Peripheral Hyperinsulinemia of Simple Obesity: Pancreatic Hypersecretion or Impaired Insulin Metabolism?*

Bonora, Enzo; Zavaroni, Ivana; Bruschi, F.; Alpi, O.; Pezzarossa, A.; Guerra, L.; Dall’Aglio, Elisabetta; Coscelli, C; Butturini, U

doi:10.1210/jcem-59-6-1121

Cited by 71 publications

(34 citation statements)

References 37 publications

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“…Several crosssectional studies have confirmed these findings of basal hyperinsulinemia (3,13,14,31,38). Furthermore, higher insulin concentrations of obese subjects have been shown in response to various stimuli such as a meal (31,37) or an oral (3,13,28) or iv glucose load (17,18,27,31,41,42).…”

Section: Discussionmentioning

confidence: 65%

“…On the other hand, it cannot totally be excluded that, due to BIA measurement in the present study, the change of body fat might have been underestimated. Basal hyperinsulinemia of obese subjects has been attributed to an increase of insulin secretion in most studies (3,13,14,31). An additional contribution of clearance was reported by Rossell et al (38).…”

Section: Discussionmentioning

confidence: 93%

“…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), or an intravenous glucose load (17,18,27,31,41,42), respectively.…”

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confidence: 99%

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

Erdmann

Kallabis²,

Oppel³

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

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-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), ...

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Section: Discussionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 93%

mentioning

confidence: 99%

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

Erdmann

Kallabis²,

Oppel³

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

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“…Although they showed a normalization of insulin secretion rate, these studies could not separate the contribution from insulin sensitivity versus weight as both simultaneously improved. This issue is important because obesity has been implicated to increase insulin secretion (13,28,29). In addition, methods to estimate GS-ISR were different from the current study and used single glucose injection (10,12) or fixed glucose infusion (11) with subsequent quantification of C-peptide response.…”

Section: Discussionmentioning

confidence: 91%

Rosiglitazone Reduces Glucose-Stimulated Insulin Secretion Rate and Increases Insulin Clearance in Nondiabetic, Insulin-Resistant Individuals

et al. 2005

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Compensatory hyperinsulinemia permitting insulin-resistant individuals to maintain normal glucose tolerance is associated with a left shift in the glucosestimulated insulin secretion rate (GS-ISR) doseresponse curve and decrease in the insulin metabolic clearance rate (I-MCR). To see whether these changes would reverse with improvement in insulin sensitivity, 14 nondiabetic insulin-resistant subjects received rosiglitazone for 12 weeks (4 mg daily for 4 weeks and then 8 mg daily for 8 weeks). Insulin-mediated glucose uptake was quantified by measuring the steady-state plasma glucose concentration during the insulin suppression test. GS-ISR and I-MCR were determined during a 240-min graded intravenous glucose infusion. I-MCR was also calculated during the insulin suppression test. After rosiglitazone treatment, insulin sensitivity improved with significant fall in steady-state plasma glucose (means ؎ SE from 13.5 ؎ 0.62 to 9.8 ؎ 1.02 mmol/l, P < 0.001). In response, the integrated GS-ISR decreased by 21% (P < 0.001), with a right shift in the dose-response curve. Calculated I-MCR increased by 34% (P ‫؍‬ 0.008) during the insulin suppression test and by 21% (P ‫؍‬ 0.03) during the graded glucose infusion. In conclusion, enhanced insulin sensitivity in rosiglitazone-treated nondiabetic insulin-resistant individuals was associated with a shift to the right in the GS-ISR dose-response curve and an increase in I-MCR. Diabetes 54:2447-2452, 2005 I n insulin-resistant individuals, glucose homeostasis can be maintained if the defect in insulin action is adequately compensated for by an increase in insulin concentration. This is achieved by a shift to the left of the glucose-stimulated insulin secretion rate (GS-ISR) dose-response curve, as well as by a decrease in the insulin metabolic clearance rate (I-MCR) (1,2). Therefore, for any given plasma glucose concentration, there is more insulin secreted by pancreatic ␤-cells and less insulin cleared in insulin-resistant individuals when compared with their insulin-sensitive counterparts. Although the ensuing hyperinsulinemia is capable of preventing gross decompensation of glucose tolerance, it increases the likelihood that insulin-resistant/hyperinsulinemic individuals will develop a variety of clinical syndromes including cardiovascular disease, essential hypertension, polycystic ovary syndrome, nonalcoholic fatty liver disease, and certain forms of cancer (3-9).Studies in nondiabetic, insulin-resistant obese individuals have demonstrated that GS-ISR and the I-MCR can return toward normal when insulin sensitivity improves with weight loss (10 -12). However, because obesity may be independently associated with an increase in insulin secretion (13) and a decrease in insulin clearance (14), the impact of improving insulin sensitivity apart from weight loss is unknown. The current study was initiated to understand whether the changes in GS-ISR and I-MCR, already noted when weight loss occurs in overweight insulin-resistant subjects, would also occur when enhanced insulin sensi...

