A low-carbohydrate high-fat diet increases weight gain and does not improve glucose tolerance, insulin secretion or β-cell mass in NZO mice

Abstract

Background/objectives: Dietary guidelines for the past 20 years have recommended that dietary fat should be minimized. In contrast, recent studies have suggested that there could be some potential benefits for reducing carbohydrate intake in favor of increased fat. It has also been suggested that low-carbohydrate diets be recommended for people with type 2 diabetes. However, whether such diets can improve glycemic control will likely depend on their ability to improve β-cell function, which has not been studied. The objective of the study was to assess whether a low-carbohydrate and therefore high-fat diet (LCHFD) is beneficial for improving the endogenous insulin secretory response to glucose in prediabetic New Zealand Obese (NZO) mice.

Methods: NZO mice were maintained on either standard rodent chow or an LCHFD from 6 to 15 weeks of age. Body weight, food intake and blood glucose were assessed weekly. Blood glucose and insulin levels were also assessed after fasting and re-feeding and during an oral glucose tolerance test. The capacity of pancreatic β-cells to secrete insulin was assessed in vivo with an intravenous glucose tolerance test. β-Cell mass was assessed in histological sections of pancreata collected at the end of the study.

Results: In NZO mice, an LCHFD reduced plasma triglycerides (P=0.001) but increased weight gain (P<0.0001), adipose tissue mass (P=0.0015), high-density lipoprotein cholesterol (P=0.044) and exacerbated glucose intolerance (P=0.013). Although fasting insulin levels tended to be higher (P=0.08), insulin secretory function in LCHFD-fed mice was not improved (P=0.93) nor was β-cell mass (P=0.75).

Conclusions: An LCHFD is unlikely to be of benefit for preventing the decline in β-cell function associated with the progression of hyperglycemia in type 2 diabetes.

Figure 1

(a) Body weight of NZO mice fed either chow or an LCHFD was measured weekly (n=9 mice per group). (b) Average daily energy intake for NZO mice was calculated from weekly food consumption (for each cage) and the energy content of the respective diets (n=5 cages per group). (c) Gonadal fat pad weight measured at the end of the 9-week study (n=9). Values are presented as mean±s.e.m., *P<0.05 vs chow.

Figure 2

Plasma triglyceride and cholesterol measured in chow and LDHFD-fed NZO mice at the end of the 9-week study (n=8–9). Blood samples were collected after overnight fasting. Values are presented as mean±s.e.m., *P<0.05 vs chow.

Figure 3

(a) Weekly random-fed blood glucose in NZO mice fed either a chow or LCHFD (n=9). (b) Blood glucose and (c) plasma insulin measured after an overnight fast (fasted) and then 4 h after the return of either the chow- or LCHFD-fed mice to the cages (fed). Values are presented as mean±s.e.m. *P<0.05 LCHFD vs control, ^#P<0.05 fed vs fasted (n=8–9).

Figure 4

(a) Blood glucose at various time points and (b) area under the curve (AUC) for glucose after an oral glucose challenge demonstrate that LCHFD-fed NZO mice had impaired glucose tolerance compared with the chow-fed group. (c) Plasma insulin was measured in samples collected at 0, 10 and 60 min. Values are presented as mean±s.e.m. *P<0.05 vs control (n=9).

Figure 5

(a) Plasma glucose and (b) insulin concentrations in chow- and LCHFD-fed NZO mice during an IVGTT. Area under the curve (AUC) for plasma (c) glucose and (d) insulin were also calculated. Values are presented as mean±s.e.m. *P<0.05 vs control (n=8-9).

Figure 6

(a) Pancreas weight, (b) islet density, (c) islet size and (d) β-cell mass was assessed in the pancreata from NZO mice, collected after 9 weeks of either LCHFD or chow diet. Values are presented as mean±s.e.m. (n=7–8 for panels (a) and (d), n=3 for panels (b) and (c)).