The pathophysiology of type 2 diabetes is complex and characterized by insulin resistance  and pancreatic insulin hypersecretion to overcome the insulin resistance early in the evolution of the disease. Both β- cell dysfunction and decreased insulin sensitivity are pivotal in the pathogenesis and progression of type 2 diabetes. Insulin resistance drives accumulation of free fatty acids in target cells (liver, skeletal muscle, and adipose tissue). Measures of insulin resistance such as the homeostatic model assessment of insulin resistance (HOMA- IR) correlate with visceral fat mass, total fat mass, BMI, and waist circumference, but to a much lesser extent with subcutaneous fat, highlighting the importance of adipose distribution. This interplay between obesity and diabetes is further emphasized by the impact of accumulated adipose tissue on insulin resistance that drives cardiometabolic disease progression towards type 2 diabetes, NAFLD, and cardiovascular disease. The bidirectional contribution of NAFLD to both type 2 diabetes and obesity is also well established. However, there exists a wide variation in insulin resistance and β- cell dysfunction and inflammation within the current diabetes classification. This heterogeneity relates to the effects of epigenetic, genetic, environmental, and lifestyle factors on the disease and its progression and complications. Attempts to increase the precision of diagnosis suggest six subtypes of diabetes, of which two are associated with a high BMI. Severe insulin- resistant diabetes is characterized by late onset, high BMI, most insulin resistant, highest liver fat content, fatty liver index, NAFLD fibrosis score, and prevalence of NAFLD. Severe insulin- resistant diabetes has the highest risk for macroalbuminuria, chronic renal disease, and ischaemic heart disease and stroke. By contrast, a subgroup characterized by a more benign course of their disease is termed mild obesity- related diabetes, with high BMI, early- onset diabetes with intermediate insulin resistance and an intermediate prevalence and risk of diabetes- related complications.

A model (the twin- cycle model) links obesity to the development of type 2 diabetes and explains how weight loss can reverse the process (Figure 1). The model describes how a positive energy balance promotes the deposition of fat in the liver by a process promoted by insulin. The presence of elevated insulin levels drives liver fat accumulation, resulting in decreased hepatic insulin sensitivity, which impairs insulin suppression of hepatic glucose output. This leads to both an increase in blood glucose levels and basal insulin secretion, forming the first vicious cycle. The second vicious cycle results from a spillover of liver- derived triglyceride- rich, very low- density lipoprotein (VLDL). Once subcutaneous fat stores are replete, this drives ectopic fat deposition in other tissues and exposes pancreatic β cells to triacylglycerol accumulation. Since pancreatic β cells are particularly susceptible to fatty acids, this impairs the function and response to post- meal glucose, which combine to elevate blood glucose levels and further impair glucose homeostasis. The resulting chronic hyperglycaemia increases insulin secretion, which results in increased fat deposition in the liver and increased hepatic lipogenesis, so driving both cycles faster. Once these effects on β cells reach a certain threshold, β- cell decompensation occurs, with the onset of clinically overt type 2 diabetes.

Fig1. Pathways in the twin cycle hypothesis. VLDL, very low- density lipoprotein.

It has long been known that these effects are readily reversible, particularly in early type 2 diabetes. Both negative energy balance from energy restriction and weight loss can improve insulin resistance and hyperglycaemia, and this has led to a reawakening of interest in the role of therapeutic weight loss in the management of type 2 diabetes.

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مواضيع ذات صلة

Production of Steroid Hormones—An Introduction

Profile of Bodily Cholesterol

Classes of Steroids

Modulation of the intestinal microbiome can alter in insulin sensitivity

The obesity and diabetes syndemic

Obesity: definitions and phenotypes

Homeostasis—Maintenance of A Nearly Constant Internal Environment

Extracellular Fluid —The “Internal Environment”

Formation of Bone

THE PERIOSTEUM

Fibrocartilage

Elastic Cartilage