Nutrient regulation of ß-cell function: what do islet cell/animal studies tell us?

Diabetes mellitus is widely recognised as one of the most serious metabolic diseases worldwide, and its incidence in Asian countries is growing at an alarming rate. Type 2 diabetes (T2DM) is closely associated with age, sedentary lifestyle and poor diet. In T2DM, ß-cell dysfunction will occur before hyperglycaemia develops. Excessive levels of glucose, lipid and various inflammatory factors interact at the level of the pancreatic islet to promote ß-cell dysfunction. Pancreatic ß-cell lines have been widely utilised since the early 1980s and have contributed a large volume of important information regarding molecular, metabolic and genetic mechanisms that regulate insulin secretion. The purpose of this review is to describe the origin and characteristics of the most commonly used ß-cell lines and their contribution to discovery of fundamental regulatory processes that control insulin production and release. Pancreatic islets obtained from rodents as well as other animals have additionally provided information on the architecture and three-dimensional design of this endocrine tissue that allows precise regulation of hormone release. Understanding the nature of failure of physiologic and metabolic processes leading to insufficient insulin release and subsequent diabetes has allowed development of novel anti-diabetic therapeutics, now in common use, worldwide.

The bioenergetics of inflammation: insights into obesity and type 2 diabetes.

Diabetes mellitus is one of the most common chronic metabolic disorders worldwide, and its incidence in Asian countries is alarmingly high. Type 2 diabetes (T2DM) is closely associated with obesity, and the staggering rise in obesity is one of the primary factors related to the increased frequency of T2DM. Low-grade chronic inflammation is also accepted as an integral metabolic adaption in obesity and T2DM, and is believed to be a major player in the onset of insulin resistance. However, the exact mechanism(s) that cause a persistent chronic low-grade infiltration of leukocytes into insulin-target tissues such as adipose, skeletal muscle and liver are not entirely known. Recent developments in the understanding of leukocyte metabolism have revealed that the inflammatory polarization of immune cells, and consequently their immunological function, are strongly connected to their metabolic profile. Therefore, it is hypothesized that dysfunctional immune cell metabolism is a central cellular mechanism that prevents the resolution of inflammation in chronic metabolic conditions such as that observed in obesity and T2DM. The purpose of this review is to explore the metabolic demands of different immune cell types, and identify the molecular switches that control immune cell metabolism and ultimately function. Understanding of these concepts may allow the development of interventions that can correct immune function and may possibly decrease chronic low-grade inflammation in humans suffering from obesity and T2DM. We also review the latest clinical techniques used to measure metabolic flux in primary leukocytes isolated from obese and T2DM patients.

Death-associated protein kinase increases glycolytic rate through binding and activation of pyruvate kinase.

Death-associated protein kinase (DAPk), a multi-domain serine/threonine kinase, regulates numerous cell death mechanisms and harbors tumor suppressor functions. In this study, we report that DAPk directly binds and functionally activates pyruvate kinase M2 (PKM2), a key glycolytic enzyme, which contributes to the regulation of cancer cell metabolism. PKM2 was identified as a novel binding partner of DAPk by a yeast two-hybrid screen. This interaction was validated in vitro by enzyme-linked immunosorbent assay using purified proteins and in vivo by co-immunoprecipitation of the two endogenous proteins from cells. In vitro interaction with full-length DAPk resulted in a significant increase in the activity of PKM2. Conversely, a fragment of DAPk harboring only the functional kinase domain (KD) could neither bind PKM2 in cells nor activate it in vitro. Indeed, DAPk failed to phosphorylate PKM2. Notably, transfection of cells, with a truncated DAPk lacking the KD, elevated endogenous PKM2 activity, suggesting that PKM2 activation by DAPk occurs independently of its kinase activity. DAPk-transfected cells displayed changes in glycolytic activity, as reflected by elevated lactate production, whereas glucose uptake remained unaltered. A mild reduction in cell proliferation was detected as well in these transfected cells. Altogether, this work identifies a new role for DAPk as a metabolic regulator, suggesting the concept of direct interactions between a tumor suppressor and a key glycolytic enzyme to limit cell growth. Moreover, the work documents a unique function of DAPk that is independent of its catalytic activity and a novel mechanism to activate PKM2 by protein-protein interaction.

The G1888A variant in the mitochondrial 16S rRNA gene may be associated with Type 2 diabetes in Caucasian-Brazilian patients from southern Brazil.

AIM: To compare the frequencies of the G1888A variant in the mitochondrial 16S rRNA gene between patients with Type 2 diabetes and non-diabetic control subjects from southern Brazil. METHODS: We analysed 520 Type 2 diabetic patients (389 Caucasian- and 131 African-Brazilians) and 530 control subjects (400 Caucasian- and 130 African-Brazilians). DNA samples were amplified by polymerase chain reaction and digested with the RsaI enzyme. Variant frequency in patients and control subjects was compared using chi2 test, Fisher's exact test or odds ratio test. We also investigated the frequency of the G1888A variant in a subgroup of the patients with a maternal history of Type 2 diabetes plus two or more features of maternally inherited diabetes and deafness. RESULTS: The 1888A allele does not seem to be associated with Type 2 diabetes in African-Brazilians (frequency of 3.8% in patients and 0.8% in control subjects; PFisher=0.213). However, in Caucasian-Brazilians, the 1888A allele was significantly associated with diabetes (12.3% in patients vs. 3.5% in control subjects; OR=3.881; 95% CI 2.106-7.164; P<0.001) and also with higher levels of insulin resistance. The majority of the patients carrying the 1888A allele did not have clinical features of maternally inherited diabetes and deafness. CONCLUSION: The present study indicates the association of the mitochondrial G1888A variant with Type 2 diabetes and insulin resistance in Caucasian-Brazilian patients from southern Brazil. However, further studies are required to confirm its effects on mitochondrial function and the role of these effects on the pathogenesis of Type 2 diabetes.