For microvascular outcomes, there is compelling historical and contemporary evidence for intensive blood glucose reduction in patients with either type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM). There is also strong evidence to support macrovascular benefit with intensive blood glucose reduction in T1DM. Similar evidence remains elusive for T2DM. Because cardiovascular outcome trials utilizing conventional algorithms to attain intensive blood glucose reduction have not demonstrated superiority to less aggressive blood glucose reduction (Action to Control Cardiovascular Risk in Diabetes; Action in Diabetes and Vascular Disease: Preterax and Diamicron modified Release Controlled Evaluation; and Veterans Affairs Diabetes Trial), it should be considered that the means by which the blood glucose is reduced may be as important as the actual blood glucose.
Methods:
By identifying quantitative differences between antidiabetic agents on carbohydrate exposure (CE), hepatic glucose uptake (HGU), hepatic gluconeogenesis (GNG), insulin resistance (IR), peripheral glucose uptake (PGU), and peripheral insulin exposure (PIE), we created a pharmacokinetic/pharmacodynamic model to characterize the effect of the agents on the glucose supply and insulin demand dynamic. Glucose supply was defined as the cumulative percentage decrease in CE, increase in HGU, decrease in GNG, and decrease in IR, while insulin demand was defined as the cumulative percentage increase in PIE and PGU. With the glucose supply and insulin demand effects of each antidiabetic agent summated, the glucose supply (numerator) was divided by the insulin demand (denominator) to create a value representative of the glucose supply and insulin demand dynamic (SD ratio).
Results:
Alpha-glucosidase inhibitors (1.25), metformin (2.20), and thiazolidinediones (TZDs; 1.25–1.32) demonstrate a greater effect on glucose supply (SD ratio >1), while secretagogues (0.69–0.81), basal insulins (0.77–0.79), and bolus insulins (0.62–0.67) demonstrate a greater effect on insulin demand (SD ratio <1).
Conclusion:
Alpha-glucosidase inhibitors, metformin, and TZDs demonstrate a greater effect on glucose supply, while secretagogues, basal insulin, and bolus insulin demonstrate a greater effect on insulin demand. Because T2DM cardiovascular outcome trials have not demonstrated macrovascular benefit with more aggressive blood glucose reduction when using conventional algorithms that predominantly focus on insulin demand, it would appear logical to consider a model that incorporates both the extent of blood glucose lowering (hemoglobin A1c) and the means by which the blood glucose was reduced (SD ratio) when considering macrovascular outcomes.
The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med.; 1993;329 (14): 977–86.
2.
UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet.; 1998;352 (9131): 837–53.
3.
NathanDMClearyPABacklundJYGenuthSMLachinJMOrchardTJRaskinPZinmanB, Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med.2005;353 (25): 2643–53.
4.
HolmanRRPaulSKBethelMAMatthewsDRNeilHA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med.2008;359 (15): 1577–89.
5.
NathanDM. Glycemic management of type 2 diabetes: how tight is right and how to get there. Arch Intern Med.2008;168 (19): 2064–6.
6.
Action to Control Cardiovascular Risk in Diabetes Study Group, GersteinHCMillerMEByingtonR PGoffDCJrBiggerJTBuseJBCushmanWCGenuthSIsmail-BeigiFGrimmRHJrProbstfieldJLSimons-MortonDGFriedewaldWT. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med.2008;358 (24): 2545–59.
7.
ADVANCE Collaborative GroupPatelAMacMahonSChalmersJNealBBillotLWoodwardMMarreMCooperMGlasziouPGrobbeeDHametPHarrapSHellerSLiuLManciaGMogensenCEPanCPoulterNRodgersAWilliamsBBompointSde GalanBEJoshiRTravertF. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med.2008;358 (24): 2560–72.
8.
DuckworthWAbrairaCMoritzTRedaDEmanueleNReavenPDZieveFJMarksJDavisSNHaywardRWarrenSRGoldmanSMcCarrenMVitekMEHendersonWGHuangGDInvestigatorsVADT. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med.2009;360 (2): 129–39.
9.
DeFronzoRA. Impaired glucose tolerance: do pharmacological therapies correct the underlying metabolic disturbance?Br J Diabetes Vasc Dis.2003;3 (1): S24–S40.
10.
CusiKMaezonoKOsmanAPendergrassMPattiMEPratipanawatrTDeFronzoRAKahnCRMandarinoLJ. Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle. J Clin Invest.2000;105 (3): 311–20.
11.
RobertsonRP. Chronic oxidative stress as a central mechanism for glucose toxicity in pancreatic islet beta cells in diabetes. J Biol Chem.2004;279 (41): 42351–4.
12.
DuXMatsumuraTEdelsteinDRossettiLZsengellérZSzabóCBrownleeM. Inhibition of GAPDH activity by poly(ADP-ribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells. J Clin Invest.2003;112 (7): 1049–57.
13.
DeFronzoRAFerranniniEHendlerRWahrenJFeligP. Influence of hyperinsulinemia, hyperglycemia, and the route of glucose administration on splanchnic glucose exchange. Proc Natl Acad Sci USA.1978;75 (10): 5173–7.
14.
