Use of biosynthetic human C-peptide in the measurement of insulin secretion rates in normal volunteers and type I diabetic patients.

Polonsky, Kenneth S.; Licinio, Júlio; Given, Bruce D.; Pugh, William; Rue, Paul A.; Galloway, John A.; Karrison, Theodore; Frank, Bruce H.

doi:10.1172/jci112308

Cited by 375 publications

(246 citation statements)

References 40 publications

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“…The reference method for clinical measurement of pre-hepatic pancreatic insulin secretion is deconvolution of plasma C-peptide concentrations using rate constants and volumes of distribution derived by two-compartment modelling of the decay of plasma C-peptide concentrations after a bolus injection of synthetic C-peptide [42,43]. In a recent methodological comparison, both the combined model and population parameter deconvolution approaches to estimating pancreatic secretion rates provided secretion measures which were consistent with those from the reference method [44].…”

Section: Discussionmentioning

confidence: 93%

Loss of beta cell function as fasting glucose increases in the non-diabetic range

2004

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Aims/hypothesis. Our aim was to define the level of glycaemia at which pancreatic insulin secretion, particularly first-phase insulin release, begins to decline. Methods. Plasma glucose and insulin concentrations were measured during an IVGTT in 553 men with non-diabetic fasting plasma glucose concentrations. In 466 of the men C-peptide was also estimated. IVGTT insulin secretion in first and late phases was assessed by: (i) the circulating insulin response; (ii) population parameter deconvolution analysis of plasma C-peptide concentrations; and (iii) a combined model utilising both insulin and C-peptide concentrations. Measurements of insulin sensitivity and elimination were also derived by modelling analysis.Results. As fasting plasma glucose (FPG) increased, IVGTT first-phase insulin secretion declined by 73%, 71% and 68% for the three methods respectively. The FPG values at which this decline began, determined by change point regression, were 4.97, 5.16 and 5.42 mmol/l respectively. The sensitivity of late-phase insulin secretion to glucose declined at FPG concentrations above 6.0 mmol/l. Insulin elimination, but not insulin sensitivity, varied with FPG. IntroductionThe respective roles of insulin deficiency and insulin resistance in the development of Type 2 diabetes mellitus remain controversial [1,2]. In response to a glucose stimulus, two phases of insulin secretion may be distinguished [3]. The first occurs as an immediate response to a rise in blood glucose concentrations. Low first-phase insulin release is an early abnormality in deteriorating glucose homeostasis and predicts the subsequent development of Type 2 diabetes [4,5,6,7]. Late-phase insulin release is more prolonged, but of lesser amplitude. It includes the progressively increasing second phase of insulin secretion seen in response to sustained hyperglycaemia [3], and also the compensatory insulin secretion that is the feedback response to a continued increase in circulating glucose. This late-phase insulin secretion may seem to be preserved even when glucose metabolism is defective,In the course of this work, our colleague and co-author James Jeffs died unexpectedly after a short illness. His contribution will be greatly missed.

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Section: Discussionmentioning

confidence: 93%

Loss of beta cell function as fasting glucose increases in the non-diabetic range

2004

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“…There is no evidence of a changed metabolic clearance rate of either proinsulin or C-peptide in diabetic subjects [21][22][23]. Thus, apart from the possible modulating effect of insulin, it seems justified that the plateau-shaped further elevation of proinsutin/C-peptide ratio in the placebo group reflects alterations of B-cell function during remission and relapse.…”

Section: Discussionmentioning

confidence: 96%

Proinsulin and C-peptide at onset and during 12 months cyclosporin treatment of Type 1 (insulin-dependent) diabetes mellitus

