Deficiency of phosphofructo-1-kinase/muscle subtype in humans impairs insulin secretion and causes insulin resistance.

Ristow, Michael; Vorgerd, Matthias; Möhlig, Matthias; Schatz, H.; Pfeiffer, Andreas F.H.

doi:10.1172/jci119831

Cited by 37 publications

(30 citation statements)

References 44 publications

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“…Indeed, many of the enzymes identified showed elevated levels of lysine malonylation (supplemental Table S6). Dysfunction of glucose metabolic enzymes, including glucokinase (27, 28), glucose-6-phosphatase (29,30), phosphofructokinase (31), and glycogen phosphorylase (32), is known to be involved in type 2 diabetes. Although the role of lysine malonylation in dysfunction of metabolic enzymes remains unknown, the high levels of lysine malonylation on metabolic enzymes in db/db livers indicates an association between lysine malonylation and metabolic disorders of type 2 diabetes.…”

Section: Protein Lysine Malonylation Elevate In Liver Tissues Of Db/dmentioning

confidence: 99%

Lysine Malonylation Is Elevated in Type 2 Diabetic Mouse Models and Enriched in Metabolic Associated Proteins

Cai

et al. 2015

Molecular & Cellular Proteomics

109

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Protein lysine malonylation, a newly identified protein post-translational modification (PTM), has been proved to be evolutionarily conserved and is present in both eukaryotic and prokaryotic cells. However, its potential roles associated with human diseases remain largely unknown. In the present study, we observed an elevated lysine malonylation in a screening of seven lysine acylations in liver tissues of db/db mice, which is a typical model of type 2 diabetes. We also detected an elevated lysine malonylation in ob/ob mice, which is another model of type 2 diabetes. We then performed affinity enrichment coupled with proteomic analysis on liver tissues of both wild-type (wt) and db/db mice and identified a total of 573 malonylated lysine sites from 268 proteins. There were more malonylated lysine sites and proteins in db/db than in wt mice. Five proteins with elevated malonylation were verified by immunoprecipitation coupled with Western blot analysis. Bioinformatic analysis of the proteomic results revealed the enrichment of malonylated proteins in metabolic pathways, especially those involved in glucose and fatty acid metabolism. In addition, the biological role of lysine malonylation was validated in an enzyme of the glycolysis pathway. Together, our findings support a potential role of protein lysine malonylation in type 2 diabetes with possible implications for its therapy in the future. Molecular & Cellular

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Section: Protein Lysine Malonylation Elevate In Liver Tissues Of Db/dmentioning

confidence: 99%

Lysine Malonylation Is Elevated in Type 2 Diabetic Mouse Models and Enriched in Metabolic Associated Proteins

Cai

et al. 2015

Molecular & Cellular Proteomics

109

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“…Ten-minute periodicity means. The plasma glucose and serum insulin concentration changes occurring as a consequence of glucose infusion every 10 min were assessed by calculating average concentrations for all 9 cycles in data from glucose pulse induction every 10 min for 90 min; i.e., concentrations at 10,20,30,40, and 50 to yield a mean 10-min periodicity. The mean concentration change of the oscillation was calculated in each data set by subtracting the lowest concentration from the highest concentration.…”

Section: Subjectsmentioning

confidence: 99%

“…In healthy humans, high-frequency insulin concentration pulses recurring at intervals between 6 and 13 min have been reported (4,6) along with oscillations of larger amplitude and a longer periodicity of ~120 min (7,8). The cellular mechanisms that generate and regulate oscillatory insulin secretion by the ␤-cell are elusive, although a pivotal role of phosphofructokinase M has been suggested recently (9,10). Analogously, coordination within and between islets is complex and only partly understood, but intraislet communication through gap junctions and via the neuronal network within the pancreas is likely of importance (11).…”

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confidence: 99%

Failure of physiological plasma glucose excursions to entrain high-frequency pulsatile insulin secretion in type 2 diabetes.

