Temporal and dietary fat content–dependent islet adaptation to high-fat feeding–induced glucose intolerance in mice

Abstract

The high-fat fed mouse is an experimental model for studies of islet dysfunction as a mechanism for glucose intolerance and for evaluation of therapeutic targets. This model is, however, dynamic with a temporal and dietary fat content-dependent impact on islet function and glucose tolerance, the details of which are unknown. This study therefore examined the time course of changes in the insulin response to intravenous glucose (1g/kg) in relation to glucose tolerance in female mice after 1, 3, 8 or 16 weeks of feeding diets containing 11% fat (normal diet-ND), 30% fat (medium-fat diet-MFD) or 58% fat (high-fat diet-HFD; by energy). HFD increased body weight and body fat content, whereas MFD did not. The insulin response (postglucose suprabasal mean 1 and 5 min insulin), was impaired after one week on MFD (481± 33 pM) or HFD (223± 31 pM) compared to the ND (713±46 pM; both P<0.001).This was accompanied by impaired glucose elimination compared to ND (both P<0.001).Over the 16-week study period, the insulin response adaptively increased in the groups fed HFD and MFD; to be not significantly different from ND after 16 weeks. This compensation normalized glucose tolerance in MFD, whereas the glucose tolerance was still below normal in HFD. Insulin clearance, as judged by elimination of intravenous human insulin, was not altered in HFD, suggested that the observed changes in insulin responses to glucose are due to changes in insulin secretion rather than to changes in insulin clearance. We conclude that time-and dietary fat-dependent dynamic adaptive islet compensation evolves after introducing high-fat diet in mice, and that MFD-fed mice is a novel non-obese model of glucose intolerance.Key words: Insulin secretion, dietary fat, beta cell dysfunction, obesity 2 Glucose intolerance and type 2 diabetes are characterized by insufficient islet compensation to insulin resistance [1][2][3][4][5]. These conditions are associated with high dietary fat intake [6-9] and may be due to insulin resistance and beta-cell dysfunction instituted by fatty acid species [10][11][12]. The model of high-fat fed C57BL/6J mouse has been developed to study the impact of dietary fat for islet dysfunction in the pathogenesis of type 2 diabetes, and to explore novel therapeutic targets [13,14]. This model is associated with insulin resistance as demonstrated by the euglycemic clamp technique and estimation of the insulin sensitivity index from data obtained from the intravenous glucose tolerance test [15]. The model is also associated with glucose intolerance, as evident by impaired glucose disposal following glucose challenge [13][14][15]. As has previously been observed during long-term studies, the high-fat fed mouse model is a dynamic model in which compensatory adaptations may change by time. Hence, one study demonstrated failure of insulin secretion to compensate for insulin resistance during the first 4 weeks of dieting with a diet containing a very high (58%) amount of fat, followed by a clear compensatory increase at later time...

In adipose tissue, increased mitochondrial emission of reactive oxygen species is important for short-term high-fat diet-induced insulin resistance in mice

“…1d). These results are consistent with previous studies showing skeletal muscle insulin resistance does not develop after only 1 week of HFD [26,27].…”

Shortened Blood Coagulation Times in Genetically Obese Rats and Diet-Induced Obese Mice

“…Furthermore, aPTT, PT and TT were significantly shorter in the DIO mice than the lean mice (Table 2), suggesting enhanced blood coagulation. Unlike in fa/fa rats, there was no significant increase in blood glucose levels in the DIO mice, but like in fa/fa rats, a significantly high HOMA-IR value was evident consistent with a previous report [19]. The high HOMA-IR suggests increased insulin resistance [14], which plays a major role in metabolic syndrome.…”

The augmenting effect on insulin secretion by oral versus intravenous glucose is exaggerated by high-fat diet in mice

“…This model has previously been shown to induce insulin resistance (Pacini et al 2001, Winzell & Ahrén 2004). On a short-term basis, such as the 8-week period used in this study, the high-fat food also results in impaired glucose-stimulated insulin secretion (Ahrén et al 1997, Simonsson & Ahrén 1998, whereas on a long-term basis, upregulated insulin secretion develops (Winzell et al 2007). In the present study, impaired glucose-stimulated insulin secretion was evident in the high-fat fed mice by estimating the insulin response to i.v.…”