Insufficiently treated type 1 diabetic patients exhibit inappropriate postprandial hyperglycemia and reduction in liver glycogen stores. To examine the effect of acute improvement of metabolic control on hepatic glycogen metabolism, lean young type 1 diabetic (HbA1c 8.8 ± 0.3%)and matched nondiabetic subjects (HbA1c 5.4 ± 0.1%) were studied during the course of a day with three isocaloric mixed meals. Hepatic glycogen concentrations were determined noninvasively using in vivo 13C nuclear magnetic resonance spectroscopy. Rates of net glycogen synthesis and breakdown were calculated from linear regression of the glycogen concentration time curves from 7:30-10:30 P.M. and from 10:30 P.M. to 8:00 A.M., respectively. The mean plasma glucose concentration was ∼2.4-fold higher in diabetic than in nondiabetic subjects (13.6 ± 0.4 vs. 5.8± 0.1 mmol/l, P < 0.001). Rates of net glycogen synthesis and net glycogen breakdown were reduced by ∼74% (0.11 ± 0.02 vs. 0.43 ± 0.04 mmol/l liver/min, P < 0.001) and by ∼47%(0.10 ± 0.01 vs. 0.19 ± 0.01 mmol/l liver/min, P <0.001) in diabetic patients, respectively. During short-term (24-h)intensified insulin treatment, the mean plasma glucose level was not different between diabetic and nondiabetic subjects (6.4 ± 0.1 mmol/l). Net glycogen synthesis and breakdown increased by ∼92% (0.23 ± 0.04 mmol/l liver/min, P = 0.017) and by ∼40% (0.14 ± 0.01 mmol/l liver/min, P = 0.011), respectively. In conclusion, poorly controlled type 1 diabetic patients present with marked reduction in both hepatic glycogen synthesis and breakdown. Both defects in glycogen metabolism are improved but not normalized by short-term restoration of insulinemia and glycemia.
After a mixed meal, glucose is removed by the liver from the portal vein and the systemic circulation, and it is temporarily stored as glycogen(1). During the subsequent fasting period, the liver accounts for at least 80% of endogenous glucose production(2,3,4),45% of which in healthy individuals is contributed by glucose derived from glycogen breakdown (5). Poorly controlled type 1 diabetic patients exhibit impaired suppression of endogenous glucose production after a mixed meal(6) and reduction in hepatic glycogen accumulation, which becomes most prominent after dinner(7). After an overnight fast,endogenous glucose production is also elevated and correlates with the degree of fasting hyperglycemia(8,9,10). However, no information is currently available on rates of glycogen breakdown during fasting in type 1 diabetes. It is of note that hepatic glycogenolysis also accounts for at least ∼85% of the initial increase in endogenous glucose production during hypoglycemia(11) or glucagon exposure(12,13). Reduction in hepatic glycogen stores may therefore impair the rapid response of glucose production to hypoglycemia in type 1 diabetes. This is of particular clinical relevance, because intensive insulin therapy aiming at tight glycemic control in order to prevent diabetes-associated long-term complications increases the prevalence of hypoglycemic episodes(14,15).
Insufficient insulin replacement, decreased portal insulin-to-glucagon ratios and/or hyperglycemia-induced insulin resistance may account for the abnormalities of hepatic glucose metabolism in type 1 diabetes. However,hyperinsulinemic clamp tests and intensive insulin treatment completely normalized endogenous glucose production in some(6,8,16)but not in all studies (10). Even intraportal hyperinsulinemia does not reverse all of the alterations in hepatic carbon fluxes (17). In addition, chronic near-normoglycemia alone was not sufficient to reduce endogenous glucose production, which was suppressed only by plasma insulin concentrations as high as ∼6 nmol/l(18). It has been suggested that only a near-physiological mode of insulin delivery by intermittent infusion will reactivate liver metabolism and reduce both HbA1clevels and the frequency of hypoglycemic events in patients with brittle diabetes (19). Nevertheless,it is unknown at present whether or not improvement of both insulinemia and glycemia reverses the defects in hepatic glycogen metabolism in type 1 diabetes under physiological conditions of mixed meal ingestion.
