Variants in ARHGEF11, a Candidate Gene for the Linkage to Type 2 Diabetes on Chromosome 1q, Are Nominally Associated With Insulin Resistance and Type 2 Diabetes in Pima Indians

Elevated blood branched-chain amino acids (BCAA) are often associated with insulin resistance and type 2 diabetes, which might result from a reduced cellular utilization and/or incomplete BCAA oxidation. White adipose tissue (WAT) has become appreciated as a potential player in whole body BCAA metabolism. We tested if expression of the mitochondrial BCAA oxidation checkpoint, branched-chain α-ketoacid dehydrogenase (BCKD) complex, is reduced in obese WAT and regulated by metabolic signals. WAT BCKD protein (E1α subunit) was significantly reduced by 35–50% in various obesity models ( fa/fa rats, db/db mice, diet-induced obese mice), and BCKD component transcripts significantly lower in subcutaneous (SC) adipocytes from obese vs. lean Pima Indians. Treatment of 3T3-L1 adipocytes or mice with peroxisome proliferator-activated receptor-γ agonists increased WAT BCAA catabolism enzyme mRNAs, whereas the nonmetabolizable glucose analog 2-deoxy-d-glucose had the opposite effect. The results support the hypothesis that suboptimal insulin action and/or perturbed metabolic signals in WAT, as would be seen with insulin resistance/type 2 diabetes, could impair WAT BCAA utilization. However, cross-tissue flux studies comparing lean vs. insulin-sensitive or insulin-resistant obese subjects revealed an unexpected negligible uptake of BCAA from human abdominal SC WAT. This suggests that SC WAT may not be an important contributor to blood BCAA phenotypes associated with insulin resistance in the overnight-fasted state. mRNA abundances for BCAA catabolic enzymes were markedly reduced in omental (but not SC) WAT of obese persons with metabolic syndrome compared with weight-matched healthy obese subjects, raising the possibility that visceral WAT contributes to the BCAA metabolic phenotype of metabolically compromised individuals.

Download Full-text

Analysis of PBX1 as a candidate gene for type 2 diabetes mellitus in Pima Indians

Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression ◽

10.1016/s0167-4781(01)00189-0 ◽

2001 ◽

Vol 1518 (1-2) ◽

pp. 215-220 ◽

Cited By ~ 7

Author(s):

Farook Thameem ◽

Johanna K Wolford ◽

Clifton Bogardus ◽

Michal Prochazka

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Candidate Gene ◽

Pima Indians

Download Full-text

Psammomys obesus and the albino rat-two different models of nutritional insulin resistance, representing two different types of human populations

Laboratory Animals ◽

10.1258/0023677011911949 ◽

2001 ◽

Vol 35 (4) ◽

pp. 346-352 ◽

Cited By ~ 11

Author(s):

R. Kalman ◽

E. Ziv ◽

E. Shafrir ◽

H. Bar-On ◽

R. Perez

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Body Weight ◽

High Energy ◽

Low Energy ◽

Albino Rats ◽

Human Populations ◽

Psammomys Obesus ◽

Pima Indians

Animal models for insulin resistance and type 2 diabetes are required for the study of the mechanism of these phenomena and for a better understanding of diabetes complications in human populations. Type 2 diabetes is a syndrome that affects 5-10% of the adult population. Hyperinsulinaemia, hypertriglyceridaemia, decreased high-density lipoprotein (HDL) cholesterol levels, obesity and hypertension, all form a cluster of risk factors that increase the risk of coronary artery disease, and are known as insulin resistance syndrome or syndrome X. The gerbil, Psammomys obesus is characterized by primary insulin resistance and is a well-defined model for dietary induced type 2 diabetes. Weanling Psammomys and Albino rats were held individually for several weeks on high energy (HE) and low energy (LE) diets in order to determine the development of metabolic changes leading to diabetes. Feeding Psammomys on HE diet resulted in hyperglycaemia (303 ± 40 mg/dl), hyperinsulinaemia (194 ± 31 µU/ml) and a moderate elevation in body weight, obesity and plasma triglycerides. Albino rats on HE diet demonstrated an elevation in plasma insulin (30 ± 4 µU/ml), hypertriglyceridaemia (170 µ 11 mg/dl), an elevation in body weight and obesity, but maintained normoglycaemia (98 µ 6 mg/dl). Psammomys represent a model that is similar to human populations, with primary insulin resistance expressed in young age, which leads to a high percentage of adult type 2 diabetes. Examples for such populations are the Pima Indians, Australian Aborigines and many other Third World populations. The results indicate that the metabolism of Psammomys is well adapted towards life in a low energy environment, where Psammomys takes advantage of its capacity for a constant accumulation of adipose tissue that will serve for maintenance and breeding in periods of scarcity. This metabolism known as 'thrifty metabolism', is compromised at a high nutrient intake.

Download Full-text