ToschiECamastraSSironiAMMasoniAGastaldelliAMariAFerranniniENataliA. Effect of acute hyperglycemia on insulin secretion in humans. Diabetes.2002;51Suppl 1: S130–3.
15.
ElahiDNagulesparanMHershcopfRJMullerDCTobinJDBlixPMRubensteinAHUngerRHAndresR. Feedback inhibition of insulin secretion by insulin: relation to the hyperinsulinemia of obesity. N Engl J Med.1982;306 (20): 1196–202.
16.
ErdmannJMayrMOppelUSypchenkoOWagenpfeilSSchusdziarraV. Weight-dependent differential contribution of insulin secretion and clearance to hyperinsulinemia of obesity. Regul Pept.2009;152 (1–3): 1–7.
17.
GastaldelliACasolaroAPettitiMNannipieriMCiociaroDFrascerraSBuzzigoliEBaldiSMariAFerranniniE. Effect of pioglitazone on the metabolic and hormonal response to a mixed meal in type II diabetes. Clin Pharmacol Ther.2007;81 (2): 205–12.
18.
GastaldelliAToschiEPettitiMFrascerraSQuiñones-GalvanASironiAMNataliAFerranniniE. Effect of physiological hyperinsulinemia on gluconeogenesis in nondiabetic subjects and in type 2 diabetic patients. Diabetes.2001;50 (8): 1807–12.
19.
MatthewsDRHoskerJPRudenskiASNaylorBATreacherDFTurnerRC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia.1985;28 (7): 412–9.
20.
GannonMCNuttallFQ. Effect of a high-protein, low-carbohydrate diet on blood glucose control in people with type 2 diabetes. Diabetes.2004;53 (9): 2375–82.
21.
BasuRBasuAJohnsonCMSchwenkWFRizzaRA. Insulin dose-response curves for stimulation of splanchnic glucose uptake and suppression of endogenous glucose production differ in nondiabetic humans and are abnormal in people with type 2 diabetes. Diabetes.2004;53 (8): 2042–50.
22.
MeneillyGSRyanEARadziukJLauDCYaleJFMoraisJChiassonJLRabasa-LhoretRMaheuxPTessierDWoleverTJosseRGElahiD. Effect of acarbose on insulin sensitivity in elderly patients with diabetes. Diabetes Care.2000;23 (8): 1162–7.
23.
LaubeH. Acarbose: an update of its therapeutic use in diabetes treatment. Clin Drug Invest.2002;22 (3): 141–56.
24.
RadziukJKemmerFMorishimaTBerchtoldPVranicM. The effects of an alpha-glucoside hydrolase inhibitor on glycemia and the absorption of sucrose in man determined using a tracer method. Diabetes.1984;33 (3): 207–13.
25.
SobajimaHMoriMNiwaTMuramatsuMSugimotoYKatoKNaruseSKondoTHayakawaT. Carbohydrate malabsorption following acarbose administration. Diabet Med.1998;15 (5): 393–7.
26.
ConiffRFShapiroJARobbinsDKleinfieldRSeatonTBBeisswengerPMcGillJB. Reduction of glycosylated hemoglobin and postprandial hyperglycemia by acarbose in patients with NIDDM. A placebo-controlled dose-comparison study. Diabetes Care.1995;18 (6): 817–24.
27.
HanefeldMFischerSSchulzeJSpenglerMWargenauMSchollbergKFückerK. Therapeutic potentials of acarbose as first-line drug in NIDDM insufficiently treated with diet alone. Diabetes Care.1991;14 (8): 732–7.
28.
SchnackCPragerRJWinklerJKlauserRMSchneiderBGSchernthanerG. Effects of 8-wk alpha-glucosidase inhibition on metabolic control, C-peptide secretion, hepatic glucose output, and peripheral insulin sensitivity in poorly controlled type II diabetic patients. Diabetes Care.1989;12 (8): 537–43.
29.
SelsJPKingmaPJWolffenbuttelBHMenheerePPBranolteJHKrusemanAC Nieuwenhuijzen. Effect of miglitol (BAY m-1099) on fasting blood glucose in type 2 diabetes mellitus. Neth J Med.1994;44 (6): 198–201.
30.
Calle-PascualAGarcia-HonduvillaJMartin-AlvarezPJCalleJRMaranesJP. Influence of 16-week monotherapy with acarbose on cardiovascular risk factors in obese subjects with non-insulin-dependent diabetes mellitus: a controlled, double-blind comparison study with placebo. Diabetes Metab.1996;22 (3): 201–2.
31.
ChiassonJLJosseRGLeiterLAMihicMNathanDMPalmasonCCohenRMWoleverTM. The effect of acarbose on insulin sensitivity in subjects with impaired glucose tolerance. Diabetes Care.1996;19 (11): 1190–3.
32.
ShinozakiKSuzukiMIkebuchiMHiroseJHaraYHaranoY. Improvement of insulin sensitivity and dyslipidemia with a new alpha-glucosidase inhibitor, voglibose, in nondiabetic hyperinsulinemic subjects. Metabolism.1996;45 (6): 731–7.
33.