Therefore, this study was designed with the following intentions: 1) to determine rates of net hepatic glycogen synthesis after ingestion of a standardized mixed meal dinner, 2) to determine rates of net hepatic glycogen breakdown during nighttime in type 1 diabetic and nondiabetic subjects, and 3) to test the hypothesis that hepatic glycogen deposition can be completely restored to normal levels by short-term improvement of insulin treatment and glycemia for 24 h using variable intravenous insulin infusion. We applied 13C nuclear magnetic resonance (NMR) spectroscopy to noninvasively follow the time course of hepatic glycogen concentrations in vivo(20). This method enables quantification of both net glycogen synthesis and breakdown during mixed meal ingestion(1,7,21)and avoids limitations of other experimental approaches such as liver biopsies(22), hepatic venous cannulation (23), or isotopic dilution methodology(6,24).
RESEARCH DESIGN AND METHODS
Type 1 diabetic patients (six men and one woman, age 30 ± 4 years,BMI 25.0 ± 0.9 kg/m2, diabetes duration 9.6 ± 4.1 years, HbA1c 8.8 ± 0.3%, mean insulin dosage 40 ± 4 U/day) were administered either a conventional insulin regimen consisting of two subcutaneous injections of a mixed insulin or multiple insulin injections. They had no history of hypoglycemic episodes for at least 1 week before the study. Individuals presenting diabetes-related complications were excluded from participation in this study. Nondiabetic subjects matched for age and body weight (six men and one woman, age 29 ± 2 years, BMI 24.6 ±0.6 kg/m2, HbA1c 5.4 ± 0.1%) served as a control group. None had a family history of diabetes. Informed consent was obtained from all of the subjects after the nature and possible consequences of the study were explained to them. The protocol was reviewed and approved by the Human Ethics Committee of the University of Vienna Medical School.
Experimental protocol. All subjects were advised to ingest a carbohydraterich weight-maintaining diet and to refrain from strenuous physical exercise for at least 3 days before the study. Diabetic patients were instructed to omit NPH or Zn insulin and to correct plasma glucose concentrations with regular insulin (Actrapid; Novo Nordisk, Copenhagen,Denmark) for 24 h before admission. Nondiabetic subjects were studied once,whereas type 1 diabetic patients were studied twice: once during current metabolic control with correction of plasma glucose by subcutaneous insulin injection (protocol 1) and once during improved glycemic control by variable intravenous insulin infusion (protocol 2).
On the first study day, nondiabetic and diabetic subjects in protocol 1 were admitted to the clinical research facility at ∼7:00 A.M. Teflon catheters were inserted in antecubital veins of the left arm for blood sampling. Three standard mixed meals (60% carbohydrate, 20% protein, and 20%fat) were served at 8:00 A.M. (720 kcal solid), 12:30 P.M. (710 kcal solid),and 5:00 P.M. (800 kcal liquid meal). During protocol 1, diabetic patients received subcutaneous insulin injections before the meals to avoid excessive increases of plasma glucose concentrations >22.2 mmol/l. Plasma glucose concentrations were measured every 15 min between 7:30 A.M. and midnight and,when appropriate, during nighttime.
During protocol 2, diabetic patients were admitted to the clinical research facility at ∼12:00 A.M. on the day before the study. Teflon catheters were inserted in antecubital veins of the right and left arm for blood sampling and for insulin infusion, respectively. Insulin was administered as a variable intravenous infusion (0.2 to 1.5 mU · kg-1 ·min-1) to slowly lower the plasma glucose level and keep it between 5.56-6.67 mmol/l. On the next day, three standard mixed meals were served as described above. To achieve plasma glucose concentrations obtained in control subjects, insulin infusion rates were frequently adjusted based on the actual plasma glucose concentration and increased accordingly before ingestion of each meal. Plasma glucose concentrations were measured every 15 min during protocol 2.
