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Patients with NAFLD are characterized by insulin resistance (IR) and hyperinsulinism. However, prior studies have been unable to predict NAFLD based on IR measurements. The aim of this study was to explore the application of a newly validated measurement of intact insulin by mass spectrometry to predict NAFLD in patients without diabetes. Ninety-eight patients were recruited and underwent: a 2-hour OGTT with measurements of insulin every 30 min, and a liver magnetic resonance spectroscopy (1H-MRS) to measure liver fat and diagnose NAFLD. A mass spectrometry method was used to measure intact molecules of insulin. A total of 62 patients had NAFLD (48±11 yr, 66% male, BMI: 34.4±4.6kg/m2, A1c: 5.8±0.4%); and 36 did not have NAFLD (52±12 yr, 56% male, BMI: 30.5±6.8kg/m2, A1c: 5.5±0.4%). Fasting insulin levels were higher in NAFLD patients (17±10 vs. 7±3 μU/ml, p Conclusions: In patients without diabetes, accurate measurement of fasting intact insulin levels by mass spectrometry constitutes an easy and non-invasive strategy to predict presence of NAFLD. Disclosure F. Bril: None. M. J. Mcphaul: Employee; Self; Quest Diagnostics. S. Kalavalapalli: None. R. Lomonaco: None. D. Barb: None. E. Godinez: None. K. Cusi: None. Funding The Obesity Society; University of Florida

Glycaemic traits fasting insulin (FI), fasting glucose (FG), 2-hour glucose (2hGlu) and glycated haemoglobin (HbA1c) are used to diagnose and monitor type 2 diabetes (T2D). MAGIC (Meta-Analysis of Glucose and Insulin-related traits Consortium) identified 242 loci associated with these traits in 281,416 individuals, from 6 ancestries. European (EUR) ancestry fine-mapping resulted in credible sets accounting for 99% of the posterior probability of association (99CS) with a median of 55 SNPs. Trans-ancestry (TA) fine-mapping led to 99CS with a median of 45 SNPs. Here, we investigated whether fine-mapping resolution could be improved by leveraging data across multiple related traits. We used the novel method FLexible And SHared information Fine-Mapping (flashfm), which takes advantage of sharing of information between traits. We compared its performance with single-trait FINEMAP results. We conducted EUR fine-mapping for 53 loci associated with ≥2 glycaemic traits (p Disclosure J. Soenksen: None. J. Chen: None. J. L. Asimit: None. Magic: n/a. I. Barroso: Stock/Shareholder; Self; Incyte Corporation, Stock/Shareholder; Spouse/Partner; GlaxoSmithKline plc. Funding Research England; Medical Research Council (MR/R021368/1)

Ecological studies have shown different risks for diabetes (DM) among many ethnic groups, but whether they are due to genetic or non-genetic factors is hard to dissect. We conducted a community-based study aimed at identifying risk factors for DM and related traits in Pacific Islanders from Guam and Saipan. We analyzed the genetic structure of our sample and estimated individual-level admixture using genome-wide SNP data (49,300 variants). We found that genetic ancestry largely derived from 5 populations, representing Marianas Islanders (MI) (mean % heritage, or μ=43%), East Asians (EA, μ=22%), Micronesians (MC, μ=19%), Europeans (EU, μ=13%), and Melanesians (ML, μ=3%). We then tested the association of ancestry estimates with DM, fasting glucose and fasting insulin levels in study participants (n=1,853). Covariates included age, sex and end-stage kidney disease. For fasting insulin, only nondiabetic subjects were used in analyses. All 3 traits were associated with genetic ancestry (p In summary, there were large and statistically significant differences in DM-related traits among Pacific Islanders with different genetic ancestral backgrounds. Although genetic ancestry estimates may still be confounded by shared environmental factors, the present findings suggest that admixture mapping may be a potentially powerful approach for identifying unique DM loci in Pacific Islanders. Disclosure W. Hsueh: None. P. Kumar: None. S. Safabakhsh: None. L. Jones: None. J. Curran: None. W.C. Knowler: None. R.G. Nelson: None. R.L. Hanson: None.

