Maturity Onset Diabetes of the Young (MODY)

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147788/1/dme199613s690.pd

Supersymmetric Models With Tan(beta) Close to Unity

Within the framework of supersymmetric grand unification, estimates of the $b$ quark mass based on the asymptotic relation $m_b \simeq m_\tau$ single out the region with $\tan\beta$ close to unity, particularly if $m_t(m_t) \stackrel{_<}{_\sim} 170\ GeV$. We explore the radiative breaking of the electroweak symmetry and the associated sparticle and higgs spectroscopy in models with $1 < \tan\beta \stackrel{_<}{_\sim} 1.6$. The lightest scalar higgs is expected to have a mass below $100\ GeV$, while the remaining four higgs masses exceed $300\ GeV$. The lower bounds on some of the sparticle masses are within the range of LEP 200.Comment: 13 pages in plain LaTeX, BA-94-02, 15 figures (available on request

The NuTeV Anomaly, Neutrino Mixing, and a Heavy Higgs Boson

Recent results from the NuTeV experiment at Fermilab and the deviation of the Z invisible width, measured at LEP/SLC, from its Standard Model (SM) prediction suggest the suppression of neutrino-Z couplings. Such suppressions occur naturally in models which mix the neutrinos with heavy gauge singlet states. We postulate a universal suppression of the Z-nu-nu couplings by a factor of (1-epsilon) and perform a fit to the Z-pole and NuTeV observables with epsilon and the oblique correction parameters S and T. Compared to a fit with S and T only, inclusion of epsilon leads to a dramatic improvement in the quality of the fit. The values of S and T preferred by the fit can be obtained within the SM by a simple increase in the Higgs boson mass. However, if the W mass is also included in the fit, a non-zero U parameter becomes necessary which cannot be supplied within the SM. The preferred value of epsilon suggests that the seesaw mechanism may not be the reason why neutrinos are so light.Comment: 19 pages, REVTeX4, 8 postscript figures. Updated references. Typos correcte

Dark Matter And Bs→μ+μ−B_s \to \mu^+ \mu^- With Minimal SO10SO_{10} Soft SUSY Breaking

CMSSM boundary conditions are usually used when calculating cosmological dark matter densities. In this paper we calculate the cosmological density of dark matter in the MSSM using minimal $SO_{10}$ soft SUSY breaking boundary conditions. These boundary conditions incorporate several attractive features: they are consistent with $SO_{10}$ Yukawa unification, they result in a "natural" inverted scalar mass hierarchy and they reduce the dimension 5 operator contribution to the proton decay rate. With regards to dark matter, on the other hand, this is to a large extent an unexplored territory with large squark and slepton masses $m_{16}$, large $A_0$ and small $\{\mu, M_{1/2} \}$. We find that in most regions of parameter space the cosmological density of dark matter is considerably less than required by the data. However there is a well--defined, narrow region of parameter space which provides the observed relic density of dark matter, as well as a good fit to precision electroweak data, including top, bottom and tau masses, and acceptable bounds on the branching fraction of $B_s \to \mu^+ \mu^-$. We present predictions for Higgs and SUSY spectra, the dark matter detection cross section and the branching ratio ${\rm BR}(B_s\to \mu^+ \mu^-)$ in this region of parameter space.Comment: 15 pages, 5 figure

Modulation of glucose regulation and insulin secretion by circadian rhythmicity and sleep

To define the roles of circadian rhythmicity (intrinsic effects of time of day independent of the sleep or wake condition) and sleep (intrinsic effects of the sleep condition, irrespective of the time of day) on the 24-h variation in glucose tolerance, eight normal men were studied during constant glucose infusion for a total of 53 h. The period of study included 8 h of nocturnal sleep, 28 h of continuous wakefulness, and 8 h of daytime sleep. Blood samples for the measurement of glucose, insulin, C-peptide, cortisol, and growth hormone were collected at 20-min intervals throughout the entire study. Insulin secretion rates were derived from C-peptide levels by deconvolution. Sleep was polygraphically monitored. During nocturnal sleep, levels of glucose and insulin secretion increased by 31 ±5% and 60±11%, respectively, and returned to baseline in the morning. During sleep deprivation, glucose levels and insulin secretion rose again to reach a maximum at a time corresponding to the beginning of the habitual sleep period. The magnitude of the rise above morning levels averaged 17±5% for glucose and 49±8% for calculated insulin secretion. Serum insulin levels did not parallel the circadian variation in insulin secretion, indicating the existence of an approximate 40% increase in insulin clearance during the night. Daytime sleep was associated with a 16±3% rise in glucose levels, a 55±7% rise in insulin secretion, and a 39±5% rise in serum insulin. The diurnal variation in insulin secretion was inversely related to the cortisol rhythm, with a significant correlation of the magnitudes of their morning to evening excursions. Sleep-associated rises in glucose correlated with the amount of concomitant growth hormone secreted. These studies demonstrate previously underappreciated effects of circadian rhythmicity and sleep on glucose levels, insulin secretion, and insulin clearance, and suggest that these effects could be partially mediated by cortisol and growth hormone.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Oscillations in Insulin Secretion During Constant Glucose Infusion in Normal Man: Relationship to Changes in Plasma Glucose

