MEDizzy - A 28-year-old male develops diabetes, as noted by constant,

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Glycolysis and Gluconeogenesis

A 28-year-old male develops diabetes, as noted by constant, mildly elevated hyperglycemia. His father had similar symptoms at the same age as did his paternal grandmother. This patient is not obese, does not have hypertension, does not have dyslipidemia, and does not have antibodies directed against islet cells. This alteration in glucose homeostasis may be due to a mutation in which of the following enzymes?

ExplanationThe answer is A: Pancreatic glucokinase. The boy has developed MODY (maturity-onset diabetes of the young), and one variant of MODY is a mutated glucokinase (an inheritable disorder) such that the Km for glucose has increased, and insulin release only occurs when hyperglycemia is present. Both an increase in ATP and NADPH are required for the pancreatic β-cell to release insulin. When pancreatic glucokinase has an increased Km for glucose, ATP levels can only increase at greater than normal levels of glucose. Thus, moderate hyperglycemia is not sufficient to induce insulin release. As insulin release occurs from the pancreas, liver, muscle, or intestinal hexokinase will not affect the process. The pancreas does not express hexokinase, only glucokinase. MODY is a monogenetic autosomal dominant disease of insulin secretion. There are at least six amino acid substitutions known in a number of different proteins. MODY1 is a mutation in the transcription factor HNF4-α:∼ MODY2 is a mutation in pancreatic glucokinase. MODY3 is a mutation in the transcription factor HNF1-α while MODY4 contains a mutation in insulin promoter factor 1. MODY5 is a mutation in another transcription factor, HNF1-β. MODY6 is a mutation in neurogenic differentiation factor 1. MODY is not insulin resistance. Therefore, all the other aspects of insulin resistance syndrome are not present (obesity, hypertension, and hypertriglyceridemia). Since MODY is autosomal dominant, it can be traced through the family tree. It was thought at one time that the patient had to be young to present with this disorder, but patients up to age 50 have been reported. It is not type 1 diabetes mellitus as no islet cell antibodies are present.