the possibility to intervene with lifestyle intervention on at-risk populations. The main question is: Who is to be considered at high risk? Subjects originating from South Asia, China, and Africa develop T2DM at a higher rate, at an earlier age, and at lower ranges of BMI than their European counterparts. Risk assessment of future type 2 diabetes is usually based on blood glucose levels, and prevention strategies are focused on high-risk subjects. However, when considering ethnic minorities which are known to have high prevalence of type 2 diabetes, limitations in the high-risk approach may be represented by low compliance at screening and follow-up and by the problematic contact with undocumented migrants. A new perspective for an approach specifically involving the whole communities can be considered. Health promotion, usually based on assumptions of a self-investment, should leave the approach to individuals when the aim is to involve societies with a collectivist history.
Chapter
Changes occurring in Asian countries have now implications also for Europe where a high prevalence of T2DM was observed among subjects originating from India, Pakistan, Bangladesh, Sri Lanka, Nepal, Bhutan, and the Maldives. The Chinese community in Italy and Spain, mostly represented by first-generation migrants, is numerically consistent. The prevalence of prediabetes and type 2 diabetes mellitus in this ethnic group was recently found as high as in China. The potential consequences of ineffective prevention and management of diabetes and other cardiovascular risk factors in Chinese communities living in Europe on the future burden of cardiovascular diseases might be remarkable. However, cultural factors may limit the possibility to reach minority groups with interventions addressed to the native population so that implementation of specific intervention strategies is specifically needed.
Chapter
Type 2 diabetes (T2D) is well established as an important risk factor for cardiovascular disease. The global burden of T2D is increasing rapidly, in particular, in low- and middle-income countries. Ethnic minority groups in Europe are up to four times more likely to be affected by T2D compared to Europeans and are also disproportionally affected compared to their compatriots in their countries of origin. The reasons for this disproportionate burden are unclear but are believed to be an interplay between genetic and environmental factors. The underlying pathophysiology of T2D seems to differ between ethnic groups, with most ethnic minority groups having higher insulin resistance compared to Europeans even in a normoglycaemic state. Furthermore, while obesity is an important determinant of T2D across ethnic groups, higher levels of obesity in ethnic minority groups only explain part of their higher T2D burden. Health-related behaviours such as diet and physical activity can contribute to T2D among ethnic minority groups either mediated via obesity or directly. Few genetic factors have been identified that may predispose ethnic minority groups to T2D, but more diversity in genetics research is needed to get a better picture of genetic predispositions for T2D among ethnic minority groups. In the meantime, adaptation of population-based lifestyle interventions to ethnic minority groups, and evaluation of these interventions, is crucial to curb the rise of T2D among ethnic minority groups. Early detection is essential for prevention of micro- and macrovascular complications contributing to cardiovascular disease.
Article
Full-text available
Aims: Physical function is a determinant of survival in chronic diseases, however, little is known about functional capacity (FC) and self-reported health status of patients with type-2 diabetes (T2D). This study investigated the relationship between FC and health related quality of life (HRQoL) of patients with T2D. Materials and methods: This cross-sectional survey recruited 150 patients with T2D from a Nigerian university teaching hospital using purposive sampling technique. Socio-demographic and physical characteristics were assessed. FC and HRQoL including physical and mental health component summary (PCS and MCS) were assessed using the six minute walk test (6MWT) and Short-Form (SF-12) questionnaire respectively. Maximum oxygen consumption (VO2 max) was estimated, pre and post 6MWT cardiovascular parameters and fasting blood glucose (FBG) were assessed. Data were analyzed using descriptive and inferential statistics. Alpha level was set at p<0.05. Results: There were 83(55.3%) women, means of age and FBG of participants were 64.2±8.7years and 7.4±2.4mmol/L respectively. The means of 6-min walk distance (6-MWD) and estimated VO2 max were 341.55±41.82m and 9.2±0.7mL/kg/min respectively. Significant differences were found between pre and post HR (t=-44.71; p=0.001), SBP (t=-38.38; p=0.001) and DBP (t=-38.58; p=0.001) following 6MWT. The means of PCS and MCS of HRQoL were 48.67±5.51 and 58.39±2.86 respectively. There were significant correlations between FC and each of PCS (r=0.678; p=0.001) and MCS (r=0.211; p=0.009). Conclusion: Patients with T2D demonstrated low functional capacity and reduced HRQoL. Significant relationship exists between FC and physical and mental component summary of HRQoL. Exercise intervention to improve FC and HRQoL were recommended.
Article
Objectives. To better understand how diabetes care and control are being administered by general practitioners/nonspecialists in private practice in nine countries of Latin America, and to identify the most significant patient-and physician-related barriers to care. Methods. A multicenter, cross-sectional, epidemiological survey was conducted in nine countries in Latin America: Argentina, Brazil, Chile, Costa Rica, Ecuador, Guatemala, Mexico, Peru, and Venezuela. General practitioners in private practice were asked to provide care and control data for patients 18 to 75 years of age with type 2 diabetes mellitus (T2DM), including demographics, medical and medication history, laboratory exams, and information on the challenges of patient management. Results. Of the 3 592 patient questionnaires returned by 377 physicians, 60% of the patients had a family history of diabetes, 58% followed a poor diet, 71% were sedentary, and 79% were obese or overweight. Poor glycemic control ( fasting blood glucose = 110 mg/dL) was observed in 78% of patients. The number of patients with HbA1c < 7.0% was 43.2%. Glycemic control decreased significantly with increased duration of T2DM. Comorbid conditions associated with T2DM were observed in 86% of patients; insulin use and comorbid conditions, especially those associated with microvascular complications, increased significantly disease duration. Ensuring compliance with recommended diet and exercise plans was the most-cited patient management challenge. Conclusions. Blood glucose levels are undercontrolled in T2DM patients in the private health care system in Latin America, particularly among those who have had the disease the longest (> 15 years). Considering the differences between private and public health care in Latin America, especially regarding the quality of care and access to medication, further studies are called for in the public setting. Overall, a more efficient and intensive program of T2DM control is required, including effective patient education programs, adjusted to the realities of Latin America.