Peripheral plasma or serum concentrations of glucose, insulin, C-peptide, glucagon, and cortisol and insulin secretory rates (ISR) were determined at 15-min intervals in eight normal subjects during a constant iv infusion of 4.5 mg glucose/kg� min for a 24-h period. During each sampling interval, the secretory rate of insulin was calculated by deconvolution of the peripheral plasma C-peptide concentration using C-peptide kinetic parameters derived after bolus injections of C-peptide in individual subjects. Periodogram analysis of the individual glucose curves demonstrated a circadian rhythm in all subjects, with a major nocturnal acrophase occurring at an average clock time of 0228 h (range, 0045-0350 h). In five of the eight subjects, a minor acrophase occurred at an average time of 1774 h (range, 1530-2045 h). This diurnal variation in plasma glucose levels was not paralleled by a similar pattern in insulin secretion. Although glucose was infused at a constant rate, significant pulses were found in glucose, insulin, and C-peptide levels and ISR; the pulse durations of these parameters were 182 ± 30 (± SE), 89 ± 5, 100 ± 8, and 85 ± 5 min, respectively, and their periodicities were 208 ± 33, 106 ± 7, 114 ± 10, and 106 ± 7 min. The durations and frequencies for pulses of insulin, C-peptide, and ISR were not significantly different, whereas glucose pulses had a longer duration and were less frequent (P < 0.05, by analysis of variance). On the average, 54 ± 9% of the C-peptide pulses and 47 ± 8% of the ISR pulses were concomitant with a pulse in glucose levels. Moreover, approximately half of the Cpeptide and ISR pulses that were not concomitant with a glucose pulse occurred in synchrony with a shoulder on the up-stroke or down-stroke of glucose pulses. Analysis of glucagon and cortisol profiles revealed no significant associations with the insulin and glucose oscillations. In conclusion, during a constant glucose infusion in normal subjects, regular oscillations of insulin secretion occur at 80- to 120-min intervals. Their tight coupling with glucose oscillations and the lack of association with fluctuations of glucagon and cortisol suggest that these oscillations represent a dynamic property of the insulin-glucose feedback loop. (J Clin Endocrinol Metab 67: 307, 1988). © 1988 by The Endocrine Society.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Abnormalities in the ultradian oscillations of insulin secretion and glucose levels in Type 2 (non-insulin-dependent) diabetic patients

To investigate the temporal organization of insulin secretion and glucose concentration during fasting in Type 2 (non-insulin-dependent) diabetes mellitus, we studied seven patients with Type 2 diabetes, eight obese non-diabetic control subjects and eight normal weight non-diabetic subjects. Blood sampling for glucose, insulin and C-peptide was performed at 15-min intervals during a 24-h period of fasting for the diabetic and the obese control subjects and during an 8-h fasting period for the normal subjects. Insulin secretion rates were calculated from the peripheral C-peptide concentration profiles. Ultradian oscillations of glucose levels and insulin secretion rates were evident during fasting in all subjects. An additional study with blood sampling at 2-min intervals for 8 h further indicated that this ultradian periodicity is expressed independently of rapid 10-15 min insulin oscillations. There were no differences between diabetic and non-diabetic subjects in the frequency of the ultradian oscillations of insulin secretion (which averaged 12-15 oscillations per 24 h) and in the rate of concomitancy of oscillations of insulin secretion with oscillations in glucose levels, which averaged 63-65%. The relative amplitudes of both the insulin and glucose oscillations were also similar in diabetic and non-diabetic subjects. The major abnormality in patients with Type 2 diabetes was evidenced by spectral analysis, and confirmed by calculations of the distributions of inter-pulse intervals. It consisted of a slowing of the glucose oscillations, without a similar slowing of the oscillations in insulin secretion. This slowing of the glucose oscillations in fasting Type 2 diabetic patients is consistent with our previous observations of sluggish and irregular glucose oscillations in diabetic subjects receiving mixed meals. This partial dissociation between the oscillatory patterns of insulin secretion and glucose levels could represent a sensitive quantitative marker of the breakdown of the insulin-glucose feedback loop in diabetes.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Differential effects of glucose stimulation upon rapid pulses and ultradian oscillations of insulin secretion

