Liver ATP Synthesis Is Lower and Relates to Insulin Sensitivity in Patients With Type 2 Diabetes

Abstract

OBJECTIVESteatosis associates with insulin resistance and may even predict type 2 diabetes and cardiovascular complications. Because muscular insulin resistance relates to myocellular fat deposition and disturbed energy metabolism, we hypothesized that reduced hepatic ATP turnover (fATP) underlies insulin resistance and elevated hepatocellular lipid (HCL) contents.RESEARCH DESIGN AND METHODSWe measured hepatic fATP using 31P magnetic resonance spectroscopy in patients with type 2 diabetes and age- and body mass–matched controls. Peripheral (M and M/I) and hepatic (suppression of endogenous glucose production) insulin sensitivity were assessed with euglycemic-hyperinsulinemic clamps.RESULTSDiabetic individuals had 29% and 28% lower peripheral and hepatic insulin sensitivity as well as 42% reduced fATP than controls. After adjusting for HCL, fATP correlated positively with peripheral and hepatic insulin sensitivity but negatively with waist circumference, BMI, and fasting plasma glucose. Multiple regression analysis identified waist circumference as an independent predictor of fATP and inorganic phosphate (PI) concentrations, explaining 65% (P = 0.001) and 56% (P = 0.003) of the variations. Hepatocellular PI primarily determined the alterations in fATP.CONCLUSIONSIn patients with type 2 diabetes, insulin resistance relates to perturbed hepatic energy metabolism, which is at least partly accounted for by fat depots.

Common variation in oxidative phosphorylation genes is not a major cause of insulin resistance or type 2 diabetes

“…Moreover, although we cannot completely rule out the possibility that some SNPs in or near OxPhos genes may contribute to impaired glucose-stimulated insulin secretion, our results provide evidence that the major role played by insulin resistance in the pathogenesis of type 2 diabetes cannot be explained by such genetic variants. The hypothesis of a potential association between common variation in OxPhos genes and type 2 diabetes was strongly supported a priori by numerous metabolic and physiological studies [7][8][9][10][11][12][13][14][15][16][17][18]. This makes our study unique compared with replication studies and meta-analysis of previously identified type 2 diabetes risk alleles, for most of which knowledge of the underlying phenotype leading to type 2 diabetes is limited [23].…”

“…Based on the substantial evidence that mitochondrial dysfunction is linked to insulin resistance and beta cell dysfunction, and is present in multiple tissues relevant to the pathogenesis of type 2 diabetes [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22], we hypothesised that common variation in OxPhos genes contributes to an increased risk of type 2 diabetes or influences metabolic traits related to the disease. OxPhos gene variants showing nominal association with type 2 diabetes in a meta-analysis of three GWA studies that were part of the DIAGRAM Study [28] were selected for follow-up in an independent cohort of Danish individuals.…”

“…Evidence of mitochondrial dysfunction in other tissues relevant to the pathogenesis of type 2 diabetes is also emerging. This includes reports of reduced expression of electron transport chain (ETC) genes in adipose tissue of women with type 2 diabetes [16], and of impaired mitochondrial respiratory capacity in heart muscle [17] and liver from type 2 diabetic individuals [18]. Finally, mitochondrial ATP production is known to play a critical regulatory role in glucosestimulated insulin secretion, and several recent studies have suggested that defects in mitochondrial OxPhos could contribute to beta cell dysfunction in patients with type 2 diabetes [19][20][21][22].…”

Lower Fasting Muscle Mitochondrial Activity Relates to Hepatic Steatosis in Humans

“…In support of this contention, lower liver ATP levels (21), fATP (6), and ATP recovery upon fructose challenge (24) provide evidence for lower hepatic mitochondrial function, at least in insulin-resistant groups such as severe obesity or type 2 diabetes. Furthermore, impaired hepatic energy metabolism could subsequently raise plasma FFA via lipolysis of VLDL (3) and in turn induce lipid-mediated muscle insulin resistance (25).…”

“…Increased insulinstimulated de novo hepatic lipogenesis after carbohydrate intake might represent an important sink for excess glucose, ultimately improving glucose homeostasis. On the other hand, steatosis may result from inadequate hepatic oxidation rates (6), subsequently leading to increased lipid flux to skeletal muscle. Indeed, insulin resistance frequently associates with accumulation of IMCL or lipid metabolites (3).…”