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Reviews/Commentaries/ADA Statements PERSPECTIVES ON THE NEWS Diabetes Treatment ZACHARY T. BLOOMGARDEN, MD insulin-stimulated state the insulin resis- tance of type 2 diabetes is largely ac- counted for by skeletal muscle insulin his is the third of six articles based the program found a 7.9% prevalence of resistance. Intramyocellular defects in- on presentations at the American diabetic retinopathy among individuals clude impaired glucose transport and de- T Diabetes Association Scientific Ses- with IGT. At the time of diabetes diagno- creased glycogen synthesis. Insulin action sions held 6–10 June 2008 in San Fran- sis, 12.6% had retinopathy, although the begins with insulin receptor auto- cisco, California. mean A1C was only 6.1%. Peripheral phosphorylation, then causing phosphor- neuropathy also was seen in 5–10% of ylation of insulin receptor substrate Type 2 diabetes treatment participants with IGT. DeFronzo con- (IRS)-1, leading to activation of a number approaches cluded that individuals with IGT are near of intracellular processes, with a decrease Ralph DeFronzo (San Antonio, TX) sug- maximally insulin resistant, with de- in the ability of the insulin receptor to gested an interesting set of approaches to creased ␤-cell function and mass, and tyrosine phosphorylate IRS-1 in insulin the treatment of type 2 diabetes. De- with appreciable prevalence of diabetic resistance. At the same time, the mito- Fronzo noted that the natural history of complications. genic insulin response pathway is rela- type 2 diabetes involves a reduction in ␤-cell failure occurs, DeFronzo said, tively increased, with activation of insulin sensitivity during the progression in an age-related fashion and clusters in proinflammatory pathways, abnormali- from lean to obese with normal tolerance, families. The transcription factor 7–like 2 ties which only respond to pharmacologic and that the subsequent progression to gene (TCF7L2) polymorphism is associated intervention with thiazolidinediones impaired glucose tolerance (IGT) is asso- with reduced insulin secretion, perhaps (TZDs). ciated with a further decrease in insulin from reduced insulin responsiveness to glu- DeFronzo showed fascinating differ- sensitivity and a relative deficiency in insu- cagon-like peptide (GLP)-1. Carriers of the ences between the effects of oral and par- lin secretory function. As IGT progresses to abnormal gene have a 60% increase in dia- enteral glucose. The latter only increases diabetes, insulin secretion decreases betes development. Deficiency of GLP-1 hepatic glucose uptake when plasma glu- without a further worsening in insulin and resistance to glucose-dependent insuli- cose levels increase, even during hyperin- sensitivity. DeFronzo presented studies of notropic peptide (GIP) action also occur in sulinemia. Oral glucose, in contrast, normal glucose-tolerant, impaired glu- type 2 diabetes. Lipotoxicity from increased markedly increases hepatic glucose up- cose-tolerant, and type 2 diabetic individ- plasma free fatty acids (FFAs) is another take in normal individuals, acting to a uals that demonstrated an increase in the factor impairing insulin secretion. A 48-h lesser extent in type 2 diabetic patients, absolute rate of glucose-induced insulin infusion of heparin with triglyceride which suggests an abnormality of a gut secretion during the progression from emulsion elevating FFAs in normal glu- factor. Increased FFAs may play a role in normal to varying degrees of IGT, with cose tolerant offspring of two diabetic inhibiting muscle glucose uptake, in- insulin secretion subsequently decreasing parents led to decreased insulin secretion. creasing hepatic glucose production, and progressively with worsening degrees of Increased glucose levels also impair insu- decreasing insulin secretion. The use of diabetes. Examining the ratio of insulin lin secretion, the phenomenon of gluco- lipid plus heparin infusion to elevate FFA secretion to insulin resistance (the dispo- toxicity; DeFronzo’s studies of phlorizen, in normal individuals decreases hepatic and sition index), DeFronzo showed that the which reduces glucose levels by increas- muscle insulin signaling via a number of ty- logarithm of insulin secretion/insulin re- ing glycosuria, showed improvement in rosine phosphorylation steps and results in sistance is inversely proportional to the ␤-cell function. Increased amyloid a doubling of muscle lipid content. Piogli- log of the 2-h glucose, and that with ad- polypeptide(IAPP) deposition is another taozne increases the expression of perox- vanced degrees of IGT, ϳ80% of insulin factor leading to ␤-cell failure, with rela- isome proliferators–activated receptor secretory capacity is lost, implying that tive islet amyloid area increased in