In all studies, blood samples were taken every 2 h to allow determination of plasma concentrations of free insulin, C-peptide, glucagon, and free fatty acids (FFAs).
Analytical methods. Plasma glucose concentrations were measured using the glucose oxidase method (Glucose Analyzer II; Beckman Instruments,Fullerton, CA). HbA1c was quantified by using high-performance liquid chromatography (Bio-Rad, Richmond, CA). Plasma concentrations of FFAs were determined by using a colorimetric assay (intra- and interassay CVs 4.3 and 5.7%) (Wako, Neuss, Germany). Free insulin (CVs ≤ 8%)(Pharmacia-Upjohn, Uppsala, Sweden), C-peptide (CVs ≤ 9%) (CIS,Gif-Sur-Yvette, France), and glucagon (CVs ≤ 8%) (Biochem, Freiburg,Germany) were determined by radioimmunoassay.
13C NMR spectroscopy. After dinner, liver glycogen concentrations were determined in all subjects from 7:30 P.M. until the plateau was reached (∼10:30 P.M.) and from 7:00 A.M. to 8:00 A.M. on the morning of the next day. These time periods were chosen because the difference in net hepatic glycogen accumulation between nondiabetic and diabetic subjects becomes maximal after dinner(7). In three subjects, the measurements were performed except for short breaks from 7:30 P.M. until 8:00 A.M. of the next morning to confirm linear decrease of liver glycogen concentrations between 10:30 P.M. and 8:00 A.M.(5).
In vivo 13C NMR spectroscopy was performed on the 3 T Medspec 30/80-DBX system (Bruker Medical, Ettlingen, Germany) installed at the General Hospital of Vienna, Austria. A double-tuned 1H (125.6 MHz) and 13C (31.5 MHz) 10-cm circular coil was used for data collection. Subjects were lying in the supine position in the magnet with the coil positioned rigidly over the lateral aspect of the liver. The liver borders were determined by percussion, and the correct position of the coil was confirmed with a multislice gradient echoimage. Magnetic field homogeneity was optimized on the water signal to a line width of 60-80 Hz. Spectra were acquired using a modified 1D-ISIS sequence(20) without proton decoupling(pulse length 150 μs/135° in the coil plane, time of resonance 150 ms,acquisition time 25.6 ms, number of scans 5,000, total scan time 13 min). Spectra were zero filled to 4k, gaussian and exponentially filtered, and phase-corrected manually. Hepatic glycogen was quantified by integration of the C1 glycogen doublet at 100.5 ppm using the same frequency bandwidth for all spectra (± 300 Hz). Absolute quantification of the hepatic glycogen concentration was obtained by comparing the peak integral with that of a glycogen standard solution obtained under identical conditions. Corrections for loading and sensitive volume of the coil were performed.
Because hepatic glycogen synthase and phosphorylase are simultaneously active in humans, 13C NMR spectroscopy does not measure total changes but does measure net changes in liver glycogen concentrations so that rates of net glycogen synthesis and net glycogenolysis can be assessed. Individual rates of net glycogen synthesis and net glycogen breakdown were calculated from linear regression of the net glycogen concentration-time curves between 7:30 and 10:30 P.M. and from 10:30 P.M. to 8:00 A.M.,respectively.
Determination of liver volume. In all subjects, liver volumes were measured using magnetic resonance imaging in a 1.5 T Vision imager (Siemens,Munich, Germany) using a body array coil and inphase and postphase multislice FLASH imaging sequences. Slice number and position were chosen to cover the whole organ. Liver tissue was manually segmented, and the area of each region of interest was determined in each slice. Areas were added and multiplied by the sum of slice thickness (0.8 mm) and interslice distance (8 mm). Liver volumes were determined 2 h after dinner on the first study day.
Calculations and statistics. Data are means ± SE. One-way analysis of variance with Bartlett's test for equal variances and post hoc testing by the Newman-Keuls test was used for statistical comparisons between and within the different groups. In addition, data of type 1 diabetic patients before and during short-term intensified insulin treatment were compared using the paired Student's t test. Statistical significance was considered at P < 0.05. All calculations were performed using the Sigma Stat software package (Jandel, San Rafael, CA).
