LAURENTI, MARCELLO C.

In prediabetes, anthropometric characteristics as well as insulin action do not alter the hepatic response to glucagon. The postprandial suppression or lack of suppression of glucagon secretion is an important factor governing postprandial glucose tolerance independent of insulin secretion.

Abstract Context Familial partial lipodystrophy (FPL), Dunnigan variety is characterized by skeletal muscle hypertrophy and insulin resistance besides fat loss from the extremities. The cause for the muscle hypertrophy and its functional consequences is not known. Objective To compare muscle strength and endurance, besides muscle protein synthesis rate between subjects with FPL and matched controls (n = 6 in each group). In addition, we studied skeletal muscle mitochondrial function and gene expression pattern to help understand the mechanisms for the observed differences. Methods Body composition by dual-energy X-ray absorptiometry, insulin sensitivity by minimal modelling, assessment of peak muscle strength and fatigue, skeletal muscle biopsy and calculation of muscle protein synthesis rate, mitochondrial respirometry, skeletal muscle transcriptome, proteome, and gene set enrichment analysis. Results Despite increased muscularity, FPL subjects did not demonstrate increased muscle strength but had earlier fatigue on chest press exercise. Decreased mitochondrial state 3 respiration in the presence of fatty acid substrate was noted, concurrent to elevated muscle lactate and decreased long-chain acylcarnitine. Based on gene transcriptome, there was significant downregulation of many critical metabolic pathways involved in mitochondrial biogenesis and function. Moreover, the overall pattern of gene expression was indicative of accelerated aging in FPL subjects. A lower muscle protein synthesis and downregulation of gene transcripts involved in muscle protein catabolism was observed. Conclusion Increased muscularity in FPL is not due to increased muscle protein synthesis and is likely due to reduced muscle protein degradation. Impaired mitochondrial function and altered gene expression likely explain the metabolic abnormalities and skeletal muscle dysfunction in FPL subjects.

Pancreatic β-cells are responsible for the synthesis and exocytosis of insulin in response to an increase in circulating glucose. Insulin secretion occurs in a pulsatile manner, with oscillatory pulses superimposed on a basal secretion rate. Insulin pulses are a marker of β-cell health, and secretory parameters, such as pulse amplitude, time interval and frequency distribution, are impaired in obesity, aging and type 2 diabetes. In this review, we detail the mechanisms of insulin production and β-cell synchronization that regulate pulsatile insulin secretion, and we discuss the challenges to consider when measuring fast oscillatory secretion in vivo. These include the anatomical difficulties of measuring portal vein insulin noninvasively in humans before the hormone is extracted by the liver and quickly removed from the circulation. Peripheral concentrations of insulin or C-peptide, a peptide cosecreted with insulin, can be used to estimate their secretion profile, but mathematical deconvolution is required. Parametric and nonparametric approaches to the deconvolution problem are evaluated, alongside the assumptions and trade-offs required for their application in the quantification of unknown insulin secretory rates from known peripheral concentrations. Finally, we discuss the therapeutical implication of targeting impaired pulsatile secretion and its diagnostic value as an early indicator of β-cell stress.

Adipose inflammation is proposed to be at the nexus of the systemic inflammation and metabolic derangements associated with obesity. The present study provides evidence to support adipose inflammation as a central feature of the pathophysiology of obesity. Adipose inflammation is associated with systemic and peripheral metabolic derangements, including increased systemic inflammation, reduced insulin sensitivity and reduced skeletal muscle mitochondrial respiration.

Abstract Objective Pulsatile insulin secretion is impaired in diseases such as type 2 diabetes that are characterized by insulin resistance. This has led to the suggestion that changes in insulin pulsatility directly impair insulin signaling. We sought to examine the effects of pulse characteristics on insulin action in humans, hypothesizing that a decrease in pulse amplitude or frequency is associated with impaired hepatic insulin action. Methods We studied 29 nondiabetic subjects on two occasions. On 1 occasion, hepatic and peripheral insulin action was measured using a euglycemic clamp. The deuterated water method was used to estimate the contribution of gluconeogenesis to endogenous glucose production. On a separate study day, we utilized nonparametric stochastic deconvolution of frequently sampled peripheral C-peptide concentrations during fasting to reconstruct portal insulin secretion. In addition to measuring basal and pulsatile insulin secretion, we used approximate entropy to measure orderliness and Fourier transform to measure the average, and the dispersion of, insulin pulse frequencies. Results In univariate analysis, basal insulin secretion (R2 = 0.16) and insulin pulse amplitude (R2 = 0.09) correlated weakly with insulin-induced suppression of gluconeogenesis. However, after adjustment for age, sex, and weight, these associations were no longer significant. The other pulse characteristics also did not correlate with the ability of insulin to suppress endogenous glucose production (and gluconeogenesis) or to stimulate glucose disappearance. Conclusions Overall, our data demonstrate that insulin pulse characteristics, considered independently of other factors, do not correlate with measures of hepatic and peripheral insulin sensitivity in nondiabetic humans.