Background: Insulin resistance(IR) is a key determinant of CV Risk and is highly prevalent in Asian Indians. However, there is limited data on IR in healthy non-obese individuals. Quantification of IR in clinical practice is a challenge and HOMA IR is the commonly used method. Triglyceride-Glucose(TyG) Index, a simple method for measuring IR, is not much used in clinical practice. This study assessed the prevalence of IR using TyG index in comparison to HOMA-IR in healthy non-obese Indians. Aims and Objectives: 1. To assess the prevalence of IR using TyG index in healthy non-obese individuals 2. To assess TyG (Triglyceride-Glucose Index)Index as a measure of IR in comparison to HOMA IR. Methodology: A total of 170 healthy non-obese individuals visiting for routine health checks were recruited in the study. Relevant anthropometric and laboratory parameters were recorded. IR was calculated using TyG index and HOMA IR using following formulae: TyG = ln (Triglycerides in mg/dL x Glucose in mg/dL/2)8 IRHOMA = (I0 × G0)/405 (I0 -fasting insulin in mIU/L, G0-fasting glucose in mg/dL)1 IR was defined as HOMA-IR >2.8 or TyG index >4.65. Prevalence of IR in the study population was calculated using both and compared. Results: Mean age of study population was 43.45±15.72 years and 55% were males. Average BMI was 22.09± 2.29 Kg/m². Systolic and diastolic BP were 117.29±7.90 and 72.12±8.37 mmHg respectively. Mean fasting blood glucose was 92.79±6.92 mg/dL, mean triglycerides 107.48 ± 28.95 mg/dL and fasting serum insulin was 11.42 ± 8.53 μU/ml. Prevalence of IR defined by TyG index was 44% as compared to 34% by HOMA IR. There was a strong correlation between TyG index and HOMA IR(p=0.006). TyG index had a high negative predictive value (74%). Conclusions: Prevalence of IR in healthy Indians is high and affects more than a third of healthy non-obese individuals. TyG index appears to be a better tool for evaluation of IR in clinical practice and has a strong correlation with HOMA IR. Disclosure C. Sharma: None. M. Arora: None. D. Gupta: None. B.M. Makkar: Advisory Panel; Self; Abbott, AstraZeneca, Biocon, Boehringer Ingelheim Pharmaceuticals, Inc., Eris Lifesciences, Novartis AG, Novo Nordisk Inc., Sanofi, USV Private Limited. Speaker’s Bureau; Self; Janssen Pharmaceuticals, Inc.

The prevalence of type 2 diabetes(T2DM) in Hispanic Americans, at 22.6%, is twice that of non-hispanic whites. The NIDDK Diabetes Prevention Program (DPP) showed that an intensive lifestyle intervention can reduce the incidence of T2DM by 58% in many ethnic/racial groups. The DPP at Fair Haven Community Heath Care (FHCHC) in New Haven, CT is a modified NIDDK/CDC DPP which aims to promote weight loss, physical activity and reduced incidence of T2DM among Hispanic patients. A previous randomized controlled study showed that female participants in this DPP benefited with decreased weight, lower glucose excursions and improved fasting insulin one year after enrolling compared to controls. The purpose of this follow-up study is to assess the long-term effectiveness of the FHCHC DPP. Methods: This study took place at FHCHC after obtaining IRB approval. A retrospective chart review was conducted comparing participants randomly assigned to the DPP with those assigned to control group. Measures abstracted included fasting glucose, 2-hour OGTT, HbA1c, lipids, blood pressure, BMI and medications from all medical visits between the date of enrollment and October 2018. Results: All 66/66 original subjects in the DPP intervention group as well as 66/66 controls had clinical data beyond 1 year. An average of over 7 years follow-up was available for analysis. ANCOVA test comparing change of weight from baseline to specific time periods showed a significant difference between groups in change from baseline to year 1 of 20.86 lbs. (p=.001), change to year 2 and 3 of 13.8 lbs. (p=.004), but not year 4 and 5 of 11.3 lbs. (p=.067) or year 6+ 10. 0 lbs. (p=.163). There was no statistically significant difference between the two groups in fasting glucose, two-hour glucose tolerance test, or HbAlc. Conclusion: Weight loss shown after 1 year of the FHCHC DPP was sustained at years 2 and 3 but not at years 4 through 7. HbA1C, two-hour glucose, and fasting glucose were not significantly different between groups after the first 1 year. Disclosure P.D. Shah: None. R. Feinn: None. J. Rockfeld: None. A.W. Camp: None.

