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Unformatted text preview: Studies on Islet Hormone Secretion in MODY1: RW Pedigree with Q268X Mutation in HNF-4 Gene
Three groups of 4 to 7 subjects each: No mutation identified, not diabetic: ND () Mutation identified, not diabetic: ND (+) Mutation identified, diabetic: D (+) MODY1 (RW Pedigree): Plasma C-Peptide Levels in Response to L-Arginine Infused IV Alone and Again During Hyperglycemic Clamp MODY1 (RW Pedigree): Insulin Secretion Rates (ISR) by Deconvolution of Plasma C-Peptide Levels During IV L-Arginine Infusion MODY1 (RW Pedigree): Plasma Amylin Levels in Response to L-Arginine Infused IV Alone and Again During Hyperglycemic Clamp MODY1 (RW Pedigree): Plasma Glucagon Response Areas (AUC) During IV Infusion of L-Arginine MODY1 (RW Pedigree): Plasma Pancreatic Polypeptide Response Areas (AUC) to Insulin-Induced Hypoglycemia Conclusions Regarding Pancreatic Islet Function in MODY1 (HNF-4 Mutation) [1/2]
Nondiabetic as well as diabetic subjects have a defect in insulin secretion in response to administered arginine as well as to glucose administered arginine glucagon secretion in response to pancreatic polypeptide (PP) secretion in response to insulin-induced hypoglycemia Conclusions Regarding Pancreatic Islet Function in MODY1 (HNF-4 Mutation) [2/2]
The secretory defect in the three islet- cell types ( -, - and PP-cells) may be at a common step in signal transduction, or due to a decrease in the mass of the respective cell type, or signal transduction and cell mass defects Course of the Insulin-Secretory Defect in MODY1 (HNF-4 Mutation)
Progressive decrease in insulin secretion at a rate of 1-4% per year over a period of 3 decades (observed in the RW Pedigree) Pathogenesis of MODY1 (HNF-4 Mutation)
HNF-4 protein is a member of the steroid hormone receptor superfamily of nuclear transcription factors plays a role in tissue-specific regulation of expression of multiple genes in the liver, pancreas, kidney, intestine, including the genes that regulate glucose transport and glycolysis
(Stoffel & Duncan) Pathogenesis of -cell Dysfunction in MODY1 (HNF-4 Mutation)
Defective insulin secretion associated with HNF-4 mutation is linked to impaired mitochondrial oxidation (Wang et al) HNF-4 regulates gene expression
al), in islet -cells by influencing the function of the HNF-1 protein (Wang et and vice versa
(Thomas et al; Hanson et al) The -Cell & MODY-Related Proteins Hepatocyte Dysfunction Causing Plasma Lipid Changes in MODY1 (HNF-4 Mutation)
HNF-4 is essential in controlling transcription of many genes involved in lipoprotein metabolism in the liver subjects, HNF-4 mutation leads to hepatocyte secretory defects in lipoproteins, resulting in decreased serum levels of triglycerides, lipoprotein (a), and apolipoproteins A-II and C-III In prediabetic and diabetic MODY1 Serum Levels of Lipoprotein (a) and Triglycerides in Subjects with HNF-4 (RW) and other (MODY-X) Mutations Clinical Implications of Genetic Heterogeneity of MODY [1/2]
MODY1 and MODY3 Progressive clinical course in terms of hyperglycemia, with increasing treatment requirements Development of microvascular, macrovascular and neuropathic complications of diabetes in a frequency similar to that seen in type 2 diabetes Clinical Implications of Genetic Heterogeneity of MODY [2/2]
MODY2 Mild to moderate elevation in plasma glucose levels Not progressive Complications rare Molecular-genetic diagnosis has important implications for clinical management of all MODY subtypes Differences in Clinical Parameters Among Diabetic MODY Subtypes [1/2]