AbstractBackgroundThe fasting proinsulin to insulin ratio is elevated in people with type 2 diabetes and has been suggested as a marker of β‐cell health. However, its utility in discriminating between individuals with varying degrees of β‐cell dysfunction is unclear. Proinsulin has a very different half‐life to insulin and unlike insulin does not undergo hepatic extraction prior to reaching the systemic circulation. Given these limitations, we sought to examine the relationship between fasting and postprandial concentrations of β‐cell polypeptides (proinsulin, insulin and C‐peptide) in people with normal and impaired glucose tolerance in differing metabolic environments.DesignSubjects were studied on two occasions in random order while undergoing an oral challenge. During one study day, free fatty acids were elevated (to induce insulin resistance) by infusion of Intralipid with heparin. Proinsulin to insulin and proinsulin to C‐peptide ratios were calculated for the 0‐, 30‐, 60‐ and 240‐minute time points. Insulin action (Si) and β‐cell responsivity (Φ) indices were calculated using the oral minimal model.ResultsThe fasting proinsulin to c‐peptide or fasting proinsulin to insulin ratios did not differ between groups and did not predict subsequent β‐cell responsivity to glucose during the glycerol or Intralipid study days in either group.ConclusionsAmong nondiabetic individuals, the fasting proinsulin to insulin ratio is not a useful marker of β‐cell function.

State-of-the-art measurement of insulin secretion in humans is accomplished by deconvolution of peripheral C-peptide concentrations using population-derived parameters of C-peptide kinetics. In contrast, knowledge of the kinetic parameters of glucagon in humans is lacking so that measurement of glucagon secretion to date is largely qualitative. This series of experiments enabled measurement of glucagon kinetics in 51 subjects, and subsequently, stepwise linear regression was used to correlate these parameters with anthropometric characteristics. This enabled the development of a population-based model using anthropometric characteristics to predict the volume of distribution and the rate of clearance. This is a necessary first step in the development of a model to quantitate of glucagon secretion and action (and its contribution to glucose tolerance) in large populations.

BACKGROUND Metabolic disorders such as type 2 diabetes have been associated with a decrease in insulin pulse frequency and amplitude. We hypothesized that the T allele at rs7903146 in TCF7L2, previously associated with β cell dysfunction, would be associated with changes in these insulin pulse characteristics. METHODS Twenty-nine nondiabetic subjects (age 46 ± 2, BMI 28 ± 1 kg/m 2 ) participated in this study. Of these, 16 were homozygous for the C allele at rs7903146 and 13 were homozygous for the T allele. Deconvolution of peripheral C-peptide concentrations allowed the reconstruction of portal insulin secretion over time. These data were used for subsequent analyses. Pulse orderliness was assessed by approximate entropy (ApEn), and the dispersion of insulin pulses was measured by a frequency dispersion index (FDI) after a Fast Fourier Transform (FFT) of individual insulin secretion rates. RESULTS During fasting conditions, the CC genotype group exhibited decreased pulse disorderliness compared with the TT genotype group (1.10 ± 0.03 vs. 1.19 ± 0.04, P = 0.03). FDI decreased in response to hyperglycemia in the CC genotype group, perhaps reflecting less entrainment of insulin secretion during fasting. CONCLUSION Diabetes-associated variation in TCF7L2 is associated with decreased orderliness and pulse dispersion, unchanged by hyperglycemia. Quantification of ApEn and FDI could represent novel markers of β cell health. FUNDING This work was funded by US NIH (DK78646, DK116231), University of Padova research grant CPDA145405, and Mayo Clinic General Clinical Research Center (UL1 TR000135).