Handbook of Diabetes. Rudy Bilous

Over the last 20 years, incidence rates among the Pima Indians has not changed, although the age of onset of type 2 diabetes has been declining.

      The occurrence of type 2 diabetes in adolescence is a great cause for concern worldwide. In US Asian and Pacific Islanders, for example, rates of 12.1/100,000 patient–years have been reported in 10–19‐year‐olds, which is similar to rates reported for type 1 diabetes. In the UK, the overall incidence for <16‐year‐olds is much lower, at 0.53 per/100,000 patient–years, but 10 times more common in South Asian or black African compared to white children.

The rural–n ratio remains for diabetes incidence rates even in the presence of other risk factors such as central obesity. In Japan, there is an approximately threefold increase in the incidence among obese urban compared to rural populations (15.8 versus 5.8% over 10 years). Similarly, there is a twofold increase in incidence for USA versus Mexican Hispanic people corrected for age and economic circumstance, probably a reflection of changes in diet and lifestyle.

Figure 7.6 A league table of countries showing widely different prevalence rates of type 2 diabetes and impaired glucose tolerance. A mixture of genes and environment account for these differences. Forouhi NG and Wareham NJ. Medicine, 2006; 34(2): 57–60.

Risk factors for type 2 diabetes

      Obesity

About 80% of people with type 2 diabetes are obese, and the risk of developing diabetes increases progressively as the BMI (weight (kg)/height (m)²) increases (Figure 7.1). A BMI >35 kg/m² increases the risk of type 2 diabetes developing over a 10‐year period by 80‐fold, as compared to those with a BMI <22 kg/m². Small increments in body weight translate into large increases in type 2 diabetes risk (Figure 7.10).

      The latest data from the US NHANES survey confirms a 6–10‐fold higher lifetime risk of type 2 diabetes for 18‐year‐olds with a BMI >35 kg/m² compared to those with BMI <18.5 kg/m², with an associated 6–7 year reduction in overall life expectancy.

Obesity is still widely defined as a BMI >30 kg/m² although BMI is not an accurate reflection of fat mass or its distribution, particularly in Asian people. A simple waist circumference may be better. The pattern of obesity is also important in that central fat deposition is associated with greater insulin resistance and confers a much higher risk for developing diabetes compared to gluteofemoral deposition (Figure 7.11). In clinical practice, ‘central’ obesity can be assessed by measuring the ratio of waist:hip circumference, but it is unclear whether this has any advantage over a simple measurement of waist circumference alone.

      Fat deposition at other sites, particularly in skeletal muscle, liver and in the pancreatic islets, may contribute to metabolic defects and insulin resistance. This ‘ectopic’ fat deposition leads to lipotoxicity, which in turn causes insulin resistance and (in islets) impairs insulin secretion.

      Physical exercise and diet

Low levels of physical exercise also predict the development of type 2 diabetes, possibly because exercise increases insulin sensitivity and helps prevent obesity (Figure 7.12). People who exercise the most have a 25–60% lower risk of developing type 2 diabetes regardless of their other risk factors such as obesity and family history.

      The Diabetes Prevention Programme and the Diabetes Prevention Study have shown that lifestyle modifications with moderate exercise and modest weight loss can dramatically reduce the number progressing from IGT to type 2 diabetes and reinforce the importance of lifestyle factors in the cause of diabetes.

      Insulin resistance

      Whole‐body ‘insulin resistance’ can be estimated from the amount of glucose that needs to be infused intravenously in order to maintain a constant blood glucose level during a simultaneous intravenous infusion of insulin. This (euglycaemic hyperinsulinaemic ‘clamp’) method is cumbersome, so for studying populations the HOMA (homeostasis model assessment) methods are more practical for estimating steady‐state beta‐cell function (HOMA B) and insulin sensitivity (HOMA S) as percentages of normal. These estimates can be derived from a single fasting measurement of plasma C‐peptide, insulin and glucose concentrations.

Figure 7.7 Deaths attributable to diabetes are highest in low‐ and middle‐income countries. IDF Diabetes Atlas. © 2017 International Diabetes Federation.

Figure 7.8 The relationship between HbA1c and the incidence of cardiovascular disease. This is a linear relationship which extends down into the prediabetic range (i.e HbA1c<6.5%). Bain et al. Diabetes, Obesity and Metabolism, 2016; 18(12): 1157–1166.

Insulin resistance (or, more correctly, diminished insulin sensitivity) precedes the onset of diabetes and can worsen with increasing duration (Figure 7.13). Insulin resistance is a major factor in the aetiology of type 2 diabetes, and affects the muscle, liver, and adipose tissues (Figure 7.14).

Figure 7.9 Varying prevalence rates of type 2 diabetes by ethnicity/region and location (red, rural; blue, urban) for 2007. UAE, United Arab Emirates.

      Data from Diabetes Atlas.

      Hormones and cytokines

      Visceral fat liberates large amounts of non‐esterified fatty acids (NEFAs) through lipolysis, which increases gluoconeogenesis in the liver and impairs glucose uptake and utilisation in muscle. NEFAs may also inhibit insulin secretion, possibly by enhancing the accumulation of triglycerides within the β cells. In addition, adipose tissue produces cytokines, such as TNF‐α, resistin and IL‐6, all of which have been shown experimentally to interfere with insulin action. TNF‐α has been shown to inhibit tyrosine kinase activity at the insulin receptor and decrease expression of the glucose transporter GLUT‐4.

Adiponectin is a hormone with anti‐inflammatory and insulin‐sensitising properties that is secreted solely by fat cells. It suppresses hepatic gluconeogenesis and stimulates fatty acid oxidation in the liver and skeletal muscles, as well as increasing muscle glucose uptake and insulin release from the β cells. Circulating adiponectin is reduced in obesity and a recent meta‐analysis showed that the relative risk for diabetes was 0.72 for every 1‐log μg/mL increment in adiponectin level.