DelgadoHLehmannTBobbioni-HarschEYbarraJGolayA. Acarbose improves indirectly both insulin resistance and secretion in obese type 2 diabetic patients. Diabetes Metab.2002;28 (3): 195–200.
34.
LaubeHLinnTHeyenP. The effect of acarbose on insulin sensitivity and proinsulin in overweight subjects with impaired glucose tolerance. Exp Clin Endocrinol Diabetes.1998;106 (3): 231–3.
35.
ReavenGMLardinoisCKGreenfieldMSSchwartzHCVremanHJ. Effect of acarbose on carbohydrate and lipid metabolism in NIDDM patients poorly controlled by sulfonylureas. Diabetes Care.1990;13Suppl 3: 32–6.
36.
JenneyAProiettoJO'DeaKNankervisATraianedesKD'EmbdenH. Low-dose acarbose improves glycemic control in NIDDM patients without changes in insulin sensitivity. Diabetes Care.1993;16 (2): 499–502.
37.
KinoshitaTMaedaHUrataSHiraoK. Effect of acarbose versus sulfonylurea therapy on insulin sensitivity: an insulin clamp study. Curr Ther Res.1999;61 (2): 97–104.
38.
FischerSPatzakARietzschHSchwanebeckUKöhlerCWildbrettJFueckerKTemelkova-KurktschievTHanefeldM. Influence of treatment with acarbose or glibenclamide on insulin sensitivity in type 2 diabetic patients. Diabetes Obes Metab.2003;5 (1): 38–44.
39.
HillebrandIBoehmeKGraefeKHWehlingK. The effect of new alpha-glucosidase inhibitors (BAY m 1099 and BAY o 1248) on meal-stimulated increases in glucose and insulin levels in man. Klin Wochenschr.1986;64 (8): 393–6.
40.
HillebrandIBoehmeKFrankGFinkHBerchtoldP. The effects of the alpha-glucosidase inhibitor BAY g 5421 (Acarbose) on meal-stimulated elevations of circulating glucose, insulin, and triglyceride levels in man. Res Exp Med (Berl).1979;175 (1): 81–6.
41.
HanefeldMHaffnerSMMenschikowskiMKoehlerCTemelkova-KurktschievTWildbrettJFischerS. Different effects of acarbose and glibenclamide on proinsulin and insulin profiles in people with type 2 diabetes. Diabetes Res Clin Pract.2002;55 (3): 221–7.
42.
UttenthalLOUkponmwanOOWoodSMGhiglioneMGhateiMATraynerIMBloomSR. Long-term effects of intestinal alpha-glucosidase inhibition on postprandial glucose, pancreatic and gut hormone responses and fasting serum lipids in diabetics on sulphonylureas. Diabet Med.1986;3 (2): 155–60.
43.
HoffmannJSpenglerM. Efficacy of 24-week monotherapy with acarbose, glibenclamide, or placebo in NIDDM patients. The Essen Study. Diabetes Care.1994;17 (6): 561–6.
44.
InoueITakahashiKNojiSAwataTNegishiKKatayamaS. Acarbose controls postprandial hyperproinsulinemia in non-insulin dependent diabetes mellitus. Diabetes Res Clin Pract.1997;36 (3): 143–51.
45.
RosakCHauptEWalterTWernerJ. The effect of combination treatment with acarbose and glibenclamide on postprandial glucose and insulin profiles: additive blood glucose lowering effect and decreased hypoglycaemia. Diabetes Nutr Metab.2002;15 (3): 143–51.
46.
SeifarthCBergmannJHolstJJRitzelRSchmiegelWNauckMA. Prolonged and enhanced secretion of glucagon-like peptide 1 (7–36 amide) after oral sucrose due to alpha-glucosidase inhibition (acarbose) in type 2 diabetic patients. Diabet Med.1998;15 (6): 485–91.
47.
GutzwillerJ P.Glucagon like peptide-1 is a physiologic regulator of food intake in humans. Gastroenterology.1997;112: A1153.
48.
DeFronzoRATobinJDAndresR. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol.1979;237 (3): E214–23.
49.
HolmanRRCullCATurnerRC. A randomized double-blind trial of acarbose in type 2 diabetes shows improved glycemic control over 3 years (U.K. Prospective Diabetes Study 44). Diabetes Care.1999;22 (6): 960–4.
50.
PaolissoGAmatoLEccellenteRGambardellaATagliamonteMRVarricchioGCarellaCGiuglianoDD'OnofrioF. Effect of metformin on food intake in obese subjects. Eur J Clin Invest.1998;28 (6): 441–6.
51.
HermannLS. Metformin: a review of its pharmacological properties and therapeutic use. Diabete Metab.1979;5 (3): 233–45.
52.
LeeAMorleyJE. Metformin decreases food consumption and induces weight loss in subjects with obesity with type II non-insulin-dependent diabetes. Obes Res.1998;6 (1): 47–53.
CzyzykATaweckiJSadowskiJPonikowskaISzczepanikZ. Effect of biguanides on intestinal absorption of glucose. Diabetes.1968;17 (8): 492–8.
55.
BergerWKunzliH. Effect of dimethylbiguanide on insulin, glucose and lactic acid contents observed in portal vein blood and peripheral venous blood in the course of intraduodenal glucose tolerance tests. Diabetologia.1970;6: 37.