RESULTS
Plasma glucose. Fasting plasma glucose concentrations were approximately two times higher in poorly controlled type 1 diabetic than in nondiabetic subjects (11.55 ± 1.05 vs. 5.44 ± 0.12 mmol/l,poorly controlled diabetic subjects vs. control subjects, respectively; P < 0.05) (Fig. 1A). Overnight intravenous insulin infusion normalized fasting plasma glucose concentrations in the diabetic subjects (6.21 ±0.18 mmol/l in insulin-infused diabetic subjects; NS vs. control subjects). During the course of the study, the mean plasma glucose concentration (7:30 A.M. to 8:00 A.M. of the next day) was markedly higher in poorly controlled diabetic subjects than in control subjects (13.61 ± 0.38 mmol/l in poorly controlled diabetic subjects vs. 5.76 ± 0.08 mmol/l in control subjects, P < 0.001), but was not different from control subjects during short-term intensified insulin treatment (6.39 ± 0.14 mmol/l in insulin-infused diabetic subjects; NS vs. control subjects; P <0.001 vs. poorly controlled diabetic subjects). Similarly, the daytime mean plasma glucose concentration (8:00 A.M. to 7:00 P.M.) was higher in poorly controlled diabetic subjects than in control subjects (13.60 ± 0.40 vs. 5.79 ± 0.09 mmol/l, respectively; P < 0.001) and normalized during short-term intensified insulin treatment (6.34 ± 0.15 mmol/l in insulin-infused diabetic subjects; NS vs. control subjects). The mean plasma glucose concentration during nighttime (7:30 P.M. to 8:00 A.M.) was also higher in diabetic subjects than in control subjects (13.14 ± 1.29 vs. 5.40 ± 0.04 mmol/l, respectively; P < 0.001). During insulin infusion, the nighttime mean plasma glucose concentration markedly improved (6.82 ± 0.31 mmol/l in insulin-infused diabetic subjects; P < 0.001 vs. poorly controlled diabetic subjects) and was not significantly different from glycemia in nondiabetic subjects. Peak individual rates of insulin infusion required to maintain such plasma glucose concentrations ranged from 5-12 mU · kg-1 ·min-1 and were adjusted in time periods as low as 5 min. Figure 1B depicts the time course of insulin infusion rates during short-term intensified insulin treatment in one representative diabetic subject.
Plasma C-peptide, insulin, glucagon, and FFAs. Fasting plasma C-peptide concentrations were markedly lower in diabetic subjects (0.32± 0.06 ng/ml in poorly controlled diabetic subjects vs. 0.26 ±0.01 ng/ml in insulin-infused diabetic subjects, NS) than in nondiabetic subjects (1.61 ± 0.18 ng/ml; P < 0.001 vs. poorly controlled diabetic subjects and insulin-infused diabetic subjects). Whereas plasma C-peptide concentrations were below the detection limit (0.25 ng/ml) in five diabetic patients, two patients exhibited detectable plasma C-peptide levels (0.57 and 0.54 ng/ml). Plasma C-peptide did not change from fasting levels in the diabetic subjects, but increased (P < 0.0001) in the control subjects. Following correction of glycemia by subcutaneous or intravenous insulin before 8:00 A.M., mean fasting plasma insulin was slightly, but not significantly, higher in diabetic subjects (134 ± 62 pmol/l in poorly controlled diabetic subjects and 180 ± 84 pmol/l in insulin-infused diabetic subjects) than in control subjects (40 ± 6 pmol/l) (Fig. 2A). During the study day, mean plasma insulin concentration was higher in diabetic patients during intensive insulin treatment (396 ± 87 pmol/l in insulin-infused diabetic subjects) than during poor metabolic control (205± 22 pmol/l in poorly controlled diabetic subjects, P <0.05) and increased compared with nondiabetic control subjects (109 ±20 pmol/l, P < 0.01). Plasma glucagon concentrations were not different in the fasting state (160 ± 24, 156 ± 21, and 181± 28 pg/ml in poorly controlled diabetic patients, insulin-infused diabetic patients, and control subjects, respectively) and throughout the studies (165 ± 7, 177 ± 5, and 187 ± 7 pg/ml in poorly controlled diabetic patients, insulin-infused diabetic patients, and control subjects, respectively) (Fig. 2B). Fasting plasma FFA concentrations were slightly higher in diabetic patients during poor metabolic control (524 ± 97μmol/l in the poorly controlled diabetic subjects) than during intensified insulin treatment (319 ± 38 μmol/l in the insulin-infused diabetic subjects, NS) and control studies (353 ± 56 μmol/l, NS)(Fig. 2C). After 10:00 P.M., plasma FFA increased further only in diabetic patients during protocol 1(698 ± 64 μmol/l in poorly controlled diabetic patients),∼1.8-fold higher than during protocol 2 (396 ± 66 μmol/l in insulin-infused diabetic patients; P < 0.025) and during control studies (380 ± 56 μmol/l; P < 0.01) performed at 3:30 A.M.