Article
Objectives: The aim of this paper is to report the safety and effectiveness of initiating or switching to insulin analogue therapy in the Argentinean subpopulation of the A 1chieve study. Materials and methods: Observational, non-interventional study. The Argentinean cohort included 607 patients with type 2 diabetes (T2D), both insulin-naïve and prior insulin users, who initiated treatment with biphasic insulin aspart 30, insulin detemir or insulin aspart ± oral antidiabetic agents. Results: Baseline HbA1c (±SD) was poor: 9.4 ± 2.1%. At 6 months, a reduction in the HbA1c of -1.8 ± 2.1% was observed in the entire cohort, and of -2.3 ± 2.1% and -1.1 ± 1.8% in insulin-naïve patients and prior insulin users, respectively. Overall, the rate of hypoglycaemia increased in insulin-naïve patients, whereas a reduction was observed in those switching from other insulins. An increase in the body weight (±SD) was noted in insulin-naïve patients (0.8 ± 4.3 kg). Conclusions: Poor glycemic control was observed in the Argentinean population of the A1chieve study. The initiation of insulin analogue therapy showed an improvement in HbA1c, in both insulin-naïve patients and previous insulin users, which was a good opportunity for improvements in self-care and metabolic control, regardless of the type of insulin regimen used, with a good tolerability and safety profile. These findings are consistent with those obtained from the entire A1chieve study cohort. Copyright © 2013 por la Sociedad Argentina de Endocrinologí a y Metabolismo.
Article
Full-text available
Background and Aims: The relative role of insulin deficiency and insulin resistance seem to vary in T2D patients depending on race, age, body weight and other factors. The present study was undertaken to measure insulin secretion and insulin sensitivity in middle aged, normal to overweight Bangladeshi T2D subjects who constitute major bulk of diabetic patients in the country. Materials and Methods: Twenty-five newly diagnosed T2D patients, 10 age- and BMI-matched IGT and 10 control subjects were studied. Insulin secretory capacity was evaluated by glucagon stimulated C-peptide value and insulin sensitivity was measured by short insulin tolerance test. Results: T2D patients showed substantially lower insulin secretory capacity compared to Controls and IGT subjects as evidenced by serum C-peptide levels in response to unit glucose both in basal [Fasting- C-peptide/glucose ratio, mean ± SD, nmol/mmol: 0.13 ± 0.03 in Control; 0.09 ± 0.04 in T2D and 0.12 ± 0.05 in IGT, M ± SD; p<0.006 for Control vs T2D and p<0.05 for IGT vs T2D groups] and in glucagon stimulated [GSC-pep-glucose ratio: 0.26 ± 0.09 in Control; 0.23 ± 0.09 in IGT and 0.14 ± 0.07 in T2D, p<0.001 for Control vs T2D and p<0.003 for IGT vs T2D] state. There was no fasting hyperinsulinemia in the diabetic subjects; however their insulin sensitivity was found to be significantly compromised compared to Controls [K ITT in mmol/l/min: 0.097 (0.07-0.27) in Control vs 0.065 (0.02-0.12) in T2D subjects, median (range); p<0.001]. Insulin sensitivity of IGT subjects did not differ significantly from Control subjects. Conclusions: The data suggest that deficient insulin secretory capacity and insulin resistance both are present in the majority of Bangladeshi type 2 diabetic subjects.
Article
There is increasing awareness that ethnic and cultural influences can alter individual responses to medications (Lambert & Minas, 1998). Ethno-psychopharmacology investigates cultural variations and differences that influence the effectiveness of prescription medicines used in the treatment of mental illnesses. Differences in response can be explained by both genetic and psychosocial variations. They range from genetic variants in drug metabolism to cultural practices, which may affect diet, adherence to prescribed patterns of medication use, placebo response, and the simultaneous use of traditional and alternative healing methods (Lin et al., 1991). However, predictions regarding genetic expression based on ethnicity alone need to be exercised with caution. Although connections between ethnicity and drug metabolism were recognized early, for example primaquine induced hemolysis based on G6PD deficiency in some Afro-Americans (Alving et al., 1956), such differences are based more on genetic endowment per se rather than racial or ethnic divisions. The validity of therapy based solely on racial differences has been questioned, for example, in relation to differential drug responses in cardiology for Black and White patients (Schwartz, 2001). All populations irrespective of racial group exhibit substantial intra-population variability (Jorde & Wooding, 2004). Within a single racial population between 93 and 95% of all human genetic variability is captured (Jones & Perlis, 2006). A small amount of genetic variation (~0.02% of all nucleotides) distinguishes populations from each other and no single marker can identify race or ancestry. © C. H. Ng, K.-M. Lin, B. S. Singh and E. Y. K. Chiu 2008 and Cambridge University Press, 2009.
Article
Full-text available
This study focuses on the effects of the organic ligand 4-ethylresorcinol on the crystal structure of human insulin using powder X-ray crystallography. For this purpose, systematic crystallization experiments have been conducted in the presence of the organic ligand and zinc ions within the pH range 4.50–8.20, while observing crystallization behaviour around the isoelectric point of insulin. High-throughput crystal screening was performed using a laboratory X-ray diffraction system. The most representative samples were selected for synchrotron X-ray diffraction measurements, which took place at the European Synchrotron Radiation Facility (ESRF) and the Swiss Light Source (SLS). Four different crystalline polymorphs have been identified. Among these, two new phases with monoclinic symmetry have been found, which are targets for the future development of microcrystalline insulin drugs.
Article
Full-text available
Disease genes cause or contribute genetically to the development of the most complex diseases. Drugs are the major approaches to treat the complex disease through interacting with their targets. Thus, drug targets are critical for treatment efficacy. However, the interrelationship between the disease genes and drug targets is not clear. In this study, we comprehensively compared the network properties of disease genes and drug targets for five major disease categories (cancer, cardiovascular disease, immune system disease, metabolic disease, and nervous system disease). We first collected disease genes from genome-wide association studies (GWAS) for five disease categories and collected their corresponding drugs based on drugs' Anatomical Therapeutic Chemical (ATC) classification. Then, we obtained the drug targets for these five different disease categories. We found that, though the intersections between disease genes and drug targets were small, disease genes were significantly enriched in targets compared to their enrichment in human protein-coding genes. We further compared network properties of the proteins encoded by disease genes and drug targets in human protein-protein interaction networks (interactome). The results showed that the drug targets tended to have higher degree, higher betweenness, and lower clustering coefficient in cancer Furthermore, we observed a clear fraction increase of disease proteins or drug targets in the near neighborhood compared with the randomized genes. The study presents the first comprehensive comparison of the disease genes and drug targets in the context of interactome. The results provide some foundational network characteristics for further designing computational strategies to predict novel drug targets and drug repurposing.