56.
GyrMBergerWFridrichRDenesAStadlerGA. Der Einfluss von Dimethylbiguanid auf die Magenentleerung und die orale glucosetoleranz. Schw Med Wschr.1971;101: 1876–9.
57.
AdnittPFraynKN. Effect of metformin on intestinal absorption and intravenous glucose tolerance in man. J Pharmacol.1971;2: 202–4.
58.
FossatiPFontainePBeuscartRRomonMBourdelle-HegoMFLePoutre-VaastD. Escape of non insulin dependent diabetes (NIDD) to the oral hypoglycemic agents control. Rev Fr Endocrinol Clin.1985;26: 105–16.
59.
CuberJCBosshardAVidalHVegaFWiernspergerNRapinJR. Metabolic and drug distribution studies do not support direct inhibitory effects of metformin on intestinal glucose absorption. Diabete Metab.1994;20 (6): 532–9.
60.
BaileyCJ. Metformin and intestinal glucose handling. Diabetes Metab Rev.1995;11Suppl 1: S23–32.
61.
CasparyWFCreutzfieldtW. Analysis of the inhibitory effect of biguanides on glucose absorption: inhibition of active sugar transport. Diabetologia.1971;7 (5): 379–85.
62.
LorchE. Inhibition of intestinal absorption and improvement of oral glucose tolerance by biguanides in the normal and in the streptozotocin-diabetic rat. Diabetologia.1971;7 (3): 195–203.
63.
CouparIMMcCollI. Glucose absorption from the rat jejunum during acute exposure to metformin and phenformin. J Pharm Pharmacol.1974;26 (12): 997–8.
64.
WilcockCBaileyCJ. Accumulation of metformin by tissues of the normal and diabetic mouse. Xenobiotica.1994;24 (1): 49–57.
65.
WilcockCBaileyCJ. Reconsideration of inhibitory effect of metformin on intestinal glucose absorption. J Pharm Pharmacol.1991;43 (2): 120–1.
66.
KesslerMMeierWStorelliCSemenzaG. The biguanide inhibition of D-glucose transport in membrane vesicles from small intestine brush borders. Biochim Biophys Acta.1975;413 (3): 444–52.
67.
JacksonRAHawaMIJaspanJBSimBMDisilvioLFeatherbeDKurtzAB. Mechanism of metformin action in non-insulin-dependent diabetes. Diabetes.1987;36 (5): 632–40.
68.
PénicaudLHitierYFerréPGirardJ. Hypoglycaemic effect of metformin in genetically obese (fa/fa) rats results from an increased utilization of blood glucose by intestine. Biochem J.1989;262 (3): 881–5.
69.
BaileyCJMynettKJPageT. Importance of the intestine as a site of metformin-stimulated glucose utilization. Br J Pharmacol.1994;112 (2): 671–5.
70.
BaileyCJWilcockCDayC. Effect of metformin on glucose metabolism in the splanchnic bed. Br J Pharmacol.1992;105 (4): 1009–13.
71.
IozzoPHallstenKOikonenVVirtanenKAParkkolaRKemppainenJSolinOLonnqvistFFerranniniEKnuutiJNuutilaP. Effects of metformin and rosiglitazone monotherapy on insulin-mediated hepatic glucose uptake and their relation to visceral fat in type 2 diabetes. Diabetes Care.2003;26 (7): 2069–74.
72.
StumvollMNurjhanNPerrielloGDaileyGGerichJE. Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. N Engl J Med.1995;333 (9): 550–4.
73.
HundalRSKrssakMDufourSLaurentDLebonVChandramouliVInzucchiSESchumannWCPetersenKFLandauBRShulmanGI. Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes.2000;49 (12): 2063–9.
74.
TiikkainenMHäkkinenAMKorsheninnikovaENymanTMäkimattilaSYki-JärvinenH. Effects of rosiglitazone and metformin on liver fat content, hepatic insulin resistance, insulin clearance, and gene expression in adipose tissue in patients with type 2 diabetes. Diabetes.2004;53 (8): 2169–76.
75.
SharmaPKBhansaliASialyRMalhotraSPandhiP. Effects of pioglitazone and metformin on plasma adiponectin in newly detected type 2 diabetes mellitus. Clin Endocrinol (Oxf).2006;65 (6): 722–8.
76.
MatherKJVermaSAndersonTJ. Improved endothelial function with metformin in type 2 diabetes mellitus. J Am Coll Cardiol.2001;37 (5): 1344–50.
77.
SalpeterSRBuckleyNSKahnJASalpeterEE. Meta-analysis: metformin treatment in persons at risk for diabetes mellitus. Am J Med.2008;121 (2): 149–57.e2.
78.
InzucchiSEMaggsDGSpollettGRPageSLRifeFSWaltonVShulmanGI. Efficacy and metabolic effects of metformin and troglitazone in type II diabetes mellitus. N Engl J Med.1998;338 (13): 867–72.
79.
BaileyCJFlattPREwanC. Anorectic effect of metformin in lean and genetically obese hyperglycaemic (ob/ob) mice. Arch Int Pharmacodyn Ther.1986;282 (2): 233–9.