Hepatic glycogen synthesis and breakdown. Liver glycogen concentrations linearly increased from 8:00 A.M. to 11:00 P.M. Figure 3 illustrates the time course of liver glycogen concentrations and determination of rates of net glycogen synthesis by a line-fitting procedure in one nondiabetic subject. After dinner, hepatic glycogen concentrations were ∼29% lower (P< 0.001) in poorly controlled diabetic subjects than in nondiabetic subjects (Table 1). Rates of net glycogen synthesis were ∼74% lower (P < 0.001) in diabetic patients (Fig. 4A). Short-term improvement of metabolic control resulted in an increase of∼23% (P < 0.01) of maximal liver glycogen contents(Table 1), which was still reduced (P < 0.05) compared with control studies. Similarly, net glycogen synthesis doubled (P = 0.017 vs. poorly controlled diabetic subjects), but was ∼52% lower (P < 0.001) than in nondiabetic subjects.
During overnight fasting, liver glycogen linearly decreased from 11:00 P.M. to 8:00 A.M. (Fig. 3). The maximum decrement was lower in poorly controlled diabetic subjects than in nondiabetic subjects (-58 ± 9 mmol/l liver vs. -113 ± 13 mmol/l liver; P < 0.001) and gradually increased during tight metabolic control (-82 ± 8 mmol/l liver in the insulin-infused diabetic subjects; P < 0.05 vs. poorly controlled diabetic subjects; P <0.01 vs. control subjects). Rates of net glycogen breakdown were reduced by∼47% in poorly controlled diabetic patients (P < 0.001 vs. control subjects), but improved during protocol 2 (P = 0.011 vs. insulin-infused and P < 0.05 vs. control subjects)(Fig. 4B). The following morning, hepatic glycogen had decreased (P < 0.001) in all protocols, with no differences among them(Table 1).
Mean liver volume was not different between diabetic and nondiabetic subjects (1,627 ± 102 cm3 in the poorly controlled diabetic subjects vs. 1,502 ± 43 cm3 in the control subjects,unpaired Student's t test: NS).
DISCUSSION
These results demonstrate a marked defect of net hepatic glycogen accumulation in poorly controlled type 1 diabetes. Although older studies using the biopsy technique reported increased glycogen deposition in such patients(25,26),the observed reduction by ∼29% in peak liver glycogen content is in accordance with the only other study performed in type 1 diabetic patients under near-physiological conditions of mixed meal ingestion(7).
