Development of hyperinsulinemia and insulin resistance during the early stage of weight gain

Abstract

-Obesity is associated with insulin resistance and hyperinsulinemia, which is considered to be a core component in the pathophysiology of obesity-related comorbidities. As yet it is unknown whether insulin resistance and hyperinsulinemia already develop during weight gain within the normal range. In 10 healthy male subjects the effect of intentional weight gain by 2 BMI points was examined on insulin. C-peptide and glucose levels following a meal, 75 g of glucose, and a two-step hyperglycemic clamp increased plasma glucose by 1.38 and 2.75 mmol/l, respectively. Baseline insulin, C-peptide, and glucose concentrations were significantly higher after weight gain from 21.8 to 23.8 kg/m 2 BMI within 41/2 mo. Calculations of insulin secretion and clearance indicate that reduced insulin clearance contributes more to post-weight gain basal hyperinsulinemia than insulin secretion. Following oral or intravenous stimulation insulin concentrations were significantly higher postweight gain during all three test conditions, whereas C-peptide and glucose levels did not differ. Calculations of insulin secretion and clearance demonstrated that higher stimulated insulin concentrations are entirely due to clearance but not secretion. Despite significantly higher insulin levels, the rate of intravenous glucose required to maintain the defined elevation of glucose levels was either identical (1.38 mmol/l) or even significantly lower (2.75 mmol/l) following weight gain. The present study demonstrates for the first time that insulin resistance already develops during weight gain within the normal range of body weight. The associated basal and stimulated hyperinsulinemia is the result of differentiated changes of insulin secretion and clearance, respectively. insulin secretion; obesity; insulin clearance OVERWEIGHT AND OBESITY represent a worldwide increasing problem that greatly raises the risk of the development of cardiovascular disease, severe metabolic disorders such as type 2 diabetes mellitus or various malignances (22), and related mortality (5). Obesity is associated with insulin resistance and subsequent hyperinsulinemia, which has been known for more than 40 years (21, 35), and it is considered to be a core component in the pathophysiology of obesity-related comorbidities (19).Increased peripheral plasma insulin concentrations can be attributed to stimulation of pancreatic insulin secretion. On the other hand, insulin is extracted to a considerable and varying degree during its passage through the liver, which is an important physiological mechanism for the postprandial increase of peripheral plasma insulin concentrations (29, 39). Several studies have reported that both mechanisms of action contribute to the pathophysiologically relevant hyperinsulinemia of overweight and obese subjects. In the basal state, hypersecretion (3, 13, 14, 31) as well as decreased hepatic insulin clearance (38) have been demonstrated. Similarly, both mechanisms are relevant during stimulation by a meal (31, 37), an oral glucose load (3, 13, 28), ...

A family history of type 2 diabetes increases risk factors associated with overfeeding

“…This is consistent with previous studies of short-term (3-days) [15] and long-term 272 (4.5-months) overfeeding [32] in healthy lean men. Our initial hypothesis was that FH+ 273 would have greater metabolic defects associated with overfeeding.…”

“…Consistently, in response to 5-days overfeeding, healthy lean 280 men increased insulin secretion during IVGTT [12]. In longer term overfeeding studies, 281 reduced insulin clearance was observed after 4.5-months and significant weight gain in lean 282 young men [32]. These findings are similar to those in moderately fat fed dogs, where an 283 initial increase in beta cell secretion is observed at 6-weeks, which is no longer evident at 3-284 months when hyperinsulinemia is maintained via reduced insulin clearance by the liver [33].…”

Effects of brief perturbations in energy balance on indices of glucose homeostasis in healthy lean men

“…Likewise, previous studies have found a consistent decrease in IS in response to short-term OF (X7 days) in healthy lean subjects, as assessed by hyperinsulinemic euglycemic clamp, 14,15 and by oral or intravenous glucose tolerance test. 14,16 In these studies, including OF up to 14 days, mean weight change varied between 0.3 and 3.0 kg, 12,15,16 which is similar to the 1.6 kg weight gain in our subjects (Figure 1b). The observed decrease in IS with OF might be due to metabolic effects of increased energy and macronutrient intake per se, as well as to alterations in body composition (i.e., an accumulation of ectopic fat).…”

“…In lean men, clamp-derived IS remained unchanged following 3 days OF at þ 50% energy, 13 whereas an increase in body mass index by two units has been shown to impair IS in the fasting state, in response to oral and intravenous glucose load, as well as during an euglycemic glucose clamp protocol. 14 A more recent study on lean men has shown that 5 days of high-fat OF at þ 50% energy needs induced a decline in hepatic IS as assessed by clamp, which was compensated by increased insulin secretion. 12 As insulin secretion may compensate for changes in IS in healthy individuals, it is crucial to examine IS in relation to insulin secretion.…”

Acute exercise restores insulin clearance in diet-induced obese mice

“…Although insulin secretion has been extensively studied (Mayhew et al 1969, Meglasson & Matschinsky 1986, Prentki et al 2013, less attention has been paid to insulin clearance. However, this process seems to be as important (or even more) as insulin secretion in the establishment of hyperinsulinemia in obese patients (Erdmann et al 2008(Erdmann et al , 2009). …”