80.
SmithSRDe JongeLVolaufovaJLiYXieHBrayGA. Effect of pioglitazone on body composition and energy expenditure: a randomized controlled trial. Metabolism.2005;54 (1): 24–32.
81.
StrowigSMRaskinP. The effect of rosiglitazone on overweight subjects with type 1 diabetes. Diabetes Care.2005;28 (7): 1562–7.
82.
CominaciniLYoungMMCapriatiAGarbinUPasiniA FrattaCampagnolaMDavoliARigoniAContessiGBLo CascioV. Troglitazone increases the resistance of low density lipoprotein to oxidation in healthy volunteers. Diabetologia.1997;40 (10): 1211–8.
83.
BajajMSuraamornkulSPratipanawatrTHardiesLJPratipanawatrWGlassLCersosimoEMiyazakiYDeFronzoRA. Pioglitazone reduces hepatic fat content and augments splanchnic glucose uptake in patients with type 2 diabetes. Diabetes.2003;52 (6): 1364–70.
84.
KawamoriRMatsuhisaMKinoshitaJMochizukiKNiwaMArisakaTIkedaMKubotaMWadaMKandaTIkebuchiMTohdoRYamasakiY. Pioglitazone enhances splanchnic glucose uptake as well as peripheral glucose uptake in non-insulin-dependent diabetes mellitus. AD-4833 Clamp-OGL Study Group. Diabetes Res Clin Pract.1998;41 (1): 35–43.
85.
GastaldelliAMiyazakiYPettitiMSantiniECiociaroDDefronzoRAFerranniniE. The effect of rosiglitazone on the liver: decreased gluconeogenesis in patients with type 2 diabetes. J Clin Endocrinol Metab.2006;91 (3): 806–12.
86.
LangenfeldMRForstTHohbergCKannPLübbenGKonradTFüllertSDSacharaCPfütznerA. Pioglitazone decreases carotid intima-media thickness independently of glycemic control in patients with type 2 diabetes mellitus: results from a controlled randomized study. Circulation.2005;111 (19): 2525–31.
87.
GoldbergRBKendallDMDeegMABuseJBZagarAJPinaireJATanMHKhanMAPerezATJacoberSJ, GLAI Study Investigators. A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care.2005;28 (7): 1547–54.
88.
DeegMABuseJBGoldbergRBKendallDMZagarAJJacoberSJKhanMAPerezATTanMH, GLAI Study Investigators. Pioglitazone and rosiglitazone have different effects on serum lipoprotein particle concentrations and sizes in patients with type 2 diabetes and dyslipidemia. Diabetes Care.2007;30 (10): 2458–64.
89.
YatagaiTNakamuraTNagasakaSKusakaIIshikawaSEYoshitakaAIshibashiS. Decrease in serum C-reactive protein levels by troglitazone is associated with pretreatment insulin resistance, but independent of its effect on glycemia, in type 2 diabetic subjects. Diabetes Res Clin Pract.2004;63 (1): 19–26.
90.
MiyazakiYMatsudaMDeFronzoRA. Dose-response effect of pioglitazone on insulin sensitivity and insulin secretion in type 2 diabetes. Diabetes Care.2002;25 (3): 517–23.
91.
MiyazakiYDeFronzoRA. Rosiglitazone and pioglitazone similarly improve insulin sensitivity and secretion, glucose tolerance and adipocytokines in type 2 diabetic patients. Diabetes Obes Metab.2008;10 (12): 1204–11.
92.
GrossmanSP. The role of glucose, insulin and glucagon in the regulation of food intake and body weight. Neurosci Biobehav Rev.1986;10 (3): 295–315.
93.
GrossmanMISteinIFJr.Vagotomy and the hunger-producing action of insulin in man. J Appl Physiol.1948;1 (4): 263–9.
94.
ThompsonDACampbellRG. Hunger in humans induced by 2-deoxy-D-glucose: glucoprivic control of taste preference and food intake. Science.1977;198 (4321): 1065–8.
95.
WestphalSAPalumboPJ. Weight gain and management concerns in patients on insulin therapy. Insulin.2007;2: 31–6.
96.
HenryRRGumbinerBDitzlerTWallacePLyonRGlauberHS. Intensive conventional insulin therapy for type II diabetes. Metabolic effects during a 6-mo outpatient trial. Diabetes Care.1993;16 (1): 21–31.
97.
MäkimattilaSNikkiläKYki-JärvinenH. Causes of weight gain during insulin therapy with and without metformin in patients with type II diabetes mellitus. Diabetologia.1999;42 (4): 406–12.
98.
LindströmTErikssonPOlssonAGArnqvistHJ. Long-term improvement of glycemic control by insulin treatment in NIDDM patients with secondary failure. Diabetes Care.1994;17 (7): 719–21.
99.
Yki-JärvinenHRyysyLKauppilaMKujansuuELahtiJMarjanenTNiskanenLRajalaSSaloSSeppäläPTulokasTViikariJTaskinenMR. Effect of obesity on the response to insulin therapy in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab.1997;82 (12): 4037–43.
100.
