“Staircase” Glucose Stimulation of Insulin Secretion in Obesity: Measure of Beta-cell Sensitivity and Capacity

Karam, John H.; Grodsky, Gerold M.; Ching, K N; Schmid, Florence G.; Burrill, Karen C.; Forsham, Peter H.

doi:10.2337/diab.23.9.763

Cited by 29 publications

(7 citation statements)

References 16 publications

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“…Comparison of responses across healthy nonobese, obese nondiabetic, and T2DM subjects assessed using a GGI confirmed prior observations that insulin secretory capacity is significantly blunted in T2DM and tends to be exuberant in obese nondiabetics, presumably as a compensatory response to insulin resistance (8,21,22). The insulin secretory response in T2DM was diminished 3.5-fold compared with BMI-matched nondiabetic controls and was about one-half that of the healthy nonobese.…”

Section: Discussionsupporting

confidence: 75%

“…In prior literature addressing the ␤-cell response to hyperglycemia in vitro and in vivo, including GGI studies, some investigators have reported a plateau in the insulin secretory response (8,19,21,25), whereas others have reported linear relationships in individual populations over a limited range of glycemia (7,23,33). In the current set of studies, we did not detect a plateau in the relationship between hyperglycemia and insulin secretory response in any of the tested populations across a fairly wide range of glycemia.…”

Section: Discussioncontrasting

confidence: 65%

See 1 more Smart Citation

Linearity of β-cell response across the metabolic spectrum and to pharmacology: insights from a graded glucose infusion-based investigation series

Shankar

Mixson

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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earity of ␤-cell response across the metabolic spectrum and to pharmacology: insights from a graded glucose infusion-based investigation series. Am J Physiol Endocrinol Metab 310: E865-E873, 2016. First published April 12, 2016 doi:10.1152/ajpendo.00527.2015The graded glucose infusion (GGI) examines insulin secretory response patterns to continuously escalating glycemia. The current study series sought to more fully appraise its performance characteristics. Key questions addressed were comparison of the GGI to the hyperglycemic clamp (HGC), comparison of insulin secretory response patterns across three volunteer populations known to differ in ␤-cell function (healthy nonobese, obese nondiabetic, and type 2 diabetic), and characterization of effects of known insulin secretagogues in the context of a GGI. Insulin secretory response was measured as changes in insulin, C-peptide, insulin secretion rates (ISR), and ratio of ISR to prevailing glucose (ISR/G). The GGI correlated well with the HGC (r ϭ 0.72 for ISR/G, P Ͻ 0.01). The insulin secretory response in type 2 diabetes (T2DM) was significantly blunted (P Ͻ 0.001), whereas it was significantly increased in obese nondiabetics compared with healthy nonobese (P Ͻ 0.001). Finally, robust (P Ͻ 0.001 over placebo) pharmacological effects were observed in T2DM and healthy nonobese volunteers. Collectively, the findings of this investigational series bolster confidence that the GGI has solid attributes for assessing insulin secretory response to glucose across populations and pharmacology. Notably, the coupling of insulin secretory response to glycemic changes was distinctly and uniformly linear across populations and in the context of insulin secretagogues. (Clinical Trial Registration Nos. NCT00782418, NCT01055340, NCT01373450) graded glucose infusion; hyperglycemic clamp; nonobese; obese; diabetes; exenatide; liraglutide THE ABILITY TO APPROPRIATELY MODULATE insulin secretion in response to acute changes in prevailing glucose is the sine qua non of ␤-cell health (26,29,30). Glucose responsiveness of ␤-cells is diminished in individuals with type 2 diabetes mellitus (T2DM) (22), yet few clinical investigations describe the pattern of this impairment across a dynamic range of hyperglycemic stimulation. Instead, most extant clinical investigation literature centers upon insulin secretory response to a single level of hyperglycemic challenge (e.g., a hyperglycemic clamp) (10) or measured insulin secretion to a bolus glucose challenge (e.g., an IVGTT) (1). The intrinsic property of the ␤-cell to sense and respond to changes in circulating glucose is perhaps best described using the dynamic relationship between insulin secretion and glucose. Insulin secretory responses using data from an oral glucose or mixed-meal challenge have been examined in relation to the range of glycemia attained during that particular challenge (11, 12). Isolating and delineating ␤-cell response to glycemia alone, across a broad range of hyperglycemia, independent of incretin hormone responses ev...