Article
Full-text available
To evaluate the prevalence of NIDDM and IGT in the urban and rural areas in southern India. Two populations of the same ethnic background, but different socioeconomic background were chosen for this study. Nine-hundred urban people and 1038 rural subjects were studied. Fasting and 2-h post-glucose capillary blood samples after a 75 g oral glucose load (WHO criteria) were obtained in these randomly selected adults (greater than or equal to 20 yr of age). Using the WHO criteria, the prevalence of NIDDM, adjusted to the age of the respective general population, was 8.2% in the urban and 2.4% in the rural populations. The prevalence was 8.4 and 7.9%, respectively, in urban men and women, and 2.6 and 1.6% in rural men and women. The age-adjusted prevalence of IGT was 8.7 and 7.8% in the urban and rural areas, respectively. The prevalence of IGT was 8.8% in urban men and 8.3% in women; the corresponding values for rural men and women were 8.7 and 6.4%. The prevalence of NIDDM increased with age, markedly so in the urban people. The urban-rural difference was significant for NIDDM (chi 2 = 29.4, P less than 0.001) but not for IGT. In the urban population, 65% of the NIDDM patients were known cases, whereas in the rural area, the known cases accounted for only 24%. Bivariate analysis showed an association of BMI, STR, and WHR with prevalence of NIDDM plus IGT. In the multiple logistic regression analysis, age, BMI, STR, and WHR were associated significantly with glucose intolerance in the urban population, whereas only age was significant in the rural population. The best predictors of NIDDM were age, BMI, WHR, and urbanization. The study showed a high prevalence of NIDDM in the urban southern Indian population. The prevalence of NIDDM in the same ethnic group in rural areas was significantly lower. The prevalence of IGT was similar in both populations. Upper body adiposity was a significant predictor of NIDDM in this population with low rates of obesity.
Article
Full-text available
The Pima Indians of Arizona have the highest reported prevalences of obesity and non-insulin-dependent diabetes mellitus (NIDDM). In parallel with abrupt changes in lifestyle, these prevalences in Arizona Pimas have increased to epidemic proportions during the past decades. To assess the possible impact of the environment on the prevalences of obesity and NIDDM, data were collected on members of a population of Pima ancestry (separation 700-1,000 years ago) living in a remote mountainous location in northwestern Mexico, with a lifestyle contrasting markedly with that in Arizona. Pima heritage was established by history and by use of Pima language. Measurements of weight, height, body fat (bioimpedance), blood pressure, plasma levels of glucose, cholesterol, and HbA1c were obtained in 19 women (36 +/- 13 years of age) and 16 men (48 +/- 14 years of age) and compared with sex-, age- and diabetes status-matched Pimas living in Arizona (10 Arizona Pimas for each Mexican Pima). Mexican Pimas were lighter (64.2 +/- 13.9 vs. 90.2 +/- 21.1 kg, P < 0.0001; means +/- SD) and shorter (160 +/- 8 vs. 164 +/- 8 cm, P < 0.01) with lower body mass indexes (24.9 +/- 4.0 vs. 33.4 +/- 7.5 kg/m2, P < 0.0001) and lower plasma total cholesterol levels (146 +/- 30 vs. 174 +/- 31 mg/dl, P < 0.0001) than Arizona Pimas. Only two women (11%) and one man (6%) had NIDDM, contrasting with the expected prevalences of 37 and 54% in female and male Arizona Pimas, respectively. This preliminary investigation shows that obesity, and perhaps NIDDM, is less prevalent among people of Pima heritage living a "traditional" lifestyle than among Pimas living in an "affluent" environment. These findings suggest that, despite a similar potential genetic predisposition to these conditions, a traditional lifestyle, characterized by a diet including less animal fat and more complex carbohydrates and by greater energy expenditure in physical labor, may protect against the development of cardiovascular disease risk factors, obesity, and NIDDM.
Article
Full-text available
Summary In the present study we measured PC-1 content, tumour necrosis factor (TNF)-α gene expression, and insulin stimulation of insulin receptor tyrosine-kinase activity in adipose tissue from non-obese, non-diabetic subjects. These parameters were correlated with in vivo insulin action as measured by the intravenous insulin tolerance test (Kitt values). PC-1 content was negatively correlated with Kitt values (r = –0.5, p = 0.04) and positively with plasma insulin levels both fasting (r = 0.58, p = 0.009) and after 120 min during oral glucose tolerance test (OGTT) (r = 0.67, p = 0.002). Moreover, adipose tissue PC-1 content was higher in relatively insulin-resistant subjects (Kitt values lower than 6) than in relatively insulin-sensitive subjects (Kitt values higher than 6) (525 ± 49 ng/mg protein vs 336 ± 45, respectively, p = 0.012). Adipose tissue insulin receptor tyrosine-kinase activity in response to insulin was significantly lower at all insulin concentrations tested (p = 0.017, by two-way analysis of variance test) in insulin-resistant than in insulin-sensitive subjects (Kitt values lower or higher than 6, respectively). In contrast to PC-1, no significant correlation was observed between adipose tissue TNF-α mRNA content and Kitt values, and plasma insulin levels, both fasting and at after 120 min during OGTT. Also, no difference was observed in TNF-α mRNA content between subjects with Kitt values higher or lower than 6. These studies in adipose tissue, together with our previous studies in skeletal muscle raise the possibility that PC-1, by regulating insulin receptor function, may play a role in the degree of insulin sensitivity in non-obese, non-diabetic subjects. [Diabetologia (1997) 40: 282–289]
Article
Full-text available
The hallmark of type 2 diabetes, the most common metabolic disorder, is a defect in insulin-stimulated glucose transport in peripheral tissues. Although a role for phosphoinositide-3-kinase (PI3K) activity in insulin-stimulated glucose transport and glucose transporter isoform 4 (Glut4) translocation has been suggested in vitro, its role in vivo and the molecular link between activation of PI3K and translocation has not yet been elucidated. To determine the role of PI3K in glucose homeostasis, we generated mice with a targeted disruption of the gene encoding the p85alpha regulatory subunit of PI3K (Pik3r1; refs 3-5). Pik3r1-/- mice showed increased insulin sensitivity and hypoglycaemia due to increased glucose transport in skeletal muscle and adipocytes. Insulin-stimulated PI3K activity associated with insulin receptor substrates (IRSs) was mediated via full-length p85 alpha in wild-type mice, but via the p50 alpha alternative splicing isoform of the same gene in Pik3r1-/- mice. This isoform switch was associated with an increase in insulin-induced generation of phosphatidylinositol(3,4,5)triphosphate (PtdIns(3,4,5)P3) in Pik3r1-/- adipocytes and facilitation of Glut4 translocation from the low-density microsome (LDM) fraction to the plasma membrane (PM). This mechanism seems to be responsible for the phenotype of Pik3r1-/- mice, namely increased glucose transport and hypoglycaemia. Our work provides the first direct evidence that PI3K and its regulatory subunit have a role in glucose homeostasis in vivo.
