The relationship between obesity and type 2 diabetes has been known for decades and the recent important increase in such diseases represents a major medical problem worldwide. Several prospective studies present both impaired insulin release and insulin resistance as the major factors for the development of type 2 diabetes. The factor that dominates in obesity is the permanent elevation of plasma FFA and the predominant utilization of lipids by the muscle inducing a diminution of glucose uptake and, therefore, insulin resistance. The rise in insulin secretion appears to be a compensatory mechanism that responds to the increased levels of circulating glucose. The fall in insulin secretion occurs as a late phenomenon. The present review aims at analysing the mechanisms that lead human obesity to type 2 diabetes and using the pathophysiological information for the prevention of diabetes. The partial reversibility of the evolution of obesity towards diabetes is well demonstrated today by lifestyle changes and multidisciplinary weight loss programs.

The glucose-induced thermogenesis (GIT) following a 100-g oral glucose load has been measured by continuous indirect calorimetry in 55 nondiabetic and diabetic obese subjects of various ages and compared with two control groups of 17 young and 13 elderly nonobese subjects. The obese subjects were divided into four groups: group A, normal glucose tolerance; group B, impaired glucose tolerance; group C, diabetes with increased insulin response; group D, diabetes with reduced insulin response. The glucose-induced thermogenesis measured during 3 h represented 8.6 ± 0.7% of the energy content of the load in the young control group. In all obese groups, the glucose-induced thermogenesis was significantly lower than in the young control group, i.e., 6.6 ± 0.9%, 6.4 ± 0.6%, 3.7 ± 0.7%, and 2.2 ± 0.4% in groups A, B, C, and D, respectively. Since the obese diabetics were older than the other groups, their glucose-induced thermogenesis was compared with that of the elderly control group; the latter (5.8 ± 0.3%) was significantly lower (P < 0.05) than that of the young control group. The obese diabetics also had a significantly lower glucose-induced thermogenesis than the elderly control group (P < 0.02 and P < 0.001 for groups C and D, respectively). When corrected for glucosuria and after taking into account the glucosuria and the changes in the glucose space, the corrected glucose-induced thermogenesis (i.e., related to glucose “uptake”), was still significantly reduced in group A versus the young control group (6.6 ± 0.9 versus 8.6 ± 0.7%, P < 0.05), and in group D versus the elderly (matched for age) control group (4.2 ± 0.7 versus 5.8 ± 0.3%, P < 0.05). It is concluded that the postprandial thermogenesis induced by glucose ingestion is decreased in the presence of insulin resistance and/or reduced insulin response to the glucose load in obese subjects. In addition, age itself contributes to decrease glucose-induced thermogenesis.

Glucose and lipid metabolism were studied in 12 patients with hyperthyroid Graves' disease for 3 h during an oral glucose tolerance test (100 g) by continuous indirect calorimetry. In the postabsorptive state, glucose oxidation was not different from that in normal subjects, but lipid oxidation was significantly increased. Impaired glucose tolerance was found, but total glucose oxidation increased after the glucose load to 47.1 +/- 2.0 (+/- SEM) vs. 33.4 +/- 1.4 g/3 h in the control group (P less than 0.001). Total glucose oxidation corresponded, in hyperthyroid patients, to the highest rate obtained with progressively increasing insulin and glucose administration in normal man. Glucose storage was clearly lower in hyperthyroid patients. After treatment in 7 patients, glucose tolerance improved significantly, and the metabolic patterns almost normalized. In the 12 hyperthyroid patients and the 7 patients after treatment (n = 19), a correlation was found between total serum T3 concentration and both basal lipid oxidation and suprabasal glucose oxidation. It is concluded that the decrease in glucose tolerance in hyperthyroidism cannot be explained by an alteration in glucose oxidation, but, rather, by a defect in nonoxidative glucose uptake in the periphery.

This finding suggests that the hormonal system of the duodenal mucosa is sensitive to glucose as an activator. Activation has been shown to occur in two phases.

(6_ 14 C) glucose (1.5-2 gm/kg body weight) was administered orally to fasted rats fed for five weeks from weaning a fat or a carbohydrate synthetic diet. Rats were killed by deca-PAtation at 30, 60, 120 and 180 minutes after the load. ein the gut, glucose (6-14 C) glucose and insulin in the serum, glycogen and (1~C) glycogen in the liver, were measured. Fat-adapted rats exhibited impaired glucose tolerance and sensitivity to endogenous insulin which resulted in higher levels of exogenous glucose in the serum and in some slackening of disposal of the load by the tissues. An altered r~ lease of glucose by the liver does not seem to be a major factor of hyperglycaemia in these conditions. The level of liver glycogen before the load and throughout the experiment is higher in the fat group. As in the contral group, hepatic glycogen synthesis after glucose administration develops linearly between 30 and 120 minutes without any evident relation to the time variation of the level and the specific radioactivity of serum glucose. In addition, the specific activity of glycogen stabilized to a value much low• er than that of the load glucose. After fat diet, a significant reduction of the amount of 14 carbon incorporated into liver glycogen was observed which can contribute to the decrease of tolerance to orally administered glucose.