The International Association of Diabetes and Pregnancy Study Groups recommend early testing for gestational diabetes (GDM) using fasting glucose (FG) of 5.1-6.9 mmol/L at the first prenatal visit. Nonetheless, the optimal approach to diagnosing GDM remains debatable given the limited data on glycemia in the first half of pregnancy. We evaluated the diagnostic performance of FG, insulin, and HOMA-IR in the first and second trimesters in prediction of GDM diagnosis in the third trimester. In a nested case-control study within the prospective Pregnancy Environment and Lifestyle Study (PETALS) pregnancy cohort, 193 GDM cases were diagnosed at gestational weeks 24-28 using the Carpenter-Coustan criteria and matched to 386 controls on age and race/ethnicity. FG, insulin and HOMA-IR were assessed at gestational weeks 10-13 and 16-19, respectively. The mean (SD) of FG and insulin were 4.4 (0.4) mmol/L and 8.4 (10.9) µU/mL at weeks 10-13, and 4.4 (0.5) mmol/L and 11.5 (18.3) µU/mL at weeks 16-19, respectively. The sensitivity of GDM diagnosis using FG of 5.1-6.9 mmol/L was 0.25 (95% CI 0.19-0.32) at gestational weeks 10-13, 0.29 (0.22-0.36) at weeks 16-19, and 0.39 (0.32-0.47) at either weeks 10-13 or 16-19; the corresponding specificity was 0.97 (0.94-0.98), 0.94 (0.91-0.96), and 0.91 (0.88-0.94). By lowering the cutoff to 4.9 mmol/L (90th percentile among controls) for FG, the corresponding sensitivity was 0.38 (0.31-0.45), 0.42 (0.35-0.49), and 0.54 (0.46-0.61) at gestational weeks 10-13, 16-19, or either, with specificity ranging from 0.81-0.90. Diagnostic performance of GDM was not enhanced by using fasting insulin or HOMA-IR. Our data show that only 25% or 29% of GDM can be diagnosed using FG ≥5.1 mmol/L at gestational weeks 10-13 or 16-19 and thus do not support a single FG value of 5.1-6.9 mmol/L in the first or second trimester as the criteria for GDM diagnosis. It is still imperative to conduct an OGTT at gestational weeks 24-28 to confirm or rule out GDM. Disclosure Y. Zhu: None. M.M. Hedderson: None. J. Feng: None. C. Quesenberry: None. A. Ferrara: None. Funding National Institutes of Health

There exists close relationship between thyroid function and obesity. Laparoscopic sleeve gastrectomy (LSG) is an effective bariatric surgery in weight loss and obesity-associated comorbidities. However, only a few studies involve in the alteration of thyroid hormones after LSG with inconsistent results. This study aimed to investigate the impact of LSG on thyroid function profiles in Chinese euthyroid obese subjects. A retrospective study was performed of prospectively collected data in 36 obese patients (17 males and 19 females) who underwent LSG. Thyroid function profiles (TT4, FT4, TT3, FT3 and TSH, all within normal reference ranges), anthropometric data, and glucose-lipid metabolic parameters were recorded at baseline, 3 and 6 months after LSG (abbreviated as 3M/6M Post-LSG). Correlations between TSH with other parameters were evaluated. In all individuals, BMI was dramatically decreased at 3M/6M Post-LSG accompanied by decreased fasting blood glucose, fasting insulin, fasting C-peptide, triglyceride and increased HDL-c (P In summary, we speculate that euthyroid obese subjects are adept at preserving their thyroid function homeostasis despite of morbid obesity at baseline as well as dramatic weight loss and significant improvement of glucose-lipid metabolism after LSG. In addition, δBMI/%TWL/%EWL may be the predictor of improved TSH levels after LSG in female but not male obese patients. Disclosure L. Li: None. X. Wang: None. J. Gao: None. S. Qu: None.