Parameter Plasma glucose Fasting MODY1 Normal to severely MODY2 Mildly Mildly MODY3 Normal to severely Greatly Severe Common Low Post-prandial Greatly Progression of Microvascular hyperglycemia Severe complications for glucose Common Normal None or mild Rare Normal Renal threshold Differences in Clinical Parameters Among Diabetic MODY Subtypes [2/2]
Parameter Sensitivity to MODY1 Normal MODY2 Normal MODY3 Increased Progressive 1/3 oral agent 1/3 insulin Apo M sulfonylurea Treatment Progressive Rare requirements 1/3 oral agent 1/3 insulin Plasma Triglycerides lipoproteins Lp (a) Apo AII Apo CIII MODY5 is associated with congenital glomerulocystic, uterine and genital developmental disorders. Chronic Complications of Diabetes in MODY
Microvascular and neuropathic complications as common in MODY1 and MODY3 as in Type 2 diabetes matched for duration and degree of hyperglycemia most likely determined by the degree of glycemic control MODY: Clinical Strategies Molecular-genetic screening and diagnosis are feasible for young subjects at risk for MODY, and have important prognostic implications. Genetically susceptible subjects can be counseled to have periodic evaluation of glucose tolerance beginning at a young age. Attainment of normoglycemia beginning at time of appearance of metabolic abnormalities can prevent vascular and neuropathic complications. Estimated Worldwide Prevalence of MODY 2 to 5 % of all diabetic patients Distribution of MODY Subtypes
MODY1 MODY2 MODY3 MODY4 MODY5 MODY"X" (unknown) United Kingdom
5% 12% 64% 2% 1% 16% France
0% 63% 21% 0% 0% 16% MODY: Expectations for the Future Understanding of the pathophysiology of MODY emerging from molecularbiological and physiological studies will lead to new therapeutic approaches that delay, prevent or correct the decline in pancreatic islet -cell function. MODY could serve as a paradigm for similar studies in genetically more complex forms of diabetes. Potential Future Development of Drugs That Target HNF-4 Haplo-Insufficiency In MODY1: Agonist agents specifically acting on the islet -cell, to increase HNF-4 activity, and improve insulin secretion In MODY3: Similar agonist agents to increase HNF-1 activity In non-MODY subjects with dyslipoproteinemia: Antagonist agents selectively acting on the liver and intestine, to improve lipoprotein metabolism MODY: Extension to Type 2 Diabetes [1/2]
Recent evidence suggests that misregulation of the HNF transcription factor network in pancreatic islets and liver, and particularly HNF-4 , may contribute to Type 2 diabetes.
(Odom DT et al. Science 2004;303:1378-81; Kulkarni RN, Kahn CR. Science 2004;303:1311-2.) MODY: Extension to Type 2 Diabetes [2/2] Genetic studies in an Ashkenazi-Jewish population (1), and in families resident in Finland (2) revealed significant haplotypetag single nucleotide polymorphisms (htSNPs) in the HNF-4 region of chromosome 20q, which increase susceptibility to Type 2 diabetes.
(1) Love-Gregory LD, et al. Diabetes 2004;53:1134-40. (2) Silander K, et al. Diabetes 2004;53:1141-49. Collaborators in Investigations on the RW Pedigree (MODY1; HNF-4 ) [1/3]
1960s and 1970s: John C Floyd, Jr Sumer B Pek 1973-1974 in clinical genetics: Robert B Tattersall Collaborators in Investigations on the RW Pedigree (MODY1; HNF-4 ) [2/3]
1980s and 1990s in molecular genetics: M A Permutt (Washington U) S C Elbein (U Utah) G I Bell (U Chicago) D W Bowden (Bowman Gray U) M Stoffel (Rockefeller U) Collaborators in Investigations on the RW (MODY1, HNF-4 ) & P (MODY3, HNF-1 ) Pedigrees [3/3]
1990s in pathogenesis, insulin secretion/action, etc: W H Herman (U Michigan) J B Halter (U Michigan) M J Smith (U Michigan) L L Ilag (U Michigan J Sturis (U Chicago) M M Byrne (U Chicago) K S Polonsky (U Chicago) ...
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