MudaliarSEdelmanSV. Insulin therapy in type 2 diabetes. Endocrinol Metab Clin North Am.2001;30 (4): 935–82.
101.
RodinJWackJFerranniniEDeFronzoRA. Effect of insulin and glucose on feeding behavior. Metabolism.1985;34 (9): 826–31.
102.
HellerS. Weight gain during insulin therapy in patients with type 2 diabetes mellitus. Diabetes Res Clin Pract.2004;65Suppl 1: S23–7.
103.
AndrewsWJVasquezBNagulesparanMKlimesIFoleyJUngerRReavenGM. Insulin therapy in obese, non-insulin-dependent diabetes induces improvements in insulin action and secretion that are maintained for two weeks after insulin withdrawal. Diabetes.1984;33 (7): 634–42.
104.
OhkuboYKishikawaHArakiEMiyataTIsamiSMotoyoshiSKojimaYFuruyoshiNShichiriM. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract.1995;28 (2): 103–17.
105.
InukaiKWatanabeMNakashimaYSawaTTakataNTanakaMKashiwabaraHYokotaKSuzukiMKuriharaSAwataTKatayamaS. Efficacy of glimepiride in Japanese type 2 diabetic subjects. Diabetes Res Clin Pract.2005;68 (3): 250–7.
106.
KoshibaKNomuraMNakayaYItoS. Efficacy of glimepiride on insulin resistance, adipocytokines, and atherosclerosis. J Med Invest.2006;53 (1–2): 87–94.
107.
ScarlettJAGrayRSGriffinJOlefskyJMKoltermanOG. Insulin treatment reverses the insulin resistance of type II diabetes mellitus. Diabetes Care.1982;5 (4): 353–63.
108.
GarveyWTOlefskyJMGriffinJHammanRFKoltermanOG. The effect of insulin treatment on insulin secretion and insulin action in type II diabetes mellitus. Diabetes.1985;34 (3): 222–34.
109.
DorkhanMFridAGroopL. Differences in effects of insulin glargine or pioglitazone added to oral anti-diabetic therapy in patients with type 2 diabetes: what to add—insulin glargine or pioglitazone?Diabetes Res Clin Pract.2008;82 (3): 340–5.
110.
LiJTianHLiQWangNWuTLiuYNiZYuHLiangJLuoRLiYHuangL. Improvement of insulin sensitivity and beta-cell function by nateglinide and repaglinide in type 2 diabetic patients - a randomized controlled double-blind and double-dummy multicentre clinical trial. Diabetes Obes Metab.2007;9 (4): 558–65.
111.
UwaifoGIRatnerRE. Differential effects of oral hypoglycemic agents on glucose control and cardiovascular risk. Am J Cardiol.2007;99 (4A): 51B–67B.
112.
GenuthS. Insulin use in NIDDM. Diabetes Care.1990;13 (12): 1240–64.
113.
GroopLWåhlin-BollEGroopPHTöttermanKJMelanderATolppanenEMFyhrqvistF. Pharmacokinetics and metabolic effects of glibenclamide and glipizide in type 2 diabetics. Eur J Clin Pharmacol.1985;28 (6): 697–704.
114.
StrangePSchwartzSLGrafRJPolvinoWWestonIMarburyTCHuangWCGoldbergRB. Pharmacokinetics, pharmacodynamics, and dose-response relationship of repaglinide in type 2 diabetes. Diabetes Technol Ther.1999;1 (3): 247–56.
115.
McLeodJF. Clinical pharmacokinetics of nateglinide: a rapidly-absorbed, short-acting insulinotropic agent. Clin Pharmacokinet.2004;43 (2): 97–120.
116.
PlankJWutteABrunnerGSiebenhoferASemlitschBSommerRHirschbergerSPieberTR. A direct comparison of insulin aspart and insulin lispro in patients with type 1 diabetes. Diabetes Care.2002;25 (11): 2053–7.
117.
MudaliarSRLindbergFAJoyceMBeerdsenPStrangePLinAHenryRR. Insulin aspart (B28 asp-insulin): a fast-acting analog of human insulin: absorption kinetics and action profile compared with regular human insulin in healthy nondiabetic subjects. Diabetes Care.1999;22 (9): 1501–6.
118.
HeinemannLLinkeschovaRRaveKHompeschBSedlakMHeiseT. Time-action profile of the long-acting insulin analog insulin glargine (HOE901) in comparison with those of NPH insulin and placebo. Diabetes Care.2000;23 (5): 644–9.
119.
HeineRJBiloHJFonkTvan der VeenEAvan der MeerJ. Absorption kinetics and action profiles of mixtures of short- and intermediate-acting insulins. Diabetologia.1984;27 (6): 558–62.
120.
LeporeMPampanelliSFanelliCPorcellatiFBartocciLDi VincenzoACordoniCCostaEBrunettiPBolliGB. Pharmacokinetics and pharmacodynamics of subcutaneous injection of long-acting human insulin analog glargine, NPH insulin, and ultralente human insulin and continuous subcutaneous infusion of insulin lispro. Diabetes.2000;49 (12): 2142–8.
121.
