Changes in human behaviour and lifestyle over the last century have resulted in a dramatic increase in the incidence of diabetes worldwide. The epidemic is chiefly of type 2 diabetes and also the associated conditions known as 'diabesity' and 'metabolic syndrome'. In conjunction with genetic susceptibility, particularly in certain ethnic groups, type 2 diabetes is brought on by environmental and behavioural factors such as a sedentary lifestyle, overly rich nutrition and obesity. The prevention of diabetes and control of its micro- and macrovascular complications will require an integrated, international approach if we are to see significant reduction in the huge premature morbidity and mortality it causes.

Global and societal implications of the diabetes epidemic

The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus.

Obesity is now so common within the world's population that it is beginning to replace undernutrition and infectious diseases as the most significant contributor to ill health. In particular, obesity is associated with diabetes mellitus, coronary heart disease, certain forms of cancer, and sleep-breathing disorders. Obesity is defined by a body-mass index (weight divided by square of the height) of 30 kg m(-2) or greater, but this does not take into account the morbidity and mortality associated with more modest degrees of overweight, nor the detrimental effect of intra-abdominal fat. The global epidemic of obesity results from a combination of genetic susceptibility, increased availability of high-energy foods and decreased requirement for physical activity in modern society. Obesity should no longer be regarded simply as a cosmetic problem affecting certain individuals, but an epidemic that threatens global well being.

Obesity as a medical problem

Obesity is associated with an increased risk of developing insulin resistance and type 2 diabetes In obese individuals, adipose tissue releases increased amounts of non-esterified fatty acids, glycerol, hormones, pro-inflammatory cytokines and other factors that are involved in the development of insulin resistance When insulin resistance is accompanied by dysfunction of pancreatic islet beta-cells - the cells that release insulin - failure to control blood glucose levels results Abnormalities in beta-cell function are therefore critical in defining the risk and development of type 2 diabetes This knowledge is fostering exploration of the molecular and genetic basis of the disease and new approaches to its treatment and prevention

Mechanisms linking obesity to insulin resistance and type 2 diabetes

Homeostatic model assessment (HOMA) is a method for assessing beta-cell function and insulin resistance (IR) from basal (fasting) glucose and insulin or C-peptide concentrations. It has been reported in >500 publications, 20 times more frequently for the estimation of IR than beta-cell function. This article summarizes the physiological basis of HOMA, a structural model of steady-state insulin and glucose domains, constructed from physiological dose responses of glucose uptake and insulin production. Hepatic and peripheral glucose efflux and uptake were modeled to be dependent on plasma glucose and insulin concentrations. Decreases in beta-cell function were modeled by changing the beta-cell response to plasma glucose concentrations. The original HOMA model was described in 1985 with a formula for approximate estimation. The computer model is available but has not been as widely used as the approximation formulae. HOMA has been validated against a variety of physiological methods. We review the use and reporting of HOMA in the literature and give guidance on its appropriate use (e.g., cohort and epidemiological studies) and inappropriate use (e.g., measuring beta-cell function in isolation). The HOMA model compares favorably with other models and has the advantage of requiring only a single plasma sample assayed for insulin and glucose. In conclusion, the HOMA model has become a widely used clinical and epidemiological tool and, when used appropriately, it can yield valuable data. However, as with all models, the primary input data need to be robust, and the data need to be interpreted carefully.

/pdf/use-and-abuse-of-homa-modeling-4yfshtsw2c.pdf

Use and Abuse of HOMA Modeling

In this contribution we put forward a novel hypothesis concerning the aetiology of Type 2 (non-insulin dependent) diabetes mellitus. The concept underlying our hypothesis is that poor foetal and early post-natal nutrition imposes mechanisms of nutritional thrift upon the growing individual. We propose that one of the major long-term consequences of inadequate early nutrition is impaired development of the endocrine pancreas and a greatly increased susceptibility to the development of Type 2 diabetes. In the first section we outline our research which has led to this hypothesis. We will then review the relevant literature. Finally we show that the hypothesis suggests a reinterpretation of some findings and an explanation of others which are at present not easy to understand.

/pdf/type-2-non-insulin-dependent-diabetes-mellitus-the-thrifty-wkzyogfl8p.pdf

Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis.