Article
Full-text available
When overexpressed, the membrane glycoprotein PC-1 may play a role in human insulin resistance through the inhibition of insulin receptor (IR) autophosphorylation. A PC-1 variant (K121Q, with lysine 121 replaced by glutamine) is also associated with whole-body insulin resistance when not overexpressed. To better understand the effects of the Q allele on IR function and downstream signaling, we transfected cultured cells with cDNAs for either the Q or the K alleles. In human MCF-7 cells, the Q allele was severalfold more effective (P < 0.05-0.01) than the K allele in reducing insulin stimulation of IR autophosphorylation, insulin receptor substrate-1 phosphorylation, phosphatidylinositol 3-kinase activity, glycogen synthesis, and cell proliferation. Similar data on IR autophosphorylation inhibition were also obtained in mouse R-/hIR and human HEK 293 cell lines. In transfected MCF-7 cells, 125I-labeled insulin binding and IR content were unchanged, and PC-1 overexpression did not influence IGF-1 stimulation of IGF-1 receptor autophosphorylation. Both the Q and K alleles directly interacted with the IR, as documented by coimmunoprecipitation assays. This interaction was greater for the Q allele than for the K allele (P < 0.01), suggesting that direct PC-1-IR interactions are important for the PC-1 inhibitory effect on insulin signaling. In conclusion, the Q allele has stronger inhibitory activity on IR function and insulin action than the more common K allele, and this is likely a consequence of the intrinsic characteristics of the molecule, which more strongly interacts with the IR.
Article
Full-text available
Changes in human behaviour and lifestyle over the last century have resulted in a dramatic increase in the incidence of diabetes worldwide. The epidemic is chiefly of type 2 diabetes and also the associated conditions known as 'diabesity' and 'metabolic syndrome'. In conjunction with genetic susceptibility, particularly in certain ethnic groups, type 2 diabetes is brought on by environmental and behavioural factors such as a sedentary lifestyle, overly rich nutrition and obesity. The prevention of diabetes and control of its micro- and macrovascular complications will require an integrated, international approach if we are to see significant reduction in the huge premature morbidity and mortality it causes.
Article
Full-text available
To investigate the relationship of the K121Q polymorphism of the plasma cell glycoprotein 1 (PC-1) gene with insulin resistance, insulin secretion, and lipids and lipoproteins. Altogether, 110 normoglycemic subjects (group I) underwent a hyperinsulinemic-euglycemic clamp for evaluation of insulin sensitivity. The first-phase insulin secretion was determined by the intravenous glucose tolerance test (IVGTT) in a separate sample of 295 normoglycemic subjects (group II). The 121Q allele (genotypes K121Q and Q121Q) compared with the K121K genotype was related to higher fasting insulin levels (group I: 69.6 +/- 45.6 vs. 51.9 +/- 28.4 pmol/l [mean +/- SD], P = 0.050; group II: 66.6 +/- 38.8 vs. 53.8 +/- 26.6 pmol/l, P = 0.009). In group I, subjects carrying the 121Q allele compared with subjects with the K121K genotype had lower rates of whole-body glucose uptake (51.17 +/- 12.07 vs. 60.12 +/- 14.86 micro mol x kg(-1) x min(-1), P = 0.012) and nonoxidative glucose disposal (33.71 +/- 10.51 vs. 41.51 +/- 13.36 micro mol x kg(-1) x min(-1), P = 0.015) during the clamp. In group II, there was no significant difference between the 121Q allele carriers and subjects with the K121K genotype in total first-phase insulin secretion during the first 10 min of the IVGTT (2,973 +/- 2,224 vs. 2,520 +/- 1,492 pmol. l(-1). min(-1), P = 0.415). No association of the K121Q polymorphism with serum lipids and lipoproteins was found. In healthy normoglycemic Finnish subjects, the K121Q polymorphism of the PC-1 gene is associated with insulin resistance but not with impaired insulin secretion or dyslipidemia.
Article
Full-text available
Genetic susceptibility may be responsible for high prevalence of insulin resistance in Asian Indians. This study was carried out in samples of local Asian Indians and Caucasians to determine whether plasma cell membrane glycoprotein (PC)-1 K121Q and insulin receptor substrate-1 (IRS-1) G972A polymorphisms contribute significantly to susceptibility to insulin resistance in Asian Indians. The frequency of carrying at least one copy of the PC-1 121Q variant in Asian Indians was significantly higher than that in Caucasians (P = 0.01), but the frequency was similar for IRS-1 972A (6% and 7%). A significantly higher insulin area under the curve during oral glucose tolerance testing (P < 0.0001) and lower insulin sensitivity during hyperinsulinemic-euglycemic clamps (P = 0.04) were found in Asian Indians with PC-1 121Q variant compared with Asian Indians with wild-type PC-1 and with Caucasians with or without the polymorphism. IRS-1 972A was not associated with any change in insulin sensitivity. We conclude that the PC-1 K121Q polymorphism associates with primary insulin resistance in migrant Asian Indians. A relatively high frequency of this polymorphism thus may be one factor contributing to insulin resistance susceptibility in Asian Indians. This finding indicates the need for expanded studies on the association between PC-1 K121Q and insulin resistance in a representative sample of the Asian Indian population.
Article
Full-text available
To investigate the effect of the K121Q plasma cell membrane glycoprotein (PC-1) polymorphism on the components of the insulin resistance syndrome in a population-based nationwide multicenter study in Spain. The subjects of the study were 293 nonrelated adults (44.7% men and 55.3% women) ages 35 to 64 years randomly chosen from a nationwide population-based survey on obesity and related conditions, including insulin resistance and cardiovascular risk factors. Obesity-related anthropometric measurements included blood pressure, oral glucose tolerance test, lipid profile (total cholesterol, high-density lipoprotein- and low-density lipoprotein-cholesterol, and triglycerides), plasma leptin, insulin levels by radioimmunoassay, and insulin resistance (homeostasis model assessment). K121Q PC-1 genotypes were determined by restriction fragment-length polymorphism-polymerase chain reaction. Overall Q allele frequency was 0.14, with no differences between obese and nonobese individuals (0.15 vs. 0.13). After adjustment for sex, age, BMI, and degree of glucose tolerance, the Q allele was associated with high plasma leptin and triglyceride levels, but not with insulin resistance. The results showed that the K121Q PC-1 polymorphism in the Spanish population has no significant impact on insulin sensitivity.