RosskampRWernicke-PantenKDraegerE. Clinical profile of the novel sulphonylurea glimepiride. Diabetes Res Clin Pract.1996;31Suppl: S33–42.
122.
KabadiMUKabadiUM. Effects of glimepiride on insulin secretion and sensitivity in patients with recently diagnosed type 2 diabetes mellitus. Clin Ther.2004;26 (1): 63–9.
123.
NataliAToschiECamastraSGastaldelliAGroopLFerranniniE. Determinants of postabsorptive endogenous glucose output in non-diabetic subjects. European Group for the Study of Insulin Resistance (EGIR). Diabetologia.2000;43 (10): 1266–72.
124.
HotamisligilGSShargillNSSpiegelmanBM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science.1993;259 (5091): 87–91.
125.
YudkinJSStehouwerCDEmeisJJCoppackSW. C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue?Arterioscler Thromb Vasc Biol.1999;19 (4): 972–8.
126.
Mohamed-AliVGoodrickSRaweshAKatzDRMilesJMYudkinJSKleinSCoppackSW. Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo. J Clin Endocrinol Metab.1997;82 (12): 4196–200.
127.
LundgrenCHBrownSLNordtTKSobelBEFujiiS. Elaboration of type-1 plasminogen activator inhibitor from adipocytes. A potential pathogenetic link between obesity and cardiovascular disease. Circulation.1996;93 (1): 106–10.
128.
DandonaPAljadaAMohantyPGhanimHHamoudaWAssianEAhmadS. Insulin inhibits intranuclear nuclear factor kappaB and stimulates IkappaB in mononuclear cells in obese subjects: evidence for an anti-inflammatory effect?J Clin Endocrinol Metab.2001;86 (7): 3257–65.
129.
AljadaAGhanimHMohantyPKapurNDandonaP. Insulin inhibits the pro-inflammatory transcription factor early growth response gene-1 (Egr)-1 expression in mononuclear cells (MNC) and reduces plasma tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1) concentrations. J Clin Endocrinol Metab.2002;87 (3): 1419–22.
130.
DandonaPAljadaABandyopadhyayA. inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol.2004;25 (1): 4–7.
131.
CrookMATuttPPickupJC. Elevated serum sialic acid concentration in NIDDM and its relationship to blood pressure and retinopathy. Diabetes Care.1993;16 (1): 57–60.
132.
PickupJCMattockMBChusneyGDBurtD. NIDDM as a disease of the innate immune system: association of acute-phase reactants and interleukin-6 with metabolic syndrome X. Diabetologia.1997;40 (11): 1286–92.
133.
SchmidtMIDuncanBBSharrettARLindbergGSavagePJOffenbacherSAzambujaMITracyRPHeissG. Markers of inflammation and prediction of diabetes mellitus in adults (Atherosclerosis Risk in Communities study): a cohort study. Lancet.1999;353 (9165): 1649–52.
134.
DuncanBBSchmidtMIPankowJSBallantyneCMCouperDVigoAHoogeveenRFolsomARHeissG, Atherosclerosis Risk in Communities Study. Low-grade systemic inflammation and the development of type 2 diabetes: the atherosclerosis risk in communities study. Diabetes.2003;52 (7): 1799–805.
135.
DuncanBBSchmidtMIChamblessLEFolsomARCarpenterMHeissG. Fibrinogen, other putative markers of inflammation, and weight gain in middle-aged adults—the ARIC study. Atherosclerosis Risk in Communities. Obes Res.2000;8 (4): 279–86.
136.
PradhanADMansonJERifaiNBuringJERidkerPM. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA.2001;286 (3): 327–34.
137.
BarzilayJIAbrahamLHeckbertSRCushmanMKullerLHResnickHETracyRP. The relation of markers of inflammation to the development of glucose disorders in the elderly: the Cardiovascular Health Study. Diabetes.2001;50 (10): 2384–9.
138.
HanTSSattarNWilliamsKGonzalez-VillalpandoCLeanMEHaffnerSM. Prospective study of C-reactive protein in relation to the development of diabetes and metabolic syndrome in the Mexico City Diabetes Study. Diabetes Care.2002;25 (11): 2016–21.
139.
PradhanADCookNRBuringJEMansonJERidkerPM. C-reactive protein is independently associated with fasting insulin in nondiabetic women. Arterioscler Thromb Vasc Biol.2003;23 (4): 650–5.
140.
DandonaPAljadaAChaudhuriABandyopadhyayA. The potential Influence of inflammation and insulin resistance on the pathogenesis and treatment of atherosclerosis-related complications in type 2 diabetes. J Clin Endocrinol Metab.2003;88 (6): 2422–9.
141.
GhanimHAljadaAHofmeyerDSyedTMohantyPDandonaP. Circulating mononuclear cells in the obese are in a proinflammatory state. Circulation.2004;110 (12): 1564–71.
142.
HanefeldMChiassonJLKoehlerCHenkelESchaperFTemelkova-KurktschievT. Acarbose slows progression of intima-media thickness of the carotid arteries in subjects with impaired glucose tolerance. Stroke.2004;35 (5): 1073–8.
143.