The glycemic profiles of poorly controlled type 1 diabetic patients exhibited a prolonged inappropriate increase of plasma glucose, particularly after breakfast. Most likely, this results from peripheral insulin resistance due to the diurnal secretion pattern of growth hormone(7,27)and is further supported by the observed nocturnal rise of plasma FFA, which strongly correlates with peripheral insulin resistance(28,29)and per se reduces skeletal muscle glucose uptake and glycogen synthesis(30,31). Although mean peripheral plasma insulin and glucagon concentrations were comparable with that of nondiabetic humans, portal hypoinsulinemia and a decreased insulin-to-glucagon ratio may account for the defect in postprandial glycogen accumulation. Net hepatic glycogen synthesis, as measured in this study, is the result of simultaneously active fluxes through glycogen synthase and phosphorylase (32), which are differentially regulated by glucose, insulin, and glucagon under in vivo conditions(33,34). Rates of net glycogen synthesis of nondiabetic subjects were in agreement with previous reports using either liver biopsies(35) or 13C NMR spectroscopy(1,7,21). In the poorly controlled diabetic subjects, the prevailing hyperglycemia will primarily inhibit glycogen phosphorylase flux, while hypoinsulinemia and relative hyperglucagonemia in the portal vein may stimulate glycogen cycling(33,34). Furthermore, even short periods of hyperglycemia are sufficient to reduce nonoxidative glucose disposal(36). In addition to the effects of acute endocrine and metabolic changes, chronic alterations in the activities of hepatic glucoregulatory enzymes, such as glucokinase(37), may contribute to reduced glycogen synthesis. Such a defect was recently suggested in type 2 diabetic subjects, because both UDP-glucose flux and percent contribution of extracellular glucose to hepatic glycogen synthesis were reduced(38). The finding that glucokinase-deficient type 2 maturity-onset diabetes of young (MODY-2)patients exhibit only ∼12% lower peak liver glycogen concentrations after dinner as compared with healthy subjects(21) also indicates that other enzymes, such as glycogen synthase(39,40),might add to defective glycogen accumulation in poorly controlled type 1 diabetes.
In addition, this study followed the time course of liver glycogen breakdown during overnight fasting. The decrease of intrahepatic glycogen concentrations was linear and allowed us to calculate rates of net glycogen breakdown(1,5,20). Corrections for changes in liver volume were not performed, because previous studies found no (5) or only minor loss (20) of liver volumes in subjects fasted for ≤64 h. Such decreases in liver size will result in changes of glycogen concentrations that are below the detection limit of the applied NMR technique. To the extent that simultaneous glycogen synthesis occurs, net glycogen breakdown will underestimate the flux through glycogen phosphorylase. Rates of glycogen breakdown in nondiabetic subjects(∼0.19 mmol/l liver/min) were identical to previous reports(1,41),whereas no data were available for type 1 diabetes. The observed decrease of rates of net glycogen breakdown in poorly controlled type 1 diabetic patients may result from hyperglycemia that inhibits glycogen phosphorylase(34) and/or relative portal vein hyperglucagonemia (33). In addition, as individual net glycogenolytic rates are correlated with the initial hepatic glycogen concentration(5), the lower maximal postprandial liver glycogen concentrations may have contributed to reduced glycogen breakdown. Finally, the defects in liver glycogen metabolism could partly be because of the action of epinephrine, cortisol, and growth hormone,which stimulate splanchnic glucose output after glucose ingestion in humans(42,43)and worsen hyperglycemia in insulin-deficient dogs(44) and in human type 1 diabetes (45).
During hyperglycemic-hyperinsulinemic clamp tests, hepatic glycogen synthesis was normalized in 90%-pancreatectomized rats(46), as well as in five poorly controlled type 1 diabetic subjects(17). However,supraphysiological plasma concentrations of glucose (∼17 and 9 mmol/l) and insulin (∼3,300 and 400 pmol/l) were required to achieve this effect. Moreover, administration of somatostatin without concomitant glucagon infusion will have caused portal hypoglucagonemia in those type 1 diabetic patients(17), which favors net hepatic glycogen synthesis (33). In the present study, improvement of insulin replacement by variable intravenous insulin infusion resulted in glycemic profiles close to that of nondiabetic subjects. Under these conditions, more likely reflecting the aim of improved metabolic control in clinical practice, net glycogen accumulation of type 1 diabetic patients doubled, but was still half of that in control subjects. The failure to normalize glycogen synthesis could result, in part, from the decrease of ∼57% of plasma glucose during short-term improvement of metabolic control. It is conceivable that hyperglycemia per se may compensate for defective glycogen synthesis in the poorly controlled diabetic patients. This could be because of glucose-induced glycogen synthesis following a portal glucose load (47) and/or because of reduction of simultaneous ongoing glycogenolysis(34). Alternatively,hyperglycemia may increase glycogen repletion by the indirect (gluconeogenic)pathway in diabetic rats (46)and humans who also exhibit reduced hepatic pyruvate oxidation(17).