Insulin and glucose parabolas of OGTT were studied in 1030 subjects, not previously diagnosed as having T2DM. The parabola shape was mainly influenced by adiposity, peripheral Insulin resistance (PIR), beta cell(BC) mass and glucose dose. Fasting hyperinsulinemia(HI) was strongly related to body mass index(BMI). Continued calorie excess(CCE) and BMI along with increase in insulin area under curve, which suggested recruitment of new insulin receptors, acted as BC stressor leading to HI. Fasting HI appears to be a physiological response to incremental BMI, independent of PIR. The rate of rise of insulin (RIR) sustained an angle theta with baseline and both were related to BMI and PIR. The RIR was directly related to rising BMI, fasting insulin and glucose but was inversely related to PIR, 120 min insulin and glucose. CCE affected the Degree of HI whereas PIR affected the Duration of HI (Fig 1). From NoDM category as CCE begins, RIR and theta increase until PIR becomes unmasked. RIR, which is related to PIR, can not rise further. As CCE continues, at variable maximum level of insulin, the individual’s BC capacity, betamax, is reached. The RIR and theta start falling hereafter, until the final values for DM category. Gene-Calorie hypothesis proposes that PIR is an inherited predisposing factor where as CCE with adiposity is an acquired precipitating factor which together cause continuous BC stress and subsequent BC failure leading to T2DM. Disclosure S.N. Shinde: Advisory Panel; Self; USV Private Limited, Alkem Laboratories, Lupin Laboratories, Troikka Ltd, IPCA laboratories. R.S. Shinde: None.

Background: Medical nutrition therapy (MNT) is the first-line therapy to achieve glycemic control in women with gestational diabetes mellitus (GDMw). It has been associated with better pregnancy outcomes. Whether MNT can make pregnancy outcomes like women without GDM remains unknown. Objective: To assess if a Mediterranean-diet-based medical nutrition therapy (MNT) facilitates near-normoglycemia (determined by HbA1c levels) at 36-38 gestational weeks in GDMw, and observe its effects on adverse pregnancy outcomes. Study Design: A sub-analysis of the St Carlos GDM Prevention Study. It was conducted between January-December 2015 in the Hospital Clínico San Carlos (Madrid, Spain). One thousand consecutive normoglycemic women were included before 12th gestational weeks, and 874 included in the final analysis: 177 were diagnosed with GDM (IADPSG criteria) and 697 had normal glucose tolerance. GDMw received Mediterranean diet-based MNT, with a daily intake of ≥40 ml extra-virgin olive oil and a handful of nuts (mainly pistachios). Results: GDMw had higher HbA1c levels, fastinG insulin and HOMA-IR at 24-28 gestational weeks as compared with NGT. At 36-38 gestational weeks these values became similar. Insulin therapy was necessary in 26.6% of GDMw. Rates of macrosomia, large-for-gestational-age, pregnancy-induced hypertensive disorders, prematurity and c-sections were similar between groups. Crude RR analysis showed that GDMw had a higher risk of insufficient weight gain [2.37(1.64-3.30), P=.001], urinary tract infection [1.69(1.20-2.38), P=.005], small-for-gestational age newborns [2.05(1.29-3.24), P=.009] and neonate ICU admission [3.42(1.45-8.04), P=.006]. Conclusions: Using a Mediterranean-diet-based MNT in GDMw helps to achieve a near-normoglycemia, making most pregnancy outcomes similar to women with NGT. The higher rates of small-for-gestational-age and insufficient weight gain require further analysis. Disclosure A. Duran: None. C. Assaf-Balut: None. N. Garcia de la Torre: None. M. Fuentes: None. E. Bordiu: None. L. Del Valle: None. A.M. Barabash: None. M. Cuesta: None. M.A. Rubio: None. A.L. Calle: None.

Objective: The relation between type 2 diabetes mellitus (T2DM) and serum-25-hydroxyvitamin D (25[OH]D) is unclear. We aimed to explore the association of 25(OH)D with islet β cell function and insulin resistance in patients with T2DM. Methods: A total of 466 patients with T2DM and 364 healthy people in our hospital from 2016 to 2017 were enrolled. The difference of 25(OH)D between T2DM group and non-DM group was compared. Patients with T2DM were divided into low 25(OH)D group (LVD group, 47.7nmol/L, n=140). The correlation between fasting plasma glucose(FPG), fasting insulin(FINS), fasting c-peptid(FCP), glycosylated hemoglobin(HbAlc), HOMA-IR, HOMA-β and 25(OH)D were compared. Results: Serum level of 25(OH)D in T2DM group was significantly lower than non-DM group (42.33±13.79 vs.69.16±10.78, P0.05). The 25(OH)D of Duration ≥ 5 years was lower than the Duration < 5 years (42.39±13.96 vs. 42.46±13.45, P=0.964). The 25(OH)D of HbAlc ≥ 7% was lower than HbAlc < 7% (42.02±13.85 vs. 44.19±13.50, P=0.192). The 25(OH)D in microvascular group was lower than non-microvascular group (40.86±13.82 vs. 43.35±13.72, P=0.059). The 25(OH)D in macrovascular group was higher than non-macrovascula group (42.49±13.95 vs. 42.09±13.23, P=0.807). Conclusion: The 25(OH)D in patients with T2DM is lower than healthy people and is downtrend with the increase of diabetic duration and HbAlc. There is no definite correlation between 25(OH)D and the pancreatic islet function. The critical significance should be further studied. Disclosure N. Li: None. M. Chen: None. J. Dong: None. S. Yang: None. L. Xu: None. Y. Wang: None. H. Sun: None. H. Li: None. S. Qu: None.

