HNF1α defect influences post-prandial lipid regulation

Abstract

PurposeHepatocyte nuclear factor 1 alpha (HNF1α) defects cause Mature Onset Diabetes of the Young type 3 (MODY3), characterized by defects in beta-cell insulin secretion. However, HNF1α is involved in many other metabolic pathways with relevance for monogenic or polygenic type 2 diabetes. We aimed to investigate gut hormones, lipids, and insulin regulation in response to a meal test in HNF1α defect carriers (MODY3) compared to non-diabetic subjects (controls) and type 2 diabetes (T2D).MethodsWe administered a standardized liquid meal to each participant. Over 6 hours, we measured post-meal responses of insulin regulation (blood glucose, c-peptide, insulin), gut hormones (ghrelin, glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1) and lipids (non-esterified fatty acids [NEFA] and triglycerides).ResultsWe found that MODY3 participants had lower insulin secretion indices than controls and T2D participants, showing the expected β-cell defect. MODY3 had similar glycated hemoglobin levels (HbA1c median [IQR]: 6.5 [5.6–7.6]%) compared to T2D (median: 6.6 [6.2–6.9]%; P<0.05). MODY3 had greater insulin sensitivity (Matsuda index: 71.9 [29.6; 125.5]) than T2D (3.2 [4.0; 6.0]; P<0.05). MODY3 experienced a larger decrease in the ratio of NEFA to insulin (NEFA 30–0 / insulin 30–0: -39 [-78; -30] x104) in the early post-prandial period (0–30 minutes) compared to controls and to T2D (-2.0 [-0.6; -6.4] x104; P<0.05). MODY3 had lower fasting (0.66 [0.46; 1.2] mM) and post-meal triglycerides levels compared to T2D (fasting: 2.3 [1.7; 2.7] mM; P<0.05). We did not detect significant post-meal differences in ghrelin and incretins between MODY3 and other groups.ConclusionIn response to a standard meal test, MODY3 showed greater early post-prandial NEFA diminution in response to relatively low early insulin secretion, and they maintained very low post-prandial triglycerides levels.

[Retracted] Exercise or Dietotherapy Is Not Better than Returning to a Regular Diet to Rebuild Lipid Homeostasis of Rats

“…insulin level and lipometabolic disorders might be related to targeted tissues of insulin, i.e., liver and surrounding adipose. Deficiency of HNF1α in liver lipometabolism may lead to diabetes and hypercholesterolemia by increasing bile acid and cholesterol synthesis [20]. The cross-talking of insulin levels and AMPKα/HNF1α supports AMPK-mTOR-HNF1α…”

Regulating AMPKα and insulin level by Vinegar, Swimming and Refeeding on High-Fat Diet Rats to Rebuild Lipid Homeostasis

“…HNF1α and CTRP6 are supposed to be the substance metabolic indicators of these two targets during lowering lipid (32, 33). Deficiency of HNF1α in liver lipometabolism may lead to diabetes and hypercholesterolemia by increasing bile acid and cholesterol synthesis (34, 35). The cross-talking of insulin level and AMPKα/HNF1α supports AMPK-mTOR-HNF1α pathway for the treatment of lipometabolism and insulin dysfunction (36).…”

Using Clinical Indices to Distinguish MODY2 (GCK Mutation) and MODY3 (HNF1A Mutation) from Type 1 Diabetes in a Young Chinese Population

“…LPL encodes lipoprotein lipase, which is mostly found in the endothelial surfaces of capillaries in organs such as adipose tissues, liver, and skeletal muscle, where it hydrolyzes triglyceride-rich lipoprotein, including VLDL and chylomicrons [20]. This is why a previous study demonstrated that triglyceride levels were lower in MODY3 than in T2D [21]. Lipid levels in MODY3 patients were found to be no different from those in T1D patients in our study and in a previous study by Fendler et al [22]; this may be explained by small sample sizes.…”