Snorgaard¹,

Hartling²,

Binder³

1990

Diabetologia

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Smnmary. An increased proinsulin to C-peptide molar ratio at the onset of Type i (insulin-dependent) diabetes mellitus has been suggested. We studied fasting proinsulin levels and proinsulin/C-peptide ratios in the newly diagnosed diabetic subjects participating in the Canadian/European placebo controlled cyclosporin study at entry, during the one year treatment period and six months of follow-up. Available entry data from 176 out of the 188 allocated patients were compared to 60 age and weight matched control subjects. Fasting proinsulin was significantly elevated in male patients compared to male control subjects (p < 0.01), whereas the levels only tended to be elevated in female patients. The proinsulin/C-peptide ratio was three to fourfold elevated in the diabetic groups of both sexes, (p < 0.001). Further, proinsulin and C-peptide were studied in 83 cyclosporin and 86 placebo-treated subjects during the trial and follow-up. An additional increase of proinsulin/C-peptide ratio was observed during the first three months of placebo treatment. It remained constantly high for nine months and then declined to entry level. This pattern was not seen in the cyclosporintreated group, where the ratio was unchanged during the 12 months trial and follow-up. The effect of cyclosporin on the induction of non-insulin requiring remission was unrelated to fasting and glucagon stimulated C-peptide levels at entry, whereas 64% of the cyclosporin-treated against 28% of the placebo-treated subjects (p < 0.01) went into remission if the proinsulin/C-peptide ratio at entry was above 0.024. If the ratio was below 0.024 at entry, 42% and 33% went into noninsulin requiring remission, respectively (NS). We conclude that fasting proinsulin to C-peptide molar ratio is elevated at the onset of Type i diabetes mellitus. A further plateaushape elevation lasting nine months was seen during the remission period. Cyclosporin seems to inhibit or delay this development. The proinsulin/C-peptide ratio at diagnosis may show to be of value in the prediction of remission during cyclosporin treatment.

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“…Standard parameters for C-peptide kinetics [13] were utilized to derive insulin secretory rates (ISR's) from the plasma C-peptide concentrations by deconvolution as previously described [14]. The C-peptide profiles were smoothed with a 2-point moving average before calculating the ISR's.…”

Section: Methodsmentioning

confidence: 99%

Insulin secretory responses to rising and falling glucose concentrations are delayed in subjects with impaired glucose tolerance

et al. 2002

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Impaired glucose tolerance (IGT) is defined by an increase in plasma glucose in response to an oral glucose challenge to levels intermediate between normal and diabetic [1] and is a risk factor for the subsequent development of diabetes [2]. The transition from normal glucose tolerance to IGT is characterized by a reduction in the ability of the pancreatic beta cell to sustain its compensatory response to insulin resistance [3]. When compared to subjects with normal glucose tolerance, those with IGT have a blunted insulin secretory response to the rise in glucose during a rapidly sampled intravenous glucose tolerance test (IVGTT) and a shift to the right in the dose-response curve relating the plasma glucose concentration to the insulin secretion rate [4,5]. IGT is additionally Diabetologia (2002) Abstract Aims/hypothesis. We hypothesized that beta-cell responses to changes in glucose would not be normal in subjects with impaired glucose tolerance (IGT). Methods. Three groups of 6 subjects were studied: normal weight with normal glucose tolerance (control subjects); obese with normal glucose tolerance (Obese-NGT); and obese with IGT (Obese-IGT). All subjects had a graded glucose infusion protocol to increase (step-up) and then decrease (step-down) plasma glucose. We obtained average insulin-secretion rates (ISR) over the glucose range common to all three groups during step-up and step-down phases, minimal model indices of beta-cell function (φ b , φ d , φ s , T up , T down ), and insulin sensitivity (Si). Results. ISR differed significantly between step-up and -down phases only in Obese-IGT individuals. Basal (φ b ) and stimulated (φ d , φ s ) beta-cell sensitivity to glucose were similar in the three groups. Delays between glucose stimulus and beta-cell response during both step-up (T up ) and -down (T down ) phases were higher in Obese-IGT compared to Controls and Obese-NGT individuals. The product ISR Si (10 ±5´m in ±2 l) was lower in Obese-IGT compared to Controls, both during step-up (919 851 vs 3192 1185, p < 0.05) and step-down (1455 1203 vs 3625 691, p < 0.05) phases. Consistently, the product φ s Si (10 ±14´m in ±2´p mol ±1 l) was lower in Obese-IGT than in control subjects (27.6 25.4 vs 103.1 20.2, p < 0.05). Conclusion/interpretation. Subjects with IGT are not able to secrete insulin to compensate adequately for insulin resistance. They also show delays in the timing of the beta-cell response to glucose when glucose levels are either rising or falling. [Diabetologia (2002) 45:509±517]

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Use of biosynthetic human C-peptide in the measurement of insulin secretion rates in normal volunteers and type I diabetic patients.

Cited by 375 publications

References 40 publications

Loss of beta cell function as fasting glucose increases in the non-diabetic range

Loss of beta cell function as fasting glucose increases in the non-diabetic range

Proinsulin and C-peptide at onset and during 12 months cyclosporin treatment of Type 1 (insulin-dependent) diabetes mellitus

Insulin secretory responses to rising and falling glucose concentrations are delayed in subjects with impaired glucose tolerance

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