One might speculate that infusion of insulin into a peripheral vein instead of physiological insulin delivery might be responsible for the difference between nondiabetic and type 1 diabetic subjects, despite their acutely improved metabolic control. During insulin infusion, mean plasma insulin concentration in the peripheral vein doubled and was ∼190 pmol/l higher in the diabetic patients. Thus, portal vein insulin concentrations were likely to be similar in both groups(48). The observed increase in systemic insulin will decrease hepatic and renal gluconeogenesis, as well as lipolysis, which is mirrored by the observed decrease of plasma FFA concentrations. Consequently, endogenous glucose production should fall, net hepatic glucose output should approach zero(49), and glycogen synthesis should be maximal. It is of note that the efficacy of insulin to inhibit hepatic glucose production also depends on its pulsatile secretion pattern(50). However, in the present study, frequent adjustments of the insulin infusion at intervals as low as 5 min and peak rates of up to 12 mU · kg-1 ·min-1 should have provided for near-physiological conditions(19,51). On the other hand, given comparable glycemic profiles in the absence of glucosuria, whole-body glucose disposal has to be similar in well- controlled diabetic and nondiabetic subjects. Therefore, in the well-controlled diabetic patients, the higher peripheral insulin concentration could have increased muscular glucose uptake, leaving less glucose available for hepatic glycogen formation.
Nevertheless, insufficient duration of normalized glycemia and insulinemia may account for the failure to completely restore glycogen synthesis and breakdown in our type 1 diabetic patients. Near-normalization of glycemia by intensive subcutaneous insulin therapy for ≥2 weeks was required to decrease tracer-determined glucose production to the normal range in the fasted(6,16,18)and in the postprandial state(6). This time period might be necessary to overcome hepatic insulin resistance, which is a common feature of insulin-dependent diabetes, despite physiological daily insulin requirements(8,52),as observed in our patients, whose nocturnal suppression of plasma FFA albeit indicates normal insulin sensitivity.
In conclusion, poorly controlled type 1 diabetic subjects present with 1) markedly impaired hepatic glycogen synthesis after a mixed meal dinner, 2) reduced glycogen breakdown during overnight fasting, and 3) improved, but not normalized, glycogen synthesis and breakdown during refined insulinemia and glycemia. Postprandial enlargement of hepatic glycogen storage can provide more glucose for the immediate increase in endogenous glucose production during hypoglycemia counterregulation. Therefore, despite potentially increased frequency of hypoglycemia(14,15),intensive insulin therapy might rather serve to protect against severe hypoglycemic episodes.
FFA, free fatty acid; NMR, nuclear magnetic resonance.
Article Information
This study was supported by grants from the Austrian Science Foundation(Fonds zur Förderung der Wissenschaftlichen Forschung) (P13213-MOB and P13722-MED) to M.R., the Austrian National Bank(ÖNB 8196) to W.W. and M.R., the Austrian Academy of Sciences to H.S. (427/97), and Novo-Nordisk to W.W.
We gratefully acknowledge the excellent technical assistance of A. Hofer,H. Lentner, P. Nowotny, and the laboratory staff of the Division of Endocrinology and Metabolism, as well as the radiological technical assistants of the Department of Radiology. We also thank Prof. H. Imhof, MD, MR Unit, and Prof. E. Moser, PhD, Institute of Medical Physics, University of Vienna, for cooperation and support.