HanefeldMCagatayMPetrowitschTNeuserDPetzinnaDRuppM. Acarbose reduces the risk for myocardial infarction in type 2 diabetic patients: meta-analysis of seven long-term studies. Eur Heart J.2004;25 (1): 10–6.
144.
HanefeldM. Treatment of impaired glucose tolerance with acarbose and its effect on intima-media thickness: a substudy of the STOP-NIDDM trial (study to prevent non-insulin-dependent diabetes mellitus). Endocr Pract.2006;12Suppl 1: 56–9.
145.
ChiassonJLJosseRGGomisRHanefeldMKarasikALaaksoM, STOP-NIDDM Trial Research Group. Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial. JAMA.2003;290 (4): 486–94.
146.
ZeymerUSchwarzmaier-D'assieAPetzinnaDChiassonJL, STOP-NIDDM Trial Research Group. Effect of acarbose treatment on the risk of silent myocardial infarctions in patients with impaired glucose tolerance: results of the randomised STOP-NIDDM trial electrocardiography substudy. Eur J Cardiovasc Prev Rehabil.2004;11 (5): 412–5.
147.
ChiassonJL. Acarbose for the prevention of diabetes, hypertension, and cardiovascular disease in subjects with impaired glucose tolerance: the Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM) Trial. Endocr Pract.2006;12Suppl 1: 25–30.
148.
DeFronzoRAGoodmanAM. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. The Multicenter Metformin Study Group. N Engl J Med.1995;333 (9): 541–9.
149.
UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet.; 1998;352 (9131): 854–65.
150.
DormandyJACharbonnelBEcklandDJErdmannEMassi-BenedettiMMoulesIKSkeneAMTanMHLefèbvrePJMurrayGDStandlEWilcoxRGWilhelmsenLBetteridgeJBirkelandKGolayAHeineRJKorányiLLaaksoMMokánMNorkusAPiragsVPodarTScheenAScherbaumWSchernthanerGSchmitzOSkrhaJSmithUTatonJ, PROactive investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet.2005;366 (9493): 1279–89.
151.
MeinertCLKnatterudGLProutTEKlimtCR. A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. II. Mortality results. Diabetes.1970;19: Suppl: 789–830.
152.
HuupponenR. Adverse cardiovascular effects of sulphonylurea drugs. Clinical significance. Med Toxicol.1987;2 (3): 190–209.
153.
PogatsaGKoltaiMZJermendyGSimonJAranyiZBallagi-PordanyG. The effect of sulphonylurea therapy on the outcome of coronary heart diseases in diabetic patients. Acta Med Hung.1992;49 (1–2): 39–51.
154.
Yki-JärvinenHYoungAALamkinCFoleyJE. Kinetics of glucose disposal in whole body and across the forearm in man. J Clin Invest.1987;79 (6): 1713–9.
155.
ZangenehFAroraPSDyckPJBekrisLLernmarkAAchenbachSJObergALRizzaRA. Effects of duration of type 2 diabetes mellitus on insulin secretion. Endocr Pract.2006;12 (4): 388–93.
156.
LevyJAtkinsonABBellPMMcCanceDRHaddenDR. Beta-cell deterioration determines the onset and rate of progression of secondary dietary failure in type 2 diabetes mellitus: the 10-year follow-up of the Belfast Diet Study. Diabet Med.1998;15 (4): 290–6.
157.
UK Prospective Diabetes Study Group. UK prospective diabetes study 16. Overview of 6 years' therapy of type II diabetes: a progressive disease. Diabetes.; 1995;44 (11): 1249–58.
158.
SaadMFKnowlerWCPettittDJNelsonRGMottDMBennettPH. Sequential changes in serum insulin concentration during development of non-insulin-dependent diabetes. Lancet.1989;1 (8651): 1356–9.
159.
BorgHGottsäterAFernlundPSundkvistG. A 12-year prospective study of the relationship between islet antibodies and beta-cell function at and after the diagnosis in patients with adult-onset diabetes. Diabetes.2002;51 (6): 1754–62.
160.
NiskanenLKarjalainenJSiitonenOUusitupaM. Metabolic evolution of type 2 diabetes: a 10-year follow-up from the time of diagnosis. J Intern Med.1994;236 (3): 263–70.
161.
Mauvais-JarvisFSobngwiEPorcherRRivelineJPKevorkianJPVaisseCCharpentierGGuillausseauPJVexiauPGautierJF. Ketosis-prone type 2 diabetes in patients of sub-Saharan African origin: clinical pathophysiology and natural history of beta-cell dysfunction and insulin resistance. Diabetes.2004;53 (3): 645–53.
162.
LiljenquistJEHorwitzDLJenningsASChiassonJLKellerURubensteinAH. Inhibition of insulin secretion by exogenous insulin in normal man as demonstrated by C-peptide assay. Diabetes.1978;27 (5): 563–70.
163.
ArgoudGMSchadeDSEatonRP. Insulin suppresses its own secretion in vivo. Diabetes.1987;36 (8): 959–62.
164.
Fruehwald-SchultesBKernWBornJFehmHLPetersA. Comparison of the inhibitory effect of insulin and hypoglycemia on insulin secretion in humans. Metabolism.2000;49 (7): 950–3.
