Vella, Adrian

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).

OBJECTIVE The MHC region harbors the strongest loci for latent autoimmune diabetes in adults (LADA); however, the strength of association is likely attenuated compared with that for childhood-onset type 1 diabetes. In this study, we recapitulate independent effects in the MHC class I region in a population with type 1 diabetes and then determine whether such conditioning in LADA yields potential genetic discriminators between the two subtypes within this region. RESEARCH DESIGN AND METHODS Chromosome 6 was imputed using SNP2HLA, with conditional analysis performed in type 1 diabetes case subjects (n = 1,985) and control subjects (n = 2,219). The same approach was applied to a LADA cohort (n = 1,428) using population-based control subjects (n = 2,850) and in a separate replication cohort (656 type 1 diabetes case, 823 LADA case, and 3,218 control subjects). RESULTS The strongest associations in the MHC class II region (rs3957146, β [SE] = 1.44 [0.05]), as well as the independent effect of MHC class I genes, on type 1 diabetes risk, particularly HLA-B*39 (β [SE] = 1.36 [0.17]), were confirmed. The conditional analysis in LADA versus control subjects showed significant association in the MHC class II region (rs3957146, β [SE] = 1.14 [0.06]); however, we did not observe significant independent effects of MHC class I alleles in LADA. CONCLUSIONS In LADA, the independent effects of MHC class I observed in type 1 diabetes were not observed after conditioning on the leading MHC class II associations, suggesting that the MHC class I association may be a genetic discriminator between LADA and childhood-onset type 1 diabetes.

The characteristics of pulsatile insulin secretion are important determinants of type 2 diabetes pathophysiology, but they are understudied due to the difficulties in measuring pulsatile insulin secretion noninvasively. Deconvolution of either peripheral C-peptide or insulin concentrations offers an appealing alternative to hepatic vein catheterization. However, to do so, there are a series of methodological challenges to overcome. C-peptide has a relatively long half-life and accumulates in the circulation. On the other hand, peripheral insulin concentrations reflect relatively fast clearance and hepatic extraction as it leaves the portal circulation to enter the systemic circulation. We propose a method based on nonparametric stochastic deconvolution of C-peptide concentrations, using individually determined C-peptide kinetics, to overcome these limitations. The use of C-peptide (instead of insulin) concentrations allows estimation of portal (and not post-hepatic) insulin pulses, whereas nonparametric stochastic deconvolution allows evaluation of pulsatile signals without any a priori assumptions of pulse shape and occurrence. The only assumption required is the degree of smoothness of the (unknown) secretion rate. We tested this method first on simulated data and then on 29 nondiabetic subjects studied during euglycemia and hyperglycemia and compared our estimates with the profiles obtained from hepatic vein insulin concentrations. This method produced satisfactory results both in the ability to fit the data and in providing reliable estimates of pulsatile secretion, in agreement with hepatic vein measurements. In conclusion, the proposed method enables reliable and noninvasive measurement of pulsatile insulin secretion. Future studies will be needed to validate this method in people with type 2 diabetes.

A hepatoselective glucokinase activator reduced hyperglycemia without hypoglycemia or adverse effects on lipids, liver enzymes, or blood pressure.

OBJECTIVELatent autoimmune diabetes in adults (LADA) shares clinical features with both type 1 and type 2 diabetes; however, there is ongoing debate regarding the precise definition of LADA. Understanding its genetic basis is one potential strategy to gain insight into appropriate classification of this diabetes subtype.RESEARCH DESIGN AND METHODSWe performed the first genome-wide association study of LADA in case subjects of European ancestry versus population control subjects (n = 2,634 vs. 5,947) and compared against both case subjects with type 1 diabetes (n = 2,454 vs. 968) and type 2 diabetes (n = 2,779 vs. 10,396).RESULTSThe leading genetic signals were principally shared with type 1 diabetes, although we observed positive genetic correlations genome-wide with both type 1 and type 2 diabetes. Additionally, we observed a novel independent signal at the known type 1 diabetes locus harboring PFKFB3, encoding a regulator of glycolysis and insulin signaling in type 2 diabetes and inflammation and autophagy in autoimmune disease, as well as an attenuation of key type 1–associated HLA haplotype frequencies in LADA, suggesting that these are factors that distinguish childhood-onset type 1 diabetes from adult autoimmune diabetes.CONCLUSIONSOur results support the need for further investigations of the genetic factors that distinguish forms of autoimmune diabetes as well as more precise classification strategies.

Glucose tolerance after meal ingestion in vivo is the result of multiple processes that occur in parallel. Insulin secretion together with reciprocal inhibition of glucagon secretion contributes to glucose tolerance. However, other factors beyond glucose effectiveness and insulin action require consideration. The absorption of ingested nutrients and their subsequent systemic rate of appearance largely depend on the rate of delivery of nutrients to the proximal small intestine. This is determined by the integrated response of the upper gastrointestinal tract to a meal. While gastric emptying is probably the most significant component, other factors need to be considered. This review will examine all processes that could potentially alter the fraction and rate of appearance of ingested nutrients in the peripheral circulation. Several of these processes may be potential therapeutic targets for the prevention and treatment of diabetes. Indeed, there is increased interest in gastrointestinal contributions to nutritional homeostasis, as demonstrated by the advent of antidiabetes therapies that alter gastrointestinal motility, the effect of bariatric surgery on diabetes remission, and the potential of the intestinal microbiome as a modulator of human metabolism. The overall goal of this review is to examine current knowledge of the gastrointestinal contributions to metabolic control.