Article
1) The Epidemiology Data Committee started in 1988 to compile information from the literature regarding the prevalence and incidence of diabetes among Japanese people. Information was collected from on-line searches of the Japanese Medical Literature and by various other methods. Main sources of data included original articles in medical journals,proceedings from meetings,nd official publications from the Ministry of Health and Welfare. Each article was evaluated by two members of the Committee. Approximately 60 articles were finally adoped and the principal data are summarized in 13 tables. 2) Community-based studies on adult diabetes gave only prevalnce data. In early studies,people were first screened by urine glucose tests at arbitrary times of 1-2 hours after a meal or glucose loading. Subjects who were positive for glucosuria were further evaluated by glucose tolerance tests (GTTs).Recent studies used 75g GTTs without prior urine screening.but 50g GTTs were more popular in earlier studies. Before 1984,most reports used the criteria advocated by the Japan Diabetes Society(1970),in which the blood glucose levels defining diabetic type were lower than in the present WHO criteria(1980).After 1985 WHO criteria were used widely, Before 1984, the prevalence of diabetes in subjects aged 40 years of older was 1.3-4.7% by urine glucose screening followed byGTTs. After 1985,the prevalence of diabetes in subjects older than 40 years was 2.1 -5. 4% when first screened by urine glucose tests,and 4-11%when all participants were tested using GTTs. The prevalence was as high as 10% in several studies carried out in 1988-1990,despite that WHO criteria being more stringent in defining diabetes than those from the Japan Diabetes Societ (1970).The prevalence of diabetes was higher in men than in women. The men:women ratio ranged 2:1 to1:1. 3)The incidence of diabetes in people younger than 18 years was 0.8-2.3 per 100,000 per year. The peak incidence was observed among 10-14 year-old age group. There was no clear increasing temporal trend in IDDM incidence,nor were there any significant differences between northern and southern parts of Japan. The prevalence of IDDM in young people(<18years)was0.5-1.5 per 10,000 when both types of diabetes were included. 4) Approximately 100,000 atomic bomb survivors have been prospectively followed up for health evaluations since 1960’s. As the exposure to the atomic bomb did not affect the development of diabetes,the data are regarded as equivalent to the community-based survey. These people are now older than 43 years.and the prevalence of diabetes was recently estimated to be 9.9%in men and 8.0%in women. There was an increase in prevalence of diabetes during the follow-up period. 5) Diabetes is more prevalent in the first and second generations of Japanese immigrants into Hawaii, Los Angelos and Seattle,in the USA.Recent studies in Seattle revealed that the prevalence of diabetes in the second generation immigrants older than 45 years of age was 21.5%in men and 16.1% in women. 6) Some publications from the Ministry of Health and Welfare in the government of Japan included the data on diabetes. These data were based on information on the known diabetic patients who were visiting medical clinics or hospitals. Naturally,the estimated prevalence was much lower than that obtained by the community surveys. However,this is a good source of information regarding long-term trends in the number of diabetic patients,because the data were collected nationwide using the same methods since 1950’s or 1960’s. The estimated prevalence of diabetes was 1.7% from the 1987 Patient Survey,and 1.1%from the 1989 Comprehensive Survey of Living Conditions of the People on Health and Welfare. This represented a 30-fold increase in the number of diabetic patients compared to early surveys. However,this increasing trend may be overestimated. More public awareness for diabetes in recent years,the increase in proportion of the population in the older age groups,and the increasing opportunity of health evalutions probably contributed to the apparent increasing prevalence of diabetes. 7) Continued effort to collect precise data on the prevalence and incidence of diabetes in Japan is important. In the future survey,following points are to be stressed. (a)The age and sex distribution and other demographic characteristics of the target population should be clearly difined.(b)The report should mention the number of patients with known diabetes. (c)The report should compare the demographic structure of test subjects with those for the target population.(d)The final diagnosis should depend on a 75 g GTT.(e)The distribution of fasting and 2-hr plasma glucose should be presented along with the prevalence of diabetes.(f)Effort should be made to collect as much information as possible from subjects who did not respond to the survey.
Article
Membrane glycoprotein PC-1, an inhibitor of insulin signaling, produces insulin resistance when overexpressed in cells transfected with PC-1 cDNA. In the present study, we determined whether PC-1 plays a role in the insulin resistance of skeletal muscle in obesity. Rectus abdominus muscle biopsies were taken from patients undergoing elective surgery. Subjects included both NIDDM patients (n = 14) and nondiabetic patients (n = 34) across a wide range of BMI values (19.5–90.1). Insulin-stimulated glucose transport was measured in incubated muscle strips, and PC-1 content, enzymatic activity, and insulin receptor content were measured in solubilized muscle extracts. Increasing BMI correlated with both an increase in the content of PC-1 in muscle (r = 0.55, P < 0.001) and a decrease in insulin stimulation of muscle glucose transport (r = −0.58, P = 0.008). NIDDM had no effect on either PC-1 content or glucose transport for any given level of obesity. Insulin stimulation of muscle glucose transport was negatively related to muscle PC-1 content (r = −0.68, P = 0.001) and positively related to insulin receptor content (r = 0.60, P = 0.005). Multivariate analysis indicated that both skeletal muscle PC-1 content and insulin receptor content, but not BMI, were independent predictors of insulin-stimulated glucose transport. Muscle PC-1 content accounted for 42% and insulin receptor content for 17% of the variance in glucose transport values. These studies raise the possibility that increased expression of PC-1 and a decreased insulin receptor content in skeletal muscle may be involved in the insulin resistance of obesity.
Article
MOST patients with non-insulin-dependent diabetes mellitus are resistant to both endogenous and exogenous insulin1. Insulin resistance precedes the onset of this disease2 -4, suggesting that it may be an initial abnormality. Insulin-receptor kinase activity is impaired in muscle, fibroblasts and other tissues of many patients with non-insulin-dependent diabetes mellitus5, but abnormalities in the insulin-receptor gene do not appear to be the cause of this decreased kinase activity6, 7. Skin fibroblasts from certain insulin-resistant patients contain an inhibitor of insulin-receptor tyrosine kinase8, 9. Here we show that this inhibitor is a membrane glycoprotein, termed PC-1 (refs 10,11). We find that PC-1 activity is increased in fibroblasts from seven of nine patients with typical non-insulin-dependent diabetes mellitus. In addition, overexpression of PC-1 in transfected cultured cells reduces insulin-stimulated tyrosine kinase activity. These studies raise the possibility that PC-1 has a role in the insulin resistance of non-insulin-dependent diabetes mellitus.