Insulin resistance (IR) is a characteristic feature of non-insulin-dependent diabetes mellitus (NIDDM) as well as obesity, and a majority of NIDDM patients are obese. To assess the effect of obesity independent of NIDDM on IR, we studied the relationship between IR and obesity in 65 normal and 58 NIDDM subjects; we used body mass index (BMI) as a measure of obesity and glucose infusion rate (GINF) during a euglycemic hyperinsulinemic (120 mU · m −2 · min −1 ) glucose clamp as a measure of IR. In lean normal subjects, GINF was 57.7 ± 2.2 μmol · kg −1 · min −1 (10.4 ± 0.4 mg · kg −1 · min −1 ) and the lean NIDDM subjects were markedly insulin-resistant, with a GINF of 34.4 ± 2.8 μmol · kg −1 · min −1 (6.2 ± 0.5 mg · kg −1 · min −1 ). Obese normal subjects were also insulin-resistant compared with lean normal subjects, with a GINF of 36.1 ± 2.2 μmol · kg −1 · min −1 (6.5 ± 0.4 mg · kg −1 · min −1 ), and obesity caused an increase in IR in NIDDM, with a GINF of 21.1 ± 1.4 μmol · kg −1 · min −1 (3.8 ± 0.25 mg · kg −1 · min −1 ) in the obese NIDDM subjects. Therefore, ∼61% of the IR in obese NIDDM subjects is due to NIDDM, with 39% due to obesity, demonstrating a greater impact of NIDDM than of obesity in causing IR. The correlation between GINF and BMI was much better in normal subjects ( r = −0.75) than in NIDDM subjects ( r = −0.50) as was the relationship between fasting insulin level and BMI ( r = −0.59 in normal subjects, r = −0.48 in NIDDM subjects). As expected, the fasting insulin level was also strongly correlated to GINF in normal subjects ( r = −0.61); however, this relationship was weaker in NIDDM subjects ( r = −0.46). In conclusion, 1 ) obesity has a major impact to cause insulin resistance in nondiabetic subjects, but the effect of obesity on IR in NIDDM is less; 2 ) NIDDM per se is the major contributor to IR in NIDDM; and 3 ) the fasting insulin level is a better surrogate marker of IR in nondiabetic subjects than in NIDDM patients.

This investigation was undertaken to study whether the risk to develop non-insulin-dependent diabetes mellitus (NIDDM) among 50-year-old men during a 10-year follow-up period was related to the fatty acid composition of their serum cholesterol esters. There were highly significant differences in the initial health survey between the fatty acid composition in serum in subjects who remained normoglycemic (n = 1,753) and in those who later developed NIDDM (n = 75). The main differences were that the latter had higher proportions of saturated fatty acids and palmitoleic acid (16:1 omega-7), a low proportion of linoleic acid (18:2 omega-6), and a relatively high content of gamma-linolenic (18:3 omega-6) and dihomo-gamma-linolenic (20:3 omega-6) acids in the serum cholesterol esters. The picture was similar also after adjusting for differences in body mass index. In a logistic model, a high proportion of dihomo-gamma-linolenic acid remained a significant contributor to the development of diabetes, along with the height of the insulin index, the blood glucose concentration at 60 min, and the fasting insulin concentration. The increased risk to develop NIDDM related to the serum cholesterol ester fatty acid composition may be mediated by diet and/or genetic factors.