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Section: Discussionsupporting

confidence: 75%

Section: Discussioncontrasting

confidence: 65%

Linearity of β-cell response across the metabolic spectrum and to pharmacology: insights from a graded glucose infusion-based investigation series

Shankar

Mixson

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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“…The overall magnitude of insulin response to the same intravenous glycaemic stimulus is markedly con-ditioned by the antecedent carbohydrate intake. High carbohydrate diet stimulates the islets, in particular the late insulin output [9], significantly more than an ordinary diet. Regarding the biphasic pattern of insulin release, similar effects were seen in both sucrose fed and starch fed rats.…”

Section: Discussionmentioning

confidence: 92%

Insulin secretion and biosynthesis in sucrose fed rats

et al. 1976

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Summary. Long term feeding of a sucrose rich diet to rats is accompanied by a decreased glucose assimilation rate, despite high plasma insulin levels. Hyperinsulinism is at least partially based on a relative obesity, with increased amounts of abdominal-and retroperitoneal fat tissue, but unchanged total body weight compared to starch fed controls. The " secretory pattern of insulin release was studied following glucose, arginine, fructose and sulfonylurea administration in the isolated perfused pancreas of sucrose and isocaloric starch fed rats. In addition, isolated islets of Langerhans were used to demonstrate the effects of glucose on insulin secretion and the incorporation of H-3 leucine into the proinsulin and insulin fraction of islet proteins. Following 11 mM glucose, the dynamics of insulin release in the isolated perfused pancreas of sucrose fed rats is characterized by a markedly elevated, late plateau-like response, usually seen only at higher glucose concentrations. Hyperinsulinism, as compared to starch fed controls, can also be demonstrated following arginine and the sulfonylurea HB-4t9, whereas fructose has no effect in the presence of low glucose concentrations. During incubation of the pancreatic islets, the hyperinsulinism in sucrose-, compared to starch fed rats, is more pronounced at 11 mM glucose than at 5.5 mM glucose. The incorporation of H-3 leucine into the proinsulininsulin fraction of islet proteins in sucrose compared to starch fed rats, however, is significantly greater with glucose 5.5 mM than at high glucose level. In sucrose fed rats, secretion and biosynthesis of insulin thus appear to be elevated but closely linked only at physiological glucose concentration. * This work was supported by Deutsche Forschungsgemeinschaft SFB 87, Endokrinotogie, Ulm.Key words: Sucrose, increased body fat, isolated perfused pancreas, dynamics of insulin secretion, hyperinsulinism, insulin biosynthesis, isolated islets of Langerhans.High sucrose concentration in the diet leads to a diabetic glucose tolerance in rats [4], despite elevated levels of glucose-induced insulin secretion [12]. This effect was correlated by some authors with the preferential rate of liver metabolism of fructose compared to glucose [24]. Others, however, considered this as a consequence of the fast postprandial blood sugar rise, resulting in a massive impact of glucose on the carbohydrate regulating mechanisms of the body, in particular the B-ceU [3]. Since delayed but increased insulin release and slow glucose assimilation rate are known to be frequently determined by diet composition [8] and obesity [1], we decided to analyze to what extent changes in the diet, in particular a high sucrose content, might affect the body fat content and the quantity of insulin release in rats.As there is no strict correlation between insulin secretion and biosynthesis [22], further studies, aimed at revealing the connection between both specific processes of the B-cell in sucrose induced diabetic metabolism in rats, were carried out. Materi...

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“…This "first" phase is followed by "second"-phase insulin secretion with less rapid rates of change but a much longer d~r a t i o n .~ First-phase insulin secretion has also been observed during hyperglycaemic glucose glucagon injection," and stepped glucose infusion. 12 The two phases are not apparent in experiments with oral glucose.…”

Section: First-and Second-phase Secretionmentioning

confidence: 98%