Article
Whenever normal concentrations of insulin produce a biologic response that is less than normal, insulin resistance should be suspected. Insulin resistance may occur in many different disease states and may involve an entire organism, a single tissue or cell, or even a single metabolic pathway of insulin action. This report outlines current knowledge about the mechanism of insulin resistance, as well as specific examples of disease states in which it occurs.
Article
Insulin receptor substrate-1 (IRS-1), an endogenous substrate for the insulin receptor tyrosine kinase, mediates many or all of the metabolic actions of insulin. Recently, polymorphism at codons 513 and 972 of the IRS-1 gene resulting in 2 amino acid substitutions that were associated with type II diabetes were found in a Caucasian population. Using allele specific oligonucleotide (ASO) hybridization, we screened 242 diabetic and 190 nondiabetic Pima Indians, a population with a very high prevalence of type II diabetes. Neither of the two mutations was present in either diabetic or nondiabetic subjects. We conclude that polymorphism at codons 513 and 972 of the IRS-1 gene observed in certain Caucasian populations is very rare or absent in Pima Indians.
Article
Variations in the coding regions of the insulin receptor substrate-1 (IRS-1) gene have recently been suggested to contribute to the susceptibility of non-insulin-dependent diabetes mellitus (NIDDM). The purpose of this study was to examine the role of the IRS-1 missense mutations at codons 972 (glycine to arginine) and 513 (alanine to proline) in two diverse populations from South India and Finland at high risk for NIDDM. DNA was amplified and digested with restriction enzymes BstN1 to detect the codon 972 mutation and Dra III to detect the codon 513 mutation. The codon 513 mutation was not found in the study subjects. The codon 972 mutation was present in 10.3% of 126 middle-aged NIDDM subjects and 5.3% of 95 matched control subjects in the South Indians (p = 0.17). In elderly Finnish subjects the frequency of the mutation was 7.5% in 40 NIDDM subjects and 7% in 42 matched control subjects. The frequency of codon 972 mutation in the South Indian NIDDM subjects was very similar to the two previously published studies in Danish and French subjects although each study individually fails to reach conventional levels of significance. The data from all four ethnic groups were analysed together after ascertaining that significant heterogeneity did not exist between the studies. Overall, the frequency of the codon 972 mutation is found in 10.7% NIDDM subjects and 5.8% control subjects (p = 0.02). These studies suggest that the codon 972 mutation of the IRS-1 gene might act as a susceptibility gene predisposing to NIDDM in certain ethnic groups.
Article
Since relative or absolute insulin deficiency and insulin insensitivity are involved in the aetiology of non-insulin-dependent diabetes mellitus (NIDDM), we examined whether patients with NIDDM exhibit genetic variability in the coding region of insulin receptor substrate-1 (IRS-1), a candidate gene that is ubiquitous in insulin-sensitive and insulin-like growth factor 1 (IGF1) sensitive tissues, including those that determine glucose production and clearance and those with regulatory effects on pancreatic beta-cell function. IRS-1 has a central role as an adaptor molecule that links the insulin-receptor and IGF1-receptor kinases with enzymes that regulate cellular metabolism and growth. Single-stranded conformation polymorphism analysis and direct nucleotide sequencing were applied to genomic DNA from 86 unrelated patients with NIDDM and 76 normoglycaemic controls. 10 of the patients with NIDDM and 3 of the controls were heterozygous at codon 972 for a polymorphism in which glycine was substituted with arginine. Moreover, at codon 513, 6 patients with NIDDM and 2 controls had a heterozygous polymorphism with a transition from alanine to proline. None of the polymorphism carriers had both aminoacid variants and the total allelic frequency of IRS-1 polymorphisms was about three times higher in patients with NIDDM than in controls (p = 0.02). Both aminoacid substitutions were located close to tyrosine phosphorylation motifs that are putative recognition sites for insulin and IGF1 signal transmission proteins. Analysis of the phenotypes showed that patients with NIDDM who had IRS-1 variants did not differ in their degree of insulin resistance compared with patients without known IRS-1 polymorphisms. However, carriers of the codon 972 variant had significantly lower plasma levels of fasting insulin and C-peptide. Our results suggest that aminoacid polymorphisms in IRS-1 may be involved in the aetiology of a subset of late-onset NIDDM.
Article
To date, mutations of the insulin receptor remain the only well-established causes of severe insulin resistance. There is a broad correlation between the extent of impairment of signal transduction seen when the mutant receptors are expressed in vitro with the severity of the clinical phenotype. Thus leprechaunism, Rabson-Mendenhall syndrome and Type A insulin resistance appear to represent points on a continuum of severity of receptor dysfunction, rather than completely distinct syndromes. In other syndromes of insulin resistance, insulin receptor abnormalities remain the exception. However, functional studies of expressed naturally occurring insulin receptor mutations have acted as experiments of nature and greatly aided attempts to dissect the structure-function relationships of the receptor. The next few years will no doubt begin to reveal the contributions made by defects in the post-receptor signalling cascade to the syndromes of insulin resistance in man.
Article
Membrane glycoprotein PC-1, an inhibitor of insulin signaling, produces insulin resistance when overexpressed in cells transfected with PC-1 cDNA. In the present study, we determined whether PC-1 plays a role in the insulin resistance of skeletal muscle in obesity. Rectus abdominus muscle biopsies were taken from patients undergoing elective surgery. Subjects included both NIDDM patients (n = 14) and nondiabetic patients (n = 34) across a wide range of BMI values (19.5-90.1). Insulin-stimulated glucose transport was measured in incubated muscle strips, and PC-1 content, enzymatic activity, and insulin receptor content were measured in solubilized muscle extracts. Increasing BMI correlated with both an increase in the content of PC-1 in muscle (r = 0.55, P < 0.001) and a decrease in insulin stimulation of muscle glucose transport (r = -0.58, P = 0.008). NIDDM had no effect on either PC-1 content or glucose transport for any given level of obesity. Insulin stimulation of muscle glucose transport was negatively related to muscle PC-1 content (r = -0.68, P = 0.001) and positively related to insulin receptor content (r = 0.60, P = 0.005). Multivariate analysis indicated that both skeletal muscle PC-1 content and insulin receptor content, but not BMI, were independent predictors of insulin-stimulated glucose transport. Muscle PC-1 content accounted for 42% and insulin receptor content for 17% of the variance in glucose transport values. These studies raise the possibility that increased expression of PC-1 and a decreased insulin receptor content in skeletal muscle may be involved in the insulin resistance of obesity.