The metabolic consequences of hemipancreatectomy in living pancreas donors were tested in a dog model in which a 50% lobe-specific pancreatectomy was performed. Removal of the dorsal lobe (analogous to a donor, n = 4) resulted in a progressive increase in fasting glucose during 12 mo from 5.32 +/- 0.16 to 8.17 +/- 0.28 mM and a decrease in fasting insulin from 54 +/- 3 to 6.0 +/- 2.4 pM and glucose clearance (Kg) from 3.00 +/- 0.22 to 1.00 +/- 0.06 mM. Removal of the ventral lobe (analogous to a recipient, n = 5) did not result in a change in fasting glucose or Kg during 12 mo, although fasting insulin was reduced from 36.0 +/- 1.8 to 18.00 +/- 1.93 pM. In vitro perfusion of the remnants after 1 yr showed a deterioration in glucose-stimulated insulin secretion (5-11 mM) by the dorsal remnant (18 +/- 11 vs., 232 +/- 37%) and the ventral remnant (2.6 +/- 19 vs. 87 +/- 13%). The dorsal remnant had a higher response than the ventral remnant (46 +/- 23 vs. -16 +/- 10%, respectively) to severe hyperglucosuria (11-27.7 mM). Insulin content was unchanged in the dorsal remnant (224 +/- 16 vs. 180 +/- 14 micrograms/g), but was reduced in the ventral remnant (65 +/- 14 vs. 154 +/- 15 micrograms/g). In vitro insulin pulse intervals were reduced in both remnants (5.3 +/- 0.2 min vs. control 7.00 +/- 0.18 min). Because of the above effects on the donor when the dorsal lobe is removed, the continued use of hemipancreatectomy as a source of transplantable tissue must be questioned.

The pattern of insulin response to oral glucose over a wide range of glucose tolerance has been studied in two separate ethnic groups—Polynesians and Micronesians. Fasting insulin concentrations were relatively unchanged over the entire range of glucose tolerance in both populations, irrespective of whether comparable lean or obese samples of both groups were studied. The patterns of 2-h plasma insulins were similar over the whole range of glucose tolerance in Polynesians and Micronesians. However, in the comparisons of all subjects, or lean or obese groups of these populations, the plasma insulin concentrations of the Micronesians were both consistently and significantly higher. As the data analysis was arranged to take into account groups with identical 2-h plasma glucose concentrations and comparable degrees of obesity, the differences cannot be attributed to differences in the glucose levels or in obesity. In the presence of similar fasting insulin concentrations, these findings imply an ethnic variability in the pancreatic beta-cell response to oral glucose.

The effect of glyburide on glucose metabolism was examined in 10 non-insulin-dependent diabetic subjects (NIDDM) and 7 young, control subjects. After 3 mo of glyburide treatment in NIDDM, fasting plasma glucose declined from 198 to 141 mg/dl (P < 0.01) without change in fasting insulin levels. Basal hepatic glucose production (HGP) was slightly elevated in NIDDM versus controls (2.35 versus 2.18 mg/kg · min, P = NS) and was positively correlated with the fasting glucose concentration (r = 0.93, P < 0.001). With chronic glyburide therapy, HGP declined to 1.72 mg/kg · min (P < 0.01 versus preglyburide) and remained highly correlated with the fasting glucose concentration (r = 0.85, P < 0.005). Basal glucose clearance in NIDDM was reduced by 48% compared with age-matched controls (1.22 versus 2.32 ml/kg · min, P < 0.001) and was unchanged after 3 mo of glyburide. Thus, the most important factor responsible for the decline in fasting plasma glucose concentration was an inhibition of hepatic glucose output. The decrease in basal hepatic glucose production and fasting plasma glucose concentration occurred without any change in fasting plasma insulin or C-peptide concentration. Insulin-mediated glucose metabolism (insulin clamp technique) was reduced by 55% in NIDDM (2.91 versus 6.39 mg/kg · min, P < 0.001). After glyburide, insulin-mediated glucose metabolism increased by 26% to 3.67 mg/kg · min (P < 0.01). This increase in tissue sensitivity to insulin was unassociated with any change in insulin binding to monocytes. Beta cell secretion of insulin (hyperglycemie clamp technique) was markedly impaired in NIDDM (mean plasma insulin response: 24 versus 54 μU/ml, P < 0.001). After glyburide, the plasma insulin response increased to 36 μU/ ml (P < 0.01). These results indicate that improved glucose tolerance in NIDDM after glyburide results from both enhanced tissue sensitivity to insulin and increased insulin secretion. Glyburide administration to young, healthy, control subjects also increased insulin-mediated glucose metabolism (from 6.45 to 7.61 mg/kg · min, P < 0.05) without any change in insulin binding to monocytes. Insulin secretion, however, was unaltered. Thus, the primary mechanism responsible for the improvement in glucose metabolism in young controls was enhanced tissue sensitivity tO insulin.