To determine the effect of glucose stimulation on the rapid 8- to 15-min pulses and the ultradian 80- to 170-min oscillations of insulin secretion, peripheral concentrations of glucose, insulin, and C-peptide were measured at 2-min intervals over 2 h (i.e. rapid experiments), at 15-min intervals over 8-20 h (i.e. ultradian experiments) in 17 normal subjects during saline infusion, or during constant glucose infusion at a rate of 3 mg/(kg.min) (i.e. low dose) or 6 mg/(kg.min) (i.e. high dose). In the ultradian experiments, insulin secretory rates (ISR) were calculated by deconvolution of the plasma C-peptide concentrations. Significant oscillations with 125- to 166-min periods were detected in all glucose and ISR profiles. The numbers of ISR oscillations per 24 h were similar during saline infusion and low and high dose glucose infusion. In contrast, the amplitude of the ISR peaks increased progressively from 14 ± 1 pmol/min during saline infusion to 50 ± 7 pmol/min and further to 97 ± 9 pmol/min during low and high dose glucose infusions, respectively. When expressed as percent increment, the amplitude of the ISR oscillations increased significantly from 31 ± 5% during saline infusion to 41 ± 4% during low dose glucose infusion and 44 ± 3% during high dose glucose infusion (P < 0.05). In all profiles obtained from the 2-min sampling experiments, rapid pulses of glucose, insulin, and C-peptide were apparent. The number of insulin pulses during saline and glucose infusions corresponded to a mean periodicity of 10 min. The amplitude of these rapid insulin pulses increased from 17.3 ± 2.9 to 39.8 ± 11.8 pmol/L (P < 0.01) in response to glucose. In contrast to the ultradian oscillations, the relative amplitude of the rapid insulin pulses decreased significantly from 28.8 ± 3.4% during saline infusion to 13.6 ± 1.6% during high dose glucose infusion (P < 0.01). Our findings demonstrate that the pancreatic response to glucose stimulation is different for the rapid pulses and the ultradian oscillations. When the rate of glucose stimulation is increased, the absolute amplitude of both the rapid pulses and the ultradian oscillations increases. However, when expressed as percent increment, the amplitude of the rapid pulses decreases during glucose stimulation, whereas the amplitude of the ultradian oscillations increases. These findings suggest that the two oscillatory modes have a different origin and physiological significance. © 1993 by The Endocrine Society.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Nocturnal elevation of glucose levels during fasting in noninsulin-dependent diabetes

To define the spontaneous diurnal variations in glucose regulation during fasting in noninsulin-dependent diabetes (NIDDM), we measured circulating levels of glucose, insulin, C-peptide, GH, cortisol, and glucagon at 15-min intervals in 11 patients with untreated diabetes and 7 matched control subjects studied during a 24-h period. The rates of insulin secretion were derived from the concentrations of C-peptide by deconvolution using a two-compartment mathematical model for C-peptide distribution and metabolism.In both groups of subjects, despite continued fasting, glucose levels stopped declining in the evening and subsequently rose throughout the night to reach a morning maximum. Elevated levels persisted until noon. The morning glucose maximum corresponded to a relative increase of 23.8 ± 5.5% above the evening nadir in NIDDM patients and 13.2 ± 4.6% in nondiabetic subjects (P < 0.05). In NIDDM patients, insulin levels and insulin secretion rates did not parallel the nocturnal glucose changes. In contrast, in control subjects, this nocturnal glucose rise coincided with a similar increase in insulin secretion rates.Cortisol concentrations in patients with NIDDM were higher than those in control subjects throughout the study period (P < 0.001) and rose earlier in the evening than in control subjects, thus failing to demonstrate the normal nocturnal suppression. In both groups of subjects, the nighttime glucose elevation was temporally and quantitatively correlated with the circadian cortisol rise. GH secretion was increased in the evening and nighttime periods compared to the daytime values, and in NIDDM patients, but not in control subjects, the size of the morning glucose elevation was directly related to the magnitude of this increase in GH secretion (r = 0.88; P < 0.01). Glucagon concentrations were similar in both groups of subjects and remained essentially constant throughout the study period.We hypothesize that the nocturnal glucose rise that occurs during fasting represents a normal diurnal variation in the setpoint of glucose regulation amplified by counterregulatory mechanisms activated by the fasting condition. © 1991 by The Endocrine Society.SCOPUS: ar.jinfo:eu-repo/semantics/publishe