associ- (PPAR)-␥ coactivator (PGC)-1, thereby insulin deficiency begins well before the ation with decreased insulin secretion and reducing intramyocellular lipid and fatty onset of diabetes as currently defined. He increased fasting glucose in a nonhuman acylCoA content, an effect similar to that cited an autopsy study showing that by primate study. with administration of the nicotinic acid the time elevations occur in fasting glu- DeFronzo discussed insulin resis- derivative acipimox to reduce circulating cose, there is a 50% loss of ␤-cell mass, tance in type 2 diabetes, noting potential FFAs. Decreased incretin effect is another with a further decrease in ␤-cell volume differences between the fasting and insu- factor in the pathogenesis of type 2 diabe- with progression to diabetes (1). lin-stimulated states. In type 2 diabetic tes. A 2-week course of exenatide in type The Diabetes Prevention Program patients, elevation in basal hepatic glu- 2 diabetic patients showed beneficial ef- further raises concern about the clinical cose production correlates strongly with fects, inlcuding an improved ratio of in- implications of the term “pre-diabetes,” as increase in fasting glucose, while in the sulin secretion to 2-h glucose and ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● increased splanchnic glucose uptake. Ab- Zachary T. Bloomgarden, MD, is a practicing endocrinologist in New York, New York, and is affiliated with normalities of ␣-cell function may be an- the Division of Endocrinology, Mount Sinai School of Medicine, New York, New York. other factor in the pathogenesis of type 2 DOI: 10.2337/dc09-zb03 © 2009 by the American Diabetes Association. Readers may use this article as long as the work is properly diabetes. Marking another benefit of in- cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons. cretin treatment approaches, glucagon se- org/licenses/by-nc-nd/3.0/ for details. cretion is increased and correlates with DIABETES CARE, VOLUME 32, NUMBER 3, MARCH 2009 e25 Perspectives on the News increased fasting glucose levels, and this effect on AMPK might explain its effect on those receiving combined sulfonylurea- further improves after administration of gluconeogenesis. (Abstract numbers refer metformin treatment. Spanheimer et al. somatostatin. In addition, there are cen- to the ADA Scientific Sessions, Diabetes (abstract 299) reported that 33% of pa- tral nervous system effects on glycemia, 57 [Suppl. 2], 2008). tients in the PROspective pioglitAzone and the hyperinsulinemia of obesity may This work was supported by Baverel Clinical Trial In macroVascular Events involve central insulin resistance, with et al. (abstract 38), who found a dose- (PROactive) were treated with insulin, evidence of altered hypothalamic func- dependent inhibition by metformin of 39% with a nitrate, and 70% with an tion in obese individuals after glucose gluconeogenesis from lactate in liver angiotensin-directed agent, with no evi- ingestion. slices from Zucker diabetic fatty rats and a dence of these treatments increasing risk Given the variety of pathogenic reduction of cellular ATP levels and of of stroke, myocardial infarction, or mor- abnormalities in type 2 diabetes, its treat- CO2 production from lactate, while lac- tality. Seung Jin Han et al. (abstract 435) ment requires multiple drugs in combina- tate production and ketogenesis nearly administered pioglitazone versus placebo tion. Metformin and TZDs act on the liver, doubled with increased ␤-hydroxybu- to 75 nondiabetic renal allograft recipi- and TZDs act on muscle, the adipocyte, tyrate–acetoacetate ratio, reflecting the ents for 12 months, and found a signifi- and the ␤-cell, suggesting to DeFronzo mitochondrial redox state. Schaefer et al. cant increase versus decrease in insulin that these agents are preferable to met- (abstract 97) treated 19 nondiabetic obese sensitivity and a decrease versus increase formin and to sulfonylureas. All long- adults with 850 mg metformin daily for in carotid intima-media thickness. Bao term TZD studies, he said, including one week, then twice daily for three more et al. (abstract 441) studied outcome PERISCOPE, CHICAGO, ADOPT, and weeks, showing a reduction in 24-h en- among 3,713 diabetic patients treated the UKPDS, show that sulfonylureas do ergy expenditure by 3% with carbohy- with metformin alone for at least 12 not give durable glycemic benefit, while drate and fat oxidation increasing 17% months; 29 and 71% of the patients sub- long-term glucose-lowering is seen with and decreasing 33%, respectively. sequently took rosiglitazone and a sulfo- TZDs in type 2 diabetic patients and in A number of other agents may regulate nylurea, respectively. On average, the prevention studies such as the DPP, TRI- pathways

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