The influence of pregnancy on serum glucose, serum insulin, and plasma glucagon concentrations was studied in eight normal women and 14 nonobese gestational diabetics. Each normal individual was subjected to an oral glucose tolerance test in midpregnancy, and all subjects were investigated late in pregnancy and again four to six weeks postpartum. As compared with the postpartum values, fasting glucose concentration decreased during gestation in the normals and increased in the gestational diabetics, but the changes were small and insignificant. In contrast, fasting insulin concentration increased equally and significantly in pregnancy in both groups. Likewise, the glucagon concentration was enhanced in the fasting state in both groups in pregnancy. However, the molar insulin-to-glucagon ratio was significantly elevated in both normals and gestational diabetics. In late pregnancy the magnitude of the insulin response to oral glucose (i.e., the incremental insulin area above fasting baseline) was equally and significantly enhanced in the normals and the gestational diabetics. However, when the insulin response during the first 60 minutes of the OGTT was expressed per unit of glucose stimulus (i.e., the Δinsulin/Δglucose ratio) a significantly higher mean response was found in the normal pregnants than in the gestational diabetics. In pregnancy and postpartum, plasma glucagon always decreased to levels significantly below fasting levels after glucose ingestion. In normal midpregnancy the degree of suppression of glucagon was close to that of postpartum, whereas an exaggerated and prolonged suppression was found in late pregnancy in the normals as well as the gestational diabetics. These findings indicate that plasma glucagon and serum insulin concentrations are profoundly influenced by pregnancy. As the changes, however, lead to an increased insulin-to-glucagon ratio, the diabetogenicity of pregnancy is not explained by this relationship.

Overnight basal insulin requirements to maintain eugycemia were determined in six insulin-requiring diabetic subjects using a feedback-controlled (closed loop) insulin infusion system. Mean hourly insulin infusion rates, required to maintain plasma glucose concentrations at approximately 100 mg/dl, were remarkably stable from 2400 h to 0600 h; however, a twofold to threefold increase in insulin requirements was observed in each subject between 0600 h and 0900 h. This increase in amount of basal insulin required was not associated with increases in plasma glucagon or growth hormone concentrations, but occurred simultaneously with normal diurnal increases in plasma cortisol. These findings suggest that normal diurnal increases in plasma cortisol, independent of the content of the morning meal, contribute to the increased amount of morning insulin required in diabetic subjects. Programs designed for optimal open loop insulin delivery may benefit from modifications designed to coincide with this increase in amount of basal insulin required in the early morning.

Cyclosporin or placebo was administered in a randomized, double-blind fashion to 13 patients with multiple sclerosis for 1 yr to determine whether cyclosporin adversely affects glucose homeostasis or β-cell function. No significant differences were observed in fasting glucose, fasting insulin, intravenous glucose tolerance, or glucose-induced insulin secretion before treatment or at 3 wk, 6 mo, or 1 yr during treatment. Longer therapeutic trials with larger patient groups will be necessary to decide whether cyclosporin can be safely given for many years without risk of developing diabetes mellitus.

SUMMARY Overnight basal insulin requirements to maintain euglycemia were determined in five insulin-dependent diabetic subjects using a closed-loop insulin infusion system. A significant increase in hourly insulin requirements occurred between 0600 h and 0900 h as compared with 0100 h–0600 h. Although the increased insulin requirement was coincident with only the physiologic diurnal increase in plasma cortisol, the oral administration of the 11-beta hydroxylase inhibitor, metyrapone, decreased only the total overnight (0100 h–0900 h) basal insulin requirement, but not the early morning (0600 h-0900 h) rise in insulin required to maintain euglycemia. It would appear that although cortisol is an important counterregulatory factor, its diurnal elevation cannot account for the increase in early morning basal insulin requirements to maintain euglycemia in insulin-dependent diabetics.