Article
Insulin receptor substrate-1 (IRS-1) is one of the major substrates of insulin receptor tyrosine kinase and mediates various insulin signals downstream. In this study, we have examined the impact of three natural IRS-1 mutations identified in NIDDM patients (G971R, P170R, and M209T) on insulin signaling. G971R is located near src homology 2 protein binding sites, and P170R and M209T are located in the phosphotyrosine binding domain of IRS-1. 32D-IR cells, stably overexpressing human insulin receptor, were transfected with wild-type human IRS-1 cDNA (WT) or three mutant IRS-1 cDNAs and analyzed. All the cell lines expressing mutant IRS-1 showed a significant reduction in [3H]thymidine incorporation compared with WT. Upon insulin stimulation, cells expressing G971R showed a 39% decrease (P < 0.005) in phosphatidylinositol 3-kinase (PI 3-kinase) activity, a 43% decrease (P < 0.01) in binding of the 85-kDa regulatory subunit of PI 3-kinase, and a 22% decrease (P < 0.05) in mitogen-activated protein kinase activity compared with those expressing WT. Cells expressing P170R and M209T showed slight but significant decreases in PI 3-kinase activity (17 and 14%, respectively; both P < 0.05) and in binding of p85 (22 and 16%, respectively; both P < 0.05) and a greater decrease in mitogen-activated protein kinase activity (41 and 43%, respectively; both P < 0.005) compared with WT. After insulin stimulation, cells expressing P170R and M209T showed significant decreases in IRS-1 phosphorylation (37 and 42%, respectively; both P < 0.05) and in IRS-1 binding to the insulin receptor (48 and 53%, respectively; P < 0.01) compared with WT. G971R showed no changes in IRS-1 phosphorylation and in IRS-1 binding to the insulin receptor compared with WT. These data suggest that the impaired mitogenic response of P170R and M209T was mainly due to reduced binding to the insulin receptor, whereas the impaired response of G971R was mainly due to reduced association with PI 3-kinase p85.
Article
An elevated content of membrane glycoprotein PC-1 has been observed in cells and tissues of insulin resistant patients. In addition, in vitro overexpression of PC-1 in cultured cells induces insulin resistance associated with diminished insulin receptor tyrosine kinase activity. We now find that PC-1 overexpression also influences insulin receptor signaling at a step downstream of insulin receptor tyrosine kinase, independent of insulin receptor tyrosine kinase. In the present studies, we employed Chinese hamster ovary cells that overexpress the human insulin receptor (CHO IR cells; approximately 10(6) receptors per cell), and transfected them with human PC-1 c-DNA (CHO IR PC-1). In CHO IR PC-1 cells, insulin receptor tyrosine kinase activity was unchanged, following insulin treatment of cells. However, several biological effects of insulin, including glucose and amino acid uptake, were decreased. In CHO IR PC-1 cells, insulin stimulation of mitogen-activated protein (MAP) kinase activity was normal, suggesting that PC-1 overexpression did not affect insulin receptor activation of Ras, which is upstream of MAP kinase. Also, insulin-stimulated phosphatidylinositol (PI)-3-kinase activity was normal, suggesting that PC-1 overexpression did not interfere with the activation of this enzyme by insulin receptor substrate-1. In these cells, however, insulin stimulation of p70 ribosomal S6 kinase activity was diminished. These studies suggest, therefore, that, in addition to blocking insulin receptor tyrosine kinase activation, PC-1 can also block insulin receptor signaling at a post-receptor site.
Article
Membrane glycoprotein PC-1 inhibits insulin receptor (IR) tyrosine kinase activity and subsequent cellular signaling. PC-1 content is elevated in muscle and adipose tissue from insulin-resistant subjects, and its elevation correlates with in vivo insulin resistance. To determine whether elevated PC-1 content is a primary cause of insulin resistance, we have now measured PC-1 content in cultured skin fibroblasts from nonobese nondiabetic insulin-resistant subjects and found that 1) PC-1 content was significantly higher in these cells when compared with cells from insulin-sensitive subjects (6.7 +/- 0.9 vs. 3.1 +/- 0.6 ng/0.1 mg protein, mean +/- SE, P < 0.01); 2) PC-1 content in fibroblasts was highly correlated with PC-1 content in muscle tissue (r = 0.95, P = 0.01); 3) PC-1 content in fibroblasts negatively correlated with both decreased in vivo insulin sensitivity and decreased in vitro IR autophosphorylation; and 4) in cells from insulin-resistant subjects, insulin stimulation of glycogen synthetase was decreased. These studies indicate, therefore, that the elevation of PC-1 content may be a primary factor in the cause of insulin resistance.
Article
Insulin was discovered more than 75 years ago, but only recently have we begun to understand the mechanisms by which insulin promotes the uptake of glucose into cells. This review discusses recent advances, their contribution to our understanding of the pathogenesis of diabetes mellitus, and their implications for the design of new therapies to prevent and treat diabetes and its complications. Role of Glucose Transporters in Maintaining Glucose Homeostasis Carbohydrates, and glucose in particular, are an important source of energy for most living organisms. Tissues such as the brain need glucose constantly, and low blood concentrations of glucose can cause . . .
Article
The prevalence of type 2 diabetes, impaired glucose tolerance and associated risk factors were compared in sample surveys in Africa and the Caribbean with the Third National Health and Nutrition Survey (NHANES-III) from the United States. A total of 856 Nigerians, 1286 Jamaicans, and 1827 US blacks were included in the study. Body mass index (BMI) increased in a stepwise fashion across the three populations groups, ie, 23 kg/m2 in Nigerians, 26 kg/m2 in Jamaicans, and 28 kg/m2 in US blacks. The corresponding age-adjusted prevalences of type 2 diabetes among persons aged 25-74, were 1%, 12%, 13%. Jamaican women were found to have the same prevalence of type 2 diabetes as US women (14 vs 13%, respectively); mean BMI was likewise very similar (28 kg/m2 in Jamaican and 29 kg/m2 in US women). BMI and waist-to-hip ratio were both associated with type 2 diabetes prevalence. Findings of this study confirm the marked gradient in type 2 diabetes risk among these genetically related populations and suggest that the blacks in the island nations of the Caribbean and the United States are at particularly high risk. Nigerians exhibited remarkably well-preserved glucose tolerance. Understanding the factors that limit the risk of type 2 diabetes in West Africa, beyond relative absence of obesity, would have considerable public health significance.