OBJECTIVE--To discover whether reduced fetal and infant growth is associated with non-insulin dependent diabetes and impaired glucose tolerance in adult life. DESIGN--Follow up study of men born during 1920-30 whose birth weights and weights at 1 year were known. SETTING--Hertfordshire, England. SUBJECTS--468 men born in east Hertfordshire and still living there. MAIN OUTCOME MEASURES--Fasting plasma glucose, insulin, proinsulin, and 32-33 split pro-insulin concentrations and plasma glucose and insulin concentrations 30 and 120 minutes after a 75 g glucose drink. RESULTS--93 men had impaired glucose tolerance or hitherto undiagnosed diabetes. They had had a lower mean birth weight and a lower weight at 1 year. The proportion of men with impaired glucose tolerance fell progressively from 26% (6/23) among those who had weighted 18 lb (8.16 kg) or less at 1 year to 13% (3/24) among those who had weighed 27 lb (12.25 kg) or more. Corresponding figures for diabetes were 17% (4/23) and nil (0/24). Plasma glucose concentrations at 30 and 120 minutes fell with increasing birth weight and weight at 1 year. Plasma 32-33 split proinsulin concentration fell with increasing weight at 1 year. All these trends were significant and independent of current body mass. Blood pressure was inversely related to birth weight and strongly related to plasma glucose and 32-33 split proinsulin concentrations. CONCLUSIONS--Reduced growth in early life is strongly linked with impaired glucose tolerance and non-insulin dependent diabetes. Reduced early growth is also related to a raised plasma concentration of 32-33 split proinsulin, which is interpreted as a sign of beta cell dysfunction. Reduced intrauterine growth is linked with high blood pressure, which may explain the association between hypertension and impaired glucose tolerance.

https://www.bmj.com/content/bmj/303/6809/1019.full.pdf

Fetal and infant growth and impaired glucose tolerance at age 64.

The thrifty phenotype hypothesis proposes that the epidemiological associations between poor fetal and infant growth and the subsequent development of type 2 diabetes and the metabolic syndrome result from the effects of poor nutrition in early life, which produces permanent changes in glucose-insulin metabolism. These changes include reduced capacity for insulin secretion and insulin resistance which, combined with effects of obesity, ageing and physical inactivity, are the most important factors in determining type 2 diabetes. Since the hypothesis was proposed, many studies world-wide have confirmed the initial epidemiological evidence, although the strength of the relationships has varied from one study to another. The relationship with insulin resistance is clear at all ages studied. Less clear is the relationship with insulin secretion. The relative contribution of genes and environment to these relationships remains a matter of debate. The contributions of maternal hyperglycaemia and the trajectory of postnatal growth need to be clarified.

/pdf/the-thrifty-phenotype-hypothesis-40kgfmvkvb.pdf

The thrifty phenotype hypothesis.

Two follow-up studies were carried out to determine whether lower birthweight is related to the occurrence of syndrome X-Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia. The first study included 407 men born in Hertfordshire, England between 1920 and 1930 whose weights at birth and at 1 year of age had been recorded by health visitors. The second study included 266 men and women born in Preston, UK, between 1935 and 1943 whose size at birth had been measured in detail. The prevalence of syndrome X fell progressively in both men and women, from those who had the lowest to those who had the highest birthweights. Of 64-year-old men whose birthweights were 2.95 kg (6.5 pounds) or less, 22% had syndrome X. Their risk of developing syndrome X was more than 10 times greater than that of men whose birthweights were more than 4.31 kg (9.5 pounds). The association between syndrome X and low birthweight was independent of duration of gestation and of possible confounding variables including cigarette smoking, alcohol consumption and social class currently or at birth. In addition to low birthweight, subjects with syndrome X had small head circumference and low ponderal index at birth, and low weight and below-average dental eruption at 1 year of age. It is concluded that Type 2 diabetes and hypertension have a common origin in sub-optimal development in utero, and that syndrome X should perhaps be re-named "the small-baby syndrome".

/pdf/type-2-non-insulin-dependent-diabetes-mellitus-hypertension-c95voh2h4l.pdf

Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(97)07244-9.pdf

C. N. Hales

Papers

Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis.

Fetal and infant growth and impaired glucose tolerance at age 64.

The thrifty phenotype hypothesis.

Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth

Glucose tolerance in adults after prenatal exposure to famine.