β-Cell Dysfunction, Hepatic Lipid Metabolism, and Cardiovascular Health in Type 2 Diabetes: New Directions of Research and Novel Therapeutic Strategies

Abstract

Cardiovascular disease (CVD) remains a major problem for people with type 2 diabetes mellitus (T2DM), and dyslipidemia is one of the main drivers for both metabolic diseases. In this review, the major pathophysiological and molecular mechanisms of β-cell dysfunction and recovery in T2DM are discussed in the context of abnormal hepatic lipid metabolism and cardiovascular health. (i) In normal health, continuous exposure of the pancreas to nutrient stimulus increases the demand on β-cells. In the long term, this will not only stress β-cells and decrease their insulin secretory capacity, but also will blunt the cellular response to insulin. (ii) At the pre-diabetes stage, β-cells compensate for insulin resistance through hypersecretion of insulin. This increases the metabolic burden on the stressed β-cells and changes hepatic lipoprotein metabolism and adipose tissue function. (iii) If this lipotoxic hyperinsulinemic environment is not removed, β-cells start to lose function, and CVD risk rises due to lower lipoprotein clearance. (iv) Once developed, T2DM can be reversed by weight loss, a process described recently as remission. However, the precise mechanism(s) by which calorie restriction causes normalization of lipoprotein metabolism and restores β-cell function are not fully established. Understanding the pathophysiological and molecular basis of β-cell failure and recovery during remission is critical to reduce β-cell burden and loss of function. The aim of this review is to highlight the link between lipoprotein export and lipid-driven β-cell dysfunction in T2DM and how this is related to cardiovascular health. A second aim is to understand the mechanisms of β-cell recovery after weight loss, and to explore new areas of research for developing more targeted future therapies to prevent T2DM and the associated CVD events.

Keywords: adipose tissue; cardiovascular disease; diabetes remission; lipoprotein metabolism; lipotoxicity; novel therapies; type 2 diabetes; weight loss; β-cell dysfunction.

Figure 1

Schematic hypothetical diagram of the interplay between hepatic very low density lipoprotein triglyceride (VLDL-TG) export and intrapancreatic fat in type 2 diabetes. Pancreas function is accomplished through the synergy between endocrine and exocrine compartments. Abnormalities in lipid metabolism are the drivers of metabolic events that affect overall pancreas structure and function. The extent of each colored triangle represents the degree of function in that parameter (gray color means loss of function). Lipid-driven changes that cause dysfunction of β-cells in type 2 diabetes mellitus (T2DM) and the loss of the acinar cells mass are likely to be related to hepatic VLDL-TG export and increase in intrapancreatic fat. β-cell: Beta cell; VLDL-TG: very low density lipoprotein triglyceride; FGF-21: fibroblast growth factor 21; NEFA: non-esterified fatty acids; BCAAs: branched-chain amino acids; GDF-15: growth differentiation factor-15; GLP-1: glucagon-like peptide-1; C-myc: cellular myelocytomatosis oncogene; IFG-1: insulin-like growth factor-1; DNL: de novo lipogenesis; ApoE: apolipoprotein E, ApoC-III: apolipoprotein C-III; SAT: subcutaneous adipose tissue; VAT: visceral adipose tissue.

Figure 2

Change in lipid parameters and β-cell function during remission and relapse of type 2 diabetes. Change from baseline in fasting plasma glucose (A), fasting plasma insulin (B), liver fat (C), hepatic VLDL1-TG production (D), fasting plasma VLDL1-TG (E), total plasma triglycerides (TGs) (F), intrapancreatic fat (G), and β-cell function (H) at 5 months (responders n = 38; relapsers n = 13), 12 months (n = 28/n = 13, respectively), and 24 months (n = 20/n = 13, respectively). Responders are presented as a solid black line and relapsers as a dashed line. The dotted line is the gridline at y value = 0. Paired data between baseline and each time point are presented. Data are presented as mean ± SEM except for first-phase insulin (median with IQ range) vs. 5 months in relapsers: * p < 0.05, ** p < 0.01, *** p < 0.001. Figure is presented with permission [43].

Figure 3

Restoration of pancreas morphology and β-cell functional capacity after 2 years of remission of type 2 diabetes. Surface-rendered image of pancreas morphology in a representative responder (A), and pancreas volume (B), fractal dimension (C), and maximal insulin secretion (D) in responders compared with non-diabetic controls at baseline, 5 months, 12 months, and 24 months. Horizontal dashed lines indicate the level for non-diabetic controls. Data paired with baseline at each timepoint are presented as mean (SD) for pancreas volume and fractal dimension and median (IQR) for insulin secretion. * Responders versus non-diabetic comparator group. † Responders versus baseline. Figure is presented with permission from The Lancet Diabetes and Endocrinology [172].

Figure 4

New directions of research for developing novel therapies to manage type 2 diabetes. T2DM: type 2 diabetes mellitus; GDF-15: growth differentiation factor 15; FGF-21: fibroblast growth factor 21; C-myc: cellular myelocytomatosis oncogene; β-cell: beta cell; CD36: cluster differentiation 36; DNL: de novo lipogenesis; ApoB: apolipoprotein B; ApoE: apolipoprotein E; ApoC-III: apolipoprotein C-III; LP(a): lipoprotein (a); VLDL-TG: very low density lipoprotein triglyceride; PPARγ: peroxisome proliferator-activated receptor-γ; PLIN5: perilipin 5.