et al. 2000

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Insulin is released in high-frequency pulsatile bursts at intervals of 6-13 min. Intrapancreatic mechanisms are assumed to coordinate pulsatile insulin release, but small oscillations in plasma glucose concentrations may contribute further. To gain additional insight into ␤-cell (patho)physiology, we explored the ability of repetitive small glucose infusions (6 mg/kg over 1 min every 10 min) to modify rapid pulsatile insulin secretion in 10 type 2 diabetic individuals (plasma glucose 9.3 ± 1.0 mmol/l, HbA 1c 7.9 ± 0.5%, mean ± SE) and 10 healthy subjects. All subjects were investigated twice in randomly assigned order: during saline and during glucose exposure. Blood was collected every minute for 90 min to create a plasma insulin concentration time-series for analysis using 3 complementary algorithms: namely, spectral analysis, autocorrelation analysis, and approximate entropy (ApEn). During saline infusion, none of the algorithms were able to discriminate between diabetic and control subjects (P > 0.20). During glucose entrainment, spectral density peaks (SP) and autocorrelation coefficients (AC) increased significantly (P < 0.001), and ApEn decreased (P < 0.01), indicating more regular insulin time-series in the healthy volunteers. However, no differences were observed in the diabetic individuals between the glucose and saline conditions. Even elevating the glucose infusion rate in the diabetic subjects to achieve comparable relative (and hence higher absolute) glucose excursions (~4.9%) failed to entrain pulsatile insulin secretion in this group. In conclusion, the present study demonstrates that failure to respond adequately with regular oscillatory insulin secretion to recurrent high-frequency and (near)-physiological glucose excursion is a manifest feature of ␤-cell malfunction in type 2 diabetes. Whether the model will be useful in unmasking subtle (possible prediabetic) defects in ␤-cell sensitivity to glucose drive remains to be determined.

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“…Similarly, the TCA cycle genes (see Supporting Information Information Table 2.2). HK2 and PFKM are implicated in insulin resistance [50,51]. ENO3 expression has been reported to be significantly increased in livers of morbidly obese individuals [52], while the PCK1 gene contributes to the development of non-insulin-dependent diabetes mellitus [53].…”

Section: Discussionmentioning

confidence: 99%

Carbohydrate metabolic pathway genes associated with quantitative trait loci (QTL) for obesity and type 2 diabetes: Identification by data mining

Varma

Wise

Kaput

2010

Biotechnology Journal

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Increasing consumption of refined carbohydrates is now being recognized as a primary contributor to the development of nutritionally related chronic diseases such as obesity and type 2 diabetes mellitus (T2DM). A data mining approach was used to evaluate the role of carbohydrate metabolic pathway genes in the development of obesity and T2DM. Data from public databases were used to map the position of the carbohydrate metabolic pathway genes to known quantitative trait loci (QTL) for obesity and T2DM and for examining the pathway genes for the presence of sequence and structural genetic variants such as single nucleotide polymorphisms (SNPs) and copy number variants (CNS), respectively. The results demonstrated that a majority of the genes of the carbohydrate metabolic pathways are associated with QTL for obesity and many for T2DM. In addition, some key genes of the pathways also encode non-synonymous SNPs that exhibit significant differences in population frequencies. This study emphasizes the significance of the metabolic pathways genes in the development of disease phenotypes, its differential occurrence across populations and between individuals, and a strategy for interpreting an individuals' risk for disease.

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Deficiency of phosphofructo-1-kinase/muscle subtype in humans impairs insulin secretion and causes insulin resistance.

Cited by 37 publications

References 44 publications

Lysine Malonylation Is Elevated in Type 2 Diabetic Mouse Models and Enriched in Metabolic Associated Proteins

Lysine Malonylation Is Elevated in Type 2 Diabetic Mouse Models and Enriched in Metabolic Associated Proteins

Failure of physiological plasma glucose excursions to entrain high-frequency pulsatile insulin secretion in type 2 diabetes.

Carbohydrate metabolic pathway genes associated with quantitative trait loci (QTL) for obesity and type 2 diabetes: Identification by data mining

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