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“…Insulin metabolism was evaluated indirectly from the molar ratio of C-peptide to insulin at fasting and after ingestion of glucose as well as from the difference between incremental areas of C-peptide and insulin divided by incremental area of C-peptide. Such an approach was used by other investigators and our selves in studies concerning obesity [27][28][29][30][31], glucose intolerance [32][33][34], pregnancy [35], chronic liver dis ease [36][37][38][39], elderly subjects [40], hyperthyroidism [41 ]. as well as investigations in healthy subjects with a family history of diabetes [42,43] or undergoing a comparison between oral and intravenous glucose loads [44.…”

Section: Methodsmentioning

confidence: 99%

Insulin Metabolism Is a Major Factor Responsible for High or Low Peripheral Insulin Levels in Response to Oral Glucose Loading in the Healthy Man

Bonora¹,

Coscelli²,

Butturini³

1986

Ann Nutr Metab

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In the present study we evaluated C-peptide peripheral levels after an oral glucose load in 30 healthy subjects (18 females, 12 males, aged from 15 to 55) with high or low insulin response to glucose challenge in order to clarify whether or not their β-cell secretion rate keeps pace with peripheral insulin levels. Moreover, by the study of the relations between C-peptide and insulin in peripheral blood, we had an insight into the extent of insulin metabolism. On the basis of an insulin incremental area higher or lower than the mean ± 1 SD after a 100-gram oral glucose load, 6 subjects were classified as ‘high insulin responders’ and 6 other subjects as ‘low insulin responders’. Their insulin incremental area after glucose averaged 0.25 ± 0.01 nmol·l^-1·min and 0.078 ± 0.005 nmol·l^-1·min, respectively (p < 0.001). The two groups were matched for sex, age and body weight. The glycemic profile after oral glucose load was higher in low insulin responders than in high insulin responders. C-peptide concentrations after glucose load were similar in the two groups, as well as C-peptide incremental areas (0.92 ± 0.12 vs. 0.74 ± 0.08 nmol·l^-1·min in high insulin responders and low insulin responders, respectively). The molar ratios of C-peptide to insulin after oral glucose load, as well as the relations between the incremental areas of the two peptides, were significantly lower in high insulin responders than in low insulin responders. We conclude that in the healthy man a ‘low’ or ‘high’ peripheral insulin response to oral glucose loading is not synonymous with decreased or exaggerated production and/or release of insulin by the pancreatic β-cell. Differences in the metabolic clearance rate of insulin seem primarily to account for the great variability of peripheral insulin levels after glucose challenge.

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Peripheral Hyperinsulinemia of Simple Obesity: Pancreatic Hypersecretion or Impaired Insulin Metabolism?*

Cited by 71 publications

References 37 publications

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

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

Rosiglitazone Reduces Glucose-Stimulated Insulin Secretion Rate and Increases Insulin Clearance in Nondiabetic, Insulin-Resistant Individuals

Insulin Metabolism Is a Major Factor Responsible for High or Low Peripheral Insulin Levels in Response to Oral Glucose Loading in the Healthy Man

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