Article
The genes responsible for insulin resistance are poorly defined. Plasma cell differentiation antigen (PC-1) glycoprotein inhibits insulin receptor signaling and is associated with insulin resistance. We describe here a novel polymorphism in exon 4 of the PC-1 gene (K121Q) and demonstrate that it is strongly associated with insulin resistance in 121 healthy nonobese (BMI <30 kg/m2) nondiabetic (by oral glucose tolerance test [OGTT]) Caucasians from Sicily. Compared with 80 KK subjects, Q allele carriers (n = 41, 39 KQ and 2 QQ) showed higher glucose and insulin levels during OGTT (P < 0.001 by two-way analysis of variance) and insulin resistance by euglycemic clamp (M value = 5.25 +/- 1.38 [n = 24] vs. 6.30 +/- 1.39 mg x kg(-1) x min(-1) [n = 49], P = 0.005). Q carriers had higher risk of being hyperinsulinemic and insulin resistant (odds ratio [CI]: 2.99 [1.28-7.0], P < 0.001). Insulin receptor autophosphorylation was reduced (P < 0.01) in cultured skin fibroblasts from KQ versus KK subjects. Skeletal muscle PC-1 content was not different in 11 KQ versus 32 KK subjects (33 +/- 16.1 vs. 17.5 +/- 15 ng/mg protein, P = 0.3). These results suggest a cause-effect relationship between the Q carrying genotype and the insulin resistance phenotype, and raise the possibility that PC-1 genotyping could identify individuals who are at risk of developing insulin resistance, a condition that predisposes to type 2 diabetes and coronary artery disease.
Article
We studied whether there is an association between the single nucleotide polymorphism c.533A>C (K121Q) in the glycoprotein PC-1 gene and features of the metabolic syndrome in case-control and intrafamily association studies in 922 subjects from Finland and Sweden. No difference was observed in the Q allele frequency between control subjects and type 2 diabetic subjects (12.9 vs. 15.1%). The QK genotype was associated with higher fasting plasma glucose (FPG) concentrations than the KK genotype in type 2 diabetic patients (P <0.001) and their relatives (P <0.05). A permutation test of siblings discordant for the QK and KK genotypes also showed that the nondiabetic siblings with the QK genotype had higher FPG (6.1 +/- 2.0 vs. 5.4 +/- 0.6 mmo/l, P <0.001) and fasting insulin (7.0 +/- 3.6 vs. 4.8 +/- 2.6 mU/l, P <0.05) concentrations than the carriers of the KK genotype. In addition, diabetic siblings with the QK genotype had higher systolic blood pressure (147.0 +/- 18.0 vs. 140.0 +/- 18.7 mmHg, P <0.05) and higher fasting (9.9 +/- 3.0 vs. 8.8 +/- 2.8 mmol/l, P <0.05) and 2-h plasma glucose (17.3 +/- 8.5 vs. 12.9 +/- 4.2 mmol/l, P < 0.05) concentrations than the diabetic carriers of the KK genotype. The present study shows that, although the Q allele of the human glycoprotein PC-1 gene is associated with surrogate measures of insulin resistance, it may not be enough to increase the susceptibility to type 2 diabetes.
Article
Genetic association studies are viewed as problematic and plagued by irreproducibility. Many associations have been reported for type 2 diabetes, but none have been confirmed in multiple samples and with comprehensive controls. We evaluated 16 published genetic associations to type 2 diabetes and related sub-phenotypes using a family-based design to control for population stratification, and replication samples to increase power. We were able to confirm only one association, that of the common Pro12Ala polymorphism in peroxisome proliferator-activated receptor-gamma(PPARgamma) with type 2 diabetes. By analysing over 3,000 individuals, we found a modest (1.25-fold) but significant (P=0.002) increase in diabetes risk associated with the more common proline allele (85% frequency). Moreover, our results resolve a controversy about common variation in PPARgamma. An initial study found a threefold effect, but four of five subsequent publications failed to confirm the association. All six studies are consistent with the odds ratio we describe. The data implicate inherited variation in PPARgamma in the pathogenesis of type 2 diabetes. Because the risk allele occurs at such high frequency, its modest effect translates into a large population attributable risk-influencing as much as 25% of type 2 diabetes in the general population.
Article
Positional cloning of common disease genes is a central but elusive goal of human geneticists. Progress is now reported by Bell and colleagues in their study of NIDDM1, a locus implicated in type 2 diabetes. The complex nature of the reported association illustrates the challenge of implicating a specific gene and mutation in the causation of polygenic disease.
Article
Insulin receptor substrate (IRS) proteins mediate a variety of the metabolic and growth-promoting actions of insulin and IGF-1. After phosphorylation by activated receptors, these intracellular signaling molecules recruit various downstream effector pathways including phosphatidylinositol 3-kinase and Grb2. Ablation of the IRS-2 gene produces a diabetic phenotype; mice lacking IRS-2 display peripheral insulin resistance and beta-cell dysfunction characterized by a 50% reduction in beta-cell mass. In contrast, deletion of IRS-1 retards somatic growth and enhances beta-cell mass. IRS1-/- mice are 50% smaller than controls but have a twofold increase in pancreatic beta-cell mass. Thus, observations from these recently developed animal models implicate the IRS signaling systems in the response of classical insulin target tissues, and they suggest a critical role for these proteins in the regulation of beta-cell function. In humans, type 2 diabetes generally occurs when insulin-secretory reserves fail to compensate for peripheral insulin resistance. Study and identification of the signals downstream of IRS proteins in beta-cells may provide unique insights into the compensatory mechanisms by which these cells respond to insulin resistance. Therefore, the intent of this review is to summarize recent observations regarding the regulation of beta-cell function by members of the IRS protein family.
Article
Both type 2 diabetes mellitus (T2DM) and insulin resistance are complex traits in which multiple gene effects and metabolic and environmental factors combine to contribute to the overall pathogenesis of these conditions. This complexity has complicated the search for susceptibility genes and has led to different but complementary approaches being used for the detection of gene effects. These include the study of monogenic cases of insulin resistance and T2DM, association studies of candidate genes and genome-wide scans. The peroxisome proliferator-activated receptor gamma (PPARgamma) and calpain-10 (CAPN10) genes have recently been identified as T2DM susceptibility genes, and the lessons learnt from these studies are helping to shape future strategies to search for additional susceptibility genes in T2DM and insulin resistance.