Hepatic glucose production and insulin sensitivity preceding diabetes in monkeys

Bodkin, Noni L.; Metzger, Bonnie L.; Hansen, Barbara C.

doi:10.1152/ajpendo.1989.256.5.e676

Cited by 68 publications

(80 citation statements)

References 2 publications

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“…The situation is more complex following food ingestion when glucose appearance equals the sum of EGP and the rate of appearance of the ingested glucose (6). There is currently limited data as to the contribution of these processes to fasting hyperglycemia (7,8) and no data regarding the regulation of postprandial glucose metabolism in individuals with IFG. The latter is of particular interest since while most individuals with IFG also have either IGT or diabetes, some have normal glucose tolerance (NGT).…”

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confidence: 99%

Pathogenesis of Pre-Diabetes

et al. 2006

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Thirty-two subjects with impaired fasting glucose (IFG) and 28 subjects with normal fasting glucose (NFG) ingested a labeled meal and 75 g glucose (oral glucose tolerance test) on separate occasions. Fasting glucose, insulin, and C-peptide were higher (P < 0.05) in subjects with IFG than in those with NFG, whereas endogenous glucose production (EGP) did not differ, indicating hepatic insulin resistance. EGP was promptly suppressed, and meal glucose appearance comparably increased following meal ingestion in both groups. In contrast, glucose disappearance (R d ) immediately after meal ingestion was lower (P < 0.001) in subjects with IFG/impaired glucose tolerance (IGT) and IFG/diabetes but did not differ in subjects with IFG/normal glucose tolerance (NGT) or NFG/NGT. Net insulin action (S i ) and insulin-stimulated glucose disposal (S i *) were reduced (P < 0.001, ANOVA) in subjects with NFG/IGT, IFG/IGT, and IFG/diabetes but did not differ in subjects with NFG/NGT or IFG/NGT. Defective insulin secretion also contributed to lower postprandial R d since disposition indexes were lower (P < 0.001, ANOVA) in subjects with NFG/IGT, IFG/IGT, and IFG/diabetes but did not differ in subjects with NFG/NGT and IFG/NGT. We conclude that postprandial hyperglycemia in individuals with early diabetes is due to lower rates of glucose disappearance rather than increased meal appearance or impaired suppression of EGP, regardless of their fasting glucose. In contrast, insulin secretion, action, and the pattern of postprandial turnover are essentially normal in individuals with isolated IFG. Diabetes 55: 3536 -3549, 2006

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confidence: 99%

Pathogenesis of Pre-Diabetes

et al. 2006

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“…In addition, longitudinal studies in American Pima Indians (38,39), in rhesus monkeys (40), and recently in offspring of two diabetic parents (15,17) have demonstrated that insulin resistance precedes the development of frank NIDDM. These consistent findings in several independent population studies have led to the widespread view that genetically determined peripheral insulin resistance may be the primary underlying abnormality of glucose metabolism responsible for the development of NIDDM.…”

Section: Discussionmentioning

confidence: 99%

Insulin secretion, insulin action, and hepatic glucose production in identical twins discordant for non-insulin-dependent diabetes mellitus.

Vaag¹,

Henriksen²,

Madsbad³

et al. 1995

J. Clin. Invest.

189

121

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12 identical twin pairs discordant for non-insulin-dependent diabetes mellitus (NIDDM) were studied for insulin sensitivity (euglycemic insulin clamp, 40 mU/m2 per min), hepatic glucose production (HGP, [3-3H] glucose infusion), and insulin secretion (oral glucose tolerance test and hyperglycemic [12 mM] clamp, including glucagon administration). Five of the nondiabetic twins had normal and seven had impaired glucose tolerance. 13 matched, healthy subjects without a family history of diabetes were included as control subjects. The NIDDM twins were more obese compared with their non-diabetic co-twins. The nondiabetic twins were insulin resistant and had a delayed insulin and C-peptide response during oral glucose tolerance tests compared with controls. Furthermore, the nondiabetic twins had a decreased first-phase insulin response and a decreased maximal insulin secretion capacity during hyperglycemic clamping and intravenous glucagon administration. Nondiabetic twins and controls had similar rates of HGP. Compared with both nondiabetic twins and controls, the NIDDM twins had an elevated basal rate of HGP, a further decreased insulin sensitivity, and a further impaired insulin secretion pattern as determined by all tests. In conclusion, defects of both in vivo insulin secretion and insulin action are present in non-and possibly prediabetic twins who possess the necessary NIDDM susceptibility genes. However, all defects of both insulin secretion and glucose metabolism are expressed quantitatively more severely in their identical co-twins with overt NIDDM. (J. Clin. Invest. 1995. 95:690-698.)

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“…The spontaneously obese diabetic rhesus monkey is extraordinarily similar to human NIDDM with respect to its clinical presentation and underlying pathophysiology (29)(30)(31). When maintained in a protective environment and allowed ad lib.…”

Section: Introductionmentioning

confidence: 99%

Hyperinsulinemia is associated with altered insulin receptor mRNA splicing in muscle of the spontaneously obese diabetic rhesus monkey.

Huang¹,

Bodkin²,

Ortmeyer³

et al. 1994

J. Clin. Invest.

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The human insulin receptor has two isoforms derived from alternative splicing of exon 11 of the insulin receptor gene. The type B (containing exon 11, or exon 11 + ) isoform binds insulin with twofold lower affinity than the type A (lacking exon 11, or exon 11-) isoform. In efforts to resolve the controversy over whether altered splicing is involved in the development of insulin resistance and non-insulin-dependent diabetes mellitus (NIDDM), the spontaneously obese diabetic rhesus monkey, a unique model that is extraordinarily similar to human NIDDM, was used. Cross-sectional studies of insulin receptor mRNA splicing variants in vastus lateralis muscle were performed on 19 rhesus monkeys. When monkeys were divided into four groups based upon the known stages of progression to NIDDM: normal (normoglycemic/normoinsulinemic), prediabetic (normoglycemic/hyperinsulinemic), early NIDDM (hyperglycemic/hyperinsulinemic), and late NIDDM (hyperglycemic/ hypoinsulinemic), both hyperinsulinemic groups had significantly higher percentages of the exon 11-mRNA splicing variant compared to the normal (74.8±1.7 vs 59.0 ±2.3%; P < 0.005) and late NIDDM groups (74.8±1.7 vs 64.2±3.9%; P < 0.05). Our findings provide the first direct evidence linking hyperinsulinemia to alterations in insulin receptor mRNA splicing, and suggest that alterations of insulin receptor mRNA splicing in muscle is an early molecular marker that may play an important role in NIDDM.

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Hepatic glucose production and insulin sensitivity preceding diabetes in monkeys

Cited by 68 publications

References 2 publications

Pathogenesis of Pre-Diabetes

Pathogenesis of Pre-Diabetes

Insulin secretion, insulin action, and hepatic glucose production in identical twins discordant for non-insulin-dependent diabetes mellitus.

Hyperinsulinemia is associated with altered insulin receptor mRNA splicing in muscle of the spontaneously obese diabetic rhesus monkey.

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